Hepatic glutathione metabolism and lipid peroxidation in response to excess dietary selenomethionine and selenite in mallard ducklings

USGS Publications Warehouse

Hoffman, D.J.; Heinz, G.H.; Krynitsky, A.J.

1989-01-01

Selenium from selenomethionine accumulated in a dose-dependent manner in the liver, resulting in a decrease in hepatic-reduced glutathione with a corresponding decrease in total hepatic thiols. There was a dose-dependent increase in the oxidized to reduced glutathione ratio, and an increase in lipid peroxidation. These findings indicate that Se in the diet at 10 ppm and higher causes significant sublethal alterations in mallard ducklings, and 20-40 ppm causes significant hepatotoxicity.

Dependence of pentobarbital kinetics upon the dose of the drug and its pharmacodynamic effects.

PubMed

Kozlowski, K H; Szaykowski, A; Danysz, A

1977-01-01

Pentobarbital (PB), at dose range of 20--50 mg/kg, displays in rabbits non-linear, dose-dependent kinetics. Pharmacokinetics parameters of drug elimination depend largely upon the dose, while the distribution phase is dose-independent. The rate of disappearance of PB from the central compartment (plasma) decreases with the increase of the dose. The analysis of pharmacodynamic parameters has shown that this dose-dependent retardation of PB elimination is probably caused by an impairment of metabolic processes, resulting from disturbance of the circulatory system. A close correlation has been found between the hypotensive effect of PB and the elimination constant, k13, and also between the hypotensive effect and beta.Vd(extrap), a coefficient proportional to the rate of metabolism of PB [23, 29]. The results indicate the necessity of considering the changes in the functional state of the organism, related to the action of a drug, in pharmacokinetic studies.

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation

PubMed Central

Fischer, Bradford D.; Teixeira, Laura P.; van Linn, Michael L.; Namjoshi, Ojas A.; Cook, James M.; Rowlett, James K.

2013-01-01

Rationale Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. Objective The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Methods Squirrel monkeys (n=6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1–10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032–1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist) and HZ-166 (0.1–10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem and HZ-166 were assessed with flumazenil (0.1–3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1–3.2 mg/kg and 0.32–10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). Results Chlordiazepoxide, zolpidem and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCt and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCt and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. Conclusions These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine. PMID:23354533

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation.

PubMed

Fischer, Bradford D; Teixeira, Laura P; van Linn, Michael L; Namjoshi, Ojas A; Cook, James M; Rowlett, James K

2013-05-01

Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with βCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, βCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both βCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats.

PubMed

Hulin, Mary W; Lawrence, Michelle N; Amato, Russell J; Weed, Peter F; Winsauer, Peter J

2015-03-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under a FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the interval of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the interval for food reinforcement was low and maintained under a variable-interval schedule. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

PubMed Central

Hulin, Mary W.; Lawrence, Michelle N.; Amato, Russell J.; Weed, Peter F.; Winsauer, Peter J.

2015-01-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under an FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the density of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the density for food reinforcement was low and maintained under a variable-interval schedule. PMID:25620274

Elevated mu-opioid receptor expression in the nucleus of the solitary tract accompanies attenuated withdrawal signs after chronic low dose naltrexone in opiate-dependent rats.

PubMed

Van Bockstaele, E J; Rudoy, C; Mannelli, P; Oropeza, V; Qian, Y

2006-02-15

We previously described a decrease in withdrawal behaviors in opiate-dependent rats that were chronically treated with very low doses of naltrexone in their drinking water. Attenuated expression of withdrawal behaviors correlated with decreased c-Fos expression and intracellular signal transduction elements [protein kinase A regulatory subunit II (PKA) and phosphorylated cAMP response element binding protein (pCREB)] in brainstem noradrenergic nuclei. In this study, to determine whether similar cellular changes occurred in forebrain nuclei associated with drug reward, expressions of PKA and pCREB were analyzed in the ventral tegmental area, frontal cortex, striatum, and amygdala of opiate-treated rats that received low doses of naltrexone in their drinking water. No significant difference in PKA or pCREB was detected in these regions following drug treatment. To examine further the cellular mechanisms in noradrenergic nuclei that could underlie attenuated withdrawal behaviors following low dose naltrexone administration, the nucleus of the solitary tract (NTS) and locus coeruleus (LC) were examined for opioid receptor (OR) protein expression. Results showed a significant increase in muOR expression in the NTS of morphine-dependent rats that received low doses of naltrexone in their drinking water, and increases in muOR expression were also found to be dose dependent. Protein expression of muOR in the LC and deltaOR in either brain region remained unchanged. In conclusion, our previously reported decreases in c-Fos and PKA expression in the NTS following pretreatment with low doses of naltrexone may be partially explained by a greater inhibition of NTS neurons resulting from increased muOR expression in this region.

Dual role of betel leaf extract on thyroid function in male mice.

PubMed

Panda, S; Kar, A

1998-12-01

The effects of betel leaf extract (0.10, 0.40, 0.80 and 2.0 g kg-1 day-1 for 15 days) on the alterations in thyroid hormone concentrations. lipid peroxidation (LPO) and on the activities of superoxide dismutase (SOD) and catalase (CAT) were investigated in male Swiss mice. Administration of betel leaf extract exhibited a dual role, depending on the different doses. While the lowest dose decreased thyroxine (T4) and increased serum triiodothyronine (T3) concentrations, reverse effects were observed at two higher doses. Higher doses also increased LPO with a concomitant decrease in SOD and CAT activities. However, with the lowest dose most of these effects were reversed. These findings suggest that betel leaf can be both stimulatory and inhibitory to thyroid function, particularly for T3 generation and lipid peroxidation in male mice, depending on the amount consumed.

Dose-related cerebellar abnormality in rats with prenatal exposure to X-irradiation by magnetic resonance imaging volumetric analysis.

PubMed

Sawada, Kazuhiko; Saito, Shigeyoshi; Horiuchi-Hirose, Miwa; Mori, Yuki; Yoshioka, Yoshichika; Murase, Kenya

2013-09-01

Cerebellar abnormalities in 4-week-old rats with a single whole body X-irradiation at a dose of 0.5, 1.0, or 1.5 Gy on embryonic day (ED) 15 were examined by magnetic resonance imaging (MRI) volumetry. A 3D T2 W-MRI anatomical sequence with high-spatial resolution at 11.7-tesla was acquired from the fixed rat heads. By MRI volumetry, whole cerebellar volumes decreased dose-dependently. Multiple linear regression analysis revealed that the cortical volume (standardized β=0.901; P<0.001) was a major explanatory variable for the whole cerebellar volume, whereas both volumes of the white matter and deep cerebellar nuclei also decreased depending on the X-irradiation dose. The present MRI volumetric analysis revealed a dose-related cerebellar cortical hypoplasia by prenatal exposure to X-irradiation on E15. © 2013 The Authors. Congenital Anomalies © 2013 Japanese Teratology Society.

Long-term dose-dependent response of Mequindox on aldosterone, corticosterone and five steroidogenic enzyme mRNAs in the adrenal of male rats.

PubMed

Huang, Xian-Ju; Ihsan, Awais; Wang, Xu; Dai, Meng-Hong; Wang, Yu-Lian; Su, Shi-Jia; Xue, Xi-Juan; Yuan, Zong-Hui

2009-12-15

Mequindox (MEQ) is a synthetic quinoxaline 1,4-dioxides (QdNOs) derivative which can effectively improve growth and feed efficiency in animals. This study was to investigate the dose-dependent long-term toxicity in the adrenal of male rats exposed to 180 days of MEQ feed. Our data demonstrated that high doses of MEQ in the diet for 180 days led to adrenal damage and steroid hormone decrease, combined with sodium decrease and potassium increase in rat plasma. Significant changes of GSH and SOD in plasma were observed in the high doses (110, 275 mg/kg) groups. At the same doses, MEQ treatment down-regulated the mRNA levels of CYP11A1, CYP11B1 and CYP11B2 which located in mitochondria, but up-regulated mRNA levels of CYP21 and 3beta-HSD which located in endoplasmic reticulum. In conclusion, we reported the dose-dependent long-term toxicity of MEQ on adrenal gland in male rats, which raise awareness of its toxic effects to animals and consumers, and its mechanism may involve in oxidative stress and steroid hormone biosynthesis pathway.

Dosimetric properties of radiophotoluminescent glass detector in low-energy photon beams.

PubMed

Kadoya, Noriyuki; Shimomura, Kouhei; Kitou, Satoshi; Shiota, Yasuo; Fujita, Yukio; Dobashi, Suguru; Takeda, Ken; Jingu, Keiichi; Matsushita, Haruo; Namito, Yoshihito; Ban, Syuichi; Koyama, Syuji; Tabushi, Katsuyoshi

2012-10-01

A radiophotoluminescent glass rod dosimeter (RGD) has recently become commercially available. It is being increasingly used for dosimetry in radiotherapy to measure the absorbed dose including scattered low-energy photons on the body surface of a patient and for postal dosimetry audit. In this article, the dosimetric properties of the RGD, including energy dependence of the dose response, reproducibly, variation in data obtained by the RGD for each energy, and angular dependence in low-energy photons, are discussed. An RGD (GD-301, Asahi Techno Glass Corporation, Shizuoka, Japan) was irradiated with monochromatic low-energy photon beams generated by synchrotron radiation at Photon Factory, High Energy Accelerator Research Organization (KEK). The size of GD-301 was 1.5 mm in diameter and 8.5 mm in length and the active dose readout volume being 1 mm diameter and 0.6 mm depth located 0.7 mm from the end of the detector. The energy dependence of the dose response and reproducibility and variation were investigated for RGDs irradiated with a plastic holder and those irradiated without the plastic holder. Response of the RGD was obtained by not only conventional single field irradiation but also bilateral irradiation. Angular dependence of the RGD was measured in the range of 0°-90° for 13, 17, 40, and 80 keV photon beams by conventional single field irradiation. The dose responses had a peak at around 40 keV. For the energy range of less than 25 keV, all dose response curves steeply decreased in comparison with the ratio of mass energy absorption coefficient of the RGD to that of air. As for the reproducibility and variation in data obtained by the RGD, the coefficient of variance increased with decrease in photon energy. Furthermore, the variation for bilateral irradiation was less than that for single field irradiation. Regarding angular dependence of the RGD, for energies of 13 and 17 keV, the response decreased with increase in the irradiation angle, and the minimum values were 93.5% and 86%, respectively. Our results showed the dosimetric properties of the RGD, including the energy dependence of the dose response, reproducibly, variation, and angular dependence in low-energy photons and suggest that the accuracy of the absorbed dose in low-energy photons is affected by the readout method and the distribution of radiophotoluminescence centers in the RGD.

Measurement of air dose rates over a wide area around the Fukushima Dai-ichi Nuclear Power Plant through a series of car-borne surveys.

PubMed

Andoh, Masaki; Nakahara, Yukio; Tsuda, Shuichi; Yoshida, Tadayoshi; Matsuda, Norihiro; Takahashi, Fumiaki; Mikami, Satoshi; Kinouchi, Nobuyuki; Sato, Tetsuro; Tanigaki, Minoru; Takamiya, Koichi; Sato, Nobuhiro; Okumura, Ryo; Uchihori, Yukio; Saito, Kimiaki

2015-01-01

A series of car-borne surveys using the Kyoto University RAdiation MApping (KURAMA) and KURAMA-II survey systems has been conducted over a wide area in eastern Japan since June 2011 to evaluate the distribution of air dose rates around the Fukushima Dai-ichi Nuclear Power Plant and to evaluate the time-dependent trend of decrease in air dose rates. An automated data processing system for the KURAMA-II system was established, which enabled rapid analysis of large amounts of data obtained using about 100 KURAMA-II units. The initial data used for evaluating the migration status of radioactive cesium were obtained in the first survey, followed by other car-borne surveys conducted over more extensive and wider measurement ranges. By comparing the measured air dose rates obtained in each survey (until December 2012), the decreasing trend of air dose rates measured through car-borne surveys was found to be more pronounced than those expected on the basis of the physical decay of radioactive cesium and of the air dose rates measured using NaI (Tl) survey meters in the areas surrounding the roadways. In addition, it was found that the extent of decrease in air dose rates depended on land use, wherein it decreased faster for land used as building sites than for forested areas. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cathinone, an active principle of Catha edulis, accelerates oxidative stress in the limbic area of swiss albino mice.

PubMed

Safhi, Mohammed M; Alam, Mohammad Firoz; Hussain, Sohail; Hakeem Siddiqui, Mohammed Abdul; Khuwaja, Gulrana; Jubran Khardali, Ibrahim Abdu; Al-Sanosi, Rashad Mohammed; Islam, Fakhrul

2014-10-28

Cathinone hydrochloride is an active principle of the khat plant (Catha edulis) that produces pleasurable and stimulating effects in khat chewers. To the best of our knowledge no data of cathinone on oxidative stress in limbic areas of mice is available. This is the first study of cathinone on oxidative stress in limbic areas of the brain in Swiss albino male mice. The animals were divided into four groups. Group-I was the control group and received vehicle, while groups-II to IV received (-)-cathinone hydrochloride (0.125, 0.25 and 0.5 mg/kg body wt., i.p.) once daily for 15 days. The level of lipid peroxidation (LPO) was elevated dose-dependently and was significant (p<0.05, p<0.01) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. In contrast, the content of reduced glutathione (GSH) was decreased significantly (p<0.01, p<0.001) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. The activity of antioxidant enzymes (GPx, GR, GST, CAT, and SOD) was also decreased dose-dependently: the decreased activity of GPx, GR, catalase and SOD was significant with doses of 0.25 and 0.5 mg of cathinone as compared to control group, while the activity of GST was decreased dose-dependently and was significant with 0.5mg of cathinone as compared to control group. The results indicate that the cathinone generated oxidative stress hampered antioxidant enzymes, glutathione and lipid peroxidation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

3,3′,4,4′,5-Pentachlorobiphenyl (PCB 126) Decreases Hepatic and Systemic Ratios of Epoxide to Diol Metabolites of Unsaturated Fatty Acids in Male Rats

PubMed Central

Wu, Xianai; Yang, Jun; Morisseau, Christophe; Robertson, Larry W.; Hammock, Bruce; Lehmler, Hans-Joachim

2016-01-01

Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3-month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 µg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention. PMID:27208083

Reduction of spermatogenesis in mice after tributyltin administration.

PubMed

Chen, Yufang; Zuo, Zhenghong; Chen, Shuzhen; Yan, Feihuang; Chen, Yixin; Yang, Zengming; Wang, Chonggang

2008-09-29

Organotin compounds, such as tributyltin (TBT) used as an antifouling biocide, can induce masculinization in female mollusks. However, few studies addressing the effect of TBT on spermatogenesis in mammalian have been reported. This study was conducted to investigate the effects of TBT at low doses (0.5, 5, and 50 microg/kg, respectively) on spermatogenesis in mice as exposed from puberty and gave insight into the mechanism. After exposure for 30 days, the gonadosomatic index (GSI) was significantly decreased. The testosterone levels in the testes were not altered and the 17beta-estradiol levels were significantly decreased in a dose-dependent manner, spermatogenesis of the testis was significantly inhibited. Estrogen receptor (ER-alpha and ER-beta) levels in testes of the mice exposed to TBT were decreased in a dose-dependent manner. The results suggest that ER play an important role in TBT-mediated inhibition of spermatogenesis.

Inhibitory effect of heparin on neutrophil phagocytosis and burst production using a new whole-blood cytofluorometric method for determination.

PubMed

Salih, H; Husfeld, L; Adam, D

1997-12-31

The influence of heparin on Polymorphonuclear (PMN s) leukocytes was investigated using a new whole-blood cytofluorometric method (patent granted for the test with the number P 4334935.8-41) with Candida albicans and Staphylococcus aureus as test microorganisms. After comparing the effect of equal volumes of two widely used heparins we examined the influence of 5 different heparin-concentrations. Using both yeasts and bacteria, we found a significant, dose-depending decrease of the percentage of phagocyting PMN's and of phagocytized microorganisms as well as of the resulting percentage of PMN s producing respiratory burst along the kinetics. Furthermore we could demonstrate that heparin independently of phagocytosis produces a dose-dependent decrease of burst production of PMN's. Our results indicate that the use of heparins as anticoagulant for immunological investigations as well as clinically with patients under immunosuppressive therapy should be critically reconsidered. This applies even more because due to the evaluated dose-dependent decrease of phagocyte function no boundary for the inhibiting effect can be declared.

Glucuronidation and Sulfation Kinetics of Diflunisal in Man.

NASA Astrophysics Data System (ADS)

Loewen, Gordon Rapheal

Diflunisal is a nonsteroidal anti-inflammatory drug used in the treatment of arthritis and musculoskeletal pain. Diflunisal exhibits concentration- and dose-dependent kinetics, the mechanism of which has not been determined. The purpose of this study was to determine the mechanism(s) responsible for non-linear disposition of diflunisal and to examine environmental factors which may affect the elimination of diflunisal. The metabolites of diflunisal, including a new metabolite, the sulphate conjugate, were purified by column and semi-preparative high pressure liquid chromatography. Assays for the quantitation of diflunisal and conjugates in urine and diflunisal in plasma were developed. Plasma protein binding of diflunisal in blank plasma and in plasma obtained following multiple doses of diflunisal was determined by equilibrium dialysis. Total body clearance of diflunisal decreased when dose increased from 100 to 750 mg. Total clearance increased when dose increased from 750 to 1000 mg. The percent of recovered dose eliminated as the acyl glucuronide decreased and the percent eliminated as the sulphate increased with increasing dose of diflunisal. Plasma protein binding of diflunisal was concentration dependent over a range of diflunisal plasma concentrations of 3 to 257 mug/ml. Total clearance, and to a lesser degree, unbound clearance of diflunisal were decreased following multiple dose administration of 250 and 500 mg diflunisal. Percent of recovered dose eliminated as the acyl glucuronide decreased and percent eliminated as the sulphate conjugate increased following multiple dosing. Plasma protein binding of diflunisal was similar in blank plasma and plasma obtained at steady state. Unbound clearance of diflunisal exceeded liver plasma flow. Frequency distributions of the elimination of the conjugates of diflunisal were normally distributed. Sex, smoking, and use of vitamins or oral contraceptives were identified as factors which may affect the elimination of diflunisal.

Cocaine. Selective regional effects on central monoamines.

PubMed

Hadfield, M G

1995-01-01

Cocaine HCl (0, 10, or 50 mg/kg) was injected into adult male ICR mice ip. Thirty minutes later, the brains were removed, and nine regions were isolated: olfactory bulbs, olfactory tubercles, prefrontal cortex, septum, striatum, amygdala, hypothalamus, hippocampus, and thalamus. Using high-performance liquid chromatography, concentrations of norepinephrine, dopamine, serotonin, and their major metabolites and the metabolite/neurotransmitter ratios were determined as an indicator of utilization. Serotonergic systems responded most dramatically. 5HIAA/5-HT decreases were seen in all the brain regions, except the septum, hippocampus, and olfactory bulbs. In most instances, the alterations were dose-dependent. The most profound changes were seen in the amygdala, prefrontal cortex, hypothalamus, and thalamus. For noradrenergic systems, significant responses were seen only in the amygdala, prefrontal cortex, and hypothalamus, but then only at the lower dose. The dopaminergic responses were more complex and not always dose-dependent. The DOPAC/DA ratio was decreased only in the amygdala and striatum at the lower dose, and the olfactory tubercles at the higher dose. It was increased in the septum. The HVA/DA ratios were decreased in the amygdala, prefrontal cortex, and hypothalamus, but only at the lower dose (like MHPG/NE). The 3MT/DA ratio was decreased in the thalamus at the lower dose and in the olfactory tubercles at the higher dose, whereas it was increased in the prefrontal cortex at the lower dose. The HVA and DOPAC routes of degradation were both utilized only by the amygdala. Thus, cocaine produced its most comprehensive effects in this nucleus, as well as the greatest absolute percentage changes for all three of the monoamine systems studied.

Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial.

PubMed

Strain, E C; Bigelow, G E; Liebson, I A; Stitzer, M L

1999-03-17

Methadone hydrochloride treatment is the most common pharmacological intervention for opioid dependence, and recent interest has focused on expanding methadone treatment availability beyond traditional specially licensed clinics. However, despite recommendations regarding effective dosing of methadone, controlled clinical trials of higher-dose methadone have not been conducted. To compare the relative clinical efficacy of moderate- vs high-dose methadone in the treatment of opioid dependence. A 40-week randomized, double-blind clinical trial starting in June 1992 and ending in October 1995. Outpatient substance abuse treatment research clinic at the Johns Hopkins University Bayview Campus, Baltimore, Md. One hundred ninety-two eligible clinic patients. Daily oral methadone hydrochloride in the dose range of 40 to 50 mg (n = 97) or 80 to 100 mg (n = 95), with concurrent substance abuse counseling. Opioid-positive urinalysis results and retention in treatment. By intent-to-treat analysis through week 30 patients in the high-dose group had significantly lower rates of opioid-positive urine samples compared with patients in the moderate-dose group (53.0% [95% confidence interval [CI], 46.9%-59.2%] vs 61.9% [95% CI, 55.9%-68.0%]; P = .047. These differences persisted during withdrawal from methadone. Through day 210 no significant difference was evident between dose groups in treatment retention (high-dose group mean retention, 159 days; moderate-dose group mean retention, 157 days). Nineteen (33%) of 57 patients in the high-dose group and 11 (20%) of 54 patients in the moderate-dose group completed detoxification. Both moderate- and high-dose methadone treatment resulted in decreased illicit opioid use during methadone maintenance and detoxification. The high-dose group had significantly greater decreases in illicit opioid use.

Intrathecal Huperzine A Increases Thermal Escape Latency and Decreases Flinching Behavior in the Formalin Test in Rats

PubMed Central

Park, Paula; Schachter, Steven; Yaksh, Tony

2010-01-01

Huperzine A (HupA) is an alkaloid isolated from the Chinese club moss Huperzia serrata and has been used for improving memory, cognitive and behavioral function in patients with Alzheimer's disease in China. It has NMDA antagonist and anticholinesterase activity and has shown anticonvulsant and antinociceptive effects in preliminary studies when administered intraperitoneally to mice. To better characterize the antinociceptive effects of HupA at the spinal level, Holtzman rats were implanted with intrathecal catheters to measure thermal escape latency using Hargreaves thermal escape testing system and flinching behavior using the formalin test. Intrathecal (IT) administration of HupA showed a dose-dependent increase in thermal escape latency with an ED50 of 0.57 μg. Atropine reversed the increase in thermal escape latency produced by 10 μg HupA, indicating an antinociceptive mechanism through muscarinic cholinergic receptors. The formalin test showed that HupA decreased flinching behavior in a dose-dependent manner. Atropine also reversed the decrease in flinching behavior caused by 10 μg HupA. A dose-dependent increase of side effects including scratching, biting, and chewing tails was observed, although antinociceptive effects were observed in doses that did not produce any adverse effects. PMID:20026382

Intrathecal huperzine A increases thermal escape latency and decreases flinching behavior in the formalin test in rats.

PubMed

Park, Paula; Schachter, Steven; Yaksh, Tony

2010-02-05

Huperzine A (HupA) is an alkaloid isolated from the Chinese club moss Huperzia serrata and has been used for improving memory, cognitive and behavioral function in patients with Alzheimer's disease in China. It has NMDA antagonist and anticholinesterase activity and has shown anticonvulsant and antinociceptive effects in preliminary studies when administered intraperitoneally to mice. To better characterize the antinociceptive effects of HupA at the spinal level, Holtzman rats were implanted with intrathecal catheters to measure thermal escape latency using Hargreaves thermal escape testing system and flinching behavior using the formalin test. Intrathecal (IT) administration of HupA showed a dose-dependent increase in thermal escape latency with an ED50 of 0.57 microg. Atropine reversed the increase in thermal escape latency produced by 10 microg HupA, indicating an antinociceptive mechanism through muscarinic cholinergic receptors. The formalin test showed that HupA decreased flinching behavior in a dose-dependent manner. Atropine also reversed the decrease in flinching behavior caused by 10 microg HupA. A dose-dependent increase of side effects including scratching, biting, and chewing tails was observed, although antinociceptive effects were observed in doses that did not produce any adverse effects. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

Effects of aqueous, methanolic and chloroform extracts of rhizome and aerial parts of Valeriana officinalis L. on naloxone-induced jumping in morphine-dependent mice.

PubMed

Sharifzadeh, Mohammad; Hadjiakhoondi, Abbas; Khanavi, Mahnaz; Susanabadi, Maryam

2006-06-01

In the present study, the effects of rhizomes and aerial parts extracts of Valeriana officinalis L. on morphine dependence in mice have been investigated. Animals were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily (10 am, 1 pm and 4 pm) for 3 days, and a last dose of morphine (50 mg/kg) was administered on the fourth day. Withdrawal syndrome (jumping) was precipitated by naloxone (5 mg/kg) which was administered intraperitoneally 2 hours after the last dose of morphine. To study the effects of the aqueous, methanolic and chloroform extracts of both aerial parts and rhizome of the V. officinalis L. on naloxone-induced jumping in morphine-dependent animals, 10 injections of morphine (three administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Intraperitoneal injection of different doses (1, 5, 25 and 50 mg/kg) of aqueous, methanolic and chloroform extracts of the rhizome of V. officinalis L. 60 minutes before naloxone injection decreased the jumping response dose-dependently. Pre-treatment of animals with different doses (1, 5, 25, 50 and 100 mg/kg) of aqueous and methanolic extracts of aerial parts of V. officinalis L. 60 minutes before naloxone injection caused a significant decrease on naloxone-induced jumping. The chloroform extract of the aerial parts of V. officinalis L. did not show any significant changes on jumping response in morphine-dependent animals. It is concluded that the extracts of V. officinalis L. could affect morphine withdrawal syndrome via possible interactions with inhibitory neurotransmitters in nervous system.

Dual Effects of N,N-dimethylformamide on Cell Proliferation and Apoptosis in Breast Cancer

PubMed Central

Zhang, Jihong; Zhou, Daibing; Zhang, Lingyun; Lin, Qunbo; Ren, Weimin; Zhang, Jinguo; Nadeem, Lubna; Xu, Guoxiong

2017-01-01

N,N-dimethylformamide (DMF) has been widely used as an organic solvent in industries. DMF is a potential medication. However, the antitumorigenic role of DMF in breast cancer remains unclear. Here, we examined dose-dependent effects of DMF on proliferation and apoptosis in breast cancer MCF-7 and nontumorous MCF-12A cells. We found that DMF had a growth inhibitory effect in MCF-12A cells in a dose-dependent manner. By contrast, however, DMF had dual effects on cell proliferation and apoptosis in MCF-7 cells. DMF at a high dose (100 mM) significantly inhibited MCF-7 cell growth while at a low dose (1 mM) significantly stimulated MCF-7 cell growth (both P < .05). The inhibitory effect of DMF on cell proliferation was accompanied by the decrease of cyclin D1 and cyclin E1 protein expression, leading to the cell cycle arrest at the G0/G1 phase. Furthermore, a high-dose DMF significantly increased the number of early apoptotic cells by increasing cleaved caspase-9 and proapoptotic protein Bax expression and decreased the ratio of Bcl-xL/Bax (P < .01). Thus, our data demonstrated for the first time that DMF has dual effects on breast cancer cell behaviors depending upon its dose. Caution must be warranted in determining its effective dose for targeting breast cancer. PMID:29238273

Diuretic effects of medetomidine compared with xylazine in healthy dogs.

PubMed

Talukder, Md Hasanuzzaman; Hikasa, Yoshiaki

2009-07-01

This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 microg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine's effect is less dose-dependent than xylazine's effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation.

Safety of orally administered, USP-compliant levothyroxine sodium tablets in dogs.

PubMed

Hare, J E; Morrow, C M K; Caldwell, J; Lloyd, W E

2018-04-01

The safety of synthetic levothyroxine sodium tablets (Thyro-Tabs® Canine; LLOYD, Inc.) in dogs was evaluated in a randomized, sham-dose controlled, parallel-group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0×, 2× (0.044 mg/kg), 6× (0.132 mg/kg), or 10× (0.22 mg/kg) the labeled starting dose of 0.022 mg kg -1  day -1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose-dependent increase in serum concentrations of total and free thyroxine with dose-dependent suppression of the hypothalamic-pituitary-thyroid axis as evidenced by decreased serum thyroid-stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose-response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10× the labeled starting dose were well tolerated in healthy dogs. © 2017 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Effect of tributyltin on testicular development in Sebastiscus marmoratus and the mechanism involved.

PubMed

Zhang, Jiliang; Zuo, Zhenghong; He, Chengyong; Cai, Jiali; Wang, Yuqing; Chen, Yixin; Wang, Chonggang

2009-07-01

Organotin compounds, such as tributyltin (TBT), that have been used as antifouling biocides can induce masculinization in female mollusks. However, few studies addressing the effects of TBT on fishes have been reported. The present study was conducted to investigate the effects of TBT at environmentally relevant concentrations (1, 10, and 100 ng/L) on testicular development in Sebastiscus marmoratus and to gain insight into its mechanism of action. After exposure for 48 d, the gonadosomatic index had decreased in a dose-dependent manner. Although the testosterone levels in the testes were elevated and the 17beta-estradiol levels were decreased, spermatogenesis was suppressed. Moreover, gamma-glutamyl transpeptidase activity (which is used as a Sertoli cell marker) was decreased in a dose-dependent manner after TBT exposure, and serious interstitial fibrosis was observed in the interlobular septa of the testes in the 100 ng/L TBT test group. Increases in the retinoid X receptors and peroxisome proliferator activated receptor gamma expression and the progressive enlargement of lipid droplets in the testes were observed after TBT exposure. Estrogen receptor alpha levels in the testes of the fish exposed to TBT decreased in a dose-dependent manner. The reduction of estrogen receptor alpha mRNA resulted from the decrease of 17beta-estradiol levels, and the progressive enlargement of lipid droplets may have contributed to the dysfunction of the Sertoli cells, which then disrupted spermatogenesis.

Effect of bucladesine, pentoxifylline, and H-89 as cyclic adenosine monophosphate analog, phosphodiesterase, and protein kinase A inhibitor on acute pain.

PubMed

Salehi, Forouz; Hosseini-Zare, Mahshid S; Aghajani, Haleh; Seyedi, Seyedeh Yalda; Hosseini-Zare, Maryam S; Sharifzadeh, Mohammad

2017-08-01

The aim of this study was to determine the effects of cyclic adenosine monophosphate (cAMP) and its dependent pathway on thermal nociception in a mouse model of acute pain. Here, we studied the effect of H-89 (protein kinase A inhibitor), bucladesine (Db-cAMP) (membrane-permeable analog of cAMP), and pentoxifylline (PTX; nonspecific phosphodiesterase (PDE) inhibitor) on pain sensation. Different doses of H-89 (0.05, 0.1, and 0.5 mg/100 g), PTX (5, 10, and 20 mg/100 g), and Db-cAMP (50, 100, and 300 nm/mouse) were administered intraperitoneally (I.p.) 15 min before a tail-flick test. In combination groups, we injected the first and the second compounds 30 and 15 min before the tail-flick test, respectively. I.p. administration of H-89 and PTX significantly decreased the thermal-induced pain sensation in their low applied doses. Db-cAMP, however, decreased the pain sensation in a dose-dependent manner. The highest applied dose of H-89 (0.5 mg/100 g) attenuated the antinociceptive effect of Db-cAMP in doses of 50 and 100 nm/mouse. Surprisingly, Db-cAMP decreased the antinociceptive effect of the lowest dose of H-89 (0.05 mg/100 g). All applied doses of PTX reduced the effect of 0.05 mg/100 g H-89 on pain sensation; however, the highest dose of H-89 compromised the antinociceptive effect of 20 mg/100 g dose of PTX. Co-administration of Db-cAMP and PTX increased the antinociceptive effect of each compound on thermal-induced pain. In conclusion, PTX, H-89, and Db-cAMP affect the thermal-induced pain by probably interacting with intracellular cAMP and cGMP signaling pathways and cyclic nucleotide-dependent protein kinases. © 2017 Société Française de Pharmacologie et de Thérapeutique.

Treatment of Narcolepsy with Methamphetamine

PubMed Central

Miller, Merrill M.; Hajdukovic, Roza; Erman, Milton K.

2008-01-01

Summary Eight pairs of subjects (each consisting of a narcoleptic and a control matched on the basis of age, sex, educational background and job) were evaluated under the following double-blind, randomized treatment conditions: baseline, placebo, low dose and high dose methamphetamine. Subjects were drug-free for 2 weeks prior to beginning the protocol. Methamphetamine was the only drug taken during the protocol and was given in a single morning dose of 0, 20 or 40–60 mg to narcoleptics and 0, 5 or 10 mg to controls. The protocol was 28 days long, with each of the four treatment conditions lasting 4 days followed by 3 days of washout. Nighttime polysomnography and daytime testing were done during the last 24 hours of each treatment condition. Daytime sleep tendency was assessed with the multiple sleep latency test (MSLT). Daytime performance was assessed with performance tests including a simple, computer-based driving task. Narcoleptics’ mean MSLT sleep latency increased from 4.3 minutes on placebo to 9.3 minutes on high dose, compared with an increase from 10.4 to 17.1 minutes for controls. Narcoleptics’ error rate on the driving task decreased from 2.53% on placebo to 0.33% on high dose, compared with a decrease from 0.22% to 0.16% for controls. The effects of methamphetamine on nocturnal sleep were generally dose-dependent and affected sleep continuity and rapid eye movement (REM) sleep. Elimination half life was estimated to be between 15.9 and 22.0 hours. Mild side effects emerged in a dose-dependent fashion and most often involved the central nervous system and gastrointestinal tract. We concluded that methamphetamine caused a dose-dependent decrease in daytime sleep tendency and improvement in performance in both narcoleptics and controls. Methamphetamine at doses of 40–60 mg allowed narcoleptics to function at levels comparable to those of unmedicated controls. PMID:8341891

Subjective, cognitive, and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers

PubMed Central

Bedi, Gillinder; Cooper, Ziva D.; Haney, Margaret

2011-01-01

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 (CB1) agonist oral Δ9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal, but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers, and compare these with dronabinol's effects. Participants (4F; 10M) smoking marijuana 6.6 (SD = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over 7 sessions, the time-dependent subjective, cognitive, and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect, and/or `high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements, and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol and effects were more dose-related, suggesting improved bioavailability. Nabilone was well-tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence. PMID:22260337

Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers.

PubMed

Bedi, Gillinder; Cooper, Ziva D; Haney, Margaret

2013-09-01

Marijuana dependence is a substantial public health problem, with existing treatments showing limited efficacy. In laboratory and clinical studies, the cannabinoid receptor 1 agonist oral Δ9tetrahydrocannabinol (THC; dronabinol) has been shown to decrease marijuana withdrawal but not relapse. Dronabinol has poor bioavailability, potentially contributing to its failure to decrease relapse. The synthetic THC analogue, nabilone, has better bioavailability than dronabinol. We therefore aimed to characterize nabilone's behavioral and physiological effects across a range of acute doses in current marijuana smokers and compare these with dronabinol's effects. Participants (4 female; 10 male) smoking marijuana 6.6 (standard deviation = 0.7) days/week completed this outpatient, within-subjects, double-blind, randomized protocol. Over seven sessions, the time-dependent subjective, cognitive and cardiovascular effects of nabilone (2, 4, 6, 8 mg), dronabinol (10, 20 mg) and placebo were assessed. Nabilone (4, 6, 8 mg) and dronabinol (10, 20 mg) increased ratings of feeling a good effect, a strong effect and/or 'high' relative to placebo; nabilone had a slower onset of peak subjective effects than dronabinol. Nabilone (6, 8 mg) modestly lowered psychomotor speed relative to placebo and dronabinol. There were dose-dependent increases in heart rate after nabilone, and nabilone (2 mg) and dronabinol (10 mg) decreased systolic blood pressure. Thus, nabilone produced sustained, dose-related increases in positive mood, few cognitive decrements and lawful cardiovascular alterations. It had a longer time to peak effects than dronabinol, and effects were more dose-related, suggesting improved bioavailability. Nabilone was well tolerated by marijuana smokers, supporting further testing as a potential medication for marijuana dependence. © 2012 The Authors, Addiction Biology © 2012 Society for the Study of Addiction.

2,3-Butanedione monoxime facilitates successful resuscitation in a dose-dependent fashion in a pig model of cardiac arrest.

PubMed

Lee, Byung Kook; Kim, Mu Jin; Jeung, Kyung Woon; Choi, Sung Soo; Park, Sang Wook; Yun, Seong Woo; Lee, Sung Min; Lee, Dong Hun; Min, Yong Il

2016-06-01

Ischemic contracture compromises the hemodynamic effectiveness of cardiopulmonary resuscitation (CPR) and resuscitability from cardiac arrest. In a pig model of cardiac arrest, 2,3-butanedione monoxime (BDM) attenuated ischemic contracture. We investigated the effects of different doses of BDM to determine whether increasing the dose of BDM could improve the hemodynamic effectiveness of CPR further, thus ultimately improving resuscitability. After 16minutes of untreated ventricular fibrillation and 8minutes of basic life support, 36 pigs were divided randomly into 3 groups that received 50mg/kg (low-dose group) of BDM, 100mg/kg (high-dose group) of BDM, or an equivalent volume of saline (control group) during advanced cardiovascular life support. During advanced cardiovascular life support, the control group showed an increase in left ventricular (LV) wall thickness and a decrease in LV chamber area. In contrast, the BDM-treated groups showed a decrease in the LV wall thickness and an increase in the LV chamber area in a dose-dependent fashion. Mixed-model analyses of the LV wall thickness and LV chamber area revealed significant group effects and group-time interactions. Central venous oxygen saturation at 3minutes after the drug administration was 21.6% (18.4-31.9), 39.2% (28.8-53.7), and 54.0% (47.5-69.4) in the control, low-dose, and high-dose groups, respectively (P<.001). Sustained restoration of spontaneous circulation was attained in 7 (58.3%), 10 (83.3%), and 12 animals (100%) in the control, low-dose, and high-dose groups, respectively (P=.046). 2,3-Butanedione monoxime administered during CPR attenuated ischemic contracture and improved the resuscitability in a dose-dependent fashion. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessment of organ-specific neutron equivalent doses in proton therapy using computational whole-body age-dependent voxel phantoms

NASA Astrophysics Data System (ADS)

Zacharatou Jarlskog, Christina; Lee, Choonik; Bolch, Wesley E.; Xu, X. George; Paganetti, Harald

2008-02-01

Proton beams used for radiotherapy will produce neutrons when interacting with matter. The purpose of this study was to quantify the equivalent dose to tissue due to secondary neutrons in pediatric and adult patients treated by proton therapy for brain lesions. Assessment of the equivalent dose to organs away from the target requires whole-body geometrical information. Furthermore, because the patient geometry depends on age at exposure, age-dependent representations are also needed. We implemented age-dependent phantoms into our proton Monte Carlo dose calculation environment. We considered eight typical radiation fields, two of which had been previously used to treat pediatric patients. The other six fields were additionally considered to allow a systematic study of equivalent doses as a function of field parameters. For all phantoms and all fields, we simulated organ-specific equivalent neutron doses and analyzed for each organ (1) the equivalent dose due to neutrons as a function of distance to the target; (2) the equivalent dose due to neutrons as a function of patient age; (3) the equivalent dose due to neutrons as a function of field parameters; and (4) the ratio of contributions to secondary dose from the treatment head versus the contribution from the patient's body tissues. This work reports organ-specific equivalent neutron doses for up to 48 organs in a patient. We demonstrate quantitatively how organ equivalent doses for adult and pediatric patients vary as a function of patient's age, organ and field parameters. Neutron doses increase with increasing range and modulation width but decrease with field size (as defined by the aperture). We analyzed the ratio of neutron dose contributions from the patient and from the treatment head, and found that neutron-equivalent doses fall off rapidly as a function of distance from the target, in agreement with experimental data. It appears that for the fields used in this study, the neutron dose lateral to the field is smaller than the reported scattered photon doses in a typical intensity-modulated photon treatment. Most importantly, our study shows that neutron doses to specific organs depend considerably on the patient's age and body stature. The younger the patient, the higher the dose deposited due to neutrons. Given the fact that the risk also increases with decreasing patient age, this factor needs to be taken into account when treating pediatric patients of very young ages and/or of small body size. The neutron dose from a course of proton therapy treatment (assuming 70 Gy in 30 fractions) could potentially (depending on patient's age, organ, treatment site and area of CT scan) be equivalent to up to ~30 CT scans.

Tier-2 studies on monocrotaline immunotoxicity in C57BL/6 mice.

PubMed

Deyo, J A; Kerkvliet, N I

1991-01-01

Monocrotaline (MCT) is a member of a class of naturally occurring phytotoxins known as pyrrolizidine alkaloids, and is a toxicological concern to both man and his livestock. The purpose of these studies was to evaluate the effect of a 14-day oral MCT (0-100 mg/kg per day) exposure on the functional integrity of various immunocyte effector systems in C57BL/6 mice, as well as to investigate potential mechanisms for its immunotoxicity. Decreases in lymphoid organ weights and cellularity, and resident peritoneal exudate cell (PEC) number were only observed after exposure to the highest dose of 100 mg/kg MCT. This dose also inhibited NK cell cytotoxicity, while the total number of NK lytic units per spleen was decreased (-53%) after exposure to 50 mg/kg MCT. Following i.p. injection of SRBC, the percentage of PEC macrophages containing engulfed SRBC was significantly increased in MCT-exposed mice, while the percentage of large vacuolated (activated) macrophages was decreased in a dose-dependent manner. Exposure to MCT significantly decreased the total number of Ig+ cells without altering the number of CD4+ and CD8+ cells. The antibody responses (PFC/10(6) spleen cells) to two T cell-independent antigens, TNP-LPS and DNP-Ficoll, were significantly decreased at all MCT doses, and the degree of suppression of both responses was identical at coincident doses. MCT exposure (25 mg/kg) significantly suppressed the blastogenic response to the T cell mitogen concanavalin A (-38%), and to the B cell mitogen lipopolysaccharide (-58%). These results indicate that exposure to MCT can alter the functional integrity of various immune effector responses in a dose-dependent manner, and suggest that the B cell may be a relatively more sensitive target of MCT immunotoxicity compared to T cells, macrophages and NK cells.

Inhaled nitric oxide, oxygen, and alkalosis: dose-response interactions in a lamb model of pulmonary hypertension.

PubMed

Heidersbach, R S; Johengen, M J; Bekker, J M; Fineman, J R

1999-07-01

Inhaled nitric oxide (NO) is currently used as an adjuvant therapy for a variety of pulmonary hypertensive disorders. In both animal and human studies, inhaled NO induces selective, dose-dependent pulmonary vasodilation. However, its potential interactions with other simultaneously used pulmonary vasodilator therapies have not been studied. Therefore, the objective of this study was to determine the potential dose-response interactions of inhaled NO, oxygen, and alkalosis therapies. Fourteen newborn lambs (age 1-6 days) were instrumented to measure vascular pressures and left pulmonary artery blood flow. After recovery, the lambs were sedated and mechanically ventilated. During steady-state pulmonary hypertension induced by U46619 (a thromboxane A2 mimic), the lambs were exposed to the following conditions: Protocol A, inhaled NO (0, 5, 40, and 80 ppm) and inspired oxygen concentrations (FiO2) of 0.21, 0.50, and 1.00; and Protocol B, inhaled NO (0, 5, 40, and 80 ppm) and arterial pH levels of 7.30, 7.40, 7.50, and 7.60. Each condition (in randomly chosen order) was maintained for 10 min, and all variables were allowed to return to baseline between conditions. Inhaled NO, oxygen, and alkalosis produced dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). Systemic arterial pressure remained unchanged. At 5 ppm of inhaled NO, alkalosis and oxygen induced further dose-dependent decreases in mean pulmonary arterial pressures (P < 0.05). At inhaled NO doses > 5 ppm, alkalosis induced further dose-independent decreases in mean pulmonary arterial pressure, while oxygen did not. We conclude that in this animal model, oxygen, alkalosis, and inhaled NO induced selective, dose-dependent pulmonary vasodilation. However, when combined, a systemic arterial pH > 7.40 augmented inhaled NO-induced pulmonary vasodilation, while an FiO2 > 0.5 did not. Therefore, weaning high FiO2 during inhaled NO therapy should be considered, since it may not diminish the pulmonary vasodilating effects. Further studies are warranted to guide the clinical weaning strategies of these pulmonary vasodilator therapies.

The Effects of Gamma and Proton Radiation Exposure on Hematopoietic Cell Counts in the Ferret Model

PubMed Central

Sanzari, Jenine K.; Wan, X. Steven; Krigsfeld, Gabriel S.; Wroe, Andrew J.; Gridley, Daila S.; Kennedy, Ann R.

2014-01-01

Exposure to total-body radiation induces hematological changes, which can detriment one's immune response to wounds and infection. Here, the decreases in blood cell counts after acute radiation doses of γ-ray or proton radiation exposure, at the doses and dose-rates expected during a solar particle event (SPE), are reported in the ferret model system. Following the exposure to γ-ray or proton radiation, the ferret peripheral total white blood cell (WBC) and lymphocyte counts decreased whereas neutrophil count increased within 3 hours. At 48 hours after irradiation, the WBC, neutrophil, and lymphocyte counts decreased in a dose-dependent manner but were not significantly affected by the radiation type (γ-rays verses protons) or dose rate (0.5 Gy/minute verses 0.5 Gy/hour). The loss of these blood cells could accompany and contribute to the physiological symptoms of the acute radiation syndrome (ARS). PMID:25356435

Effects of the food additive, citric acid, on kidney cells of mice.

PubMed

Chen, Xg; Lv, Qx; Liu, Ym; Deng, W

2015-01-01

Citric acid is a food additive that is widely used in the food and drink industry. We investigated the effects of citric acid injection on mouse kidney. Forty healthy mice were divided into four groups of 10 including one control group and three citric acid-treated groups. Low dose, middle dose and high dose groups were given doses of 120, 240 and 480 mg/kg of citric acid, respectively. On day 7, kidney tissues were collected for histological, biochemical and molecular biological examination. We observed shrinkage of glomeruli, widened urinary spaces and capillary congestion, narrowing of the tubule lumen, edema and cytoplasmic vacuolated tubule cells, and appearance of pyknotic nuclei. The relation between histopathological changes and citric acid was dose dependent. Compared to the control, T-SOD and GSH-Px activities in the treated groups decreased with increasing doses of citric acid, NOS activity tended to increase, and H2O2 and MDA contents gradually decreased, but the differences between any treated group and the control were not statistically significant. The apoptosis assay showed a dose-dependent increase of caspase-3 activity after administering citrate that was statistically significant. DNA ladder formation occurred after treatment with any dose of citric acid. We concluded that administration of citric acid may cause renal toxicity in mice.

3,3',4,4',5-Pentachlorobiphenyl (PCB 126) Decreases Hepatic and Systemic Ratios of Epoxide to Diol Metabolites of Unsaturated Fatty Acids in Male Rats.

PubMed

Wu, Xianai; Yang, Jun; Morisseau, Christophe; Robertson, Larry W; Hammock, Bruce; Lehmler, Hans-Joachim

2016-08-01

Disruption of the homeostasis of oxygenated regulatory lipid mediators (oxylipins), potential markers of exposure to aryl hydrocarbon receptor (AhR) agonists, such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126), is associated with a range of diseases, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Here we test the hypothesis that PCB 126 exposure alters the levels of oxylipins in rats. Male Sprague-Dawley rats (5-weeks old) were treated over a 3-month period every 2 weeks with intraperitoneal injections of PCB 126 in corn oil (cumulative doses of 0, 19.8, 97.8, and 390 µg/kg b.w.; 6 injections total). PCB 126 treatment caused a reduction in growth rates at the highest dose investigated, a dose-dependent decrease in thymus weights, and a dose-dependent increase in liver weights. Liver PCB 126 levels increased in a dose-dependent manner, while levels in plasma were below or close to the detection limit. The ratios of several epoxides to diol metabolites formed via the cytochrome P450 (P450) monooxygenase/soluble epoxide hydrolase (sEH) pathway from polyunsaturated fatty acids displayed a dose-dependent decrease in the liver and plasma, whereas levels of oxylipins formed by other metabolic pathways were generally not altered by PCB 126 treatment. The effects of PCB 126 on epoxide-to-diol ratios were associated with an increased CYP1A activity in liver microsomes and an increased sEH activity in liver cytosol and peroxisomes. These results suggest that oxylipins are potential biomarkers of exposure to PCB 126 and that the P450/sEH pathway is a therapeutic target for PCB 126-mediated hepatotoxicity that warrants further attention. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. for Permissions, please e-mail: journals.permissions@oup.com.

Valeriana wallichii root extract improves sleep quality and modulates brain monoamine level in rats.

PubMed

Sahu, Surajit; Ray, Koushik; Yogendra Kumar, M S; Gupta, Shilpa; Kauser, Hina; Kumar, Sanjeev; Mishra, Kshipra; Panjwani, Usha

2012-07-15

The present study was performed to investigate the effects of Valeriana wallichi (VW) aqueous root extract on sleep-wake profile and level of brain monoamines on Sprague-Dawley rats. Electrodes and transmitters were implanted to record EEG and EMG in freely moving condition and the changes were recorded telemetrically after oral administration of VW in the doses of 100, 200 and 300 mg/kg body weight. Sleep latency was decreased and duration of non-rapid eye movement (NREM) sleep was increased in a dose dependent manner. A significant decrease of sleep latency and duration of wakefulness were observed with VW at doses of 200 and 300 mg/kg. Duration of NREM sleep as well as duration of total sleep was increased significantly after treatment with VW at the doses of 200 and 300 mg/kg. VW also increased EEG slow wave activity during NREM sleep at the doses of 200 and 300 mg/kg. Level of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and hydroxy indole acetic acid (HIAA) were measured in frontal cortex and brain stem after VW treatment at the dose of 200mg/kg. NE and 5HT level were decreased significantly in both frontal cortex and brain stem. DA and HIAA level significantly decreased only in cortex. DOPAC level was not changed in any brain region studied. In conclusion it can be said that VW water extract has a sleep quality improving effect which may be dependent upon levels of monoamines in cortex and brainstem. Copyright © 2012 Elsevier GmbH. All rights reserved.

Diuretic effects of medetomidine compared with xylazine in healthy dogs

PubMed Central

Talukder, Md. Hasanuzzaman; Hikasa, Yoshiaki

2009-01-01

This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 μg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine’s effect is less dose-dependent than xylazine’s effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation. PMID:19794896

Memory Formation: Evidence for a Specific Neurochemical System in the Amygdala

ERIC Educational Resources Information Center

Gallagher, Michela; And Others

1977-01-01

Reports bita-Adrenergic antagonists injected into rats trained in a passive avoidance task produced time-dependent and dose-dependent decreases in retention of the task. Results were stereospecific and reversed by norepinephrine. (SL)

Consequences of copper treatment on pigeon pea photosynthesis, osmolytes and antioxidants defense.

PubMed

Sharma, Poonam; Sirhindi, Geetika; Singh, Anil Kumar; Kaur, Harpreet; Mushtaq, Ruqia

2017-10-01

An attempt was made to explore the effect of copper sulphate treatment on growth, photosynthesis, osmolytes and antioxidants in 15 days old seedlings of C. cajan (Pigeonpea). C. cajan seedlings were grown in 0, 1, 5 and 10 mM concentrations of copper sulphate in petriplates lined with Whatman filter paper for 15 days. Root length and shoot length was decreased in a dose dependent manner with highest decrease of 82.80 and 45.92% in 10 mM Cu stress. Photosynthetic efficiency (qP, qN and Y) was decreased in a dose dependent manner whereas NPQ was increased in 1 and 5 mM and decreased in 10 mM Cu. Photosynthetic pigments viz total chlorophyll and carotenoids were increased in low concentrations and decreased in high concentrations of Cu. Osmolytes such as proline, glycine betaine and sugars were found to be increased in a dose dependent manner. Similarly antioxidants such as superoxide dismutase and catalase increased to 129.17 and 169.7%, respectively under Cu stress. Vitamin C and vitamin E was also increased in different concentrations of Cu to a significant level. It can be concluded from the present study that C. cajan can tolerate Cu stress up to 5 mM by adjusting the proportion of proline, glycine betaine, sugars and vitamins along with increasing the activity of some of the antioxidant enzymes.

Repeated Post- or Presession Cocaine Administration: Roles of Dose and Fixed-Ratio Schedule

ERIC Educational Resources Information Center

Pinkston, Jonathan W.; Branch, Marc N.

2004-01-01

Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no…

Relationship between noise, dose, and pitch in cardiac multi-detector row CT.

PubMed

Primak, Andrew N; McCollough, Cynthia H; Bruesewitz, Michael R; Zhang, Jie; Fletcher, Joel G

2006-01-01

In spiral computed tomography (CT), dose is always inversely proportional to pitch. However, the relationship between noise and pitch (and hence noise and dose) depends on the scanner type (single vs multi-detector row) and reconstruction mode (cardiac vs noncardiac). In single detector row spiral CT, noise is independent of pitch. Conversely, in noncardiac multi-detector row CT, noise depends on pitch because the spiral interpolation algorithm makes use of redundant data from different detector rows to decrease noise for pitch values less than 1 (and increase noise for pitch values > 1). However, in cardiac spiral CT, redundant data cannot be used because such data averaging would degrade the temporal resolution. Therefore, the behavior of noise versus pitch returns to the single detector row paradigm, with noise being independent of pitch. Consequently, since faster rotation times require lower pitch values in cardiac multi-detector row CT, dose is increased without a commensurate decrease in noise. Thus, the use of faster rotation times will improve temporal resolution, not alter noise, and increase dose. For a particular application, the higher dose resulting from faster rotation speeds should be justified by the clinical benefits of the improved temporal resolution. RSNA, 2006

Glucose and insulin do not decrease in a dose-dependent manner after increasing doses of mixed fibers that are consumed in muffins for breakfast.

PubMed

Willis, Holly J; Thomas, William; Eldridge, Alison L; Harkness, Laura; Green, Hilary; Slavin, Joanne L

2011-01-01

Conventional wisdom suggests that fiber consumption leads to lower postprandial glucose and insulin response. We hypothesized that increasing doses of mixed, viscous fiber would lower glucose and insulin levels in a dose-dependent manner. Healthy men (n = 10) and women (n = 10) with a body mass index of 24 ± 2 (mean ± SEM) participated in this double-blind, crossover study. On 4 separate visits, fasting subjects consumed an approximately 2093 kJ (500 calorie) muffin with 0, 4, 8, or 12 g of mixed fibers. Blood was drawn to measure glucose and insulin at regular intervals throughout a 3-hour test period. Area under the curve (AUC) glucose was significantly lower after 0 g of fiber than after 4, 8, or 12 g of fiber (arbitrary AUC units ± SEM: 25.3 ± 5.2 vs 44.6 ± 7.7, 49.7 ± 7.9, 51.5 ± 6.6, respectively; P < .006). Area under the curve glucose increased with increasing fiber doses (P for trend = .0003). Area under the curve insulin was higher after the 4-g dose than after the 0-, 8-, and 12-g doses (arbitrary AUC units ± SEM: 84.4 ± 8.0 vs 60.1 ± 6.5, 69.4 ± 8.7, 69.7 ± 8.5, respectively; P < .05); it did not change in a dose-dependent manner. Area under the curve glucose and AUC insulin did not correlate with each other. Glucose and insulin did not decrease in a dose-dependent manner after 0, 4, 8, and 12 g of mixed fibers were consumed in muffins for breakfast. The lack of differences was largely based on the individual variation in glucose response. Caution should be used when making general claims about the expected impact of fiber on glucose and insulin levels. Copyright © 2011 Elsevier Inc. All rights reserved.

Molecular effects of the phosphatidylinositol-3-kinase inhibitor NVP-BKM120 on T and B-cell acute lymphoblastic leukaemia.

PubMed

Pereira, João Kleber Novais; Machado-Neto, João Agostinho; Lopes, Matheus Rodrigues; Morini, Beatriz Corey; Traina, Fabiola; Costa, Fernando Ferreira; Saad, Sara Teresinha Olalla; Favaro, Patricia

2015-09-01

Constitutive activation of the PI3K pathway in T cell acute lymphoblastic leukaemia (T-ALL) has been reported and in a mouse model, PI3K activation, together with MYC, cooperates in Burkitt lymphoma (BL) pathogenesis. We investigated the effects of NVP-BKM120, a potent pan-class I PI3K inhibitor, in lymphoblastic leukaemia cell lines. Effects of NVP-BKM120 on cell viability, clonogenicity, apoptosis, cell cycle, cell signalling and autophagy were assessed in vitro on T-ALL (Jurkat and MOLT-4) and BL (Daudi and NAMALWA) cell lines. NVP-BKM120 treatment decreased cell viability and clonogenic growth in all tested cells. Moreover, the drug arrested cell cycling in association with a decrease in Cyclin B1 protein levels, and increased apoptosis. Immunoblotting analysis of cells treated with the drug revealed decreased phosphorylation, in a dose-dependent manner, of AKT, mTOR, P70S6K and 4EBP1, with stable total protein levels. Additionally, we observed a dose-dependent decrease in BAD phosphorylation, in association with augmented BAX:BCL2 ratio. Quantification of autophagy showed a dose-dependent increase in acidic vesicular organelles in all cells tested. In summary, our present study establishes that NVP-BKM120 presents an effective antitumour activity against T-ALL and BL cell lines. Copyright © 2015 Elsevier Ltd. All rights reserved.

HDAC inhibitors induce global changes in histone lysine and arginine methylation and alter expression of lysine demethylases.

PubMed

Lillico, Ryan; Sobral, Marina Gomez; Stesco, Nicholas; Lakowski, Ted M

2016-02-05

Histone deacetylase (HDAC) inhibitors are cancer treatments that inhibit the removal of the epigenetic modification acetyllysine on histones, resulting in altered gene expression. Such changes in expression may influence other histone epigenetic modifications. We describe a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify lysine acetylation and methylation and arginine methylation on histones extracted from cultured cells treated with HDAC inhibitors. The HDAC inhibitors vorinostat, mocetinostat and entinostat induced 400-600% hyperacetylation in HEK 293 and K562 cells. All HDAC inhibitors decreased histone methylarginines in HEK 293 cells but entinostat produced dose dependent reductions in asymmetric dimethylarginine, not observed in K562 cells. Vorinostat produced increases in histone lysine methylation and decreased expression of some lysine demethylases (KDM), measured by quantitative PCR. Entinostat had variable effects on lysine methylation and decreased expression of some KDM while increasing expression of others. Mocetinostat produced dose dependent increases in histone lysine methylation by LC-MS/MS. This was corroborated with a multiplex colorimetric assay showing increases in histone H3 lysine 4, 9, 27, 36 and 79 methylation. Increases in lysine methylation were correlated with dose dependent decreases in the expression of seven KDM. Mocetinostat functions as an HDAC inhibitor and a de facto KDM inhibitor. Copyright © 2015 Elsevier B.V. All rights reserved.

Hepatic effects of orally administered styrene in rats.

PubMed

Srivastava, S P; Das, M; Mushtaq, M; Chandra, S V; Seth, P K

1982-08-01

Adult male rats receiving styrene by gavage (200 or 400 mg kg-1, 6 days a week) for 100 days exhibited a significant dose-dependent increase in hepatic benzo[a]pyrene hydroxylase and aminopyrine-N-demethylase, a decrease in glutathione-S-transferase and no change in glucose-6-phosphatase. A decrease in the activity of mitochondrial succinic dehydrogenase and beta-glucuronidase was also observed. Activity of acid phosphatase was decreased only at the higher dose level. Levels of serum glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were elevated only at the higher dose level. The absolute and relative weights of the liver of control and treated animals showed no significant difference. Histopathological studies of the liver tissue revealed tiny areas of focal necrosis, consisting of few degenerated hepatocytes and inflammatory cells at the higher dose level only.

Radiation exposure of German aircraft crews under the impact of solar cycle 23 and airline business factors.

PubMed

Frasch, Gerhard; Kammerer, Lothar; Karofsky, Ralf; Schlosser, Andrea; Stegemann, Ralf

2014-12-01

The exposure of German aircraft crews to cosmic radiation varies both with solar activity and operational factors of airline business. Data come from the German central dose registry and cover monthly exposures of up to 37,000 German aircraft crewmembers that were under official monitoring. During the years 2004 to 2009 of solar cycle 23 (i.e., in the decreasing phase of solar activity), the annual doses of German aircraft crews increased by an average of 20%. Decreasing solar activity allows more galactic radiation to reach the atmosphere, increasing high-altitude doses. The rise results mainly from the less effective protection from the solar wind but also from airline business factors. Both cockpit and cabin personnel differ in age-dependent professional and social status. This status determines substantially the annual effective dose: younger cabin personnel and the elder pilots generally receive higher annual doses than their counterparts. They also receive larger increases in their annual dose when the solar activity decreases. The doses under this combined influence of solar activity and airline business factors result in a maximum of exposure for German aircrews for this solar cycle. With the increasing solar activity of the current solar cycle 24, the doses are expected to decrease again.

Physical and radiological properties of radiochromic gel as of its composition

NASA Astrophysics Data System (ADS)

Lee, Sang Hoon; Kim, Juree; Shim, Su Jung; Chang, Kyung Hwan; Lim, Sangwook; Huh, Hyun Do; Shin, Dong Oh; Cho, Sam Ju

2014-04-01

In the research, we evaluated the use of leuco crystal violet (LCV) gel as a dosimeter for therapeutic radiation by investigating its optical characteristics at various component concentrations. We also investigated the aging effect of the LCV gel at different beam energies, doserates, and dosing times to evaluate the LCV's applicability to radiation therapy. We confirmed that the optimal optical wavelength of the LCV gel dosimeter was 600 nm. The dose sensitivity increased with increasing concentration of LCV; however, the optimal concentration was 1 mM LCV because the transparency of the gel dosimeter is important for use in optical CT scanners. However, the dose sensitivity decreased with increasing concentration of trichloroacetic acid (TAA). Moreover, the transparency of LCV rapidly decreased because of the generation of a white precipitate at TAA concentrations below 25 mM. Thus, an optimal TAA concentration of 30 mM was used in this study. Triton X-100 (8 mM) was identified as the optimal reagent for determining the optimum gel transparency and dose sensitivity. Thus, we present an LCV gel dosimeter composed of 4% gelatin by mass, 1 mM LCV, 30 mM TAA, and 8-mM Triton X-100 for use with an optical CT scanner. We showed good dose linearity up to 30 Gy. There was a little doserate dependency at a beam energy of 6 MV while the doserate dependence was more than 4.2% at a beam energy of 10 MV. To evaluate the energy dependence of the LCV gel dosimeter, we irradiated it at 20 Gy by using 6 MV and 10 MV beams. At the high doserate, the difference in the dose energy dependence was relatively small at approximately 1%, but the difference increased to 4.6% at the low doserate. With respect to the radiation absorbance at a photon energy of 6 MV, the absorbance at an electron energy of 6 MeV decreased by 5.4%, and the absorbances at 9, 12, and 15 MeV increased by 3, 18.7, and 12.2%, respectively. Furthermore, the aging effect was larger in the low-dose group then in the high-dose group. Moreover, we observed that the absorbance between 24 and 48 h after irradiation increased by approximately 5% at 5 Gy. For gel groups tested at high doses, the aging effect was reduced by approximately 1%.

Dependence of normal brain integral dose and normal tissue complication probability on the prescription isodose values for γ-knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun

2001-11-01

A recent multi-institutional clinical study suggested possible benefits of lowering the prescription isodose lines for stereotactic radiosurgery procedures. In this study, we investigate the dependence of the normal brain integral dose and the normal tissue complication probability (NTCP) on the prescription isodose values for γ-knife radiosurgery. An analytical dose model was developed for γ-knife treatment planning. The dose model was commissioned by fitting the measured dose profiles for each helmet size. The dose model was validated by comparing its results with the Leksell gamma plan (LGP, version 5.30) calculations. The normal brain integral dose and the NTCP were computed and analysed for an ensemble of treatment cases. The functional dependence of the normal brain integral dose and the NCTP versus the prescribing isodose values was studied for these cases. We found that the normal brain integral dose and the NTCP increase significantly when lowering the prescription isodose lines from 50% to 35% of the maximum tumour dose. Alternatively, the normal brain integral dose and the NTCP decrease significantly when raising the prescribing isodose lines from 50% to 65% of the maximum tumour dose. The results may be used as a guideline for designing future dose escalation studies for γ-knife applications.

Objective assessment of gait in xylazine-induced ataxic horses.

PubMed

Nout-Lomas, Y S; Page, K M; Kang, H G; Aanstoos, M E; Greene, H M

2017-05-01

There is poor agreement between observers of equine neurological gait abnormalities using the modified Mayhew grading scale. To stimulate a dose-dependent ataxia in horses through xylazine administration and identify quantifiable relevant gait parameters. Balanced, randomised, 2-way crossover design. Eight horses were assessed before and after administration of xylazine (low dose and high dose). Gait analyses performed before and after xylazine administration included: 1) kinematic data collected on an equine high-speed treadmill (flat and 10% decline) and from accelerometers placed on head and sacrum; and 2) kinetic data collected on a force plate. All horses developed dose-dependent ataxia. Horses developed a dose-dependent increased stride time, stride length, and time of contact (P<0.0001), and a decreased stride frequency (P<0.0002) after administration of xylazine. Although pelvic acceleration increased in the mediolateral direction (P<0.05) in horses walked on the treadmill, this movement decreased when walking over ground after administration of xylazine (P<0.05). Furthermore, centre of pressure and path length indices changed significantly in horses following administration of xylazine (P<0.05). This study examined one breed of horse (Arabian), all of similar height and weight. Accelerometers were attached to skin, not bone; no correction was made for artefacts from skin displacement. The sedative drug effect is of certain duration, limiting the data collection period. Administration of xylazine induced a dose-dependent ataxia in horses and resulted in significant changes of gait parameters, pelvic accelerations, and stabilographic variables, some of which changed in a dose-dependent fashion. Some of the altered gait parameters in this model were probably a result of overall slowing down of the stride cycle secondary to the sedative effect. Continued efforts to discover and evaluate quantifiable gait parameters that are susceptible to change following development of clinical neurological disease in horses is warranted. © 2016 EVJ Ltd.

An attempt to evaluate the effect of vitamin K3 using as an enhancer of anticancer agents.

PubMed

Matzno, Sumio; Yamaguchi, Yuka; Akiyoshi, Takeshi; Nakabayashi, Toshikatsu; Matsuyama, Kenji

2008-06-01

The possibility of vitamin K3 (VK3) as an anticancer agent was assessed. VK3 dose-dependently diminished the cell viability (measured as esterase activity) with IC50 of 13.7 microM and Hill coefficient of 3.1 in Hep G2 cells. It also decreased the population of S phase and arrested cell cycle in the G2/M phase in a dose-dependent manner. G2/M arrest was regulated by the increment of cyclin A/cdk1 and cyclin A/cdk2 complex, and contrasting cyclin B/cdk1 complex decrease. Finally, combined application demonstrated that VK3 significantly enhanced the cytotoxicity of etoposide, a G2 phase-dependent anticancer agent, whereas it reduced the cytotoxic activity of irinotecan, a S phase-dependent agent. These findings suggest that VK3 induces G2/M arrest by inhibition of cyclin B/cdk1 complex formation, and is thus useful as an enhancer of G2 phase-dependent drugs in hepatic cancer chemotherapy.

A comparison of dehydroepiandrosterone and 7-keto dehydroepiandrosterone with other drugs that modulate ethanol intake in rats responding under a multiple schedule

PubMed Central

Amato, Russell J.; Hulin, Mary W.; Winsauer, Peter J.

2012-01-01

Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectively for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol- and food-maintained responding, compared to control, while also decreasing blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared to food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, while not affecting ethanol-maintained responding compared to control. Low to intermediate doses of rauwolscine produced small, non-significant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence. PMID:22473025

Images in electroconvulsive therapy: ECS dose-dependently increases cell proliferation in the subgranular region of the rat hippocampus.

PubMed

Smitha, Jangama S M; Roopa, Ravindranath; Sagar, B K Chandrasekhar; Kutty, Bindu M; Andrade, Chittaranjan

2014-09-01

Stress and depression are associated with impaired neuroplasticity in the hippocampus; there is a decrease in neurogenesis, which is hypothesized to decrease the adaptative competence of the organism. Representative light microscopy images are presented which show that 6 once-daily electroconvulsive shocks (ECS), dose-dependently increased new cell formation in the subgranular region of the hippocampus in healthy adult male Wistar rats (10 sections per rat, 3 rats in each of sham ECS, 10 mC, and 40 mC groups). These neuroplasticity changes, demonstrated 1 month after the last ECS, may explain a part of the mechanism of action of electroconvulsive therapy in conditions such as depression.

Pharmacokinetics and pharmacodynamics of single and multiple doses of the glucagon receptor antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus.

PubMed

Vajda, Eric G; Logan, Douglas; Lasseter, Kenneth; Armas, Danielle; Plotkin, Diane J; Pipkin, J D; Li, Yong-Xi; Zhou, Rong; Klein, David; Wei, Xiaoxiong; Dilzer, Stacy; Zhi, Lin; Marschke, Keith B

2017-01-01

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral glucagon receptor antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). In the single ascending dose study, LGD-6972 (2-480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma glucagon were observed, but glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycaemia. Inhibition of glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycaemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock.

PubMed

Hebbar, Kiran B; Stockwell, Jana A; Leong, Traci; Fortenberry, James D

2011-05-01

Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion. We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need. Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids. Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039). Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.

Measurement of ambient dose equivalent rates by walk survey around Fukushima Dai-ichi Nuclear Power Plant using KURAMA-II until 2016.

PubMed

Andoh, Masaki; Yamamoto, Hideaki; Kanno, Takashi; Saito, Kimiaki

2018-05-17

Ambient dose equivalent rates in various environments related to human lives were measured by walk surveys using the KURAMA-II systems from 2013 to 2016 within an 80-km radius of the Fukushima Dai-ichi Nuclear Power Plant. The dose rate of the locations where the walk survey was performed decreased to about 38% of its initial value in the 42 months from June 2013 to the December 2016, which was beyond that attributable to the physical decay of radiocaesium. The ecological half-life of the slow decreasing component was evaluated to be 4.1 ± 0.2 y. The air dose rates decreased depending on the level of the evacuation areas, and the decrease in the dose rates was slightly larger in populated areas where humans are active. The dose rates as measured by walk surveys exhibited a good correlation with those by car-borne surveys, suggesting that car-borne survey data are reflecting the air dose rates in living environments surrounding roads. The comparison of walk survey data with car-borne survey data indicated that the air dose rate varies largely even within a 100 m square area, and the variation is enhanced by human activities. The dose rates measured by the walk surveys were estimated to be medial of those along roads and those of undisturbed flat ground, and they were found to be decreasing quickly compared with the air dose rate from the flat ground fixed-point measurements. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine.

PubMed

Hiranita, Takato; Soto, Paul L; Tanda, Gianluigi; Katz, Jonathan L

2010-02-01

sigma-Receptor (sigmaR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of sigmaR ligands in rats trained to self-administer cocaine (0.032-1.0 mg/kg/inj i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine, or by the sigmaR agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084; 0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the sigmaR antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047), N-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with sigmaR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (-)-2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the sigmaR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by sigmaR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although sigmaR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at sigmaRs. However, the self-administration of sigmaR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by sigmaR-agonist pretreatment, and the facilitation of sigmaR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and sigmaR-mediated actions of the drugs.

Reinforcing Effects of σ-Receptor Agonists in Rats Trained to Self-Administer Cocaine

PubMed Central

Hiranita, Takato; Soto, Paul L.; Tanda, Gianluigi

2010-01-01

σ-Receptor (σR) antagonists have been reported to block certain effects of psychostimulant drugs. The present study examined the effects of σR ligands in rats trained to self-administer cocaine (0.032–1.0 mg/kg/inj i.v.) under fixed-ratio 5-response schedules of reinforcement. Maximal rates of responding were maintained by 0.32 mg/kg/inj cocaine, or by the σR agonists, 1,3-di-(2-tolyl)guanidine (DTG; 1.0 mg/kg/inj) or 2-(4-morpholinethyl) 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084; 0.32 mg/kg/inj), when substituted for cocaine. Lower response rates were maintained at higher and lower doses of the compounds. No dose of the σR antagonists [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine (BD 1047), N-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine (BD 1063)] maintained responding appreciably above levels obtained when responding had no consequences. Presession treatment with σR agonists dose-dependently shifted the cocaine self-administration dose-effect curve leftward. The dopamine-uptake inhibitor, (−)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), dose-dependently shifted the DTG and PRE-084 self-administration dose-effect curves leftward. Treatment with the σR antagonists dose-dependently decreased response rates maintained by DTG or PRE-084, but did not affect cocaine self-administration. Response rates maintained by maximally effective DTG or PRE-084 doses were decreased by σR antagonists at lower doses than those that decreased response rates maintained by food reinforcement. Although σR antagonists block some cocaine-induced effects, the lack of effect on cocaine self-administration suggests that the primary reinforcing effects of cocaine do not involve direct effects at σRs. However, the self-administration of σR agonists in cocaine-trained subjects, facilitation of cocaine self-administration by σR-agonist pretreatment, and the facilitation of σR-agonist self-administration by WIN 35,428, together suggest enhanced abuse-related effects resulting from concomitant dopaminergically mediated actions and σR-mediated actions of the drugs. PMID:19892920

Development, food intake, and ethinylestradiol influence hepatic triglyceride lipase and LDL-receptor mRNA levels in rats.

PubMed

Staels, B; Jansen, H; van Tol, A; Stahnke, G; Will, H; Verhoeven, G; Auwerx, J

1990-07-01

The influence of development and ethinylestradiol on low density lipoprotein (LDL)-receptor mRNA and hepatic triglyceride lipase (HTGL) activity and mRNA levels was studied in rat liver and intestine. Intestinal LDL-receptor mRNA levels are maximal in the perinatal period, whereas liver LDL-receptor and HTGL mRNA levels are highest after weaning in adult life. All mRNA levels reach a maximum between day 15 and 20 when rats still consume a lipid-rich diet, and increase twofold during weaning. Liver and intestinal LDL-receptor mRNA levels are not influenced by ovariectomy, but increase after ethinylestradiol treatment. Liver LDL-receptor mRNA shows a dose-dependent increase after ethinylestradiol and a sevenfold rise in liver LDL-receptor mRNA is attained with a dose of 2000 micrograms/day. Intestinal LDL-receptor mRNA increases slightly more than twofold after ethinylestradiol and this increase is not dose-dependent. Changes in LDL-receptor mRNA are independent of changes in food intake induced by ethinylestradiol treatment, since they are still observed after pair-feeding. The ethinylestradiol-induced increases in LDL-receptor mRNA levels are reflected by decreased serum apoB levels. HTGL mRNA levels increase after ovariectomy and show a dose-dependent decrease after ethinylestradiol. Pair-feeding abolishes the increase seen after ovariectomy, while the estrogen-mediated decrease is attenuated. These alterations in HTGL mRNA are reflected by similar changes in liver HTGL activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent decrease in anti-oxidant capacity of whole blood after irradiation: A novel potential marker for biodosimetry.

PubMed

Sun, Lue; Inaba, Yohei; Sato, Keizo; Hirayama, Aki; Tsuboi, Koji; Okazaki, Ryuji; Chida, Koichi; Moritake, Takashi

2018-05-09

Many reports have demonstrated that radiation stimulates reactive oxygen species (ROS) production by mitochondria for a few hours to a few days after irradiation. However, these studies were performed using cell lines, and there is a lack of information about redox homeostasis in irradiated animals and humans. Blood redox homeostasis reflects the body condition well and can be used as a diagnostic marker. However, most redox homeostasis studies have focused on plasma or serum, and the anti-oxidant capacity of whole blood has scarcely been investigated. Here, we report changes in the anti-oxidant capacity of whole blood after X-ray irradiation using C57BL/6 J mice. Whole-blood anti-oxidant capacity was measured by electron spin resonance (ESR) spin trapping using a novel spin-trapping agent, 2-diphenylphosphinoyl-2-methyl-3,4-dihydro-2H-pyrrole N-oxide (DPhPMPO). We found that whole-blood anti-oxidant capacity decreased in a dose-dependent manner (correlation factor, r > 0.9; P < 0.05) from 2 to 24 days after irradiation with 0.5-3 Gy. We further found that the red blood cell (RBC) glutathione level decreased and lipid peroxidation level increased in a dose-dependent manner from 2 to 6 days after irradiation. These findings suggest that blood redox state may be a useful biomarker for estimating exposure doses during nuclear and/or radiation accidents.

New insights into the mechanism and actions of growth hormone (GH) in poultry.

PubMed

Vasilatos-Younken, R; Wang, X H; Zhou, Y; Day, J R; McMurtry, J P; Rosebrough, R W; Decuypere, E; Buys, N; Darras, V; Beard, J L; Tomas, F

1999-10-01

Despite well documented anabolic effects of GH in mammals, a clear demonstration of such responses in domestic poultry is lacking. Recently, comprehensive dose-response studies of GH have been conducted in broilers during late post-hatch development (8 to 9 weeks of age). GH reduced feed intake (FI) and body weight gain in a dose-dependent manner, whereas birds pair-fed to the level of voluntary FI of GH-infused birds did not differ from controls. The reduction in voluntary FI may involve centrally mediated mechanisms, as hypothalamic neuropeptide Y protein and mRNA were reduced with GH, coincident with the maximal depression in FI. Growth of breast muscle was also reduced in a dose-dependent manner. Circulating IGF-I was not enhanced by GH, despite evidence that early events in the GH signaling pathway were intact. A GH dose-dependent increase in circulating 3,3',5-triiodothyronine(T3) paralleled decreases in hepatic 5D-III monodeiodinase activity, whereas 5'D-I activity was not altered. This confirms that a marked hyperthyroid response to GH occurs in late posthatch chickens, resulting from a decrease in the degradative pathway of T3 metabolism. This secondary hyperthyroidism would account for the decreased skeletal muscle mass (52) and lack of enhanced IGF-I (53) in GH-treated birds. Based upon these studies, it is now evident that GH does in fact have significant effects in poultry, but metabolic responses may confound the anabolic potential of the hormone.

Short-term treatment with transdermal nicotine affects the function of canine saphenous veins.

PubMed

Clouse, W D; Rud, K S; Hurt, R D; Miller, V M

2000-01-01

Experiments were designed to determine the effects of nicotine treatment on the functions of saphenous veins used for coronary artery bypass grafts in dogs. Dogs received either no treatment or transdermal nicotine for 5 weeks at doses of 11 mg, 22 mg or 44 mg/day. Saphenous veins were removed and suspended for the measurement of isometric force in organ chambers. Endothelium was removed mechanically from some rings. N(G)-mono-methyl-L-arginine (L-NMMA; 10(-4) M) was used to inhibit the production of nitric oxide. Contractions to alpha2-adrenergic stimulation were decreased in veins from dogs treated with a 22-mg/day dose of transdermal nicotine. In addition, endothelium-dependent relaxations to adenosine-diphosphate (10(-8)-10(-4) M) and the calcium ionophore A23,187 (10(-8)-10(-6) M) were decreased in veins from dogs with a 22-mg/day dose and increased in veins from dogs treated with a 44-mg/day dose. These relaxations were inhibited by L-NMMA. Plasma concentrations of oxidized products of nitric oxide were decreased only in dogs treated with 22 mg/day of nicotine. The relaxation of rings without endothelium (direct response on the smooth muscle) to nitric oxide were not altered by nicotine treatment. These results suggest that the short-term treatment of dogs with intermediate (22 mg/day) but not low (11 mg/day) or high (44 mg/day) doses of transdermal nicotine decreases the endothelial function of veins used for coronary artery bypass grafts. Therefore, changes in plasma products of nitric oxide and endothelium-dependent relaxations mediated by nitric oxide are related to the dose of nicotine treatment.

Aripiprazole maintenance increases smoked cocaine self-administration in humans

PubMed Central

Rubin, Eric; Foltin, Richard W.

2011-01-01

Rationale Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence. Objective This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D2 receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers. Methods In order to achieve steady-state concentrations, participants (n=8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose–response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a “sample” trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00. Results Cocaine’s reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo. Conclusions These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence. PMID:21373790

New insight into mitochondrial changes in vascular endothelial cells irradiated by gamma ray.

PubMed

Hu, Shunying; Gao, Yajing; Zhou, Hao; Kong, Fanxuan; Xiao, Fengjun; Zhou, Pingkun; Chen, Yundai

2017-05-01

To investigate alterations of mitochondria in irradiated endothelial cells to further elucidate the mechanism underlying radiation-induced heart disease. Experiments were performed using human umbilical vein endothelial cells (HUVECs). HUVECs were irradiated with single gamma ray dose of 0, 5, 10 and 20 Gy, respectively. Apoptosis was assessed by flow cytometry at 24, 48 and 72 h post-irradiation, respectively. The intracellular reactive oxygen species (ROS) was measured with 2',7'-dichlorofluorescein-diacetate (DCFH-DA) at 24 h post-irradiation. Mitochondrial membrane potential (ΔΨm) by JC-1 and the opening of mitochondrial permeability transition pore (mPTP) by a calcein-cobalt quenching method were detected at 24 h post-irradiation in order to measure changes of mitochondria induced by gamma ray irradiation. Gamma ray irradiation increased HUVECs apoptosis in a dose-dependent and time-dependent manner. Irradiation also promoted ROS production in HUVECs in a dose-dependent manner. At 24 h post-irradiation, the results showed that irradiation decreases ΔΨm, however, paradoxically, flow cytometry showed green fluorescence instensity higher in irradiated HUVECs than in control HUVECs in an irradiation dose-dependent manner which indicated gamma ray irradiation inhibited mPTP opening in HUVECs. Gamma ray irradiation induces apoptosis and ROS production of endothelial cells, and decreases ΔΨm meanwhile contradictorily inhibiting the opening of mPTP.

Effects of polyaluminum chloride and lanthanum-modified bentonite on the growth rates of three Cylindrospermopsis raciborskii strains

PubMed Central

van Oosterhout, Frank; Becker, Vanessa; Attayde, José Luiz; Lürling, Miquel

2018-01-01

In tropical and subtropical lakes, eutrophication often leads to nuisance blooms of Cylindrospermopsis raciborskii. In laboratory experiments, we tested the combined effects of flocculant polyaluminum chloride (PAC) and lanthanum-modified bentonite (LMB) on the sinking and growth rates of three C. raciborskii strains. We tested the hypothesis that the combination of PAC and LMB would (1) effectively sink C. raciborskii in a test tube experiment and (2) impair C. raciborskii growth, irrespective of the biomass of the inoculum (bloom) and the strain in the growth experiment. We tested the recommended (LMB1) and a three-times higher dose of LMB (LMB3). The combined addition of PAC and LMB enhanced the sedimentation of all C. raciborskii strains. Moreover, both the PAC and LMB doses decreased the phosphate concentration. PAC and LMB1 decreased the growth rate of all strains, but the efficacy depended on the biomass and strain. The combined addition of PAC and LMB3 inhibited the growth of all strains independently of the biomass and strain. We conclude that a low dose of PAC in combination with the recommended dose of LMB decreases C. raciborskii blooms and that the efficiency of the technique depends on the biomass of the bloom. A higher dose of LMB is needed to obtain a more efficient control of C. raciborskii blooms. PMID:29614118

Effects of polyaluminum chloride and lanthanum-modified bentonite on the growth rates of three Cylindrospermopsis raciborskii strains.

PubMed

Araújo, Fabiana; van Oosterhout, Frank; Becker, Vanessa; Attayde, José Luiz; Lürling, Miquel

2018-01-01

In tropical and subtropical lakes, eutrophication often leads to nuisance blooms of Cylindrospermopsis raciborskii. In laboratory experiments, we tested the combined effects of flocculant polyaluminum chloride (PAC) and lanthanum-modified bentonite (LMB) on the sinking and growth rates of three C. raciborskii strains. We tested the hypothesis that the combination of PAC and LMB would (1) effectively sink C. raciborskii in a test tube experiment and (2) impair C. raciborskii growth, irrespective of the biomass of the inoculum (bloom) and the strain in the growth experiment. We tested the recommended (LMB1) and a three-times higher dose of LMB (LMB3). The combined addition of PAC and LMB enhanced the sedimentation of all C. raciborskii strains. Moreover, both the PAC and LMB doses decreased the phosphate concentration. PAC and LMB1 decreased the growth rate of all strains, but the efficacy depended on the biomass and strain. The combined addition of PAC and LMB3 inhibited the growth of all strains independently of the biomass and strain. We conclude that a low dose of PAC in combination with the recommended dose of LMB decreases C. raciborskii blooms and that the efficiency of the technique depends on the biomass of the bloom. A higher dose of LMB is needed to obtain a more efficient control of C. raciborskii blooms.

Transient impairment of hippocampus-dependent learning and memory in relatively low-dose of acute radiation syndrome is associated with inhibition of hippocampal neurogenesis.

PubMed

Kim, Joong-Sun; Lee, Hae-June; Kim, Jong Choon; Kang, Seong Soo; Bae, Chun-Sik; Shin, Taekyun; Jin, Jae-Kwang; Kim, Sung Ho; Wang, Hongbing; Moon, Changjong

2008-09-01

Neurogenesis in the adult hippocampus, which occurs constitutively, is vulnerable to ionizing radiation. In the relatively low-dose exposure of acute radiation syndrome (ARS), the change in the adult hippocampal function is poorly understood. This study analyzed the changes in apoptotic cell death and neurogenesis in the DGs of hippocampi from adult ICR mice with single whole-body gamma-irradiation using the TUNEL method and immunohistochemical markers of neurogenesis, Ki-67 and doublecortin (DCX). In addition, the hippocampus-dependent learning and memory tasks after single whole-body gamma-irradiation were examined in order to evaluate the hippocampus-related behavioral dysfunction in the relatively low-dose exposure of ARS. The number of TUNEL-positive apoptotic nuclei in the dentate gyrus (DG) was increased 6-12 h after acute gamma-irradiation (a single dose of 0.5 to 4 Gy). In contrast, the number of Ki-67- and DCX-positive cells began to decrease significantly 6 h postirradiation, reaching its lowest level 24 h after irradiation. The level of Ki-67 and DCX immunoreactivity decreased in a dose-dependent manner within the range of irradiation applied (0-4 Gy). In passive avoidance and object recognition memory test, the mice trained 1 day after acute irradiation (2 Gy) showed significant memory deficits, compared with the sham controls. In conclusion, the pattern of the hippocampus-dependent memory dysfunction is consistent with the change in neurogenesis after acute irradiation. It is suggested that a relatively low dose of ARS in adult ICR mice is sufficiently detrimental to interrupt the functioning of the hippocampus, including learning and memory, possibly through the inhibition of neurogenesis.

Gestational Lead Exposure Selectively Decreases Retinal Dopamine Amacrine Cells and Dopamine Content in Adult Mice

PubMed Central

Fox, Donald A.; Hamilton, W. Ryan; Johnson, Jerry E.; Xiao, Weimin; Chaney, Shawntay; Mukherjee, Shradha; Miller, Diane B.; O’Callaghan, James P.

2011-01-01

Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤1, ≤10, ~25 and ~40 µg/dL, respectively, on PN10 and by PN30 all were ≤1 µg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. PMID:21703292

Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice.

PubMed

Fox, Donald A; Hamilton, W Ryan; Johnson, Jerry E; Xiao, Weimin; Chaney, Shawntay; Mukherjee, Shradha; Miller, Diane B; O'Callaghan, James P

2011-11-01

Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was ≤ 1, ≤ 10, ~25 and ~40 μg/dL, respectively, on PN10 and by PN30 all were ≤ 1 μg/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. Copyright © 2011 Elsevier Inc. All rights reserved.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

PubMed

Tran, Jonathan Q; Hartung, Jeffrey P; Peach, Robert J; Boehm, Marcus F; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L; Timony, Gregg A; Olson, Allan D; Gujrathi, Sheila; Frohna, Paul A

2017-08-01

The sphingosine-1-phosphate 1 receptor (S1P 1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P 1R and S1P 5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

SU-F-T-378: Evaluation of Dose-Volume Variability and Parameters Between Prostate IMRT and VMAT Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chow, J; Jiang, R; Kiciak, A

2016-06-15

Purpose: This study compared the rectal dose-volume consistency, equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) in prostate intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Methods: For forty prostate IMRT and fifty VMAT patients treated using the same dose prescription (78 Gy/39 fraction) and dose-volume criteria in inverse planning optimization, the rectal EUD and NTCP were calculated for each patient. The rectal dose-volume consistency, showing the variability of dose-volume histogram (DVH) among patients, was defined and calculated based on the deviation between the mean and corresponding rectal DVH. Results: From both the prostate IMRT andmore » VMAT plans, the rectal EUD and NTCP were found decreasing with the rectal volume. The decrease rates for the IMRT plans (EUD = 0.47 × 10{sup −3} Gy cm{sup −3} and NTCP = 3.94 × 10{sup −2} % cm{sup −3}) were higher than those for the VMAT (EUD = 0.28 × 10{sup −3} Gy cm{sup −3} and NTCP = 2.61 × 10{sup −2} % cm{sup −3}). In addition, the dependences of the rectal EUD and NTCP on the dose-volume consistency were found very similar between the prostate IMRT and VMAT plans. This shows that both delivery techniques have similar variations of the rectal EUD and NTCP on the dose-volume consistency. Conclusion: Dependences of the dose-volume consistency on the rectal EUD and NTCP were compared between the prostate IMRT and VMAT plans. It is concluded that both rectal EUD and NTCP decreased with an increase of the rectal volume. The variation rates of the rectal EUD and NTCP on the rectal volume were higher for the IMRT plans than VMAT. However, variations of the rectal dose-volume consistency on the rectal EUD and NTCP were found not significant for both delivery techniques.« less

A Randomized, Placebo-Controlled Study of High-Dose Baclofen in Alcohol-Dependent Patients-The ALPADIR Study.

PubMed

Reynaud, Michel; Aubin, Henri-Jean; Trinquet, Francoise; Zakine, Benjamin; Dano, Corinne; Dematteis, Maurice; Trojak, Benoit; Paille, Francois; Detilleux, Michel

2017-07-01

Alcohol dependence is a major public health issue with a need for new pharmacological treatments. The ALPADIR study assessed the efficacy and safety of baclofen at the target dose of 180 mg/day for the maintenance of abstinence and the reduction in alcohol consumption in alcohol-dependent patients. Three hundred and twenty adult patients (158 baclofen and 162 placebo) were randomized after alcohol detoxification. After a 7-week titration, the maintenance dose was provided for 17 weeks, then progressively decreased over 2 weeks before stopping. The percentage of abstinent patients during 20 consecutive weeks (primary endpoint) was low (baclofen: 11.9%; placebo: 10.5%) and not significantly different between groups (OR 1.20; 95%CI: 0.58 to 2.50; P = 0.618). A reduction in alcohol consumption was observed from month 1 in both groups, but the difference of 10.9 g/day at month 6 between groups, in favour of baclofen, was not statistically significant (P = 0.095). In a subgroup of patients with high drinking risk level at baseline, the reduction was greater with a difference at month 6 of 15.6 g/day between groups in favour of baclofen (P = 0.089). The craving assessed with Obsessive-Compulsive Drinking Scale significantly decreased in the baclofen group (P = 0.017). No major safety concern was observed. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence at the target dose of 180 mg/day. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. Baclofen was assessed versus placebo for maintenance of abstinence and reduction in alcohol consumption in alcohol-dependent patients. This study did not demonstrate the superiority of baclofen in the maintenance of abstinence. A tendency towards a reduction in alcohol consumption and a significantly decreased craving were observed in favour of baclofen. © The Author 2017. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Effect of ammonium metavanadate on the murine immune response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cohen, M.D.; Wei, C.I.; Tan, H.

1986-01-01

Female B/sub 6/C/sub 3/F/sub 1/ mice were exposed to ammonium metavanadate (NH/sub 4/VO/sub 3/) by intraperitoneal injection every 3 d at 2.5, 5.0, or 10 mg V/kg for 3, 6, or 9 w and were then assayed for alterations in immunoresponsiveness. Resistance to Escherichia coli endotoxin lethality increased in a dose-dependent manner up to 6 w of exposure, while resistance to viable gram-positive Listeria lethality was depressed in a dose-dependent manner. Comparison of LD20 values indicated a 250-fold decrease in resistance to Listeria at the lowest vanadium exposure and a 40% increase in resistance to endotoxin after the highest vanadiummore » exposure. Peritoneal macrophage phagocytic capacities were decreased in a dose-dependent manner, but viabilities remained unaffected. Rosetting capacity of splenic lymphocytes was increased following vanadium exposure. Liver and splenic enlargement was observed, and examination of splenic tissue indicated enhanced formation of megakaryocytes and red blood cell precursors. Subchronic exposure to vanadium may thus disrupt the normal function of the immune system.« less

Hydrostatic Compress Force Enhances the Viability and Decreases the Apoptosis of Condylar Chondrocytes through Integrin-FAK-ERK/PI3K Pathway.

PubMed

Ma, Dandan; Kou, Xiaoxing; Jin, Jing; Xu, Taotao; Wu, Mengjie; Deng, Liquan; Fu, Lusi; Liu, Yi; Wu, Gang; Lu, Haiping

2016-11-07

Reduced mechanical stimuli in many pathological cases, such as hemimastication and limited masticatory movements, can significantly affect the metabolic activity of mandibular condylar chondrocytes and the growth of mandibles. However, the molecular mechanisms for these phenomena remain unclear. In this study, we hypothesized that integrin-focal adhesion kinase (FAK)-ERK (extracellular signal-regulated kinase)/PI3K (phosphatidylinositol-3-kinase) signaling pathway mediated the cellular response of condylar chondrocytes to mechanical loading. Primary condylar chondrocytes were exposed to hydrostatic compressive forces (HCFs) of different magnitudes (0, 50, 100, 150, 200, and 250 kPa) for 2 h. We measured the viability, morphology, and apoptosis of the chondrocytes with different treatments as well as the gene, protein expression, and phosphorylation of mechanosensitivity-related molecules, such as integrin α2, integrin α5, integrin β1, FAK, ERK, and PI3K. HCFs could significantly increase the viability and surface area of condylar chondrocytes and decrease their apoptosis in a dose-dependent manner. HCF of 250 kPa resulted in a 1.51 ± 0.02-fold increase of cell viability and reduced the ratio of apoptotic cells from 18.10% ± 0.56% to 7.30% ± 1.43%. HCFs could significantly enhance the mRNA and protein expression of integrin α2, integrin α5, and integrin β1 in a dose-dependent manner, but not ERK1, ERK2, or PI3K. Instead, HCF could significantly increase phosphorylation levels of FAK, ERK1/2, and PI3K in a dose-dependent manner. Cilengitide, the potent integrin inhibitor, could dose-dependently block such effects of HCFs. HCFs enhances the viability and decreases the apoptosis of condylar chondrocytes through the integrin-FAK-ERK/PI3K pathway.

Hydrostatic Compress Force Enhances the Viability and Decreases the Apoptosis of Condylar Chondrocytes through Integrin-FAK-ERK/PI3K Pathway

PubMed Central

Ma, Dandan; Kou, Xiaoxing; Jin, Jing; Xu, Taotao; Wu, Mengjie; Deng, Liquan; Fu, Lusi; Liu, Yi; Wu, Gang; Lu, Haiping

2016-01-01

Reduced mechanical stimuli in many pathological cases, such as hemimastication and limited masticatory movements, can significantly affect the metabolic activity of mandibular condylar chondrocytes and the growth of mandibles. However, the molecular mechanisms for these phenomena remain unclear. In this study, we hypothesized that integrin-focal adhesion kinase (FAK)-ERK (extracellular signal–regulated kinase)/PI3K (phosphatidylinositol-3-kinase) signaling pathway mediated the cellular response of condylar chondrocytes to mechanical loading. Primary condylar chondrocytes were exposed to hydrostatic compressive forces (HCFs) of different magnitudes (0, 50, 100, 150, 200, and 250 kPa) for 2 h. We measured the viability, morphology, and apoptosis of the chondrocytes with different treatments as well as the gene, protein expression, and phosphorylation of mechanosensitivity-related molecules, such as integrin α2, integrin α5, integrin β1, FAK, ERK, and PI3K. HCFs could significantly increase the viability and surface area of condylar chondrocytes and decrease their apoptosis in a dose-dependent manner. HCF of 250 kPa resulted in a 1.51 ± 0.02-fold increase of cell viability and reduced the ratio of apoptotic cells from 18.10% ± 0.56% to 7.30% ± 1.43%. HCFs could significantly enhance the mRNA and protein expression of integrin α2, integrin α5, and integrin β1 in a dose-dependent manner, but not ERK1, ERK2, or PI3K. Instead, HCF could significantly increase phosphorylation levels of FAK, ERK1/2, and PI3K in a dose-dependent manner. Cilengitide, the potent integrin inhibitor, could dose-dependently block such effects of HCFs. HCFs enhances the viability and decreases the apoptosis of condylar chondrocytes through the integrin-FAK-ERK/PI3K pathway. PMID:27827993

A spectrum of exercise training reduces soluble Aβ in a dose-dependent manner in a mouse model of Alzheimer's disease.

PubMed

Moore, Kaitlin M; Girens, Renee E; Larson, Sara K; Jones, Maria R; Restivo, Jessica L; Holtzman, David M; Cirrito, John R; Yuede, Carla M; Zimmerman, Scott D; Timson, Benjamin F

2016-01-01

Physical activity has long been hypothesized to influence the risk and pathology of Alzheimer's disease. However, the amount of physical activity necessary for these benefits is unclear. We examined the effects of three months of low and high intensity exercise training on soluble Aβ40 and Aβ42 levels in extracellular enriched fractions from the cortex and hippocampus of young Tg2576 mice. Low (LOW) and high (HI) intensity exercise training animals ran at speeds of 15m/min on a level treadmill and 32 m/min at a 10% grade, respectively for 60 min per day, five days per week, from three to six months of age. Sedentary mice (SED) were placed on a level, non-moving, treadmill for the same duration. Soleus muscle citrate synthase activity increased by 39% in the LOW group relative to SED, and by 71% in the HI group relative to LOW, indicating an exercise training effect in these mice. Soluble Aβ40 concentrations decreased significantly in an exercise training dose-dependent manner in the cortex. In the hippocampus, concentrations were decreased significantly in the HI group relative to LOW and SED. Soluble Aβ42 levels also decreased significantly in an exercise training dose-dependent manner in both the cortex and hippocampus. Five proteins involved in Aβ clearance (neprilysin, IDE, MMP9, LRP1 and HSP70) were elevated by exercise training with its intensity playing a role in each case. Our data demonstrate that exercise training reduces extracellular soluble Aβ in the brains of Tg2576 mice in a dose-dependent manner through an up-regulation of Aβ clearance. Copyright © 2015 Elsevier Inc. All rights reserved.

CT dose modulation using automatic exposure control in whole-body PET/CT: effects of scout imaging direction and arm positioning.

PubMed

Inoue, Yusuke; Nagahara, Kazunori; Kudo, Hiroko; Itoh, Hiroyasu

2018-01-01

Automatic exposure control (AEC) modulates tube current and consequently X-ray exposure in CT. We investigated the behavior of AEC systems in whole-body PET/CT. CT images of a whole-body phantom were acquired using AEC on two scanners from different manufactures. The effects of scout imaging direction and arm positioning on dose modulation were evaluated. Image noise was assessed in the chest and upper abdomen. On one scanner, AEC using two scout images in the posteroanterior (PA) and lateral (Lat) directions provided relatively constant image noise along the z-axis with the arms at the sides. Raising the arms increased tube current in the head and neck and decreased it in the body trunk. Image noise increased in the upper abdomen, suggesting excessive reduction in radiation exposure. AEC using the PA scout alone strikingly increased tube current and reduced image noise in the shoulder. Raising the arms did not substantially influence dose modulation and decreased noise in the abdomen. On the other scanner, AEC using the PA scout alone or Lat scout alone resulted in similar dose modulation. Raising the arms increased tube current in the head and neck and decreased it in the trunk. Image noise was higher in the upper abdomen than in the middle and lower chest, and was not influenced by arm positioning. CT dose modulation using AEC may vary greatly depending on scout direction. Raising the arms tended to decrease radiation exposure; however, the effect depends on scout direction and the AEC system.

Plasma cannabinoid concentrations during dronabinol pharmacotherapy for cannabis dependence.

PubMed

Milman, Garry; Bergamaschi, Mateus M; Lee, Dayong; Mendu, Damodara R; Barnes, Allan J; Vandrey, Ryan; Huestis, Marilyn A

2014-04-01

Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic, daily cannabis smokers who received high-dose oral THC pharmacotherapy and later a smoked cannabis challenge. Eleven daily cannabis smokers received 0, 30, 60, or 120 mg/d THC for four 5-day medication sessions, each separated by 9 days of ad libitum cannabis smoking. On the fifth day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the first and fifth days was quantified by two-dimensional gas chromatography mass spectrometer for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5-100 for THC, 1-50 for 11-OH-THC, and 0.5-200 for THCCOOH. During placebo dosing, THC, 11-OH-THC, and THCCOOH concentrations consistently decreased, whereas all cannabinoids increased dose dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during the 60- and 120-mg/d doses, and THCCOOH increased significantly only during the 120-mg/d dose. THC, 11-OH-THC, and THCCOOH concentrations peaked within 0.25 hours after cannabis smoking, except after 120 mg/d THC when THCCOOH peaked 0.5 hours before smoking. The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 hour, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 hours after overnight oral dronabinol abstinence but cannot distinguish oral THC dosing from the smoked cannabis intake.

Plasma Cannabinoid Concentrations during Dronabinol Pharmacotherapy for Cannabis Dependence

PubMed Central

Milman, Garry; Bergamaschi, Mateus M.; Lee, Dayong; Mendu, Damodara R.; Barnes, Allan J.; Vandrey, Ryan; Huestis, Marilyn A.

2013-01-01

Background Recently, high-dose oral synthetic delta-9-tetrahydrocannabinol (THC) was shown to alleviate cannabis withdrawal symptoms. The present data describe cannabinoid pharmacokinetics in chronic daily cannabis smokers who received high-dose oral THC pharmacotherapy and later, a smoked cannabis challenge. Methods 11 daily cannabis smokers received 0, 30, 60, or 120 mg/day THC for four 5-day medication sessions, each separated by 9-days of ad-libitum cannabis smoking. On the 5th day, participants were challenged with smoking one 5.9% THC cigarette. Plasma collected on the 1st and 5th days was quantified by GC-GC-MS for THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THCCOOH). Linear ranges (ng/mL) were 0.5–100 for THC, 1–50 11-OH-THC, and 0.5–200 THCCOOH. Results During placebo dosing, THC, 11-OH-THC and THCCOOH concentrations consistently decreased, while all cannabinoids increased dose-dependently during active dronabinol administration. THC increase over time was not significant after any dose, 11-OH-THC increased significantly during 60 and 120 mg/day doses, and THCCOOH increased significantly only during the 120 mg/day dose. THC and 11-OH-THC, and THCCOOH concentrations peaked within 0.25 h after cannabis smoking, except after 120 mg/day THC when THCCOOH peaked 0.5 h before smoking. Conclusions The significant withdrawal effects noted during placebo dronabinol administration were supported by significant plasma THC and 11-OH-THC concentration decreases. During active dronabinol dosing, significant dose-dependent increases in THC and 11-OH-THC concentrations support withdrawal symptom suppression. THC concentrations after cannabis smoking were only distinguishable from oral THC doses for 1 h, too short a period to feasibly identify cannabis relapse. THCCOOH/THC ratios were higher 14 h after overnight oral dronabinol abstinence, but cannot distinguish oral THC dosing from smoked cannabis intake. PMID:24067260

Characterization of the Exradin W1 scintillator for use in radiotherapy.

PubMed

Carrasco, P; Jornet, N; Jordi, O; Lizondo, M; Latorre-Musoll, A; Eudaldo, T; Ruiz, A; Ribas, M

2015-01-01

To evaluate the main characteristics of the Exradin W1 scintillator as a dosimeter and to estimate measurement uncertainties when used in radiotherapy. We studied the calibration procedure, energy and modality dependence, short-term repeatability, dose-response linearity, angular dependence, temperature dependence, time to reach thermal equilibrium, dose-rate dependence, water-equivalent depth of the effective measurement point, and long-term stability. An uncertainty budget was derived for relative and absolute dose measurements in photon and electron beams. Exradin W1 showed a temperature dependence of -0.225% °C(-1). The loss of sensitivity with accumulated dose decreased with use. The sensitivity of Exradin W1 was energy independent for high-energy photon and electron beams. All remaining dependencies of Exradin W1 were around or below 0.5%, leading to an uncertainty budget of about 1%. When a dual channel electrometer with automatic trigger was not used, timing effects became significant, increasing uncertainties by one order of magnitude. The Exradin W1 response is energy independent for high energy x-rays and electron beams, and only one calibration coefficient is needed. A temperature correction factor should be applied to keep uncertainties around 2% for absolute dose measurements and around 1% for relative measurements in high-energy photon and electron beams. The Exradin W1 scintillator is an excellent alternative to detectors such as diodes for relative dose measurements.

Rosuvastatin protects against angiotensin II-induced renal injury in a dose-dependent fashion.

PubMed

Park, Joon-Keun; Mervaala, Eero Ma; Muller, Dominik N; Menne, Jan; Fiebeler, Anette; Luft, Friedrich C; Haller, Hermann

2009-03-01

We showed earlier that statin treatment ameliorates target-organ injury in a transgenic model of angiotensin (Ang) II-induced hypertension. We now test the hypothesis that rosuvastatin (1, 10, and 50 mg/kg/day) influences leukocyte adhesion and infiltration, prevents induction of inducible nitric oxide synthase (iNOS), and ameliorates target-organ damage in a dose-dependent fashion. We treated rats harboring the human renin and human angiotensinogen genes (dTGR) from week 4 to 8 (n = 20 per group). Untreated dTGR developed severe hypertension, cardiac hypertrophy, and renal damage, with a 100-fold increased albuminuria and focal cortical necrosis. Mortality of untreated dTGR at age 8 weeks was 59%. Rosuvastatin treatment decreased mortality dose-dependently. Blood pressure was not affected. Albuminuria was reduced dose-dependently. Interstitial adhesion molecule (ICAM)-1 expression was markedly reduced by rosuvastatin, as were neutrophil and monocyte infiltration. Immunohistochemistry showed an increased endothelial and medial iNOS expression in small vessels, infiltrating cells, afferent arterioles, and glomeruli of dTGR. Immunoreactivity was stronger in cortex than medulla. Rosuvastatin markedly reduced the iNOS expression in both cortex and medulla. Finally, matrix protein (type IV collagen, fibronectin) expression was also dose- dependently reduced by rosuvastatin. Our findings indicate that rosuvastatin dose- dependently ameliorates angiotensin II-induced-organ damage and almost completely prevents inflammation at the highest dose. The data implicate 3-hydroxy-3-methylglutaryl coenzyme A function in signaling events leading to target-organ damage.

Distinctions in manifestation of the hemorrhagic syndrome related to chronic, long-term and acute irradiation. [Rats;. gamma. rays

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arlashchenko, N.I.; Gorlov, V.G.; Maksimova, E.N.

Two phenomena, decrease in strength of the vascular wall and decreased amount of thrombocytes in blood, must coincide for manifestation of the hemorrhagic syndrome. Either almost simultaneous injury to the vascular wall and thrombocyte function (with acute irradiation) or dissociation of these two processes (with long-term irradiation) may be observed, depending on the radiation dose. Chronic exposure at low (subliminal) dose rates does not elicit hemorrhagic manifestations or death of rats due to pathological bleeding.

Propofol-induced increase in vascular capacitance is due to inhibition of sympathetic vasoconstrictive activity.

PubMed

Hoka, S; Yamaura, K; Takenaka, T; Takahashi, S

1998-12-01

Venodilation is thought to be one of the mechanisms underlying propofol-induced hypotension. The purpose of this study is to test two hypotheses: (1) propofol increases systemic vascular capacitance, and (2) the capacitance change produced by propofol is a result of an inhibition of sympathetic vasoconstrictor activity. In 33 Wistar rats previously anesthetized with urethane and ketamine, vascular capacitance was examined before and after propofol infusion by measuring mean circulatory filling pressure (Pmcf). The Pmcf was measured during a brief period of circulatory arrest produced by inflating an indwelling balloon in the right atrium. Rats were assigned into four groups: an intact group, a sympathetic nervous system (SNS)-block group produced by hexamethonium infusion, a SNS-block + noradrenaline (NA) group, and a hypovolemic group. The Pmcf was measured at a control state and 2 min after a bolus administration of 2, 10, and 20 mg/kg of propofol. The mean arterial pressure (MAP) was decreased by propofol dose-dependently in intact, hypovolemic, and SNS-block groups, but the decrease in MAP was less in the SNS-block group (-25%) than in the intact (-50%) and hypovolemic (-61%) groups. In the SNS-block + NA group, MAP decreased only at 20 mg/kg of propofol (-18%). The Pmcf decreased in intact and hypovolemic groups in a dose-dependent fashion but was unchanged in the SNS-block and SNS-block + NA groups. The results have provided two principal findings: (1) propofol decreases Pmcf dose-dependently, and (2) the decrease in Pmcf by propofol is elicited only when the sympathetic nervous system is intact, suggesting that propofol increases systemic vascular capacitance as a result of an inhibition of sympathetic nervous system.

Omega-3 fatty acid therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation, however, did not significantly improve insulin sensitivity in patients with hypertriglyceridemia.

PubMed

Oh, Pyung Chun; Koh, Kwang Kon; Sakuma, Ichiro; Lim, Soo; Lee, Yonghee; Lee, Seungik; Lee, Kyounghoon; Han, Seung Hwan; Shin, Eak Kyun

2014-10-20

Experimental studies demonstrate that higher intake of omega-3 fatty acids (n-3 FA) improves insulin sensitivity, however, we reported that n-3 FA 2g therapy, most commonly used dosage did not significantly improve insulin sensitivity despite reducing triglycerides by 21% in patients. Therefore, we investigated the effects of different dosages of n-3 FA in patients with hypertriglyceridemia. This was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Forty-four patients (about 18 had metabolic syndrome/type 2 diabetes mellitus) in each group were given placebo, n-3 FA 1 (O1), 2 (O2), or 4 g (O4), respectively daily for 2 months. n-3 FA therapy dose-dependently and significantly decreased triglycerides and triglycerides/HDL cholesterol and improved flow-mediated dilation, compared with placebo (by ANOVA). However, each n-3 FA therapy did not significantly decrease high-sensitivity C-reactive protein and fibrinogen, compared with placebo. O1 significantly increased insulin levels and decreased insulin sensitivity (determined by QUICKI) and O2 significantly decreased plasma adiponectin levels relative to baseline measurements. Of note, when compared with placebo, each n-3 FA therapy did not significantly change insulin, glucose, adiponectin, glycated hemoglobin levels and insulin sensitivity (by ANOVA). We observed similar results in a subgroup of patients with the metabolic syndrome. n-3 FA therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation. Nonetheless, n-3 FA therapy did not significantly improve acute-phase reactants and insulin sensitivity in patients with hypertriglyceridemia, regardless of dosages. Copyright © 2014. Published by Elsevier Ireland Ltd.

Acute haemodynamic effects of felodipine and verapamil in man, singly and with metoprolol.

PubMed

Rönn, O; Bengtsson, B; Edgar, B; Raner, S

1985-01-01

In a single-blind randomised study in 9 healthy men we compared the acute haemodynamic effects of the calcium antagonists felodipine and verapamil, singly and in combination with metoprolol. Three different cumulative intravenous doses of 0.25, 0.75 and 1.5 mg felodipine and of 2.0, 4.0 and 8.0 mg verapamil or placebo were given as constant infusions over 5 minutes on 3 occasions and were followed by intravenous metoprolol (15 mg). Felodipine caused a significant and dose-dependent decrease in the total peripheral resistance, and an increase in the forearm blood flow by 8, 48 and 163% with progressively increasing doses showing that the drug is a potent arteriolar vasodilator. A significant and dose-dependent increase in heart rate and a decrease in the pre-ejection period/left ventricular ejection time (PEP/LVET) ratio of up to 15% was also recorded, mainly reflecting a reflexogenic increase in the sympathetic tone. Total peripheral resistance, forearm blood flow, heart rate and the systolic time intervals were mainly unchanged after verapamil, whereas the PQ interval was prolonged. Metoprolol given after the 2 calcium antagonists caused a decrease in heart rate and blood flow and an increase in the total peripheral resistance and PEP/LVET ratio. The tolerability was good to all infusions.

Antidiarrhoeal activity of Psidium guajava Linn. (Myrtaceae) leaf aqueous extract in rodents.

PubMed

Ojewole, John A O; Awe, Emmanuel O; Chiwororo, Witness D H

2008-12-01

The leaf of Psidium guajava Linn. (family: Myrtaceae) is used traditionally in African folk medicine to manage, control and/or treat a plethora of human ailments, including diarrhoea. In this study, we examined the antidiarrhoeal activity of Psidium guajava leaf aqueous extract (PGE) on experimentally-induced diarrhoea in rodents. PGE (50-400 mg/kg p.o.) produced dose-dependent and significant (P<0.05-0.01) protection of rats and mice against castor oil-induced diarrhoea, inhibited intestinal transit, and delayed gastric emptying. Like atropine (1 mg/kg, p.o.), PGE produced dose-dependent and significant (P<0.05-0.01) antimotility effect, and caused dose-related inhibition of castor oil-induced enteropooling in the animals. Like loperamide (10 mg/kg, p.o.), PGE dose-dependently and significantly (P<0.05-0.01) delayed the onset of castor oil-induced diarrhoea, decreased the frequency of defaecation, and reduced the severity of diarrhoea in the rodents. Compared with control animals, PGE dose-dependently and significantly (P<0.05-0.01) decreased the volume of castor oil-induced intestinal fluid secretion, and reduced the number, weight and wetness of faecal droppings. PGE also produced concentration-related and significant (P<0.05-0.01) inhibitions of the spontaneous, rhythmic, pendular contractions of the rabbit isolated duodenum. The findings of this study indicate that PGE possesses antidiarrhoeal activity, and thus lend pharmacological credence to the suggested folkloric use of the plant as a natural remedy for the treatment, management and/or control of diarrhoea in some rural communities of southern Africa.

Effects of Charged Particles on Human Tumor Cells

PubMed Central

Held, Kathryn D.; Kawamura, Hidemasa; Kaminuma, Takuya; Paz, Athena Evalour S.; Yoshida, Yukari; Liu, Qi; Willers, Henning; Takahashi, Akihisa

2016-01-01

The use of charged particle therapy in cancer treatment is growing rapidly, in large part because the exquisite dose localization of charged particles allows for higher radiation doses to be given to tumor tissue while normal tissues are exposed to lower doses and decreased volumes of normal tissues are irradiated. In addition, charged particles heavier than protons have substantial potential clinical advantages because of their additional biological effects, including greater cell killing effectiveness, decreased radiation resistance of hypoxic cells in tumors, and reduced cell cycle dependence of radiation response. These biological advantages depend on many factors, such as endpoint, cell or tissue type, dose, dose rate or fractionation, charged particle type and energy, and oxygen concentration. This review summarizes the unique biological advantages of charged particle therapy and highlights recent research and areas of particular research needs, such as quantification of relative biological effectiveness (RBE) for various tumor types and radiation qualities, role of genetic background of tumor cells in determining response to charged particles, sensitivity of cancer stem-like cells to charged particles, role of charged particles in tumors with hypoxic fractions, and importance of fractionation, including use of hypofractionation, with charged particles. PMID:26904502

SU-E-T-315: The Change of Optically Stimulated Luminescent Dosimeters (OSLDs) Sensitivity by Accumulated Dose and High Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, S; Jung, H; Kim, M

2014-06-01

Purpose: The objective of this study is to evaluate radiation sensitivity of optical stimulated luminance dosimeters (OSLDs) by accumulated dose and high dose. Methods: This study was carried out in Co-60 unit (Theratron 780, AECL, and Canada) and used InLight MicroStar reader (Landauer, Inc., Glenwood, IL) for reading. We annealed for 30 min using optical annealing system which contained fluorescent lamps (Osram lumilux, 24 W, 280 ∼780 nm). To evaluate change of OSLDs sensitivity by repeated irradiation, the dosimeters were repeatedly irradiated with 1 Gy. And whenever a repeated irradiation, we evaluated OSLDs sensitivity. To evaluate OSLDs sensitivity after accumulatedmore » dose with 5 Gy, We irradiated dose accumulatively (from 1 Gy to 5 Gy) without annealing. And OSLDs was also irradiated with 15, 20, 30 Gy to certify change of OSLDs sensitivity after high dose irradiation. After annealing them, they were irradiated with 1Gy, repeatedly. Results: The OSLDs sensitivity increased up to 3% during irradiating seven times and decreased continuously above 8 times. That dropped by about 0.35 Gy per an irradiation. Finally, after 30 times irradiation, OSLDs sensitivity decreased by about 7%. For accumulated dose from 1 Gy to 5 Gy, OSLDs sensitivity about 1 Gy increased until 4.4% after second times accumulated dose compared with before that. OSLDs sensitivity about 1 Gy decreased by 1.6% in five times irradiation. When OSLDs were irradiated ten times with 1Gy after irradiating high dose (10, 15, 20 Gy), OSLDs sensitivity decreased until 6%, 9%, 12% compared with it before high dose irradiation, respectively. Conclusion: This study certified OSLDs sensitivity by accumulated dose and high dose. When irradiated with 1Gy, repeatedly, OSLDs sensitivity decreased linearly and the reduction rate of OSLDs sensitivity after high dose irradiation had dependence on irradiated dose.« less

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

PubMed

Guan, Xi-ting; Shao, Feng; Xie, Xi; Chen, Lin; Wang, Weiwen

2014-09-01

Aspirin (ASP) is the most commonly used non-steroidal anti-inflammatory drug in the world. Recent clinical and preclinical evidence suggests that ASP may also exert psychoactive effects. It remains unclear whether ASP has antidepressant-like activity, and any molecular mechanisms underlying such activity have yet to be elucidated. Using the forced swimming test (FST), a well-established animal model of depression widely used to screen potential antidepressants in rodents, we investigated the effects of subacute treatment with ASP (0, 6, 12, 25, and 50mg/kg, i.p.) on immobility in the FST, and on FST-induced changes in endocrine and immune parameters in rats, in comparison to the clinical antidepressants imipramine (IMI) and fluoxetine (FLU). Serum levels of corticosterone, pro-inflammatory cytokine interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. ASP dose-dependently decreased immobility in the FST, without altering the locomotor activity in the open-field test. The inhibitory effects of higher doses (25 and 50mg/kg) of ASP on immobility were similar to that of FLU and IMI at a dose of 10mg/kg. In addition, the levels of corticosterone, IL-6, and TNF-α in peripheral blood were significantly increased after the FST exposure. IMI, but not FLU and ASP at any dose tested, significantly attenuated corticosterone responses in the FST. Both FLU and IMI treatment reduced the increase of IL-6 and TNF-α levels following the FST exposure. ASP dose-dependently decreased FST-induced increase of cytokine levels, as manifested by significantly stronger effects on IL-6 and TNF-α levels at higher doses (25 and 50mg/kg) than the lowest dose of ASP (6 mg/kg). In all, these results indicate that ASP treatment dose-dependently decreased the immobility time and the release of pro-inflammatory cytokines in the FST, suggesting that the anti-inflammatory effects of ASP might be involved in the antidepressant-like effect. Copyright © 2014 Elsevier Inc. All rights reserved.

Toxicological profile of ultrapure 2,2',3,4,4',5,5'-heptachlorbiphenyl (PCB 180) in adult rats.

PubMed

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T M; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

Toxicological Profile of Ultrapure 2,2′,3,4,4′,5,5′-Heptachlorbiphenyl (PCB 180) in Adult Rats

PubMed Central

Viluksela, Matti; Heikkinen, Päivi; van der Ven, Leo T. M.; Rendel, Filip; Roos, Robert; Esteban, Javier; Korkalainen, Merja; Lensu, Sanna; Miettinen, Hanna M.; Savolainen, Kari; Sankari, Satu; Lilienthal, Hellmuth; Adamsson, Annika; Toppari, Jorma; Herlin, Maria; Finnilä, Mikko; Tuukkanen, Juha; Leslie, Heather A.; Hamers, Timo; Hamscher, Gerd; Al-Anati, Lauy; Stenius, Ulla; Dervola, Kine-Susann; Bogen, Inger-Lise; Fonnum, Frode; Andersson, Patrik L.; Schrenk, Dieter; Halldin, Krister; Håkansson, Helen

2014-01-01

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions. PMID:25137063

Effect of radiocesium transfer on ambient dose rate in forest environments affected by the Fukushima Nuclear Power Plant accident

NASA Astrophysics Data System (ADS)

Kato, H.

2015-12-01

We investigated the transfer of canopy-intercepted radiocesium to the forest floor during 3 years following the Fukushima Daiichi Nuclear Power Plant accident. The cesium-137 (Cs-137) contents in throughfall, stemflow, and litterfall were monitored in two coniferous stands (plantation of Japanese cedar) and a deciduous broad-leaved forest stand (Japanese oak with red pine). We also measured the ambient dose rate (ADR) at different heights in the forest using a survey meter and a portable Ge gamma-ray detector. Total Cs-137 deposition flux from the canopy to forest floor for the mature cedar, young cedar, and the mixed broad-leaved stands were 166 kBq/m2, 174 kBq/m2, and 60 kBq/m2, respectively. These values correspond to 38%, 40% and 13% of total atmospheric input after the accident. The ambient dose rate in forest exhibited height dependency and its vertical distribution varied with forest type and stand age. The ambient dose rate showed an exponential decrease with time for all the forest sites, however the decreasing trend differed depending on the height of dose measurement and forest type. The ambient dose rate at the canopy (approx. 10 m-height) decreased faster than that expected from physical decay of the two radiocesium isotopes, whereas those at the forest floor varied between the three forest stands. The radiocesium deposition via throughfall seemed to increase ambient dose rate during the first 200 days after the accident, however there was no clear relationship between litterfall and ambient dose rate since 400 days after the accident. These data suggested that the ambient dose rate in forest environment varied both spatially and temporally reflecting the transfer of radiocesium from canopy to forest floor. However, further monitoring investigation and analysis are required to determine the effect of litterfall on long-term trend of ambient dose rate in forest environments.

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

PubMed

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

2013-08-01

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

The affect of low-coherent light on microbial colony forming ability and morphology of some gram-positive and gram-negative bacteria

NASA Astrophysics Data System (ADS)

Popov, Denis E.; Tuchina, Elena S.; Chernova, Julia A.; Podshibyakin, Dmitry; Rudik, Dmitry V.; Samsonova, Maria; Gromov, Igor; Tuchin, Valery V.

2005-06-01

Gram-negative E. coli, gram-positive facultative anaerobe cocci Staphylococcus lugdensis, Micrococcus halobius, and Stomatococcus mucilaginosus as subjects of study were chosen. LEDs with spectrum maxima at 405 nm (without any exogenous sensitizer) and 660 nm (in conjunction with methylene blue) and power densities of 23 mW/cm2 and 5.7 mW/cm2 accordingly as continuous light sources were chosen. Photosensitized light's affect by methylene blue was studied on E. coli only. The original scheme of experiment set up was developed. It permits one to increase expositions quantity in each experiment for more certain trend's construction over dose curves and decrease parasite flora sowing. As a result of accomplished studies it was established that blue low-coherent light have unalike weak light's dose depending suppressing effect on cocci whereas red low-coherent light have a moderate dose-depended suppressing effect at low irradiation doses and a moderate dose-depended stimulating effect at high irradiation doses on sensitized by MeBlue E. coli. For all ofthis, but Staphylococcus morphology changes were observed.

The Molecular Effect of Diagnostic Absorbed Doses from 131I on Papillary Thyroid Cancer Cells In Vitro.

PubMed

Stasiołek, Mariusz; Adamczewski, Zbigniew; Śliwka, Przemysław W; Puła, Bartosz; Karwowski, Bolesław; Merecz-Sadowska, Anna; Dedecjus, Marek; Lewiński, Andrzej

2017-06-15

Diagnostic whole-body scan is a standard procedure in patients with thyroid cancer prior to the application of a therapeutic dose of 131 I. Unfortunately, administration of the radioisotope in a diagnostic dose may decrease further radioiodine uptake-the phenomenon called "thyroid stunning". We estimated radiation absorbed dose-dependent changes in genetic material, in particular in the sodium iodide symporter (NIS) gene promoter, and the NIS protein level in a K1 cell line derived from the metastasis of a human papillary thyroid carcinoma exposed to 131 I in culture. The different activities applied were calculated to result in absorbed doses of 5, 10 and 20 Gy. Radioiodine did not affect the expression of the NIS gene at the mRNA level, however, we observed significant changes in the NIS protein level in K1 cells. The decrease of the NIS protein level observed in the cells subjected to the lowest absorbed dose was paralleled by a significant increase in 8-oxo-dG concentrations ( p < 0.01) and followed by late activation of the DNA repair pathways. Our findings suggest that the impact of 131 I radiation on thyroid cells, in the range compared to doses absorbed during diagnostic procedures, is not linear and depends on various factors including the cellular components of thyroid pathology.

The acute and long-term neurotoxic effects of MDMA on marble burying behaviour in mice.

PubMed

Saadat, Kathryn S; Elliott, J Martin; Colado, M Isabel; Green, A Richard

2006-03-01

When mice are exposed to harmless objects such as marbles in their cage they bury them, a behaviour sometimes known as defensive burying. We investigated the effect of an acute dose of MDMA (èecstasy') and other psychoactive drugs on marble burying and also examined the effect of a prior neurotoxic dose of MDMA or p-chloroamphetamine (PCA) on burying. Acute administration of MDMA produced dose-dependent inhibition of marble burying (EC50: 7.6 micro mol/kg). Other drugs that enhance monoamine function also produced dose-dependent inhibition: methamphetamine PCA paroxetine MDMA GBR 12909 methylphenidate. None of these drugs altered locomotor activity at a dose that inhibited burying. A prior neurotoxic dose of MDMA, which decreased striatal dopamine content by 60%, but left striatal 5-HT content unaltered, did not alter spontaneous marble burying 18 or 40 days later. However, a neurotoxic dose of PCA which decreased striatal dopamine by 60% and striatal 5-HT by 70% attenuated marble burying 28 days later. Overall, these data suggest that MDMA, primarily by acutely increasing 5-HT function, acts like several anxiolytic drugs in this behavioural model. Long-term loss of cerebral 5-HT content also produced a similar effect. Since this change was observed only after 28 days, it is probably due to an adaptive response in the brain.

Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats

PubMed Central

Williams, Michael T.; Moran, Mary S.; Vorhees, Charles V.

2009-01-01

The investigation of methamphetamine exposure during neonatal development in rats has demonstrated that long-term spatial learning deficits are induced. A previous dose–response study showed that administration of 5 mg/kg methamphetamine, four times daily from postnatal days 11 to 20 produced these deficits, although the effects were not as severe as at higher doses of 10 or 15 mg/kg. This study examined concentrations of methamphetamine at or below 5 mg/kg given over the same period of time. Five different concentrations of methamphetamine (i.e., 5, 2.5, 1.25, 0.625, or 0) were administered every 2 h four times daily from postnatal days 11 to 20. Body weights, zero maze performance, and Morris water maze learning were examined. A dose-dependent decrease in body weight was observed during the period of methamphetamine administration and these lower weights continued throughout adulthood for the 5, 2.5, and 1.25 mg/kg concentrations, although the adult decreases were negligible. No differences were noted in the zero maze. In the Morris water maze during the acquisition period, dose-dependent differences in spatial orientation were seen, however non-dose related deficits were observed for other parameters. During the shifted platform phase (“reversal”), a similar dose-dependent difference in spatial orientation was observed, although no other effects were noted during this phase. Females performed worse than males regardless of treatment or the phase of learning in the Morris water maze. These data suggest that even lower doses of methamphetamine can alter learning and memory in adulthood, although with less consistent results than with doses higher than 5 mg/kg/dose. These data would caution against even casual use of methamphetamine by women during pregnancy since even low doses could alter the ability of the child to learn. PMID:15380827

Dexmedetomidine reduces pain associated with rocuronium injection without causing a decrease in BIS values: a dose-response study.

PubMed

Joo, Jin; Baek, Jungwon; Lee, Jaemin

2014-09-01

To examine whether dexmedetomidine reduces the injection pain of propofol and rocuronium and to investigate whether the decrease in injection pain is associated with the known sedative action of dexmedetomidine. Randomized, double-blind, placebo-controlled clinical comparison study. Patients undergoing general anesthesia with intubation received 40 mg of 1% lidocaine (lidocaine group; n = 28), 0.25 μg/kg of dexmedetomidine (low-dose group; n = 27), 0.5 μg/kg of dexmedetomidine (subclinical dose group; n = 28), 1.0 μg/kg of dexmedetomidine (clinical dose group, n = 27), or normal saline (saline group; n = 28) before anesthetic induction. Pain associated with propofol and rocuronium injection was assessed using a 10-point verbal analog scale (VAS) and a 4-point withdrawal movement scale, respectively. The BIS value was measured 60 seconds after administration of the study drug, and at the time of rocuronium injection and intubation. The overall incidence of withdrawal movements due to rocuronium decreased significantly as the dose of dexmedetomidine increased (92.8%, 85.2%, 78.6%, and 51.9% in the saline, low-dose, subclinical dose, and clinical dose groups, respectively; P = 0.001). There was no significant difference in BIS values among the groups 60 seconds after study drug administration or at the time of rocuronium injection. Dexmedetomidine reduced pain associated with rocuronium injection in a dose-dependent manner. This effect was not associated with the decrease in BIS value. Copyright © 2014 Elsevier Inc. All rights reserved.

Programming of metabolic effects in C57BL/6JxFVB mice by exposure to bisphenol A during gestation and lactation.

PubMed

van Esterik, J C J; Dollé, M E T; Lamoree, M H; van Leeuwen, S P J; Hamers, T; Legler, J; van der Ven, L T M

2014-07-03

The global rise in prevalence of obesity is not fully explained by genetics or life style factors. The developmental origins of health and disease paradigm suggests that environmental factors during early life could play a role. In this perspective, perinatal exposure to bisphenol A (BPA) has been indicated as a programming factor for obesity and related metabolic disorders later in life. Here we study early life programming by BPA using an experimental design that is relevant for human exposure. C57BL/6JxFVB hybrid mice were exposed during gestation and lactation via maternal feed to 8 non-toxic doses (0-3000 μg/kg body weight/day (μg/kg bw/d)) of BPA. After weaning, offspring were followed for 20 weeks without further exposure. Adult male offspring showed dose-dependent increases of body and liver weights, no effects on fat pad weights and a dose-dependent decrease in circulating glucagon. Female offspring showed a dose-dependent decrease in body weight, liver, muscle and fat pad weights, adipocyte size, serum lipids, serum leptin and adiponectin. Physical activity was decreased in exposed males and suggested to be increased in exposed females. Brown adipose tissue showed slightly increased lipid accumulation in males and lipid depletion in females, and ucp1 expression was dose-dependently increased in females. The effects in females were more reliable and robust than in males due to wide confidence intervals and potential confounding by litter size for male data. The lowest derived BMDL (lower bound of the (two-sided) 90%-confidence interval for the benchmark dose) of 233 μg/kg bw/d (for interscapular weight in females) was below the proposed BMDL of 3633 μg/kg bw/d as a basis for tolerable daily intake. Although these results suggest that BPA can program for an altered metabolic phenotype, the sexual dimorphism of effects and diversity of outcomes among studies similar in design as the present study do not mark BPA as a specific obesogen. The consistency within the complex of observed metabolic effects suggests that upstream key element(s) in energy homeostasis are modified. Sex-dependent factors contribute to the final phenotypic outcome. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Inhibition of monoamine oxidase by moclobemide: effects on monoamine metabolism and secretion of anterior pituitary hormones and cortisol in healthy volunteers.

PubMed Central

Koulu, M; Scheinin, M; Kaarttinen, A; Kallio, J; Pyykkö, K; Vuorinen, J; Zimmer, R H

1989-01-01

1. Single oral doses (100, 200 and 300 mg) of moclobemide, a reversible inhibitor of monoamine oxidase (MAO) with predominant effects on the A-type of the enzyme, were administered to eight young, healthy male volunteers in a double-blind, random-order, placebo-controlled study. The investigation was thereafter continued in an open fashion by administering a single 10 mg dose of the MAO-B inhibitor deprenyl to the same subjects. 2. Deamination of catecholamines was powerfully and dose-dependently inhibited by moclobemide, as evidenced by up to 40% decreases in the urinary excretion of deaminated catecholamine metabolites, corresponding increases in the excretion of non-deaminated, methylated metabolites, and up to 79% average decreases in the plasma concentration of 3,4-dihydroxyphenylglycol (DHPG), a deaminated metabolite of noradrenaline (NA), and up to 75% average decreases in the plasma concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a deaminated metabolite of dopamine. The urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) was only slightly reduced. In contrast, deprenyl, in a dose which almost totally inhibited MAO-B activity in blood platelets, did not appreciably affect the plasma concentrations of DHPG or DOPAC. 3. Due to the rapid, reversible, dose-dependent and MAO-A specific effect of moclobemide on plasma concentrations of DHPG, it is suggested that DHPG in plasma may be a useful indicator of the magnitude and duration of MAO-A inhibition in man. 4. Sympatho-adrenal function at rest was not significantly altered by moclobemide, as judged by unchanged plasma catecholamine concentrations and stable blood pressure and heart rate recordings. 5. Monoamine oxidase type B activity in blood platelets was slightly (less than 30%) and transiently inhibited after moclobemide. 6. The secretion of prolactin was dose-dependently stimulated by moclobemide, whereas the plasma concentrations of growth hormone (hGH) and cortisol remained unchanged. PMID:2469451

Dose-dependent effects of fish oil on cardio-metabolic biomarkers in healthy middle-aged and elderly Chinese people: a double-blind randomized controlled trial.

PubMed

Song, Jia; Hu, Manjiang; Li, Cheng; Yang, Bo; Ding, Qing; Wang, Chunhong; Mao, Limei

2018-06-20

n-3PUFA consumption has been widely accepted as a nutritional strategy for the secondary prevention of cardiovascular events in patients at high risk of cardiovascular disease (CVD), but little is known about the dose-response relationship between dietary n-3PUFA and serum biomarkers associated with cardiovascular health in the general population. The present study involved a 12-week double-blind, randomized controlled trial to explore the effects of fish oil with different doses (0.31, 0.62 and 1.24 g d-1 of EPA and DHA) on serum fatty acids and cardio-metabolic biomarkers including adiponectin, inflammatory markers, lipid profiles and fasting glucose in healthy middle-aged and elderly Chinese people. 240 volunteers met our inclusion criteria. A total of 39 subjects dropped out and 201 finally completed the intervention. No significant differences in baseline characteristics and daily intakes of dietary nutrients were detected among all groups. After a 12-week intervention, fish oil dose-dependently enhanced serum EPA, DHA, n-3PUFA and adiponectin (except for 0.31 g d-1), but decreased serum n-6/n-3PUFA, TG and fasting glucose. Changes in the above indicators from the baseline to week 12 in fish oil groups significantly differed from those in the control. Meanwhile, all the doses of EPA and DHA led to decreases in serum CRP; only 1.24 g d-1 led to an increase in HDL-C with a concurrent decrease in TC/HDL-C even though these changes were not significantly different among all groups. All the findings suggested that fish oil dose-dependently regulated serum PUFA and cardio-metabolic biomarkers including adiponectin, CRP, lipid profiles and fasting glucose in healthy middle-aged and elderly Chinese people who consumed insufficient dietary n-3PUFA, and the most desirable changes were observed for 1.24 g d-1.

Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study.

PubMed

Coelingh Bennink, Herjan J T; Verhoeven, Carole; Zimmerman, Yvette; Visser, Monique; Foidart, Jean-Michel; Gemzell-Danielsson, Kristina

2017-06-01

Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated. This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers. Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent. In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.

Large Yellow Tea Attenuates Macrophage-Related Chronic Inflammation and Metabolic Syndrome in High-Fat Diet Treated Mice.

PubMed

Xu, Na; Chu, Jun; Wang, Min; Chen, Ling; Zhang, Liang; Xie, Zhongwen; Zhang, Jinsong; Ho, Chi-Tang; Li, Daxiang; Wan, Xiaochun

2018-04-18

Large yellow tea is a traditional beverage in China with a unique toasty flavor. A preliminary study using 3T3-L1 cells indicated that large yellow tea possessed more potent lipid-lowering efficacy than green, black, dark, and white teas. In the present study we further investigated its influence on metabolic syndrome in a high-fat diet (HFD) mouse model with an emphasis on dose response. Thirty-two C57BL/6 male mice were randomly divided into 4 groups: low-fat diet (LFD), HFD, HFD + 2.5% large yellow tea hot-water extract (YT, equivalent to 10 cups of tea daily for humans), HFD + 0.5% YT. Our data indicated that YT treatment for 12 weeks significantly reduced body weight, liver weight, and adipose tissue weight of the mice; lowered serum insulin and leptin; and raised serum adiponectin with dose effect. H&E staining showed that the HFD group exhibited significant enlargement of adipose cell sizes and the corresponding decrease of adipose cell numbers, which were dose-dependently attenuated in both YT groups. IHC results revealed that YT decreased macrophage recruitment in the liver, epididymal adipose tissue, and subcutaneous adipose tissue and depressed serum inflammatory cytokines including TNF-α, MCP-1, IFN-γ, IL-6, and IL-1β, in a dose-dependent manner. In addition, YT decreased serum glucose, TC, TG, LDL-C, and HDL-C, as well as ameliorated glucose intolerance and insulin resistance independent of dose. Overall, YT would be a unique tea with dose-independent antihyperglycemic and robust lipid-lowering efficacies.

Serum biomarkers for acute hepatotoxicity of Echis pyramidum snake venom in rats.

PubMed

Asmari, Abdulrahman K Al; Khan, Haseeb A; Banah, Faisal A; Buraidi, Ahmed A Al; Manthiri, Rajamohammed A

2015-01-01

Echis pyramidum is a venomous viper responsible for most cases of envenomation in Arabian Peninsula. We determined the acute phase (3-6 h) changes in serum markers of liver function including alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and bilirubin in adult male Sprague Dawley rats injected with Echis pyramidum venom (EPV) in the doses of 0.00 (control), 0.25, 0.50 and 1.00 mg/kg bodyweight. We also analyzed markers of oxidative stress including superoxide dismutase (SOD), catalase (CAT), total thiols (T-SH) and thiobarbituric acids reactive substances (TBARS) in liver. The results showed significant and dose- and time-dependent increases in serum ALT, ALP and GGT activities after a single injection of EPV. Serum bilirubin was significantly increased by medium and high doses of EVP after 3 h post-injection and then decreased at 6 h. The low dose of EPV neither affected the activity of SOD nor altered the levels of liver T-SH and TBARS, however, it significantly decreased the activity of CAT at 6 h post-injection of EPV. The medium dose of EPV significantly reduced liver SOD activity after 6 h whereas the high dose significantly reduced the SOD activity at 3 h and 6 h post-dosing. Both medium and high doses of EPV caused significant as well as dose- and time-dependent reductions in liver CAT activities. The high dose significantly reduced T-SH and increased TBARS in rat liver. Further studies are warranted to test the pharmacological potential of early phase antioxidant therapy for neutralizing the toxic effects of EPV.

MO-F-CAMPUS-J-01: Effect of Iodine Contrast Agent Concentration On Cerebrovascular Dose for Synchrotron Radiation Microangiography Based On a Simple Mouse Head Model and a Voxel Mouse Head Phantom

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, H; Jing, J; Xie, C

Purpose: To find effective setting methods to mitigate the irradiation injure in synchrotron radiation microangiography(SRA) by Monte Carlo simulation. Methods: A mouse 1-D head model and a segmented voxel mouse head phantom were simulated by EGSnrc/Dosxyznrc code to investigate the dose enhancement effect of the iodine contrast agent irradiated by a monochromatic synchrotron radiation(SR) source. The influence of, like iodine concentration (IC), vessel width and depth, with and without skull layer protection and the various incident X ray energies, were simulated. The dose enhancement effect and the absolute dose based on the segmented voxel mouse head phantom were evaluated. Results:more » The dose enhancement ratio depends little on the irradiation depth, but strongly on the IC, which is linearly increases with IC. The skull layer protection cannot be ignored in SRA, the 700µm thick skull could decrease 10% of the dose. The incident X-ray energy can significantly affact the dose. E.g. compared to the dose of 33.2keV for 50mgI/ml, the 32.7keV dose decreases 38%, whereas the dose of 33.7 keV increases 69.2%, and the variation will strengthen more with enhanced IC. The segmented voxel mouse head phantom also showed that the average dose enhancement effect and the maximal voxel dose per photon depends little on the iodine voxel volume ratio, but strongly on IC. Conclusion: To decrease dose damage in SRA, the high-Z contrast agent should be used as little as possible, and try to avoid radiating locally the injected position immediately after the contrast agent injection. The fragile vessel containing iodine should avoid closely irradiating. Avoiding irradiating through the no or thin skull region, or appending thin equivalent material from outside to protect is also a better method. As long as SRA image quality is ensured, using incident X-ray energy as low as possible.« less

Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

PubMed

Selby, Peter; Andriash, Katherine; Zawertailo, Laurie; Persad, Desmond; Zack, Martin; Busto, Usoa E

2013-10-01

Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

Characterization of optically stimulated luminescent dosimeters, OSLDs, for clinical dosimetric measurements.

PubMed

Jursinic, Paul A

2007-12-01

Optically stimulated luminescent dosimeters, OSLDs, are plastic disks infused with aluminum oxide doped with carbon (Al2O3 : C). These disks are encased in a light-tight plastic holder. Crystals of Al2O3 : C when exposed to ionizing radiation store energy that is released as luminescence (420 nm) when the OSLD is illuminated with stimulation light (540 nm). The intensity of the luminescence depends on the dose absorbed by the OSLD and the intensity of the stimulation light. OSLDs used in this work were InLight/OSL Dot dosimeters, which were read with a MicroStar reader (Landauer, Inc., Glenwood, IL). The following are dosimetric properties of the OSLD that were determined: After a single irradiation, repeated readings cause the signal to decrease by 0.05% per reading; the signal could be discharged by greater than 98% by illuminating them for more than 45 s with a 150 W tungsten-halogen light; after irradiation there was a transient signal that decayed with a 0.8 min halftime; after the transient signal decay the signal was stable for days; repeated irradiations and readings of an individual OSLD gave a signal with a coefficient of variation of 0.6%; the dose sensitivity of OSLDs from a batch of detectors has a coefficient of variation of 0.9%, response was linear with absorbed dose over a test range of 1-300 cGy; above 300 cGy a small supra-linear behavior occurs; there was no dose-per-pulse dependence over a 388-fold range; there was no dependence on radiation energy or mode for 6 and 15 MV x rays and 6-20 MeV electrons; for Ir-192 gamma rays OSLD had 6% higher sensitivity; the dose sensitivity was unchanged up to an accumulated dose of 20 Gy and thereafter decreased by 4% per 10 Gy of additional accumulated dose; dose sensitivity was not dependent on the angle of incidence of radiation; the OSLD in its light-tight case has an intrinsic buildup of 0.04 g/cm2; dose sensitivity of the OSLD was not dependent on temperature at the time of irradiation in the range of 10-40 degrees C. The clinical use of OSLDs for in vivo dosimetric measurements is shown to be feasible.

Characterization of optically stimulated luminescent dosimeters, OSLDs, for clinical dosimetric measurements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jursinic, Paul A.

2007-12-15

Optically stimulated luminescent dosimeters, OSLDs, are plastic disks infused with aluminum oxide doped with carbon (Al{sub 2}O{sub 3}:C). These disks are encased in a light-tight plastic holder. Crystals of Al{sub 2}O{sub 3}:C when exposed to ionizing radiation store energy that is released as luminescence (420 nm) when the OSLD is illuminated with stimulation light (540 nm). The intensity of the luminescence depends on the dose absorbed by the OSLD and the intensity of the stimulation light. OSLDs used in this work were InLight/OSL Dot dosimeters, which were read with a MicroStar reader (Landauer, Inc., Glenwood, IL). The following are dosimetricmore » properties of the OSLD that were determined: After a single irradiation, repeated readings cause the signal to decrease by 0.05% per reading; the signal could be discharged by greater than 98% by illuminating them for more than 45 s with a 150 W tungsten-halogen light; after irradiation there was a transient signal that decayed with a 0.8 min halftime; after the transient signal decay the signal was stable for days; repeated irradiations and readings of an individual OSLD gave a signal with a coefficient of variation of 0.6%; the dose sensitivity of OSLDs from a batch of detectors has a coefficient of variation of 0.9%, response was linear with absorbed dose over a test range of 1-300 cGy; above 300 cGy a small supra-linear behavior occurs; there was no dose-per-pulse dependence over a 388-fold range; there was no dependence on radiation energy or mode for 6 and 15 MV x rays and 6-20 MeV electrons; for Ir-192 gamma rays OSLD had 6% higher sensitivity; the dose sensitivity was unchanged up to an accumulated dose of 20 Gy and thereafter decreased by 4% per 10 Gy of additional accumulated dose; dose sensitivity was not dependent on the angle of incidence of radiation; the OSLD in its light-tight case has an intrinsic buildup of 0.04 g/cm{sup 2}; dose sensitivity of the OSLD was not dependent on temperature at the time of irradiation in the range of 10-40 deg. C. The clinical use of OSLDs for in vivo dosimetric measurements is shown to be feasible.« less

Enhancement of Chaperone Activity of Plant-Specific Thioredoxin through γ-Ray Mediated Conformational Change.

PubMed

Lee, Seung Sik; Jung, Hyun Suk; Park, Soo-Kwon; Lee, Eun Mi; Singh, Sudhir; Lee, Yuno; Lee, Kyun Oh; Lee, Sang Yeol; Chung, Byung Yeoup

2015-11-13

AtTDX, a thioredoxin-like plant-specific protein present in Arabidopsis is a thermo-stable and multi-functional enzyme. This enzyme is known to act as a thioredoxin and as a molecular chaperone depending upon its oligomeric status. The present study examines the effects of γ-irradiation on the structural and functional changes of AtTDX. Holdase chaperone activity of AtTDX was increased and reached a maximum at 10 kGy of γ-irradiation and declined subsequently in a dose-dependent manner, together with no effect on foldase chaperone activity. However, thioredoxin activity decreased gradually with increasing irradiation. Electrophoresis and size exclusion chromatography analysis showed that AtTDX had a tendency to form high molecular weight (HMW) complexes after γ-irradiation and γ-ray-induced HMW complexes were tightly associated with a holdase chaperone activity. The hydrophobicity of AtTDX increased with an increase in irradiation dose till 20 kGy and thereafter decreased further. Analysis of the secondary structures of AtTDX using far UV-circular dichroism spectra revealed that the irradiation remarkably increased the exposure of β-sheets and random coils with a dramatic decrease in α-helices and turn elements in a dose-dependent manner. The data of the present study suggest that γ-irradiation may be a useful tool for increasing holdase chaperone activity without adversely affecting foldase chaperone activity of thioredoxin-like proteins.

Maintenance on naltrexone+amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys.

PubMed

Moerke, Megan J; Banks, Matthew L; Cheng, Kejun; Rice, Kenner C; Negus, S Stevens

2017-12-01

Cocaine use disorder remains a significant public health issue for which there are no FDA-approved pharmacotherapies. Amphetamine maintenance reduces cocaine use in preclinical and clinical studies, but the mechanism of this effect is unknown. Previous studies indicate a role for endogenous opioid release and subsequent opioid receptor activation in some amphetamine effects; therefore, the current study examined the role of mu-opioid receptor activation in d-amphetamine treatment effects in an assay of cocaine-vs-food choice. Adult male rhesus monkeys with double-lumen intravenous catheters responded for concurrently available food pellets and cocaine injections (0-0.1mg/kg/injection) during daily sessions. Cocaine choice and overall reinforcement rates were evaluated during 7-day treatments with saline or test drugs. During saline treatment, cocaine maintained a dose-dependent increase in cocaine-vs.-food choice. The mu-opioid receptor agonist morphine (0.032-0.32mg/kg/h) dose-dependently increased cocaine choice and decreased rates of reinforcement. A dose of the mu-selective opioid receptor antagonist naltrexone (0.0032mg/kg/h) that completely blocked morphine effects had no effect on cocaine choice when it was administered alone, but it enhanced the effectiveness of a threshold dose of 0.032mg/kg/h amphetamine to decrease cocaine choice without also enhancing nonselective behavioral disruption by this dose of amphetamine. Conversely, the kappa-selective opioid antagonist norbinalorphimine did not enhance amphetamine effects on cocaine choice. These results suggest that amphetamine maintenance produces mu opioid-receptor mediated effects that oppose its anti-cocaine effects. Co-administration of naltrexone may selectively enhance amphetamine potency to decrease cocaine choice without increasing amphetamine potency to produce general behavioral disruption. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of the Effects of Typical and Atypical Anxiolytics on Learning in Monkeys and Rats,

DTIC Science & Technology

kg) and alprazolam (0.032-0.32 mg/kg) produced dose-dependent decreases in overall response rate in all subjects. However, with buspirone and 8-OH-DPAT...monkeys were variable across drugs and drug classes. Both 8-OH-DPAT and alprazolam produced large increases in percent errors in acquisition at doses

Density Dependence and Growth Rate: Evolutionary Effects on Resistance Development to Bt (Bacillus thuringiensis).

PubMed

Martinez, Jeannette C; Caprio, Michael A; Friedenberg, Nicholas A

2018-02-09

It has long been recognized that pest population dynamics can affect the durability of a pesticide, but dose remains the primary component of insect resistance management (IRM). For transgenic pesticidal traits such as Bt (Bacillus thuringiensis Berliner (Bacillales: Bacillaceae)), dose (measured as the mortality of susceptibles caused by a toxin) is a relatively fixed characteristic and often falls below the standard definition of high dose. Hence, it is important to understand how pest population dynamics modify durability and what targets they present for IRM. We used a deterministic model of a generic arthropod pest to examine how timing and strength of density dependence interacted with population growth rate and Bt mortality to affect time to resistance. As in previous studies, durability typically reached a minimum at intermediate doses. However, high population growth rates could eliminate benefits of high dose. The timing of density dependence had a more subtle effect. If density dependence operated simultaneously with Bt mortality, durability was insensitive to its strengths. However, if density dependence was driven by postselection densities, decreasing its strength could increase durability. The strength of density dependence could affect durability of both single traits and pyramids, but its influence depended on the timing of density dependence and size of the refuge. Our findings suggest the utility of a broader definition of high dose, one that incorporates population-dynamic context. That maximum growth rates and timing and strength of interactions causing density dependent mortality can all affect durability, also highlights the need for ecologically integrated approaches to IRM research. © The Author(s) 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Dose dependence of true stress parameters in irradiated bcc, fcc, and hcp metals

NASA Astrophysics Data System (ADS)

Byun, T. S.

2007-04-01

The dose dependence of true stress parameters has been investigated for nuclear structural materials: A533B pressure vessel steels, modified 9Cr-1Mo and 9Cr-2WVTa ferritic martensitic steels, 316 and 316LN stainless steels, and Zircaloy-4. After irradiation to significant doses, these alloys show radiation-induced strengthening and often experience prompt necking at yield followed by large necking deformation. In the present work, the critical true stresses for deformation and fracture events, such as yield stress (YS), plastic instability stress (PIS), and true fracture stress (FS), were obtained from uniaxial tensile tests or calculated using a linear strain-hardening model for necking deformation. At low dose levels where no significant embrittlement was detected, the true fracture stress was nearly independent of dose. The plastic instability stress was also independent of dose before the critical dose-to-prompt-necking at yield was reached. A few bcc alloys such as ferritic martensitic steels experienced significant embrittlement at doses above ∼1 dpa; and the true fracture stress decreased with dose. The materials fractured before yield at or above 10 dpa.

Time-Dependent Decline in Serum Phenytoin Concentration with Heightened Convulsive Seizure Risk by Prolonged Administration of Fosphenytoin in Japanese: A Retrospective Study.

PubMed

Ohno, Yuta; Niwa, Takashi; Hirai, Keita; Suzuki, Keiko; Yamada, Yuto; Hayashi, Yuichi; Hayashi, Hideki; Suzuki, Akio; Itoh, Yoshinori

2018-04-20

Because clinical data to confirm the safety and effectiveness of fosphenytoin, a prodrug of phenytoin, are insufficient, the length of administration of fosphenytoin is restricted. Nevertheless, some cases require fosphenytoin administration for more than a few days. The aim of this study was to retrospectively investigate the serum concentration of phenytoin in adult Japanese patients who received intravenous fosphenytoin therapy for more than 3 days. Patients injected with intravenous fosphenytoin for more than 3 days at Gifu University Hospital between January 2012 and September 2014 were enrolled. Individual pharmacokinetic parameters were predicted by Bayesian estimation using NONMEM software, and the maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration (10-20 μg/mL) was calculated from the parameters. Among a total of 8 patients, the serum trough concentration of phenytoin decreased with each day after repeated injection of fosphenytoin. The incidence rate of significant convulsive seizures was increased time-dependently (0% on day 1, 12.5% on day 2, 25% on day 3, and 66.7% on day 4 and after). Phenytoin clearance showed a time-dependent increase. The maintenance dose of fosphenytoin required to maintain the therapeutic trough concentration was simulated to be 779.8 ± 316.8 mg/day, a dose that was markedly higher than the actual maintenance dose (414.1 ± 55.7 mg/day). Prolonged use of fosphenytoin for such patients as those with autoimmune-mediated encephalopathy accompanied with reflux disease and/or ileus time-dependently decreased the serum concentration of phenytoin and increased the risk of convulsion. Therefore, the maintenance dose should be increased to maintain the therapeutic serum concentration.

Temporal Change of Environmental Contamination Conditions in Five Years after the Fukushima Accident

NASA Astrophysics Data System (ADS)

Saito, Kimiaki

2017-09-01

The temporal change of environmental contamination conditions after the Fukushima accident have been clarified based on large-scale environmental monitoring data repeatedly obtained in the 80 km zone. The decreasing tendency of air dose rates was confirmed to obviously depend on land uses. In human-related diverse environments the air dose rates have decreased much faster than the physical decay of radiocesium. The horizontal movement of radiocesium in undisturbed fields were found to be generally quite small, though it has gradually penetrated into the deeper parts of the ground.

Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells.

PubMed

Seo, Hye-Sook; Jo, Jae Kyung; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; Kim, Hyo In; Kang, Soo-Yeon; Lee, Kang Min; Nam, Koong Won; Park, Namkyu; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

2015-10-23

Phytoestrogen intake is known to be beneficial to decrease breast cancer incidence and progression. But its molecular mechanisms of action are still unknown. The present study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Apigenin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Apigenin-induced extrinsic a caspase-dependent apoptosis up-regulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly (ADP-ribose) polymerase (PARP). Whereas, apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential without affecting the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Apigenin reduced the expression of phospho-JAK1, phospho-JAK2 and phospho-STAT3 and decreased signal transducer and activator of transcription 3 (STAT3) dependent luciferase reporter gene activity in BT-474 cells. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear translocation of STAT3. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer. © 2015 Authors.

Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells

PubMed Central

Seo, Hye-Sook; Jo, Jae Kyung; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; in Kim, Hyo; Kang, Soo-yeon; Lee, Kang min; Nam, Koong Won; Park, Namkyu; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

2015-01-01

Phytoestrogen intake is known to be beneficial to decrease breast cancer incidence and progression. But its molecular mechanisms of action are still unknown. The present study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Apigenin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Apigenin-induced extrinsic a caspase-dependent apoptosis up-regulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly (ADP-ribose) polymerase (PARP). Whereas, apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential without affecting the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Apigenin reduced the expression of phospho-JAK1, phospho-JAK2 and phospho-STAT3 and decreased signal transducer and activator of transcription 3 (STAT3) dependent luciferase reporter gene activity in BT-474 cells. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear translocation of STAT3. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer. PMID:26500281

Behavioral toxicity of selected radioprotectors

NASA Astrophysics Data System (ADS)

Landauer, M. R.; Davis, H. D.; Kumar, K. S.; Weiss, J. F.

1992-10-01

Effective radioprotection with minimal behavioral disruption is essential for the selection of protective agents to be used in manned spaceflight. This overview summarizes the studies on the behavioral toxicity of selected radioprotectors classified as phosphorothioates (WR-2721, WR-3689), bioactive lipids (16, 16 dimethylprostaglandin E2(DiPGE2), platelet activating factor (PAF), leukotriene C4), and immunomodulators (glucan, synthetic trehalose dicorynomycolate, and interleukin-1). Behavioral toxicity was examined in laboratory mice using a locomotor activity test. For all compounds tested, there was a dose-dependent decrease in locomotor behavior that paralleled the dose-dependent increase in radioprotection. While combinations of radioprotective compounds (DiPGE2 plus WR-2721) increased radioprotection, they also decreased locomotor activity. The central nervous system stimulant, caffeine, was able to mitigate the locomotor decrement produced by WR-3689 or PAF.

Astaxanthin Inhibits Proliferation of Human Gastric Cancer Cell Lines by Interrupting Cell Cycle Progression.

PubMed

Kim, Jung Ha; Park, Jong-Jae; Lee, Beom Jae; Joo, Moon Kyung; Chun, Hoon Jai; Lee, Sang Woo; Bak, Young-Tae

2016-05-23

Astaxanthin is a carotenoid pigment that has antioxidant, antitumoral, and anti-inflammatory properties. In this in vitro study, we investigated the mechanism of anticancer effects of astaxanthin in gastric carcinoma cell lines. The human gastric adenocarcinoma cell lines AGS, KATO-III, MKN-45, and SNU-1 were treated with various concentrations of astaxanthin. A cell viability test, cell cycle analysis, and immunoblotting were performed. The viability of each cancer cell line was suppressed by astaxanthin in a dose-dependent manner with significantly decreased proliferation in KATO-III and SNU-1 cells. Astaxanthin increased the number of cells in the G0/G1 phase but reduced the proportion of S phase KATO-III and SNU-1 cells. Phosphorylated extracellular signal-regulated kinase (ERK) was decreased in an inverse dose-dependent correlation with astaxanthin concentration, and the expression of p27(kip-1) increased the KATO-III and SNU-1 cell lines in an astaxanthin dose-dependent manner. Astaxanthin inhibits proliferation by interrupting cell cycle progression in KATO-III and SNU-1 gastric cancer cells. This may be caused by the inhibition of the phosphorylation of ERK and the enhanced expression of p27(kip-1).

Zoledronic acid induces dose-dependent increase of antigen-specific CD8 T-cell responses in combination with peptide/poly-IC vaccine.

PubMed

Park, Hye-Mi; Cho, Hyun-Il; Shin, Chang-Ae; Shon, Hyun-Jung; Kim, Tai-Gyu

2016-03-04

Zoledronic acid (ZA) is used for treating osteoporosis and for preventing skeletal fractures in cancer patients suffering from myeloma and prostate cancer. It is also reported to directly induce cancer cell apoptosis and indirectly modulate T-cell immune response as an antitumor agent. In this study, the effect of ZA following peptide/polyinosinic-polycytidylic acid (poly-IC) vaccination was investigated in a murine tumor model. The combination of ZA with peptide/poly-IC vaccine showed a synergistic effect on the induction of antigen-specific CD8 T-cell response. Three consecutive intravenous administrations of ZA was defined to induce the highest CD8 T-cell response. Further, total splenocyte counts and antigen-specific CD8 T-cell response gradually increased depending on the dose of ZA. In tumor-bearing mice, ZA showed a dose-dependent decrease of growth and prolonged survival. Treatment with ZA only decreased the number of CD11b(+)Gr1(+) myeloid cells in blood. Our results demonstrate that the use of ZA could improve antitumor immune responses induced by the peptide/poly-IC vaccine. Copyright © 2016 Elsevier Ltd. All rights reserved.

Etanercept prevents decrease of cochlear blood flow dose-dependently caused by tumor necrosis factor alpha.

PubMed

Ihler, Friedrich; Sharaf, Kariem; Bertlich, Mattis; Strieth, Sebastian; Reichel, Christoph A; Berghaus, Alexander; Canis, Martin

2013-07-01

Tumor necrosis factor alpha (TNF-alpha) is a mediator of inflammation and microcirculation in the cochlea. This study aimed to quantify the effect of a local increase of TNF-alpha and study the effect of its interaction with etanercept on cochlear microcirculation. Cochlear lateral wall vessels were exposed surgically and assessed by intravital microscopy in guinea pigs in vivo. First, 24 animals were randomly distributed into 4 groups of 6 each. Exposed vessels were superfused repeatedly either with 1 of 3 different concentrations of TNF-alpha (5.0, 0.5, and 0.05 ng/mL) or with placebo (0.9% saline solution). Second, 12 animals were randomly distributed into 2 groups of 6 each. Vessels were pretreated with etanercept (1.0 microg/ mL) or placebo (0.9% saline solution), and then treated by repeated superfusion with TNF-alpha (5.0 ng/mL). TNF-alpha was shown to be effective in decreasing cochlear blood flow at a dose of 5.0 ng/mL (p < 0.01, analysis of variance on ranks). Lower concentrations or placebo treatment did not lead to significant changes. After pretreatment with etanercept, TNF-alpha at a dose of 5.0 ng/mL no longer led to a change in cochlear blood flow. The decreasing effect that TNF-alpha has on cochlear blood flow is dose-dependent. Etanercept abrogates this effect.

Heparin induced alterations in clearance and distribution of blood-borne microparticles following operative trauma.

PubMed

Saba, T M; Antikatzides, T G

1979-04-01

The influence of systemic heparin administration on the vascular clearance and tissue distribution of blood-borne microparticles was evaluated in normal rats and rats after operation (laparotomy plus intestinal manipulation) utilizing an (131)I- colloid which is phagocytized by the reticuloendothelial system (RES). Intravenous heparin administration (100 USP/100g body weight) into normal animals three minutes prior to colloid injection (50 mg/lOOg) induced a significant increase in pulmonary localization of the microparticles as compared to nonheparinized control rats, while hepatic and splenic uptake were decreased. Surgical trauma decreased hepatic RE uptake and increased pulmonary localization of the microparticles when injected systemically at 60 minutes postsurgery. Heparin administration 60 minutes after surgery and three minutes prior to colloid injection, magnified the increased pulmonary localization response with an associated further depression of the RES. The ability of heparin to alter both RE clearance function and lung localization of microparticles was dose dependent and a function of the interval between heparin administration and systemic particulate infusion. Thus, low dose heparin administration was capable of stimulating RE activity while heparin in doses of excess of 50 USP units/lOOg body weight decreased RE function. These findings suggest that the functional state of the hepatic RE system can be greatly affected in a dose-dependent manner by systemic heparin administration which may influence distribution of blood-borne microparticles.

High but not low ECS stimulus intensity augments apomorphine-stimulated dopamine postsynaptic receptor functioning in rats.

PubMed

Andrade, Chittaranjan; Srinivasamurthy, Gurunath M; Vishwasenani, A; Prakash, G Sai; Srihari, B S; Chandra, J Suresh

2002-06-01

Clinical research shows that the antidepressant and cognitive adverse effects of electroconvulsive therapy are both dependent on the administered electrical stimulus intensity (dose); however, dose-dependent neurotransmitter system changes in the brain, which might underlie the therapeutic or adverse effects, remain to be demonstrated. We used a behavioral model to examine dose-related effects of electroconvulsive shock (ECS) on dopamine postsynaptic receptor functioning in the rat brain. In a factorially designed study, rats (n = 100) were treated with five once-daily ECSs at three levels (sham ECS, 30 mC ECS, and 120 mC ECS), and with drug at two levels (saline, and 1 mg/kg s.c. apomorphine). Motility was assessed in the small open field. Apomorphine-elicited, dopamine postsynaptic receptor-mediated hypermotility was significantly increased by 120 mC ECS but not by 30 mC ECS. An additional but unrelated finding was that, while the ECS seizure duration expectedly decreased across time, no dose-dependent effects were observed. ECS-induced dopamine postsynaptic receptor up-regulation may depend on the intensity of the administered electrical stimulus.

The Effects of Cocaine and Stress on Lymphocyte Proliferation in Rats

DTIC Science & Technology

1993-02-22

indices of immune function while decreasing others. Bagarasa and Forman (1989) found that intraperitoneal cocaine (1 . 25, 2.5 mg/kg-10 days) at low ... doses caused an 3 increase in PFC response in male Fisher rats, but at higher doses (5 rng/kg-lO days) PFC response was suppressed. Analysis of...found that cocaine combined with Con A in vitro suppressed lymphocyte proliferation in a dose ~ dependent fashion for mice splenocytes and human

The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study.

PubMed

Pignon, Baptiste; Labreuche, Julien; Auffret, Marine; Gautier, Sophie; Deheul, Sylvie; Simioni, Nicolas; Cottencin, Olivier; Bordet, Régis; Duhamel, Alain; Rolland, Benjamin

2017-07-01

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence. Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC. One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64]). The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses. Copyright © 2017 John Wiley & Sons, Ltd.

Competitive (AP7) and non-competitive (MK-801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clow, D.W.; Lee, S.J.; Hammer, R.P. Jr.

1991-04-01

The effects of D,L-2-amino-7-phosphonoheptanoic acid (AP7), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and MK-801, a non-competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative {sup 14}C2-deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose-dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK-801 (0.1 or 1.0 mg/kg) resulted in a dose-dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK-801 also produced amore » biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK-801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK-801 treatment in primary somatosensory (SI) and visual (VI) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK-801 administration also decreased metabolic activity in granular SI relative to dysgranular SI, and in VI relative to secondary visual cortex (VII), thus providing a relative sparing of activity in dysgranular SI and VII. Thus, the non-competitive NMDA receptor antagonist suppressed activity from extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions, while the competitive NMDA antagonist depressed metabolic activity in all cortical regions.« less

Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO.

PubMed

Kapil, Vikas; Milsom, Alexandra B; Okorie, Michael; Maleki-Toyserkani, Sheiva; Akram, Farihah; Rehman, Farkhanda; Arghandawi, Shah; Pearl, Vanessa; Benjamin, Nigel; Loukogeorgakis, Stavros; Macallister, Raymond; Hobbs, Adrian J; Webb, Andrew J; Ahluwalia, Amrita

2010-08-01

Ingestion of dietary (inorganic) nitrate elevates circulating and tissue levels of nitrite via bioconversion in the entero-salivary circulation. In addition, nitrite is a potent vasodilator in humans, an effect thought to underlie the blood pressure-lowering effects of dietary nitrate (in the form of beetroot juice) ingestion. Whether inorganic nitrate underlies these effects and whether the effects of either naturally occurring dietary nitrate or inorganic nitrate supplementation are dose dependent remain uncertain. Using a randomized crossover study design, we show that nitrate supplementation (KNO(3) capsules: 4 versus 12 mmol [n=6] or 24 mmol of KNO(3) (1488 mg of nitrate) versus 24 mmol of KCl [n=20]) or vegetable intake (250 mL of beetroot juice [5.5 mmol nitrate] versus 250 mL of water [n=9]) causes dose-dependent elevation in plasma nitrite concentration and elevation of cGMP concentration with a consequent decrease in blood pressure in healthy volunteers. In addition, post hoc analysis demonstrates a sex difference in sensitivity to nitrate supplementation dependent on resting baseline blood pressure and plasma nitrite concentration, whereby blood pressure is decreased in male volunteers, with higher baseline blood pressure and lower plasma nitrite concentration but not in female volunteers. Our findings demonstrate dose-dependent decreases in blood pressure and vasoprotection after inorganic nitrate ingestion in the form of either supplementation or by dietary elevation. In addition, our post hoc analyses intimate sex differences in nitrate processing involving the entero-salivary circulation that are likely to be major contributing factors to the lower blood pressures and the vasoprotective phenotype of premenopausal women.

A placebo-controlled trial of dextromethorphan as an adjunct in opioid-dependent patients undergoing methadone maintenance treatment.

PubMed

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

2015-02-25

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. We provide evidence-decreased concomitant heroin use-of low-dose add-on DM's efficacy for treating opioid-dependent patients undergoing MMT. © The Author 2015. Published by Oxford University Press on behalf of CINP.

A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

PubMed Central

Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Chen, Shih-Heng; Chen, Po See; Huang, San-Yuan; Tzeng, Nian-Sheng; Wang, Liang-Jen; Lee, I Hui; Wang, Tzu-Yun; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong

2015-01-01

Background: Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT). Methods: Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect. Results: After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different. Conclusions: We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT. PMID:25716777

Short and long-term exposure of CNS cell lines to BPA-f a radiosensitizer for boron neutron capture therapy: safety dose evaluation by a battery of cytotoxicity tests.

PubMed

De Simone, U; Manzo, L; Ferrari, C; Bakeine, J; Locatelli, C; Coccini, T

2013-03-01

Despite the current clinical use of boronophenylalanine-fructose (BPA-f), as radiosensitizer, in BNCT application for brain tumors, still remains to be determined the safety dose of this agent. We evaluated the potential risk of primary BPA-f toxicity before neutronic irradiation at different concentrations (0-100μgBeq/ml) after short- and long-term exposure (4-48h and 7-10 days), using a battery of tests (i.e. MTT assay, calcein-AM/Propidium Iodide staining, clonogenic test) in CNS cell models (D384 and SH-SY5Y), and non-neuronal primary human fibroblasts (F26). MTT data showed: (i) no cytotoxic effects after short-term exposure (4h) to any of BPA-f concentrations tested in all cell models; (ii) dose- and time-dependent mitochondrial activity impairment in D384 and SH-SY5Y cells only (with 60% and 40% cell death in D384 and SH-SY5Y, respectively, after 48h exposure to BPA-f 100μgBeq/ml). By Calcein-AM/PI staining, BPA-f treatment was specific toward SH-SY5Y cells only: a dose-dependent cell density reduction was observed, with a more pronounced effect after 48h exposure (15-40% at doses ranging 20-100μgBeq/ml). Clonogenic data revealed dose-dependent decrease of cell proliferative capacity in all cell lines, still the SH-SY5Y cells were the most sensitive ones: the lowest dose (20μgBeq/ml) produced 90% cell decrease. These results indicate dose- and time-dependent cytotoxic effects of BPA-f, with CNS cells showing a lower tolerance compared to fibroblasts. Long-term exposure to BPA-f compromised the proliferative capacity regardless of cell model type (cell sensitivity being SH-SY5Y>D384>F26). In short-time exposure, BPA-f exhibits a safe dosage up to 40μgBeq/ml for the viability of CNS cell lines. Copyright © 2012 Elsevier Inc. All rights reserved.

[Evaluation of immunotoxicity tests using cyclosporin A-treated rats: the International Collaborative Immunotoxicity Study II (cyclosporin A)].

PubMed

Ochiai, T; Naito, K; Murakami, O; Ohno, K; Sekita, K; Furuya, T; Kurokawa, Y; Matsumoto, K; Saito, Y; Hachisuka, A

1993-01-01

Immunotoxicological effects of cyclosporin A (CsA) were studied by enhanced histopathological and functional tests in rats. Male F344 rats were orally administered with CsA in doses of 0, 2.5, 10, and 40 mg/kg/day for 28 successive days. Hematological examination revealed that the CsA treatment brought about a marked dose-dependent decrease in the number of WBCs, which was attributed to a decrease in the number of lymphocytes. In the femoral bone marrow, a significant reduction in the number of nucleated cells was observed, which was attributed to a decrease in the number of lymphocytes and erythroblasts. Histopathologically, diminution of thymic medullas, appearance of tangible body macrophages in thymic cortices, and calcification and basophilic changes in kidneys were observed in the middle and high dose groups. Immunohistological examination with anti-rat T lymphocyte antibody showed a decrease in the number of T cells at the periarterial lymphatic sheaths in the spleens. As for the functional tests, CsA treatment remarkably reduced the PFC number even in the low dose group. The Con A response of spleen cells was decreased in the middle and high dose groups. The STM response was reduced only in the high dose group. The NK activity was little affected. Thus, in the CsA-treated F344 rats, the enhanced histopathological and some functional tests which were proposed by ICICIS, were found to be useful to detect damages to the immune system.

Results From the First‐in‐Human Study With Ozanimod, a Novel, Selective Sphingosine‐1‐Phosphate Receptor Modulator

PubMed Central

Hartung, Jeffrey P.; Peach, Robert J.; Boehm, Marcus F.; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L.; Timony, Gregg A.; Olson, Allan D.; Gujrathi, Sheila; Frohna, Paul A.

2017-01-01

Abstract The sphingosine‐1‐phosphate 1 receptor (S1P1R) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune‐mediated, inflammatory diseases. This first‐in‐human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose‐escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose‐limiting toxicities. The most common ozanimod‐related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady‐state volume of distribution (73–101 L/kg), moderate oral clearance (204–227 L/h), and an elimination half‐life of approximately 17 to 21 hours. Ozanimod produced a robust dose‐dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose‐dependent negative chronotropic effect was observed following the first dose, with the dose‐escalation regimen attenuating the first‐dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once‐daily regimens under clinical investigation. PMID:28398597

Regulation of steroid hormones and energy status with cysteamine and its effect on spermatogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Yandi

Although it is well known that cysteamine is a potent chemical for treating many diseases including cystinosis and it has many adverse effects, the effect of cysteamine on spermatogenesis is as yet unknown. Therefore the objective of this investigation was to explore the effects of cysteamine on spermatogenesis and the underlying mechanisms. Sheep were treated with vehicle control, 10 mg/kg or 20 mg/kg cysteamine for six months. After that, the semen samples were collected to determine the spermatozoa motility by computer-assisted sperm assay method. Blood samples were collected to detect the levels of hormones and the activity of enzymes. Spermatozoamore » and testis samples were collected to study the mechanism of cysteamine's actions. It was found that the effects of cysteamine on spermatogenesis were dose dependent. A low dose (10 mg/kg) cysteamine treatment increased ovine spermatozoa motility; however, a higher dose (20 mg/kg) decreased both spermatozoa concentration and motility. This decrease might be due to a reduction in steroid hormone production by the testis, a reduction in energy in the testis and spermatozoa, a disruption in the blood-testis barrier, or a breakdown in the vital signaling pathways involved in spermatogenesis. The inhibitory effects of cysteamine on sheep spermatogenesis may be used to model its effects on young male patients with cystinosis or other diseases that are treated with this drug. Further studies on spermatogenesis that focus on patients treated with cysteamine during the peripubertal stage are warranted. - Highlights: • Dose dependent effects of cysteamine on spermatogenesis • A low dose (10 mg/kg) increased spermatozoa motility. • A higher dose (20 mg/kg) decreased both concentration and motility of spermatozoa. • Disruption in the blood-testis barrier caused reduction in concentration and motility.« less

Dosimetric characteristics of a MOSFET dosimeter for clinical electron beams.

PubMed

Manigandan, D; Bharanidharan, G; Aruna, P; Devan, K; Elangovan, D; Patil, Vikram; Tamilarasan, R; Vasanthan, S; Ganesan, S

2009-09-01

The fundamental dosimetric characteristics of commercially available metal oxide semiconductor field effect transistor (MOSFET) detectors were studied for clinical electron beam irradiations. MOSFET showed excellent linearity against doses measured using an ion chamber in the dose range of 20-630cGy. MOSFET reproducibility is better at high doses compared to low doses. The output factors measured with the MOSFET were within +/-3% when compared with those measured with a parallel plate chamber. From 4 to 12MeV, MOSFETs showed a large angular dependence in the tilt directions and less in the axial directions. MOSFETs do not show any dose-rate dependence between 100 and 600MU/min. However, MOSFETs have shown under-response when the dose per pulse of the beam is decreased. No measurable effect in MOSFET response was observed in the temperature range of 23-40 degrees C. The energy dependence of a MOSFET dosimeter was within +/-3.0% for 6-18MeV electron beams and 5.5% for 4MeV ones. This study shows that MOSFET detectors are suitable for dosimetry of electron beams in the energy range of 4-18MeV.

Sub-therapeutic doses of fluvastatin and valsartan are more effective than therapeutic doses in providing beneficial cardiovascular pleiotropic effects in rats: A proof of concept study.

PubMed

Janić, Miodrag; Lunder, Mojca; France Štiglic, Alenka; Jerin, Aleš; Skitek, Milan; Černe, Darko; Marc, Janja; Drevenšek, Gorazd; Šabovič, Mišo

2017-12-01

Statins and sartans can, in therapeutic doses, induce pleiotropic cardiovascular effects. Similar has recently been shown also for sub-therapeutic doses. We thus explored and compared the cardiovascular pleiotropic efficacy of sub-therapeutic vs. therapeutic doses. Wistar rats were randomly divided into 7 groups receiving fluvastatin, valsartan and their combination in sub-therapeutic and therapeutic doses, or saline. After 6weeks, the animals were euthanised, their hearts and thoracic aortas isolated, and blood samples taken. Endothelium-dependent relaxation of the thoracic aortae and ischaemic-reperfusion injury of the isolated hearts were assessed along with the related serum parameters and genes expression. Fluvastatin and valsartan alone or in combination were significantly more effective in sub-therapeutic than therapeutic doses. The sub-therapeutic combination greatly increased thoracic aorta endothelium-dependent relaxation and maximally protected the isolated hearts against ischaemia-reperfusion injury and was thus most effective. Beneficial effects were accompanied by increased levels of nitric oxide (NO) and decreased levels of asymmetric dimethylarginine (ADMA) in the serum (again prominently induced by the sub-therapeutic combination). Furthermore, nitric oxide synthase 3 (NOS3) and endothelin receptor type A (EDNRA) genes expression increased, but only in both combination groups and without significant differences between them. In the therapeutic dose groups, fluvastatin and valsartan decreased cholesterol values and systolic blood pressure. Sub-therapeutic doses of fluvastatin and valsartan are more effective in expressing cardiovascular pleiotropic effects than therapeutic doses of fluvastatin and/or valsartan. These results could be of significant clinical relevance. Copyright © 2017 Elsevier Inc. All rights reserved.

Dose-Dependent AMPK-Dependent and Independent Mechanisms of Berberine and Metformin Inhibition of mTORC1, ERK, DNA Synthesis and Proliferation in Pancreatic Cancer Cells

PubMed Central

Ming, Ming; Sinnett-Smith, James; Wang, Jia; Soares, Heloisa P.; Young, Steven H.; Eibl, Guido; Rozengurt, Enrique

2014-01-01

Natural products represent a rich reservoir of potential small chemical molecules exhibiting anti-proliferative and chemopreventive properties. Here, we show that treatment of pancreatic ductal adenocarcinoma (PDAC) cells (PANC-1, MiaPaCa-2) with the isoquinoline alkaloid berberine (0.3–6 µM) inhibited DNA synthesis and proliferation of these cells and delay the progression of their cell cycle in G1. Berberine treatment also reduced (by 70%) the growth of MiaPaCa-2 cell growth when implanted into the flanks of nu/nu mice. Mechanistic studies revealed that berberine decreased mitochondrial membrane potential and intracellular ATP levels and induced potent AMPK activation, as shown by phosphorylation of AMPK α subunit at Thr-172 and acetyl-CoA carboxylase (ACC) at Ser79. Furthermore, berberine dose-dependently inhibited mTORC1 (phosphorylation of S6K at Thr389 and S6 at Ser240/244) and ERK activation in PDAC cells stimulated by insulin and neurotensin or fetal bovine serum. Knockdown of α1 and α2 catalytic subunit expression of AMPK reversed the inhibitory effect produced by treatment with low concentrations of berberine on mTORC1, ERK and DNA synthesis in PDAC cells. However, at higher concentrations, berberine inhibited mitogenic signaling (mTORC1 and ERK) and DNA synthesis through an AMPK-independent mechanism. Similar results were obtained with metformin used at doses that induced either modest or pronounced reductions in intracellular ATP levels, which were virtually identical to the decreases in ATP levels obtained in response to berberine. We propose that berberine and metformin inhibit mitogenic signaling in PDAC cells through dose-dependent AMPK-dependent and independent pathways. PMID:25493642

SU-E-I-16: Scan Length Dependency of the Radial Dose Distribution in a Long Polyethylene Cylinder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bakalyar, D; McKenney, S; Feng, W

Purpose: The area-averaged dose in the central plane of a long cylinder following a CT scan depends upon the radial dose distribution and the length of the scan. The ICRU/TG200 phantom, a polyethylene cylinder 30 cm in diameter and 60 cm long, was the subject of this study. The purpose was to develop an analytic function that could determine the dose for a scan length L at any point in the central plane of this phantom. Methods: Monte Carlo calculations were performed on a simulated ICRU/TG200 phantom under conditions of cylindrically symmetric conditions of irradiation. Thus, the radial dose distributionmore » function must be an even function that accounts for two competing effects: The direct beam makes its weakest contribution at the center while the scatter begins abruptly at the outer radius and grows as the center is approached. The scatter contribution also increases with scan length with the increase approaching its limiting value at the periphery faster than along the central axis. An analytic function was developed that fit the data and possessed these features. Results: Symmetry and continuity dictate a local extremum at the center which is a minimum for the ICRU/TG200 phantom. The relative depth of the minimum decreases as the scan length grows and an absolute maximum can occur between the center and outer edge of the cylinders. As the scan length grows, the relative dip in the center decreases so that for very long scan lengths, the dose profile is relatively flat. Conclusion: An analytic function characterizes the radial and scan length dependency of dose for long cylindrical phantoms. The function can be integrated with the results expressed in closed form. One use for this is to help determine average dose distribution over the central cylinder plane for any scan length.« less

An atlas-based organ dose estimator for tomosynthesis and radiography

NASA Astrophysics Data System (ADS)

Hoye, Jocelyn; Zhang, Yakun; Agasthya, Greeshma; Sturgeon, Greg; Kapadia, Anuj; Segars, W. Paul; Samei, Ehsan

2017-03-01

The purpose of this study was to provide patient-specific organ dose estimation based on an atlas of human models for twenty tomosynthesis and radiography protocols. The study utilized a library of 54 adult computational phantoms (age: 18-78 years, weight 52-117 kg) and a validated Monte-Carlo simulation (PENELOPE) of a tomosynthesis and radiography system to estimate organ dose. Positioning of patient anatomy was based on radiographic positioning handbooks. The field of view for each exam was calculated to include relevant organs per protocol. Through simulations, the energy deposited in each organ was binned to estimate normalized organ doses into a reference database. The database can be used as the basis to devise a dose calculator to predict patient-specific organ dose values based on kVp, mAs, exposure in air, and patient habitus for a given protocol. As an example of the utility of this tool, dose to an organ was studied as a function of average patient thickness in the field of view for a given exam and as a function of Body Mass Index (BMI). For tomosynthesis, organ doses can also be studied as a function of x-ray tube position. This work developed comprehensive information for organ dose dependencies across tomosynthesis and radiography. There was a general exponential decrease dependency with increasing patient size that is highly protocol dependent. There was a wide range of variability in organ dose across the patient population, which needs to be incorporated in the metrology of organ dose.

Opiate self-administration as a measure of chronic nociceptive pain in arthritic rats.

PubMed

Colpaert, F C; Tarayre, J P; Alliaga, M; Bruins Slot, L A; Attal, N; Koek, W

2001-03-01

The study examined the validity of oral fentanyl self-administration (FSA) as a measure of the chronic nociceptive pain that develops in rats with adjuvant arthritis independently of acute noxious challenges. Arthritic rats self-administered more of a 0.008 mg/ml fentanyl solution (up to 3.4 g/rat per day) than non-arthritic controls (0.5 g/rat per day) and did so with a biphasic time course that reached peak during weeks 3 and 4 after inoculation with Mycobacterium butyricum. The time course paralleled both the disease process and the chronic pain. Continuous infusion of dexamethasone during weeks 3 and 4 via subcutaneous osmotic pumps at 0.0025-0.04 mg/rat per day disrupted the arthritic disease and decreased FSA to a level (i.e. by 65%) similar to that observed in non-arthritic rats. Continuous naloxone (2.5 mg/rat per day) decreased FSA (by 55%) in arthritic but not in non-arthritic animals. Continuous, subcutaneous infusion of fentanyl also decreased arthritic FSA in a manner that varied with dose at 0.04-0.16 mg/rat per day doses, but leveled off at 47% of controls with 0.31 mg/rat per day. The effects of continuous fentanyl on arthritic FSA occurred only with those doses and dose-dependent dynamics with which fentanyl also induced dependence in non-arthritic rats. The findings indicate that pain, rather than the rewarding or dependence-inducing action of fentanyl mediates FSA in arthritic rats. Paralleling patient-controlled analgesic drug intake, FSA offers a specific measure allowing the dynamic effects of neurobiological agents to be studied in this unique animal model of persistent nociceptive pain.

Gestational and lactational exposure to ethinyl estradiol, but not bisphenol A, decreases androgen-dependent reproductive organ weights and epididymal sperm abundance in the male long evans hooded rat.

PubMed

Howdeshell, Kembra L; Furr, Johnathan; Lambright, Christy R; Wilson, Vickie S; Ryan, Bryce C; Gray, L Earl

2008-04-01

Many chemicals released into the environment are capable of disrupting normal sex steroid balance, including the oral contraceptive ethinyl estradiol (EE) and the plastic monomer bisphenol A (BPA). EE and BPA are reported to impair reproductive organ development in laboratory animals; however, effects of lower doses of these chemicals have been debated. The goal of the current study was to determine whether relatively low oral doses of EE or BPA would alter male reproductive morphology and associated hormone levels of Long Evans hooded rat. Dams were gavaged with corn oil vehicle, EE (0.05-50 mug/kg/day) or BPA (2, 20, and 200 mug/kg/day) during pregnancy through lactation from gestational day 7 to postnatal day (PND) 18. Anogenital distance was measured at PND2 and nipple retention was measured at PND14 in male pups. Male offspring were euthanized beginning at PND150, and sera and organs were collected for analyses. Adult body weight was significantly decreased in males exposed to 50 mug EE/kg/day. Developmental EE exposure reduced androgen-dependent tissue weights in a dose-dependent fashion; for example, seminal vesicle and paired testes weights were reduced with >/= 5 mug EE/kg/day. Epididymal sperm counts were also significantly decreased with 50 mug EE/kg/day. In contrast, treatment with 2, 20, or 200 mug BPA/kg/day or EE at 0.05-1.5 mug/kg/day did not significantly affect any male endpoint in the current study. These results demonstrate that developmental exposure to oral micromolar doses of EE can permanently disrupt the reproductive tract of the male rat.

Pharmaco-EEG-based assessment of the interaction between ethanol and oxcarbazepine.

PubMed

Pietrzak, Bogusława; Czarnecka, Elzbieta

2010-01-01

Oxcarbazepine is a representative molecule for a new class of anticonvulsant drugs that can treat alcohol dependence in addition to other disorders. Interestingly, the central mechanism of action in oxcarbazepine is very similar to ethanol, suggesting that these two agents may interact and cause enhanced effects in the central nervous system. In this study, we used a pharmaco-EEG method to examine the influence of oxcarbazepine on the effect of ethanol on the EEG of rabbits (midbrain reticular formation, hippocampus, frontal cortex). Oxcarbazepine was administered po as a single dose (20 mg/kg or 80 mg/kg) or repeatedly at a dose of 40 mg/kg/day for 14 days. Ethanol was injected iv at a dose of 0.8 g/kg 60 min after the administration of oxcarbazepine. Ethanol caused an increase in the low frequencies (0.5-4 Hz) in the recordings, and it caused a marked decrease in higher frequencies (13-30 Hz and 30-45 Hz). Oxcarbazepine altered the EEG pattern in rabbits; this interaction was dependent on the dose of the drug and whether it was administered as a single dose or as multiple doses. Oxcarbazepine administered at a lower dose had a synergistic effect with ethanol in the frontal cortex and midbrain reticular formation, and a similar effect was observed in the hippocampus at a higher dose. Changes in EEG recordings after the administration of oxcarbazepine alone were more pronounced after multiple administrations. The drug decreased the sensitivity of the hippocampus to ethanol, an observation that may be important for the treatment of alcohol addiction.

Mechanism of antihypertensive effect of Mucuna pruriens L. seed extract and its isolated compounds.

PubMed

Khan, Mohammad Yaseen; Kumar, Vimal

2017-06-21

Background In the search of safe and effective lead molecules from natural sources, Mucuna pruriens (MP) L. (Fabaceae) seeds were utilized for exploring the antihypertensive potential. Traditionally, it is used as diuretic and hypotensive. Methods Bioassay-guided fractions were utilized for the isolation of active compounds by column chromatography. IC50 value, enzyme kinetics and inhibition mechanism were determined. In vivo time and dose-dependent hypotensive study followed by changes in mean arterial pressure (MAP) induced by angiotensin I (3 nmol/kg), angiotensin II (3 nmol/kg), and bradykinin (10 nmol/kg) in anesthetized rats was done. Plasma and tissue angiotensin I-converting enzyme (ACE) activities were also determined. Results Phytochemical analysis by spectroscopic techniques revealed the presence of known compounds like genistein, ursolic acid and L-DOPA from the ethyl acetate and water fraction, respectively. In vitro study revealed MP ethyl acetate (MPEA) fraction and genistein as the most active fraction (IC50 156.45 µg/mL) and compound (IC50 253.81 µM), respectively. Lineweaver-Burk plots revealed a non-competitive mode of inhibition. ACE protein precipitation was the suggested mechanism for inhibition. The extract showed a time- and dose-dependent decrease in MAP. Genistein was able to dose-dependently reduce the MAP, up to 53±1.5 mmHg (40 mg/kg, i.v.). As compared to control, it showed a dose-dependent decrease in plasma ACE activity of 40.61 % and 54.76 % at 10 mg/kg and 20 mg/kg, respectively. It also decreased the ACE activity in the aorta (107.67nM/ml min at 10 mg, p<0.001; 95.33nM/ml min at 20 mg p<0.001). Captopril was used as a standard for various in vitro and in vivo assays. Conclusions The study revealed the antihypertensive potential of MP seed compounds via ACE inhibition.

Transient neutropenia: Neutrophil distribution and replacement

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thakur, M.L.; Li, Jinghua; Binoy, Li

Radiolabeled polymorphonuclear (PMN) receptor-specific proteins or peptides lead the list of agents being evaluated for imaging inflammatory foci. Some of these agents induce transient neutropenia. This study was designed to quantify the degree of dose dependency of neutropenia, determine the duration of neutropenia, identify the organs in which these PMNs sequester and ascertain if these PMNs return to the circulation. Rodent anti-PMN (Gr-1) MAb RB6-8C5 (lgG-2A) and Balb/c mice served as the model, and PMN nonspecific ME 31.3 (lgG-2A) as a control. Circulating PMN number was determined several times, 30 min prior to and between 1 min and 120 hrmore » after MAb administration. Iodine-125-MAbs provided quantification of circulating activity and tissue distribution as a function of time. Data showed the severity of neutropenia increased with the amount of MAb administered (>95% PMNs lost after 150 {mu}g versus <85% after 10 {mu}g). Moreover, the recovery time for PMN counts to reach the pretreatment level also increased in a dose-dependent manner (96 hr at 150 {mu}g versus 4 hr at 10 {mu}g and 2 hr at 2 {mu}g). The blood activity, however, which declined quickly with the neutropenia, never rose again with PMN recovery. As a function of time, radioactivity in the study group decreased from all organs except from the liver and spleen, whereas in the control group; and spleen, 15.5% decrease versus 63.6% decrease in control group. The degree and duration of neutropenia is dose-dependent. PMNs, lost from the circulation, sequester in the reticuloendothelial system, and do not return to circulation. Therefore, they are not available to image inflammatory foci. The PMN concentration is restored to a pretreatment level in a dose-dependent fashion, presumably by freshly released PMNs from bone marrow. 32 refs., 5 figs.« less

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

PubMed Central

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression. PMID:26335690

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

The Peroxisome Proliferator-Activated Receptor Alpha Agonist Fenofibrate Attenuates Alcohol Self-administration in Rats

PubMed Central

Haile, Colin N.; Kosten, Therese A.

2017-01-01

Fibrates are a class of medications used to treat hypercholesterolemia and dyslipidemia that target nuclear peroxisome proliferator-activated receptors (PPARs). Studies have shown the PPARα agonist fenofibrate decreases voluntary EtOH consumption however its impact on the reinforcing and motivational effects of EtOH is unknown. We evaluated the ability of fenofibrate (25, 50 and 100mg/kg), to alter EtOH (10%, w/v) and sucrose (2%, w/v) operant self-administration in rats under a FR2 schedule of reinforcement over four days and under a progressive ratio (PR) schedule on day five of treatment. Results showed fenofibrate dose-dependently decreased EtOH self-administration under both schedules of reinforcement with the greatest effects seen after four to five days of treatment. Fenofibrate decreased responding for sucrose only under the PR schedule of reinforcement and this effect was not dose-dependent. These findings provide further evidence for fenofibrate as a potential treatment for alcohol use disorder in humans. PMID:28088358

Dietary L-cysteine improves the antioxidative potential and lipid metabolism in rats fed a normal diet.

PubMed

Lee, Seulki; Han, Kyu-Ho; Nakamura, Yumi; Kawakami, Sakura; Shimada, Ken-ichiro; Hayakawa, Touru; Onoue, Hirotake; Fukushima, Michihiro

2013-01-01

L-cysteine works as a precursor of the antioxidant, glutathione. We investigated the effects of L-cysteine (1% and 2%) on lipid metabolism and the antioxidative system in rats fed a normal diet. Administering L-cysteine dependently decreased the food intake, fat mass weight and body weight dose. Dietary L-cysteine also decreased the triglyceride levels in the serum and liver. However, there were no significant differences in the hepatic TBARS and glutathione (GSH) levels among the groups. The activities of catalase and glutathione reductase in the rats receiving 2% L-cysteine were significantly higher (p<0.05) than in the control rats. These results suggest that dietary L-cysteine dose-dependently affected the antioxidative enzyme activities, and the lipid levels in the serum and liver which might be related to the reduced food intake.

In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myllymaeki, Sari; Haavisto, Tapio; Vainio, Minna

2005-04-01

Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not havemore » detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.« less

Fibrinolytic activity and dose-dependent effect of incubating human blood clots in caffeic acid phenethyl ester: in vitro assays.

PubMed

Elnager, Abuzar; Hassan, Rosline; Idris, Zamzuri; Mustafa, Zulkifli; Wan-Arfah, Nadiah; Sulaiman, S A; Gan, Siew Hua; Abdullah, Wan Zaidah

2015-01-01

Background. Caffeic acid phenethyl ester (CAPE) has been reported to possess time-dependent fibrinolytic activity by in vitro assay. This study is aimed at investigating fibrinolytic dose-dependent activity of CAPE using in vitro assays. Methods. Standardized human whole blood (WB) clots were incubated in either blank controls or different concentrations of CAPE (3.75, 7.50, 15.00, 22.50, and 30.00 mM). After 3 hours, D-dimer (DD) levels and WB clot weights were measured for each concentration. Thromboelastography (TEG) parameters were recorded following CAPE incubation, and fibrin morphology was examined under a confocal microscope. Results. Overall, mean DD (μg/mL) levels were significantly different across samples incubated with different CAPE concentrations, and the median pre- and postincubation WB clot weights (grams) were significantly decreased for each CAPE concentration. Fibrin removal was observed microscopically and indicated dose-dependent effects. Based on the TEG test, the Ly30 fibrinolytic parameter was significantly different between samples incubated with two different CAPE concentrations (15.0 and 22.50 mM). The 50% effective dose (ED50) of CAPE (based on DD) was 1.99 mg/mL. Conclusions. This study suggests that CAPE possesses fibrinolytic activity following in vitro incubation and that it has dose-dependent activities. Therefore, further investigation into CAPE as a potential alternative thrombolytic agent should be conducted.

Evaluation of ammonium perchlorate in the endocrine disruptor screening and testing program's male pubertal protocol: ability to detect effects on thyroid endpoints.

PubMed

Stoker, T E; Ferrell, J M; Laws, S C; Cooper, R L; Buckalew, A

2006-11-10

The U.S. EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 male pubertal protocol was designed as a screen to detect endocrine-disrupting chemicals which may alter reproductive development or thyroid function. One purpose of this in vivo screening protocol is to detect thyrotoxicants via a number of different mechanisms of action, such as thyroid hormone synthesis or clearance. Here we evaluate the ability of this EDSP male pubertal protocol to detect the known thyrotoxicant ammonium perchlorate as an endocrine disruptor. Ammonium perchlorate is a primary ingredient in rocket fuel, fertilizers, paints, and lubricants. Over the past 50 years, potassium perchlorate has been used to treat hyperthyroidism in humans. Perchlorate alters thyroid hormone secretion by competitively inhibiting iodide uptake by the thyroid gland. In this study, ammonium perchlorate was administered at 62.5, 125, 250, and 500 mg/kg to male Wistar rats based on a pilot study of oral dosing. Doses of 125-500 mg/kg perchlorate decreased T4 in a dose-dependent manner. TSH was significantly increased in a dose-responsive manner at the same doses, while T3 was unchanged at any dose. Thyroid histology was significantly altered at all doses, even at the 62.5 mg/kg, with a clear dose-dependent decrease in colloid area and increase in follicular cell height. No effects on preputial separation, a marker of pubertal progression, or reproductive tract development were observed at any dose. These results demonstrate that the male pubertal protocol is useful for detecting thyrotoxicants which target the thyroid axis by this mechanism (altered uptake of iodide). This study also found that perchlorate exposure during this period did not alter any of the reproductive developmental endpoints.

Anti-inflammatory activity of 6-hydroxy-2,7-dimethoxy-1,4-henanthraquinone from tuberous roots of yam (Dioscorea batatas) through inhibition of prostaglandin D₂ and leukotriene C₄ production in mouse bone marrow-derived mast cells.

PubMed

Jin, Meihua; Lu, Yue; Yang, Ju Hye; Jo, Tae Hyung; Park, Young In; Lee, Chong-Kil; Park, Sang-Jo; Son, Kun Ho; Chang, Hyeun Wook

2011-09-01

6-Hydroxy-2,7-dimethoxy-1,4-phenanthraquinone (PAQ) isolated from the tuberous roots of Yam (Dioscorea batatas) inhibited cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1) dependent prostaglandin D(2) (PGD(2)) generation in mouse bone marrow-derived mast cells in a concentration-dependent manner with IC(50) values of 0.08 μM and 0.27 μM, respectively. In the Western blotting with specific anti-COX-2 antibodies, the decrease of the quantity of PGD(2) was accompanied by a decrease in the COX-2 protein level. But PAQ did not affect COX-1 protein level. In addition, this compound inhibited 5-lipoxygenase (5-LOX) dependent production of leukotriene C(4) in a dose-dependent manner, with an IC(50) of 0.032 μM. These results demonstrate that PAQ has a dual COX-2/5-LOX inhibitory activity. This compound also inhibited the degranulation reaction in a dose-dependent manner with an IC(50) of 2.7 μM. Thus, these results suggest that PAQ may be useful in regulating mast cell-mediated inflammatory diseases.

Oxytrex: an oxycodone and ultra-low-dose naltrexone formulation.

PubMed

Webster, Lynn R

2007-08-01

Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

Differential dose- and time-dependent effects of molindone on dopamine neurons of rat brain: mediation by irreversible inhibition of monoamine oxidase.

PubMed

Meller, E; Friedman, E

1982-03-01

The effects of molindone (2.5, 10 and 40 mg/kg) on striatal tyrosine hydroxylase activity and dopamine (DA), 3,4-dihydroxyphenylacetic acid and homovanillic acid levels were measured as a function of time (0-72 hr). Whereas a dose of 2.5 mg/kg produced effects typical of DA receptor blockade (activation of synaptosomal tyrosine hydroxylase, increased DA metabolite levels and unchanged DA levels), a dose of 40 mg/kg produced opposite effects (decreased tyrosine hydroxylase activity and metabolite concentrations and elevated DA levels). A dose of 10 mg/kg elicited intermediate effects. The atypical effects of both higher doses were long-lasting (less than 72 hr). Molindone at doses of 10 or 40 mg/kg, but nor 2.5 mg/kg, selectively, irreversibly and dose-dependently inhibited type A monoamine oxidase. This inhibition appeared to be due to a metabolite, inasmuch as the drug itself inhibited monoamine oxidase (reversibly) only at high concentrations (less than or equal to 10(-4) M). The heretofore unsuspected inhibition of monoamine oxidase by molindone provided a consistent mechanistic interpretation of the differential dose- and time-dependent effects of the drug on dopaminergic neuronal activity. This mechanism may also serve to explain the reported efficacy of molindone in animal tests for antidepressant activity as well as its inability to produce increased DA receptor binding after chronic treatment.

Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain.

PubMed

Van Bockstaele, Elisabeth J; Qian, Yaping; Sterling, Robert C; Page, Michelle E

2008-05-15

The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone-precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pre-treatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional 4 h. At the end of the experiment, animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration.

Ethanol Dose- and Time-dependently Increases α and β Subunits of Mitochondrial ATP Synthase of Cultured Neonatal Rat Cardiomyocytes.

PubMed

Mashimo, Keiko; Arthur, Peter G; Ohno, Youkichi

2015-01-01

Mitochondria are target subcellular organelles of ethanol. In this study, the effects of ethanol on protein composition was examined with 2-dimensional electrophoresis of protein extracts from cultured neonatal rat cardiomyocytes exposed to 100 mM ethanol for 24 hours. A putative β subunit of mitochondrial ATP synthase was increased, which was confirmed by Western blot. The cellular protein abundances in the α and β subunits of ATP synthase increased in dose (0, 10, 50, and 100 mM) - and time (0.5 hour and 24 hours) -dependent manners. The DNA microarray analysis of total RNA extract demonstrated that gene expression of the corresponding messenger RNAs of these subunit proteins did not significantly alter due to 24-hour ethanol exposure. Therefore, protein expression of these nuclear-encoded mitochondrial proteins may be regulated at the translational, rather than the transcriptional, level. Alternatively, degradation of these subunit proteins might be decreased. Additionally, cellular ATP content of cardiomyocytes scarcely decreased following 24-hour exposure to any examined concentrations of ethanol. Previous studies, together with this study, have demonstrated that protein abundance of the α subunit or β subunit or both subunits of ATP synthase after ethanol exposure or dysfunctional conditions might differ according to tissue: significant increases in heart but decreases in liver and brain. Thus, it is suggested that the abundance of subunit proteins of mitochondrial ATP synthase in the ethanol-exposed heart, being different from that in the liver and brain, should increase dose-dependently through either translational upregulation or decreased degradation or both to maintain ATP production, as the heart requires much more energy than other tissues for continuing sustained contractions.

The effect of O-1602, an atypical cannabinoid, on morphine-induced conditioned place preference and physical dependence.

PubMed

Alavi, Mohaddeseh Sadat; Hosseinzadeh, Hossein; Shamsizadeh, Ali; Roohbakhsh, Ali

2016-06-01

Previous studies show that some non-CB1/non-CB2 effects of cannabinoids are mediated through G protein coupled receptor 55 (GPR55). As this receptor is activated by some of cannabinoid receptor ligands and is involved in the modulation of pain, it was hypothesized that this receptor may also interact with opioids. This study examined the effect of atypical cannabinoid O-1602 as a GPR55 agonist on morphine-induced conditioned place preference (CPP) and physical dependence. We used a biased CPP model to evaluate the effect of O-1602 (0.2, 1 and 5mg/kg, intraperitoneal; ip) on the acquisition and expression of morphine-induced CPP in male mice. The locomotor activities of mice were also recorded. Moreover, repeated administration of morphine (50, 50 and 75mg/kg/day) for three days, induced physical dependence. The withdrawal signs such as jumps and diarrhea were precipitated by administration of naloxone (5mg/kg, ip). The effect of O-1602 on the development of morphine physical dependence was assessed by injection of O-1602 (0.2, 1 and 5mg/kg) before morphine administrations. Morphine (40mg/kg, subcutaneous; sc), but not O-1602 (5mg/kg) elicited significant preference in the post-conditioning phase. O-1602 at the doses of 0.2 and 1mg/kg, but not 5mg/kg reduced acquisition of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 at the doses of 0.2, 1 and 5mg/kg also reduced expression of morphine CPP with an increase in locomotor activity at the dose of 5mg/kg. O-1602 had a significant inhibitory effect on development of morphine-induced physical dependence at the dose of 5mg/kg by decreasing jumps and diarrhea during withdrawal syndrome. The present results indicate that O-1602 decreased acquisition and expression of morphine CPP and inhibited development of morphine-induced physical dependence. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Evaluation of Behavioral and Pharmacological Effects of Hydroalcoholic Extract of Valeriana prionophylla Standl. from Guatemala

PubMed Central

Holzmann, Iandra; Cechinel Filho, Valdir; Mora, Ticiana C.; Cáceres, Armando; Martínez, Jose Vicente; Cruz, Sully M.; de Souza, Márcia Maria

2011-01-01

There are few studies on the pharmacological properties of Valeriana prionophylla Standl. (VP), known as “Valeriana del monte”, and used in Mesoamerican folk medicine to treat sleep disorders. This study examines the pharmacological effects of the hydroalcoholic extract of the dry rhizome using the open field, rota rod, elevated plus-maze (EPM), forced swimming (FST), strychnine- and pentobarbital-induced sleeping time, PTZ-induced seizures, and the inhibitory avoidance tests. VP did not show any protective effect against PTZ-induced convulsions. In the EPM, exhibited an anxiolytic-like effect through the effective enhancement of the entries (38.5%) and time spent (44.7%) in the open arms, when compared with control group. Time spent and the numbers of entrances into the enclosed arms were decreased, similar to those effects observed with diazepam. In the FST, acute treatment with VP, produced a dose-dependent decrease in immobility time, similarly to imipramine. VP also produced a significant dose-dependent decrease in the latency of sleeping time, while producing an increase in total duration of sleep; influenced memory consolidation of the animals only at lower doses, unlike those that produced anti-depressant and anxiolytic effects. In summary, the results suggest that VP presents several psychopharmacological activities, including anxiolytic, antidepressant, and hypno-sedative effects. PMID:21754942

Effect of γ-irradiation on the temperature coefficient of surface resistivity of two-dimensional island platinum films

NASA Astrophysics Data System (ADS)

Bishay, A. G.; El-Gamal, S.

2011-05-01

Three sets (A, B and C) of two-dimensional island platinum films (2D-I(Pt)Fs) were prepared via the thermal evaporation technique, where the substrates are corning 7059 glass slides. The mass thickness ( d m) of the films of different sets is 5, 10 and 20 Å, respectively. The Pt films were exposed to γ-rays from 137Cs (0.662 MeV) radiation source of dose rate 0.5 Gy/min. and the different doses are 100, 200, 300, 500 and 700 Gy. The dependence of the surface resistivity ( ρ) on temperature over the range of 100-300 K was undertaken at different d m and doses then the temperature coefficient of surface resistivity ( α) was deduced. It was found that; (i) for particular d m and T, the absolute value of α decreases as the dose increases (ii) for particular dose and T, the absolute value of α decreases as d m increases (iii) for particular dose and d m, the absolute value of α decreases as T increases. Qualitative interpretation for the results was offered on the ground that the electrons transfer among islands takes place by the activated tunneling mechanism and the γ-irradiation has changed the shape of islands from spherical to prolate spheroid.

Characterization of MOSFET dosimeters for low-dose measurements in maxillofacial anthropomorphic phantoms.

PubMed

Koivisto, Juha H; Wolff, Jan E; Kiljunen, Timo; Schulze, Dirk; Kortesniemi, Mika

2015-07-08

The aims of this study were to characterize reinforced metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters to assess the measurement uncertainty, single exposure low-dose limit with acceptable accuracy, and the number of exposures required to attain the corresponding limit of the thermoluminescent dosimeters (TLD). The second aim was to characterize MOSFET dosimeter sensitivities for two dental photon energy ranges, dose dependency, dose rate dependency, and accumulated dose dependency. A further aim was to compare the performance of MOSFETs with those of TLDs in an anthropomorphic phantom head using a dentomaxillofacial CBCT device. The uncertainty was assessed by exposing 20 MOSFETs and a Barracuda MPD reference dosimeter. The MOSFET dosimeter sensitivities were evaluated for two photon energy ranges (50-90 kVp) using a constant dose and polymethylmethacrylate backscatter material. MOSFET and TLD comparative point-dose measurements were performed on an anthropomorphic phantom that was exposed with a clinical CBCT protocol. The MOSFET single exposure low dose limit (25% uncertainty, k = 2) was 1.69 mGy. An averaging of eight MOSFET exposures was required to attain the corresponding TLD (0.3 mGy) low-dose limit. The sensitivity was 3.09 ± 0.13 mV/mGy independently of the photon energy used. The MOSFET dosimeters did not present dose or dose rate sensitivity but, however, presented a 1% decrease of sensitivity per 1000 mV for accumulated threshold voltages between 8300 mV and 17500 mV. The point doses in an anthropomorphic phantom ranged for MOSFETs between 0.24 mGy and 2.29 mGy and for TLDs between 0.25 and 2.09 mGy, respectively. The mean difference was -8%. The MOSFET dosimeters presented statistically insignificant energy dependency. By averaging multiple exposures, the MOSFET dosimeters can achieve a TLD-comparable low-dose limit and constitute a feasible method for diagnostic dosimetry using anthropomorphic phantoms. However, for single in vivo measurements (<1.7 mGy) the sensitivity is too low.

The radiation environment on the Moon from galactic cosmic rays in a lunar habitat.

PubMed

Jia, Y; Lin, Z W

2010-02-01

We calculated how the radiation environment in a habitat on the surface of the Moon would have depended on the thickness of the habitat in the 1977 galactic cosmic-ray environment. The Geant4 Monte Carlo transport code was used, and a hemispherical dome made of lunar regolith was used to simulate the lunar habitat. We investigated the effective dose from primary and secondary particles including nuclei from protons up to nickel, neutrons, charged pions, photons, electrons and positrons. The total effective dose showed a strong decrease with the thickness of the habitat dome. However, the effective dose values from secondary neutrons, charged pions, photons, electrons and positrons all showed a strong increase followed by a gradual decrease with the habitat thickness. The fraction of the summed effective dose from these secondary particles in the total effective dose increased with the habitat thickness, from approximately 5% for the no-habitat case to about 47% for the habitat with an areal thickness of 100 g/cm(2).

Intra-strain dioxin sensitivity and morphometric effects in swim-up rainbow trout (Oncorhynchus mykiss)

USGS Publications Warehouse

Carvalho, Paulo S. M.; Noltie, Douglas B.; Tillitt, D.E.

2004-01-01

Inter and intra-specific differences in sensitivity of early life stage salmonids to 2,3,7,8-TCDD exposure have been reported, but intra-strain differences have not been found in the literature. Our results indicate that intra-strain variability in terms of embryo mortality (LD50) is small in Eagle Lake strain of rainbow trout, LD50 values ranging from 285 to 457 pg TCDD egg g−1. These results confirm Eagle Lake as a less sensitive strain within rainbow trout, and do not indicate overlap with reported LD50 values for brook or lake trout. Our results also demonstrate that although generalized edema in regions including the yolk-sac are frequently associated with mortality following dioxin exposure, not all edematous fish die. We detected dose-dependent decreases in cranial length, eye diameter, mass, and total length (P<0.05) in viable swim-up rainbow trout. These effects are presumed to indicate more subtle dose-dependent disruptions of the viteline vein vasculature and, therefore, in access to energy sources. A tendency for dose-dependent decrease in liver glycogen reserves concurred with previous results on salmonids and with the well described TCDD-induced alterations in intermediate metabolism of rats and chicken embryos (wasting syndrome). This syndrome could be contributing to the reduced growth that we observed.

Astaxanthin Inhibits Proliferation of Human Gastric Cancer Cell Lines by Interrupting Cell Cycle Progression

PubMed Central

Kim, Jung Ha; Park, Jong-Jae; Lee, Beom Jae; Joo, Moon Kyung; Chun, Hoon Jai; Lee, Sang Woo; Bak, Young-Tae

2016-01-01

Background/Aims Astaxanthin is a carotenoid pigment that has antioxidant, antitumoral, and anti-inflammatory properties. In this in vitro study, we investigated the mechanism of anticancer effects of astaxanthin in gastric carcinoma cell lines. Methods The human gastric adenocarcinoma cell lines AGS, KATO-III, MKN-45, and SNU-1 were treated with various concentrations of astaxanthin. A cell viability test, cell cycle analysis, and immunoblotting were performed. Results The viability of each cancer cell line was suppressed by astaxanthin in a dose-dependent manner with significantly decreased proliferation in KATO-III and SNU-1 cells. Astaxanthin increased the number of cells in the G0/G1 phase but reduced the proportion of S phase KATO-III and SNU-1 cells. Phosphorylated extracellular signal-regulated kinase (ERK) was decreased in an inverse dose-dependent correlation with astaxanthin concentration, and the expression of p27kip-1 increased the KATO-III and SNU-1 cell lines in an astaxanthin dose-dependent manner. Conclusions Astaxanthin inhibits proliferation by interrupting cell cycle progression in KATO-III and SNU-1 gastric cancer cells. This may be caused by the inhibition of the phosphorylation of ERK and the enhanced expression of p27kip-1. PMID:26470770

Prolactin is a peripheral marker of manganese neurotoxicity

PubMed Central

Marreilha dos Santos, AP; Lopes Santos, M; BatorÉu, Maria C; Aschner, M

2011-01-01

Excessive exposure to Mn induces neurotoxicity, referred to as manganism. Exposure assessment relies on Mn blood and urine analyses, both of which show poor correlation to exposure. Accordingly, there is a critical need for better surrogate biomarkers of Mn exposure. The aim of this study was to examine the relationship between Mn exposure and early indicators of neurotoxicity, with particular emphasis on peripheral biomarkers. Male Wistar rats (180–200 g) were injected intraperitoneally with 4 or 8 doses of Mn (10 mg/kg). Mn exposure was evaluated by analysis of Mn levels in brain and blood along with biochemical end-points (see below). Results Brain Mn levels were significantly increased both after 4 and 8 doses of Mn compared with controls (p<0.001). Blood levels failed to reflect a dose-dependent increase in brain Mn, with only the 8-dose treated group showing significant differences (p<0.001). Brain glutathione (GSH) levels were significantly decreased in the 8-dose-treated animals (p<0.001). A significant and dose-dependent increase in prolactin levels was found for both treated groups (p<0.001) compared to controls. In addition, a decrease in motor activity was observed in the 8-dose-treated group compared to controls. Conclusions 1) The present study demonstrates that peripheral blood level is a poor indicator of Mn brain accumulation and exposure; 2) Mn reduces GSH brain levels, likely reflecting oxidative stress; 3) Mn increases blood prolactin levels, indicating changes in the integrity of the dopaminergic system. Taken together these results suggest that peripheral prolactin levels may serve as reliable predictive biomarkers of Mn neurotoxicity. PMID:21262206

Sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells in mice

PubMed Central

Guo, Chang-Ying; Luo, Lan; Urata, Yoshishige; Goto, Shinji; Huang, Wen-Jing; Takamura, Syu; Hayashi, Fumiko; Doi, Hanako; Kitajima, Yuriko; Ono, Yusuke; Ogi, Tomoo; Li, Tao-Sheng

2015-01-01

We evaluated the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells. Adult C57BL/6 mice were daily exposed to 0, 2, 10, 50, and 250 mGy γ-ray for 1 month in succession, respectively. The damage of hematopoietic stem/progenitor cells in bone marrow were investigated within 2 hours (acute phase) or at 3 months (chronic phase) after the last exposure. Daily exposure to over 10 mGy γ-ray significantly decreased the number and colony-forming capacity of hematopoietic stem/progenitor cells at acute phase, and did not completely recover at chronic phase with 250 mGy exposure. Interestingly, the daily exposure to 10 or 50 mGy γ-ray decreased the formation of mixed types of colonies at chronic phase, but the total number of colonies was comparable to control. Immunostaining analysis showed that the formation of 53BP1 foci in c-kit+ stem/progenitor cells was significantly increased with daily exposure to 50 and 250 mGy at acute phase, and 250 mGy at chronic phase. Many genes involved in toxicity responses were up- or down-regulated with the exposures to all doses. Our data have clearly shown the sensitivity and dose dependency of radiation-induced injury in hematopoietic stem/progenitor cells of mice with daily exposures to 2 ~ 250 mGy γ-ray. PMID:25623887

γ-Oryzanol reduces adhesion molecule expression in vascular endothelial cells via suppression of nuclear factor-κB activation.

PubMed

Sakai, Satoshi; Murata, Takahisa; Tsubosaka, Yoshiki; Ushio, Hideki; Hori, Masatoshi; Ozaki, Hiroshi

2012-04-04

γ-Oryzanol (γ-ORZ) is a mixture of phytosteryl ferulates purified from rice bran oil. In this study, we examined whether γ-ORZ represents a suppressive effect on the lipopolysaccharide (LPS)-induced adhesion molecule expression on vascular endothelium. Treatment with LPS elevated the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in bovine aortic endothelial cells (BAECs). Pretreatment with γ-ORZ dose-dependently decreased the LPS-mediated expression of these genes. Western blotting also revealed that pretreatment with γ-ORZ dose-dependently inhibited LPS-induced VCAM-1 expression in human umbilical vein endothelial cells. Consistently, pretreatment with γ-ORZ dose-dependently reduced LPS-induced U937 monocyte adhesion to BAECs. In immunofluorescence, LPS caused nuclear factor-κB (NF-κB) nuclear translocation in 40% of BAECs, which indicates NF-κB activation. Pretreatment with γ-ORZ, as well as its components (cycloartenyl ferulate, ferulic acid, or cycloartenol), dose-dependently inhibited LPS-mediated NF-κB activation. Collectively, our results suggested that γ-ORZ reduced LPS-mediated adhesion molecule expression through NF-κB inhibition in vascular endothelium.

The role of gut microbiota in the regulation of standard metabolic rate in female Periplaneta americana.

PubMed

Ayayee, Paul A; Ondrejech, Andrew; Keeney, George; Muñoz-Garcia, Agustí

2018-01-01

Insect gut microbiota contribute significantly to host nutritional ecology. Disrupting insect gut microbial assemblages impacts nutrient provisioning functions, and can potentially affect host standard metabolic rate (SMR), a measure of host energy balance. In this study, we evaluated the effect of disrupting gut microbial assemblages on the SMR of female Periplaneta americana cockroaches fed dog food (DF, high protein/carbohydrate (p/c) ratio), and cellulose-amended dog food (CADF, 30% dog food, 70% cellulose, low p/c ratio) diets, supplemented with none, low, or high antibiotic doses. Bacterial loads decreased significantly between diet types ( P = 0.04) and across antibiotic doses ( P = 0.04). There was a significant diet type x antibiotic dose interaction on SMR of females on both diets ( P = 0.05) by the end of the seven-day experimental period. In CADF-fed females, SMR decreased linearly with decreasing bacterial load. However, SMR of DF-fed females on the low dose was significantly higher than those in the control and high dose groups. This is interpreted as a diet-dependent response by low dose DF-fed females to the loss of nutritional services provided by gut bacteria. Severe reductions in bacterial load at high doses reduced SMR of females on both diet types. This study provides insights into the potential role of gut bacteria as modulators of host energy expenditure under varying dietary conditions.

[Effects and mechanisms of ursodeoxycholic acid on isoprenaline-Induced myocardial fibrosis in mice].

PubMed

Li, X; Han, K Q; Shi, Y N; Men, S Z; Li, S; Sun, M H; Dong, H; Lu, J J; Ma, L J; Zhao, M; Li, D; Liu, W

2017-02-07

Objective: To investigate the effects and possible mechanisms of ursodeoxycholic acid (UDCA) on myocardial fibrosis in mice. Method: To observe the expression of transforming growth factor(TGF) -β1, CTGF, MMPs and the degree of myocardial fibrosis, 61 male Kunming mice were randomly divided into normal group, low dose UDCA group, high dose of UDCA group, spironolactone group, and the control group.Isoproterenol (ISO) injection was given subcutaneously (30 d) to make the model of myocardial fibrosis.Corresponding anti-fibrosis drugs (UDCA or spironolactone) were given by gavage.HE staining and Masson staining were performed to explore the inflammation and fibrosis in the myocardium.The expression of collagen Ⅰ and collagen Ⅲ protein was detected by immunohistochemistry to evaluate the degree of fibrosis among the groups.Western blot was used to detect the expression of transforming growth factor, (TGF)-β1, connective tissue growth factor (CTGF), matrix metalloproteinase (MMP)-2, -9, tissue inhibitor of metalloproteinase (TIMP)-4, -1 and anti-phospho-NFKBIA (p-IκB-α) inhibitor of NF-κB (IκB) protein in myocardium. Results: HE and Masson staining results showed that in the normal group, myocardial fibrosis is less, while the control group showed a large amount of fibrotic tissue ( P <0.05). Tissue fibrosis in the low/high dose UDCA group and spironolactone group was significantly reduced compared with the control group ( P <0.05), in which high dose of UDCA reduces fibrosis more significantly.Immunohistochemistry results showed that collagen Ⅰ and collagen Ⅲ protein expression was significantly increased ( P <0.05). Whereas in the low/high UDCA dose group and spironolactone group, collagen Ⅰ and collagen Ⅲ expression were significantly decreased ( P <0.05), the high UDCA dose group decreased more significantly.Western blot results suggest that TGFβ-1 expression in the myocardial tissue was significantly increased compared to the normal group ( P <0.05), whereas low/high UDCA dose group and spironolactone group, TGFβ-1 protein expression were significantly decreased [UDCA(1.52±0.16), (1.02±0.12), (1.01±0.21)vs (2.73±0.12), P <0.05], in which high UDCA dose group TGFβ-1 protein expression level decreased more significantly.However, there was no significant difference in the expression of CTGF, MMP2/9 and TIMP1/4 protein among the groups ( P >0.05). UDCA decrease p-IκB-α expression and increase IκB protein expression dose-dependently. Conclusions: UDCA can relieve isoproterenol induced myocardial fibrosis and reduce the myocardial collagen Ⅰ and collagen Ⅲ deposition in a dose dependent manner.Down-regulating of TGFβ-1 protein expression through the inhibition of TGR5-NF-κB signal transduction pathway might be a potential mechanism underlying UDCA's effects.

Necroptosis contributes to methamphetamine-induced cytotoxicity in rat cortical neurons.

PubMed

Xiong, Kun; Liao, Huidan; Long, Lingling; Ding, Yanjun; Huang, Jufang; Yan, Jie

2016-09-01

Necroptosis, a programmed necrosis, is involved in various types of neurodegenerative diseases. In this study, we investigated whether necroptosis contributed to neuronal damage in a methamphetamine injury model. Primary cultures of embryonic cortical neurons from Sprague-Dawley rats were subjected to different doses of methamphetamine with/without pre-treatment with a specific necroptosis inhibitor, Necrostatin-1. Necrosis was assessed by determining lactate dehydrogenase release and by Annexin V/propidium iodide double staining, while the neuronal ultra-structure was examined by electron microscopy. Tumor necrosis factor-α protein levels were determined by enzyme-linked immunosorbent assay. At early stages (12h) of post-treatment with methamphetamine, significant necrosis occurred and the viability of neurons decreased in a dose- and time-dependent manner in this model of acute neuronal injury. Pretreatment with Necrostatin-1 led to significant neuronal preservation compared with the methamphetamine-treated groups. Furthermore, tumor necrosis factor-α expression increased in a dose-dependent manner following methamphetamine exposure. Methamphetamine induced necrosis in rat cortical neurons in vitro, both time and dose dependently, and necroptosis may be an important newly identified mode of cortical neuronal death caused by single high-dose methamphetamine administration. Copyright © 2016 Elsevier B.V. All rights reserved.

MOLECULAR BIOLOGY OF PHARMACOLOGIC VITREOLYSIS

PubMed Central

Sebag, J

2005-01-01

Purpose Pharmacologic vitreolysis is a promising new therapy to improve vitreoretinal surgery and, ultimately, prevent disease by mitigating the contribution of vitreous to retinopathy. The mechanism of action of the agents being developed for pharmacologic vitreolysis remains unclear. The experiments in this thesis test the hypothesis that pharmacologic vitreolysis agents break down vitreous macromolecules into smaller particles. Methods Microplasmin, hyaluronidase, and collagenase were tested in solutions of hyaluronan (n = 15) and collagen (n = 15), explants of bovine vitreous (n = 15), dissected porcine vitreous (n = 9), and intact porcine eyes (n = 18). There were also 21 controls, totaling 93 specimens. Vitreous macromolecule sizes were determined with dynamic light scattering (DLS), performed at intervals from 10 minutes to 24 hours following injections. Results Studies of DLS reproducibility showed a coefficient of variance of less than 3.3% in all but one specimen. Microplasmin decreased porcine vitreous macromolecule size in a dose-dependent manner (correlation coefficient r = 0.93), with an 85% reduction after a 30-minute exposure to the maximum dose. Hyaluronidase decreased vitreous macromolecule size in hyaluronan solutions by 50% at high (1,000 IU/mL, P < .001) doses and in bovine vitreous by 20%. Collagenase decreased macromolecule size in collagen solutions by 20% at both low (1 mg/mL, P < .001) and high (10 mg/mL, P < .001) doses, but not at all in bovine vitreous. Conclusions Pharmacologic vitreolysis can induce a significant decrease in vitreous macromolecule sizes, depending upon the pharmacologic agents and the experimental model. Broad-spectrum agents were more effective than substrate-specific enzymes. Defining the molecular biology of pharmacologic vitreolysis has implications for surgical developments and may impact upon the design of clinical trials to induce prophylactic posterior vitreous detachment. PMID:17057814

¹H NMR-based metabolic profiling of naproxen-induced toxicity in rats.

PubMed

Jung, Jeeyoun; Park, Minhwa; Park, Hye Jin; Shim, Sun Bo; Cho, Yang Ha; Kim, Jinho; Lee, Ho-Sub; Ryu, Do Hyun; Choi, Donwoong; Hwang, Geum-Sook

2011-01-15

The dose-dependent perturbations in urinary metabolite concentrations caused by naproxen toxicity were investigated using ¹H NMR spectroscopy coupled with multivariate statistical analysis. Histopathologic evaluation of naproxen-induced acute gastrointestinal damage in rats demonstrated a significant dose-dependent effect. Furthermore, principal component analysis (PCA) of ¹H NMR from rat urine revealed a dose-dependent metabolic shift between the vehicle-treated control rats and rats treated with low-dose (10 mg/kg body weight), moderate-dose (50 mg/kg), and high-dose (100 mg/kg) naproxen, coinciding with their gastric damage scores after naproxen administration. The resultant metabolic profiles demonstrate that the naproxen-induced gastric damage exhibited energy metabolism perturbations that elevated their urinary levels of citrate, cis-aconitate, creatine, and creatine phosphate. In addition, naproxen administration decreased choline level and increased betaine level, indicating that it depleted the main protective constituent of the gastric mucosa. Moreover, naproxen stimulated the decomposition of tryptophan into kynurenate, which inhibits fibroblast growth factor-1 and delays ulcer healing. These findings demonstrate that ¹H NMR-based urinary metabolic profiling can facilitate noninvasive and rapid diagnosis of drug side effects and is suitable for elucidating possible biological pathways perturbed by drug toxicity. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Dose-dependent testosterone sensitivity of the steroidal passport and GC-C-IRMS analysis in relation to the UGT2B17 deletion polymorphism.

PubMed

Strahm, Emmanuel; Mullen, Jenny E; Gårevik, Nina; Ericsson, Magnus; Schulze, Jenny J; Rane, Anders; Ekström, Lena

2015-01-01

The newly implemented Steroid Module of the Athlete Biological Passport has improved doping tests for steroids. A biomarker included in this passport is the urinary testosterone glucuronide to epitestosterone glucuronide (T/E) ratio, a ratio greatly affected by a deletion polymorphism in UGT2B17. Suspect urine doping tests are further analyzed with gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the origin of the androgen. In this study, we investigated the sensitivity of the steroidal module and the IRMS analysis, in subjects administered with three doses of testosterone enanthate (500, 250, and 125 mg), in relation to the UGT2B17 polymorphism. All subjects carrying the UGT2B17 enzyme reached the traditionally used threshold, a T/E ratio of 4, after all three administered doses, whereas none of the subjects devoid of this enzyme reached a T/E of 4. On the other hand, using the athlete biological passport and IRMS analysis, all three doses could be detected to a high degree of sensitivity. The concentrations of all steroids included in the steroidal module were dose dependently increased, except for epitestosterone which decreased independent of dose. The decrease in epitestosterone was significantly associated with circulatory levels of testosterone post dose (rs =0.60 and p=0.007). In conclusion, these results demonstrate that administration of a single dose of 125-500 mg testosterone enanthate could be detected using the athlete biological passport, together with IRMS. Since IRMS is sensitive to testosterone doping independent of UGT2B17 genotype, also very small changes in the steroidal passport should be investigated with IRMS. Copyright © 2015 John Wiley & Sons, Ltd.

Bacterial Dose-Dependent Role of G Protein-Coupled Receptor Kinase 5 in Escherichia coli-Induced Pneumonia.

PubMed

Packiriswamy, Nandakumar; Steury, Michael; McCabe, Ian C; Fitzgerald, Scott D; Parameswaran, Narayanan

2016-05-01

G protein-coupled receptor kinase 5 (GRK5) is a serine/threonine kinase previously shown to mediate polymicrobial sepsis-induced inflammation. The goal of the present study was to examine the role of GRK5 in monomicrobial pulmonary infection by using an intratracheal Escherichia coli infection model of pneumonia. We used sublethal and lethal doses of E. coli to examine the mechanistic differences between low-grade and high-grade inflammation induced by E. coli infection. With a sublethal dose of E. coli, GRK5 knockout (KO) mice exhibited higher plasma CXCL1/KC levels and enhanced lung neutrophil recruitment early after infection, and lower bacterial loads, than wild-type (WT) mice. The inflammatory response was also diminished, and resolution of inflammation advanced, in the lungs of GRK5 KO mice. In contrast to the reduced bacterial loads in GRK5 KO mice following a sublethal dose, at a lethal dose of E. coli, the bacterial burdens remained high in GRK5 KO mice relative to those in WT mice. This occurred in spite of enhanced plasma CXCL1 levels as well as neutrophil recruitment in the KO mice. But the recruited neutrophils (following high-dose infection) exhibited decreased CD11b expression and reduced reactive oxygen species production, suggesting decreased neutrophil activation or increased neutrophil exhaustion in the GRK5 KO mice. In agreement with the increased bacterial burden, KO mice showed poorer survival than WT mice following E. coli infection at a lethal dose. Overall, our data suggest that GRK5 negatively regulates CXCL1/KC levels during bacterial pneumonia but that the role of GRK5 in the clinical outcome in this model is dependent on the bacterial dose. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Neutron equivalent doses and associated lifetime cancer incidence risks for head & neck and spinal proton therapy

NASA Astrophysics Data System (ADS)

Athar, Basit S.; Paganetti, Harald

2009-08-01

In this work we have simulated the absorbed equivalent doses to various organs distant to the field edge assuming proton therapy treatments of brain or spine lesions. We have used computational whole-body (gender-specific and age-dependent) voxel phantoms and considered six treatment fields with varying treatment volumes and depths. The maximum neutron equivalent dose to organs near the field edge was found to be approximately 8 mSv Gy-1. We were able to clearly demonstrate that organ-specific neutron equivalent doses are age (stature) dependent. For example, assuming an 8-year-old patient, the dose to brain from the spinal fields ranged from 0.04 to 0.10 mSv Gy-1, whereas the dose to the brain assuming a 9-month-old patient ranged from 0.5 to 1.0 mSv Gy-1. Further, as the field aperture opening increases, the secondary neutron equivalent dose caused by the treatment head decreases, while the secondary neutron equivalent dose caused by the patient itself increases. To interpret the dosimetric data, we analyzed second cancer incidence risks for various organs as a function of patient age and field size based on two risk models. The results show that, for example, in an 8-year-old female patient treated with a spinal proton therapy field, breasts, lungs and rectum have the highest radiation-induced lifetime cancer incidence risks. These are estimated to be 0.71%, 1.05% and 0.60%, respectively. For an 11-year-old male patient treated with a spinal field, bronchi and rectum show the highest risks of 0.32% and 0.43%, respectively. Risks for male and female patients increase as their age at treatment time decreases.

Exercise limits the production of endothelin in the coronary vasculature

PubMed Central

de Beer, Vincent J.; Bender, Shawn B.; Taverne, Yannick J.; Gao, Fen; Duncker, Dirk J.; Laughlin, M. Harold

2011-01-01

We previously demonstrated that endothelin (ET)-mediated coronary vasoconstriction wanes with increasing exercise intensity via a nitric oxide- and prostacyclin-dependent mechanism (Ref. 23). Therefore, we hypothesized that the waning of ET coronary vasoconstriction during exercise is the result of decreased production of ET and/or decreased ET receptor sensitivity. We investigated coronary ET receptor sensitivity using intravenous infusion of ET and coronary ET production using intravenous infusion of the ET precursor Big ET, at rest and during continuous treadmill exercise at 3 km/h in 16 chronically instrumented swine. In the systemic vasculature, Big ET and ET induced similar changes in hemodynamic parameters at rest and during continuous exercise at 3 km/h, indicating that exercise does not alter ET production or receptor sensitivity in the systemic vasculature. In the coronary vasculature, infusion of ET resulted in similar dose-dependent decreases in coronary blood flow and coronary venous oxygen tension and saturation at rest and during exercise. In contrast, administration of Big ET resulted in dose-dependent decreases in coronary blood flow, as well as coronary venous oxygen tension and saturation at rest. These effects of Big ET were significantly reduced during exercise. Altogether, our data indicate that continuous exercise at 3 km/h attenuates ET-mediated coronary vasoconstriction through reduced production of ET from Big ET rather than through reduced ET sensitivity of the coronary vasculature. The decreased ET production during exercise likely contributes to metabolic coronary vasodilation. PMID:21317308

Maternal and developmental toxicity of ayahuasca in Wistar rats.

PubMed

Oliveira, Carolina Dizioli Rodrigues; Moreira, Camila Queiroz; de Sá, Lilian Rose Marques; Spinosa, Helenice de Souza; Yonamine, Mauricio

2010-06-01

Ayahuasca is a psychotropic plant beverage initially used by shamans throughout the Amazon region during traditional religious cult. In recent years, ayahuasca has also been used in ceremonies of a number of modern syncretic religious groups, including pregnant women. However, no documented study has been performed to evaluate the risk of developmental toxicity of ayahuasca. In the present work, maternal and developmental toxicity was evaluated in Wistar rats. Ayahuasca was administered to pregnant rats in three different doses [the equivalent typical dose (TD) administered to humans, five-fold TD and 10-fold TD] during the gestational period (6-20 days). Dams treated with the highest ayahuasca dose showed maternal toxicity with decrease of weight gain and food intake. Visceral fetal findings were observed in all treatment groups. Skeletal findings were observed in the intermediate- and high-dose groups. The fetuses deriving from the highest dose group also presented a decrease in body weight. From these results, it is possible to conclude that there is a risk of maternal and developmental toxicity following ayahuasca exposure and that the level of toxicity appears to be dose-dependent.

SU-E-I-15: Quantitative Evaluation of Dose Distributions From Axial, Helical and Cone-Beam CT Imaging by Measurement Using a Two-Dimensional Diode-Array Detector

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chacko, M; Aldoohan, S; Sonnad, J

2015-06-15

Purpose: To evaluate quantitatively dose distributions from helical, axial and cone-beam CT clinical imaging techniques by measurement using a two-dimensional (2D) diode-array detector. Methods: 2D-dose distributions from selected clinical protocols used for axial, helical and cone-beam CT imaging were measured using a diode-array detector (MapCheck2). The MapCheck2 is composed from solid state diode detectors that are arranged in horizontal and vertical lines with a spacing of 10 mm. A GE-Light-Speed CT-simulator was used to acquire axial and helical CT images and a kV on-board-imager integrated with a Varian TrueBeam-STx machine was used to acquire cone-beam CT (CBCT) images. Results: Themore » dose distributions from axial, helical and cone-beam CT were non-uniform over the region-of-interest with strong spatial and angular dependence. In axial CT, a large dose gradient was measured that decreased from lateral sides to the middle of the phantom due to large superficial dose at the side of the phantom in comparison with larger beam attenuation at the center. The dose decreased at the superior and inferior regions in comparison to the center of the phantom in axial CT. An asymmetry was found between the right-left or superior-inferior sides of the phantom which possibly to angular dependence in the dose distributions. The dose level and distribution varied from one imaging technique into another. For the pelvis technique, axial CT deposited a mean dose of 3.67 cGy, helical CT deposited a mean dose of 1.59 cGy, and CBCT deposited a mean dose of 1.62 cGy. Conclusions: MapCheck2 provides a robust tool to measure directly 2D-dose distributions for CT imaging with high spatial resolution detectors in comparison with ionization chamber that provides a single point measurement or an average dose to the phantom. The dose distributions measured with MapCheck2 consider medium heterogeneity and can represent specific patient dose.« less

Repaglinide as monotherapy in Type 2 diabetes.

PubMed

Gomis, R

1999-01-01

The action of repaglinide, a carbamoylmethyl benzoic acid derivative, mimics the physiological insulin secretion that is deficient in Type 2 diabetes mellitus. Repaglinide stimulates insulin release from beta-cells only in the presence of glucose. Two placebo-controlled studies were performed to establish the effective dose range of repaglinide. In one study, repaglinide (0.25-4.0 mg preprandially) caused a dose-dependent decrease in blood glucose and a non-dose-dependent increase in insulin over 4 weeks (all doses p < 0.001 vs. placebo). In the second study, repaglinide (0.25-8.0 mg preprandially) was titrated over 6 weeks to obtain the optimum response (fasting plasma glucose < 8.9 mmol/L). The titration period was followed by a 12-week dose-maintenance period. At the end of the study, repaglinide had decreased fasting plasma glucose by 3.4 mmol/L (p < 0.05) and 2-h postprandial blood glucose by 5.8 mmol/L (p < 0.001) versus placebo. Glycated haemoglobin (HbA1c) decreased significantly from 8.5% to 7.9% in the repaglinide group and increased significantly from 8.1% to 9.2% in the placebo group (p < 0.001 between groups). In five 1-year, multicentre, randomized, double-blind, phase III trials, repaglinide (0.5-4.0 mg preprandially) was compared with the sulphonylureas glibenclamide, glipizide and gliclazide. Repaglinide was more effective than glipizide at maintaining glycaemic control and was equivalent to glibenclamide and gliclazide on the basis of change in HbA1c. Hypoglycaemic events were reported in 16% of repaglinide-treated patients and 15-20% of sulphonylurea-treated patients. These data indicate that repaglinide monotherapy, with diet and exercise, is effective in patients with Type 2 diabetes.

Testing Dose-Dependent Effects of the Nectar Alkaloid Anabasine on Trypanosome Parasite Loads in Adult Bumble Bees.

PubMed

Anthony, Winston E; Palmer-Young, Evan C; Leonard, Anne S; Irwin, Rebecca E; Adler, Lynn S

2015-01-01

The impact of consuming biologically active compounds is often dose-dependent, where small quantities can be medicinal while larger doses are toxic. The consumption of plant secondary compounds can be toxic to herbivores in large doses, but can also improve survival in parasitized herbivores. In addition, recent studies have found that consuming nectar secondary compounds may decrease parasite loads in pollinators. However, the effect of compound dose on bee survival and parasite loads has not been assessed. To determine how secondary compound consumption affects survival and pathogen load in Bombus impatiens, we manipulated the presence of a common gut parasite, Crithidia bombi, and dietary concentration of anabasine, a nectar alkaloid produced by Nicotiana spp. using four concentrations naturally observed in floral nectar. We hypothesized that increased consumption of secondary compounds at concentrations found in nature would decrease survival of uninfected bees, but improve survival and ameliorate parasite loads in infected bees. We found medicinal effects of anabasine in infected bees; the high-anabasine diet decreased parasite loads and increased the probability of clearing the infection entirely. However, survival time was not affected by any level of anabasine concentration, or by interactive effects of anabasine concentration and infection. Crithidia infection reduced survival time by more than two days, but this effect was not significant. Our results support a medicinal role for anabasine at the highest concentration; moreover, we found no evidence for a survival-related cost of anabasine consumption across the concentration range found in nectar. Our results suggest that consuming anabasine at the higher levels of the natural range could reduce or clear pathogen loads without incurring costs for healthy bees.

[Pharmacological study of nicergoline. (III). Effects on cerebral and peripheral circulation in animals].

PubMed

Shintomi, K; Ogawa, Y; Yoshimoto, K; Narita, H

1986-05-01

Effects of nicergoline on the cerebral and peripheral circulation were compared with those of dihydroergotoxine (DHE) and papaverine (PAP) in anesthetized and/or immobilized cats. The i.a. injection of nicergoline (0.032 approximately 32 micrograms/kg), similarly to PAP, caused dose-dependent increases in intramaxillary artery (as the human intracarotid artery) blood flow (IMBF) and femoral artery blood flow, but the injection of DHE had no effect on these blood flows. The i.v. injection of nicergoline (32 approximately 128 micrograms/kg) caused a dose-dependent fall in blood pressure (BP) and a transient slight decrease in cerebral vascular resistance, but did not affect IMBF, regional cerebral blood flow (r-CBF), intracranial pressure (ICP) and heart rate (HR). The i.v. injection of DHE produced a slight fall in BP and a marked long-lasting decrease in HR, without affecting other parameters. The i.v. injection of PAP (4 mg/kg) induced marked increases in IMBF, r-CBF, ICP and HR and caused a transient fall followed by a marked elevation in BP. The p.o. administration of nicergoline (0.06 approximately 4 mg/kg) caused a dose-dependent fall in BP and selective inhibition of pressure response to adrenaline (ID50: 0.25 mg/kg). The administration of DHE produced marked inhibition of pressure responses to both adrenaline and noradrenaline, accompanied with a slight fall in BP. Furthermore, the administration of nicergoline (3 approximately 100 mg/kg) induced a dose-dependent fall in BP in SHR. These results suggest that the cerebral and peripheral circulatory effects of nicergoline may be due to direct vasodilating action and alpha-blocking action in the animals.

Post Chlorine gas exposure administration of nitrite prevents lung injury: effect of administration modality

PubMed Central

Samal, Andrey A.; Honavar, Jaideep; Brandon, Angela; Bradley, Kelley M.; Doran, Stephen; Liu, Yanping; Dunaway, Chad; Steele, Chad; Postlethwait, Edward M.; Squadrito, Giuseppe L.; Fanucchi, Michelle V.; Matalon, Sadis; Patel, Rakesh P.

2012-01-01

Cl2 gas toxicity is complex and occurs during, and post exposure leading to acute lung injury (ALI) and reactive airway syndrome (RAS). Moreover, Cl2 exposure can occur in diverse situations encompassing mass casualty scenarios underscoring the need for post-exposure therapies that are efficacious and amenable to rapid and easy administration. In this study, we compared the efficacy of a single dose, post (30min) Cl2 exposure administration of nitrite (1mg/kg) via intraperitoneal (IP) or intramuscular (IM) injection in rats, to decrease ALI. Exposure of rats to Cl2 gas (400ppm, 30min) significantly increased ALI and caused RAS 6–24h post exposure as indexed by BAL sampling of lung surface protein, PMN and increased airway resistance and elastance prior to and post methacholine challenge. IP nitrite decreased Cl2 - dependent increases in BAL protein but not PMN. In contrast IM nitrite decreased BAL PMN levels without decreasing BAL protein in a xanthine oxidoreductase independent manner. Histological evaluation of airways 6h post exposure showed significant bronchial epithelium exfoliation and inflammatory injury in Cl2 exposed rats. Both IP and IM nitrite improved airway histology compared to Cl2 gas alone, but more coverage of the airway by cuboidal or columnar epithelium was observed with IM compared to IP nitrite. Airways were rendered more sensitive to methacholine induced resistance and elastance after Cl2 gas exposure. Interestingly, IM nitrite, but not IP nitrite, significantly decreased airway sensitivity to methacholine challenge. Further evaluation and comparison of IM and IP therapy showed a two-fold increase in circulating nitrite levels with the former, which was associated with reversal of post-Cl2 exposure dependent increases in circulating leukocytes. Halving the IM nitrite dose resulted in no effect in PMN accumulation but significant reduction of of BAL protein levels indicating distinct nitrite dose dependence for inhibition of Cl2 dependent lung permeability and inflammation. These data highlight the potential for nitrite as a post-exposure therapeutic for Cl2 gas induced lung injury and also suggest that administration modality is a key consideration in nitrite therapeutics. PMID:22917977

Flavonoids from Theobroma cacao down-regulate inflammatory mediators.

PubMed

Ramiro, Emma; Franch, Angels; Castellote, Cristina; Pérez-Cano, Francisco; Permanyer, Joan; Izquierdo-Pulido, Maria; Castell, Margarida

2005-11-02

In the present study, we report the effects of a cocoa extract on the secretion and RNA expression of various proinflammatory mediators by macrophages. Monocyte chemoattractant protein 1 and tumor necrosis factor alpha (TNFalpha) were significantly and dose-dependently diminished by cocoa extract, and this effect was higher than that produced by equivalent concentrations of epicatechin but was lower than that produced by isoquercitrin. Interestingly, cocoa extract added prior to cell activation resulted in a significantly greater inhibition of TNFalpha secretion. Both cocoa extract and epicatechin decreased TNFalpha, interleukin (IL) 1alpha, and IL-6 mRNA expression, suggesting that their inhibitory effect on cytokine secretion is produced, in part, at the transcriptional level. Cocoa extract also significantly decreased NO secretion in a dose-dependent manner and with a greater effect than that produced by epicatechin. In conclusion, our study shows that cocoa flavonoids not only inhibit NO release from macrophages but also down-regulate inflammatory cytokines and chemokines.

Effect of ozonation on the reactivity of lignocellulose substrates in enzymatic hydrolyses to sugars

NASA Astrophysics Data System (ADS)

Ben'ko, E. M.; Manisova, O. R.; Lunin, V. V.

2013-07-01

The efficiency of pre-treatment of aspen wood with ozone for subsequent enzymatic hydrolysis into sugars is determined by the amount of absorbed ozone. The ozone absorption rate depended on the water content in the sample being ozonized and was maximum at a relative humidity of wood of ˜40%. As a result of ozone pre-treatment, the initial rate of the enzymatic hydrolysis of wood under the action of a cellulase complex increased eightfold, and the maximum yield of sugars increased tenfold depending on the ozone dose. The ozonation at ozone doses of more than 3 mol/PPU (phenylpropane structural unit of lignin) led to a decrease in the yield of sugars because of the oxidative destruction of cellulose and hemicellulose. The alkaline ozonation in 2 and 12% NaOH was inefficient because of the accompanying oxidation of carbohydrates and considerably decreased the yield of sugars.

Effects of lorcaserin (Belviq®) on nicotine- and food-maintained responding in non-human primates.

PubMed

Jacobs, David S; Barkin, Claire E; Kohut, Michelle R; Bergman, Jack; Kohut, Stephen J

2017-12-01

Accumulating evidence suggests that the FDA-approved serotonin 5-HT 2C receptor agonist, lorcaserin (Belviq ® ), may be a promising candidate for the management of substance use disorders, including nicotine addiction. The present study was conducted to determine the efficacy and selectivity of acute or continuous lorcaserin treatment for decreasing the reinforcing effects of nicotine in a primate species. Adult rhesus monkeys (n=4) with a history of nicotine self-administration (>2years) responded for injections of nicotine (0.32-100μg/kg IV) or food pellets under a fixed-ratio schedule of reinforcement during daily 100-min sessions. When responding was stable, lorcaserin was administered either as an acute pretreatment (0.1-1.0mg/kg, IM) or by continuous infusion (0.1mg/kg/hr, SC for 3-5days). Daily activity patterns were also monitored immediately following experimental sessions. Results indicate that acute lorcaserin pretreatment produced significant and dose-dependent decreases in nicotine-maintained responding across a >100-fold range of self-administered nicotine doses. Continuous lorcaserin treatment decreased intake of 10μg/kg/inj nicotine to about 50% of baseline values. Food-maintained responding was only moderately decreased in 3 of 4 subjects after acute administration and unaffected in all subjects during continuous treatment. Daily activity also was significantly decreased-to ≤50% of control values-following experimental sessions in which acute lorcaserin was administered. These data indicate that lorcaserin reduces IV self-administration of nicotine at a dose that decreases motoric activity but less consistently disrupts food-maintained responding. Further research into lorcaserin's potential utility for the management of nicotine dependence is warranted. Copyright © 2017 Elsevier B.V. All rights reserved.

Evaluation of characteristics of high-energy electron beams using N-isopropyl-acrylamide gel dosimeter

NASA Astrophysics Data System (ADS)

Shih, Tian-Yu; Yen, Tsung-Hsien; Liu, Yan-Lin; Luzhbin, Dmytro; Wu, Jay

2017-11-01

The advantage of electron beam radiotherapy is that the absorbed dose rapidly decreases with the increasing depth, which can prevent damage to deeper organs and tissues. Accurately evaluating the absorbed dose in the superficial tumor is imperative. This study assessed the characteristics of electron beams by using the N-isopropyl-acrylamide (n-NIPAM) gel dosimeter. The n-NIPAM gel was composed of 6% gelatin, 5% monomer, and 2.5% cross-linker with 5 mM tetrakis (hydroxymethyl) phosphonium chloride for deoxygenation. The gel was irradiated with 6-, 9-, and 12-MeV electron beams with dose rates of 100-600 MU/min, respectively. The energy dependence and dose rate dependence were assessed. The beam profiles and percentage depth doses were measured and compared with the results of the Gafchromic film and ionization chamber. The linearity of the n-NIPAM gel under 6-, 9-, and 12-MeV electrons was larger than 0.990 with 2% variation in sensitivity. The sensitivity of the gel under 100-600 MU/min showed 5% variations. The energy and dose rate dependence can be negligible. The beam profiles and percentage depth doses measured by the n-NIPAM gel matched well with the results of the ionization chamber and film. This study reveals the possibility of using the n-NIPAM gel dosimeter for electron beam measurements in clinical radiotherapy.

Subchronic effects of methylmercury on plasma and organ biochemistries in great egret nestlings

USGS Publications Warehouse

Hoffman, D.J.; Spalding, M.G.; Frederick, P.C.

2005-01-01

In recent years, high concentrations of mercury have been found in wading birds in Florida, USA. Great egret (Ardea alba) chicks (2 weeks old) were dosed orally daily with the equivalent of 0, 0.5, or 5 ug/g Hg as methylmercury chloride in the diet for up to 12 weeks. Weakness of the legs or paralysis occurred in all high-dosed birds. Geometric mean blood Hg concentrations were 0.17, 10.3, and 78.5 ug/g (wet wt), respectively. Mercury concentrations for organs (ug/g wet wt), including brain (0.22, 3.4, and 35, respectively), liver (0.34, 15.1, 138, respectively), and kidney (0.28, 8.1, and 120, respectively), increased in a dose-dependent manner. Total glutathione (GSH) peroxidase activity was significantly lower in the plasma, brain, liver, and kidney of the high-dosed group. Plasma aspartate aminotransferase activity increased with mercury treatment, whereas lactate dehydrogenase activity decreased. Four other plasma chemistries were decreased significantly in the high-dosed group and included uric acid, total protein, albumin, and inorganic phosphorus. Lipid peroxidation increased in liver (low and high dose) and brain (high dose). Tissue changes in concentrations of reduced thiols included decreased total thiols and protein-bound thiols in liver, decreased protein-bound thiols in kidney, and increased GSH in kidney and brain. Activities of GSH S-transferase and oxidized glutathione reductase increased in liver. In kidney, GSH S-transferase and glucose-6-phosphate dehydrogenase activities increased with mercury dose. These findings, including apparent compensatory changes, are compared to other Hg studies where oxidative stress was reported in egrets, herons, and diving ducks in the field and mallards in the laboratory.

Comparative effects of chlordecone and mirex on rat cardiac ATPases and binding of 3H-catecholamines.

PubMed

Desaiah, D

1980-08-01

The effects of chlordecone and mirex on the rat myocardial ATPases and binding of 3H-dopamine and 3H-norepinephrine to the NAK-fraction were determined both by in vitro and in vivo treatment. The in vitro data showed that chlordecone significantly inhibited mitochondrial Mg2+ ATPase and Na+--K+ ATPase in a concentration dependent manner with ID50 values of 5 x 10(-8) and 2 x 10(-6) M, respectively. Mitrex, a close structural analog of chlordecone did not inhibit mitochondrial Mg2+ ATPase but inhibited about 15% of N+--K+ ATPase activity. Rats treated with symptomatogenic doses of chlordecone showed a marked and significant decrease of myocardial Na+--K+ ATPase and the residual Mg2+ ATPase activities. The decrease in the enzyme activities was dose dependent and significant. However, mirex treated rats showed a slight decrease in the myocardial Na+--K+ ATPase. The potency of chlordecone to inhibit the ATPase system was parallel to its ability to decrease the dopamine and norepinephrine binding of the myocardial NAK-fraction. Preincubation of the NAK-fraction with various concentrations of chlordecone resulted in a decreased binding of dopamine and norepinephrine. The decrease was significant and concentration dependent. Similar findings were observed in rats pretreated with chlordecone. Mirex did not show any effect, either in vitro or in vivo treatment, on the binding of dopamine or norepinephrine to the myocardial NAK-fraction. These results suggest that chlordecone may be altering the sodium pump activity by inhibiting both ATP hydrolysis and ATP synthesis and thus reducing other cellular events such as catecholamine uptake.

Thrombocytopenia induced by the histone deacetylase inhibitor abexinostat involves p53-dependent and -independent mechanisms.

PubMed

Ali, A; Bluteau, O; Messaoudi, K; Palazzo, A; Boukour, S; Lordier, L; Lecluse, Y; Rameau, P; Kraus-Berthier, L; Jacquet-Bescond, A; Lelièvre, H; Depil, S; Dessen, P; Solary, E; Raslova, H; Vainchenker, W; Plo, I; Debili, N

2013-07-25

Abexinostat is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia whose mechanism is only partially understood. We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human CD34(+) cells. When added at day 0 in culture, abexinostat inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. These effects required only a short incubation period. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2/STAT signaling. When added later (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet (PPT) formation. Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. DNA double-strand breaks were increased as attested by elevated γH2AX phosphorylation level. Moreover, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, and only partially the defect in PPT formation. These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation.

Non-thermal Plasma Induces Apoptosis in Melanoma Cells via Production of Intracellular Reactive Oxygen Species

PubMed Central

Sensenig, Rachel; Kalghatgi, Sameer; Cerchar, Ekaterina; Fridman, Gregory; Shereshevsky, Alexey; Torabi, Behzad; Arjunan, Krishna Priya; Podolsky, Erica; Fridman, Alexander; Friedman, Gary; Azizkhan-Clifford, Jane; Brooks, Ari D.

2012-01-01

Non-thermal atmospheric pressure dielectric barrier discharge (DBD) plasma may provide a novel approach to treat malignancies via induction of apoptosis. The purpose of this study was to evaluate the potential of DBD plasma to induce apoptosis in melanoma cells. Melanoma cells were exposed to plasma at doses that did not induce necrosis, and cell viability and apoptotic activity were evaluated by Trypan blue exclusion test, Annexin-V/PI staining, caspase-3 cleavage, and TUNEL® analysis. Trypan blue staining revealed that non-thermal plasma treatment significantly decreased the viability of cells in a dose-dependent manner 3 and 24 h after plasma treatment. Annexin-V/PI staining revealed a significant increase in apoptosis in plasma-treated cells at 24, 48, and 72 h post-treatment (p<0.001). Caspase-3 cleavage was observed 48 h post-plasma treatment at a dose of 15 J/cm2. TUNEL® analysis of plasma-treated cells demonstrated an increase in apoptosis at 48 and 72 h post-treatment (p<0.001) at a dose of 15 J/cm2. Pre-treatment with N-acetyl-L-cysteine (NAC), an intracellular reactive oxygen species (ROS) scavenger, significantly decreased apoptosis in plasma-treated cells at 5 and 15 J/cm2. Plasma treatment induces apoptosis in melanoma cells through a pathway that appears to be dependent on production of intracellular ROS. DBD plasma production of intracellular ROS leads to dose-dependent DNA damage in melanoma cells, detected by γ-H2AX, which was completely abrogated by pre-treating cells with ROS scavenger, NAC. Plasma-induced DNA damage in turn may lead to the observed plasma-induced apoptosis. Since plasma is non-thermal, it may be used to selectively treat malignancies. PMID:21046465

Dose-dependent effects of β-phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) on animal behavior.

PubMed

Tyurenkov, I N; Bagmetova, V V; Chernyshova, Yu V; Merkushenkova, O V

2014-12-01

β-Phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) in doses of 13-650 mg/kg suppressed depressive behavior of animals in the Porsolt test (i.e. produced antidepressant properties), reduced anxiety in the open-field, elevated plus maze, and Vogel conflict tests (i.e. produced anxiolytic effects). RGPU-135 in doses of 26-130 mg/kg exhibited more pronounced antidepressant action and in doses of 26 and 52 mg/kg had more pronounced anxiolytic effects. RGPU-135 in doses of 13-78 mg/kg increased locomotor and exploratory activity of animals in the open-field test. Activating effects of this agent decreased with increasing the dose. RGPU-135 in the subtoxic dose (650 mg/kg) suppressed locomotor activity of animals (produced sedative effect).

Flavonoids and Tannins from Smilax china L. Rhizome Induce Apoptosis Via Mitochondrial Pathway and MDM2-p53 Signaling in Human Lung Adenocarcinoma Cells.

PubMed

Fu, San; Yang, Yanfang; Liu, Dan; Luo, Yan; Ye, Xiaochuan; Liu, Yanwen; Chen, Xin; Wang, Song; Wu, Hezhen; Wang, Yuhang; Hu, Qiwei; You, Pengtao

2017-01-01

In vitro evidence indicates that Smilax china L. rhizome (SCR) can inhibit cell proliferation. Therefore, in the present study, we analyzed the effects in vitro of SCR extracts on human lung adenocarcinoma A549 cells. Our results showed that A549 cell growth was inhibited in a dose- and time-dependent manner after treatment with SCR extracts. Total flavonoids and total tannins from SCR induced A549 apoptosis in a dose-dependent manner, as shown by our flow cytometry analysis, which was consistent with the alterations in nuclear morphology we observed. In addition, the total apoptotic rate induced by total tannins was higher than the rate induced by total flavonoids at the same dose. Cleaved-caspase-3 protein levels in A549 cells after treatment with total flavonoids or total tannins were increased in a dose-dependent manner, followed by the activation of caspase-8 and caspase-9, finally triggering to PARP cleavage. Furthermore, total flavonoids and total tannins increased the expression of Bax, decreased the expression of Bcl-2, and promoted cytochrome [Formula: see text] release. Moreover, MDM2 and p-MDM2 proteins were decreased, while p53 and p-p53 proteins were increased, both in a dose-dependent manner, after A549 treatment with total flavonoids and total tannins. Finally, cleaved-caspase-3 protein levels in the total flavonoids or total tannins-treated H1299 (p53 null) and p53-knockdown A549 cells were increased. Our results indicated that total flavonoids and total tannins from SCR exerted a remarkable effect in reducing A549 growth through their action on mitochondrial pathway and disruption of MDM2-p53 balance. Hence, our findings demonstrated a potential application of total flavonoids and total tannins from SCR in the treatment of human lung adenocarcinoma.

Antithrombin activity of an algal polysaccharide.

PubMed

Trento, F; Cattaneo, F; Pescador, R; Porta, R; Ferro, L

2001-06-01

In an effort to reduce the risks of a possible iatrogenic transmission of bovine spongiform encephalitis (BSE) through the use of bovine-derived medicinal products, we patented in the USA in 1999 a polysaccharide from brown algae, endowed with interesting pharmacological activities: (a) concentration-dependent inhibition of thromboplastin or cephalin-kaolin-induced thrombin generation from platelets, (b) concentration-dependent inhibition of thrombin-induced platelet aggregation, (c) thrombin has hypotensive effect, which was blunted and zeroed by our fucansulfate in a dose-dependent way, (d) when aortae are stimulated with thrombin, they become stickier for polymorphonucleated leukocytes (PMNs); our fucansulfate decreased concentration-dependently, PMNs sticking to autologous rabbit aortae, (e) dose-dependent inhibition of thrombin-induced thrombosis. All the above data suggest that our fucansulfate could be a heparin substitute endowed with antithrombotic and anti-inflammatory activities, devoid or the problems caused to heparin by its animal origin, i.e., possible prion protein contamination.

Changes in optically stimulated luminescent dosimeter (OSLD) dosimetric characteristics with accumulated dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jursinic, Paul A.

2010-01-15

Purpose: A new type of in vivo dosimeter, an optically stimulated luminescent dosimeter (OSLD), has now become commercially available for clinical use. The OSLD is a plastic disk infused with aluminum oxide doped with carbon (Al{sub 2}O{sub 3}:C). Crystals of Al{sub 2}O{sub 3}:C, when exposed to ionizing radiation, store energy that is released as luminescence (420 nm) when the OSLD is illuminated with stimulation light (540 nm). The intensity of the luminescence depends on the dose absorbed by the OSLD and the intensity of the stimulation light. The effects of accumulated dose on OSLD response were investigated. Methods: The OSLDsmore » used in this work were nanodot dosimeters, which were read with a MicroStar reader (Landauer, Inc., Glenwood, IL). Dose to the OSLDs was delivered by 6 MV x rays and gamma rays from Co-60 and Ir-192. The signal on the OSLDs after irradiation is removed by optical annealing with a 150 W tungsten-halogen lamp or a 14 W compact fluorescent lamp was investigated. Results: It was found that OSLD response to dose was supralinear and this response was altered with the amount of accumulated dose to the OSLD. The OSLD response can be modeled by a quadratic and an exponential equation. For accumulated doses up to 60 Gy, the OSLD sensitivity (counts/dose) decreases and the extent of supralinear increases. Above 60 Gy of accumulated dose the sensitivity increases and the extent of supralinearity decreases or reaches a plateau, depending on how the OSLDs were optically annealed. With preirradiation of OSLDs with greater than 1 kGy, it is found that the sensitivity reaches a plateau 2.5 folds greater than that of an OSLD with no accumulated dose and the supralinearity disappears. A regeneration of the luminescence signal in the dark after full optical annealing occurs with a half time of about two days. The extent of this regeneration signal depends on the amount of accumulated dose. Conclusions: For in vivo dosimetric measurements, a precision of {+-}0.5% can be achieved if the sensitivity and extent of supralinearity is established for each OSLD and use. Methods are presented for accomplishing this task.« less

Effects of rutin on acrylamide-induced neurotoxicity

PubMed Central

2014-01-01

Background Rutin is an important flavonoid that is consumed in the daily diet. The cytoprotective effects of rutin, including antioxidative, and neuroprotective have been shown in several studies. Neurotoxic effects of acrylamide (ACR) have been established in humans and animals. In this study, the protective effects of rutin in prevention and treatment of neural toxicity of ACR were studied. Results Rutin significantly reduced cell death induced by ACR (5.46 mM) in time- and dose-dependent manners. Rutin treatment decreased the ACR-induced cytotoxicity significantly in comparison to control (P <0.01, P < 0.001). Rutin (100 and 200 mg/kg) could prevent decrease of body weight in rats. In combination treatments with rutin (50, 100 and 200 mg/kg), vitamin E (200 mg/kg) and ACR, gait abnormalities significantly decreased in a dose-dependent manner (P < 0.01 and P < 0.001). The level of malondialdehyde significantly decreased in the brain tissue of rats in both preventive and therapeutic groups that received rutin (100 and 200 mg/kg). Conclusion It seems that rutin could be effective in reducing neurotoxicity and the neuroprotective effect of it might be mediated via antioxidant activity. PMID:24524427

Dose-dependent bioavailability indicators for curcumin and two of its novel derivatives.

PubMed

Abd el Aziz, Mohamed; El-Asmer, Mohamed; Rezq, Ameen; Al-Malki, Abdulrahman; Kumosani, Taha; Fouad, Hanan; Ahmed, Hanan; Taha, Fatma; Hassouna, Amira; Hafez, Hafez

2014-01-01

Novel water-soluble curcumin derivatives have been developed to overcome low in vivo bioavailability of curcumin. The aim of this work is to assess the potential utility of certain downstream targets as bioavailability indicators of systemic activity of pure curcumin and two novel water-soluble curcumin derivatives (NCD) by constructing dose-dependent response curves and to prove whether this novel curcumin derivatives retained, improved, or abolished biological activity of pure curcumin when applied in vivo. Pure curcumin (CUR), curcumin-carboxy derivative (NCD-1), and curcumin protein conjugate (NCD-2) were administered orally to rats at escalating doses: 37, 74, 148, and 296 μM/kg body weight, respectively. Plasma levels of GST activity, cavernous tissue levels of cGMP, and enzymatic activity of both HO-1 and GST were assessed one and half and 24 hours after oral administration of curcumin formulae. This study showed that there was a progressive elevation of cavernous tissue levels of cGMP and enzymatic activity of both HO-1 and GST in a dose-dependent manner that was maintained for 24 h with CUR, NCD-1, and NCD-2. Plasma GST activity was decreased by the lowest doses on the curve. The three dose-dependent bioavailability indicators as surrogates of curcumin and two of its novel derivatives are valid in the studied range of concentration and extended time. The novel curcumin derivatives still conserve with improvement the biological activity of natural curcumin when applied in vivo. © 2013 International Union of Biochemistry and Molecular Biology.

Fibrinolytic Activity and Dose-Dependent Effect of Incubating Human Blood Clots in Caffeic Acid Phenethyl Ester: In Vitro Assays

PubMed Central

Elnager, Abuzar; Hassan, Rosline; Idris, Zamzuri; Mustafa, Zulkifli; Wan-Arfah, Nadiah; Sulaiman, S. A.; Gan, Siew Hua; Abdullah, Wan Zaidah

2015-01-01

Background. Caffeic acid phenethyl ester (CAPE) has been reported to possess time-dependent fibrinolytic activity by in vitro assay. This study is aimed at investigating fibrinolytic dose-dependent activity of CAPE using in vitro assays. Methods. Standardized human whole blood (WB) clots were incubated in either blank controls or different concentrations of CAPE (3.75, 7.50, 15.00, 22.50, and 30.00 mM). After 3 hours, D-dimer (DD) levels and WB clot weights were measured for each concentration. Thromboelastography (TEG) parameters were recorded following CAPE incubation, and fibrin morphology was examined under a confocal microscope. Results. Overall, mean DD (μg/mL) levels were significantly different across samples incubated with different CAPE concentrations, and the median pre- and postincubation WB clot weights (grams) were significantly decreased for each CAPE concentration. Fibrin removal was observed microscopically and indicated dose-dependent effects. Based on the TEG test, the Ly30 fibrinolytic parameter was significantly different between samples incubated with two different CAPE concentrations (15.0 and 22.50 mM). The 50% effective dose (ED50) of CAPE (based on DD) was 1.99 mg/mL. Conclusions. This study suggests that CAPE possesses fibrinolytic activity following in vitro incubation and that it has dose-dependent activities. Therefore, further investigation into CAPE as a potential alternative thrombolytic agent should be conducted. PMID:25664321

Efficacy and safety of tranexamic acid as an emetic in dogs.

PubMed

Kakiuchi, Hitoshi; Kawarai-Shimamura, Asako; Fujii, Yoko; Aoki, Takuma; Yoshiike, Masaki; Arai, Hayato; Nakamura, Atsushi; Orito, Kensuke

2014-12-01

To determine dose dependency of tranexamic acid-induced emesis and the time course of the antifibrinolytic potency of tranexamic acid in dogs. 10 Beagles. In a dose-escalating experiment, ascending doses of tranexamic acid (10, 20, and 30 mg/kg, IV) were administered at 5-minute intervals until vomiting was observed. In a separate single-dose experiment, ascending doses of tranexamic acid (20, 30, 40, and 50 mg/kg, IV) were administered at 1-week intervals until vomiting was observed. Time to onset of vomiting and number of vomiting episodes were measured in both experiments. In a coagulation experiment, a single 50 mg/kg bolus of tranexamic acid was administered, and blood was obtained 1 hour before and 20 minutes, 3 hours, and 24 hours after administration. Antifibrinolytic potency of tranexamic acid was evaluated by use of a modified rotational thromboelastography method. Tranexamic acid induced vomiting in a dose-dependent manner. Vomiting frequency was ≤ 2 episodes, and vomiting concluded ≤ 250 seconds after administration. Antifibrinolytic potency of tranexamic acid was significantly higher at 20 minutes following administration, but not different by 24 hours, when compared with the potency measured before administration. No adverse effects were observed in any experiment. IV administration of tranexamic acid induced emesis in a dose-dependent manner. The antifibrinolytic potency of tranexamic acid decreased in a time-dependent manner and was resolved ≤ 24 hours after administration. Further studies are warranted to investigate the emetic and other adverse effects of tranexamic acid in dogs of various breeds and ages.

Restoration of low-dose digital breast tomosynthesis

NASA Astrophysics Data System (ADS)

Borges, Lucas R.; Azzari, Lucio; Bakic, Predrag R.; Maidment, Andrew D. A.; Vieira, Marcelo A. C.; Foi, Alessandro

2018-06-01

In breast cancer screening, the radiation dose must be kept to the minimum necessary to achieve the desired diagnostic objective, thus minimizing risks associated with cancer induction. However, decreasing the radiation dose also degrades the image quality. In this work we restore digital breast tomosynthesis (DBT) projections acquired at low radiation doses with the goal of achieving a quality comparable to that obtained from current standard full-dose imaging protocols. A multiframe denoising algorithm was applied to low-dose projections, which are filtered jointly. Furthermore, a weighted average was used to inject a varying portion of the noisy signal back into the denoised one, in order to attain a signal-to-noise ratio comparable to that of standard full-dose projections. The entire restoration framework leverages a signal-dependent noise model with quantum gain which varies both upon the projection angle and on the pixel position. A clinical DBT system and a 3D anthropomorphic breast phantom were used to validate the proposed method, both on DBT projections and slices from the 3D reconstructed volume. The framework is shown to attain the standard full-dose image quality from data acquired at 50% lower radiation dose, whereas progressive loss of relevant details compromises the image quality if the dosage is further decreased.

Effects of Acute and Chronic Treatments with Dopamine D2 and D3 Receptor Ligands on Cocaine versus Food Choice in Rats.

PubMed

Thomsen, Morgane; Barrett, Andrew C; Butler, Paul; Negus, S Stevens; Caine, S Barak

2017-07-01

Dopamine D 3 receptor ligands are potential medications for psychostimulant addiction. Medication assessment may benefit from preclinical studies that evaluate chronic medication effects on choice between an abused drug and an alternative, nondrug reinforcer. This study compared acute and chronic effects of dopamine D 2 - and D 3 -preferring ligands on choice between intravenous cocaine and palatable food in rats. Under baseline conditions, cocaine maintained dose-dependent increases in cocaine choice and reciprocal decreases in food choice. Acutely, the D 2 agonist R -(-)-norpropylapomorphine (NPA) and antagonist L-741,626 [3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1 H -indole] produced leftward and rightward shifts in cocaine dose-effect curves, respectively, whereas the partial agonist terguride had no effect. All three drugs dose-dependently decreased food-maintained responding. Chronically, the effects of R -(-)-norpropylapomorphine and L-741,626 on cocaine self-administration showed marked tolerance, whereas suppression of food-reinforced behavior persisted. Acute effects of the D 3 ligands were less systematic and most consistent with nonselective decreases in cocaine- and food-maintained responding. Chronically, the D 3 agonist PF-592,379 [5-[(2 R ,5 S )-5-methyl-4-propylmorpholin-2-yl]pyridin-2-amine] increased cocaine choice, whereas an intermediate dose of the D 3 antagonist PG01037 [ N -[( E )-4-[4-(2,3-dichlorophenyl)piperazin-1-yl]but-2-enyl]-4-pyridin-2-ylbenzamide] produced a therapeutically desirable decrease in cocaine choice early in treatment; however, tolerance to this effect developed, and lower and higher doses were ineffective. D 3 ligands failed to significantly modify total cocaine intake but caused persistent decreases in food intake. Thus, D 2 -and D 3 -preferring ligands showed distinct profiles, consistent with different pharmacological actions. In addition, these results highlight the role of acute versus chronic treatment as a determinant of test drug effects. With the possible exception of the D 3 antagonist PG01037, no ligand was promising in terms of cocaine addiction treatment. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

PubMed

Arora, Shivani; Vohora, Divya

2016-08-01

As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated with alcohol withdrawal. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors.

PubMed

Hiranita, Takato; Soto, Paul L; Kohut, Stephen J; Kopajtic, Theresa; Cao, Jianjing; Newman, Amy H; Tanda, Gianluigi; Katz, Jonathan L

2011-11-01

Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of rimcazole analogs are due to dual actions at the DAT and σRs and that a combined target approach may have utility in development of medical treatments for cocaine abuse.

Radiation-Induced Carcinogenesis: Mechanistically Based Differences between Gamma-Rays and Neutrons, and Interactions with DMBA

PubMed Central

Shuryak, Igor; Brenner, David J.; Ullrich, Robert L.

2011-01-01

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis. PMID:22194850

The 5-HT(2C) receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.

PubMed

Harvey-Lewis, Colin; Li, Zhaoxia; Higgins, Guy A; Fletcher, Paul J

2016-02-01

Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dopamine and Stress System Modulation of Sex Differences in Decision Making.

PubMed

Georgiou, Polymnia; Zanos, Panos; Bhat, Shambhu; Tracy, J Kathleen; Merchenthaler, Istvan J; McCarthy, Margaret M; Gould, Todd D

2018-01-01

Maladaptive decision making is associated with several neuropsychiatric disorders, including problem gambling and suicidal behavior. The prevalence of these disorders is higher in men vs women, suggesting gender-dependent regulation of their pathophysiology underpinnings. We assessed sex differences in decision making using the rat version of the Iowa gambling task. Female rats identified the most optimal choice from session 1, whereas male rats from session 5. Male, but not female rats, progressively improved their advantageous option responding and surpassed females. Estrus cycle phase did not affect decision making. To test whether pharmacological manipulations targeting the dopaminergic and stress systems affect decision making in a sex-dependent manner, male and female rats received injections of a dopamine D 2 receptor (D 2 R) antagonist (eticlopride), D 2 R agonist (quinpirole), corticotropin-releasing factor 1 (CRF 1 ) antagonist (antalarmin), and α 2 -adrenergic receptor antagonist (yohimbine; used as a pharmacological stressor). Alterations in mRNA levels of D 2 R and CRF 1 were also assessed. Eticlopride decreased advantageous responding in male, but not female rats, whereas quinpirole decreased advantageous responding specifically in females. Yohimbine dose-dependently decreased advantageous responding in female rats, whereas decreased advantageous responding was only observed at higher doses in males. Antalarmin increased optimal choice responding only in female rats. Higher Drd2 and Crhr1 expression in the amygdala were observed in female vs male rats. Higher amygdalar Crhr1 expression was negatively correlated with advantageous responding specifically in females. This study demonstrates the relevance of dopaminergic- and stress-dependent sex differences to maladaptive decision making.

Tumor Necrosis Factor Antagonism Normalizes Rapid Eye Movement Sleep in Alcohol Dependence

PubMed Central

Irwin, Michael R.; Olmstead, Richard; Valladares, Edwin M.; Breen, Elizabeth Crabb; Ehlers, Cindy L.

2009-01-01

Background In alcohol dependence, markers of inflammation are associated with increases in rapid eye movement (REM) sleep, which is thought to be a prognostic indicator of alcohol relapse. This study was undertaken to test whether blockade of biologically active tumor necrosis factor-α (TNF-α) normalizes REM sleep in alcohol-dependent adults. Methods In a randomized, placebo-controlled, double-blind, crossover trial, 18 abstinent alcohol-dependent male adults received a single dose of etanercept (25 mg) versus placebo in a counterbalanced order. Polysomnographic sleep was measured at baseline and for 3 nights after the acute dose of etanercept or placebo. Results Compared with placebo, administration of etanercept produced significant decreases in the amount and percentage of REM sleep. Decreases in REM sleep were robust and approached low levels typically found in age-comparable control subjects. Individual differences in biologically active drug as indexed by circulating levels of soluble tumor necrosis factor receptor II negatively correlated with the percentage of REM sleep. Conclusions Pharmacologic neutralization of TNF-α activity is associated with significant reductions in REM sleep in abstinent alcohol-dependent patients. These data suggest that circulating levels of TNF-α may have a physiologic role in the regulation of REM sleep in humans. PMID:19185287

Effects of chromium picolinate on oxidative damage in primary piglet hepatocytes.

PubMed

Tan, Gao-Yi; Bi, Jin-Ming; Zhang, Min-Hong; Feng, Jing-Hai; Xie, Peng; Zheng, Shan-Shan

2008-12-01

Chromium picolinate is a popular nutritional supplement whose safety has been questioned because of the potential risk of oxidative DNA damage. To investigate this possibility, a dose-dependent study was performed in piglet hepatocyte cultures in which low (8 microM), medium (200 microM), and high (400 microM) doses of chromium picolinate were tested and compared to untreated controls. After 48 h incubation, there were no significant differences in the levels of intracellular reactive oxygen species, medium lactate dehydrogenase activity, and comet indicators between the three experimental groups and controls (p > 0.05). In the 8 microM-treated group, the intracellular malondialdehyde content was significantly decreased relative to controls (p < 0.05). All of the studied parameters showed a dose-dependent increase that was statistically significant between the low and high doses (p < 0.05). These results suggest that: (1) chromium picolinate may affect the oxidative status of piglet hepatocytes; (2) the appropriate dose (approximately physiological concentration) of chromium picolinate can inhibit lipid peroxidation, and (3) high doses of chromium picolinate have no significant effects on oxidative damage in piglet hepatocytes, but the existing evidence also imply that exposure to a higher dose appears to be unwarranted.

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

PubMed Central

Hillhouse, Todd M.; Porter, Joseph H.; Negus, S. Stevens

2014-01-01

Rationale The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern. Objectives This study examined abuse-related effects of keta-mine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison. Methods Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency–rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2–10.0 mg/kg) and MK-801 (0.032–0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2–20.0 mg/kg/day) and acute cocaine (10.0 mg/kg). Results Following acute administration, ketamine (3.2–10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032–0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS. Conclusions The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine. PMID:24522331

Evaluation of acute tacrine treatment on passive-avoidance response, open-field behavior, and toxicity in 17- and 30-day-old mice.

PubMed

Pan, S Y; Han, Y F; Yu, Z L; Yang, R; Dong, H; Ko, K M

2006-09-01

The potential of tacrine in altering cognitive/behavioral function as well as in causing toxicity was evaluated in mice of 17 and 30 days of age. Cognitive and behavioral studies were performed using a step-through passive avoidance task and a habituation open-field test with a 24-h retention interval. Tacrine was subcutaneously injected (1.25-80 micro mol/kg) 30 min prior to the first session of both tests. During the training session in step-through task, tacrine treatment dose-dependently decreased the number of footshocks, with IC(50) values being 7.8 and 23.3 micro mol/kg in 17- and 30-day-old mice, respectively. Treatment with tacrine at a low dose (5 micro mol/kg) significantly prolonged the retention latency in 17-day-old mice only, but it shortened the retention latency at high doses of 20 and 40 micro mol/kg in 17- and 30-day-old, respectively. During the acquisition session in the open-field test, tacrine treatment dose-dependently decreased the locomotor activity in 17- and 30-day-old mice, with IC(50) values being 15.1 and 24.7 micro mol/kg, respectively. High doses of tacrine invariably increased the locomotor activity during the recall session. Tacrine treatment at a dose of 40 micro mol/kg caused a significant increase in serum alanine aminotransferase activity in 17- and 30-day-old mice at 6 h post-dosing, with the extent of stimulation in 30-day-old mice being more prominent. In conclusion, tacrine was more potent in enhancing/disrupting the cognitive function, inhibiting locomotor activity as well as in causing hepatotoxicity in 17-day-old than in 30-day-old mice.

Effect of murine exposure to gamma rays on the interplay between Th1 and Th2 lymphocytes

PubMed Central

Ghazy, Amany A.; Abu El-Nazar, Salma Y.; Ghoneim, Hossam E.; Taha, Abdul-Rahman M.; Abouelella, Amira M.

2015-01-01

Gamma radiation radiotherapy is one of the widely used treatments for cancer. There is an accumulating evidence that adaptive immunity is significantly contributes to the efficacy of radiotherapy. This study is carried out to investigate the effect of gamma rays on the interplay between Th1/Th2 response, splenocyte lymphoproliferative response to polyclonal mitogenic activators and lymphocytic capacity to produce IL-12 and IL-10 in mice. Results showed that exposure of intact spleens to different doses of γ-rays (5, 10, 20 Gy) caused spontaneous and dose-dependent immune stimulation manifested by enhanced cell proliferation and elevated IL-12 production with decreased IL-10 release (i.e., Th1 bias). While exposure of splenocytes suspension to different doses of γ-rays (5, 10, 20 Gy) showed activation in splenocytes stimulated by PWM at 5 Gy then a state of conventional immune suppression that is characterized by being dose-dependent and is manifested by decreased cell proliferation and IL-12 release accompanied by increase in IL-10 production (i.e., Th2 bias). In addition, we investigated the exposure of whole murine bodies to different doses of γ-rays and found that the exposure to low dose γ-rays (0.2 Gy) caused a state of immune stimulation terminated by a remarkable tendency for immune suppression. Exposure to 5 or 10 Gy of γ-rays resulted in a state of immune stimulation (Th1 bias), but exposure to 20 Gy showed a standard state of immune suppression (Th2 bias). The results indicated that apparently we can control the immune response by controlling the dose of γ-rays. PMID:25914644

Dose-dependent consumption of farmed Atlantic salmon (Salmo salar) increases plasma phospholipid n-3 fatty acids differentially

PubMed Central

Raatz, Susan K.; Rosenberger, Thad A.; Johnson, LuAnn K.; Wolters, William W.; Burr, Gary S; Picklo, Matthew J.

2013-01-01

Enhanced omega-3 fatty acid (n-3) intake benefits cardiovascular disease (CVD) risk reduction. Increasing consumption at a population level may be better addressed by diet than through supplementation. However, limited data are available on the effect of the dose response to fish intake on plasma levels of n-3 fatty acids. To compare the effects of different doses of farmed Atlantic salmon on plasma phospholipid fatty acid (PLFA) proportions and CVD risk biomarkers (glucose, insulin, HOMAIR, hsCRP, and IL-6) in healthy subjects we performed a randomized 3-period cross-over designed trial (4 wk treatment, 4-8 wk washout) to compare the effects of twice/wk consumption of farmed Atlantic salmon at doses of 90, 180, and 270 g in 19 apparently healthy men and women with a mean age of aged 40-65 years and a BMI between 25-34.9 kg/m2. All study visits were conducted at the USDA, ARS Grand Forks Human Nutrition Research Center. EPA and total n-3 were increased (p<0.05) by all treatments in a dose response manner, with total n-3 of 8.03 ± 0.26 and 9.21 ± 0.26 % for 180 and 270 g doses, respectively. Linoleic acid did not change in response to treatment while arachidonic acid (P<0.05) and total omega-6 fatty acids (n-6) decreased dose dependently (<0.0001). The addition of farmed Atlantic salmon to the diet twice/wk for 4 wk at portions of 180g and 270g modifies PLFA proportions of n-3 and n-6 in a level associated with decreased risk for CVD. PMID:23351633

Status epilepticus induction has prolonged effects on the efficacy of antiepileptic drugs in the 6-Hz seizure model.

PubMed

Leclercq, Karine; Kaminski, Rafal M

2015-08-01

Several factors may influence the efficacy of antiepileptic drugs (AEDs) in patients with epilepsy, and treatment resistance could be related to genetics, neuronal network alterations, and modification of drug transporters or targets. Consequently, preclinical models used for the identification of potential new, more efficacious AEDs should reflect at least a few of these factors. Previous studies indicate that induction of status epilepticus (SE) may alter drug efficacy and that this effect could be long-lasting. In this context, we wanted to assess the protective effects of mechanistically diverse AEDs in mice subjected to pilocarpine-induced SE in another seizure model. We first determined seizure thresholds in mice subjected to pilocarpine-induced SE in the 6-Hz model, 2 weeks and 8 weeks following SE. We then evaluated the protective effects of mechanistically diverse AEDs in post-SE and control animals. No major differences in 6-Hz seizure susceptibility were observed between control groups, while the seizure threshold of pilocarpine mice at 8 weeks after SE was higher than at 2 weeks and higher than in control groups. Treatment with AEDs revealed major differences in drug response depending on their mechanism of action. Diazepam produced a dose-dependent protection against 6-Hz seizures in control and pilocarpine mice, both at 2 weeks and 8 weeks after SE, but with a more pronounced increase in potency in post-SE animals at 2 weeks. Levetiracetam induced a potent and dose-dependent protection in pilocarpine mice, 2 weeks after SE, while its protective effects were observed only at much higher doses in control mice. Its potency decreased in post-SE mice at 8 weeks and was very limited (30% protection at the highest tested dose) in the control group. Carbamazepine induced a dose-dependent protection at 2 weeks in control mice but only limited effect (50% at the highest tested dose) in pilocarpine mice. Its efficacy deeply decreased in post-SE mice at 8 weeks after SE. Perampanel and phenytoin showed almost comparable protective effects in all groups of mice. These experiments confirm that prior SE may have an impact on both potency and efficacy of AEDs and indicate that this effect may be dependent on the underlying epileptogenic processes. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.

Low‑dose radiation‑induced apoptosis in human leukemia K562 cells through mitochondrial pathways.

PubMed

Xin, Yong; Zhang, Hai-Bin; Tang, Tian-You; Liu, Gui-Hong; Wang, Jian-She; Jiang, Guan; Zhang, Long-Zhen

2014-09-01

High‑dose total body irradiation (TBI) has an established role as preparative regimen for bone‑marrow transplantation in the treatment of chronic myelogenous leukemia (CML), but this regimen still has a relatively high rate of acute and late toxicity. Low‑dose radiation (LDR) induces apoptosis of tumor cells and has numerous beneficial effects on normal tissues, including radiation homeostasis and adaptive response. Based on the previous evidence, in the present study, K562 cells were exposed to LDR, high‑dose radiation (HDR), and LDR in combination with HDR to investigate the possible mechanism of the apoptotic effect and hypersensitivity induced by LDR. The apoptotic rate increased in all radiation groups in a time‑dependent manner. An upregulation of Bax protein expression and a downregulation of Bcl‑xl in a dose‑dependent manner in human leukemia K562 cells was observed. However, the expression of p53 protein did not change in all of the radiation cell groups. The mitochondrial membrane potential (ΔΨm) in K562 cells decreased in all of the radiation cell groups in a dose‑dependent manner. Furthermore, the decrease of ΔΨm was enhanced in the LDR/HDR group compared with that in the LDR or HDR groups. The activity of caspase‑3 was enhanced in all of the radiation groups. In the LDR/HDR group, the activity of caspase‑3 was higher than that in the HDR or LDR groups. The present study provided preliminary experimental evidence of LDR being beneficial in combination with TBI in the treatment of CML.

Anti-diarrhoeal and anti-microbial activity of Flos populi (male inflorescence of Populus tomentosa Carrière) aqueous extracts.

PubMed

Xu, Qianqian; Shen, Zhiqiang; Wang, Yubo; Guo, Shijin; Li, Feng; Wang, Yanping; Zhou, Chunfeng

2013-07-09

Flos populi (male inflorescence of Populus tomentosa Carrière) has been traditionally used in East Asian countries for the treatment of various inflammatory diseases, strengthening the spleen and stomach, anti-rheumatic, anti-tumor and anti-diarrhoeal. To evaluate the in vivo or in vitro anti-diarrhoeal and anti-microbial activity of Flos populi aqueous extract. Acute toxicity of Flos populi aqueous extract (FPAE) was investigated. Castor oil-induced diarrhoea method was used to evaluate the anti-diarrhoeal activity, inhibition of defecation and diarrhoea were determined in mice, effects on castor oil-induced enteropooling, intestinal transit and intestinal fluid secretion in rats or mice. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of FPAE against strains of three clinical bacterial isolates and one reference strain were used to test the anti-microbial activity. The FPAE reduced the frequency of diarrhoea episodes and decreased the propulsion of charcoal meal through the gastrointestinal tract in a dose dependent manner. FPAE (100-500 mg/kg, p.o.) produced dose-dependent and significant (P<0.01) protection of mice against castor oil-induced diarrhoea. FPAE, dose-dependently and significantly (P< 0.01) delayed the onset of castor-oil induced diarrhoea, decreased the frequency of defecation, and reduced the severity of diarrhoea. Compared with control animals, FPAE, dose-dependently and significantly (P< 0.01) decreased the volume of castor oil-induced intestinal fluid secretion, and reduced the number, weight and wetness of faecal droppings. There was no deaths or abnormalities in behaviour seen in the acute toxicity test. The aqueous extract displayed anti-microbial effects to three species of bacteria in anti-microbial test. The findings of this study indicate that FPAE possesses anti-diarrhoeal property in rats and mice and confirm the ethnomedicinal use of Flos Populi as a valuable natural remedy for the treatment, management and/or control of diarrhoea. These results may support the fact that this plant is traditionally used to cure diarrhoea. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Warren, J.E.; Klaine, S.J.

The field cricket, Acheta domesticus, was used as a test organism to determine the effects of heavy metal exposure on cellular immunity. Insects were separated by sex and exposed to cadmium chloride or mercuric chloride at concentrations of 0, 2.5, and 5.0 ug/g. Exposures consisted of injecting the chemicals into the hemocoel of each insect on days 0, 2, and 4. Hemolymph was collected on day 7 of the study to determine total hemocyte counts, protein levels, and phenoloxidase activity in individual insects. Cadmium chloride decreased the total number of hemocytes in male crickets at 2.5 and 5.0 ug/g andmore » in female crickets at 5.0 ug/g. Protein levels increased in a dose dependent manner in the males but only slightly increased in the females. Mercuric chloride caused a dose-dependent increase in total hemocytes in both male and female crickets. In addition, mercuric chloride caused a dose-dependent increase in protein levels in males but not females.« less

The influence of different levels of micronized insoluble fiber on broiler performance and litter moisture.

PubMed

Rezaei, M; Karimi Torshizi, M A; Rouzbehan, Y

2011-09-01

The effects of different levels of micronized insoluble fiber (MIF) on broiler performance and litter moisture were assessed in 320 one-day-old male broilers (Ross 308). Feed was supplemented with 0, 0.3, 0.4, or 0.5% MIF during both the starter (1 to 14 d) and grower (15 to 42 d) periods. Supplementation of MIF was associated with dose dependent increases in daily BW gain and feed conversion ratio throughout the experimental period (P < 0.01), whereas feed intake was not influenced by MIF concentration. As MIF content increased, the relative weight of digestive organs was not changed (P > 0.05). Supplementation of MIF resulted in dose dependent increases in the ileal villus height:crypt depth ratio and number of goblet cells (P < 0.05), and a dose dependent decrease in litter moisture beginning during the third week (P < 0.01). These findings indicate that inclusion of 0.5% MIF in feed resulted in the greatest improvements in broiler performance, intestinal morphology, and litter moisture.

Geraniol attenuates α-synuclein expression and neuromuscular impairment through increase dopamine content in MPTP intoxicated mice by dose dependent manner.

PubMed

Rekha, Karamkolly R; Selvakumar, Govindasamy P; Santha, Karunanithi; Inmozhi Sivakamasundari, Ramu

2013-11-01

Parkinson's disease (PD) is characterized by progressive loss of dopamine (DA) neurons in the nigrostriatal system and by the presence of Lewy bodies (LB), proteinaceous inclusions mainly composed of filamentous α-synuclein (α-Syn) aggregates. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in C57BL/6 mice. In the present study, we investigated the effect of geraniol (GE) against α-Syn aggregation on MPTP induced mouse model of PD in dose dependant manner. When pretreatment of GE improved neuromuscular impairment, TH expressions and decreases α-Syn expressions in MPTP intoxicated PD mice by dose dependent manner. In addition, we confirmed that sub-chronic administration of MPTP in mice leads to permanent neuromuscular deficits and depletion of dopamine and its metabolites. Our results suggest that GE is beneficial for the treatment of PD associated with neuromuscular disability and LB aggregation. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Bias of phencyclidine discrimination by the schedule of reinforcement.

PubMed Central

McMillan, D E; Wenger, G R

1984-01-01

Pigeons, trained to discriminate phencyclidine from saline under a procedure requiring the bird to track the location of a color, received cumulative doses of phencyclidine, pentobarbital, or d-amphetamine with a variety of schedules of reinforcement in effect (across phases). When the same second-order schedules were used to reinforce responding after either saline or phencyclidine administration, stimulus control by phencyclidine did not depend on the schedule parameter. When different second-order schedules were used that biased responding toward the phencyclidine-correlated key color, pigeons responded on the phencyclidine-correlated key at lower doses of phencyclidine and pentobarbital than when the second-order schedule biased responding toward the saline key color. A similar but less marked effect was obtained with d-amphetamine. Attempts to produce bias by changing reinforcement magnitude (duration of food availability) were less successful. A signal-detection analysis of dose-effect curves for phencyclidine under two of the second-order schedules employed suggested that at low doses of phencyclidine, response bias is a major determinant of responding. As doses were increased, position preferences occurred and response bias decreased; at higher doses both response bias and position preference decreased and discriminability increased. With low doses of pentobarbital, responding again was biased but increasing doses produced position preference with only small increases in discriminability. At low doses of d-amphetamine responding also was biased, but bias did not decrease consistently with dose nor did discriminability increase. These experiments suggest that the schedule of reinforcement can be used to bias responding toward or away from making the drug-correlated response in drug discrimination experiments, and that signal-detection analysis and analysis of responding at a position can be used to separate the discriminability of the drug state from other effects of the drug on responding. PMID:6481300

Immunolocalization of Myostatin (GDF-8) Following Musculoskeletal Injury and the Effects of Exogenous Myostatin on Muscle and Bone Healing

PubMed Central

Elkasrawy, Moataz; Immel, David; Wen, Xuejun; Liu, Xiaoyan; Liang, Li-Fang

2012-01-01

The time course and cellular localization of myostatin expression following musculoskeletal injury are not well understood; therefore, the authors evaluated the temporal and spatial localization of myostatin during muscle and bone repair following deep penetrant injury in a mouse model. They then used hydrogel delivery of exogenous myostatin in the same injury model to determine the effects of myostatin exposure on muscle and bone healing. Results showed that a “pool” of intense myostatin staining was observed among injured skeletal muscle fibers 12–24 hr postsurgery and that myostatin was also expressed in the soft callus chondrocytes 4 days following osteotomy. Hydrogel delivery of 10 or 100 µg/ml recombinant myostatin decreased fracture callus cartilage area relative to total callus area in a dose-dependent manner by 41% and 80% (p<0.05), respectively, compared to vehicle treatment. Myostatin treatment also decreased fracture callus total bone volume by 30.6% and 38.8% (p<0.05), with the higher dose of recombinant myostatin yielding the greatest decrease in callus bone volume. Finally, exogenous myostatin treatment caused a significant dose-dependent increase in fibrous tissue formation in skeletal muscle. Together, these findings suggest that early pharmacological inhibition of myostatin is likely to improve the regenerative potential of both muscle and bone following deep penetrant musculoskeletal injury. PMID:22205678

The Pattern of Fatty Acids Displaced by EPA and DHA Following 12 Months Supplementation Varies between Blood Cell and Plasma Fractions.

PubMed

Walker, Celia G; West, Annette L; Browning, Lucy M; Madden, Jackie; Gambell, Joanna M; Jebb, Susan A; Calder, Philip C

2015-08-03

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0-4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n-6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%-64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology.

Immunolocalization of myostatin (GDF-8) following musculoskeletal injury and the effects of exogenous myostatin on muscle and bone healing.

PubMed

Elkasrawy, Moataz; Immel, David; Wen, Xuejun; Liu, Xiaoyan; Liang, Li-Fang; Hamrick, Mark W

2012-01-01

The time course and cellular localization of myostatin expression following musculoskeletal injury are not well understood; therefore, the authors evaluated the temporal and spatial localization of myostatin during muscle and bone repair following deep penetrant injury in a mouse model. They then used hydrogel delivery of exogenous myostatin in the same injury model to determine the effects of myostatin exposure on muscle and bone healing. Results showed that a "pool" of intense myostatin staining was observed among injured skeletal muscle fibers 12-24 hr postsurgery and that myostatin was also expressed in the soft callus chondrocytes 4 days following osteotomy. Hydrogel delivery of 10 or 100 µg/ml recombinant myostatin decreased fracture callus cartilage area relative to total callus area in a dose-dependent manner by 41% and 80% (p<0.05), respectively, compared to vehicle treatment. Myostatin treatment also decreased fracture callus total bone volume by 30.6% and 38.8% (p<0.05), with the higher dose of recombinant myostatin yielding the greatest decrease in callus bone volume. Finally, exogenous myostatin treatment caused a significant dose-dependent increase in fibrous tissue formation in skeletal muscle. Together, these findings suggest that early pharmacological inhibition of myostatin is likely to improve the regenerative potential of both muscle and bone following deep penetrant musculoskeletal injury. © The Author(s) 2012

The Pattern of Fatty Acids Displaced by EPA and DHA Following 12 Months Supplementation Varies between Blood Cell and Plasma Fractions

PubMed Central

Walker, Celia G.; West, Annette L.; Browning, Lucy M.; Madden, Jackie; Gambell, Joanna M.; Jebb, Susan A.; Calder, Philip C.

2015-01-01

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are increased in plasma lipids and blood cell membranes in response to supplementation. Whilst arachidonic acid (AA) is correspondingly decreased, the effect on other fatty acids (FA) is less well described and there may be site-specific differences. In response to 12 months EPA + DHA supplementation in doses equivalent to 0–4 portions of oily fish/week (1 portion: 3.27 g EPA+DHA) multinomial regression analysis was used to identify important FA changes for plasma phosphatidylcholine (PC), cholesteryl ester (CE) and triglyceride (TAG) and for blood mononuclear cells (MNC), red blood cells (RBC) and platelets (PLAT). Dose-dependent increases in EPA + DHA were matched by decreases in several n-6 polyunsaturated fatty acids (PUFA) in PC, CE, RBC and PLAT, but were predominantly compensated for by oleic acid in TAG. Changes were observed for all FA classes in MNC. Consequently the n-6:n-3 PUFA ratio was reduced in a dose-dependent manner in all pools after 12 months (37%–64% of placebo in the four portions group). We conclude that the profile of the FA decreased in exchange for the increase in EPA + DHA following supplementation differs by FA pool with implications for understanding the impact of n-3 PUFA on blood lipid and blood cell biology. PMID:26247960

GM1 ganglioside counteracts cholinergic and behavioral deficits induced in the rat by intracerebral injection of vincristine.

PubMed

Di Patre, P L; Abbamondi, A; Bartolini, L; Pepeu, G

1989-03-14

The intracerebroventricular injection of 0.5 mg of vincristine sulphate in adult male Wistar rats caused within 11 days the impairment of motor and reflexive behavior, evaluated by the elevated platform and hanging wire tests, a decrease in food consumption and loss of body weight, a 45% decrease in hippocampal choline acetyltransferase (ChAT) activity and a 35% decrease in the rate of high-affinity choline uptake (HACU) in the injected side. The latter effects are due to the death of neurons in the respective hemiseptum. Intrafimbrial injection of vincristine caused the same decrease in ChAT activity without behavioral alterations. Daily i.p. administration of GM1 ganglioside, beginning immediately after the vincristine injection, prevented dose dependently the decrease in ChAT activity and HACU rate. Prevention was complete with the 60 mg/kg dose. The same dose was equally active on ChAT activity when given s.c. but was inactive p.o. The ChAT decrease was also prevented when GM1 treatment began 5 days after vincristine. GM1 60 mg/kg i.p. also reduced the behavioral toxicity of vincristine. The possibility that GM1 might prevent vincristine toxicity by antagonizing its disruption of neurofilaments and axonal flow is discussed.

[Drug dependence test on a cerebral insufficiency improver, aniracetam].

PubMed

Kuwahara, A; Kubota, A; Hakkei, M; Nakamura, K

1987-01-01

Aniracetam, 1-p-anisoyl-2-pyrrolidinone, is known to be a nootropic or cognitive activator. Aniracetam protects against memory and learning deficits without causing effects on motor function and the autonomic nervous system. A drug dependence study on aniracetam utilizing the intragastric route of administration was performed in male cynomolgus monkeys. The behavioral observation test after acute administration revealed that aniracetam at the dose of 25-400 mg/kg did not change the gross behavior. In the self-administration initiation test, animals were exposed to two or three unit doses of aniracetam and references for a total available period of 7 weeks. Aniracetam at the dose of 25, 50 and 75 mg/kg/injection did not initiate self-administration in the respective group of 4, 4 and 2 animals. In the study with d-methamphetamine hydrochloride at the dose of 0.1 mg/kg/injection, 1 out of 4 animals started to consistently self-administer the drug. Self-administration of cocaine hydrochloride at the dose of 10 mg/kg/injection was confirmed in 3 out of 5 animals, and these 3 animals died from overdosing later. In the physical dependence direct induction test, animals received aniracetam (50 mg/kg) and sodium pentobarbital (25 mg/kg: the dose inducing intermediate CNS depression) intragastrically twice a day for 31 consecutive days. Abrupt withdrawal of aniracetam did not elicit abstinent signs (including changes in appetite and body weight) in all 6 animals, whereas withdrawal of pentobarbital produced typical abstinent behavioral signs and decreases in appetite and body weight. In conclusion, aniracetam was confirmed to develop neither physical dependence nor psychic dependence in cynomolgus monkeys.

Myeloid-Derived Suppressor Cells Ameliorate Cyclosporine A-Induced Hypertension in Mice.

PubMed

Chiasson, Valorie L; Bounds, Kelsey R; Chatterjee, Piyali; Manandhar, Lochana; Pakanati, Abhinandan R; Hernandez, Marcos; Aziz, Bilal; Mitchell, Brett M

2018-01-01

The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA. © 2017 American Heart Association, Inc.

Temperature dependency of the repair of sublethal damage in cultured fish cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitani, H.; Egami, N.

1984-01-01

Established culture fish cells, CAF-MMMI, derived form the goldfish, Carassium auratus, were able to grow and form colonies over a temperature range from 20 to 33/sup 0/ C. While the growth rate of these cells was dependent on incubation temperature, colony formation had no effect on cell survival after ..gamma.. irradiation at high dose rates. The lethal effect of ..gamma.. rays was decreased at low dose rates at 20-33/sup 0/ C, but not at 6/sup 0/ C. Similarly, split-dose experiments showed that recovery from sublethal damage occurred at the higher temperatures, but not at 6/sup 0/ C. These data aremore » consistent with the in vivo data on the effect of temperature on the radiosensitivity and repair of sublethal damage reported previously for live fish.« less

Clinical relevance of cannabis tolerance and dependence.

PubMed

Jones, R T; Benowitz, N L; Herning, R I

1981-01-01

Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis-induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug-seeking behavior has many determinants. Cannabis-induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.

The degree and nature of radiation damage in zircon observed by 29Si nuclear magnetic resonance

NASA Astrophysics Data System (ADS)

Farnan, I.; Salje, E. K. H.

2001-02-01

A quantitative analysis of 29Si nuclear magnetic resonance spectra of radiation damaged, natural zircons showed that the local structure in crystalline and amorphous regions depend explicitly on radiation dose. Nonpercolating amorphous islands of high density "glass" within the crystalline matrix show a low interconnectivity of SiO4 tetrahedra. This structural state is quite different from that of the high dose, percolating regions of low density glass with more polymerised tetrahedra. A continuous nonlinear dose dependence between the high and low density glass states is reported. A continuous evolution of the local structure of the crystalline phase up to the percolation point is also reported. No phase separation into binary oxides was observed. The total number of permanently displaced atoms per α-recoil event is ˜3800 atoms for low radiation doses and decreases to ˜2000 atoms for 10×1018 α events/g. No indication of partitioning of paramagnetic impurities between crystalline and amorphous regions was found for these natural zircons. The amorphous fractions of the metamict zircons were determined as a function of their accumulated radiation dose. These values coincide closely with those recently determined by x-ray diffraction studies. They are much greater than previously assumed based on density measurements. The dose dependence is consistent with the concept of direct impact amorphization in the atomic cascade following an α-recoil event.

Dose and dose rate effects of whole-body gamma-irradiation: II. Hematological variables and cytokines

NASA Technical Reports Server (NTRS)

Gridley, D. S.; Pecaut, M. J.; Miller, G. M.; Moyers, M. F.; Nelson, G. A.

2001-01-01

The goal of part II of this study was to evaluate the effects of gamma-radiation on circulating blood cells, functional characteristics of splenocytes, and cytokine expression after whole-body irradiation at varying total doses and at low- and high-dose-rates (LDR, HDR). Young adult C57BL/6 mice (n = 75) were irradiated with either 1 cGy/min or 80 cGy/min photons from a 60Co source to cumulative doses of 0.5, 1.5, and 3.0 Gy. The animals were euthanized at 4 days post-exposure for in vitro assays. Significant dose- (but not dose-rate-) dependent decreases were observed in erythrocyte and blood leukocyte counts, hemoglobin, hematocrit, lipopolysaccharide (LPS)-induced 3H-thymidine incorporation, and interleukin-2 (IL-2) secretion by activated spleen cells when compared to sham-irradiated controls (p < 0.05). Basal proliferation of leukocytes in the blood and spleen increased significantly with increasing dose (p < 0.05). Significant dose rate effects were observed only in thrombocyte counts. Plasma levels of transforming growth factor-beta 1 (TGF-beta 1) and splenocyte secretion of tumor necrosis factor-alpha (TNF-alpha) were not affected by either the dose or dose rate of radiation. The data demonstrate that the responses of blood and spleen were largely dependent upon the total dose of radiation employed and that an 80-fold difference in the dose rate was not a significant factor in the great majority of measurements.

Mitigation of paracetamol-induced reproductive damage by chrysin in male rats via reducing oxidative stress.

PubMed

Aksu, E H; Özkaraca, M; Kandemir, F M; Ömür, A D; Eldutar, E; Küçükler, S; Çomaklı, S

2016-12-01

Paracetamol (PRC) is a nonsteroidal anti-inflammatory drug used widely as a painkiller for various diseases and as the symptomatic flu cure in several countries worldwide. PRC toxicity may occur under conditions of the overdose usage. Chrysin (CR) is a flavonoid that is naturally present in several plants, honey and propolis. The aim of this study was to investigate the effects of CR (at the doses of 25 mg kg -1 and 50 mg kg -1 ) pre-treatment over seven consecutive days against PRC-induced reproductive toxicity in male rats. Our results showed that PRC toxicity decreased the sperm motility, and increased dead sperm rate, abnormal sperm cell rate, apoptosis and MDA levels in testicular tissues. Pre-treatment with CR at the dose of 25 and 50 mg kg -1 for 7 days mitigated side effects of acute PRC toxicity in male reproductive system proportionally in a dose-dependent manner. This possible protection mechanism might be dependent on the antioxidant activity of CR. In conclusion, pre-treatment with CR at the dose of 25 and 50 mg kg -1 for 7 days can be the beneficial against PRC-induced reproductive toxicity proportionally in a dose-dependent manner. © 2016 Blackwell Verlag GmbH.

RU486 did not exacerbate cytokine release in mice challenged with LPS nor in db/db mice

PubMed Central

Yang, Baichun; Trump, Ryan P; Shen, Ying; McNulty, Judi A; Clifton, Lisa G; Stimpson, Stephen A; Lin, Peiyuan; Pahel, Greg L

2008-01-01

Background Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFα levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice. Results Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFα in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFα and further increased serum corticosterone. Conclusion RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFα release, possibly due to the increased release of glucocorticoids. PMID:18474108

Human abuse liability assessment of oxycodone combined with ultra-low-dose naltrexone.

PubMed

Tompkins, David Andrew; Lanier, Ryan K; Harrison, Joseph A; Strain, Eric C; Bigelow, George E

2010-07-01

Prescription opioid abuse has risen dramatically in the United States as clinicians have increased opioid prescribing for alleviation of both acute and chronic pain. Opioid analgesics with decreased risk for abuse are needed. Preclinical and clinical studies have shown that opioids combined with ultra-low-dose naltrexone (NTX) may have increased analgesic potency and have suggested reduced abuse or dependence liability. This study addressed whether addition of ultra-low-dose naltrexone might decrease the abuse liability of oxycodone (OXY) in humans. This double-blind, placebo-controlled study systematically examined the subjective and physiological effects of combining oral OXY and ultra-low NTX doses in 14 experienced opioid abusers. Seven acute drug conditions given at least 5 days apart were compared in a within-subject crossover design: placebo, OXY 20 mg, OXY 40 mg, plus each of the active OXY doses combined with 0.0001 and 0.001 mg NTX. The methods were sensitive to detecting opioid effects on abuse liability indices, with significant differences between all OXY conditions and placebo as well as between 20 and 40 mg OXY doses on positive subjective ratings (e.g., "I feel a good drug effect" or "I like the drug"), on observer- and participant-rated opioid agonist effects, and on a drug-versus-money value rating. There were no significant differences or evident trends associated with the addition of either NTX dose on any abuse liability indices. The addition of ultra-low-dose NTX to OXY did not decrease abuse liability of acutely administered OXY in experienced opioid abusers.

Longitudinal Effects of Embryonic Exposure to Cocaine on Morphology, Cardiovascular Physiology, and Behavior in Zebrafish.

PubMed

Mersereau, Eric J; Boyle, Cody A; Poitra, Shelby; Espinoza, Ana; Seiler, Joclyn; Longie, Robert; Delvo, Lisa; Szarkowski, Megan; Maliske, Joshua; Chalmers, Sarah; Darland, Diane C; Darland, Tristan

2016-05-31

A sizeable portion of the societal drain from cocaine abuse results from the complications of in utero drug exposure. Because of challenges in using humans and mammalian model organisms as test subjects, much debate remains about the impact of in utero cocaine exposure. Zebrafish offer a number of advantages as a model in longitudinal toxicology studies and are quite sensitive physiologically and behaviorally to cocaine. In this study, we have used zebrafish to model the effects of embryonic pre-exposure to cocaine on development and on subsequent cardiovascular physiology and cocaine-induced conditioned place preference (CPP) in longitudinal adults. Larval fish showed a progressive decrease in telencephalic size with increased doses of cocaine. These treated larvae also showed a dose dependent response in heart rate that persisted 24 h after drug cessation. Embryonic cocaine exposure had little effect on overall health of longitudinal adults, but subtle changes in cardiovascular physiology were seen including decreased sensitivity to isoproterenol and increased sensitivity to cocaine. These longitudinal adult fish also showed an embryonic dose-dependent change in CPP behavior, suggesting an increased sensitivity. These studies clearly show that pre-exposure during embryonic development affects subsequent cocaine sensitivity in longitudinal adults.

Characterization of MOSFET dosimeters for low‐dose measurements in maxillofacial anthropomorphic phantoms

PubMed Central

Wolff, Jan E.; Kiljunen, Timo; Schulze, Dirk; Kortesniemi, Mika

2015-01-01

The aims of this study were to characterize reinforced metal‐oxide‐semiconductor field‐effect transistor (MOSFET) dosimeters to assess the measurement uncertainty, single exposure low‐dose limit with acceptable accuracy, and the number of exposures required to attain the corresponding limit of the thermoluminescent dosimeters (TLD). The second aim was to characterize MOSFET dosimeter sensitivities for two dental photon energy ranges, dose dependency, dose rate dependency, and accumulated dose dependency. A further aim was to compare the performance of MOSFETs with those of TLDs in an anthropomorphic phantom head using a dentomaxillofacial CBCT device. The uncertainty was assessed by exposing 20 MOSFETs and a Barracuda MPD reference dosimeter. The MOSFET dosimeter sensitivities were evaluated for two photon energy ranges (50–90 kVp) using a constant dose and polymethylmethacrylate backscatter material. MOSFET and TLD comparative point‐dose measurements were performed on an anthropomorphic phantom that was exposed with a clinical CBCT protocol. The MOSFET single exposure low dose limit (25% uncertainty, k=2) was 1.69 mGy. An averaging of eight MOSFET exposures was required to attain the corresponding TLD (0.3 mGy) low‐dose limit. The sensitivity was 3.09±0.13 mV/mGy independently of the photon energy used. The MOSFET dosimeters did not present dose or dose rate sensitivity but, however, presented a 1% decrease of sensitivity per 1000 mV for accumulated threshold voltages between 8300 mV and 17500 mV. The point doses in an anthropomorphic phantom ranged for MOSFETs between 0.24 mGy and 2.29 mGy and for TLDs between 0.25 and 2.09 mGy, respectively. The mean difference was −8%. The MOSFET dosimeters presented statistically insignificant energy dependency. By averaging multiple exposures, the MOSFET dosimeters can achieve a TLD‐comparable low‐dose limit and constitute a feasible method for diagnostic dosimetry using anthropomorphic phantoms. However, for single in vivo measurements (<1.7 mGy) the sensitivity is too low. PACS number: 87.50.wj PMID:26219008

Near infrared radio-luminescence of O{sub 2} loaded radiation hardened silica optical fibers: A candidate dosimeter for harsh environments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Di Francesca, D., E-mail: diego.di.francesca@univ-st-etienne.fr; Dipartimento di Fisica e Chimica, Università degli Studi di Palermo, I-90123 Palermo; Girard, S.

2014-11-03

We report on an experimental investigation of the infrared Radio-Luminescence (iRL) emission of interstitial O{sub 2} molecules loaded in radiation hardened pure-silica-core and fluorine-doped silica-based optical fibers (OFs). The O{sub 2} loading treatment successfully dissolved high concentrations of oxygen molecules into the silica matrix. A sharp luminescence at 1272 nm was detected when 2.5 cm of the treated OFs were irradiated with 10 keV X-rays. This emission originates from the radiative decay of the first excited singlet state of the embedded O{sub 2} molecules. The dose, dose-rate, and temperature dependencies of the infrared emission are studied through in situ optical measurements. The resultsmore » show that the iRL is quite stable in doses of up to 1 MGy(SiO{sub 2}) and is linearly dependent on the dose-rate up to the maximum investigated dose-rate of ∼200 kGy(SiO{sub 2})/h. The temperature dependency of the iRL shows a decrease in efficiency above 200 °C, which is attributed to the non-radiative decay of the excited O{sub 2} molecules. The results obtained and the long-term stability of the O{sub 2}-loading treatment (no out-gassing effect) strongly suggest the applicability of these components to real-time remote dosimetry in environments characterized by high radiation doses and dose-rates.« less

Dose-dependent cytotoxicity evaluation of graphite nanoparticles for diamond-like carbon film application on artificial joints.

PubMed

Liao, T T; Deng, Q Y; Wu, B J; Li, S S; Li, X; Wu, J; Leng, Y X; Guo, Y B; Huang, N

2017-01-24

While a diamond-like carbon (DLC)-coated joint prosthesis represents the implant of choice for total hip replacement in patients, it also leads to concern due to the cytotoxicity of wear debris in the form of graphite nanoparticles (GNs), ultimately limiting its clinical use. In this study, the cytotoxicity of various GN doses was evaluated. Mouse macrophages and osteoblasts were incubated with GNs (<30 nm diameter), followed by evaluation of cytotoxicity by means of assessing inflammatory cytokines, results of alkaline phosphatase assays, and related signaling protein expression. Cytotoxicity evaluation showed that cell viability decreased in a dose-dependent manner (10-100 μg ml -1 ), and steeply declined at GNs concentrations greater than 30 μg ml -1 . Noticeable cytotoxicity was observed as the GN dose exceeded this threshold due to upregulated receptor of activator of nuclear factor kB-ligand expression and downregulated osteoprotegerin expression. Meanwhile, activated macrophage morphology was observed as a result of the intense inflammatory response caused by the high doses of GNs (>30 μg ml -1 ), as observed by the increased release of TNF-α and IL-6. The results suggest that GNs had a significant dose-dependent cytotoxicity in vitro, with a lethal dose of 30 μg ml -1 leading to dramatic increases in cytotoxicity. Our GN cytotoxicity evaluation indicates a safe level for wear debris-related arthropathy and could propel the clinical application of DLC-coated total hip prostheses.

Effect of sodium ascorbate dose on the shelf life stability of reduced nitrite liver pâtés.

PubMed

Vossen, Els; Doolaege, Evelyne H A; Moges, Haile Demewez; De Meulenaer, Bruno; Szczepaniak, Slawomir; Raes, Katleen; De Smet, Stefaan

2012-05-01

The effect of sodium ascorbate (SA; 500, 750, 1000 mg/kg) and sodium nitrite (SN; 40, 80, 120 mg/kg) doses on the shelf-life stability of liver pâtés was investigated in a full factorial design. Clear dose-dependent responses of the added SN or SA were found for the concentrations of nitrite, ascorbic acid and dehydroascorbic acid in the raw batters and in the cooked pâtés before and after 48 h of chilled display. Decreasing the SN dose to 80 mg/kg had no negative impact on the colour stability (a* value) and lipid oxidation (TBARS), and no additional antioxidant effect of SA was noticed. Lowering SN to 40 mg/kg resulted in proper colour formation, but the colour stability was inferior and lipid oxidation increased. Yet, increasing the amount of SA, at this low SN dose, resulted in lower TBARS values. Decreasing the SN dose to 80 or 40 mg/kg had no distinct effect on protein oxidation, which was however only measured by carbonyl content. Copyright © 2011 Elsevier Ltd. All rights reserved.

Performance of Al2O3:C optically stimulated luminescence dosimeters for clinical radiation therapy applications.

PubMed

Hu, B; Wang, Y; Zealey, W

2009-12-01

A commercial Optical Stimulated Luminescence (OSL) dosimetry system developed by Landauer was tested to analyse the possibility of using OSL dosimetry for external beam radiotherapy planning checks. Experiments were performed to determine signal sensitivity, dose response range, beam type/energy dependency, reproducibility and linearity. Optical annealing processes to test OSL material reusability were also studied. In each case the measurements were converted into absorbed dose. The experimental results show that OSL dosimetry provides a wide dose response range, good linearity and reproducibility for the doses up to 800cGy. The OSL output is linear with dose up to 600cGy range showing a maximum deviation from linearity of 2.0% for the doses above 600cGy. The standard deviation in response of 20 dosimeters was 3.0%. After optical annealing using incandescent light, the readout intensity decreased by approximately 98% in the first 30 minutes. The readout intensity, I, decreased after repeated optical annealing as a power law, given by I infinity t (-1.3). This study concludes that OSL dosimetry can provide an alternative dosimetry technique for use in in-vivo dosimetry if rigorous measurement protocols are established.

A highly infective plant-associated bacterium influences reproductive rates in pea aphids

PubMed Central

Hendry, Tory A.; Clark, Kelley J.; Baltrus, David A.

2016-01-01

Pea aphids, Acyrthosiphon pisum, have the potential to increase reproduction as a defence against pathogens, though how frequently this occurs or how infection with live pathogens influences this response is not well understood. Here we determine the minimum infective dose of an environmentally common bacterium and possible aphid pathogen, Pseudomonas syringae, to determine the likelihood of pathogenic effects to pea aphids. Additionally, we used P. syringae infection to investigate how live pathogens may alter reproductive rates. We found that oral bacterial exposure decreased subsequent survival of aphids in a dose-dependent manner and we estimate that ingestion of less than 10 bacterial cells is sufficient to increase aphid mortality. Pathogen dose was positively related to aphid reproduction. Aphids exposed to low bacterial doses showed decreased, although statistically indistinguishable, fecundity compared to controls. Aphids exposed to high doses reproduced significantly more than low dose treatments and also more, but not significantly so, than controls. These results are consistent with previous studies suggesting that pea aphids may use fecundity compensation as a response to pathogens. Consequently, even low levels of exposure to a common plant-associated bacterium may therefore have significant effects on pea aphid survival and reproduction. PMID:26998321

A highly infective plant-associated bacterium influences reproductive rates in pea aphids.

PubMed

Hendry, Tory A; Clark, Kelley J; Baltrus, David A

2016-02-01

Pea aphids, Acyrthosiphon pisum, have the potential to increase reproduction as a defence against pathogens, though how frequently this occurs or how infection with live pathogens influences this response is not well understood. Here we determine the minimum infective dose of an environmentally common bacterium and possible aphid pathogen, Pseudomonas syringae, to determine the likelihood of pathogenic effects to pea aphids. Additionally, we used P. syringae infection to investigate how live pathogens may alter reproductive rates. We found that oral bacterial exposure decreased subsequent survival of aphids in a dose-dependent manner and we estimate that ingestion of less than 10 bacterial cells is sufficient to increase aphid mortality. Pathogen dose was positively related to aphid reproduction. Aphids exposed to low bacterial doses showed decreased, although statistically indistinguishable, fecundity compared to controls. Aphids exposed to high doses reproduced significantly more than low dose treatments and also more, but not significantly so, than controls. These results are consistent with previous studies suggesting that pea aphids may use fecundity compensation as a response to pathogens. Consequently, even low levels of exposure to a common plant-associated bacterium may therefore have significant effects on pea aphid survival and reproduction.

Determination of the uncertainties in radiation doses from ingestion of strontium-90

NASA Astrophysics Data System (ADS)

Apostoaei, Andrei Iulian

Quantification of the uncertainties in the internal dosimetry is important because it can impact the outcome of dose reconstruction, risk assessment or epidemiological studies. This research focused on determination of the uncertainties in the dose factors from a single ingestion of 90Sr by adults, and analyzed the changes with age and the effect of gender. The uncertainties in the estimated dose factors are a factor of 6 for the bone surface, 5 for the red bone marrow, 2.5 for bladder and stomach, 2.2 for the small intestine, 2.1 for the upper large intestine and 2.7 for the lower large intestine. For the rest of the organs the uncertainty is a factor of 3. Only four parameters of the biokinetic model showed an age-dependency within the adult age group: the fractional transfers of strontium from plasma to cortical and trabecular bone, and the removal rates from the cortical and trabecular bone, respectively. When age-dependent biokinetic parameters were used, the estimated dose-factors are very close to the dose factors obtained using age-independent kinetics (within 40%). Thus, the dose factors based on age-independent parameters should suffice for most practical purposes. The dose factors and the associated uncertainties were also calculated as a function of age-at-exposure and attained age. These age dependent curves can be used for estimating doses from continuous intakes, or doses delivered over a limited portion of time. In addition to the committed dose, an expected dose is also estimated in this work. The expected dose is calculated using the dose rate weighted by the probability of surviving up to the age when the dose-rate is delivered. For exposure at young ages the expected dose and the committed dose are similar, but the committed dose decreases to zero when exposure occurs close to age 70, while the expected dose has elevated values pass age 70. No gender differences were found for bone surface, for red bone marrow, and the large intestine. The doses to the soft tissues for females are larger by 20% than the doses for males, because of the differences in the whole-body mass between males and females.

Cell kill by megavoltage protons with high LET.

PubMed

Kuperman, Vadim Y

2016-07-21

The aim of the current study is to develop a radiobiological model which describes the effect of linear energy transfer (LET) on cell survival and relative biological effectiveness (RBE) of megavoltage protons. By assuming the existence of critical sites within a cell, analytical expression for cell survival S as a function of LET is derived. The obtained results indicate that in cases where dose per fraction is small, [Formula: see text] is a linear-quadratic (LQ) function of dose while both alpha and beta radio-sensitivities are non-linearly dependent on LET. In particular, in the current model alpha increases with increasing LET while beta decreases. Conversely, in the case of large dose per fraction, the LQ dependence of [Formula: see text] on dose is invalid. The proposed radiobiological model predicts cell survival probability and RBE which, in general, deviate from the results obtained by using conventional LQ formalism. The differences between the LQ model and that described in the current study are reflected in the calculated RBE of protons.

Intra-oral administration of rebamipide liquid prevents tongue injuries induced by X-ray irradiation in rats.

PubMed

Nakashima, Takako; Uematsu, Naoya; Sakurai, Kazushi

2017-07-01

Oral mucositis is a common and serious side effect in patients who undergo cytotoxic cancer therapies. The purpose of this study was to investigate the preventive effects of rebamipide on radiation-induced glossitis model in rats. Glossitis was induced by a single dose of 15 Gy of X-rays to the snouts of rats (day 0). A novel form of rebamipide liquid comprising its submicronized crystals was administered intra-orally. The preventive effect of rebamipide on tongue injuries was macroscopically evaluated on day 7 following irradiation. The pretreatment period, dosing frequency, and dose dependency of rebamipide were examined. Two percent rebamipide liquid, administered six times a day for 14 days from day -7 to day 6, significantly decreased the ulcer-like area. However, no significant effect was observed when rebamipide was given either from day -4 or from day -1. Four or six times daily, 2% rebamipide liquid significantly inhibited the ulcer-like injury area ratio, but not when given twice daily. Rebamipide liquid, 1, 2, and 4% six times daily significantly reduced the area ratios of total injury and ulcer-like injury in a dose-dependent manner. Gene expression and protein levels of proinflammatory cytokines and chemokines were dramatically elevated in the irradiated tongues of control rats on day 7 without rebamipide liquid treatment. They were dose-dependently and significantly suppressed in rebamipide-treated groups. Intra-oral administration of rebamipide liquid prevented oral mucositis dose-dependently accompanied by the suppression of inflammatory expression in the radiation-induced rats' glossitis model.

Yohimbine Increases Opioid-Seeking Behavior in Heroin-Dependent, Buprenorphine-Maintained Individuals

PubMed Central

Greenwald, Mark K.; Lundahl, Leslie H.; Steinmiller, Caren L.

2012-01-01

Rationale In laboratory animals, the biological stressor yohimbine (α2-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking. Objectives This clinical study tested whether yohimbine increases opioid seeking behavior. Methods Ten heroin-dependent, buprenorphine (8-mg/day) stabilized volunteers, sampled two doses of hydromorphone (12 and 24 mg IM in counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). During each of six later sessions (within-subject, double blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (Drug A or B) vs. money ($2) following different oral yohimbine pretreatment doses (0, 16.2 and 32.4 mg). Results Behavioral economic demand intensity and peak responding (Omax) were significantly higher for hydromorphone 2-mg than 1-mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (Pmax = 909, 3647 and 3225 for placebo, 16.2 and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (Pmax = 2656, 3193 and 3615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic ≈15 and diastolic ≈10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood. Conclusions These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose. PMID:23161001

Nine and Ten chemical haloacetic acid mixtures exhibit concentration-dependent departure from dose additivity

EPA Science Inventory

Disinfection of water greatly decreases waterborne disease. Disinfection byproducts (DBPs), including haloacetic acids (HAAs), are formed when oxidizing disinfectants react with inorganic and organic matter in water. Water providers routinely assay for 9 HAAs in finished drinking...

Effect of Addition of Natural Antioxidants on the Shelf-Life of “Chorizo”, a Spanish Dry-Cured Sausage

PubMed Central

Pateiro, Mirian; Bermúdez, Roberto; Lorenzo, José Manuel; Franco, Daniel

2015-01-01

The dose effect of the addition of natural antioxidants (tea, chestnut, grape seed and beer extracts) on physicochemical, microbiological changes and on oxidative stability of dry-cured “chorizo”, as well as their effect during the storage under vacuum conditions was evaluated. Color parameters were significantly (p < 0.05) affected by the addition of antioxidants so that samples that contained antioxidants were more effective in maintaining color. The improving effects were dose-dependent with highest values with the dose of 50 mg/kg during ripening and depend on the extract during vacuum packaging. Addition of antioxidants decreased (p < 0.05) the oxidation, showing thiobarbituric acid reactive substances (TBARS) values below 0.4 mg MDA/kg. Natural antioxidants matched or even improved the results obtained for butylated hydroxytoluene (BHT). Regarding texture profile analysis (TPA) analysis, hardness values significantly (p < 0.001) decreased with the addition of antioxidants, obtaining the lower results with the dose of 200 mg/kg both during ripening and vacuum packaging. Antioxidants reduced the counts of total viable counts (TVC), lactic acid bacteria (LAB), mold and yeast. Free fatty acid content during ripening and under vacuum conditions showed a gradual and significant (p < 0.05) release as a result of lipolysis. At the end of ripening, the addition of GRA1000 protected chorizos from oxidative degradation. PMID:26785337

The effect of different bleaching wavelengths on the sensitivity of Al{sub 2}O{sub 3}:C optically stimulated luminescence detectors (OSLDs) exposed to 6 MV photon beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Omotayo, Azeez A.; Cygler, Joanna E.; Sawakuchi, Gabriel O.

2012-09-15

Purpose: To determine the effect of different bleaching wavelengths on the response of Al{sub 2}O{sub 3}:C optically stimulated luminescence detectors (OSLDs) exposed to accumulated doses of 6 MV photon beams. Methods: In this study the authors used nanoDot OSLDs readout with a MicroStar reader. The authors first characterized the dose-response, fading, and OSL signal loss of OSLDs exposed to doses from 0.5 to 10 Gy. To determine the effect of different bleaching wavelengths on the OSLDs' response, the authors optically treated the OSLDs with 26 W fluorescent lamps in two modes: (i) directly under the lamps for 10, 120, andmore » 600 min and (ii) with a long-pass filter for 55, 600, and 2000 min. Changes in the OSLDs' sensitivity were determined for an irradiation-readout-bleaching-readout cycle after irradiations with 1 and 10 Gy dose fractions. Results: The OSLDs presented supralinearity for doses of 2 Gy and above. The signal loss rates for sequential readouts were (0.287 {+-} 0.007)% per readout in the reader's strong-stimulation mode, and (0.019 {+-} 0.002)% and (0.035 {+-} 0.007)% per readout for doses of 0.2 and 10 Gy, respectively, in the reader's weak-stimulation mode. Fading half-life values ranged from (0.98 {+-} 0.14) min to (1.77 {+-} 0.24) min and fading showed dose dependence for the first 10-min interval. For 10 and 55 min bleaching using modes (i) and (ii), the OSL signal increased 14% for an accumulated dose of 7 Gy (1 Gy fractions). For OSLDs exposed to 10 Gy fractions, the OSL signal increased 30% and 25% for bleaching modes (i) and (ii) and accumulated dose of 70 Gy, respectively. For 120 and 600 min bleaching using modes (i) and (ii), the OSL signal increased 2.7% and 1.5% for an accumulated dose of 7 Gy (1 Gy fractions), respectively. For 10 Gy fractions, the signal increased 14% for bleaching mode (i) (120 min bleaching) and decreased 1.3% for bleaching mode (ii) (600 min bleaching) for an accumulated dose of 70 Gy. For 600 and 2000 min bleaching using modes (i) and (ii), the signal increased 2.3% and 1.8% for an accumulated dose of 7 Gy (1 Gy fractions), respectively. For 10 Gy fractions, the signal increased 10% for mode (i) (600 min bleaching) and decreased 2.5% for mode (ii) (2000 min bleaching) for an accumulated dose of 70 Gy. Conclusions: The dose-response of nanoDot OSLDs read using the MicroStar reader presented supralinearity for doses of 2 Gy and above. The signal loss as a function of sequential readouts depended on dose. Fading also depended on dose for the first 10-min interval. For dose fractions of 1 and 10 Gy, OSLDs may be reused within 3% and 5% accuracies up to the maximum accumulated dose of 7 and 70 Gy investigated in this study, respectively. These accuracies were obtained after the OSLDs were bleached with a light source with wavelengths above about 495 nm. The authors also concluded that changes in sensitivity of OSLDs depended on bleaching time, accumulated dose, and wavelength spectrum of the bleaching source.« less

Emulsification Increases the Acute Ketogenic Effect and Bioavailability of Medium-Chain Triglycerides in Humans

PubMed Central

Courchesne-Loyer, Alexandre; Lowry, Carolyn-Mary; St-Pierre, Valérie; Vandenberghe, Camille; Fortier, Mélanie; Castellano, Christian-Alexandre; Wagner, J Richard; Cunnane, Stephen C

2017-01-01

Abstract Background: Lower-brain glucose uptake is commonly present before the onset of cognitive deterioration associated with aging and may increase the risk of Alzheimer disease. Ketones are the brain's main alternative energy substrate to glucose. Medium-chain triglycerides (MCTs) are rapidly β-oxidized and are ketogenic but also have gastrointestinal side effects. We assessed whether MCT emulsification into a lactose-free skim-milk matrix [emulsified MCTs (MCT-Es)] would improve ketogenesis, reduce side effects, or both compared with the same oral dose of MCTs consumed without emulsification [nonemulsified MCTs (MCT-NEs)]. Objectives: Our aims were to show that, in healthy adults, MCT-Es will induce higher ketonemia and have fewer side effects than MCT-NEs and the effects of MCT-NEs and MCT-Es on ketogenesis and plasma medium-chain fatty acids (MCFAs) will be dose-dependent. Methods: Using a metabolic study day protocol, 10 healthy adults were each given 3 separate doses (10, 20, or 30 g) of MCT-NEs or MCT-Es with a standard breakfast or no treatment [control (CTL)]. Blood samples were taken every 30 min for 4 h to measure plasma ketones (β-hydroxybutyrate and acetoacetate), octanoate, decanoate, and other metabolites. Participants completed a side-effects questionnaire at the end of each study day. Results: Compared with CTL, MCT-NEs increased ketogenesis by 2-fold with no significant differences between doses. MCT-Es increased total plasma ketones by 2- to 4-fold in a dose-dependent manner. Compared with MCT-NEs, MCT-Es increased plasma MCFA bioavailability (F) by 2- to 3-fold and decreased the number of side effects by ∼50%. Conclusions: Emulsification increased the ketogenic effect and decreased side effects in a dose-dependent manner for single doses of MCTs ≤30 g under matching conditions. Further investigation is needed to establish whether emulsification could sustain ketogenesis and minimize side effects and therefore be used as a treatment to change brain ketone availability over a prolonged period of time. This trial was registered at clinicaltrials.gov as NCT02409927.

N-acetylcysteine inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes.

PubMed

Araki, Shunsuke; Dobashi, Kazushige; Kubo, Kazuyasu; Kawagoe, Rinko; Yamamoto, Yukiyo; Shirahata, Akira

2007-12-01

The present study was designed to determine whether N-acetylcysteine (NAC), a potent antioxidant, modulates nitric oxide (NO) production stimulated by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) in adipocytes. Stimulation by the combination of 5 microg/ml of LPS and 100 ng/ml of TNF-alpha (LT) significantly enhanced NO production in 3T3-L1 adipocytes. Preincubation of the cells with NAC (5-20 mM) for 24 h suppressed the increased NO production in a dose-dependent manner. The production of NO was decreased by 49% at the concentration of 20 mM of NAC. The decrease in NO production by NAC was accompanied by a decrease in inducible nitric oxide synthase (iNOS) protein, detected by immunoblot analysis, and iNOS mRNA, determined by real-time reverse-transcriptase coupled polymerase chain reaction analysis. Nuclear factor-kappa B (NF-kappa B) was significantly activated by LT-treatment, while the pretreatment with 20 mM of NAC prevented the activity by 42%. Pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, also inhibited the LT-mediated NO production dose-dependently. One hundred microM of PDTC inhibited the NO production by 46%. We also investigated the effect of NAC and PDTC on the production of interleukein-6 (IL-6), which is regulated transcriptionally by NF-kappa B in 3T3-L1 adipocytes. IL-6 production was markedly increased by LT stimulus, and the enhanced secretion of IL-6 was suppressed in a dose-dependent manner by pretreatment with NAC or PDTC. These results suggest that NAC regulates iNOS expression and NO production in adipocytes through the modulating activation of NF-kappa B.

Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

NASA Astrophysics Data System (ADS)

Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, Start A.; Toloczko, Mychailo B.

2014-01-01

The temperature dependence of fracture toughness in HT9 steel irradiated to 3-145 dpa at 380-503 °C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm × 3 mm × 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than the irradiation dose. At an irradiation temperature <430 °C, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180-200 MPa √{m} at 350-450 °C, and then decreased with the test temperature. At an irradiation temperature ⩾430 °C, the fracture toughness was nearly unchanged up to about 450 °C and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.

Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, S

2014-01-01

The temperature dependence of fracture toughness in HT9 steel irradiated to 3 145 dpa at 380 503 C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm 3mm 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperaturemore » than the irradiation dose. At an irradiation temperature <430 C, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180 200 MPa ffiffiffiffiffi m p at 350 450 C, and then decreased with the test temperature. At an irradiation temperatureP430 C, the fracture toughness was nearly unchanged up to about 450 C and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.« less

Dose- and time-dependence of the host-mediated response to paclitaxel therapy: a mathematical modeling approach.

PubMed

Benguigui, Madeleine; Alishekevitz, Dror; Timaner, Michael; Shechter, Dvir; Raviv, Ziv; Benzekry, Sebastien; Shaked, Yuval

2018-01-05

It has recently been suggested that pro-tumorigenic host-mediated processes induced in response to chemotherapy counteract the anti-tumor activity of therapy, and thereby decrease net therapeutic outcome. Here we use experimental data to formulate a mathematical model describing the host response to different doses of paclitaxel (PTX) chemotherapy as well as the duration of the response. Three previously described host-mediated effects are used as readouts for the host response to therapy. These include the levels of circulating endothelial progenitor cells in peripheral blood and the effect of plasma derived from PTX-treated mice on migratory and invasive properties of tumor cells in vitro . A first set of mathematical models, based on basic principles of pharmacokinetics/pharmacodynamics, did not appropriately describe the dose-dependence and duration of the host response regarding the effects on invasion. We therefore provide an alternative mathematical model with a dose-dependent threshold, instead of a concentration-dependent one, that describes better the data. This model is integrated into a global model defining all three host-mediated effects. It not only precisely describes the data, but also correctly predicts host-mediated effects at different doses as well as the duration of the host response. This mathematical model may serve as a tool to predict the host response to chemotherapy in cancer patients, and therefore may be used to design chemotherapy regimens with improved therapeutic outcome by minimizing host mediated effects.

Beam energy considerations for gold nano-particle enhanced radiation treatment.

PubMed

Van den Heuvel, F; Locquet, Jean-Pierre; Nuyts, S

2010-08-21

A novel approach using nano-technology enhanced radiation modalities is investigated. The proposed methodology uses antibodies labeled with organically inert metals with a high atomic number. Irradiation using photons with energies in the kilo-electron volt (keV) range shows an increase in dose due to a combination of an increase in photo-electric interactions and a pronounced generation of Auger and/or Coster-Krönig (A-CK) electrons. The dependence of the dose deposition on various factors is investigated using Monte Carlo simulation models. The factors investigated include agent concentration, spectral dependence looking at mono-energetic sources as well as classical bremsstrahlung sources. The optimization of the energy spectrum is performed in terms of physical dose enhancement as well as the dose deposited by Auger and/or Coster-Krönig electrons and their biological effectiveness. A quasi-linear dependence on concentration and an exponential decrease within the target medium is observed. The maximal dose enhancement is dependent on the position of the target in the beam. Apart from irradiation with low-photon energies (10-20 keV) there is no added benefit from the increase in generation of Auger electrons. Interestingly, a regular 110 kVp bremsstrahlung spectrum shows a comparable enhancement in comparison with the optimized mono-energetic sources. In conclusion we find that the use of enhanced nano-particles shows promise to be implemented quite easily in regular clinics on a physical level due to the advantageous properties in classical beams.

Beam energy considerations for gold nano-particle enhanced radiation treatment

NASA Astrophysics Data System (ADS)

Van den Heuvel, F.; Locquet, Jean-Pierre; Nuyts, S.

2010-08-01

A novel approach using nano-technology enhanced radiation modalities is investigated. The proposed methodology uses antibodies labeled with organically inert metals with a high atomic number. Irradiation using photons with energies in the kilo-electron volt (keV) range shows an increase in dose due to a combination of an increase in photo-electric interactions and a pronounced generation of Auger and/or Coster-Krönig (A-CK) electrons. The dependence of the dose deposition on various factors is investigated using Monte Carlo simulation models. The factors investigated include agent concentration, spectral dependence looking at mono-energetic sources as well as classical bremsstrahlung sources. The optimization of the energy spectrum is performed in terms of physical dose enhancement as well as the dose deposited by Auger and/or Coster-Krönig electrons and their biological effectiveness. A quasi-linear dependence on concentration and an exponential decrease within the target medium is observed. The maximal dose enhancement is dependent on the position of the target in the beam. Apart from irradiation with low-photon energies (10-20 keV) there is no added benefit from the increase in generation of Auger electrons. Interestingly, a regular 110 kVp bremsstrahlung spectrum shows a comparable enhancement in comparison with the optimized mono-energetic sources. In conclusion we find that the use of enhanced nano-particles shows promise to be implemented quite easily in regular clinics on a physical level due to the advantageous properties in classical beams.

Comparative effects of Rauwolfia vomitoria and chlorpromazine on locomotor behaviour and anxiety in mice.

PubMed

Bisong, Sunday Agba; Brown, Richard; Osim, Eme Effiom

2010-10-28

Since remedies for mental disorders have been sought through both orthodox and traditional medicine this study compared the effects of the antipsychotic, chlorpromazine (Cpz), the herb Rauwolfia vomitoria (RV) and its alkaloid reserpine (Res) in mice. Ninety male CD-1 strain of mice (75-80 days old; 30-34 g body weight) were divided into 3 major groups and each consisting 5 subgroups (n=6). Cpz (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.), was administered 30 min before testing. RV (0.0, 0.25, 1.0, 2.0 and 4.0 mg/kg, i.p.) and Res (0.0, 0.1, 0.4, 0.8, 1.6 mg/kg, i.p.) were administered 24 h before testing. The open field test was used to assess locomotor and exploratory behaviour, acceleratory rotarod for motor coordination, light/dark box for anxiety. CPZ dose-dependently decreased locomotor and exploration behaviour and impaired motor coordination (p<0.01). RV also decreased locomotor behaviour at 4.0 mg/kg (p<0.5) but did not alter exploration and motor coordination. Res however, decreased locomotion and exploration and impaired motor coordination 0.8 and 1.6 mg/kg (p<0.05). In the light/dark box, CPZ increased anxiety related behaviour at 1.0, 2.0 mg/kg (p<0.05) whereas RV dose-dependently decreased anxiety from 1.0 to 4.0 mg/kg (p<0.01). Res, unlike RV, dose-dependently increased anxiety related behaviour from 0.4 to 1.6 mg/kg. Root bark extract from Rauwolfia vomitoria produced better behavioural effects with less distortion in motor coordination when compared to chlorpromazine and so has a great potential as an alternative antipsychotic agent compared to chlorpromazine. Since Res did not produce same effects as RV, the effect of RV may not be due solely to Res as claimed. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Dose- and time-dependent activation of rat alveolar macrophages by glucocorticoids

PubMed Central

BROUG-HOLUB, E; KRAAL, G

1996-01-01

Effects of glucocorticoids on immune functions are generally thought to be suppressive and anti-inflammatory. However, most reports dealing with this issue describe effects of long-term treatment with high doses of glucocorticoids on immune functions. In the present study we have investigated both dose and timing effects of exposure of alveolar macrophages with dexamethasone on lipopolysaccharide (LPS)-induced IL-1β and nitric oxide secretion. For this purpose, alveolar macrophages were preincubated with various doses of dexamethasone during varying intervals, followed by stimulation of the cells with endotoxin, either in the absence or presence of dexamethasone. Subsequently, the effects of this treatment on IL-1β and nitric oxide secretion were measured. It was shown that both short-term incubation of alveolar macrophages with high doses of dexamethasone and long-term incubation with low doses of dexamethasone lead to enhanced nitric oxide and enhanced IL-1β secretion upon subsequent stimulation of the cells with LPS. In contrast, long-term incubation of alveolar macrophages with high-dose dexamethasone leads to decreased IL-1β and nitric oxide secretion upon subsequent stimulation. Thus, it is concluded that the effects of dexamethasone on rat alveolar macrophages are both time- and dose-dependent. It is therefore argued that effects of glucocorticoids on immune functions are not a priori suppressive, but that both dose and timing effects should be taken into account. PMID:8625529

Development, beam characterization and chromosomal effectiveness of X-rays of RBC characteristic X-ray generator.

PubMed

Endo, Satoru; Hoshi, Masaharu; Takada, Jun; Takatsuji, Toshihiro; Ejima, Yosuke; Saigusa, Shin; Tachibana, Akira; Sasaki, Masao S

2006-06-01

A characteristic hot-filament type X-ray generator was constructed for irradiation of cultured cells. The source provides copper K, iron K, chromium K, molybdenum L, aluminium K and carbon K shell characteristic X-rays. When cultured mouse m5S cells were irradiated and frequencies of dicentrics were fitted to a linear-quadratic model, Y = alphaD + betaD2, the chromosomal effectiveness was not a simple function of photon energy. The alpha-terms increased with the decrease of the photon energy and then decreased with further decrease of the energy with an inflection point at around 10 keV. The beta-terms stayed constant for the photon energy down to 10 keV and then increased with further decrease of energy. Below 10 keV, the relative biological effectiveness (RBE) at low doses was proportional to the photon energy, which contrasted to that for high energy X- or gamma-rays where the RBE was inversely related with the photon energy. The reversion of the energy dependency occurred at around 1-2 Gy, where the RBE of soft X-rays was insensitive to X-ray energy. The reversion of energy-RBE relation at a moderate dose may shed light on the controversy on energy dependency of RBE of ultrasoft X-rays in cell survival experiments.

2,3,7,8-TCDD effects on visual structure and function in swim-up rainbow trout

USGS Publications Warehouse

Carvalho, Paulo S. M.

2004-01-01

An understanding of mechanisms of contaminant effects across levels of biological organization is essential in ecotoxicology if we are to generate predictive models for population-level effects. We applied a suite of biochemical, histological, and behavioral end points related to visual structure and function and foraging behavior to evaluate effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on swim-up rainbow trout. We detected a dose-dependent decrease in densities of retinal ganglion cells (RGC), key retinal neurons that link the eye with the brain. These changes resulted in corresponding deficits in visual/motor function including reductions in visual acuity and in scotopic and photopic thresholds due to TCDD. The loss of RGCs suggests an increase in convergence of synapses from photoreceptors to RGCs as a cellular mechanism for the visual deficits. Dose-dependent increases in immunohistochemical detection of CYP1A protein in the vasculature of the brain and eye choroid was proportional with decreased ganglion cell densities in the retina. TCDD-induced AHR-regulated effects on these tissues might be involved in the detected decrease in ganglion cell densities. Prey capture rate decreased after TCDD exposure only at the highest treatment groups evaluated. Collectively, these results show that TCDD causes biochemical and structural changes in the eye and brain of rainbow trout that are associated with behavioral deficits leading to decreased individual fitness.

Effects of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus.

PubMed

Kazierad, D J; Bergman, A; Tan, B; Erion, D M; Somayaji, V; Lee, D S; Rolph, T

2016-08-01

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the glucagon receptor antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1-5: 5-150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1-2: 15 or 30 mg once daily) for 14-28 days. A mixed-meal tolerance test (MMTT) was administered on days -1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7-22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in glucagon and total glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia. © 2016 John Wiley & Sons Ltd.

Effect of radiation protraction on BED in the case of large fraction dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuperman, V. Y.

2013-08-15

Purpose: To investigate the effect of radiation protraction on biologically effective dose (BED) in the case when dose per fraction is significantly greater than the standard dose of 2 Gy.Methods: By using the modified linear-quadratic model with monoexponential repair, the authors investigate the effect of long treatment times combined with dose escalation.Results: The dependences of the protraction factor and the corresponding BED on fraction time were determined for different doses per fraction typical for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). In the calculations, the authors consider changes in the BED to the normal tissue under the conditionmore » of fixed BED to the target.Conclusion: The obtained results demonstrate that simultaneous increase in fraction time and dose per fraction can be beneficial for SRS and SBRT because of the related decrease in BED to normal structures while BED to the target is fixed.« less

The UF/NCI family of hybrid computational phantoms representing the current US population of male and female children, adolescents, and adults—application to CT dosimetry

NASA Astrophysics Data System (ADS)

Geyer, Amy M.; O'Reilly, Shannon; Lee, Choonsik; Long, Daniel J.; Bolch, Wesley E.

2014-09-01

Substantial increases in pediatric and adult obesity in the US have prompted a major revision to the current UF/NCI (University of Florida/National Cancer Institute) family of hybrid computational phantoms to more accurately reflect current trends in larger body morphometry. A decision was made to construct the new library in a gridded fashion by height/weight without further reference to age-dependent weight/height percentiles as these become quickly outdated. At each height/weight combination, circumferential parameters were defined and used for phantom construction. All morphometric data for the new library were taken from the CDC NHANES survey data over the time period 1999-2006, the most recent reported survey period. A subset of the phantom library was then used in a CT organ dose sensitivity study to examine the degree to which body morphometry influences the magnitude of organ doses for patients that are underweight to morbidly obese in body size. Using primary and secondary morphometric parameters, grids containing 100 adult male height/weight bins, 93 adult female height/weight bins, 85 pediatric male height/weight bins and 73 pediatric female height/weight bins were constructed. These grids served as the blueprints for construction of a comprehensive library of patient-dependent phantoms containing 351 computational phantoms. At a given phantom standing height, normalized CT organ doses were shown to linearly decrease with increasing phantom BMI for pediatric males, while curvilinear decreases in organ dose were shown with increasing phantom BMI for adult females. These results suggest that one very useful application of the phantom library would be the construction of a pre-computed dose library for CT imaging as needed for patient dose-tracking.

The effects of boric acid on sister chromatid exchanges and chromosome aberrations in cultured human lymphocytes.

PubMed

Arslan, Mehmet; Topaktas, Mehmet; Rencuzogullari, Eyyüp

2008-02-01

The aim of this study was to determine the possible genotoxic effects of boric acid (BA) (E284), which is used as an antimicrobial agent in food, by using sister chromatid exchange (SCEs) and chromosome aberration (CAs) tests in human peripheral lymphocytes. The human lymphocytes were treated with 400, 600, 800, and 1000 mug/mL concentrations of BA dissolved in dimethyl sulfoxide (DMSO), for 24 h and 48 h treatment periods. BA did not increase the SCEs for all the concentrations and treatment periods when compared to control and solvent control (DMSO). BA induced structural and total CAs at all the tested concentrations for 24 and 48 h treatment periods. The induction of the total CAs was dose dependent for the 24 h treatment period. However, BA did not cause numerical CAs. BA showed a cytotoxic effect by decreasing the replication index (RI) and mitotic index (MI). BA decreased the MI in a dose-dependent manner for the 24 h treatment period.

Statins Inhibit Monocyte Chemotactic Protein 1 Expression in Endometriosis

PubMed Central

Cakmak, Hakan; Basar, Murat; Seval-Celik, Yasemin; Osteen, Kevin G.; Duleba, Antoni J.; Taylor, Hugh S.; Lockwood, Charles J.; Arici, Aydin

2012-01-01

Statins are potent inhibitors of the endogenous mevalonate pathway. Besides inhibiting cholesterol biosynthesis, statins may also demonstrate anti-inflammatory properties. Inflammation is implicated in the attachment and invasion of endometrial cells to the peritoneal surface and growth of ectopic endometrium by inducing proliferation and angiogenesis. In this study, the effect of statins on monocyte chemotactic protein 1 (MCP-1) expression in endometriotic implants in nude mouse model and in cultured endometriotic cells was evaluated. In mouse model, simvastatin decreased MCP-1 expression in a dose-dependent manner in endometriotic implants (P < .05). Similarly, both simvastatin and mevastatin revealed a dose-dependent inhibition of MCP-1 production in cultured endometriotic cells (P < .01). This inhibitory effect of the statins on MCP-1 production was reversed by the downstream substrates of the mevalonate pathway. Moreover, statins decreased MCP-1 messenger RNA expression in cultured endometriotic cells (P < .05). In conclusion, statins exert anti-inflammatory effect in endometriotic cells and could provide a potential treatment of endometriosis in the future. PMID:22267540

Premilitary Tobacco Use by Male Marine Corps Recruits

DTIC Science & Technology

2007-10-01

numerous dele- terious effects on dental health, including gingival recession, tooth loss , periodontal soft and hard tissue destruction, and cancers of the...decreased readiness. A pronounced, negative dose-response relationship exists between smoking and physical performance,5 and to- bacco use is one of the...Colby SM, Tiffany ST, Shiffman S, Niaura RS: Are adolescent smokers dependent on nicotine: a review of the evidence. Drug Alcohol Depend 2000; 59(Suppl 1

High-temperature thermoluminescence of anion-deficient alumina and possibilities of its application in high-dose dosimetry

NASA Astrophysics Data System (ADS)

Surdo, A. I.; Milman, I. I.; Abashev, R. M.; Vlasov, M. I.

2014-12-01

Results of studies of the thermoluminescence (TL) of anion-deficient alumina (α-Al2O3 - δ) single crystals and based on them TLD-500 detectors exposed to pulsed X-ray and electron radiation in a wide range of doses D, pulsed dose rates P p , and temperatures are described. The TL responses of α-Al2O3 - δ for continuous and pulsed X-ray irradiation at D = 0.05-150 Gy are compared. Unlike continuous irradiation, in the case of pulsed irradiation at P p ≥ 6 × 106 Gy/s, a linear increase in the TL response as a function of D is registered in the main and "chromium" peaks at 450 and 580 K, respectively, with a decrease in the slope of the dose dependence at D > 2 Gy for the peak at 450 K. It is found that high-dose irradiation (>60 Gy) leads to the formation of a new TL peak at 830 K and the preferential redistribution of the stored light sums into this peak. The dose dependence for the TL peak at 830 K is studied. It is established that it is linear in a super-high dose range of 104 to 6 × 106 Gy at P p = 2.6 × 1011 Gy/s.

New image-processing and noise-reduction software reduces radiation dose during complex endovascular procedures.

PubMed

Kirkwood, Melissa L; Guild, Jeffrey B; Arbique, Gary M; Tsai, Shirling; Modrall, J Gregory; Anderson, Jon A; Rectenwald, John; Timaran, Carlos

2016-11-01

A new proprietary image-processing system known as AlluraClarity, developed by Philips Healthcare (Best, The Netherlands) for radiation-based interventional procedures, claims to lower radiation dose while preserving image quality using noise-reduction algorithms. This study determined whether the surgeon and patient radiation dose during complex endovascular procedures (CEPs) is decreased after the implementation of this new operating system. Radiation dose to operators, procedure type, reference air kerma, kerma area product, and patient body mass index were recorded during CEPs on two Philips Allura FD 20 fluoroscopy systems with and without Clarity. Operator dose during CEPs was measured using optically stimulable, luminescent nanoDot (Landauer Inc, Glenwood, Ill) detectors placed outside the lead apron at the left upper chest position. nanoDots were read using a microStar ii (Landauer Inc) medical dosimetry system. For the CEPs in the Clarity group, the radiation dose to surgeons was also measured by the DoseAware (Philips Healthcare) personal dosimetry system. Side-by-side measurements of DoseAware and nanoDots allowed for cross-calibration between systems. Operator effective dose was determined using a modified Niklason algorithm. To control for patient size and case complexity, the average fluoroscopy dose rate and the dose per radiographic frame were adjusted for body mass index differences and then compared between the groups with and without Clarity by procedure. Additional factors, for example, physician practice patterns, that may have affected operator dose were inferred by comparing the ratio of the operator dose to procedural kerma area product with and without Clarity. A one-sided Wilcoxon rank sum test was used to compare groups for radiation doses, reference air kermas, and operating practices for each procedure type. The analysis included 234 CEPs; 95 performed without Clarity and 139 with Clarity. Practice patterns of operators during procedures with and without Clarity were not significantly different. For all cases, procedure radiation dose to the patient and the primary and assistant operators were significantly decreased in the Clarity group by 60% compared with the non-Clarity group. By procedure type, fluorography dose rates decreased from 44% for fenestrated endovascular repair and up to 70% with lower extremity interventions. Fluoroscopy dose rates also significantly decreased, from about 37% to 47%, depending on procedure type. The AlluraClarity system reduces the patient and primary operator's radiation dose by more than half during CEPs. This feature appears to be an effective tool in lowering the radiation dose while maintaining image quality. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

PubMed

Sun, Bing; Xie, Yuan; Jiang, Jinfa; Wang, Yiping; Xu, Xiaolin; Zhao, Cuimei; Huang, Feifei

2015-04-14

Cardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia. Rats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared. At baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P<0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P<0.05). Fenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites.

PubMed

Ye, Jian; Zhu, Rui; He, Xiaosheng; Feng, Yingying; Yang, Liangle; Zhu, Xiaoyan; Deng, Qifei; Wu, Tangchun; Zhang, Xiaomin

2014-01-01

Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all Ptrend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (Ptrend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all Ptrend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all Ptrend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups.

Association of Plasma IL-6 and Hsp70 with HRV at Different Levels of PAHs Metabolites

PubMed Central

He, Xiaosheng; Feng, Yingying; Yang, Liangle; Zhu, Xiaoyan; Deng, Qifei; Wu, Tangchun; Zhang, Xiaomin

2014-01-01

Background Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. Objectives We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. Methods HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. Results We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all P trend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (P trend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all P trend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all P trend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. Conclusions In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups. PMID:24722336

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

PubMed Central

Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel; Piludu, Maria Antonietta; Río-Alamos, Cristóbal; Giorgi, Osvaldo; Corda, Maria G.; Aznar, Susana; González-Maeso, Javier; Gerbolés, Cristina; Blázquez, Gloria; Cañete, Toni; Tobeña, Adolf

2017-01-01

Rationale Animal models with predictive and construct validity are necessary for developing novel and efficient therapeutics for psychiatric disorders. Objectives We have carried out a pharmacological characterization of the Roman high-(RHA-I) and low-avoidance (RLA-I) rat strains with different acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). Results RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI in either strain, but decreased locomotion in a dose-dependent manner in both rat strains. The mixed dopamine D1/D2 agonist, apomorphine, at the dose of 0.05 mg/kg, decreased PPI in RHA-I, but not RLA-I rats. The hallucinogen drug DOI (5-HT2A agonist; 0.1–1.0 mg/kg) disrupted PPI in RLA-I rats in a dose-dependent manner at the 70 dB prepulse intensity, while in RHA-Irats, only the 0.5 mg/kg dose impaired PPI at the 80 dB prepulse intensity. DOI slightly decreased locomotion in both strains. Finally, clozapine attenuated the PPI impairment induced by the NMDA receptor antagonist MK-801 only in RLA-I rats. Conclusions These results add experimental evidence to the view that RHA-I rats represent a model with predictive and construct validity of some dopamine and 5-HT2A receptor-related features of schizophrenia. PMID:28154892

Azathioprine-Induced Warfarin Resistance

PubMed Central

Vazquez, Sara R; Rondina, Matthew T; Pendleton, Robert C

2011-01-01

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin–azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogan’s syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient’s warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966–December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin–azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75–200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine. PMID:18505911

Effect of detomidine on visceral and somatic nociception and duodenal motility in conscious adult horses.

PubMed

Elfenbein, Johanna R; Sanchez, L Chris; Robertson, Sheilah A; Cole, Cynthia A; Sams, Richard

2009-03-01

To evaluate the effects of detomidine on visceral and somatic nociception, heart and respiratory rates, sedation, and duodenal motility and to correlate these effects with serum detomidine concentrations. Nonrandomized, experimental trial. Five adult horses, each with a permanent gastric cannula weighing 534 +/- 46 kg. Visceral nociception was evaluated by colorectal (CRD) and duodenal distension (DD). The duodenal balloon was used to assess motility. Somatic nociception was assessed via thermal threshold (TT). Nose-to-ground (NTG) height was used as a measure of sedation. Serum was collected for pharmacokinetic analysis. Detomidine (10 or 20 microg kg(-1)) was administered intravenously. Data were analyzed by means of a three-factor anova with fixed factors of treatment and time and random factor of horse. When a significant time x treatment interaction was detected, differences were compared with a simple t-test or Bonferroni t-test. Significance was set at p < 0.05. Detomidine produced a significant, dose-dependent decrease in NTG height, heart rate, and skin temperature and a significant, nondose-dependent decrease in respiratory rate. Colorectal distension threshold was significantly increased with 10 microg kg(-1) for 15 minutes and for at least 165 minutes with 20 microg kg(-1). Duodenal distension threshold was significantly increased at 15 minutes for the 20 microg kg(-1) dose. A significant change in TT was not observed at either dose. A marked, immediate decrease in amplitude of duodenal contractions followed detomidine administration at both doses for 50 minutes. Detomidine caused a longer period of visceral anti-nociception as determined by CRD but a shorter period of anti-nociception as determined by DD than has been previously reported. The lack of somatic anti-nociception as determined by TT testing may be related to the marked decrease in skin temperature, likely caused by peripheral vasoconstriction and the low temperature cut-off of the testing device.

Effect of N-acetylcysteine administration on homocysteine level, oxidative damage to proteins, and levels of iron (Fe) and Fe-related proteins in lead-exposed workers.

PubMed

Kasperczyk, Sławomir; Dobrakowski, Michał; Kasperczyk, Aleksandra; Romuk, Ewa; Rykaczewska-Czerwińska, Monika; Pawlas, Natalia; Birkner, Ewa

2016-09-01

N-Acetylcysteine (NAC) could be included in protocols designed for the treatment of lead toxicity. Therefore, in this study, we decided to investigate the influence of NAC administration on homocysteine (Hcy) levels, oxidative damage to proteins, and the levels of iron (Fe), transferrin (TRF), and haptoglobin (HPG) in lead (Pb)-exposed workers. The examined population (n = 171) was composed of male employees who worked with Pb. They were randomized into four groups. Workers who were not administered any antioxidants, drugs, vitamins, or dietary supplements were classified as the reference group (n = 49). The remaining three groups consisted of workers who were treated orally with NAC at three different doses (1 × 200, 2 × 200, or 2 × 400 mg) for 12 weeks. After the treatment, blood Pb levels significantly decreased in the groups receiving NAC compared with the reference group. The protein concentration was not affected by NAC administration. In contrast, Hcy levels significantly decreased or showed a strong tendency toward lower values depending on the NAC dose. Levels of the protein carbonyl groups were significantly decreased in all of the groups receiving NAC. Conversely, glutamate dehydrogenase activity was significantly elevated in all of the groups receiving NAC, while the level of protein thiol groups was significantly elevated only in the group receiving 200 mg of NAC. Treatment with NAC did not significantly affect Fe and TRF levels, whereas HPG levels showed a tendency toward lower values. Treatment with NAC normalized the level of Hcy and decreased oxidative stress as measured by the protein carbonyl content; this effect occurred in a dose-dependent manner. Moreover, small doses of NAC elevated the levels of protein thiol groups. Therefore, NAC could be introduced as an alternative therapy for chronic Pb toxicity in humans. © The Author(s) 2015.

EFFECT OF RADIATION DOSE LEVEL ON ACCURACY AND PRECISION OF MANUAL SIZE MEASUREMENTS IN CHEST TOMOSYNTHESIS EVALUATED USING SIMULATED PULMONARY NODULES

PubMed Central

Söderman, Christina; Johnsson, Åse Allansdotter; Vikgren, Jenny; Norrlund, Rauni Rossi; Molnar, David; Svalkvist, Angelica; Månsson, Lars Gunnar; Båth, Magnus

2016-01-01

The aim of the present study was to investigate the dependency of the accuracy and precision of nodule diameter measurements on the radiation dose level in chest tomosynthesis. Artificial ellipsoid-shaped nodules with known dimensions were inserted in clinical chest tomosynthesis images. Noise was added to the images in order to simulate radiation dose levels corresponding to effective doses for a standard-sized patient of 0.06 and 0.04 mSv. These levels were compared with the original dose level, corresponding to an effective dose of 0.12 mSv for a standard-sized patient. Four thoracic radiologists measured the longest diameter of the nodules. The study was restricted to nodules located in high-dose areas of the tomosynthesis projection radiographs. A significant decrease of the measurement accuracy and intraobserver variability was seen for the lowest dose level for a subset of the observers. No significant effect of dose level on the interobserver variability was found. The number of non-measurable small nodules (≤5 mm) was higher for the two lowest dose levels compared with the original dose level. In conclusion, for pulmonary nodules at positions in the lung corresponding to locations in high-dose areas of the projection radiographs, using a radiation dose level resulting in an effective dose of 0.06 mSv to a standard-sized patient may be possible in chest tomosynthesis without affecting the accuracy and precision of nodule diameter measurements to any large extent. However, an increasing number of non-measurable small nodules (≤5 mm) with decreasing radiation dose may raise some concerns regarding an applied general dose reduction for chest tomosynthesis examinations in the clinical praxis. PMID:26994093

EFFECT OF RADIATION DOSE LEVEL ON ACCURACY AND PRECISION OF MANUAL SIZE MEASUREMENTS IN CHEST TOMOSYNTHESIS EVALUATED USING SIMULATED PULMONARY NODULES.

PubMed

Söderman, Christina; Johnsson, Åse Allansdotter; Vikgren, Jenny; Norrlund, Rauni Rossi; Molnar, David; Svalkvist, Angelica; Månsson, Lars Gunnar; Båth, Magnus

2016-06-01

The aim of the present study was to investigate the dependency of the accuracy and precision of nodule diameter measurements on the radiation dose level in chest tomosynthesis. Artificial ellipsoid-shaped nodules with known dimensions were inserted in clinical chest tomosynthesis images. Noise was added to the images in order to simulate radiation dose levels corresponding to effective doses for a standard-sized patient of 0.06 and 0.04 mSv. These levels were compared with the original dose level, corresponding to an effective dose of 0.12 mSv for a standard-sized patient. Four thoracic radiologists measured the longest diameter of the nodules. The study was restricted to nodules located in high-dose areas of the tomosynthesis projection radiographs. A significant decrease of the measurement accuracy and intraobserver variability was seen for the lowest dose level for a subset of the observers. No significant effect of dose level on the interobserver variability was found. The number of non-measurable small nodules (≤5 mm) was higher for the two lowest dose levels compared with the original dose level. In conclusion, for pulmonary nodules at positions in the lung corresponding to locations in high-dose areas of the projection radiographs, using a radiation dose level resulting in an effective dose of 0.06 mSv to a standard-sized patient may be possible in chest tomosynthesis without affecting the accuracy and precision of nodule diameter measurements to any large extent. However, an increasing number of non-measurable small nodules (≤5 mm) with decreasing radiation dose may raise some concerns regarding an applied general dose reduction for chest tomosynthesis examinations in the clinical praxis. © The Author 2016. Published by Oxford University Press.

Does selenium supplementation affect thyroid function? Results from a randomized, controlled, double-blinded trial in a Danish population.

PubMed

Winther, Kristian Hillert; Bonnema, Steen Joop; Cold, Frederik; Debrabant, Birgit; Nybo, Mads; Cold, Søren; Hegedüs, Laszlo

2015-06-01

Selenium is present in the active site of proteins important for thyroid hormone synthesis and metabolism. The objective of this study is to investigate the effect of selenium supplementation in different doses on thyroid function, under conditions of suboptimal dietary selenium intake. The Danish PREvention of Cancer by Intervention with SElenium pilot study (DK-PRECISE) is a randomized, double-blinded, placebo-controlled trial. A total of 491 males and females aged 60-74 years were randomized to 100 μg (n=124), 200 μg (n=122), or 300 μg (n=119) selenium-enriched yeast or matching yeast-based placebo tablets (n=126). A total of 361 participants, equally distributed across treatment groups, completed the 5-year intervention period. Plasma samples were analyzed for selenium and serum samples for TSH, free triiodothyronine (FT3), and free thyroxine (FT4) at baseline, and after 6 months, and 5 years of supplementation. Plasma selenium concentrations increased significantly and dose-dependently in treatment groups receiving selenium (P<0.001). Serum TSH and FT4 concentrations decreased significantly and dose-dependently by 0.066 mIU/l (P=0.010) and 0.11 pmol/l (P=0.015), respectively, per 100 μg/day increase, with insignificant differences between 6 months and 5 years. No significant effects were found for FT3 and FT3:FT4 ratio. In euthyroid subjects, selenium supplementation minutely and dose-dependently affects thyroid function, when compared with placebo, by decreasing serum TSH and FT4 concentrations. Based on these findings, selenium supplementation is not warranted under conditions of marginal selenium deficiency. However, a role for selenium supplementation in the treatment of autoimmune thyroid diseases is still unresolved. © 2015 European Society of Endocrinology.

Recombinant adenovirus-p21 attenuates proliferative responses associated with excessive scarring.

PubMed

Gu, Danling; Atencio, Isabella; Kang, David W; Looper, L David; Ahmed, C M I; Levy, Alina; Maneval, Dan; Zepeda, Monica L

2005-01-01

Excessive cutaneous scarring is an important clinical disorder resulting in adverse tissue growth and function as well as undesirable cosmetic appearance. p21WAF-1/Cip-1 is a cyclin-dependent kinase inhibitor that blocks cell cycle progression and inhibits cell proliferation. We used a recombinant adenovirus containing the human p21WAF-1/Cip-1 cDNA (rAd-p21) to evaluate proliferative responses in skin models. In vitro dose-response studies using primary human dermal fibroblasts resulted in a dose-dependent expression of p21WAF-1/Cip-1 protein and a 3- to 80-fold reduction in cell proliferation as measured by 5-bromodeoxyuridine incorporation. Further, rAd-p21 reduced type I procollagen production when compared to control virus. A rat polyvinyl alcohol sponge model was used to determine rAd-p21 effects on granulation tissue formation in vivo. Sponges pretreated with a granulation tissue stimulator, rAd-PDGF-B and subsequently rAd-p21 on a second injection, showed a p21WAF-1/Cip-1 specific dose-dependent decrease in percent granulation fill as the rAd-p21 dose increased (p < 0.001). Immunohistochemistry identified human p21WAF-1/Cip-1 expression in sponges treated with rAd-p21 5 days postinjection. Additionally, 5-bromodeoxyuridine and Ki67 staining in sponges treated with rAd-p21 showed a significant decrease in proliferation when compared to rAd-platelet-derived growth factor-B alone or vehicle control groups (p < 0.01). These data support the utility of p21WAF-1/Cip-1 in targeting hyperproliferative disorders of the skin.

Ketamine induces toxicity in human neurons differentiated from embryonic stem cells via mitochondrial apoptosis pathway

PubMed Central

Bosnjak, Zeljko J.; Yan, Yasheng; Canfield, Scott; Muravyeva, Maria Y.; Kikuchi, Chika; Wells, Clive; Corbett, John; Bai, Xiaowen

2013-01-01

Ketamine is widely used for anesthesia in pediatric patients. Growing evidence indicates that ketamine causes neurotoxicity in a variety of developing animal models. Our understanding of anesthesia neurotoxicity in humans is currently limited by difficulties in obtaining neurons and performing developmental toxicity studies in fetal and pediatric populations. It may be possible to overcome these challenges by obtaining neurons from human embryonic stem cells (hESCs) in vitro. hESCs are able to replicate indefinitely and differentiate into every cell type. In this study, we investigated the toxic effect of ketamine on neurons differentiated from hESCs. Two-week-old neurons were treated with different doses and durations of ketamine with or without the reactive oxygen species (ROS) scavenger, Trolox. Cell viability, ultrastructure, mitochondrial membrane potential (ΔΨm), cytochrome c distribution within cells, apoptosis, and ROS production were evaluated. Here we show that ketamine induced ultrastructural abnormalities and dose- and time-dependently caused cell death. In addition, ketamine decreased ΔΨm and increased cytochrome c release from mitochondria. Ketamine also increased ROS production and induced differential expression of oxidative stress-related genes. Specifically, abnormal ultrastructural and ΔΨm changes occurred earlier than cell death in the ketamine-induced toxicity process. Furthermore, Trolox significantly decreased ROS generation and attenuated cell death caused by ketamine in a dose-dependent manner. In conclusion, this study illustrates that ketamine time- and dose-dependently induces human neurotoxicity via ROS-mediated mitochondrial apoptosis pathway and that these side effects can be prevented by the antioxidant agent Trolox. Thus, hESC-derived neurons might provide a promising tool for studying anesthetic-induced developmental neurotoxicity and prevention strategies. PMID:22873495

Low- and high-LET radiation drives clonal expansion of lung progenitor cells in vivo

PubMed Central

Farin, Alicia M.; Manzo, Nicholas D.; Kirsch, David G.; Stripp, Barry R.

2015-01-01

Abundant populations of epithelial progenitor cells maintain the epithelium along the proximal-to-distal axis of the airway. Exposure of lung tissue to ionizing radiation leads to tissue remodeling and potential cancer initiation or progression. However, little is known about the effects of ionizing radiation on airway epithelial progenitor cells. We hypothesized that ionizing radiation exposure will alter the behavior of airway epithelial progenitor cells in a radiation dose- and quality-dependent manner. To address this hypothesis, we cultured primary airway epithelial cells isolated from mice exposed to various doses of 320 kVp X-ray or 600 MeV/nucleon 56Fe ions in a 3D epithelial-fibroblast co-culture system. Colony-forming efficiency of the airway epithelial progenitor cells was assessed at culture day 14. In vivo clonogenic and proliferative potentials of airway epithelial progenitor cells were measured after exposure to ionizing radiation by lineage tracing and IdU incorporation. Exposure to both X-rays and 56Fe resulted in a dose dependent decrease in the ability of epithelial progenitors to form colonies in vitro. In vivo evidence for increased clonogenic expansion of epithelial progenitors was observed after exposure to both X-rays and 56Fe. Interestingly, we found no significant increase in the epithelial proliferative index, indicating that ionizing radiation does not promote increased turnover of the airway epithelium. Therefore, we propose a model in which radiation induces a dose-dependent decrease in the pool of available progenitor cells, leaving fewer progenitors able to maintain the airway long-term. This work provides novel insights into the effects of ionizing radiation exposure on airway epithelial progenitor cell behavior. PMID:25564721

Variation of rabbit sperm physiologic parameters after the X-ray exposure.

PubMed

Klepko, A V; Gorban, L V; Motryna, O A; Kondratova, Y A; Chernyshov, A V; Andreychenko, S V

2013-01-01

To study the impact of X-irradiation on the morpho-functional characteristics of rabbit spermatozoa and the contents of fructose, L-carnitine, α-tocopherol, ascorbate and citrate in the animal sperm. The total body irradiation of rabbits (Soviet Shinchilla) was performed at the RUM-17 device in the dose range of 1.0-7.0 Gy with 2.8·10-3 Gy/sec intensity. The animal sperm was collected by the artificial vagina and then separated on seminal plasma and spermatozoa through centrifugation. Sperm concentration, motility, morphology and linear velocity were identified using the "MBI-6" light microscope. The quantitative determination of ascorbate, α-tocopherol and L-carnitine in seminal plasma was made on the "Agilent 1200" liquid chromatograph, while the concentration of fructose and citrate was measured on a spectrophotometer. The X-ray irradiation was shown to cause a dose-dependent suppressing effect on the prostate, seminal vesicles and epididymices expresed through the decreased content of fructose, citrate, L-carnitine, α-tocopherol and ascorbate in a rabbit sperm. Simultaneously the exacerbation of morphologic anomalies (damage of acrosomes, heads and tails) in spermatozoa along with spermatozoid motility and linear velocity decrease were elucidated. The run-time pattern of morpho-functional changes in spermatozoa together with component content of rabbit sperm in response to the total body irradiation was studied. Consequently the dose dependent raise of morphologic anomalies (damage of acrosomes, heads and tails) in spermatozoa and the slowing of spermatozoid linear velocity was found out. The sperm capacity to fulfill the post-radiation recovery was proven up. The effectiveness of the latter was shown to be dependent upon the radiation dose absorbed and the duration of post-irradiation period. Klepko A. V., Gorban L. V., Motryna O. A., Kondratova Ju. A., Chernyshov A. V., Andrejchenko S. V., 2013.

SU-F-T-68: Characterizes of Microdetectors in Electron Beam Dosimetry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Das, I; Andersen, A; Akino, Y

Purpose: Electron beam dosimetry requires high resolution data due to finite range that can be accomplished with small volume detectors. The small-field used in advance technologies in photon beam has created a market for microdetectors, however characteristics are significantly variable in photon beams and relatively unknown in electron beam that is investigated in this study. Methods: Among nearly 2 dozen microdetectors that have been investigated in small fields of photon beam, two popular detectors (microDiamond 60019 (PTW)) and W1 plastic scintillator detector (Standard Imaging)) that are tissue equivalent and have very small sensitive volume are selected. Electron beams from Varianmore » linear accelerators were used to investigate dose linearity dose rate dependence, energy dependence, depth dose and profiles in a reference condition in a water phantom. For W1 that has its own Supermax electrometer point by point measurements were performed. For microDiamond, a PTW-scanning tank was used for both scanning and point dose measurements. Results: W1 detector showed excellent dose linearity (r{sup 2} =1.0) from 5–500 MU either with variation of dose rate or beam energy. Similar findings were also observed for microdiamond with r{sup 2}=1.0. Percent variations in dose/MU for W1 and microDiamond were 0.2–1.1% and 0.4–1.2%, respectively among dose rate and beam energy. This variation was random for microDiamond, whereas it decreased with beam energy and dose rate for W1. The depth dose and profiles were within ±1 mm for both detectors. Both detectors did not show any energy dependence in electron beams. Conclusion: Both microDiamond and W1 detectors provided superior characteristics of beam parameters in electron beam including dose, dose rate linearity and energy independence. Both can be used in electron beam except W1 require point by point measurements and microdiamond requires 1500 MU for initial quenching.« less

Behavioral Economic Analysis of Opioid Consumption In Heroin-Dependent Individuals: Effects of Alternative Reinforcer Magnitude and Post-Session Drug Supply

PubMed Central

Greenwald, Mark K; Steinmiller, Caren L

2009-01-01

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand were influenced by HYD unit price (UP), alternative money reinforcement magnitude and post-session HYD supply. Heroin dependent research volunteers (n=13) stabilized on buprenorphine 8 mg/day first sampled two HYD doses (12 and 24 mg IM, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could earn a HYD unit dose (2 mg, fixed) or money ($2 or $4, varied across sessions), administered immediately after the work session. Before the PR task, volunteers were told which HYD supplemental dose (none, Drug A or B) would be available 3 hr after receiving the PR-contingent dose. PR-contingent HYD choice significantly decreased when $4 relative to $2 was concurrently available. Information about the post-session HYD supplement moderated this effect: when subjects were told a supplemental dose was available, HYD-seeking behavior decreased when the money alternative was smaller ($2), but this information did not further attenuate HYD choice, which was already low, when the money alternative was higher ($4). HYD demand elasticity was only increased by the $4 relative to $2 alternative without the HYD supplement. In summary, opioid-seeking behavior is influenced by the availability of concurrent non-drug and drug alternatives. These findings show that drug availability and non-drug alternatives interact to modulate drug-seeking behavior. PMID:19464125

Locomotor activity and tissue levels following acute ...

EPA Pesticide Factsheets

Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5 h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29 mg/kg) compared to λ-cyhalothrin (2.65 mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administ

Cardiovascular effects of the essential oil of Alpinia zerumbet leaves and its main constituent, Terpinen-4-ol, in rats: role of the autonomic nervous system.

PubMed

Lahlou, Saad; Galindo, Charles Antonio Barros; Leal-Cardoso, José Henrique; Fonteles, Manassés Claudino; Duarte, Gloria Pinto

2002-12-01

Cardiovascular effects of intravenous ( i. v.) treatment with the essential oil of Alpinia zerumbet (EOAZ) were investigated in rats. Additionally this study examined (I) whether the autonomic nervous system is involved in the mediation of EOAZ-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II) whether these changes could be, at least in part, attributed to the actions of terpinen-4-ol (Trp-4-ol), the major constituent of EOAZ. In both pentobarbitone-anaesthetised and conscious rats, i. v. bolus injections of EOAZ (1 to 20 mg/kg) elicited immediate and dose-dependent decreases in MAP. In anaesthetised rats, EOAZ decreased HR only at higher doses (10 and 20 mg/kg), while changes of this parameter were not uniform in conscious rats. Hypotensive responses to EOAZ were of the same order of magnitude or duration, irrespective of whether the animal was under general anaesthesia. Pretreatment of anaesthetised rats with bilateral vagotomy did not modify significantly the hypotensive and bradycardic responses to EOAZ. In conscious rats, i. v. injections of bolus doses (1 to 10 mg/kg) of Trp-4-ol also elicited immediate and dose-dependent decreases in MAP. However, these hypotensive effects were significantly greater than those evoked by the same doses of EOAZ (1 to 10 mg/kg). Intravenous pretreatment of conscious rats with either methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no significant effects on the EOAZ-induced hypotension. These data show that i. v. treatment with the EOAZ in either anaesthetised or conscious rats induced an immediate and significant hypotension, an effect that could be partially attributed to the actions of Trp-4-ol. The hypotension appears independent of the presence of an operational sympathetic nervous system, suggesting that the EOAZ may be a direct vasorelaxant agent.

Chronic aspirin via dose-dependent and selective inhibition of cardiac proteasome possibly contributed a potential risk to the ischemic heart.

PubMed

Tan, Chunjiang; Chen, Wenlie; Wu, Yanbin; Lin, Jiumao; Lin, Ruhui; Tan, Xuerui; Chen, Songming

2013-08-01

Impaired cardiac proteasome has been reported in ischemic heart and heart failure. Recent data highlighted aspirin as an inhibitor of the ubiquitin-proteasome system, however, it's unclear whether it affects cardiac proteasome functions. Myocardial infarction (MI), sham or normal male SD rats were injected intraperitoneally with high (300 mg/kg), low (5 mg/kg) aspirin or saline (control) once a day for seven weeks. Parallel experiments were performed in the hypoxia/reoxygenated human ventricular myocytes. Dose-related increases in heart and ventricular weight, and impaired cardiac functions, were found more exacerbated in the aspirin-treated MI rat hearts than the saline-treated MI counterparts. The activity of 26S, 20S and 19S declined by about 30%, or the 20S proteasome subunits β5, β2 and β1 decreased by 40%, 20% and 30%, respectively, in the MI rats compared with the non-MI rats (P<0.05). Compared with the saline-treated MI rats, 26S and 20S in high or low dose aspirin-treated MI rats further decreased by 30% and 20%, β5 by 30% and 12%, and β1 by 40% and 30%, respectively, and the lost activity was correlated with the compromised cardiac functions or the decreased cell viability. The dose-related and selective inhibition of 26S and 20S proteasome, or the 20S proteasome subunits β5 and β1 by aspirin was comparable to their protein expressions in the MI rats and in the cultured cells. The impaired cardiac proteasome, enhanced by chronic aspirin treatment, attenuated the removal of oxidative and ubiquitinated proteins, and chronic aspirin treatment via selective and dose-dependent inhibition of cardiac proteasome possibly constituted a potential risk to ischemic heart. Copyright © 2013 Elsevier Inc. All rights reserved.

Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.

PubMed

Wolf, Douglas C; Allen, James W; George, Michael H; Hester, Susan D; Sun, Guobin; Moore, Tanya; Thai, Sheau-Fung; Delker, Don; Winkfield, Ernest; Leavitt, Sharon; Nelson, Gail; Roop, Barbara C; Jones, Carlton; Thibodeaux, Julie; Nesnow, Stephen

2006-01-01

Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for triadimefon-induced thyroid gland tumors was not supported by the data.

Physiological responses and toxin production of Microcystis aeruginosa in short-term exposure to solar UV radiation.

PubMed

Hernando, Marcelo; Minaglia, Melina Celeste Crettaz; Malanga, Gabriela; Houghton, Christian; Andrinolo, Darío; Sedan, Daniela; Rosso, Lorena; Giannuzzi, Leda

2018-01-17

The aim of this study was to evaluate the effects of short-term (hours) exposure to solar UV radiation (UVR, 280-400 nm) on the physiology of Microcystis aeruginosa. Three solar radiation treatments were implemented: (i) PAR (PAR, 400-700 nm), (ii) TUVA (PAR + UVAR, 315-700 nm) and (iii) TUVR (PAR + UVAR + UVBR, 280-700 nm). Differential responses of antioxidant enzymes and the reactive oxygen species (ROS) production to UVR were observed. Antioxidant enzymes were more active at high UVR doses. However, different responses were observed depending on the exposure to UVAR or UVBR and the dose level. No effects were observed on the biomass, ROS production or increased activity of superoxide dismutase (SOD) and catalase (CAT) compared to the control when UVR + PAR doses were lower than 9875 kJ m -2 . For intermediate doses, UVR + PAR doses between 9875 and 10 275 kJ m -2 , oxidative stress increased while resistance was imparted through SOD and CAT in the cells exposed to UVAR. Despite the increased antioxidant activity, biomass decrease and photosynthesis inhibition were observed, but no effects were observed with added exposure to UVBR. At the highest doses (UVR + PAR higher than 10 275 kJ m -2 ), the solar UVR caused decreased photosynthesis and biomass with only activation of CAT by UVBR and SOD and CAT by UVAR. In addition, for such doses, a significant decrease of microcystins (MCs, measured as MC-LR equivalents) was observed as a consequence of UVAR. This study facilitates our understanding of the SOD and CAT protection according to UVAR and UVBR doses and cellular damage and reinforces the importance of UVR as an environmental stressor. In addition, our results support the hypothesized antioxidant function of MCs.

The Influence of Changes in Tumor Hypoxia on Dose-Painting Treatment Plans Based on {sup 18}F-FMISO Positron Emission Tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin Zhixiong; Mechalakos, James; Nehmeh, Sadek

2008-03-15

Purpose: To evaluate how changes in tumor hypoxia, according to serial fluorine-18-labeled fluoro-misonidazole ({sup 18}F-FMISO) positron emission tomography (PET) imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting. Methods and Materials: Seven patients with head and neck cancers were imaged twice with FMISO PET, separated by 3 days, before radiotherapy. Intensity-modulated radiotherapy plans were designed, on the basis of the first FMISO scan, to deliver a boost dose of 14 Gy to the hypoxic volume, in addition to the 70-Gy prescription dose. The same plans were then applied to hypoxic volumes from the second FMISO scan, and the efficacymore » of dose painting evaluated by assessing coverage of the hypoxic volumes using D{sub max}, D{sub min}, D{sub mean}, D{sub 95}, and equivalent uniform dose (EUD). Results: Similar hypoxic volumes were observed in the serial scans for 3 patients but dissimilar ones for the other 4. There was reduced coverage of hypoxic volumes of the second FMISO scan relative to that of the first scan (e.g., the average EUD decreased from 87 Gy to 80 Gy). The decrease was dependent on the similarity of the hypoxic volumes of the two scans (e.g., the average EUD decrease was approximately 4 Gy for patients with similar hypoxic volumes and approximately 12 Gy for patients with dissimilar ones). Conclusions: The changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the EUD of the hypoxic volumes.« less

[Effect of sodium valproate on aggressive behavior of male mice with various aggression experience].

PubMed

Smagin, D A; Bondar', N P; Kudriavtseva, N N

2010-01-01

Sector of Social Behavior Neurogenetics, Institute of Cytology and Genetics, Siberian Branch, Effects of sodium valproate on the aggressive behavior of male mice with 2- and 20-day positive fighting experience have been studied. It is established that valproate administered in a singe dose of 100 mg/kg has no effect on the behavior of male mice with a 2-day experience of aggression. The treatment of mice with 300 mg/kg of valproate significantly decreased the level of aggressive motivation and the percentage of animals demonstrating attacks and threats. In male mice with a 20-day experience of aggression, valproate decreased the time of hostile behavior in a dose-dependent manner. Valproate in a single dose of 300 mg/kg significantly decreased the level of aggressive motivation, but also produced a toxic effect, whereby 73% of aggressive males demonstrated long-term immobility and 45% exhibited movement abnormalities (falls) upon the treatment. It is suggested that changes in the brain neurochemical activity, which are caused by a prolonged experience of aggression, modify the effects of sodium valproate.

Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner.

PubMed

Fahmi, Alaa N A; Shehatou, George S G; Shebl, Abdelhadi M; Salem, Hatem A

2016-03-01

The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.

Alpha-, gamma- and delta-tocopherols reduce inflammatory angiogenesis in human microvascular endothelial cells.

PubMed

Wells, Shannon R; Jennings, Merilyn H; Rome, Courtney; Hadjivassiliou, Vicky; Papas, Konstantinos A; Alexander, Jonathon S

2010-07-01

Vitamin E, a micronutrient (comprising alpha-, beta-, gamma- and delta-tocopherols, alpha-, beta-, gamma- and delta-tocotrienols), has documented antioxidant and non-antioxidant effects, some of which inhibit inflammation and angiogenesis. We compared the abilities of alpha-, gamma- and delta-tocopherols to regulate human blood cytotoxicity (BEC) and lymphatic endothelial cytotoxicity (LEC), proliferation, invasiveness, permeability, capillary formation and suppression of TNF-alpha-induced VCAM-1 as in vitro models of inflammatory angiogenesis. alpha-, gamma- and delta-tocopherols were not toxic to either cell type up to 40 microM. In BEC, confluent cell density was decreased by all concentrations of delta- and gamma-tocopherol (10-40 microM) but not by alpha-tocopherol. LEC showed no change in cell density in response to tocopherols. delta-Tocopherol (40 microM), but not other isomers, decreased BEC invasiveness. In LEC, all doses of gamma-tocopherol, as well as the highest dose of alpha-tocopherol (40 microM), decreased cell invasiveness. delta-Tocopherol had no effect on LEC invasiveness at any molarity. delta-Tocopherol dose dependently increased cell permeability at 48 h in BEC and LEC; alpha- and gamma-tocopherols showed slight effects. Capillary tube formation was decreased by high dose (40 microM) concentrations of alpha-, gamma- and delta-tocopherol, but showed no effects with smaller doses (10-20 microM) in BEC. gamma-Tocopherol (10-20 microM) and alpha-tocopherol (10 microM), but not delta-tocopherol, increased LEC capillary tube formation. Lastly, in BEC, alpha-, gamma- and delta-tocopherol each dose-dependently reduced TNF-alpha-induced expression of VCAM-1. In LEC, there was no significant change to TNF-alpha-induced VCAM-1 expression with any concentration of alpha-, gamma- or delta-tocopherol. These data demonstrate that physiological levels (0-40 microM) of alpha-, gamma- and delta-tocopherols are nontoxic and dietary tocopherols, especially delta-tocopherol, can limit several BEC and LEC endothelial behaviors associated with angiogenesis. Tocopherols may therefore represent important nutrient-signals that limit cell behaviors related to inflammation/angiogenesis, which when deficient, may predispose individuals to risks associated with elevated angiogenesis such as inflammation and cancer; further differences seen from the tocopherols may be due to their blood or lymphatic cell origin. (c) 2010 Elsevier Inc. All rights reserved.

Decreases in Cocaine Self-Administration with Dual Inhibition of the Dopamine Transporter and σ Receptors

PubMed Central

Hiranita, Takato; Soto, Paul L.; Kohut, Stephen J.; Kopajtic, Theresa; Cao, Jianjing; Newman, Amy H.; Tanda, Gianluigi

2011-01-01

Sigma receptor (σR) antagonists attenuate many behavioral effects of cocaine but typically not its reinforcing effects in self-administration procedures. However, the σR antagonist rimcazole and its N-propylphenyl analogs, [3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]diphenylamine hydrochloride (SH 3-24) and 9-[3-(cis-3,5-dimethyl-4-[3-phenylpropyl]-1-piperazinyl)-propyl]carbazole hydrobromide (SH 3-28), dose-dependently decreased the maximal rates of cocaine self-administration without affecting comparable responding maintained by food reinforcement. In contrast, a variety of σR antagonists [N-phenethylpiperidine oxalate (AC927), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine dihydrobromide (BD 1008), N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino) ethylamine dihydrobromide (BD 1047), N-[2-(3,4-dichlorophenyl) ethyl]-4-methylpiperazine dihydrochloride (BD 1063), and N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100)] had no effect on cocaine self-administration across the range of doses that decreased rates of food-maintained responding. Rimcazole analogs differed from selective σR antagonists in their dual affinities for σRs and the dopamine transporter (DAT) assessed with radioligand binding. Selective DAT inhibitors and σR antagonists were studied alone and in combination on cocaine self-administration to determine whether actions at both σRs and the DAT were sufficient to reproduce the effects of rimcazole analogs. Typical DAT inhibitors [2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428), methylphenidate, and nomifensine] dose-dependently shifted the cocaine dose-effect curve leftward. Combinations of DAT inhibitor and σR antagonist doses that were behaviorally inactive alone decreased cocaine self-administration without effects on food-maintained responding. In addition, whereas the DAT inhibitors were self-administered at rates similar to those of cocaine, neither rimcazole analogs nor typical σR antagonists (NE-100 and AC927) maintained responding above control levels across a wide range of doses. These findings suggest that the unique effects of rimcazole analogs are due to dual actions at the DAT and σRs and that a combined target approach may have utility in development of medical treatments for cocaine abuse. PMID:21859929

Acute oral toxicity of 3-MCPD mono- and di-palmitic esters in Swiss mice and their cytotoxicity in NRK-52E rat kidney cells.

PubMed

Liu, Man; Gao, Bo-Yan; Qin, Fang; Wu, Ping-Ping; Shi, Hai-Ming; Luo, Wei; Ma, Ai-Niu; Jiang, Yuan-Rong; Xu, Xue-Bing; Yu, Liang-Li Lucy

2012-10-01

The acute oral toxicity of 1-palmitoyl-3-chloropropanediol (3-MCPD 1-monopalmitate) and 1,2-bis-palmitoyl-3-chloropropanediol (3-MCPD dipalmitate) in Swiss mice were examined, along with their cytotoxicity in NRK-52E rat kidney cells. LD50 (median lethal dose) value of 3-MCPD 1-monopalmitate was determined 2676.81 mg/kg body weight (BW). The results showed that 3-MCPD 1-monopalmitate dose-dependently decreased the mean body weight, and caused significant increase of serum urea nitrogen and creatinine in dead mice compared to the control and survived mice. Major histopathological changes in mice fed 3-MCPD 1-monopalmitate were renal tubular necrosis, protein casts and spermatids decrease in the seminiferous tubules. According to the limit test for 3-MCPD dipalmitate, LD50 value of 3-MCPD dipalmitate was presumed to be greater than 5000 mg/kg BW. Obvious changes were not observed on mean body weight, absolute and relative organ weight or serum urea nitrogen and creatinine levels in mice fed 3-MCPD dipalmitate. However, renal tubular necrosis, protein casts and spermatids decrease were also observed in the dead mice. In addition, MTT and LDH assay results only showed the cytotoxicity of 3-MCPD 1-monopalmitate in NRK-52E rat kidney cells in a dose-dependent manner. Together, the results indicated a greater toxicity of 3-MCPD 1-monopalmitate compared to 3-MCPD dipalmitate. Copyright © 2012 Elsevier Ltd. All rights reserved.

SU-E-I-10: Automatic Monitoring of Accumulated Dose Indices From DICOM RDSR to Improve Radiation Safety in X-Ray Angiography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Omar, A; Bujila, R; Nowik, P

2014-06-01

Purpose: To investigate the potential benefits of automatic monitoring of accumulated patient and staff dose indicators, i.e., CAK and KAP, from DICOM Radiation Dose Structured Reports (RDSR) in x-ray angiography (XA). Methods: Recently RDSR has enabled the convenient aggregation of dose indices and technique parameters for XA procedures. The information contained in RDSR objects for three XA systems, dedicated to different types of clinical procedures, has been collected and aggregated in a database for over one year using a system developed with open-source software at the Karolinska University Hospital. Patient weight was complemented to the RDSR data via an interfacemore » with the Hospital Information System (HIS). Results: The linearly approximated trend in KAP over a time period of a year for cerebrovascular, pelvic/peripheral vascular, and cardiovascular procedures showed a decrease of 12%, 20%, and 14%, respectively. The decrease was mainly due to hardware/software upgrades and new low-dose imaging protocols, and partially due to ongoing systematic radiation safety education of the clinical staff. The CAK was in excess of 3 Gy for 15 procedures, and exceeded 5 Gy for 3 procedures. The dose indices have also shown a significant dependence on patient weight for cardiovascular and pelvic/peripheral vascular procedures; a 10 kg shift in mean patient weight can result in a dose index increase of 25%. Conclusion: Automatic monitoring of accumulated dose indices can be utilized to notify the clinical staff and medical physicists when the dose index has exceeded a predetermined action level. This allows for convenient and systematic follow-up of patients in risk of developing deterministic skin injuries. Furthermore, trend analyses of dose indices over time is a valuable resource for the identification of potential positive or negative effects (dose increase/decrease) from changes in hardware, software, and clinical work habits.« less

Influence of increased mechanical loading by hypergravity on the microtubule cytoskeleton and prostaglandin E2 release in primary osteoblasts

NASA Technical Reports Server (NTRS)

Searby, Nancy D.; Steele, Charles R.; Globus, Ruth K.

2005-01-01

Cells respond to a wide range of mechanical stimuli such as fluid shear and strain, although the contribution of gravity to cell structure and function is not understood. We hypothesized that bone-forming osteoblasts are sensitive to increased mechanical loading by hypergravity. A centrifuge suitable for cell culture was developed and validated, and then primary cultures of fetal rat calvarial osteoblasts at various stages of differentiation were mechanically loaded using hypergravity. We measured microtubule network morphology as well as release of the paracrine factor prostaglandin E2 (PGE2). In immature osteoblasts, a stimulus of 10x gravity (10 g) for 3 h increased PGE2 2.5-fold and decreased microtubule network height 1.12-fold without affecting cell viability. Hypergravity (3 h) caused dose-dependent (5-50 g) increases in PGE2 (5.3-fold at 50 g) and decreases (1.26-fold at 50 g) in microtubule network height. PGE2 release depended on duration but not orientation of the hypergravity load. As osteoblasts differentiated, sensitivity to hypergravity declined. We conclude that primary osteoblasts demonstrate dose- and duration-dependent sensitivity to gravitational loading, which appears to be blunted in mature osteoblasts.

Caffeine and length dependence of staircase potentiation in skeletal muscle.

PubMed

Rassier, D E; Tubman, L A; MacIntosh, B R

1998-01-01

Skeletal muscle sensitivity to Ca2+ is greater at long lengths, and this results in an optimal length for twitch contractions that is longer than optimal length for tetanic contractions. Caffeine abolishes this length dependence of Ca2+ sensitivity. Muscle length (ML) also affects the degree of staircase potentiation. Since staircase potentiation is apparently caused by an increased Ca2+ sensitivity of the myofilaments, we tested the hypothesis that caffeine depresses the length dependence of staircase potentiation. In situ isometric twitch contractions of rat gastrocnemius muscle before and after 10 s of 10-Hz stimulation were analyzed at seven different lengths to evaluate the length dependence of staircase potentiation. In the absence of caffeine, length dependence of Ca2+ sensitivity was observed, and the degree of potentiation after 10-Hz stimulation showed a linear decrease with increased length (DT = 1.47 - 0.05 ML, r2 = 0.95, where DT is developed tension). Length dependence of Ca2+ sensitivity was decreased by caffeine when caffeine was administered in amounts estimated to result in 0.5 and 0.75 mM concentrations. Furthermore, the negative slope of the relationship between staircase potentiation and muscle length was diminished at the lower caffeine dose, and the slope was not different from zero after the higher dose (DT = 1.53 - 0.009 ML, r2 = 0.43). Our study shows that length dependence of Ca2+ sensitivity in intact skeletal muscle is diminished by caffeine. Caffeine also suppressed the length dependence of staircase potentiation, suggesting that the mechanism of this length dependence may be closely related to the mechanism for length dependence of Ca2+ sensitivity.

A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor

PubMed Central

Waterfall, J. F.

1989-01-01

1 Cilazapril is the monoethyl ester prodrug form of the di-acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2 An oral dose of 0.1 mg kg-1 cilazapril evoked the same maximum degree of plasma ACE inhibition (∼76%) in the rat as 0.25 mg kg-1 enalapril. Cilazapril (0.25 mg kg-1 p.o.) inhibited plasma ACE by > 95%. The rate of recovery of ACE activity was slower with cilazapril (5-6% h-1) than with enalapril (10% h-1). 3 In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5×) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4 Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2-4.5× more potent than enalapril as an ACE inhibitor. 5 In cats cilazapril (0.1 and 0.3 mg kg-1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at ≥ 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3-4 h. 6 Daily oral dosing of cilazapril (30 mg kg-1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7 Cilazapril (10 mg kg-1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 ± 6 mm Hg. 8 Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and myocardial contractile force were seen at high doses. 9 Cilazapril had no adverse effect on cardiovascular reflexes. There was no impairment of the baroreflex in rats. Exercise-induced tachycardia and pressor responses in conscious cats were unchanged. 10 Cilazapril is exceptionally well absorbed by the oral route (98% in rats). PMID:2527528

Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning.

PubMed

Catlow, Briony J; Song, Shijie; Paredes, Daniel A; Kirstein, Cheryl L; Sanchez-Ramos, Juan

2013-08-01

Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5-HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I-NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5-HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions.

In vitro anticancer activities of osthole against renal cell carcinoma cells.

PubMed

Liu, Lei; Mao, Jun; Wang, Qifei; Zhang, Zhiwei; Wu, Guangzhen; Tang, Qizhen; Zhao, Bin; Li, Lianhong; Li, Quanlin

2017-10-01

Renal cell carcinoma (RCC) is a common urinary malignancy that is resistant to chemotherapy and radiotherapy. Osthole, a monomer compound extracted from a traditional Chinese herb, has potent anti-tumor effects on various types of cancer cells. However, the therapeutic effects of osthole on RCC remain unclear. In our study, osthole could suppress the proliferation and colony formation of two RCC cell lines, ACHN and 786-O cells, in a dose-dependent manner. Treatment with osthole resulted in a significant, dose-dependent increase in the expression of pro-apoptotic proteins (cleaved caspase-3 and Bax) and decreased expression of anti-apoptotic proteins (Bcl-2 and survivin), which were consistent with evidence of apoptotic nuclear morphology revealed by DAPI staining. Pre-treatment with osthole attenuated the migratory and invasive abilities of RCC cells in a dose-dependent manner, as evidenced by a reduction in migrating cells in a Transwell assay and a decreased wound closure ratio in a scratch assay as compared with the control. Additionally, osthole down-regulated the expression of migration/invasion-related proteins matrix metalloproteinase (MMP)-2 and MMP-9. Osthole significantly up-regulated epithelial biomarkers (E-cadherin and beta-catenin) and down-regulated mesenchymal biomarkers (N-cadherin and vimentin). Furthermore, our results suggest that osthole suppressed the expression of epithelial-mesenchymal transition transcriptional factors Smad-3, Snail-1, and Twist-1. Taken together, the results of this study suggest that osthole might be a potential novel herbal agent against RCC. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Changes in the Chemical Composition of Plum Distillate During Maturation with Oak Chips under Different Conditions

PubMed Central

2017-01-01

Summary This study investigates the effect of ageing on the qualitative and quantitative composition of plum distillate in contact with oak wood chips. Maturation was performed with lightly toasted French oak (Quercus sessiflora and Quercus robur) chips or oak chips made from fragments of empty barrels that had been used for ageing cognac. The effects of oak chip dose, process temperature, ageing system (static or circulatory) and ultrasound treatment were assessed. Maturation of plum distillate samples with oak chips resulted in higher levels of extractable organics (including tannins) and colour changes, which were correlated with the type and dose of oak chips, and the conditions of maturation. The content of sugars such as glucose, xylose and arabinose also increased, depending on the conditions and type of oak chips. Degradation of lignin resulted in liberation of sinapaldehyde, syringaldehyde, coniferaldehyde and vanillin, with intensities depending on the applied parameters. In terms of volatiles, decreases in the concentration of higher alcohols and aliphatic aldehydes were observed in the majority of maturation experiments, while concentrations of furanic aldehydes increased depending on the type and dose of oak chips, as well as on the conditions of maturation. The quantities of esters such as ethyl acetate decreased in the majority of experimental variants, whereas concentrations of ethyl caproate, ethyl caprylate and ethyl caprate increased gradually. Some phenols and lactones were detected in all matured samples, with the lowest levels found in the samples aged with oak chips made from cognac barrels. PMID:29089848

Changes in the Chemical Composition of Plum Distillate During Maturation with Oak Chips under Different Conditions.

PubMed

Balcerek, Maria; Pielech-Przybylska, Katarzyna; Dziekońska-Kubczak, Urszula; Patelski, Piotr; Strąk, Ewelina

2017-09-01

This study investigates the effect of ageing on the qualitative and quantitative composition of plum distillate in contact with oak wood chips. Maturation was performed with lightly toasted French oak ( Quercus sessiflora and Quercus robur ) chips or oak chips made from fragments of empty barrels that had been used for ageing cognac. The effects of oak chip dose, process temperature, ageing system (static or circulatory) and ultrasound treatment were assessed. Maturation of plum distillate samples with oak chips resulted in higher levels of extractable organics (including tannins) and colour changes, which were correlated with the type and dose of oak chips, and the conditions of maturation. The content of sugars such as glucose, xylose and arabinose also increased, depending on the conditions and type of oak chips. Degradation of lignin resulted in liberation of sinapaldehyde, syringaldehyde, coniferaldehyde and vanillin, with intensities depending on the applied parameters. In terms of volatiles, decreases in the concentration of higher alcohols and aliphatic aldehydes were observed in the majority of maturation experiments, while concentrations of furanic aldehydes increased depending on the type and dose of oak chips, as well as on the conditions of maturation. The quantities of esters such as ethyl acetate decreased in the majority of experimental variants, whereas concentrations of ethyl caproate, ethyl caprylate and ethyl caprate increased gradually. Some phenols and lactones were detected in all matured samples, with the lowest levels found in the samples aged with oak chips made from cognac barrels.

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

PubMed Central

Neumaier, Teresa; Swenson, Joel; Pham, Christopher; Polyzos, Aris; Lo, Alvin T.; Yang, PoAn; Dyball, Jane; Asaithamby, Aroumougame; Chen, David J.; Bissell, Mina J.; Thalhammer, Stefan; Costes, Sylvain V.

2012-01-01

The concept of DNA “repair centers” and the meaning of radiation-induced foci (RIF) in human cells have remained controversial. RIFs are characterized by the local recruitment of DNA damage sensing proteins such as p53 binding protein (53BP1). Here, we provide strong evidence for the existence of repair centers. We used live imaging and mathematical fitting of RIF kinetics to show that RIF induction rate increases with increasing radiation dose, whereas the rate at which RIFs disappear decreases. We show that multiple DNA double-strand breaks (DSBs) 1 to 2 μm apart can rapidly cluster into repair centers. Correcting mathematically for the dose dependence of induction/resolution rates, we observe an absolute RIF yield that is surprisingly much smaller at higher doses: 15 RIF/Gy after 2 Gy exposure compared to approximately 64 RIF/Gy after 0.1 Gy. Cumulative RIF counts from time lapse of 53BP1-GFP in human breast cells confirmed these results. The standard model currently in use applies a linear scale, extrapolating cancer risk from high doses to low doses of ionizing radiation. However, our discovery of DSB clustering over such large distances casts considerable doubts on the general assumption that risk to ionizing radiation is proportional to dose, and instead provides a mechanism that could more accurately address risk dose dependency of ionizing radiation. PMID:22184222

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

PubMed

Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Crockett, R S; Howes, John; Darpo, Borje; Zhou, Meijian; Weis, Holger; Friedhoff, Lawrence

2016-11-01

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C max and was slowly eliminated (mean t 1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. © 2016, The American College of Clinical Pharmacology.

Necrotizing Enterocolitis and Human Milk Feeding: A Systematic Review.

PubMed

Cacho, Nicole Theresa; Parker, Leslie A; Neu, Josef

2017-03-01

This article summarizes evidence regarding whether a donor human milk (DHM) and/or an exclusively human milk (EHM) diet decreases the incidence of necrotizing enterocolitis (NEC) and the dose of human milk (HM) necessary to reduce the risk of NEC in premature infants. Additional research regarding protection afforded by DHM and EHM is necessary as well as research elucidating the exact dose of HM necessary for NEC risk reduction. Research is also needed to determine whether there is a dose-dependent effect of DHM, a combination of mother's own milk and DHM, and an EHM diet on NEC incidence. Copyright © 2016 Elsevier Inc. All rights reserved.

Dose- and time-dependent increase of lysosomal enzymes in embryonic cartilage in vitro after ionizing radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cornelissen, M.; de Ridder, L.

Radiation doses of 20, 50 or 100 Gy caused the same time related decrease for RNA and proteoglycan (PG) synthesis in embryonic cartilage in vitro (4 days culture). In this paper, participation of lysosomes in this radiation response is investigated. Therefore, we employ a cytochemical method using beta-glycerophosphate as substrate for acid phosphatase (AP) detection. Increase of AP was found 2 days after irradiation and increased during the whole culture period. The increase was more pronounced with a higher radiation dose. Stimulation of AP activity explains the observed radiation response of RNA and PG synthesis.

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist.

PubMed

Newman, L A; Gold, P E

2016-03-01

Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist-to decrease scopolamine-induced increases in acetylcholine output or to decrease postsynaptic acetylcholine receptor activation-may mediate the negative effects on memory of muscarinic antagonists.

[Mechanisms of opioid-induced overdose: experimental approach to clinical concerns].

PubMed

Baud, F-J

2009-09-01

The widely used term "overdose" denotes a toxic effect: opioid-induced intoxication and a mechanism: the poisoning results only from an overdose. Surprisingly, our understanding of the pathophysiology of this deadly complication is limited. In drug users, we attempted to: (1) improve knowledge of drug-induced respiratory effects; (2) clarify the mechanisms of drug interactions; (3) identify factors of variability and vulnerability. A prospective study of opioid overdoses confirmed that poisonings involving buprenorphine do exist. However, the mechanisms of buprenorphine poisoning are more complex than only an overdose, particularly the severity is less than that induced by heroin. In contrast, methadone overdose is life-threatening. Experimental studies addressed several clinical questions and also showed limited discrepancies. At pharmacological doses, opioids decrease the ventilatory response to CO(2). However, this effect does not account for the morbimortality of opioid poisonings. The mechanisms of opioid-induced morbimortality are different. Buprenorphine at doses near its median lethal dose did not induce acute respiratory failure as defined by a decrease in the partial pressure of oxygen in arterial blood (PaO(2)). In contrast, the combination of buprenorphine with flunitrazepam results in a decrease in PaO(2). This harmful interaction does not exist with other benzodiazepines in the rat, except for very high doses of nordazepam. The interaction results from a pharmacokinetic process. In contrast, methadone causes a dose-dependent decrease in PaO(2,) even significant before hypercapnia. We are assessing the relationships between on one hand alterations of ventilatory pattern and of arterial blood gas and on the other hand the different types of opiate receptors in the rats.

Dose dependence of the excision of ultraviolet-induced pyrimidine dimers from nuclear deoxyribonucleic acids of haploid and diploid Saccharomyces cerevisiae.

PubMed Central

Waters, R; Moustacchi, E

1975-01-01

The yield of ultraviolet-induced dimers is similar for a fixed dose in both haploid and diploid Saccharomyces cerevisiae. The excision of these photo-products from the nuclear deoxyribonucleic acids of cells of both ploidies after ultraviolet incident doses of 2 times 10-3 to 4 times 10-3 ergs/mm2 decreased with the corresponding increasing dose. Postirradiation incubation in saline followed by a further incubation in nutrient medium increases the excision as compared to that seen in either nutrient medium or saline alone. Previous data regarding both pyrimidine dimer removal and the survival of haploid and diploid cells after ultraviolet irradiation and either immediate or delayed plating are discussed. PMID:1090608

[Effects of berberine on mRNA expression levels of PPARγ and adipocytokines in insulin-resistant adipocytes].

PubMed

Tu, Jun; Luo, Xin-Xin; Li, Bing-Tao; Li, Yu; Xu, Guo-Liang

2016-06-01

Adipocytokines are closely associated with insulin resistance (IR) in adipose tissues, and they are more and more seriously taken in the study of the development of diabetes. This experiment was mainly to study the effect of berberine on mRNA expression levels of PPARγ and adipocytokines in insulin resistant adipocytes, and investigate the molecular mechanism of berberine in enhancing insulin sensitization and application advantages of droplet digital PCR (ddPCR). ddPCR absolute quantification analysis was taken in this experiment to simply and intuitively determine the appropriate reference genes. ddPCR and quantitative Real-time PCR (qPCR) were used to compare the effect of different doses of berberine (10, 20, 50, 100 μmol•L⁻¹) on mRNA expression levels of PPARγ, adiponectin, resistin and leptin in IR 3T3-L1adipocytes. Antagonist GW9662 was added to study the inherent correlation between PPARγ and adiponectin mRNA expression levels. ddPCR results showed that the expression level of β-actin in adipocytes was stable, and suitable as reference gene for normalization of quantitative PCR data. Both of ddPCR and qPCR results showed that, as compared with IR models, the mRNA expression levels of adiponectin were decreased in the treatment with berberine (10, 20, 50, 100 μmol•L⁻¹) in a dose-dependent manner (P<0.01); the expression of PPARγ was decreased by 20, 50, 100 μmol•L⁻¹ berberine in a dose-dependent manner in qPCR assay (P<0.01) and decreased only by 50 and 100 μmol•L⁻¹ berberine in ddPCR assay (P<0.05). PPARγ specific antagonist GW9662 intervention experiment showed that adiponectin gene expression was directly relevant with PPARγ (P<0.05). ddPCR probe assay showed that various doses of berberine could significantly reduce mRNA expression levels of resistin and leptin (P<0.01) in a dose-dependent manner. In conclusion, berberine enhanced insulin sensitization effect not by up-regulating adiponect in expression of transcriptional level in PPARγ-dependent manner, but may by the elevated multimerization of adiponectin in the posttranslational regulation level. Berberine down-regulated the resistin and leptin expression levels, which could alleviate lipolysis and improve IR in adipocytes. ddPCR provided better sensitivity and linear range than qPCR, with obvious technical advantages for the detection of low abundance expression of target genes. Copyright© by the Chinese Pharmaceutical Association.

Dissipation and adsorption of isoproturon, tebuconazole, chlorpyrifos and their main transformation products under laboratory and field conditions.

PubMed

Papadopoulou, Evangelia S; Karas, Panagiotis A; Nikolaki, Sofia; Storck, Veronika; Ferrari, Federico; Trevisan, Marco; Tsiamis, George; Martin-Laurent, Fabrice; Karpouzas, Dimitrios G

2016-11-01

Assessment of dissipation constitutes an integral part of pesticides risk assessment since it provides an estimate of the level and the duration of exposure of the terrestrial ecosystem to pesticides. Within the frame of an overall assessment of the soil microbial toxicity of pesticides, we investigated the dissipation of a range of dose rates of three model pesticides, isoproturon (IPU), tebuconazole (TCZ), and chlorpyrifos (CHL), and the formation and dissipation of their main transformation products following a tiered lab-to-field approach. The adsorption of pesticides and their transformation products was also determined. IPU was the least persistent pesticide showing a dose-dependent increase in its persistence in both laboratory and field studies. CHL dissipation showed a dose-dependent increase under laboratory conditions and an exact opposite trend in the field. TCZ was the most persistent pesticide under lab conditions showing a dose-dependent decrease in its dissipation, whereas in the field TCZ exhibited a biphasic dissipation pattern with extrapolated DT90s ranging from 198 to 603.4days in the ×1 and ×2 dose rates, respectively. IPU was demethylated to mono- (MD-IPU) and di-desmethyl-isoproturon (DD-IPU) which dissipated following a similar pattern with the parent compound. CHL was hydrolyzed to 3,5,6-trichloro-2-pyridinol (TCP) which dissipated showing a reverse dose-dependent pattern compared to CHL. Pesticides adsorption affinity increased in the order IPU

Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors, decreases ethanol consumption in alcohol-preferring UChB rats.

PubMed

Quiroz, Gabriel; Guerra-Díaz, Nicolás; Iturriaga-Vásquez, Patricio; Rivera-Meza, Mario; Quintanilla, María Elena; Sotomayor-Zárate, Ramón

2018-09-03

Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0 mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8 mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2 mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2 mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10 mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment. Copyright © 2018 Elsevier B.V. All rights reserved.

Bedtime Routines for Young Children: A Dose-Dependent Association with Sleep Outcomes

PubMed Central

Mindell, Jodi A.; Li, Albert M.; Sadeh, Avi; Kwon, Robert; Goh, Daniel Y.T.

2015-01-01

Background: Establishment of a consistent bedtime routine (the activities that occur right before lights out) is often recommended as part of healthy sleep habits. However, no studies have investigated the dose-dependent association of a bedtime routine with sleep outcomes, especially in young children for whom they are particularly recommended. Thus, the aim of this study was to examine the associations of a consistent bedtime routine with sleep outcomes in young children (ages 0 through 5 y) in a large global sample and assess whether there is a dose-dependent relationship between the frequency of a bedtime routine both concurrently and retrospectively with sleep outcomes. Participants: Mothers of 10,085 children (Australia-New Zealand, Canada, China, Hong Kong, India, Japan, Korea, Malaysia, Philippines, Singapore, Thailand, United Kingdom, United States) completed the Brief Infant/Child Sleep Questionnaire. Results: A consistent bedtime routine was associated with better sleep outcomes, including earlier bedtimes, shorter sleep onset latency, reduced night wakings, and increased sleep duration. Decreased parent-perceived sleep problems and daytime behavior problems were also related to institution of a regular bedtime routine. Furthermore, there was a dose-dependent relationship, with better outcomes associated with increased “doses” of having a bedtime routine, both currently and retrospectively, and was found within both predominantly Asian and predominantly Caucasian cultural regions. Conclusions: These results indicate that having a regular nightly bedtime routine is associated with improved sleep in young children, and suggests that the more consistently a bedtime routine is instituted and the younger started the better. Citation: Mindell JA, Li AM, Sadeh A, Kwon R, Goh DY. Bedtime routines for young children: a dose-dependent association with sleep outcomes. SLEEP 2015;38(5):717–722. PMID:25325483

Impact of the Nationwide Intravenous Selenium Product Shortage on the Development of Selenium Deficiency in Infants Dependent on Long-Term Parenteral Nutrition.

PubMed

Chen, Connie H; Harris, Mary Beth; Partipilo, M Luisa; Welch, Kathleen B; Teitelbaum, Daniel H; Blackmer, Allison B

2016-08-01

For patients dependent on parenteral nutrition (PN), selenium must be supplemented intravenously. A nationwide intravenous selenium shortage began in April 2011. The impact of this shortage on PN-dependent infants was evaluated by examining the provision of selenium, development of biochemical deficiency, and costs associated with the shortage. This single-center, retrospective study included PN-dependent infants aged ≤1 year who weighed ≤30 kg, received PN for ≥1 month, and had ≥1 serum selenium measurement. The primary outcome was the incidence of biochemical selenium deficiency. Secondary outcomes included severity of biochemical deficiency, clinical manifestations, costs, and relationship between serum selenium levels and selenium dose. The average selenium dose decreased 2-fold during the shortage (2.1 ± 1.2 µg/kg/d; range, 0.2-4.6 µg/kg/d) versus the nonshortage period (3.8 ± 1 µg/kg/d; range, 2.4-6 µg/kg/d; P < .001). A linear relationship between serum selenium concentration and selenium dose was observed (r(2) = 0.42), with a dose of 6 µg/kg/d expected to result in normal serum levels in most cases. Similar proportions of patients developed biochemical deficiency in both groups: shortage period, 59.1%; nonshortage, 66.7%; P = .13. The severity of biochemical deficiency was similar between groups. A significant increase in incremental cost during the shortage was observed. This is the first study examining the impact of the intravenous selenium shortage on PN-dependent infants. Both groups exhibited similarly high incidences of biochemical selenium deficiency, suggesting higher empiric doses may benefit this population. However, ongoing shortages limit the ability to provide supplementation. © 2015 American Society for Parenteral and Enteral Nutrition.

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

PubMed Central

Todd, John A.; Porter, Linsey; Smyth, Deborah J.; Rainbow, Daniel B.; Ferreira, Ricardo C.; Yang, Jennie H.; Bell, Charles J. M.; Schuilenburg, Helen; Challis, Ben; Clarke, Pamela; Coleman, Gillian; Dawson, Sarah; Goymer, Donna; Kennet, Jane; Brown, Judy; Greatorex, Jane; Goodfellow, Ian; Evans, Mark; Mander, Adrian P.; Bond, Simon; Wicker, Linda S.

2016-01-01

Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015–0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%–48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%–85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only. Conclusions The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2–3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%–50%, with the eventual goal of preventing T1D. Trial Registration ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735 PMID:27727279

Dose-dependent heart rate reducing effect of nizatidine, a histamine H2-receptor antagonist.

PubMed Central

Hinrichsen, H; Halabi, A; Fuhrmann, G; Kirch, W

1993-01-01

1. Twelve healthy subjects were treated in a randomised placebo-controlled crossover study with placebo, 150 mg, 300 mg, and 600 mg nizatidine, 100 mg pirenzepine, and 300 mg nizatidine plus 100 mg pirenzepine for 1 week each. 2. On the seventh treatment day, heart rate, blood pressure, systolic time intervals, impedance cardiographic and Doppler ultrasound variables were measured. 3. Stroke volume and blood pressure were not altered by nizatidine and/or pirenzepine. By contrast, heart rate and cardiac output significantly (P < 0.05) decreased in a dose-dependent manner 1.5 and 3 h after administration of 300 and 600 mg nizatidine. Treatment with 150 mg nizatidine led to similar though non-significant trends. 4. While a slightly insignificant rise in heart rate was detected with pirenzepine alone, heart rate and cardiac output remained unchanged upon combined nizatidine and pirenzepine treatment as compared with placebo and baseline values. 5. In conclusion, nizatidine reduced heart rate and cardiac output in a dose-dependent manner, whereas this negative chronotropic effect was counteracted by concurrent administration of the anti-cholinergic drug pirenzepine. PMID:8099802

Dependences of mucosal dose on photon beams in head-and-neck intensity-modulated radiation therapy: a Monte Carlo study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chow, James C.L., E-mail: james.chow@rmp.uhn.on.ca; Department of Radiation Oncology, University of Toronto, Toronto, Ontario; Department of Physics, Ryerson University, Toronto, Ontario

2012-07-01

Dependences of mucosal dose in the oral or nasal cavity on the beam energy, beam angle, multibeam configuration, and mucosal thickness were studied for small photon fields using Monte Carlo simulations (EGSnrc-based code), which were validated by measurements. Cylindrical mucosa phantoms (mucosal thickness = 1, 2, and 3 mm) with and without the bone and air inhomogeneities were irradiated by the 6- and 18-MV photon beams (field size = 1 Multiplication-Sign 1 cm{sup 2}) with gantry angles equal to 0 Degree-Sign , 90 Degree-Sign , and 180 Degree-Sign , and multibeam configurations using 2, 4, and 8 photon beams inmore » different orientations around the phantom. Doses along the central beam axis in the mucosal tissue were calculated. The mucosal surface doses were found to decrease slightly (1% for the 6-MV photon beam and 3% for the 18-MV beam) with an increase of mucosal thickness from 1-3 mm, when the beam angle is 0 Degree-Sign . The variation of mucosal surface dose with its thickness became insignificant when the beam angle was changed to 180 Degree-Sign , but the dose at the bone-mucosa interface was found to increase (28% for the 6-MV photon beam and 20% for the 18-MV beam) with the mucosal thickness. For different multibeam configurations, the dependence of mucosal dose on its thickness became insignificant when the number of photon beams around the mucosal tissue was increased. The mucosal dose with bone was varied with the beam energy, beam angle, multibeam configuration and mucosal thickness for a small segmental photon field. These dosimetric variations are important to consider improving the treatment strategy, so the mucosal complications in head-and-neck intensity-modulated radiation therapy can be minimized.« less

Study of damage to red blood cells exposed to different doses of γ-ray irradiation.

PubMed

Xu, Deyi; Peng, Mingxi; Zhang, Zhe; Dong, Guofei; Zhang, Yiqin; Yu, Hongwei

2012-07-01

The aims of this research were to study alterations in the ultrastructure of red blood cells, the changes in concentrations of plasma electrolytes and the killing effect of lymphocytes in samples of blood exposed to different doses of γ-ray irradiation. Blood samples were treated with different doses of γ-ray irradiation and then preserved for different periods. Specimens were prepared for standard electron microscopy and transmission electron microscopy. At the same time, changes in the concentrations of Na(+), K(+) and Cl(-) and pH values in the plasma as well as Fas and FasL expression of lymphocytes before and after irradiation were determined. The proportions of reversibly and irreversibly transformed cells, for example, echinocytes, sphero-echinocytes, and degenerated forms, increased with increasing doses of irradiation and storage period, while the number of discocyte shaped red blood cells decreased. The change in K(+) concentration was greater than that of Na+ or Cl(-) after irradiation and was dosage-dependent. Plasma pH was influenced by different doses of radiation and storage time. After exposure to (137)Cs γ-irradiation, the expression of both Fas and FasL in lymphocytes differed significantly from that in the control group: the expression was positively correlated with irradiation dose (r=0.95, 0.96), but no significant difference in the Fas/FasL ratio was observed (P>0.05). We conclude that the ultrastructure of red blood cells is not changed obviously by irradiation with some doses of γ-rays and various periods of storage. However, irradiation does have some dose-dependent and time-dependent adverse effects on the erythrocytes.

Ocular allergy modulation to hi-dose antigen sensitization is a Treg-dependent process.

PubMed

Lee, Hyun Soo; Schlereth, Simona; Khandelwal, Payal; Saban, Daniel R

2013-01-01

A reproducible method to inhibit allergic immune responses is accomplished with hi-dose Ag sensitization, via intraperitoneal (IP) injection. However, the role of CD4+ CD25+ FoxP3+ T regulatory cells (Treg) in this process is unknown, as is whether such modulation extends to ocular allergy. We therefore determined herein whether hi-dose sensitization modulates ocular allergy, and whether CD4+ CD25+ FoxP3+ Treg are involved. C57BL/6 mice were IP sensitized via low-dose (100 µg) versus hi-dose (1000 µg) ovalbumin (OVA), in aluminum hydroxide (1 mg) and pertussis-toxin (300 ng). Other mice received anti-CD25 Ab (PC61) to ablate Treg during sensitization. In another experiment, Treg from hi-dose sensitized mice were adoptively transferred into low-dose sensitized mice. Once daily OVA challenges were administered. Clinical signs, IgE, T cell cytokines, and eosinophils were assessed. Data revealed that hi-dose, but not low-dose, sensitization led to allergy modulation, indicated by decreased clinical signs, serum IgE levels, Th2 recall responses, and eosinophil recruitment. T cells from hi-dose sensitized mice showed a robust increase in TGF-b production, and Treg from these mice were able to efficiently suppress effector T cell proliferation in vitro. In addition, in vivo Treg ablation in hi-dose sensitized mice revoked allergy modulation. Lastly, Treg from hi-dose sensitized mice were able to adoptively transfer allergy modulation to their low-dose sensitized counterparts. Collectively, these findings indicate that modulation to hi-dose sensitization, which is extended to ocular allergy, occurs in a Treg-dependent manner. In addition, our data suggest that hi-dose sensitization may henceforth facilitate the further examination of CD4+ CD25+ FoxP3+ Treg in allergic disease.

Magnetic-field-induced dose effects in MR-guided radiotherapy systems: dependence on the magnetic field strength.

PubMed

Raaijmakers, A J E; Raaymakers, B W; Lagendijk, J J W

2008-02-21

Several institutes are currently working on the development of a radiotherapy treatment system with online MR imaging (MRI) modality. The main difference between their designs is the magnetic field strength of the MRI system. While we have chosen a 1.5 Tesla (T) magnetic field strength, the Cross Cancer Institute in Edmonton will be using a 0.2 T MRI scanner and the company Viewray aims to use 0.3 T. The magnetic field strength will affect the severity of magnetic field dose effects, such as the electron return effect (ERE): considerable dose increase at tissue air boundaries due to returning electrons. This paper has investigated how the ERE dose increase depends on the magnetic field strength. Therefore, four situations where the ERE occurs have been simulated: ERE at the distal side of the beam, the lateral ERE, ERE in cylindrical air cavities and ERE in the lungs. The magnetic field comparison values were 0.2, 0.75, 1.5 and 3 T. Results show that, in general, magnetic field dose effects are reduced at lower magnetic field strengths. At the distal side, the ERE dose increase is largest for B = 0.75 T and depends on the irradiation field size for B = 0.2 T. The lateral ERE is strongest for B = 3 T but shows no effect for B = 0.2 T. Around cylindrical air cavities, dose inhomogeneities disappear if the radius of the cavity becomes small relative to the in-air radius of the secondary electron trajectories. At larger cavities (r > 1 cm), dose inhomogeneities exist for all magnetic field strengths. In water-lung-water phantoms, the ERE dose increase takes place at the water-lung transition and the dose decreases at the lung-water transition, but these effects are minimal for B = 0.2 T. These results will contribute to evaluating the trade-off between magnetic field dose effects and image quality of MR-guided radiotherapy systems.

GABAergic modulation of human social interaction in a prisoner's dilemma model by acute administration of alprazolam.

PubMed

Lane, Scott D; Gowin, Joshua L

2009-10-01

Recent work in neuroeconomics has used game theory paradigms to examine neural systems that subserve human social interaction and decision making. Attempts to modify social interaction through pharmacological manipulation have been less common. Here we show dose-dependent modification of human social behavior in a prisoner's dilemma model after acute administration of the γ-aminobutyric acid (GABA)-A modulating benzodiazepine alprazolam. Nine healthy adults received doses of placebo, 0.5, 1.0, and 2.0 mg alprazolam in a counterbalanced within-subject design, while completing multiple test blocks per day on an iterated prisoner's dilemma game. During test blocks in which peak subjective effects of alprazolam were reported, cooperative choices were significantly decreased as a function of dose. Consistent with previous reports showing that high acute doses of GABA-modulating drugs are associated with violence and other antisocial behavior, our data suggest that at sufficiently high doses, alprazolam can decrease cooperation. These behavioral changes may be facilitated by changes in inhibitory control facilitated by GABA. Game theory paradigms may prove useful in behavioral pharmacology studies seeking to measure social interaction, and may help inform the emerging field of neuroeconomics.

GABAergic modulation of human social interaction in a prisoner’s dilemma model via acute administration of alprazolam

PubMed Central

Lane, Scott D.; Gowin, Joshua L.

2010-01-01

Recent work in neuroeconomics has utilized game theory paradigms to examine neural systems that subserve human social interaction and decision making. Attempts to modify social interaction through pharmacological manipulation have been less common. Here we show dose-dependent modification of human social behavior in a prisoner’s dilemma (PD) model following acute administration of the GABA-A modulating benzodiazepine alprazolam. Nine healthy adults received doses of placebo, 0.5, 1.0, and 2.0 mg alprazolam in a counterbalanced within-subject design, while completing multiple test blocks per day on an iterated PD game. During test blocks in which peak subjective effects of alprazolam were reported, cooperative choices were significantly decreased as a function of dose. Consistent with previous reports showing that high acute doses of GABA-modulating drugs are associated with violence and other antisocial behavior, our data suggest that at sufficiently high doses, alprazolam can decrease cooperation. These behavioral changes may be facilitated by changes in inhibitory control facilitated by GABA. Game theory paradigms may prove useful in behavioral pharmacology studies seeking to measure social interaction, and may help inform the emerging field of neuroeconomics. PMID:19667972

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PubMed

Vučićević, Katarina; Jovanović, Marija; Golubović, Bojana; Kovačević, Sandra Vezmar; Miljković, Branislava; Martinović, Žarko; Prostran, Milica

2015-02-01

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

Effect of somatostatin on meal-induced gastric secretion in duodenal ulcer patients.

PubMed

Konturek, S J; Swierczek, J; Kwiecień, N; Mikoś, E; Oleksy, J; Wierzbicki, Z

1977-11-01

The effect of somatostatin, a growth hormone releasing-inhibiting hormone (GH-RIH) on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 microgram/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 microgram/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dose-dependent reduction in serum growth hormone and insulin levels measured by radioimmunoassay. GH-RIH used in a single dose of 2.5 microgram/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.

Effect of ganaxolone and THIP on operant and limited-access ethanol self-administration

PubMed Central

Ramaker, Marcia J.; Strong, Moriah N.; Ford, Matthew M.; Finn, Deborah A.

2013-01-01

Recent evidence suggests that GABAA receptor ligands may regulate ethanol intake via effects at both synaptic and extrasynaptic receptors. For example, the endogenous neurosteroid, allopregnanolone (ALLO) has a similar pharmacological profile as ethanol, and it alters ethanol intake in rodent models. Additionally, recent evidence suggests that δ-subunit containing extrasynaptic GABAA receptors may confer high sensitivity to both ethanol and neurosteroids. The purpose of the present study was to determine the effects of ganaxolone (GAN; an ALLO analogue) and gaboxadol (THIP; a GABAA receptor agonist with selectivity for the extrasynaptic δ-subunit) on ethanol intake, drinking patterns, and bout characteristics in operant and limited access self-administration procedures. In separate studies, the effects of GAN (0 – 10 mg/kg) and THIP (2 – 16 mg/kg) were tested in C57BL/6J male mice provided with two-hour access to a two-bottle choice of water or 10% ethanol or trained to respond for 30 minutes of access to 10% ethanol. GAN had no overall significant effect on operant ethanol self-administration, but tended to decrease the latency to consume the first bout. In the limited-access procedure, GAN dose-dependently decreased ethanol intake. THIP dose-dependently decreased ethanol intake in both paradigms, altering both the consummatory and appetitive processes of operant self-administration as well as shifting the drinking patterns in both procedures. These results add to literature suggesting time-dependent effects of neurosteroids to promote the onset, and to subsequently decrease, ethanol drinking behavior, and they support a role for extrasynaptic GABAA receptor activation in ethanol reinforcement. PMID:22613838

Interleukin-6 Directly Impairs the Erythroid Development of Human TF-1 Erythroleukemic Cells

PubMed Central

McCranor, Bryan J.; Kim, Min Jung; Cruz, Nicole M.; Xue, Qian-Li; Berger, Alan E.; Walston, Jeremy D.; Civin, Curt I.; Roy, Cindy N.

2013-01-01

Anemia of inflammation or chronic disease is a highly prevalent form of anemia. The inflammatory cytokine interleukin-6 (IL-6) negatively correlates with hemoglobin concentration in many disease states. The IL-6-hepcidin antimicrobial peptide axis promotes iron-restricted anemia; however the full role of IL-6 in anemia of inflammation is not well-defined. We previously reported that chronic inflammation had a negative impact on maturation of erythroid progenitors in a mouse model. We hypothesized that IL-6 may be responsible for impaired erythropoiesis, independent of iron restriction. To test the hypothesis we utilized the human erythroleukemia TF-1 cell line to model erythroid maturation and exposed them to varying doses of IL-6 over six days. At 10 ng/ml, IL-6 significantly repressed erythropoietin-dependent TF-1 erythroid maturation. While IL-6 did not decrease the expression of genes associated with hemoglobin synthesis, we observed impaired hemoglobin synthesis as demonstrated by decreased benzidine staining. We also observed that IL-6 down regulated expression of the gene SLC4a1 which is expressed late in erythropoiesis. Those findings suggested that IL-6-dependent inhibition of hemoglobin synthesis might occur. We investigated the impact of IL-6 on mitochondria. IL-6 decreased the mitochondrial membrane potential at all treatment doses, and significantly decreased mitochondrial mass at the highest dose. Our studies indicate that IL-6 may impair mitochondrial function in maturing erythroid cells resulting in impaired hemoglobin production and erythroid maturation. Our findings may indicate a novel pathway of action for IL-6 in the anemia of inflammation, and draw attention to the potential for new therapeutic targets that affect late erythroid development. PMID:24119518

Intranasal Opioid Administration in Rhesus Monkeys: PET Imaging and Antinociception.

PubMed

Saccone, Phillip A; Lindsey, Angela M; Koeppe, Robert A; Zelenock, Kathy A; Shao, Xia; Sherman, Phillip; Quesada, Carole A; Woods, James H; Scott, Peter J H

2016-11-01

The goal of this study was to evaluate the effects of intranasally administered opioids in rhesus monkeys using the tail-withdrawal assay, and to correlate these effects with measures of receptor occupancy using positron emission tomography (PET) imaging. Initial experiments characterized the antinociceptive effects of intranasal (IN) fentanyl and buprenorphine relative to intramuscular (IM) injection. Fentanyl (0.010-0.032 mg/kg) and buprenorphine (0.1-1.0 mg/kg) produced dose-dependent increases in tail-withdrawal latency that did not differ between routes of delivery. The second experiment compared the ability of IN and intravenous (IV) naloxone (NLX) to block the antinociceptive effects IV fentanyl, and to measure receptor occupancy at equipotent doses of NLX using PET imaging. IN and IV NLX (0.0032-0.032 mg/kg) produced dose-dependent decreases in fentanyl-induced antinociception. Again, there was no difference observed in overall potency between routes. PET imaging showed that IV and IN NLX produced similar decreases in receptor occupancy as measured by [ 11 C]carfentanil blocking, although there was a trend for IV NLX to produce marginally greater occupancy changes. This study validated the first procedures to evaluate the IN effects of opioids in rhesus monkeys. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Intensity-modulated radiotherapy in the standard management of head and neck cancer: promises and pitfalls.

PubMed

Mendenhall, William M; Amdur, Robert J; Palta, Jatinder R

2006-06-10

The purpose of this article is to review the role of intensity-modulated radiotherapy (IMRT) in the standard management of patients with head and neck cancer through a critical review of the pertinent literature. IMRT may result in a dose distribution that is more conformal than that achieved with three-dimensional conformal radiotherapy (3D CRT), allowing dose reduction to normal structures and thus decreasing toxicity and possibly enhancing locoregional control through dose escalation. Disadvantages associated with IMRT include increased risk of a marginal miss, decreased dose homogeneity, increased total body dose, and increased labor and expense. Outcomes data after IMRT are limited, and follow-up is relatively short. Locoregional control rates appear to be comparable to those achieved with 3D CRT and, depending on the location and extent of the tumor, late toxicity may be lower. Despite limited data on clinical outcomes, IMRT has been widely adopted as a standard technique in routine practice and clinical trials. The use of IMRT involves a learning curve for the practitioner and will continue to evolve, requiring continuing education and monitoring of outcomes from routine practice. Additional standards pertaining to a variety of issues, including target definitions and dose specification, need to be developed. Phase III trials will better define the role of IMRT in coming years.

Effect of ultra-low doses, ASIR and MBIR on density and noise levels of MDCT images of dental implant sites.

PubMed

Widmann, Gerlig; Al-Shawaf, Reema; Schullian, Peter; Al-Sadhan, Ra'ed; Hörmann, Romed; Al-Ekrish, Asma'a A

2017-05-01

Differences in noise and density values in MDCT images obtained using ultra-low doses with FBP, ASIR, and MBIR may possibly affect implant site density analysis. The aim of this study was to compare density and noise measurements recorded from dental implant sites using ultra-low doses combined with FBP, ASIR, and MBIR. Cadavers were scanned using a standard protocol and four low-dose protocols. Scans were reconstructed using FBP, ASIR-50, ASIR-100, and MBIR, and either a bone or standard reconstruction kernel. Density (mean Hounsfield units [HUs]) of alveolar bone and noise levels (mean standard deviation of HUs) was recorded from all datasets and measurements were compared by paired t tests and two-way ANOVA with repeated measures. Significant differences in density and noise were found between the reference dose/FBP protocol and almost all test combinations. Maximum mean differences in HU were 178.35 (bone kernel) and 273.74 (standard kernel), and in noise, were 243.73 (bone kernel) and 153.88 (standard kernel). Decreasing radiation dose increased density and noise regardless of reconstruction technique and kernel. The effect of reconstruction technique on density and noise depends on the reconstruction kernel used. • Ultra-low-dose MDCT protocols allowed more than 90 % reductions in dose. • Decreasing the dose generally increased density and noise. • Effect of IRT on density and noise varies with reconstruction kernel. • Accuracy of low-dose protocols for interpretation of bony anatomy not known. • Effect of low doses on accuracy of computer-aided design models unknown.

Physiological responses to glyphosate are dependent on Eucalyptus urograndis genotype

USDA-ARS?s Scientific Manuscript database

Two experiments were conducted to evaluate the response of Eucalyptus urograndis genotypes (C219 and GG100) to glyphosate in growth chambers. As glyphosate dose increased (18 up to 720 g ae ha-1), CO2 assimilation rate, transpiration rate, and stomatal conductance decreased fastest and strongest in ...

GESTATIONAL PFOA EXPOSURE OF MICE IS ASSOCIATED WITH ALTERED MAMMARY GLAND DEVELOPMENT IN DAMS AND FEMALE OFFSPRING

EPA Science Inventory

Perfluorooctanoic acid (PFOA), with diverse and widespread commercial and industrial applications, has been detected in human and wildlife sera. Previous mouse studies linked prenatal PFOA exposure to decreased neonatal body weights (BWs) and survival in a dose-dependent manner. ...

Environmentally Realistic Mixtures of the Five Regulated Haloacetic Acids Exhibit Concentration-Dependent Departures from Dose Additivity

EPA Science Inventory

Disinfection of water decreases waterborne disease. Disinfection byproducts (DBPs) are formed by the reaction of oxidizing disinfectants with inorganic and organic materials in the source water. The U.S. EPA regulates five haloacetic acid (HAA) DBPs as a mixture. The objective ...

Avoidance of physical activity is a sensitive indicator of illness.

PubMed

Skinner, Gregory W; Mitchell, Duncan; Harden, Lois M

2009-03-02

Although fever and sickness behavior are common responses to infection, it has been proposed that the sickness behaviors associated with infection, in particular lethargy and fatigue, may be more valuable clinical markers of illness and recovery in patients, than is body temperature alone. Measuring abdominal temperature, food intake and wheel running we therefore determined the dose thresholds and sensitivities of these responses to lipopolysaccharide (LPS). Male Sprague-Dawley rats were randomly assigned to receive one of three LPS doses (10, 50, 250 microg/kg), or saline, subcutaneously. Administration of LPS induced a dose-dependent increase in abdominal temperature and decrease in wheel running, food intake and body mass. Regression analysis revealed that decreased running was the most-sensitive of the sickness responses to LPS administration, with a regression slope of -41%/log microg, compared to the slopes for food intake (-30%/log microg, F(1,2)=244, P=0.004) and body mass (-2.2%/log microg, F(1,5)=7491, P<0.0001). To determine the likelihood that exercise training influenced the sickness responses we measured in our dose-response study we performed a second experiment in which we investigated whether fever and anorexia induced by LPS administration would present differently depending on whether rats had been exercising or sedentary. Six weeks of wheel running had no effect on the magnitude of fever and anorexia induced by LPS administration. Avoidance of physical activity therefore appears to be a more-sensitive indicator of a host's reaction to LPS than is anorexia and fever.

Dosimetric characteristics of a PIN diode for radiotherapy application.

PubMed

Kumar, R; Sharma, S D; Philomina, A; Topkar, A

2014-08-01

The PIN diode developed by Bhabha Atomic Research Centre (BARC) was modified for its use as a dosimeter in radiation therapy. For this purpose the diode was mounted on a printed circuit board (PCB) and provided with necessary connections so that its response against irradiation can be recorded by a standard radiotherapy electrometer. The dosimetric characteristics of the diode were studied in Co-60 gamma rays as well as high energy X-rays. The measured sensitivity of this PIN diode is 4 nC/cGy which is about ten times higher than some commercial diode dosimeters. The leakage current from the diode is 0.04 nA. The response of the PIN diode is linear in the range of 20-1000 cGy which covers the full range of radiation dose encountered in radiotherapy treatments. The non-linearity of the diode response is 3.5% at 20 cGy and it is less than 1.5% at higher dose values. Its repeatability is within 0.5%. The angular response variation is about 5.6% within 6608 with respect to normal beam incidence. The response of the PIN diode at 6 and 18 MV X-rays varies within 2% with respect to its response at Co-60 gamma rays. The source to surface distance (SSD) dependence of the PIN diode was studied for Co-60 beam. It was found that the response of the diode decreases almost linearly relative to given dose for beams with constant collimator setting but increasing SSD (decreasing dose-rate). Within this study the diode response varied by about 2.5% between the maximum and minimum SSD. The dose-rate dependence of the PIN diode for 6 and 15 MV-rays was studied. The variation in response of diode for both energies in the studied dose range is less than 1%. The field size dependence of the PIN diode response is within 1% with respect to the response of ionisation chamber. These studies indicate that the characteristics of the PIN diode are suitable for use in radiotherapy dosimetry.

Acute oral dose of sodium nitrite induces redox imbalance, DNA damage, metabolic and histological changes in rat intestine.

PubMed

Ansari, Fariheen Aisha; Ali, Shaikh Nisar; Arif, Hussain; Khan, Aijaz Ahmed; Mahmood, Riaz

2017-01-01

Industrialization and unchecked use of nitrate/nitrite salts for various purposes has increased human exposure to high levels of sodium nitrite (NaNO2) which can act as a pro-oxidant and pro-carcinogen. Oral exposure makes the gastrointestinal tract particularly susceptible to nitrite toxicity. In this work, the effect of administration of a single acute oral dose of NaNO2 on rat intestine was studied. Animals were randomly divided into four groups and given single doses of 20, 40, 60 and 75 mg NaNO2/kg body weight. Untreated animals served as the control group. An NaNO2 dose-dependent decline in the activities of brush border membrane enzymes, increase in lipid peroxidation, protein oxidation, hydrogen peroxide levels and decreased thiol content was observed in all treated groups. The activities of various metabolic and antioxidant defense enzymes were also altered. NaNO2 induced a dose-dependent increase in DNA damage and DNA-protein crosslinking. Histopathological studies showed marked morphological damage in intestinal cells. The intestinal damage might be due to nitrite-induced oxidative stress, direct action of nitrite anion or chemical modification by reaction intermediates.

Effect of gamma irradiation on the properties of tyre cords

NASA Astrophysics Data System (ADS)

Aytaç, Ayşe; Şen, Murat; Deniz, Veli; Güven, Olgun

2007-12-01

Gamma irradiation of high tenacity Nylon 6.6 (Ny 66) and polyester (PET) tyre cords was investigated. The untreated and treated tyre cords with different twist levels were irradiated at different dose rates in air. The effects of irradiation on both Ny 66 and PET cords were not found to be depending on the twist levels of the cords. The changes in the mechanical and thermal properties with absorbed dose at two different dose rates were measured. The mechanical properties were observed to deteriorate with increasing dose for Ny 66 cords, whereas remained almost unchanged for PET cords both in greige and dipped forms. Hot shrinkage value for the greige Ny 66 cords was found to be improved, i.e. decreased. This decrease was much lower for greige PET than Ny 66 cords. It is concluded that PET cord has higher radiation resistance than Ny 66 cord and the effects of high energy irradiation on tyre cords have to be taken into consideration during tyre design if pre-vulcanization with high energy radiation is to be applied.

Structural, thermal, functional, antioxidant & antimicrobial properties of β-d-glucan extracted from baker's yeast (Saccharomyces cereviseae)-Effect of γ-irradiation.

PubMed

Khan, Asma Ashraf; Gani, Adil; Masoodi, F A; Amin, Furheen; Wani, Idrees Ahmed; Khanday, Firdous Ahmad; Gani, Asir

2016-04-20

This study was carried out to evaluate the effect of γ-irradiation (0, 5, 10, 20, 30 & 50kGy) on the structural, functional, antioxidant and antimicrobial properties of yeast β-d-glucan. The samples were characterized by ATR-FTIR, gel permeation chromatography (GPC) and the thermal properties were studied using DSC. There was a decrease in the average molecular weight of β-d-glucan as the irradiation dose increased. The functional properties of irradiated yeast β-d-glucan were largely influenced by the action of gamma radiation like swelling power and viscosity decreases with increase in the irradiation dose while as fat binding capacity, emulsifying properties, foaming properties and bile acid binding capacity shows an increasing trend. All the antioxidant properties carried out using six different assays increased significantly (p≤0.05) in a dose dependent manner. The antibacterial activity of yeast β-d-glucan also showed an increasing trend with increase in the irradiation dose from 5 to 50kDa. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigation of temperature dependence of fracture toughness in high-dose HT9 steel using small-specimen reuse technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baek, Jong-Hyuk; Byun, Thak Sang; Maloy, Stuart A.

2014-01-01

The temperature dependence of fracture toughness in HT9 steel irradiated to 3–145 dpa at 380–503 degrees*C was investigated using miniature three-point bend (TPB) fracture specimens. A miniature-specimen reuse technique has been established: the tested halves of subsize Charpy impact specimens with dimensions of 27 mm *3mm* 4 mm were reused for this fracture test campaign by cutting a notch with a diamond-saw in the middle of each half, and by fatigue-precracking to generate a sharp crack tip. It was confirmed that the fracture toughness of HT9 steel in the dose range depends more strongly on the irradiation temperature than themore » irradiation dose. At an irradiation temperature <430 *degreesC, the fracture toughness of irradiated HT9 increased with the test temperature, reached an upper shelf of 180—200 MPa*m^.5 at 350–450 degrees*C, and then decreased with the test temperature. At an irradiation temperature >430 degrees*C, the fracture toughness was nearly unchanged up to about 450 *degreesC and decreased slowly with test temperatures in a higher temperature range. Such a rather monotonic test temperature dependence after high-temperature irradiation is similar to that observed for an archive material generally showing a higher degree of toughness. A brittle fracture without stable crack growth occurred in only a few specimens with relatively lower irradiation and test temperatures. In this discussion, these TPB fracture toughness data are compared with previously published data from 12.7 mm diameter disc compact tension (DCT) specimens.« less

Long-Term Effects of Radiation Exposure and Metabolic Status on Telomere Length of Peripheral Blood T Cells in Atomic Bomb Survivors.

PubMed

Yoshida, Kengo; Misumi, Munechika; Kubo, Yoshiko; Yamaoka, Mika; Kyoizumi, Seishi; Ohishi, Waka; Hayashi, Tomonori; Kusunoki, Yoichiro

2016-10-01

In a series of studies of atomic bomb survivors, radiation-dose-dependent alterations in peripheral T-cell populations have been reported. For example, reduced size in naïve T-cell pools and impaired proliferation ability of T cells were observed. Because these alterations are also generally observed with human aging, we hypothesized that radiation exposure may accelerate the aging process of the T-cell immune system. To further test this hypothesis, we conducted cross-sectional analyses of telomere length, a hallmark of cellular aging, of naïve and memory CD4 T cells and total CD8 T cells in the peripheral blood of 620 atomic bomb survivors as it relates to age and radiation dose, using fluorescence in situ hybridization with flow cytometry. Since telomere shortening has been recently demonstrated in obesity-related metabolic abnormalities and diseases, the modifying effects of metabolic status were also examined. Our results indicated nonlinear relationships between T-cell telomere length and prior radiation exposure, i.e., longer telomeres with lower dose exposure and a decreasing trend of telomere length with individuals exposed to doses higher than 0.5 Gy. There were associations between shorter T-cell telomeres and higher hemoglobin Alc levels or fatty liver development. In naïve and memory CD4 T cells, radiation dose and high-density lipoprotein (HDL) cholesterol were found to positively interact with telomere length, suggesting that the decreasing trend of telomere length from a higher radiation dose was less conspicuous in individuals with a higher HDL cholesterol. It is therefore likely that radiation exposure perturbs T-cell homeostasis involving telomere length maintenance by multiple biological mechanisms, depending on dose, and that long-term-radiation-induced effects on the maintenance of T-cell telomeres may be modified by the subsequent metabolic conditions of individuals.

Paclitaxel Induces Apoptosis in Breast Cancer Cells through Different Calcium—Regulating Mechanisms Depending on External Calcium Conditions

PubMed Central

Pan, Zhi; Avila, Andrew; Gollahon, Lauren

2014-01-01

Previously, we reported that endoplasmic reticulum calcium stores were a direct target for paclitaxel initiation of apoptosis. Furthermore, the actions of paclitaxel attenuated Bcl-2 resistance to apoptosis through endoplasmic reticulum-mediated calcium release. To better understand the calcium-regulated mechanisms of paclitaxel-induced apoptosis in breast cancer cells, we investigated the role of extracellular calcium, specifically; whether influx of extracellular calcium contributed to and/or was necessary for paclitaxel-induced apoptosis. Our results demonstrated that paclitaxel induced extracellular calcium influx. This mobilization of extracellular calcium contributed to subsequent cytosolic calcium elevation differently, depending on dosage. Under normal extracellular calcium conditions, high dose paclitaxel induced apoptosis-promoting calcium influx, which did not occur in calcium-free conditions. In the absence of extracellular calcium an “Enhanced Calcium Efflux” mechanism in which high dose paclitaxel stimulated calcium efflux immediately, leading to dramatic cytosolic calcium decrease, was observed. In the absence of extracellular calcium, high dose paclitaxel’s stimulatory effects on capacitative calcium entry and apoptosis could not be completely restored. Thus, normal extracellular calcium concentrations are critical for high dose paclitaxel-induced apoptosis. In contrast, low dose paclitaxel mirrored controls, indicating that it occurs independent of extracellular calcium. Thus, extracellular calcium conditions only affect efficacy of high dose paclitaxel-induced apoptosis. PMID:24549172

Cardiovascular effects of medetomidine, detomidine and xylazine in horses.

PubMed

Yamashita, K; Tsubakishita, S; Futaok, S; Ueda, I; Hamaguchi, H; Seno, T; Katoh, S; Izumisawa, Y; Kotani, T; Muir, W W

2000-10-01

The cardiovascular effects of medetomidine, detomidine, and xylazine in horses were studied. Fifteen horses, whose right carotid arteries had previously been surgically raised to a subcutaneous position during general anesthesia were used. Five horses each were given the following 8 treatments: an intravenous injection of 4 doses of medetomidine (3, 5, 7.5, and 10 microg/kg), 3 doses of detomidine (10, 20, and 40 microg/kg), and one dose of xylazine (1 mg/kg). Heart rate decreased, but not statistically significant. Atrio-ventricular block was observed following all treatments and prolonged with detomidine. Cardiac index (CI) and stroke volume (SV) were decreased with all treatments. The CI decreased to about 50% of baseline values for 5 min after 7.5 and 10 microg/kg medetomidine and 1 mg/kg xylazine, for 20 min after 20 microg/kg detomidine, and for 50 min after 40 microg/kg detomidine. All treatments produced an initial hypertension within 2 min of drug administration followed by a significant decrease in arterial blood pressure (ABP) in horses administered 3 to 7.5 microg/kg medetomidine and 1 mg/kg xylazine. Hypertension was significantly prolonged in 20 and 40 microg/kg detomidine. The hypotensive phase was not observed in 10 microg/kg medetomidine or detomidine. The changes in ABP were associated with an increase in peripheral vascular resistance. Respiratory rate was decreased for 40 to 120 min in 5, 7.5, and 10 microg/kg medetomidine and detomidine. The partial pressure of arterial oxygen decreased significantly in 10 microg/kg medetomidine and detomidine, while the partial pressure of arterial carbon dioxide did not change significantly. Medetomidine induced dose-dependent cardiovascular depression similar to detomidine. The cardiovascular effects of medetomidine and xylazine were not as prolonged as that of detomidine.

Investigation into the mechanism(s) that leads to platelet decreases in cynomolgus monkeys during administration of ISIS-104838, a 2'-MOE-modified antisense oligonucleotide.

PubMed

Narayanan, P K; Shen, L; Curtis, B R; Bourdon, M; Nolan, J P; Zhou, F; Christian, B; Gupta, S; Schaubhut, J L; Greenlee, S; Hoffmaster, C; Burel, S; Witztum, J L; Engelhardt, J A; Henry, S P

2018-05-29

ISIS 104838, a 2'-O-methoxyethyl (2'-MOE)-modified antisense oligonucleotide (ASO), causes a moderate, reproducible, dose-dependent, but self-limiting decrease in platelet (PLT) counts in monkeys and humans. To determine the etiology of PLT decrease in cynomolgus monkeys, a 12-week repeat dose toxicology study in 5 cynomolgus monkeys given subcutaneous injections of ISIS 104838 (30 to 60 mg/kg/week). Monkeys were also injected intravenously with 111In-oxine-labeled PLTs to investigate PLT sequestration. In response to continued dosing, PLT counts were decreased by 50 to 90% by day 30 in all monkeys. PLT decreases were accompanied by 2- to 4.5-fold increases in immunoglobulin M(IgM), which were typified by a 2-to-5-fold increase in anti-platelet factor 4 (PF4) IgM and anti-PLT IgM, respectively. Monocyte chemotactic protein 1 (MCP-1) increased upon dosing of ISIS 104838, concomitant with a 2- to 6-fold increase in monocyte-derived extracellular vesicles (EVs), indicating monocyte activation but not PLT activation. Despite a 2- to- 3-fold increase in von Willebrand factor (VWF) antigen in all monkeys following ASO administration, only two monkeys showed a 2 to 4-fold increase in endothelial EVs. Additionally, a 25-45% increase in PLT sequestration in liver and spleen was also observed. Collectively, these results suggest the overall increase in total IgM, anti-PLT IgM and/or anti-PF4 IgM, in concert with monocyte activation contributed to increased PLT sequestration in spleen and liver, leading to decreased PLTs in peripheral blood.

SU-F-18C-12: On the Relationship of the Weighted Dose to the Surface Dose In Abdominal CT - Patient Size Dependency

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Y; Scott, A; Allahverdian, J

2014-06-15

Purpose: It is possible to measure the patient surface dose non-invasively using radiolucent dosimeters. However, the patient size specific weighted dose remains unknown. We attempted to study the weighted dose to surface dose relationship as the patient size varies in abdominal CT. Methods: Seven abdomen phantoms (CIRS TE series) simulating patients from an infant to a large adult were used. Size specific doses were measured with a 100 mm CT chamber under axial scans using a Siemens Sensation 64 (mCT) and a GE 750 HD. The scanner settings were 120 kVp, 200 mAs with fully opened collimations. Additional kVps (80,more » 100, 140) were added depending on the phantom sizes. The ratios (r) of the weighted CT dose (Dw) to the surface dose (Ds) were related to the phantom size (L) defined as the diameter resulting the equivalent cross-sectional area. Results: The Dw versus Ds ratio (r) was fitted to a linear relationship: r = 1.083 − 0.007L (R square = 0.995), and r = 1.064 − 0.007L (R square = 0.953), for Siemens Sensation 64 and GE 750 HD, respectively. The relationship appears to be independent of the scanner specifics. Conclusion: The surface dose to the weighted dose ratio decreases linearly as the patient size increases. The result is independent of the scanner specifics. The result can be used to obtain in vivo CT dosimetry in abdominal CT.« less

Evaluation of Chromosomal Instability in Diabetic Rats Treated with Naringin

PubMed Central

A. Bakheet, Saleh; M. Attia, Sabry

2011-01-01

We used the bone marrow DNA strand breaks, micronucleus formations, spermatocyte chromosomal aberrations, and sperm characteristic assays to investigate the chromosomal instability in somatic and germinal cells of diabetic rats treated with multiple doses of naringin. The obtained results revealed that naringin was neither cytotoxic nor genotoxic for the rats at all tested doses. Moreover, naringin significantly reduced the diabetes-induced chromosomal instability in somatic and germinal cells in a dose-dependent manner. In addition, diabetes induced marked biochemical alterations characteristic of oxidative stress including enhanced lipid peroxidation, accumulation of oxidized glutathione, reduction in reduced glutathione, and accumulation of intracellular reactive oxygen species. Treatment with naringin ameliorated these biochemical markers dose-dependently. In conclusion, naringin confers an appealing protective effect against diabetes-induced chromosomal instability towards rat somatic and germinal cells which might be explained partially via diminishing the de novo free radical generation induced by hyperglycemia. Thus, naringin might be a good candidate to reduce genotoxic risk associated with hyperglycemia and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks, which seems especially important for diabetic patients. PMID:21941606

Total Dose Effects on Bipolar Integrated Circuits at Low Temperature

NASA Technical Reports Server (NTRS)

Johnston, A. H.; Swimm, R. T.; Thorbourn, D. O.

2012-01-01

Total dose damage in bipolar integrated circuits is investigated at low temperature, along with the temperature dependence of the electrical parameters of internal transistors. Bandgap narrowing causes the gain of npn transistors to decrease far more at low temperature compared to pnp transistors, due to the large difference in emitter doping concentration. When irradiations are done at temperatures of -140 deg C, no damage occurs until devices are warmed to temperatures above -50 deg C. After warm-up, subsequent cooling shows that damage is then present at low temperature. This can be explained by the very strong temperature dependence of dispersive transport in the continuous-time-random-walk model for hole transport. For linear integrated circuits, low temperature operation is affected by the strong temperature dependence of npn transistors along with the higher sensitivity of lateral and substrate pnp transistors to radiation damage.

Dose-response characteristics of an amorphous silicon EPID.

PubMed

Winkler, Peter; Hefner, Alfred; Georg, Dietmar

2005-10-01

Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output characteristics of the accelerator. If ghosting is prevented from affecting the results and all dose-response effects are properly corrected for, the EPID signal becomes independent of dose rate, dose, and exposure time.

Amino acid transport system - A substrate predicts the therapeutic effects of particle radiotherapy

PubMed Central

Watanabe, Mariko; Suzuki, Hiroyuki; Furusawa, Yoshiya; Arano, Yasushi

2017-01-01

L-[methyl-11C]Methionine (11C-Met) is useful for estimating the therapeutic efficacy of particle radiotherapy at early stages of the treatment. Given the short half-life of 11C, the development of longer-lived 18F- and 123I-labeled probes that afford diagnostic information similar to 11C-Met, are being sought. Tumor uptake of 11C-Met is involved in many cellular functions such as amino acid transport System-L, protein synthesis, and transmethylation. Among these processes, since the energy-dependent intracellular functions involved with 11C-Met are more reflective of the radiotherapeutic effects, we evaluated the activity of the amino acid transport System-A as an another energy-dependent cellular function in order to estimate radiotherapeutic effects. In this study, using a carbon-ion beam as the radiation source, the activity of System-A was evaluated by a specific System-A substrate, alpha-[1-14C]-methyl-aminoisobutyric acid (14C-MeAIB). Cellular growth and the accumulation of 14C-MeAIB or 14C-Met were evaluated over time in vitro in cultured human salivary gland (HSG) tumor cells (3-Gy) or in vivo in murine xenografts of HSG tumors (6- or 25-Gy) before and after irradiation with the carbon-ion beam. Post 3-Gy irradiation, in vitro accumulation of 14C-Met and 14C-MeAIB decreased over a 5-day period. In xenografts of HSG tumors in mice, tumor re-growth was observed in vivo on day-10 after a 6-Gy irradiation dose, but no re-growth was detected after the 25-Gy irradiation dose. Consistent with the growth results, the in vivo tumor accumulation of 14C-MeAIB did not decrease after the 6-Gy irradiation dose, whereas a significant decrease was observed after the 25-Gy irradiation dose. These results indicate that the activity of energy dependent System-A transporter may reflect the therapeutic efficacy of carbon-ion radiotherapy and suggests that longer half-life radionuclide-labeled probes for System-A may also provide widely available probes to evaluate the effects of particle radiotherapy on tumors at early stage of the treatment. PMID:28245294

Effects of low-dose heavy ions on embryonic development in mice and on melanocyte differentiation in the epidermis and hair bulb.

PubMed

Hirobe, Tomohisa; Eguchi-Kasai, Kiyomi; Sugaya, Kimihiko; Murakami, Masahiro

2013-05-01

The effects of prenatal low-dose irradiation with heavy ions on embryonic development in mice and on melanocyte differentiation are not well understood. We performed whole-body irradiation of pregnant C57BL/10J mice at embryonic Day 9 (E9) with a single dose of γ-rays, silicon, argon or iron ions. The number of living embryos and embryonic body weight at E18 decreased after exposure to heavy ions at high doses. Malformations such as small eyes and limb anomalies were observed in heavy-ion-treated embryos, but not in γ-ray-treated embryos. The frequency of abnormally curved tails was increased by exposure to γ-rays and argon and iron ions even at a dose of 0.1 Gy (P < 0.05). In contrast, a dose-dependent decrease in the number of epidermal melanoblasts/melanocytes and hair bulb melanocytes was observed after 0.1 Gy irradiation with γ-rays or heavy ions (P < 0.01). The decrease in the number of dorsal hair bulb melanocytes, dorsal and ventral epidermal melanoblasts/melanocytes and ventral hair bulb melanocytes was not necessarily correlated with the linear energy transfer of the radiation tested. Moreover, the effects of heavy ions were larger on the ventral skin than on the dorsal skin, indicating that the sensitivity of melanocytes to heavy ions differs between the dorsal and ventral skin. Taken together, these results suggest that the effects of the low-dose heavy ions differ between cell types and tissues, and the effects on the prenatal development of mice and melanocyte development are not necessarily greater than those of γ-rays.

Effects of low-dose heavy ions on embryonic development in mice and on melanocyte differentiation in the epidermis and hair bulb

PubMed Central

Hirobe, Tomohisa; Eguchi-Kasai, Kiyomi; Sugaya, Kimihiko; Murakami, Masahiro

2013-01-01

The effects of prenatal low-dose irradiation with heavy ions on embryonic development in mice and on melanocyte differentiation are not well understood. We performed whole-body irradiation of pregnant C57BL/10J mice at embryonic Day 9 (E9) with a single dose of γ-rays, silicon, argon or iron ions. The number of living embryos and embryonic body weight at E18 decreased after exposure to heavy ions at high doses. Malformations such as small eyes and limb anomalies were observed in heavy-ion-treated embryos, but not in γ-ray-treated embryos. The frequency of abnormally curved tails was increased by exposure to γ-rays and argon and iron ions even at a dose of 0.1 Gy (P < 0.05). In contrast, a dose-dependent decrease in the number of epidermal melanoblasts/melanocytes and hair bulb melanocytes was observed after 0.1 Gy irradiation with γ-rays or heavy ions (P < 0.01). The decrease in the number of dorsal hair bulb melanocytes, dorsal and ventral epidermal melanoblasts/melanocytes and ventral hair bulb melanocytes was not necessarily correlated with the linear energy transfer of the radiation tested. Moreover, the effects of heavy ions were larger on the ventral skin than on the dorsal skin, indicating that the sensitivity of melanocytes to heavy ions differs between the dorsal and ventral skin. Taken together, these results suggest that the effects of the low-dose heavy ions differ between cell types and tissues, and the effects on the prenatal development of mice and melanocyte development are not necessarily greater than those of γ-rays. PMID:23230241

Post-training scopolamine treatment induced maladaptive behavior in open field habituation task in rats.

PubMed

Popović, Natalija; Caballero-Bleda, María; Popović, Miroljub

2014-01-01

The effects of scopolamine on memory consolidation are controversial and depend on several factors (i.e. site of administration, time of administration and testing, dose, cognitive task, experimental protocol, specie, strain, etc.). Generally, the range dose of systemic administered scopolamine, used in memory consolidation studies, has varied from 0.05 to 50 mg/kg. However, according to the literature, the most frequently used doses of scopolamine efficient on memory consolidation, are 1 and 30 mg/kg, low and high doses, respectively. In open field habituation studies only lower doses of scopolamine were used to test memory consolidation. Therefore, in the present study we compared the effects of low (1 mg/kg) and high (30 mg/kg) scopolamine dose, on the open field habituation task, in male Wistar rats. Scopolamine was administered immediately after the acquisition task and animals were retested 48 h later on. On the retested day, the ambulation and rearing in the open field decreased in the same manner in all tested groups. In saline- and 1 mg/kg scopolamine-treated animals, the time spent in grooming significantly decreased in the habituation task, while the same parameter significantly increased in animals treated with 30 mg/kg of scopolamine. The defecation rate significantly decreased (control group), maintained (1 mg/kg of scopolamine treated animals) or significantly increased (30 mg/kg of scopolamine treated group) on retention test. In conclusion, the present data suggest that post-training scopolamine administration does not affect locomotion neither exploration in the habituation to a novel environment, but increases defecation and grooming, two behaviours associated with fearful and stressful situations.

Low grade inflammation inhibits VEGF induced HUVECs migration in p53 dependent manner

DOE Office of Scientific and Technical Information (OSTI.GOV)

Panta, Sushil; Yamakuchi, Munekazu; Kagoshima University Hospital, Kagoshima

In the course of studying crosstalk between inflammation and angiogenesis, high doses of pro-inflammatory factors have been reported to induce apoptosis in cells. Under normal circumstances also the pro-inflammatory cytokines are being released in low doses and are actively involved in cell signaling pathways. We studied the effects of low grade inflammation in growth factor induced angiogenesis using tumor necrosis factor alfa (TNFα) and vascular endothelial growth factor A (VEGF) respectively. We found that low dose of TNFα can inhibit VEGF induced angiogenesis in human umbilical vein endothelial cells (HUVECs). Low dose of TNFα induces mild upregulation and moreover nuclearmore » localization of tumor suppressor protein 53 (P53) which causes decrease in inhibitor of DNA binding-1 (Id1) expression and shuttling to the cytoplasm. In absence of Id1, HUVECs fail to upregulate β{sub 3}-integrin and cell migration is decreased. Connecting low dose of TNFα induced p53 to β{sub 3}-integrin through Id1, we present additional link in cross talk between inflammation and angiogenesis. - Highlights: • Low grade inflammation (low dose of TNF alfa) inhibits VEGF induced endothelial cells migration. • The low grade inflammation with VEGF treatment upregulates P53 to a nonlethal level. • P53 activation inhibits Id1 shuttling to the cytoplasm in endothelial cells. • Inhibition of Id1 resulted in downregulation of β{sub 3}-integrin which cause decrease in cell migration. • Inflammation and angiogenesis might cross-talk by P53 – Id1 – β{sub 3}-integrin pathway in endothelial cells.« less

Damaging Effects of Bisphenol A on the Kidney and the Protection by Melatonin: Emerging Evidences from In Vivo and In Vitro Studies

PubMed Central

Peerapanyasut, Wachirasek

2018-01-01

This study investigates the effects of bisphenol A (BPA) contamination on the kidney and the possible protection by melatonin in experimental rats and isolated mitochondrial models. Rats exposed to BPA (50, 100, and 150 mg/kg, i.p.) for 5 weeks demonstrated renal damages as evident by increased serum urea and creatinine and decreased creatinine clearance, together with the presence of proteinuria and glomerular injuries in a dose-dependent manner. These changes were associated with increased lipid peroxidation and decreased antioxidant glutathione and superoxide dismutase. Mitochondrial dysfunction was also evident as indicated by increased reactive oxygen species production, decreased membrane potential change, and mitochondrial swelling. Coadministration of melatonin resulted in the reversal of all the changes caused by BPA. Studies using isolated mitochondria showed that BPA incubation produced dose-dependent impairment in mitochondrial function. Preincubation with melatonin was able to sustain mitochondrial function and architecture and decreases oxidative stress upon exposure to BPA. The findings indicated that BPA is capable of acting directly on the kidney mitochondria, causing mitochondrial oxidative stress, dysfunction, and subsequently, leading to whole organ damage. Emerging evidence further suggests the protective benefits of melatonin against BPA nephrotoxicity, which may be mediated, in part, by its ability to diminish oxidative stress and maintain redox equilibrium within the mitochondria. PMID:29670679

Quercetin inhibits the invasion of murine melanoma B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway.

PubMed

Zhang, Xian-Ming; Huang, Shao-Peng; Xu, Qiang

2004-01-01

On the basis of the inhibitory effect of quercetin on the invasion of melanoma B16-BL6 cells previously reported by us, the mechanisms of quercetin-mediated inhibition of invasion were further investigated in the present study. The ability of B16-BL6 cells to invade and migrate was evaluated in terms of the numbers of cells penetrating a reconstituted basement membrane in the Transwell coculture system. The relative levels and activities of matrix metalloproteinase-9 (MMP-9) and MMP-2 were determined by gelatin zymography and quantified using LabWorks 4.0 software. The quercetin-mediated inhibition of invasion was partially blocked by phorbol-12,13-dibutyrate (PDB), a PKC (protein kinase C) activator, and by doxorubicin, a PKC inhibitor. Only the proforms of MMP-9 (92 kDa) and MMP-2 (72 kDa) were detected by gelatin zymography. Quercetin dose-dependently decreased the gelatinolytic activity of pro-MMP-9. Doxorubicin also markedly reversed the quercetin-induced decrease. Quercetin showed a dose-dependent antagonism of increases in gelatinolytic activity of pro-MMP-9 induced by PDB and free fatty acid (another PKC activator). Together with the report that quercetin directly reduces PKC activity, the results reported here suggest that quercetin may inhibit the invasion of B16-BL6 cells by decreasing pro-MMP-9 via the PKC pathway.

Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-02-01

Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses.

S-(N, N-diethylcarbamoyl)glutathione (carbamathione), a disulfiram metabolite and its effect on nucleus accumbens and prefrontal cortex dopamine, GABA, and glutamate: A microdialysis study

PubMed Central

Faiman, Morris D.; Kaul, Swetha; Latif, Shaheen A.; Williams, Todd D.; Lunte, Craig E.

2015-01-01

Disulfiram (DSF), used for the treatment of alcohol use disorders (AUDs) for over six decades, most recently has shown promise for treating cocaine dependence. Although DSF’s mechanism of action in alcohol abuse is due to the inhibition of liver mitochondrial aldehyde dehydrogenase (ALDH2), its mechanism of action in the treatment of cocaine dependence is unknown. DSF is a pro-drug, forming a number of metabolites each with discrete pharmacological actions. One metabolite formed during DSF bioactivation is S-(N, N-diethylcarbamoyl) glutathione (carbamathione) (carb). We previously showed that carb affects glutamate binding. In the present studies, we employed microdialysis techniques to investigate the effect of carb administration on dopamine (DA), GABA, and glutamate (Glu) in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), two brain regions implicated in substance abuse dependence. The effect of DSF on DA, GABA, and Glu in the NAc also was determined. Both studies were carried out in male rats. Carb (20, 50, 200 mg/kg i v) in a dose-dependent manner increased DA, decreased GABA, and had a biphasic effect on Glu, first increasing and then decreasing Glu in both the NAc and mPFC. These changes all occurred concurrently. After carb administration, NAc and mPFC carb, as well as carb in plasma, were rapidly eliminated with a half-life for each approximately 4 min, while the changes in DA, GABA, and GLu in the NAc and mPFC persisted for approximately two hours. The maximal increase in carb (Cmax) in the NAc and mPFC after carb administration was dose-dependent, as was the area under the curve (AUC). DSF (200 mg/kg i p) also increased DA, decreased GABA, and had a biphasic effect on Glu in the NAc similar to that observed in the NAc after carb administration. When the cytochrome P450 inhibitor N-benzylimidazole (NBI) (20 mg/kg i p) was administered before DSF dosing, no carb could be detected in the NAc and plasma and also no changes in NAc DA, GABA, and GLu occurred. Changes in these neurotransmitters occurred only if carb was formed from DSF. When NBI was administered prior to dosing with carb, the increase in DA, decrease in GABA, and biphasic effect on GLu was similar to that seen after dosing with carb only. The i p or i v administration of carb showed similar changes in DA, GABA, and GLu, except the time to reach Cmax for DA as well as the changes in GABA, and GLu after i p administration occurred later. The elimination half-life of carb and the area under the curve (AUC) were similar after both routes of administration. It is concluded that carb must be formed from DSF before any changes in DA, GABA, and GLu in the NAc and mPFC are observed. DSF and carb, when administered to rats, co-release DA, GABA, and GLu. Carb, once formed can cross the blood brain barrier and enter the brain. Although inhibition of liver ALDH2 is the accepted mechanism for DSF’s action in treating AUDs, the concurrent changes in DA, GABA, and GLu in the NAc and mPFC after DSF administration suggest that changes in these neurotransmitters as a potential mechanism of action not only for AUDs, but also for cocaine dependence cannot be excluded. PMID:23891816

Short-term exposure to nonylphenol induces pancreatic oxidative stress and alters liver glucose metabolism in adult female rats.

PubMed

Jubendradass, R; D'Cruz, Shereen Cynthia; Mathur, P P

2011-01-01

Nonylphenol is known to have estrogenic properties and has been reported to cause health hazards to animals and humans. The effects of nonylphenol on pancreas are not clearly elucidated. In this study, we sought to evaluate the effects of nonylphenol on the oxidative status of pancreas and consequential effects of nonylphenol on some of the end points of carbohydrate metabolism in the female rats. Rats were administered nonylphenol orally at the doses of 1.5, 15, and 150 mg/kg of body weight per day for 7 days. After 24 h of last dosing, the animals were sacrificed by cervical dislocation. The activities of pancreatic superoxide dismutase and catalase were significantly decreased with a concomitant increase in the levels of H2O2 and lipid peroxidation. Nonylphenol increased plasma insulin levels with a concomitant decrease in the levels of plasma glucose as compared to the control groups of rats. A dose-dependent increase in the activities of liver hexokinase and phosphofructokinase was recorded along with decreased activity of glycogen phosphorylase in liver. Western blot analysis revealed a significant decrease in the levels of GLUT-2. These results show that nonylphenol causes oxidative stress in pancreas and impairs liver glucose homeostasis. Copyright © 2010 Wiley Periodicals, Inc.

General 4-week toxicity study with EMS in the rat.

PubMed

Pfister, Thomas; Eichinger-Chapelon, Anne

2009-11-12

In this subacute toxicity study, ethyl methanesulfonate (EMS) was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 20, 60 and 180/120 mg/kg body weight (bw)/day for a period of 28 days (for 19 days in the high-dose group). A control group was treated similarly with the vehicle, bidistilled water, only. The groups comprised 10 animals per sex, which were sacrificed after 28 days, respectively 19 days in the high-dose group, of treatment. Additional five rats per sex and group were treated accordingly and then allowed a 14 days treatment-free recovery period. Additional six rats per sex and group (three rats per sex in the control group) were treated accordingly and used for hemoglobin adduct analysis after EMS exposure. All animals survived until their scheduled necropsy. Treatment with EMS had a direct dose-dependent effect on food consumption and consequently on body weight at doses > or =20mg/kgbw/day in male rats and at > or =60 mg/kgbw/day in females rats. Hence, treatment with the high dose of 180 mg/kgbw/day had to be interrupted for 9 days after which, the animals were re-dosed at 120 mg/kgbw/day. This dose was also poorly tolerated over the remaining two treatment weeks causing again a marked reduction in food consumption and body weight. A dose of 60 mg/kgbw/day was moderately tolerated over 4 weeks treatment with mean daily food consumption and body weight distinctly lower than in controls. Primary targets of systemic toxicity were the hematopoietic system, thymolymphatic system and sexual organs. Characteristic changes in hematology parameters were decreased red blood cell counts, hematocrit, and hemoglobin concentration. White blood cell counts were also decreased due to reduced lymphocyte and granulocyte populations of each fraction. The corresponding histopathology findings were fatty atrophy of bone marrow and minimal hypocellularity of the white pulp of the spleen. Similarly, treatment with EMS caused an involution of the thymolymphatic system characterized by decreased organ weight of thymus, lymph nodes, and spleen microscopically associated with atrophy of the thymus and hypocellularity of Peyer's patches, lymph nodes and the white pulp of the spleen. The effects on sexual organs included lower organ weight/reduced size for testes, epididymides, seminal vesicles, prostate, and uterus. Tubular atrophy, single cell necrosis of the germ cells and in epididymides reduced spermatozoa were recorded microscopically. The described findings occurred at doses of 60 and 180/120 mg/kgbw/day and were dose-dependent with regard to incidence and severity. Other target organs were the pancreas (acinar cell vacuolation), thyroid gland (follicular cell hypertrophy), and salivary gland (secretory depletion of convoluted ducts). The systemic exposure to EMS was monitored by hemoglobin ethylvaline adduct measurement. The concentration of hemoglobin ethylvaline adducts was linear with the dose and accumulated 11-26-fold over the treatment period. In summary, decreases in food consumption and body weight were the dose-limiting effects of treatment with EMS. Organ toxicity was characterized by depression of cell proliferation (hematopoiesis and spermatogenesis) and changes suggestive of reduced metabolism and/or physiological imbalances (e.g. thymolymphatic system and thyroid gland) without signs of inflammatory or necrotic lesions. For some findings, especially the effects on the thymolymphatic system and sexual organs, it cannot be excluded that starvation-like condition contributed to the occurrence of such changes. The low dose of 20 mg/kgbw/day was basically free of adverse effects despite of a clear evidence for hemoglobin adducts.

Ascorbic acid treatment elevates follicle stimulating hormone and testosterone plasma levels and enhances sperm quality in albino Wistar rats.

PubMed

Okon, Uduak Akpan; Utuk, Ikponoabasi Ibanga

2016-01-01

Infertility issues have been linked to the effect of oxidative reaction in the reproductive system. This study evaluated the effect of ascorbic acid, on fertility parameters of male albino Wistar rats was studied. Eighteen albino Wistar rats weighed between 178 g and 241 g were used, randomly assigned into three groups. Group 1 was the control group; oral gavaged 5 ml of distilled water; Groups 2 and 3 were administered medium dose (250 mg/kg) and high dose of ascorbic acid (400 mg/kg), respectively; twice daily for 21 days. Blood samples were obtained by cardiac puncture, and blood serum was obtained for hormonal assay, and the testes were harvested for sperm analysis. Follicle stimulating hormone levels significantly increased in the high-dose group as compared to both the control and medium dose groups. Luteinizing hormone levels in the medium dose group decreased significantly as compared to the control group. Testosterone significantly increased in both the medium- and high-dose groups as compared to the control group. Sperm motility increased significantly in the high-dose group as compared to both control and medium-dose groups. Percentage sperm concentration decreased significantly in the medium-dose group when compared to the control and increased significantly in the high-dose group as compared to the medium-dose group. For percentage normal morphology, there was a dose-dependent increase in the test groups when compared to control group. These results are indicative of a positive influence of ascorbic acid on male fertility modulators and may therefore, serve as a potential adjuvant treatment for male infertility cases.

Antidiarrheal Activity of Dissotis multiflora (Sm) Triana (Melastomataceae) Leaf Extract in Wistar Rats and Subacute Toxicity Evaluation

PubMed Central

Ndoye Foe, Chantal Florentine; Njankouo Ndam, Youchahou; Njayou, Frédéric Nico; Fonkoua, Marie Christine; Etoa, François-Xavier

2017-01-01

The present work was undertaken to evaluate antidiarrheal activity of ethanolic leaf extract of Dissotis multiflora (Sm) Triana (D. multiflora) on Shigella flexneri-induced diarrhea in Wistar rats and its subacute toxicity. Diarrhea was induced by oral administration of 1.2 × 109 cells/mL S. flexneri to rats. Antidiarrheal activity was investigated in rats with the doses of 111.42 mg/kg, 222.84 mg/kg, and 445.68 mg/kg. The level of biochemical parameters was assessed and organs histology examined by 14 days' subacute toxicity. S. flexneri stool load decreased significantly in dose-dependent manner. The level of ALT increased (p < 0.05) in male rats treated with the dose of 445.68 mg/kg while creatinine level increased in rats treated with both doses. In female rats, a significant decrease (p < 0.05) of the level of AST and creatinine was noted in rats treated with the dose of 222.84 mg/kg of D. multiflora. Histological exams of kidney and liver of treated rats showed architectural modifications at the dose of 445.68 mg/kg. This finding suggests that D. multiflora leaf extract is efficient against diarrhea caused by S. flexneri but the treatment with doses lower than 222.84 mg/kg is recommended while further study is required to define the exact efficient nontoxic dose. PMID:29234391

Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse.

PubMed

Yamashita, Fumiaki; Komoto, Ikumi; Oka, Hiroaki; Kuwata, Keizo; Takeuchi, Mayuko; Nakagawa, Fumio; Yoshisue, Kunihiro; Chiba, Masato

2015-08-01

Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated. Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay. TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner. A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.

A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.

PubMed

Scott, Victoria E; Vortherms, Timothy A; Niforatos, Wende; Swensen, Andrew M; Neelands, Torben; Milicic, Ivan; Banfor, Patricia N; King, Andrew; Zhong, Chengmin; Simler, Gricelda; Zhan, Cenchen; Bratcher, Natalie; Boyce-Rustay, Janel M; Zhu, Chang Z; Bhatia, Pramila; Doherty, George; Mack, Helmut; Stewart, Andrew O; Jarvis, Michael F

2012-02-01

Blockade of voltage-gated Ca²⁺ channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²⁺ channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC₅₀=0.8 μM and 1.4 μM, respectively) and T-type (IC₅₀=4.6 μM and 1.2 μM, respectively) Ca²⁺ channels in FLIPR based Ca²⁺ flux assays. A-686085 also potently blocked L-type Ca²⁺ channels (EC₅₀=0.6 μM), however, A-1048400 was much less active in blocking this channel (EC₅₀=28 μM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC₅₀=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²⁺ currents in rat dorsal root ganglion neurons (IC₅₀=3.0 μM and 1.6 μM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²⁺ channels coupled with pharmacological selectivity vs. L-type Ca²⁺ channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function. Copyright © 2011 Elsevier Inc. All rights reserved.

Hippocampal asymmetry in exploratory behavior to vasoactive intestinal polypeptide.

PubMed

Ivanova, Margarita; Ternianov, Alexandar; Belcheva, Stiliana; Tashev, Roman; Negrev, Negrin; Belcheva, Iren

2008-06-01

The effects of vasoactive intestinal polypeptide (VIP) microinjected uni- or bilaterally into the CA1 hippocampal area of male Wistar rats at a dose of 10, 50 and 100 ng on exploratory behavior were examined. VIP microinjected bilaterally at a high dose (100 ng) significantly decreased the horizontal movements, while at low doses (10 and 50 ng) had no effect on the exploratory activity. Microinjections of VIP into the left hippocampal CA1 area at doses 50 and 100 ng suppressed the exploratory activity, while right-side VIP administration at a dose 100 ng significantly increased horizontal movements compared to the respective controls. Vertical activity was stimulated only by VIP administered into the right hippocampal CA1 area at the three doses used. Neither bilateral nor left injections of VIP induced changes in the vertical movements. The main finding was the presence of hippocampal asymmetry in exploratory behavior to unilateral microinjections of VIP depending on the dose and the microinjected hemisphere.

Time- and dose-dependent effects of total-body ionizing radiation on muscle stem cells

PubMed Central

Masuda, Shinya; Hisamatsu, Tsubasa; Seko, Daiki; Urata, Yoshishige; Goto, Shinji; Li, Tao-Sheng; Ono, Yusuke

2015-01-01

Exposure to high levels of genotoxic stress, such as high-dose ionizing radiation, increases both cancer and noncancer risks. However, it remains debatable whether low-dose ionizing radiation reduces cellular function, or rather induces hormetic health benefits. Here, we investigated the effects of total-body γ-ray radiation on muscle stem cells, called satellite cells. Adult C57BL/6 mice were exposed to γ-radiation at low- to high-dose rates (low, 2 or 10 mGy/day; moderate, 50 mGy/day; high, 250 mGy/day) for 30 days. No hormetic responses in proliferation, differentiation, or self-renewal of satellite cells were observed in low-dose radiation-exposed mice at the acute phase. However, at the chronic phase, population expansion of satellite cell-derived progeny was slightly decreased in mice exposed to low-dose radiation. Taken together, low-dose ionizing irradiation may suppress satellite cell function, rather than induce hormetic health benefits, in skeletal muscle in adult mice. PMID:25869487

Effect of harmane on the convulsive threshold in epilepsy models in mice.

PubMed

Aricioglu, Feyza; Yillar, Okan; Korcegez, Eylem; Berkman, Kemal

2003-12-01

The study investigated the activity of harmane on maximal electroshock seizures (MES) and seizures induced by pentilentetrazole (PTZ) in mice. Initial studies established convulsive current 50 (CC(50)) values or MES and effective dose 50 (ED(50)) for PTZ to produce seizures. Harmane (2.5, 5.0, or 10 mg/kg intraperitoneally) increased the threshold of seizures in MES dose-dependently. The convulsions produced by PTZ were decreased by the low dose of harmane (2.5 mg/kg), but the high dose of harmane (10 mg/kg) resulted in worse grade V convulsions followed by more lethality compared with PTZ alone. Therefore, harmane seems to be protective against grand mal seizures in the MES model but not against a petit mal seizure model (PTZ) in mice.

The pharmacological effects of the anesthetic alfaxalone after intramuscular administration to dogs.

PubMed

Tamura, Jun; Ishizuka, Tomohito; Fukui, Sho; Oyama, Norihiko; Kawase, Kodai; Miyoshi, Kenjiro; Sano, Tadashi; Pasloske, Kirby; Yamashita, Kazuto

2015-03-01

The pharmacological effects of the anesthetic alfaxalone were evaluated after intramuscular (IM) administration to 6 healthy beagle dogs. The dogs received three IM doses each of alfaxalone at increasing dose rates of 5 mg/kg (IM5), 7.5 mg/kg (IM7.5) and 10 mg/kg (IM10) every other day. Anesthetic effect was subjectively evaluated by using an ordinal scoring system to determine the degree of neuro-depression and the quality of anesthetic induction and recovery from anesthesia. Cardiorespiratory variables were measured using noninvasive methods. Alfaxalone administered IM produced dose-dependent neuro-depression and lateral recumbency (i.e., 36 ± 28 min, 87 ± 26 min and 115 ± 29 min after the IM5, IM7.5 and IM10 treatments, respectively). The endotracheal tube was tolerated in all dogs for 46 ± 20 and 58 ± 21 min after the IM7.5 and IM10 treatments, respectively. It was not possible to place endotracheal tubes in 5 of the 6 dogs after the IM5 treatment. Most cardiorespiratory variables remained within clinically acceptable ranges, but hypoxemia was observed by pulse oximetry for 5 to 10 min in 2 dogs receiving the IM10 treatment. Dose-dependent decreases in rectal temperature, respiratory rate and arterial blood pressure also occurred. The quality of recovery was considered satisfactory in all dogs receiving each treatment; all the dog exhibited transient muscular tremors and staggering gait. In conclusion, IM alfaxalone produced a dose-dependent anesthetic effect with relatively mild cardiorespiratory depression in dogs. However, hypoxemia may occur at higher IM doses of alfaxalone.

The pharmacological effects of the anesthetic alfaxalone after intramuscular administration to dogs

PubMed Central

TAMURA, Jun; ISHIZUKA, Tomohito; FUKUI, Sho; OYAMA, Norihiko; KAWASE, Kodai; MIYOSHI, Kenjiro; SANO, Tadashi; PASLOSKE, Kirby; YAMASHITA, Kazuto

2014-01-01

The pharmacological effects of the anesthetic alfaxalone were evaluated after intramuscular (IM) administration to 6 healthy beagle dogs. The dogs received three IM doses each of alfaxalone at increasing dose rates of 5 mg/kg (IM5), 7.5 mg/kg (IM7.5) and 10 mg/kg (IM10) every other day. Anesthetic effect was subjectively evaluated by using an ordinal scoring system to determine the degree of neuro-depression and the quality of anesthetic induction and recovery from anesthesia. Cardiorespiratory variables were measured using noninvasive methods. Alfaxalone administered IM produced dose-dependent neuro-depression and lateral recumbency (i.e., 36 ± 28 min, 87 ± 26 min and 115 ± 29 min after the IM5, IM7.5 and IM10 treatments, respectively). The endotracheal tube was tolerated in all dogs for 46 ± 20 and 58 ± 21 min after the IM7.5 and IM10 treatments, respectively. It was not possible to place endotracheal tubes in 5 of the 6 dogs after the IM5 treatment. Most cardiorespiratory variables remained within clinically acceptable ranges, but hypoxemia was observed by pulse oximetry for 5 to 10 min in 2 dogs receiving the IM10 treatment. Dose-dependent decreases in rectal temperature, respiratory rate and arterial blood pressure also occurred. The quality of recovery was considered satisfactory in all dogs receiving each treatment; all the dog exhibited transient muscular tremors and staggering gait. In conclusion, IM alfaxalone produced a dose-dependent anesthetic effect with relatively mild cardiorespiratory depression in dogs. However, hypoxemia may occur at higher IM doses of alfaxalone. PMID:25428797

Low-amplitude pulses to the circulation through periodic acceleration induces endothelial-dependent vasodilatation.

PubMed

Uryash, Arkady; Wu, Heng; Bassuk, Jorge; Kurlansky, Paul; Sackner, Marvin A; Adams, Jose A

2009-06-01

Low-amplitude pulses to the vasculature increase pulsatile shear stress to the endothelium. This activates endothelial nitric oxide (NO) synthase (eNOS) to promote NO release and endothelial-dependent vasodilatation. Descent of the dicrotic notch on the arterial pulse waveform and a-to-b ratio (a/b; where a is the height of the pulse amplitude and b is the height of the dicrotic notch above the end-diastolic level) reflects vasodilator (increased a/b) and vasoconstrictor effects (decreased a/b) due to NO level change. Periodic acceleration (pG(z)) (motion of the supine body head to foot on a platform) provides systemic additional pulsatile shear stress. The purpose of this study was to determine whether or not pG(z) applied to rats produced endothelial-dependent vasodilatation and increased NO production, and whether the latter was regulated by the Akt/phosphatidylinositol 3-kinase (PI3K) pathway. Male rats were anesthetized and instrumented, and pG(z) was applied. Sodium nitroprusside, N(G)-nitro-l-arginine methyl ester (l-NAME), and wortmannin (WM; to block Akt/PI3K pathway) were administered to compare changes in a/b and mean aortic pressure. Descent of the dicrotic notch occurred within 2 s of initiating pG(z). Dose-dependent increase of a/b and decrease of mean aortic pressure took place with SNP. l-NAME produced a dose-dependent rise in mean aortic pressure and decrease of a/b, which was blunted with pG(z). In the presence of WM, pG(z) did not decrease aortic pressure or increase a/b. WM also abolished the pG(z) blunting effect on blood pressure and a/b of l-NAME-treated animals. eNOS expression was increased in aortic tissue after pG(z). This study indicates that addition of low-amplitude pulses to circulation through pG(z) produces endothelial-dependent vasodilatation due to increased NO in rats, which is mediated via activation of eNOS, in part, by the Akt/PI3K pathway.

Effects of 3-nitrooxypropanol on methane emission, digestion, and energy and nitrogen balance of lactating dairy cows.

PubMed

Reynolds, C K; Humphries, D J; Kirton, P; Kindermann, M; Duval, S; Steinberg, W

2014-01-01

The objective was to measure effects of 3-nitrooxypropanol (3 NP) on methane production of lactating dairy cows and any associated changes in digestion and energy and N metabolism. Six Holstein-Friesian dairy cows in mid-lactation were fed twice daily a total mixed ration with maize silage as the primary forage source. Cows received 1 of 3 treatments using an experimental design based on two 3 × 3 Latin squares with 5-wk periods. Treatments were a control placebo or 500 or 2,500 mg/d of 3 NP delivered directly into the rumen, via the rumen fistula, in equal doses before each feeding. Measurements of methane production and energy and N balance were obtained during wk 5 of each period using respiration calorimeters and digestion trials. Measurements of rumen pH (48 h) and postprandial volatile fatty acid and ammonia concentrations were made at the end of wk 4. Daily methane production was reduced by 3 NP, but the effects were not dose dependent (reductions of 6.6 and 9.8% for 500 and 2,500 mg/d, respectively). Dosing 3 NP had a transitory inhibitory effect on methane production, which may have been due to the product leaving the rumen in liquid outflow or through absorption or metabolism. Changes in rumen concentrations of volatile fatty acids indicated that the pattern of rumen fermentation was affected by both doses of the product, with a decrease in acetate:propionate ratio observed, but that acetate production was inhibited by the higher dose. Dry matter, organic matter, acid detergent fiber, N, and energy digestibility were reduced at the higher dose of the product. The decrease in digestible energy supply was not completely countered by the decrease in methane excretion such that metabolizable energy supply, metabolizable energy concentration of the diet, and net energy balance (milk plus tissue energy) were reduced by the highest dose of 3 NP. Similarly, the decrease in N digestibility at the higher dose of the product was associated with a decrease in body N balance that was not observed for the lower dose. Milk yield and milk fat concentration and fatty acid composition were not affected but milk protein concentration was greater for the higher dose of 3 NP. Twice-daily rumen dosing of 3 NP reduced methane production by lactating dairy cows, but the dose of 2,500 mg/d reduced rumen acetate concentration, diet digestibility, and energy supply. Further research is warranted to determine the optimal dose and delivery method of the product. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

PubMed Central

Newman, L. A.

2015-01-01

Rationale Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. Objectives The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. Results Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. Conclusions These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist—to decrease scopolamine-induced increases in acetylcholine output or to decrease post-synaptic acetylcholine receptor activation—may mediate the negative effects on memory of muscarinic antagonists. PMID:26660295

Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease.

PubMed

Black, Kevin J; Koller, Jonathan M; Campbell, Meghan C; Gusnard, Debra A; Bandak, Stephen I

2010-12-01

Adenosine A(2a) receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A(2a) antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion magnetic resonance imaging (MRI) study of the novel adenosine A(2a) antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development.

Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease

PubMed Central

Black, Kevin J.; Koller, Jonathan M.; Campbell, Meghan C.; Gusnard, Debra A.; Bandak, Stephen I.

2010-01-01

Adenosine A2a receptor antagonists reduce symptom severity in Parkinson disease (PD) and animal models. Rodent studies support the hypothesis that A2a antagonists produce this benefit by reducing the inhibitory output of the basal ganglia indirect pathway. One way to test this hypothesis in humans is to quantify regional pharmacodynamic responses with cerebral blood flow (CBF) imaging. That approach has also been proposed as a tool to accelerate pharmaceutical dose-finding, but has not yet been applied in humans to drugs in development. We successfully addressed both these aims with a perfusion MRI study of the novel adenosine A2a antagonist SYN115. During a randomized, double-blind, placebo-controlled, crossover study in 21 PD patients on levodopa but no agonists, we acquired pulsed arterial spin labeling MRI at the end of each treatment period. SYN115 produced a highly significant decrease in thalamic CBF, consistent with reduced pallidothalamic inhibition via the indirect pathway. Similar decreases occurred in cortical regions whose activity decreases with increased alertness and externally-focused attention, consistent with decreased self-reported sleepiness on SYN115. Remarkably, we also derived quantitative pharmacodynamic parameters from the CBF responses to SYN115. These results suggested that the doses tested were on the low end of the effective dose range, consistent with clinical data reported separately. We conclude that (1) SYN115 enters the brain and exerts dose-dependent regional effects, (2) the most prominent of these effects is consistent with deactivation of the indirect pathway as predicted by preclinical studies; and (3) perfusion MRI can provide rapid, quantitative, clinically relevant dose-finding information for pharmaceutical development. PMID:21123574

The modified unified interaction model: incorporation of dose-dependent localised recombination.

PubMed

Lavon, A; Eliyahu, I; Oster, L; Horowitz, Y S

2015-02-01

The unified interaction model (UNIM) was developed to simulate thermoluminescence (TL) linear/supralinear dose-response and the dependence of the supralinearity on ionisation density, i.e. particle type and energy. Before the development of the UNIM, this behaviour had eluded all types of TL modelling including conduction band/valence band (CB/VB) kinetic models. The dependence of the supralinearity on photon energy was explained in the UNIM as due to the increasing role of geminate (localised recombination) with decreasing photon/electron energy. Recently, the Ben Gurion University group has incorporated the concept of trapping centre/luminescent centre (TC/LC) spatially correlated complexes and localised/delocalised recombination into the CB/VB kinetic modelling of the LiF:Mg,Ti system. Track structure considerations are used to describe the relative population of the TC/LC complexes by an electron-hole or by an electron-only as a function of both photon/electron energy and dose. The latter dependence was not included in the original UNIM formulation, a significant over-simplification that is herein corrected. The modified version, the M-UNIM, is then applied to the simulation of the linear/supralinear dose-response characteristics of composite peak 5 in the TL glow curve of LiF:Mg,Ti at two representative average photon/electron energies of 500 and 8 keV. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Intestinal radiation syndrome: sepsis and endotoxin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geraci, J.P.; Jackson, K.L.; Mariano, M.S.

Rats were whole-body irradiated with 8-MeV cyclotron-produced neutrons and /sup 137/Cs ..gamma.. rays to study the role of enteric bacteria and endotoxin in the intestinal radiation syndrome. Decrease in intestinal weight was used as an index of radiation-induced breakdown of the mucosa. Neutron and ..gamma..-ray doses that were sublethal for intestinal death resulted in a dose-dependent decrease in intestinal weight, reaching minimal values 2 to 3 days after exposure, followed by recovery within 5 days after irradiation. Neutron and photon doses that caused intestinal death resulted in greater mucosal breakdown with little or no evidence of mucosal recovery. The presencemore » of fluid in the intestine and diarrhea, but not bacteremia or endotoxemia, were related to mucosal breakdown and recovery. Neither sepsis nor endotoxin could be detected in liver samples taken at autopsy from animals which died a short time earlier from intestinal injury. These results suggest that overt sepsis and endotoxemia do not play a significant role in the intestinal radiation syndrome.« less

Toxicological effects of mainstream whole smoke solutions on embryonic movements of the developing embryo.

PubMed

Ejaz, Sohail; Seok, Kim Bum; Woong, Lim Chae

2005-01-01

Cigarette smoking is unrivaled among developmental toxicants in terms of total adverse impact on the human population. Maternal tobacco use during pregnancy adversely affects prenatal and postnatal growth and increases the risk of behavioral and developmental defects in children and adolescents. In the current study, the effects of different preparations of nicotine and mainstream whole smoke solutions (MSWSS) on embryonic movements during neonatal development were examined in vivo, using the chicken embryo model, recorded in real-time by a video camera. It was observed that low doses of nicotine induced hyperactivity and higher doses induced hypoactivity. Accordingly, a significant (p < 0.01) decrease in movements was observed by application of 10 microg of nicotine and different preparations of MSWSS. A dose-dependent decrease in embryonic movements was observed, which did not recover by the end of experiment. It was concluded that nicotine could alter embryonic movements, which are important during embryogenesis for differentiation and maturation of the body systems.

Sustained remission of Cushing's disease with mitotane and pituitary irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schteingart, D.E.; Tsao, H.S.; Taylor, C.I.

1980-05-01

Low doses of mitotane were given orally to 36 patients with Cushing's disease, concurrently with or after pituitary cobalt irradiation. Clinical and biochemical remission occurred in 29. The response to treatment occurred early in 17 patients and late in 12. The different pattern of response to mitotane was not related to the dose given or to its serum level. Early biochemical indicators of adrenal suppression with mitotane were a sharp decrease in adrenal response to the infusion of ACTH and in plasma levels of dehydroepiandrosterone sulfate. Although mitotane was given together with pituitary irradiation, initial remission was due mainly tomore » the adrenal effect of mitotane. Plasma ACTH levels were still elevated when cortisol had returned to normal. In seventeen of the 29 patients who responded to treatment drug therapy has been discontinued, and they remain in remission of Cushing's syndrome. Side-effects have been dose dependent, with anorexia, nausea, decreased memory, and gynecomastia in men being the commonest.« less

Effect of non-nutritive sugars to decrease the survivorship of spotted wing drosophila, Drosophila suzukii

USDA-ARS?s Scientific Manuscript database

In this study, we investigated the effects of non-nutritive sugars and sugar alcohols on the survivorship of spotted wing drosophila, Drosophila suzukii, and found erythritol and erythrose as potentially toxic to the fly. In a dose-dependent study, erythritol and erythrose significantly reduced fly ...

[Cytogenetic effects of low dose radiation with different LET in human peripheral blood lymphocytes and possible mechanisms of their realization].

PubMed

Nasonova, E A; Shmakova, N L; Komova, O V; Mel'nikova, L A; Fadeeva, T A; Krasavin, E A

2006-01-01

The induction of chromosome damage by the exposure to low doses of gamma-(60)Co and accelerated carbon ions 12C in peripheral blood lymphocytes of different donors was investigated. The complex nonlinear dose-effect dependence at the range from 1 to 50-70 cGy was observed. At the doses of 1-5 cGy the cells show the highest radiosensitivity (hypersensitivity), mainly due to the chromatid-type aberration, which is typical to those spontaneously generated in the cell and believed not to be induced by the irradiation of unstimulated lymphocytes according to the classical theory of aberration formation. With the increasing dose the frequency of the aberrations decreases significantly, in some cases up to the control level. At the doses over 50-70 cGy the dose-effect curve becomes linear. The possible role of the oxidative stress, caused by radiation-induced increase in mitochondrial reactive oxigen species (ROS) release in the phenomenon of hypersensitivity (HS) at low doses is discussed as well as cytoprotective mechanisms causing the increased radioresistance at higher doses.

Anti-spermatogenic activity of ethanol extract of Dalbergia sissoo Roxb. stem bark.

PubMed

Vasudeva, Neeru; Vats, Manisha

2011-06-01

The study was undertaken to evaluate the anti-spermatogenic efficacy of ethanol extract of stem bark of Dalbergia sissoo Roxb. For the in vitro study, semen samples were obtained from 15 healthy fertile men aged 25-35 years. Sperm motility was examined by the Sander-Cramer method. A dose-dependent and time-dependent effect of ethanol extract on sperm motility and sperm viability were observed. Various concentrations affected the motility of sperm. Ethanol extract at a concentration of 20 mg/mL caused complete immobilization within 3 minutes. Sperm viability and hypo-osmotic swelling was significantly reduced at this concentration. The in vivo studies were carried out on Swiss male albino mice. Ethanol extract at a dose of 200 mg/kg body weight resulted in a significant decrease (p<0.001) in weight of the testis and epididymis. A significant decrease (p<0.01) in sperm motility and sperm count in the epididymis were observed. Histological changes in the epididymis and testis were also investigated. Copyright © 2011 Korean Pharmacopuncture Institute. Published by .. All rights reserved.

Impact of Radiotherapy on Fertility, Pregnancy, and Neonatal Outcomes in Female Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wo, Jennifer Y.; Viswanathan, Akila N.

Purpose: Radiation has many potential long-term effects on cancer survivors. Female cancer patients may experience decreased fertility depending on the site irradiated. Oncologists should be aware of these consequences and discuss options for fertility preservation before initiating therapy. Methods and Materials: A comprehensive review of the existing literature was conducted. Studies reporting the outcomes for female patients treated with cranio-spinal, abdominal, or pelvic radiation reporting fertility, pregnancy, or neonatal-related outcomes were reviewed. Results: Cranio-spinal irradiation elicited significant hormonal changes in women that affected their ability to become pregnant later in life. Women treated with abdomino-pelvic radiation have an increased ratemore » of uterine dysfunction leading to miscarriage, preterm labor, low birth weight, and placental abnormalities. Early menopause results from low-dose ovarian radiation. Ovarian transposition may decrease the rates of ovarian dysfunction. Conclusions: There is a dose-dependent relationship between ovarian radiation therapy (RT) and premature menopause. Patients treated with RT must be aware of the impact of treatment on fertility and explore appropriate options.« less

Arctigenin represses TGF-β-induced epithelial mesenchymal transition in human lung cancer cells.

PubMed

Xu, Yanrui; Lou, Zhiyuan; Lee, Seong-Ho

2017-11-18

Arctigenin (ARC) is a lignan that is abundant in Asteraceae plants, which show anti-inflammatory and anti-cancer activities. The current study investigated whether ARC affects cancer progression and metastasis, focusing on EMT using invasive human non-small cell lung cancer (NSCLC) cells. No toxicity was observed in the cells treated with different doses of ARC (12-100 μM). The treatment of ARC repressed TGF-β-stimulated changes of metastatic morphology and cell invasion and migration. ARC inhibited TGF-β-induced phosphorylation and transcriptional activity of smad2/3, and expression of snail. ARC also decreased expression of N-cadherin and increased expression of E-cadherin in dose-dependent and time-dependent manners. These changes were accompanied by decreased amount of phospho-smad2/3 in nucleus and nuclear translocation of smad2/3. Moreover, ARC repressed TGF-β-induced phosphorylation of ERK and transcriptional activity of β-catenin. Our data demonstrate anti-metastatic activity of ARC in lung cancer model. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of initial microbial density on inactivation of Giardia muris by ozone.

PubMed

Haas, Charles N; Kaymak, Baris

2003-07-01

Inactivation of microorganisms by disinfectants frequently shows non-linear behavior on a semilogarithmic plot of log survival ratio versus time. A number of models have been developed to depict these deviations from Chick's Law. Some of the models predict that the log survival ratio (at a particular disinfectant dose and contact time, even in absence of demand) would be a function of the initial concentration of microorganisms (N(0)), while other models do not predict such an effect. The effect of N(0) on the survival ratio has not been deliberately tested. This work examined the inactivation of Giardia muris by ozone in batch systems, deliberately varying the disinfectant dose and N(0). It was found that the models predicting a dependency of survival on N(0) gave a better description to the data than models that did not predict such a dependency. Hence there is an apparent decrease in disinfection efficiency of ozone against Giardia muris (at pH 8 and 15 degrees C) as the initial microorganism concentration decreases. This phenomena should be taken into account by both disinfection researchers and by process design engineers.

Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis.

PubMed

Chen, Xiaodong; Zhou, Huanjiao Jenny; Huang, Qunhua; Lu, Lin; Min, Wang

2014-01-01

Auranofin is a gold compound initially developed for the treatment of rheumatoid arthritis. Recent data suggest that auranofin has promise in the treatment of other inflammatory and proliferative diseases. However, the mechanisms of action of auranofin have not been well defined. In the present study, we identify vascular endothelial growth factor receptor-3 (VEGFR3), an endothelial cell (EC) surface receptor essential for angiogiogenesis and lymphangiogenesis, as a novel target of auranofin. In both primary EC and EC cell lines, auranofin induces downregulation of VEGFR3 in a dose-dependent manner. Auranofin at high doses (≥1 µM) decreases cellular survival protein thioredoxin reductase (TrxR2), TrxR2-dependent Trx2 and transcription factor NF-κB whereas increases stress signaling p38MAPK, leading to EC apoptosis. However, auranofin at low doses (≤0.5 µM) specifically induces downregulation of VEGFR3 and VEGFR3-mediated EC proliferation and migration, two critical steps required for in vivo lymphangiogenesis. Mechanistically, we show that auranofin-induced VEGFR3 downregulation is blocked by antioxidant N-acetyl-L-cysteine (NAC) and lysosome inhibitor chloroquine, but is promoted by proteasomal inhibitor MG132. These results suggest that auranofin induces VEGFR3 degradation through a lysosome-dependent pathway. Auranofin may be a potent therapeutic agent for the treatment of lymphangiogenesis-dependent diseases such as lymphedema and cancer metastasis.

Gating window dependency on scanned carbon-ion beam dose distribution and imaging dose for thoracoabdominal treatment.

PubMed

Mori, Shinichiro; Karube, Masataka; Yasuda, Shigeo; Yamamoto, Naoyoshi; Tsuji, Hiroshi; Kamada, Tadashi

2017-06-01

To explore the trade-off between dose assessment and imaging dose in respiratory gating with radiographic fluoroscopic imaging, we evaluated the relationship between dose assessment and fluoroscopic imaging dose in various gating windows, retrospectively. Four-dimensional (4D) CT images acquired for 10 patients with lung and liver tumours were used for 4D treatment planning for scanned carbon ion beam. Imaging dose from two oblique directions was calculated by the number of images multiplied by the air kerma per image. Necessary beam-on time was calculated from the treatment log file. Accumulated dose distribution was calculated. The gating window was defined as tumour position not respiratory phase and changed from 0-100% duty cycle on 4DCT. These metrics were individually evaluated for every case. For lung cases, sufficient dose conformation was achieved in respective gating windows [D 95 -clinical target volume (CTV) > 99%]. V 20 -lung values for 50%- and 30%-duty cycles were 2.5% and 6.0% of that for 100%-duty cycle. Maximum doses (cord/oesophagus) for 30%-duty cycle decreased 6.8%/7.4% to those for 100%-duty cycle. For liver cases, V 10 -liver values for 50%- and 30%-duty cycles were 9.4% and 12.8% of those for 100%-duty cycle, respectively. Maximum doses (cord/oesophagus) for 50%- and 30%-duty cycles also decreased 17.2%/19.3% and 24.6%/29.8% to those for 100%-duty cycle, respectively. Total imaging doses increased 43.5% and 115.8% for 50%- and 30%-duty cycles to that for the 100%-duty cycle. When normal tissue doses are below the tolerance level, the gating window should be expanded to minimize imaging dose and treatment time. Advances in knowledge: The skin dose from imaging might not be counterbalanced to the OAR dose; however, imaging dose is a particularly important factor.

Sperm Oxidative Stress Is Detrimental to Embryo Development: A Dose-Dependent Study Model and a New and More Sensitive Oxidative Status Evaluation

PubMed Central

de Castro, Letícia S.; de Assis, Patrícia M.; Siqueira, Adriano F. P.; Hamilton, Thais R. S.; Mendes, Camilla M.; Losano, João D. A.; Nichi, Marcílio; Visintin, José A.; Assumpção, Mayra E. O. A.

2016-01-01

Our study aimed to assess the impact of sperm oxidative stress on embryo development by means of a dose-dependent model. In experiment 1, straws from five bulls were subjected to incubation with increasing H2O2 doses (0, 12.5, 25, and 50 μM). Motility parameters were evaluated by Computed Assisted System Analysis (CASA). Experiment 2 was designed to study a high (50 μM) and low dose (12.5 μM) of H2O2 compared to a control (0 μM). Samples were incubated and further used for in vitro fertilization. Analyses of motility (CASA), oxidative status (CellROX green and 2'-7' dichlorofluorescein diacetate), mitochondrial potential (JC-1), chromatin integrity (AO), and sperm capacitation status (chlortetracycline) were performed. Embryos were evaluated based on fast cleavage (30 h.p.i.), cleavage (D = 3), development (D = 5), and blastocyst rates (D = 8). We observed a dose-dependent deleterious effect of H2O2 on motility and increase on the percentages of positive cells for CellROX green, capacitated sperm, and AO. A decrease on cleavage and blastocyst rates was observed as H2O2 increased. Also, we detected a blockage on embryo development. We concluded that sperm when exposed to oxidative environment presents impaired motility traits, prooxidative status, and premature capacitation; such alterations resulting in embryo development fail. PMID:26770658

Paraquat-induced ultrastructural changes and DNA damage in the nervous system is mediated via oxidative-stress-induced cytotoxicity in Drosophila melanogaster.

PubMed

Mehdi, Syed Hassan; Qamar, Ayesha

2013-08-01

Paraquat (PQ), a quaternary nitrogen herbicide, is commonly used as a pesticide despite of its high toxicity. Our study evaluated the effect of subchronic PQ exposure on the neuropathology, genotoxicity, and antioxidant activity on the nervous tissue of Drosophila melanogaster. We also explored the behavioral effect of PQ on D. melanogaster. Furthermore, we attempted to validate the mechanism by evaluating PQ-induced cytotoxicity on the D-Mel2 cell lines. The fruit fly D. melanogaster serves as a feasible model to understand the mechanism of neurodegenerative diseases. Our study shows a dose-dependent PQ-induced neuropathology in the brain tissue of D. melanogaster as evidenced by hematoxylin and eosin staining, silver nitrate staining, and transmission electron microscopy. Electron microscopic study of D. melanogaster brain tissue exhibited vacuolar degeneration and significant neuronal damage across the nervous tissue structure in comparison with control. Our findings also indicate a dose-dependent locomotor impairment and decreased superoxide dismutase (SOD) specific activity in PQ-treated D. melanogaster. These PQ-induced neuroanatomical changes and decreased SOD specific activity showed a significant association with oxidative DNA damage as observed by alkaline comet assay. Additionally, we show, for the first time, a dose-dependent PQ-induced cytotoxicity in the D-Mel2 cells suggesting loss of neuronal cell viability via cytotoxic damage. Our data suggest that PQ exposure results in neurodegeneration in D. melanogaster and that fruit fly is a suitable in vivo model for correlating the neuroanatomical changes with neurotoxic damages to nervous system.

The toxicity of graphene and its impacting on bioleaching of metal ions from sewages sludge by Acidithiobacillus sp.

PubMed

Guo, Shen; Lin, Jiajiang; Wang, Qingping; Megharaj, Mallavarapu; Chen, Zuliang

2018-03-01

The increasing production of graphene raised concerns about their releasing into sewage sludge, however, there is little information about graphene impacting on the growth of bacteria and hence their bioleaching of metal ions from sewages sludge. In this study, we reported that Acidithiobacillus sp., isolated from sewages, were used to bioleach Cu 2+ and Zn 2+ from sewages sludge in the presence of graphene. The negative effect on the growth of Acidithiobacillus sp. and dose-dependent were observed in presence of graphene, where the optical density (OD 420 ) of the culture decreased from 0.163 to 0.045, while the bioleaching efficiency of Cu 2+ (70%-16%) and Zn 2+ (80%-48%) were also reduced when the graphene dose decreased from 50 mg L -1 to 1 mg L -1 . Furthermore, scanning electron microscopy (SEM) and atomic force microscopy (AFM) confirmed that the direct contacts between graphene and cell at 1 mg L -1 graphene caused cell membrane disruption, while Acidithiobacillus sp. grew better by forming dense biofilms around the suspended graphene at a 50 mg L -1 . LIVE/DEAD staining further demonstrated that almost no live cells were detected at 1 mg L -1 graphene. The toxicity of graphene could generally be explained by depending on the concentration of graphene. The new findings provide an insight into dose dependence, which impacted on the growth of Acidithiobacillus sp. and their bioleaching of metal ion from sludge. Copyright © 2017 Elsevier Ltd. All rights reserved.

An ethanol extract of Piper betle Linn. mediates its anti-inflammatory activity via down-regulation of nitric oxide.

PubMed

Ganguly, Sudipto; Mula, Soumyaditya; Chattopadhyay, Subrata; Chatterjee, Mitali

2007-05-01

The leaves of Piper betle (locally known as Paan) have long been in use in the Indian indigenous system of medicine for the relief of pain; however, the underlying molecular mechanisms of this effect have not been elucidated. The anti-inflammatory and immunomodulatory effects of an ethanolic extract of the leaves of P. betle (100 mg kg(-1); PB) were demonstrated in a complete Freund's adjuvant-induced model of arthritis in rats with dexamethasone (0.1 mg kg(-1)) as the positive control. At non-toxic concentrations of PB (5-25 microg mL(-1)), a dose-dependent decrease in extracellular production of nitric oxide in murine peritoneal macrophages was measured by the Griess assay and corroborated by flow cytometry using the nitric oxide specific probe, 4,5-diaminofluorescein-2 diacetate. This decreased generation of reactive nitrogen species was mediated by PB progressively down-regulating transcription of inducible nitric oxide synthase in macrophages, and concomitantly causing a dose-dependent decrease in the expression of interleukin-12 p40, indicating the ability of PB to down-regulate T-helper 1 pro-inflammatory responses. Taken together, the anti-inflammatory and anti-arthrotic activity of PB is attributable to its ability to down-regulate the generation of reactive nitrogen species, thus meriting further pharmacological investigation.

Cosmetic formulations containing Lithospermum erythrorhizon root extract show moisturizing effects on human skin.

PubMed

Chang, Man-Jau; Huang, Huey-Chun; Chang, Hsien-Cheh; Chang, Tsong-Min

2008-07-01

Retention of water in the stratum corneum of skin epidermis plays an important role in regulation of skin function. Loss of water may decline skin appearance gradually and lead to irregular skin disorders. The root extract of Lithospermum erythrorhizon (LES) is known for its various pharmacological activities. However, the potential skin care effect of LES is not clear. The aim of this study was to evaluate the moisturizing efficacy and skin barrier repairing activity of LES. For this study, 30 healthy Asian females (age 20-30) with healthy skin had applied the test emulsions twice daily over a period of 28 days. The skin properties were measured by skin bioengineering techniques. Our preliminary results indicated that LES show moisturizing effect on skin hydration in a time- and dose-dependent pattern, and the maximum increase in skin humidity was 11.77 +/- 1.18% for emulsion LES5.00. Particularly, LES-containing emulsions significantly improve skin barrier function by decreasing the value of transepidermal water loss (TEWL) in a time- and dose-dependent pattern, and the maximum decrease in TEWL value was 7.68 +/- 0.79% for emulsion LES5.00. Taken together, our data demonstrate that LES is more effective in increasing skin humidity and decreasing the TEWL values, indicating the potential skin care effects of LES.

Quercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expression.

PubMed

Zhang, X; Xu, Q; Saiki, I

2000-01-01

Quercetin has been known to have anti-tumor and anti-oxidation activities. In the present study, we have investigated its in vitro anti-metastatic activity. Quercetin inhibited the invasion and mobility of murine melanoma B16-BL6 cells in a dose-dependent manner but did not affect their adhesion to either laminin, fibronectin, or type VI collagen. Moreover, quercetin significantly inhibited the proliferation of B16-BL6 cells only in the case of time incubation longer than 48 h. Quercetin dose-dependently decreased the cell rates in S and G2-M phases of cell cycle. The effect of quercetin to cause a remarkable apoptosis of B16-BL6 cells was also demonstrated by flow cytometric assay as well as DNA fragmentation with a typical 180-bp ladder band in agarose electrophoresis and a quantitative analysis. Furthermore, quercetin markedly inhibited the expression of anti-apoptotic protein Bcl-2 but hardly influenced Bcl-XL. These results suggest that the inhibition of quercetin on invasiveness and migration of B16-BL6 cells are closely associated with the arrest of cell cycle as well as the induction of apoptosis by decreasing the Bcl-2 expression.

Whole-body vibration training effect on physical performance and obesity in mice.

PubMed

Huang, Chi-Chang; Tseng, Tzu-Ling; Huang, Wen-Ching; Chung, Yi-Hsiu; Chuang, Hsiao-Li; Wu, Jyh-Horng

2014-01-01

The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity-associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity.

Whole-Body Vibration Training Effect on Physical Performance and Obesity in Mice

PubMed Central

Huang, Chi-Chang; Tseng, Tzu-Ling; Huang, Wen-Ching; Chung, Yi-Hsiu; Chuang, Hsiao-Li; Wu, Jyh-Horng

2014-01-01

The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity-associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity. PMID:25317067

Effects of Lactobacillus acidophilus supplementation on growth performance, nutrient digestibility, fecal microbial and noxious gas emission in weaning pigs.

PubMed

Lan, Ruixia; Koo, Jinmo; Kim, Inho

2017-03-01

Antibiotics used as growth promoters in livestock have been banned in the European Union since 2006. Antibiotics alternatives have focused on probiotics, such as Lactobacillus acidophilus. The concentration of L. acidophilus is considered crucial for obtaining the desired effects. However, limited studies have been conducted to test the dose-dependent effects of L. acidophilus. Therefore, the present study aimed to test the dose-dependent effects of L. acidophilus on growth performance, nutrient digestibility, fecal microbial flora and fecal noxious gas emission in weaning pigs. Lactobacillus acidophilus supplementation increased (P < 0.05) average daily gain, average daily feed intake, apparent nutrient digestibility of dry matter, nitrogen and gross energy, and Lactobacillus counts compared to the basal diet treatment, and a linear effect (P < 0.05) was observed on those criteria. Escherichia coli counts and NH 3 emission were decreased (P < 0.05) by L. acidophilus supplementation, and a linear effect (P < 0.05) was observed on E. coli counts. These results suggest that L. acidophilus could be used as an antibiotic alternative by improving growth performance, nutrient digestibility and gut balance (i.e. increased Lactobacillus counts and decreased E. coli counts), and decreasing NH3 emission, of weaning pigs. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

A consistent two-mutation model of bone cancer for two data sets of radium-injected beagles.

PubMed

Bijwaard, H; Brugmans, M J P; Leenhouts, H P

2002-09-01

A two-mutation carcinogenesis model has been applied to model osteosarcoma incidence in two data sets of beagles injected with 226Ra. Taking age-specific retention into account, the following results have been obtained: (1) a consistent and well-fitting solution for all age and dose groups, (2) mutation rates that are linearly dependent on dose rate, with an exponential decrease for the second mutation at high dose rates, (3) a linear-quadratic dose-effect relationship, which indicates that care should be taken when extrapolating linearly, (4) highest cumulative incidences for injection at young adult age, and highest risks for injection doses of a few kBq kg(-1) at these ages, and (5) when scaled appropriately, the beagle model compares fairly well with a description for radium dial painters, suggesting that a consistent model description of bone cancer induction in beagles and humans may be possible.

Low doses of six toxicants change plant size distribution in dense populations of Lactuca sativa.

PubMed

Belz, Regina G; Patama, Marjo; Sinkkonen, Aki

2018-08-01

Toxicants are known to have negligible or stimulatory, i.e. hormetic, effects at low doses below those that decrease the mean response of a plant population. Our earlier observations indicated that at such low toxicant doses the growth of very fast- and slow-growing seedlings is selectively altered, even if the population mean remains constant. Currently, it is not known how common these selective low-dose effects are, whether they are similar among fast- and slow-growing seedlings, and whether they occur concurrently with hormetic effects. We tested the response of Lactuca sativa in complete dose-response experiments to six different toxicants at doses that did not decrease population mean and beyond. The tested toxicants were IAA, parthenin, HHCB, 4-tert-octylphenol, glyphosate, and pelargonic acid. Each experiment consisted of 14,400-16,800 seedlings, 12-14 concentrations, 24 replicates per concentration and 50 germinated seeds per replicate. We analyzed the commonness of selective low-dose effects and explored if toxic effects and hormetic stimulation among fast- and slow-growing individuals occurred at the same concentrations as they occur at the population level. Irrespective of the observed response pattern and toxicant, selective low-dose effects were found. Toxin effects among fast-growing individuals usually started at higher doses compared to the population mean, while the opposite was found among slow-growing individuals. Very low toxin exposures tended to homogenize plant populations due to selective effects, while higher, but still hormetic doses tended to heterogenize plant populations. Although the extent of observed size segregation varied with the specific toxin tested, we conclude that a dose-dependent alteration in size distribution of a plant population may generally apply for many toxin exposures. Copyright © 2018 Elsevier B.V. All rights reserved.

Acute effects of caffeine on several operant behaviors in rhesus monkeys.

PubMed

Buffalo, E A; Gillam, M P; Allen, R R; Paule, M G

1993-11-01

The acute effects of 1,3-trimethylxanthine (caffeine) were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions, such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). Caffeine sulfate (0.175-20.0 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in TRD percent task completed and accuracy at doses > or = 5.6 mg/kg. Caffeine produced no systematic effects on either DMTS or PR responding, but low doses tended to enhance performance in both IRA and CPR tasks. Thus, in monkeys, performance of an operant task designed to model time estimation is more sensitive to the disruptive effects of caffeine than is performance of the other tasks in the OTB.

Effect of solute atom concentration on vacancy cluster formation in neutron-irradiated Ni alloys

NASA Astrophysics Data System (ADS)

Sato, Koichi; Itoh, Daiki; Yoshiie, Toshimasa; Xu, Qiu; Taniguchi, Akihiro; Toyama, Takeshi

2011-10-01

The dependence of microstructural evolution on solute atom concentration in Ni alloys was investigated by positron annihilation lifetime measurements. The positron annihilation lifetimes in pure Ni, Ni-0.05 at.%Si, Ni-0.05 at.%Sn, Ni-Cu, and Ni-Ge alloys were about 400 ps even at a low irradiation dose of 3 × 10 -4 dpa, indicating the presence of microvoids in these alloys. The size of vacancy clusters in Ni-Si and Ni-Sn alloys decreased with an increase in the solute atom concentration at irradiation doses less than 0.1 dpa; vacancy clusters started to grow at an irradiation dose of about 0.1 dpa. In Ni-2 at.%Si, irradiation-induced segregation was detected by positron annihilation coincidence Doppler broadening measurements. This segregation suppressed one-dimensional (1-D) motion of the interstitial clusters and promoted mutual annihilation of point defects. The frequency and mean free path of the 1-D motion depended on the solute atom concentration and the amount of segregation.

Low Doses of Allyphenyline and Cyclomethyline, Effective against Morphine Dependence, Elicit an Antidepressant-like Effect

PubMed Central

2012-01-01

This study demonstrated that cyclomethyline (2) and the corresponding enantiomers (R)-(−)-2 and (S)-(+)-2, displaying α2C-adrenoreceptor (AR) agonism/α2A-AR antagonism, similarly to allyphenyline (1) and its enantiomers, significantly decreased the naloxone-precipitated withdrawal symptoms in mice at very low doses. It also highlighted that such positive effects on morphine dependence can even be improved by additional serotoninergic 5-HT1A receptor (5-HT1A-R) activation. Indeed, 1 or the single (S)-(+)-1, 2, or both its enantiomers, all behaving as α2C-AR agonists/α2A-AR antagonists/5-HT1A-R agonists, alone and at the same low dose, improved morphine withdrawal syndrome and exerted a potent antidepressant-like effect. Therefore, considering the elevated comorbidity between opiate abuse and depressed mood and the benefit of these multifunctional compounds to both disorders, it is possible that they prove more efficacious and less toxic than a cocktail of drugs in managing opioid addiction. PMID:24900506

Effects of afala and antiestrogen ICI 182,780 in the model of hormone-dependent prostate inflammation.

PubMed

Bernoulli, J; Konkol, Y; Vuorikoski, H; Yatkin, E

2014-04-01

In the hormone-dependent prostate inflammation model induced by implantation of slow-releasing pellets (50 mg testosterone and 5 mg estradiol) to Noble male rats, intragastric administration of Afala at a dose of 7.5 ml/kg for 18 weeks reduced the number of inflamed prostatic acini. The effect of afala was comparable with that of antiestrogen ICI 182,780 (3 mg/kg subcutaneously twice a week for 18 weeks). Prolonged treatment with hormones in high doses induced severe inflammation of the prostate tissue, which was not terminated by the test preparations. As differentiated from the antiestrogen ICI 182,780, afala did not induce body weight gain and decrease in pituitary weight in experimental animals in comparison with the control group.

Upregulation of PEDF expression by PARP inhibition contributes to the decrease in hyperglycemia-induced apoptosis in HUVECs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen Haibing; Department of Ophthalmology, Anhui Provincial Hospital, Hefei; Jia Weiping

2008-05-02

Poly(ADP-ribose)polymerase (PARP) inhibitors decrease angiogenesis through reducing vascular endothelium growth factor (VEGF) induced proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). In contrast to VEGF, pigment epithelium-derived factor (PEDF) has been demonstrated to act as a strong endogenous inhibitor of angiogenesis. Here, we show that PARP inhibition with a specific inhibitor PJ-34 or specific PARP antisense oligonucleotide upregulates hyperglycemia-induced PEDF expression in HUVECs in a dose-dependent manner. This results in the retard of activation of p38 MAP kinase and the concomitant decrease in cell apoptosis. These results give the first direct demonstration that PEDF might representmore » a target for PARP inhibition treatment and the effects of PEDF on endothelial cells growth are context dependent.« less

Basis of behavioral influence of chlorpromazine.

NASA Technical Reports Server (NTRS)

Emley, G. S.; Hutchinson, R. R.

1972-01-01

Squirrel monkeys, studied during response-independent, periodic presentation of electric shock, engaged in biting attack behavior after shock and anticipatory manual and locomotor behavior prior to shock. For all subjects, administration of chlorpromazine caused a dose-dependent decrease in biting attack reactions and a simultaneous increase in anticipatory manual responses. Administration of d-Amphetamine increased while morphine decreased both responses. The results suggest that the tranquilizer, chlorpromazine, produces a shift in an organism's response tendency from post-event aggressivity toward pre-event anticipatory responding.

[The effect of tachykinins microinjections into the solitary tract nucleus on respiration and blood circulation in rats].

PubMed

Chepurnov, S A; Iniushkin, A N

1997-04-01

Administration of substance P and kassinin into the solitary tract nucleus of anesthetized rats induced a dose-dependent increase in ventilation, tidal volume, inspiratory muscle activity, and a decrease in the mean blood pressure and heart rate. Microinjections of peptides caused a decrease in ventilatory response to hypoxia and an inhibition of the Breuer-Hering reflex. The data obtained suggest involvement of tachykinins in the respiratory and circulatory control via the solitary tract nucleus.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vostrotin, Vadim; Birchall, Alan; Zhdanov, Alexey

The distribution of calculated internal doses was determined for 8043 Mayak Production Associate (Mayak PA) workers according to the epidemiological cohorts and groups of raw data used as well as the type of industrial compounds of inhaled aerosols. Statistical characteristics of point estimates of accumulated doses to 17 different tissues and organs and the uncertainty ranges were calculated. Under the MWDS-2013 dosimetry system, the mean accumulated lung dose was 185585 mGy, with a median value of 31 mGy and a maximum of 8980 mGy maximum. The ranges of relative standard uncertainty were: from 40 to 2200% for accumulated lung dose,more » from 25-90% to 2600-3000% for accumulated dose to different regions of respiratory tract, from 13-18% to 2300-2500% for systemic organs and tissues. The Mayak PA workers accumulated internal plutonium lung dose is shown to be close to lognormal. The accumulated internal plutonium dose to systemic organs was close to a log-triangle. The dependency of uncertainty of accumulated absorbed lung and liver doses on the dose estimates itself is also shown. The accumulated absorbed doses to lung, alveolar-interstitial region, liver, bone surface cells and red bone marrow, calculated both with MWDS-2013 and MWDS-2008 have been compared. In general, the accumulated lung doses increased by a factor of 1.8 in median value, while the accumulated doses to systemic organs decreased by factor of 1.3-1.4 in median value. For the cases with identical initial data, accumulated lung doses increased by a factor of 2.1 in median value, while accumulated doses to systemic organs decreased by 8-13% in median value. For the cases with both identical initial data and all of plutonium activity in urine measurements above the decision threshold, accumulated lung doses increased by a factor of 2.8 in median value, while accumulated doses to systemic organs increased by 6-12% in median value.« less

Dose-Dependent Dual Role of PIT-1 (POU1F1) in Somatolactotroph Cell Proliferation and Apoptosis

PubMed Central

Jullien, Nicolas; Roche, Catherine; Brue, Thierry; Figarella-Branger, Dominique; Graillon, Thomas; Barlier, Anne; Herman, Jean-Paul

2015-01-01

To test the role of wtPIT-1 (PITWT) or PIT-1 (R271W) (PIT271) in somatolactotroph cells, we established, using inducible lentiviral vectors, sublines of GH4C1 somatotroph cells that allow the blockade of the expression of endogenous PIT-1 and/or the expression of PITWT or PIT271, a dominant negative mutant of PIT-1 responsible for Combined Pituitary Hormone Deficiency in patients. Blocking expression of endogenous PIT-1 induced a marked decrease of cell proliferation. Overexpressing PITWT twofold led also to a dose-dependent decrease of cell proliferation that was accompanied by cell death. Expression of PIT271 induced a strong dose-dependent decrease of cell proliferation accompanied by a very pronounced cell death. These actions of PIT271 are independent of its interaction/competition with endogenous PIT-1, as they were unchanged when expression of endogenous PIT-1 was blocked. All these actions are specific for somatolactotroph cells, and could not be observed in heterologous cells. Cell death induced by PITWT or by PIT271 was accompanied by DNA fragmentation, but was not inhibited by inhibitors of caspases, autophagy or necrosis, suggesting that this cell death is a caspase-independent apoptosis. Altogether, our results indicate that under normal conditions PIT-1 is important for the maintenance of cell proliferation, while when expressed at supra-normal levels it induces cell death. Through this dual action, PIT-1 may play a role in the expansion/regression cycles of pituitary lactotroph population during and after lactation. Our results also demonstrate that the so-called “dominant-negative” action of PIT271 is independent of its competition with PIT-1 or a blockade of the actions of the latter, and are actions specific to this mutant variant of PIT-1. PMID:25822178

Comparison of captopril and enalapril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE inhibitors in high dieted methionine mice.

PubMed

Liu, Yu-Hui; Liu, Li-Ying; Wu, Jin-Xiang; Chen, Shuang-Xiu; Sun, Yin-Xue

2006-01-01

To examine the role of sulfhydryl (-SH) group in improvement of endothelial dysfunction with angiotensin-converting enzyme (ACE) inhibitors in experimental high dose of methionine dieted rats. We compared the effects of Captopril (an ACE inhibitor with -SH group), enalapril (an ACE-inhibitor without -SH group), N-acetylcysteine (only -SH group not ACE inhibitor) on endothelial dysfunction injured by methionine-induced hyperhomocysteinemia (HHcy) in rats. Male Sprague-Dawley rats were divided randomly into seven groups: control group, L-methionine group, low dose Captopril (15 mg/kg), middle dose Captopril (30 mg/kg), high dose Captopril (45 mg/kg), enalapril (20 mg/kg), N-acetylcysteine (200 mg/kg); control group were intragastric gavaged by water and others groups were intragastric gavaged by L-methionine and drugs in water one time every day. Acetylcholine (ACh)-induced endothelium-dependent relaxation (EDR), sodium nitroprusside (SNP)-induced endothelium-independent relaxation of aortic rings were examined. Paraoxonase1 (PON1) and ACE activity, malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) in serum were analyzed. It was found that a single intragastric gavage by L-methionine resulted in inhibition of endothelium-dependent relaxation, markedly increased the serum level of malondialdehyde and decreased the activity of PON1 and SOD, similarly decreased the level of NO in the serum; but had no effects on endothelium-independent relaxation and angiotensin-converting enzyme activity compared with the control group. Given the treatment with three doses of Captopril (15 approximately 45 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, and eliminated the increased level of malondialdehyde, the decreased level of NO, activity of PON1 and SOD in serum by single intragastric gavaged L-methionine. However, there were some significant differences among Captopril (30 mg/kg or 45 mg/kg), enalapril (20 mg/kg), and N-acetylcysteine particular in the activity of PON1 and ACE. These results suggested that Captopril can protect the vascular endothelium against the damages induced by L-methionine in rats, and the beneficial effects of Captopril may be related to attenuating the decrease in PON1 activity and NO levels. Furthermore, this protective effect may be concerned with the sulfhydryl group.

Characterisation of a plastic scintillation detector to be used in a multicentre stereotactic radiosurgery dosimetry audit

NASA Astrophysics Data System (ADS)

Dimitriadis, A.; Patallo, I. Silvestre; Billas, I.; Duane, S.; Nisbet, A.; Clark, C. H.

2017-11-01

Scintillation detectors are considered highly suitable for dosimetric measurement of small fields in radiotherapy due to their near-tissue equivalence and their small size. A commercially available scintillation detector, the Exradin W1 (Standard Imaging, Middleton, USA), has been previously characterised by two independent studies (Beierholm et al., 2014; Carrasco et al., 2015a, 2015b) but the results from these publications differed in some aspects (e.g. energy dependence, long term stability). The respective authors highlighted the need for more studies to be published (Beierholm et al., 2015; Carrasco et al., 2015a, 2015b). In this work, the Exradin W1 was characterised in terms of dose response, dependence on dose rate, energy, temperature and angle of irradiation, and long-term stability. The observed dose linearity, short-term repeatability and temperature dependence were in good agreement with previously published data. Appropriate corrections should therefore be applied, where possible, in order to achieve measurements with low-uncertainty. The angular dependence was characterised along both the symmetrical and polar axis of the detector for the first time in this work and a dose variation of up to 1% was observed. The response of the detector was observed to decrease at a rate of approximately 1.6% kGy-1 for the first 5 kGy delivered, and then stabilised to 0.2% kGy-1 in the subsequent 20 kGy. The main goal of this work was to assess the suitability of the Exradin W1 for use in dose verification measurements for stereotactic radiosurgery. The results obtained confirm that the detector is suitable for use in such situations. The detector is now utilised in a multi-centre stereotactic radiosurgery dosimetric audit, with the application of appropriate correction factors.

Long-term treatment with green tea polyphenols modifies the gut microbiome of female sprague-dawley rats.

PubMed

Wang, Jincheng; Tang, Lili; Zhou, Hongyuan; Zhou, Jun; Glenn, Travis C; Shen, Chwan-Li; Wang, Jia-Sheng

2018-06-01

Green tea polyphenols (GTP) have been shown to exert a spectrum of health benefits to animals and humans. It is plausible that the beneficial effects of GTP are a result of its interaction with the gut microbiota. This study evaluated the effect of long-term treatment with GTP on the gut microbiota of experimental rats and the potential linkage between changes of the gut microbiota with the beneficial effects of GTP. Six-month-old Sprague-Dawley rats were randomly allocated into three dosing regimens (0, 0.5%, and 1.5% of GTP) and followed for 6 months. At the end of month 3 or month 6, half of the animals from each group were sacrificed and their colon contents were collected for microbiome analysis using 16S ribosomal RNA and shotgun metagenomic community sequencing. GTP treatment significantly decreased the biodiversity and modified the microbial community in a dose-dependent manner; similar patterns were observed at both sampling times. Multiple operational taxonomic units and phylotypes were modified: the phylotypes Bacteroidetes and Oscillospira, previously linked to the lean phenotype in human and animal studies, were enriched; and Peptostreptococcaceae previously linked to colorectal cancer phenotype was depleted in GTP treated groups in a dose-dependent manner. Several microbial gene orthologs were modified, among which genes related to energy production and conversion were consistently enriched in samples from month 6 in a dose-dependent manner. This study showed that long-term treatment with GTP induced a dose-dependent modification of the gut microbiome in experimental rats, which might be linked to beneficial effects of GTP. Copyright © 2018 Elsevier Inc. All rights reserved.

Dose-Dependent and Lasting Influences of Intranasal Vasopressin on Face Processing in Men

PubMed Central

Price, Daniel; Burris, Debra; Cloutier, Anna; Thompson, Carol B.; Rilling, James K.; Thompson, Richmond R.

2017-01-01

Arginine vasopressin (AVP) and related peptides have diverse effects on social behaviors in vertebrates, sometimes promoting affiliative interactions and sometimes aggressive or antisocial responses. The type of influence, in at least some species, depends on social contexts, including the sex of the individuals in the interaction and/or on the levels of peptide within brain circuits that control the behaviors. To determine if AVP promotes different responses to same- and other-sex faces in men, and if those effects are dose dependent, we measured the effects of two doses of AVP on subjective ratings of male and female faces. We also tested if any influences persist beyond the time of drug delivery. When AVP was administered intranasally on an initial test day, 20 IU was associated with decreased social assessments relative to placebo and 40 IU, and some of the effects persisted beyond the initial drug delivery and appeared to generalize to novel faces on subsequent test days. In single men, those influences were most pronounced, but not exclusive, for male faces, whereas in coupled men they were primarily associated with responses to female faces. Similar influences were not observed if AVP was delivered after placebo on a second test day. In a preliminary analysis, the differences in social assessments observed between men who received 20 and 40 IU, which we suggest primarily reflect lowered social assessments induced by the lower dose, appeared most pronounced in subjects who carry what has been identified as a risk allele for the V1a receptor gene. Together, these results suggest that AVP’s effects on face processing, and possibly other social responses, differ according to dose, depend on relationship status, and may be more prolonged than previously recognized. PMID:29018407

In vitro effects of 0 to 120 Grays of irradiation on bone viability and release of growth factors.

PubMed

Sawada, Kosaku; Fujioka-Kobayashi, Masako; Kobayashi, Eizaburo; Brömme, Jens O; Schaller, Benoit; Miron, Richard J

2016-07-04

High dose radiation therapy is commonly used in maxillofacial surgeries to treat a number of head and neck tumors. Despite its widespread use, little information is available regarding the effects of irradiation on bone cell viability and release of growth factors following dose-dependent irradiation. Bone samples were collected from porcine mandibular cortical bone and irradiated at doses of 0, 7.5, 15, 30, 60 and 120 Grays. Thereafter, cell viability was quantified, and the release of growth factors including TGFβ1, BMP2, VEGF, IL1β and RANKL were investigated over time. It was observed that at only 7.5Gy of irradiation, over 85 % of cells were non-vital and by 60 Gy, all cells underwent apoptosis. Furthermore, over a 7-fold decrease in VEGF and a 2-fold decrease in TGFβ1 were observed following irradiation at all tested doses. Little change was observed for BMP2 and IL1β whereas RANKL was significantly increased for all irradiated samples. These results demonstrate the pronounced effects of irradiation on bone-cell vitality and subsequent release of growth factors. Interestingly, the largest observed change in gene expression was the 7-fold decrease in VEGF protein following irradiation. Future research aimed at improving our understanding of bone following irradiation is necessary to further improve future clinical treatments.

Cardiovascular effects of Nemopilema nomurai (Scyphozoa: Rhizostomeae) jellyfish venom in rats.

PubMed

Kim, Euikyung; Lee, Seunghwan; Kim, Jong-Shu; Yoon, Won Duk; Lim, Donghyun; Hart, Andrew J; Hodgson, Wayne C

2006-12-15

Over the past few years, populations of the giant jellyfish Nemopilema nomurai (Scyphozoa: Rhizostomeae) have increased dramatically in the waters of China, Korea, and Japan without any definitive reason. This has resulted in severe damage to fisheries in the areas. During a pilot study, we observed that the venom of N. nomurai produced a functional cardiac depression in mice. However, the mechanism of action was not examined. In the present study, we investigated the cardiovascular effects of nematocyst-derived venom from N. nomurai in anesthetized rats. Venom (0.1-2.4 mg protein/kg, i.v.) produced dose-dependent hypotension (65+/-12% of initial at a cumulative dose of 3 mg/kg) and bradycardia (80+/-5% of initial at a cumulative dose of 3 mg/kg). At the highest dose, this was characterized by a transient decrease in blood pressure (phase 1) followed by a return to basal level and then a slower decrease in blood pressure (phase 2). Venom also produced a decrease in rate and force of contraction in the rat isolated atria. Interestingly, venom induced a contraction of isolated aortic rings which was blocked by felodipine but not by prazosin, suggesting the contraction is mediated by calcium channel activation. These results suggest that the negative inotropic and chronotropic effects of the venom of N. nomurai may be due to a direct effect on the heart.

Frame average optimization of cine-mode EPID images used for routine clinical in vivo patient dose verification of VMAT deliveries

DOE Office of Scientific and Technical Information (OSTI.GOV)

McCowan, P. M., E-mail: pmccowan@cancercare.mb.ca; McCurdy, B. M. C.; Medical Physics Department, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9

Purpose: The in vivo 3D dose delivered to a patient during volumetric modulated arc therapy (VMAT) delivery can be calculated using electronic portal imaging device (EPID) images. These images must be acquired in cine-mode (i.e., “movie” mode) in order to capture the time-dependent delivery information. The angle subtended by each cine-mode EPID image during an arc can be changed via the frame averaging number selected within the image acquisition software. A large frame average number will decrease the EPID’s angular resolution and will result in a decrease in the accuracy of the dose information contained within each image. Alternatively, lessmore » EPID images acquired per delivery will decrease the overall 3D patient dose calculation time, which is appealing for large-scale clinical implementation. Therefore, the purpose of this study was to determine the optimal frame average value per EPID image, defined as the highest frame averaging that can be used without an appreciable loss in 3D dose reconstruction accuracy for VMAT treatments. Methods: Six different VMAT plans and six different SBRT-VMAT plans were delivered to an anthropomorphic phantom. Delivery was carried out on a Varian 2300ix model linear accelerator (Linac) equipped with an aS1000 EPID running at a frame acquisition rate of 7.5 Hz. An additional PC was set up at the Linac console area, equipped with specialized frame-grabber hardware and software packages allowing continuous acquisition of all EPID frames during delivery. Frames were averaged into “frame-averaged” EPID images using MATLAB. Each frame-averaged data set was used to calculate the in vivo dose to the patient and then compared to the single EPID frame in vivo dose calculation (the single frame calculation represents the highest possible angular resolution per EPID image). A mean percentage dose difference of low dose (<20% prescription dose) and high dose regions (>80% prescription dose) was calculated for each frame averaged scenario for each plan. The authors defined their unacceptable loss of accuracy as no more than a ±1% mean dose difference in the high dose region. Optimal frame average numbers were then determined as a function of the Linac’s average gantry speed and the dose per fraction. Results: The authors found that 9 and 11 frame averages were suitable for all VMAT and SBRT-VMAT treatments, respectively. This resulted in no more than a 1% loss to any of the dose region’s mean percentage difference when compared to the single frame reconstruction. The optimized number was dependent on the treatment’s dose per fraction and was determined to be as high as 14 for 12 Gy/fraction (fx), 15 for 8 Gy/fx, 11 for 6 Gy/fx, and 9 for 2 Gy/fx. Conclusions: The authors have determined an optimal EPID frame averaging number for multiple VMAT-type treatments. These are given as a function of the dose per fraction and average gantry speed. These optimized values are now used in the authors’ clinical, 3D, in vivo patient dosimetry program. This provides a reduction in calculation time while maintaining the authors’ required level of accuracy in the dose reconstruction.« less

ssDNA damage dependence from singlet oxygen concentration at photodynamic interaction

NASA Astrophysics Data System (ADS)

Klimenko, V. V.; Kaydanov, N. E.; Emelyanov, A. K.; Bogdanov, A. A.

2017-11-01

Single stranded DNA damage at photodynamic treatment with Radachlorin photosensitizer was investigated. Chemical trap method was used to evaluate generation of singlet oxygen in water solution. Interaction of singlet oxygen with ssDNA resulted into decrease of the replication activity of ssDNA. DNA stopped replicating during PCR at irradiation doses greater than 15 J/cm2 and concentration of photosensitizer [PS] = 3.8 μM. The dependence of replication activity of ssDNA on generated singlet oxygen concentration was identified.

Effects of X-ray irradiation on different stages of Sesamia nonagrioides Lefebvre (Lepidoptera: Noctuidae) and DNA damage

NASA Astrophysics Data System (ADS)

Avan Aksoy, Hatice; Yazıcı, Nizamettin; Erel, Yakup

2017-01-01

The corn stalk borer, Sesamia nonagrioides Lefebvre (Lepidoptera: Noctuidae) is an important corn pest in the Mediterranean countries. In this study, we investigated the influence of X-ray irradiation on different developmental stages, reproduction and DNA damage to the insect. Eggs (0-24 h old), larvae (5th instar), pupae (5 days after pupation) and adults (24 h after emergence) were irradiated with X-ray irradiation at target doses of 0 (control), 50, 100, 150 and 200 Gy. Eggs irradiated at all doses did not hatch. When 5th instar were irradiated pupation and adult emergence significantly decreased. Fecundity of adults from irradiated pupae was inhibited and no eggs were laid. Moreover, adult longevity decreased after irradiation compared to control. Larvae, pupae, and adults of S. nonagrioides were studied using the single-cell gel electrophoresis (DNA comet) directly after irradiation. X-ray irradiated larvae, pupae, and adults showed typical DNA fragmentation in a dose-dependent manner compared with cells from non-irradiated groups. The amount of DNA damage increased as doses increased and possibly could be used to estimate dose applied in commercial phytosanitary irradiation treatments. Furthermore, irradiation would be an effective phytosanitary treatment for shipped commodities at risk infestation with S. nonagrioides.

ATR-101, a selective ACAT1 inhibitor, decreases ACTH-stimulated cortisol concentrations in dogs with naturally occurring Cushing's syndrome.

PubMed

Langlois, Daniel K; Fritz, Michele C; Schall, William D; Bari Olivier, N; Smedley, Rebecca C; Pearson, Paul G; Bailie, Marc B; Hunt, Stephen W

2018-05-02

Cushing's syndrome in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. In both species, treatment of pituitary- and adrenal-dependent disease is met with limitations. ATR-101, a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1), is a novel small molecule therapeutic currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing's syndrome in humans. Previous studies in healthy dogs have shown that ATR-101 treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels. The purpose of this clinical study was to investigate the effects of ATR-101 in dogs with Cushing's syndrome. ATR-101 pharmacokinetics and activity were assessed in 10 dogs with naturally-occurring Cushing's syndrome, including 7 dogs with pituitary-dependent disease and 3 dogs with adrenal-dependent disease. ATR-101 was administered at 3 mg/kg PO once daily for one week, followed by 30 mg/kg PO once daily for one (n = 4) or three (n = 6) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration. ATR-101 exposure increased with increasing dose. ACTH-stimulated cortisol concentrations, the primary endpoint for the study, were significantly decreased with responders (9 of 10 dogs) experiencing a mean ± standard deviation reduction in cortisol levels of 50 ± 17% at study completion. Decreases in pre-ACTH-stimulated cortisol concentrations were observed in some dogs although overall changes in pre-ACTH cortisol concentrations were not significant. The compound was well-tolerated and no serious drug-related adverse effects were reported. This study highlights the potential utility of naturally occurring canine Cushing's syndrome as a model for human disease and provides proof of concept for ATR-101 as a novel agent for the treatment of endocrine disorders like Cushing's syndrome in humans.

Genotoxicity of 2-[2-(acetylamino)-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6) and 4-amino-3,3'-dichloro-5,4'-dinitro-biphenyl (ADDB) in goldfish (Carassius auratus) using the micronucleus test and the comet assay.

PubMed

Masuda, Shuichi; Deguchi, Yuya; Masuda, Yumi; Watanabe, Tetsushi; Nukaya, Haruo; Terao, Yoshiyasu; Takamura, Takeji; Wakabayashi, Keiji; Kinae, Naohide

2004-05-09

2-[2-(Acetylamino)-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6) and 4-amino-3,3'-dichloro-5,4'-dinitrobiphenyl (ADDB) are two compounds, which show strong mutagenicity toward bacteria, that have been identified as major mutagens in river water in Japan. In the present study, we examined the genotoxicity of PBTA-6 and ADDB in goldfish (Carassius auratus) by the micronucleus test and single-cell gel electrophoresis (comet assay). The frequencies of micronuclei in gill cells gradually increased until 96h after i.p. injection of PBTA-6 and ADDB at doses of 50mg/kg body weight, and then decreased 144h after injection. PBTA-6 induced micronuclei in gill cells dose-dependently at a dose range of 1-100mg/kg body weight, giving significantly high frequencies at doses of 50 and 100mg/kg body weight. On the other hand, no significant increase was observed in the peripheral erythrocytes of goldfish exposed to PBTA-6 or ADDB. In the comet assay, values of DNA tail moment and tail length in peripheral erythrocytes increased significantly until 6h after the i.p. injection of PBTA-6 (50mg/kg body weight), only to decrease by 9h after injection. Both the DNA tail moment and tail length were dose-dependently increased by injections of PBTA-6 at doses ranging from 1 to 50mg/kg. Significantly high values for tail moment and tail length were found in peripheral erythrocytes 3h after an i.p. injection of ADDB and persisted for up to 6h. These results show that both PBTA-6 and ADDB have genotoxic effects in goldfish.

Amelioration of cisplatin-induced nephrotoxicity by ethanolic extract of Bauhinia purpurea: An in vivo study in rats.

PubMed

Rana, Md Azmat; Khan, Rahat Ali; Nasiruddin, Mohammad; Khan, Aijaz Ahmed

2016-01-01

Our objective is to study the nephroprotective activity and antioxidant potential of Bauhinia purpurea unripe pods and bark against cisplatin-induced nephrotoxicity. Healthy adult albino rats of either sex (150-200 g) were randomly divided into six groups of six animals each Group I (vehicle control) and Group II (negative control). Group III (BBE200) and Group IV (BBE400) were administered the ethanolic extract of Bauhinia purpurea bark in doses of 200 and 400 mg/kg/day p.o., respectively, and Group V (BPE200) and Group VI (BPE400) were administered the ethanolic extract of Bauhinia purpurea unripe pods at doses of 200 and 400 mg/kg/day p.o., respectively. All the treatments were given for nine days. Cisplatin in a single dose of 6 mg/kg i.p. was given on the 4 th day to all groups, except the vehicle control group. On the 10 th day, blood and urine were collected for biochemical tests and the rats were sacrificed. The kidney was removed for histology and lipid peroxidation-antioxidant test. Cisplatin caused nephrotoxicity as evidenced by elevated blood urea, serum creatinine and urine glucose, and there was decreased creatinine clearance in Group II as compared with Group I. Administration of BBE and BPE at doses of 200 and 400 mg/kg in Group III and Group VI caused a dose-dependant reduction in the rise of blood urea, serum creatinine and urine glucose, and there was a dose-dependant increase in creatinine clearance compared with Group II. There was increased catalase and glutathione and decreased malondialdehyde levels in Group II, while BBE 400 (Group IV) and BPE 400 (Group VI) treatments significantly reversed the changes toward normal values. Histological examination of the kidney revealed protection in Group IV and Group VI compared with Group II. The ethanolic extract of Bauhinia purpurea unripe pods and bark has a nephroprotective activity against cisplatin-induced nephrotoxicity in rats.

Suberoylanilide hydroxamic acid (vorinostat): its role on equine corneal fibrosis and matrix metalloproteinase activity.

PubMed

Donnelly, Kevin S; Giuliano, Elizabeth A; Sharm, Ajay; Mohan, Rajiv R

2014-07-01

To explore the effect of suberoylanilide hydroxamic acid (SAHA) (i) on corneal fibroblast differentiation, morphology, and viability; and (ii) on the expression levels of matrix metalloproteinases (MMPs) 2 and 9 using an in vitro model of equine corneal fibrosis. Healthy donor corneas were used to generate primary cultures of equine corneal fibroblasts. The fibroblasts were exposed to 5 ng/mL TGFβ1 to induce myofibroblast formation. The cultures were treated with either 5 μm or 10 μm SAHA for 72 h in the presence of TGFβ1. Real-time PCR and immunocytochemistry were used to determine the antifibrotic efficacy of SAHA by quantifying α-smooth muscle actin (αSMA), a marker of myofibroblast formation and fibrosis. Real-time PCR was used to determine the effects of SAHA on MMP2 and MMP9 expression. Cytotoxicity of SAHA was evaluated with phase contrast microscopy and trypan blue exclusion assays. Suberoylanilide hydroxamic acid (SAHA) significantly attenuated TGFβ1-induced differentiation of equine fibroblasts to myofibroblasts as indicated by 3- to 3.5-fold (P < 0.001) decrease in αSMA mRNA and 86-88% (P < 0.001) decrease in αSMA+ immunocytochemical staining. SAHA treatment also resulted in 4.5- to 5.5-fold (P < 0.01) decrease in MMP9 expression. A dose-dependent bimodal effect of SAHA on MMP2 expression was noted (3.5-fold increase with 5 μm dose; 0.5-fold decrease with 10 μm dose). No change in fibroblast viability was observed with a 5 μm SAHA dose, whereas a 10 μm dose resulted in a moderate 17% decrease in cell viability. Suberoylanilide hydroxamic acid (SAHA) can effectively inhibit TGFβ-induced differentiation of equine corneal fibroblasts to myofibroblasts and modulates MMP production in vitro. © 2013 American College of Veterinary Ophthalmologists.

Herbex-kid Inhibits Immediate Hypersensitivity Reactions in Mice and Rats

PubMed Central

Prasad, Rawal; Jogge, Nanjan Mulla; Bhojraj, Suresh; Emerson, Solomon F.; Prabakar, S.

2008-01-01

Herbex-kid (HK), a polyherbal formulation was evaluated in various experimental allergic models of Type I hypersensitivity reactions. Compound 48/80 (C 48/80) has been shown to induce rat mesentery mast cell degranulation and HK (1.07, 10.75 and 107.5 mg ml−1) inhibited the mast cell degranulation in a dose dependent manner. HK (1.07, 10.75 and 107.5 mg kg−1; p.o.) showed dose-dependent protection against C 48/80 induced systemic anaphylaxis in male Balb/C mice. In active anaphylaxis model, male Wistar rats orally administered with 10.75 and 107.5 mg kg−1 of HK showed significant (P < 0.01) protection against mast cell degranulation, while in passive anaphylaxis model, only at 107.5 mg kg−1 showed significant (P < 0.01) reduction in mast cell degranulation. HK at all dose levels was able to significantly decrease the time spent in nasal rubbing in Wistar rats sensitized to ovalbumin, while only at 107.5 mg kg−1 it showed significant (P < 0.01) reduction in number of sneezes. In C 48/80-induced skin itch model, all dose levels of HK significantly (P < 0.001) decreased the time spent in itching and the number of itches. HK did not produce any significant inhibition in histamine induced contraction in guinea pig ileum. From the above findings we conclude that the HK possesses antiallergic activity mediated by reducing of the release mediators from mast cells and also by 5-HT antagonism without the involvement of histamine (H1) receptors. PMID:18830458

Effects of Experimental Unemployment, Employment and Punishment Analogs on Opioid Seeking and Consumption in Heroin-Dependent Volunteers

PubMed Central

Greenwald, Mark K.

2010-01-01

This study investigated the extent to which hydromorphone (HYD) choice and behavioral economic demand differed during experimental analogs of Unemployment (Drug Only: HYD and no money alternative), Employment (Drug or Money: HYD and $4 alternative), and Punishment (Drug Only + Money Loss: HYD only and $4 subtracted for each HYD choice), in the context of anticipated high vs. low post-session drug availability (HYD 24 mg vs. placebo). Eleven heroin-dependent, buprenorphine-stabilized (8-mg/day) volunteers first sampled two HYD doses (0 and 24 mg IM in randomized, counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). In each of the final six sessions, volunteers were given access to a 12-trial choice progressive ratio (PR) task and could work to receive HYD unit doses (2 mg each); cumulative dose units earned were administered in a bolus injection after the work session. Before the PR task, volunteers were told which HYD dose (Drug A or B) would be available 3 hr after the PR-contingent injection. Relative to Unemployment (Drug Only), Employment (Drug or Money) and Punishment (Drug Only + Money Loss) each significantly suppressed HYD seeking (e.g., breakpoints). Employment and Punishment also reduced HYD behavioral economic demand, but via different mechanisms: Employment increased HYD price-elasticity, whereas Punishment decreased HYD demand intensity. Adjusting for the initial level difference (i.e., normalized demand), Employment significantly decreased Pmax (i.e., lower “essential value” of HYD) and Omax (maximum HYD responding) compared to Punishment or Unemployment. These effects were not significantly altered by post-session drug availability. PMID:20537815

SU-E-T-526: On the Linearity, Stability and Beam Energy Dependence of CdSe Quantum Dots as Scintillating Probes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Delage, M-E; Centre Hospitalier Universityde Quebec, Quebec, QC; Lecavalier, M-E

2014-06-01

Purpose: Structure and energy transfer mechanisms confer colloidal quantum dots (cQDs) interesting properties, among them their potential as scintillators. CdSe multi-shell cQDs in powder were investigated under photons irradiation. The purpose of this work is to characterize signal to dose linearity, stability with time and to quantify the dependence of their light output with beam energy. Methods: The cQDs are placed at the extremity of a non-scintillating plastic collecting fiber, with the other extremity connected to an Apogee U2000C CCD camera. The CCD camera collects the fluorescence light from irradiated cQDs from which the delivered dose is extracted. This signalmore » is corrected for Cerenkov contamination at MV energies using the chromatic technique. The detector was irradiated with two devices: Xstrahl 200 orthovoltage unit for 120, 180 and 220 kVp and a Varian Clinac iX for 6 and 23 MV. Results: Linear output response with varying dose is observed for all beam energies with R2 factors > 0,999. Reproducibility measurements were performed at 120 kVp: the same set-up was irradiated at different time intervals (one week and three months). The results showed only a small relative decrease of light output of 3,2 % after a combine deposited dose of approximately 95 Gy. CdSe nanocrystals response has been studied as a function of beam energy. The output increases with decreasing energy from 120 kVp to 6 MV and increase again for 23 MV. This behavior could be explained in part by the cQDs high-Z composition. Conclusion: The fluorescence light output of CdSe cQDs was found to be linear as a function of dose. The results suggest stability of the scintillation output of cQDs over time. The specific composition of cQDs is the main cause of the observed energy dependence. We will further look into particle beam dependence of the cQDs. Bourse d'excellence aux etudes graduees du CRC (Centre de Recherche sur le Cancer, Universite Laval) Bourse d'excellence aux etudes graduees du CRC (Centre de Recherche sur le Cancer, Universite Laval)« less

Sulforaphane targets cancer stemness and tumor initiating properties in oral squamous cell carcinomas via miR-200c induction.

PubMed

Liu, Chia-Ming; Peng, Chih-Yu; Liao, Yi-Wen; Lu, Ming-Yi; Tsai, Meng-Lun; Yeh, Jung-Chun; Yu, Chuan-Hang; Yu, Cheng-Chia

2017-01-01

Cancer stem cells (CSCs) are deemed as the driving force of tumorigenesis in oral squamous cell carcinomas (OSCCs). In this study, we investigated the chemotherapeutic effect of sulforaphane, a dietary component from broccoli sprouts, on targeting OSCC-CSCs. The effect of sulforaphane on normal oral epithelial cells (SG) and sphere-forming OSCC-CSCs isolated from SAS and GNM cells was examined. ALDH1 activity and CD44 positivity of OSCC-CSCs with sulforaphane treatment was assessed by flow cytometry analysis. In vitro and in vivo tumorigenicity assays of OSCC-CSCs with sulforaphane treatment were presented. We observed that the sulforaphane dose-dependently eliminated the proliferation rate of OSCC-CSCs, whereas the inhibition on SG cells proliferation was limited. Cancer stemness properties including self-renewal, CD44 positivity, and ALDH1 activity were also decreased in OSCC-CSCs with different doses of sulforaphane treatment. Moreover, sulforaphane treatment of OSCC-CSCs decreased the migration, invasion, clonogenicity, and in vivo tumorigenicity of xenograghts. Sulforaphane treatment resulted in a dose-dependent increase in the levels of tumor suppressive miR200c. These lines of evidence suggest that sulforaphane can suppress the cancer stemness and tumor-initiating properties in OSCC-CSCs both in vitro and in vivo. Copyright © 2016. Published by Elsevier B.V.

A study on the dependence of exposure dose reduction and image evaluation on the distance from the dental periapical X-ray machine

NASA Astrophysics Data System (ADS)

Joo, Kyu-Ji; Shin, Jae-Woo; Dong, Kyung-Rae; Lim, Chang-Seon; Chung, Woon-Kwan; Kim, Young-Jae

2013-11-01

Reducing the exposure dose from a periapical X-ray machine is an important aim in dental radiography. Although the radiation exposure dose is generally low, any radiation exposure is harmful to the human body. Therefore, this study developed a method that reduces the exposure dose significantly compared to that encountered in a normal procedure, but still produces an image with a similar resolution. The correlation between the image resolution and the exposure dose of the proposed method was examined with increasing distance between the dosimeter and the X-ray tube. The results were compared with those obtained from the existing radiography method. When periapical radiography was performed once according to the recommendations of the International Commission on Radiological Protection (ICRP), the measured skin surface dose was low at 7 mGy or below. In contrast, the skin surface dose measured using the proposed method was only 1.57 mGy, showing a five-fold reduction. These results suggest that further decreases in dose might be achieved using the proposed method.

Phosphoproteomic analysis of AT1 receptor-mediated signaling responses in proximal tubules of angiotensin II-induced hypertensive rats.

PubMed

Li, Xiao C; Zhuo, Jia L

2011-09-01

The signaling mechanisms underlying the effects of angiotensin II in proximal tubules of the kidney are not completely understood. Here we measured signal protein phosphorylation in isolated proximal tubules using pathway-specific proteomic analysis in rats continuously infused with pressor or non-pressor doses of angiotensin II over a 2-week period. Of the 38 phosphoproteins profiled, 14 were significantly altered by the pressor dose. This included increased phosphorylation of the protein kinase C isoenzymes, PKCα and PKCβII, and the glycogen synthase kinases, GSK3α and GSK3β. Phosphorylation of the cAMP-response element binding protein 1 and PKCδ were decreased, whereas PKCɛ remained unchanged. By contrast, the phosphorylation of only seven proteins was altered by the non-pressor dose, which increased that of PKCα, PKCδ, and GSKα. Phosphorylation of MAP kinases, ERK1/2, was not increased in proximal tubules in vivo by the pressor dose, but was in proximal tubule cells in vitro. Infusion of the pressor dose decreased, whereas the non-pressor dose of angiotensin II increased the phosphorylation of the sodium and hydrogen exchanger 3 (NHE-3) in membrane fractions of proximal tubules. Losartan largely blocked the signaling responses induced by the pressor dose. Thus, PKCα and PKCβII, GSK3α and GSK3β, and cAMP-dependent signaling pathways may have important roles in regulating proximal tubular sodium and fluid transport in Ang II-induced hypertensive rats.

Effects of particle size, helium gas pressure and microparticle dose on the plasma concentration of indomethacin after bombardment of indomethacin-loaded poly-L-lactic acid microspheres using a Helios gun system.

PubMed

Uchida, Masaki; Natsume, Hideshi; Kobayashi, Daisuke; Sugibayashi, Kenji; Morimoto, Yasunori

2002-05-01

We investigated the effects of the particle size of indomethacin-loaded poly-L-lactic acid microspheres (IDM-loaded PLA MS), the helium pressure used to accelerate the particles, and the bombardment dose of PLA MS on the plasma concentration of IDM after bombarding with IDM-loaded PLA MS of different particle size ranges, 20-38, 44-53 and 75-100 microm, the abdomen of hairless rats using the Helios gene gun system (Helios gun system). Using larger particles and a higher helium pressure, produced an increase in the plasma IDM concentration and the area under the plasma concentration-time curve (AUC) and resultant F (relative bioavailability with respect to intracutaneous injection) of IDM increased by an amount depending on the particle size and helium pressure. Although a reduction in the bombardment dose led to a decrease in C(max) and AUC, F increased on decreasing the bombardment dose. In addition, a more efficient F was obtained after bombarding with IDM-loaded PLA MS of 75-100 microm in diameter at each low dose in different sites of the abdomen compared with that after bolus bombardment with a high dose (dose equivalent). These results suggest that the bombardment injection of drug-loaded microspheres by the Helios gun system is a very useful tool for delivering a variety of drugs in powder form into the skin and systemic circulation.

Inhibition of immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion by injected leptin in rats.

PubMed

Haque, Zeba; Akbar, Nazia; Yasmin, Farzana; Haleem, Muhammad A; Haleem, Darakhshan J

2013-05-01

Leptin, originally identified as an anti-obesity hormone, also has an important role in the regulation of mood and emotion. The present study was designed to monitor effects of injected leptin on immobilization stress-induced anorexia, behavioral deficits, and plasma corticosterone secretion in rats. Exposure to 2 h immobilization stress decreased food intake and body weight in saline-injected animals. Animals exposed to open field, elevated plus maze, and light-dark transition tests the day following immobilization exhibited anxiety-like behavior. Leptin injected at doses of 0.1 and 0.5 mg/kg also decreased food intake and body weight in unstressed animals and elicited anxiolytic effects at dose of 0.5 mg/kg, monitored on the following day. Immobilization-induced decreases in food intake, body weight, as well as stress-induced behavioral deficits in the open field, elevated plus maze, and light-dark transition test were reversed by exogenous leptin in a dose-dependent (0.1-0.5 mg/kg) manner. Acute exposure to 2 h immobilization produced a fourfold rise in plasma levels of corticosterone. Animals injected with leptin at a dose of 0.1 mg/kg, but not at dose of 0.5 mg/kg, exhibited a marginal increase in plasma corticosterone. Immobilization-induced increases of plasma corticosterone were reversed by leptin injected at doses of 0.1 or 0.5 mg/kg. The data suggest that exogenous leptin can reduce stress perception, resulting in an inhibition of stress effects on the activity of hypothalamic-pituitary-adrenal axis and behavior. The reported pharmacological effects of leptin represent an innovative approach for the treatment of stress-related disorders.

EXOCRINE FUNCTION OF THE LIVER IN RATS WITH EXPOSURE TO CОRVITIN.

PubMed

Vovkun, T V; Yanchuk, P I; Shtanova, L Y; Vesеlskyу, S P; Shalamaу, A S

In acute experiments on rats with cannulated bile duct we studied the effect of Corvitin, water-soluble analogue of quercetin, on secretion of bile. Intraportal administration of the test compound at doses of 2,5; 5 and 10 mg/kg resulted in a significant increase in the volume of secreted bile by 20,9, 31,2 and 20,4%, respectively, as compared with the control. Using the method of thin layer chromatography it was established the mild stimulating effect of Corvitin on the processes of bile acids conjugation with taurine and glycine, especially when administered at a dose of 5 mg/kg. This flavonoid did not affect the concentration of glycocholic acid, however increased the content of glycochenodeoxycholic and glycodeoxycholic acids in the mixture between 15 to 35,1%. Regarding free bile acids, the concentration of cholic acid, chenodeoxycholic and deoxycholic acids in the mixture was increased significantly relative to control only after Corvitin application at dose 10 mg/ kg. In the first case – from 17,9 to 29,8%, in the second – from 25 to 65,4%. At the dose of 5 mg/kg, Corvitin significantly increased the ratio of bile cholates conjugation (maximum by 23,2%), whereas 10 mg/kg of the drug decreased this index by 27,0%. After administration of Corvitin, the hydroxylation ratio in all experimental groups differed little from the control: at the dose of 5 and 10 mg/kg this parameter decreased by 14%. Thus, Corvitin modulates exocrine function of the liver, causing an increase in bile secretion and concentration of different cholates, dose-dependently increasing or decreasing the effectiveness of multienzyme systems providing processes of bile acids conjugation in rats.

Assessment of the effects of ISIS 2302, an anti-sense inhibitor of human ICAM-1, on cellular and humoral immunity in mice.

PubMed

Henry, Scott P; Levin, Arthur A; White, Kimber; Mennear, John H

2006-12-01

ISIS 2302 is a phosphorothioate oligonucleotide designed to inhibit human ICAM-1 and is intended for treatment of inflammatory diseases. Molecules of this class are known to elicit pro-inflammatory effects, and immunotoxicity studies were performed in mice to elucidate the nature of effects of ISIS 2302 on mammalian immune function. ISIS 2302 (1, 5, 20, or 50 mg/kg/dose) was administered intravenously every other day for 27 days. The pro-inflammatory properties of the drug were observed at doses > or = 20 mg/kg. A dose-dependent increase in spleen weight was associated with increased absolute splenocyte and B-lymphocyte counts after the 50 mg/kg/dose regimen. The mitogenic response of B-lymphocytes to bacterial lipopolysaccharide was increased after the 20 and 50 mg/kg/doses but antibody-forming cell activities remained unchanged. Total serum IgG concentration was decreased after the 20 and 50 mg/kg/dose regimens but IgM titers were unchanged. Increases in IL-6, IL-12, and MCP-1 as well as NK cell activity were observed after administration of 20 and 50 mg/kg/dose. Cytotoxic T-lymphocyte activity was decreased by the 50 mg/kg/dose regimen. Other changes in immune function were not observed in ISIS 2302-dosed mice. ISIS 3082, a murine active ICAM-1 inhibitor, was used to demonstrate the anti-inflammatory activity of ICAM-1 inhibition in the 2,4-dinitrofluorobenzene-induced contact sensitization model. Intravenous administration of 1 mg/kg of ISIS 3082 every other day for 27 days was unequivocally anti-inflammatory in the contact sensitization test. The results of these experiments support the conclusion that the prophlogistic effects of ISIS 2302 in mice are observed only at suprapharmacologic doses.

Genotoxicity testing of peptides: Folate deprivation as a marker of exaggerated pharmacology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guérard, Melanie, E-mail: melanie.guerard@roche.com; Zeller, Andreas; Festag, Matthias

2014-09-15

The incidence of micronucleated-cells is considered to be a marker of a genotoxic event and can be caused by direct- or indirect-DNA reactive mechanisms. In particular, small increases in the incidence of micronuclei, which are not associated with toxicity in the target tissue or any structurally altering properties of the compound, trigger the suspicion that an indirect mechanism could be at play. In a bone marrow micronucleus test of a synthetic peptide (a dual agonist of the GLP-1 and GIP receptors) that had been integrated into a regulatory 13-week repeat-dose toxicity study in the rat, small increases in the incidencemore » of micronuclei had been observed, together with pronounced reductions in food intake and body weight gain. Because it is well established that folate plays a crucial role in maintaining genomic integrity and pronounced reductions in food intake and body weight gain were observed, folate levels were determined from plasma samples initially collected for toxicokinetic analytics. A dose-dependent decrease in plasma folate levels was evident after 4 weeks of treatment at the mid and high dose levels, persisted until the end of the treatment duration of 13-weeks and returned to baseline levels during the recovery period of 4 weeks. Based on these properties, and the fact that the compound tested (peptide) per se is not expected to reach the nucleus and cause DNA damage, the rationale is supported that the elevated incidence of micronucleated polychromatic erythrocytes is directly linked to the exaggerated pharmacology of the compound resulting in a decreased folate level. - Highlights: • A synthetic peptide has been evaluated for potential genotoxicity • Small increases in an integrated (13-weeks) micronucleus test were observed • Further, animals had a pronounced reductions in food intake and body weight gain • A dose-dependent decrease in plasma folate levels was evident from week 4 onwards • Elevated micronuclei-incidence due to the exaggerated pharmacology.« less

In vivo and in vitro immunosuppressive effects of benzo[k]fluoranthene in female Balb/c mice.

PubMed

Jeon, Tae Won; Jin, Chun Hua; Lee, Sang Kyu; Lee, Dong Wook; Hyun, Sun Hee; Kim, Ghee Hwan; Jun, In Hye; Lee, Byung Mu; Yum, Young Na; Kim, Jun Kyou; Kim, Ok Hee; Jeong, Tae Cheon

2005-12-10

Although polycyclic aromatic hydrocarbons (PAHs) have been known to suppress immune responses, few studies have addressed the immunotoxicity of benzo[k]fluoranthene (B[k]F). In this study, we investigated the immunosuppression by B[k]F, both in vivo and in vitro, in female BALB/c mice. To assess the effects of B[k]F on humoral immunity as splenic antibody response to sheep red blood cells (SRBCs), B[k]F was given a single dose or once daily for 7 consecutive days po with 30, 60, and 120 micromol/kg. B[k]F reduced the number of antibody-forming cells (AFCs) in a dose-dependent manner. Subacute treatment with B[k]F caused weight increases in liver and decreases in spleen and thymus. The number of AFCs was dramatically decreased by B[k]F in a dose-dependent manner. In a subsequent study, mice were subacutely exposed to the same doses of B[k]F without an immunization with SRBCs, followed by splenic and thymic lymphocyte phenotypings using a flow cytometry and ex vivo mitogen-stimulated proliferation. B[k]F-exposed mice exhibited reduced splenic and thymic cellularity, decreased numbers of total T cells, CD4(+) cells, and CD8(+) cells in spleen, and immature CD4(+)CD8(+) cells, CD4(+)CD8(-) cells, and CD8(+)CD4(-) cells in thymus. The number of CD4(+) IL-2(+) cells was reduced by about 11%, 31%, and 53% following exposure of mice to 30, 60, and 120 micromol/kg of B[k]F, respectively. In the ex vivo lymphocyte proliferation assay, B[k]F inhibited splenocyte proliferation by LPS and Con A. In the in vitro mitogen-stimulated proliferation by untreated splenic suspensions, B[k]F only suppressed splenocyte proliferation to LPS. These results suggested that B[k]F-induced immunosuppression might be mediated, at least in part, through the IL-2 production, and caused by mechanisms associated with metabolic processes.

Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-08-01

The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032-0.1mg/kg/h; N=6) were also examined for comparison. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

PubMed Central

Hutsell, Blake A.; Blough, Bruce E.; Poklis, Justin L.; Negus, S. Stevens

2015-01-01

Background: Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown. Methods: This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure. Results: In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine. Conclusions: Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction. PMID:25618405

Free radical scavenging, antidiarrheal and anthelmintic activity of Pistia stratiotes L. extracts and its phytochemical analysis.

PubMed

Bin Karim, Mohammed Faisal; Imam, Hasan; Sarker, Md Moklesur-Rahman; Uddin, Nizam; Hasan, Nahid; Paul, Nirmala; Haque, Tahmina

2015-05-01

In this phyto-pharmacological screening of Pistia stratiotes L leaf and root extracts each separately in two different solvents demonstrated its potential medicinal value. Apparent antioxidant value is demonstrated by DPPH, Nitric oxide scavenging and Ferric ion reducing method. Additionally, total flavonoid and phenolic compounds were measured. The leaf methanolic extract scavenged both nitric oxide (NO) and DPPH radical with a dose dependent manner. But the pet ether fraction of root was found to have highest efficacy in Fe(3±) reducing power assay. Flavonoid was found to contain highest in the pet ether fraction of root (411.35mg/g) in terms of quercetin equivalent, similarly highest amount (34.96mg/g) of total phenolic compounds (assayed as gallic acid equivalents) were found to contain in the same fraction. The methanolic fractions appeared less cytotoxic compared to pet ether extracts. The plant extracts caused a dose dependent decrease in faecal droppings in both castor oil and magnesium sulphate induced diarrhea, where as leaf extracts in each solvent appeared most effective. Also, the plant extracts showed anthelmintic activity in earthworm by inducing paralysis and death in a dose dependent manner. At highest doses (50 mg/ml) all fractions were almost effective as the positive control piperazine citrate (10 mg/ml). Thus, besides this cytotoxic effect it's traditional claim for therapeutic use can never be overlooked.

Dependency of EBT2 film calibration curve on postirradiation time

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chang, Liyun, E-mail: liyunc@isu.edu.tw; Ding, Hueisch-Jy; Ho, Sheng-Yow

2014-02-15

Purpose: The Ashland Inc. product EBT2 film model is a widely used quality assurance tool, especially for verification of 2-dimensional dose distributions. In general, the calibration film and the dose measurement film are irradiated, scanned, and calibrated at the same postirradiation time (PIT), 1-2 days after the films are irradiated. However, for a busy clinic or in some special situations, the PIT for the dose measurement film may be different from that of the calibration film. In this case, the measured dose will be incorrect. This paper proposed a film calibration method that includes the effect of PIT. Methods: Themore » dose versus film optical density was fitted to a power function with three parameters. One of these parameters was PIT dependent, while the other two were found to be almost constant with a standard deviation of the mean less than 4%. The PIT-dependent parameter was fitted to another power function of PIT. The EBT2 film model was calibrated using the PDD method with 14 different PITs ranging from 1 h to 2 months. Ten of the fourteen PITs were used for finding the fitting parameters, and the other four were used for testing the model. Results: The verification test shows that the differences between the delivered doses and the film doses calculated with this modeling were mainly within 2% for delivered doses above 60 cGy, and the total uncertainties were generally under 5%. The errors and total uncertainties of film dose calculation were independent of the PIT using the proposed calibration procedure. However, the fitting uncertainty increased with decreasing dose or PIT, but stayed below 1.3% for this study. Conclusions: The EBT2 film dose can be modeled as a function of PIT. For the ease of routine calibration, five PITs were suggested to be used. It is recommended that two PITs be located in the fast developing period (1∼6 h), one in 1 ∼ 2 days, one around a week, and one around a month.« less

Food additives such as sodium sulphite, sodium benzoate and curcumin inhibit leptin release in lipopolysaccharide-treated murine adipocytes in vitro.

PubMed

Ciardi, Christian; Jenny, Marcel; Tschoner, Alexander; Ueberall, Florian; Patsch, Josef; Pedrini, Michael; Ebenbichler, Christoph; Fuchs, Dietmar

2012-03-01

Obesity leads to the activation of pro-inflammatory pathways, resulting in a state of low-grade inflammation. Recently, several studies have shown that the exposure to lipopolysaccharide (LPS) could initiate and maintain a chronic state of low-grade inflammation in obese people. As the daily intake of food additives has increased substantially, the aim of the present study was to investigate a potential influence of food additives on the release of leptin, IL-6 and nitrite in the presence of LPS in murine adipocytes. Leptin, IL-6 and nitrite concentrations were analysed in the supernatants of murine 3T3-L1 adipocytes after co-incubation with LPS and the food preservatives, sodium sulphite (SS), sodium benzoate (SB) and the spice and colourant, curcumin, for 24 h. In addition, the kinetics of leptin secretion was analysed. A significant and dose-dependent decrease in leptin was observed after incubating the cells with SB and curcumin for 12 and 24 h, whereas SS decreased leptin concentrations after 24 h of treatment. Moreover, SS increased, while curcumin decreased LPS-stimulated secretion of IL-6, whereas SB had no such effect. None of the compounds that were investigated influenced nitrite production. The food additives SS, SB and curcumin affect the leptin release after co-incubation with LPS from cultured adipocytes in a dose- and time-dependent manner. Decreased leptin release during the consumption of nutrition-derived food additives could decrease the amount of circulating leptin to which the central nervous system is exposed and may therefore contribute to an obesogenic environment.

Effects of prenatal low-dose beta radiation from tritiated water on learning and memory in rats and their possible mechanisms.

PubMed

Gao, W M; Wang, B; Zhou, X Y

1999-09-01

Pregnant adult Wistar rats were randomly divided into four groups. Three of these groups were irradiated with beta rays by a single intraperitoneal injection of tritiated water ((3)H(2)O) administered on the 13th day of gestation. The doses absorbed by their offspring were estimated to be 4.6, 9.2 and 27.3 cGy. The influence of radiation on the postnatal learning ability and memory behavior and on brain development of the offspring was investigated. The number of pyramidal cells (in areas CA1, CA2, CA3 and CA4) and neurons in the hippocampus of the offspring was also measured. In addition, the Ca(++) conductance of hippocampal pyramidal cells cultured in vitro was observed. The results showed that an exposure to 4.6 cGy could prolong avoidance response time significantly and decrease the number of hippocampal pyramidal cells in the CA1 area compared to controls. An exposure to 9.2 cGy significantly decreased the establishment of conditioned reflexes and the number of hippocampal pyramidal cells in the CA3 area. This exposure also induced the degeneration and malformation of hippocampal neurons cultured in vitro, in addition to decreasing the number of hippocampal neurons observed on each culture day. A dose of 27.3 cGy significantly decreased brain and body weights and the maximum electric conductance of Ca(++) in hippocampal pyramidal neurons. In general, dose-dependent effects were observed for most of the parameters assessed in the present study. Possible mechanisms are discussed.

Nutritional quality evaluation of velvet bean seeds (Mucuna pruriens) exposed to gamma irradiation.

PubMed

Bhat, Rajeev; Sridhar, Kandikere R; Seena, Sahadevan

2008-06-01

Effects of gamma irradiation on Mucuna pruriens seeds at various doses (0, 2.5, 5, 7.5, 10, 15 and 30 kGy) on the proximate composition, mineral constituents, amino acids, fatty acids and functional properties were investigated. Gamma irradiation resulted in a significant increase of crude protein at all doses, while the crude lipid, crude fibre and ash showed a dose-dependent decrease. Raw Mucuna seeds were rich in minerals (potassium, phosphorus, calcium, magnesium, iron and selenium). Sodium, copper and manganese were significantly decreased on irradiation at all the doses, while magnesium and iron showed a significant decrease only above 10 kGy. The essential amino acids of raw and gamma-irradiated Mucuna seeds were comparable with the FAO/WHO recommended pattern. A significant increase of in vitro protein digestibility was seen in seeds irradiated at 30 kGy. High amounts of unsaturated fatty acids in Mucuna seeds decreased significantly after irradiation. However, linoleic acid was not present in raw seeds but detected after irradiation and it was elevated to high level at 30 kGy. Behenic acid, a major anti-nutritional factor, was reduced significantly on irradiation, indicating the positive effect of gamma irradiation on Mucuna seeds. Significant enhancement in the water absorption and oil absorption capacities, protein solubility, emulsion activity and improvement in the gelation capacity was recorded after irradiation. Results of the present investigation reveal that application of gamma irradiation does not affect the overall nutritional composition and can be used as an effective method of preservation of Mucuna seed and their products.

An Antidepressant Decreases CSF Aβ Production in Healthy Individuals and in Transgenic AD Mice

PubMed Central

Sheline, Yvette I.; West, Tim; Yarasheski, Kevin; Swarm, Robert; Jasielec, Mateusz S.; Fisher, Jonathan R.; Ficker, Whitney D.; Yan, Ping; Xiong, Chengjie; Frederiksen, Christine; Grzelak, Monica V.; Chott, Robert; Bateman, Randall J.; Morris, John C.; Mintun, Mark A.; Lee, Jin-Moo; Cirrito, John R.

2014-01-01

Serotonin signaling suppresses generation of amyloid-β (Aβ) in vitro and in animal models of Alzheimer’s disease (AD). We show that in an aged transgenic AD mouse model (APP/PS1 plaque-bearing mice), the antidepressant citalopram, a selective serotonin reuptake inhibitor (SSRI), decreased Aβ in brain interstitial fluid (ISF) in a dose-dependent manner. Growth of individual amyloid plaques was assessed in plaque-bearing mice that were chronically administered citalopram. Citalopram arrested the growth of pre-existing plaques and reduced the appearance of new plaques by 78%. In healthy human volunteers, citalopram’s effects on Aβ production and Aβ concentrations in cerebrospinal fluid (CSF) were measured prospectively using stable-isotope labeling kinetics (SILK), with CSF sampling during acute dosing of citalopram. Aβ production in CSF was slowed by 37% in the citalopram group compared to placebo. This change was associated with a 38% decrease in total CSF Aβ concentrations in the drug-treated group. The ability to safely decrease Aβ concentrations is potentially important as a preventive strategy for AD. This study demonstrates key target engagement for future AD prevention trials. PMID:24828079

Radiation equivalent dose simulations for long-term interplanetary flights

NASA Astrophysics Data System (ADS)

Dobynde, M. I.; Drozdov, A.; Shprits, Y. Y.

2016-12-01

Cosmic particle radiation is a limiting factor for the human interplanetary flights. The unmanned flights inside heliosphere and human flights inside of magnetosphere tend to become a routine procedure, whereas there have been only few shot term human flights out of it (Apollo missions 1969-1972) with maximum duration less than a month. Long-term human flights set much higher requirements to the radiation shielding, primarily because of long exposition to cosmic radiation. Inside the helosphere there are two main sources of cosmic radiation: galactic cosmic rays (GCR) and soalr particle events (SPE). GCR come from the outside of heliosphere forming a background of overall radiation that affects the spacecraft. The intensity of GCR is varied according to solar activity, increasing with solar activity decrease and backward, with the modulation time (time between nearest maxima) of 11 yeas. SPE are shot term events, comparing to GCR modulation time, but particle fluxes are much more higher. The probability of SPE increases with the increase of solar activity. Time dependences of the intensity of these two components encourage looking for a time window of flight, when intensity and effect of GCR and SPE would be minimized. Combining GEANT4 Monte Carlo simulations with time dependent model of GCR spectra and data on SPE spectra we show the time dependence of the radiation dose in an anthropomorphic human phantom inside the shielding capsule. Different types of particles affect differently on the human providing more or less harm to the tissues. We use quality factors to recalculate absorbed dose into biological equivalent dose, which give more information about risks for astronaut's health. Incident particles provide a large amount of secondary particles while propagating through the shielding capsule. We try to find an optimal combination of shielding material and thickness, that will effectively decrease the incident particle energy, at the same time minimizing flow of secondary induced particles and minimizing most harmful particle types flows.

[Apoptosis of multiple myeloid cells induced by polysaccharides extracts from Hedyotis diffusa and its mechanism].

PubMed

Lin, Sheng-yun; Shen, Chu-yun; Jiang, Jian-ping; Wu, Li-qiang; Dai, Tie-ying; Qian, Wen-bing; Meng, Hai-tao

2013-04-01

To explore the proliferation inhibition and apoptosis effects of polysaccharides extracts from Hedyotis diffusa (PEHD) on multiple myeloma (MM) cell line RPMI 8226 cells in vitro, so as to provide experimental theory for the clinical application in the treatment of MM. MTT assay was used to examine the effects of PEHD on cell growth. The apoptotic cells were analyzed by flow cytometry with AnnexinⅤ/PI staining. Hoechst staining was used to observe the morphological changes of RPMI 8226 cell apoptosis. The expression levels of caspase-3,-8,-9, PARP, nucleoprotein NF-κB protein and other channel protein were assayed by Western blotting method. The growth of RPMI 8226 cells were suppressed after treatment with PEHD, the highest inhibition rate reached to 92.3%, the results in the doses from 1 to 4 mg/ml showed a dose-and-time-dependent manner. The proportion of apoptotic cells in 1, 2 and 3 mg/ml PEHD treatment groups for 24 h were 22.52%, 62.31% and 69.94%, respectively, and significantly higher than that of control 8.93%. After treated with PEHD, apoptotic body appeared in RPMI 8226 cells nucleus and the number of apoptotic body increased in a dose-dependent manner. With the increasing of PEHD concentration, the expression of caspase-8,-9,-3 and PARP protein increased. The expression of Mcl-1, Bcl-xl, Bid and Bim protein decreased gradually, but the expression of Bax, Bak and Bad protein increased, and the expression of p-AKT protein (60 kDa) and NF-κB obviously decreased. PEHD could inhibited the growth of RPMI 8226 cells and displayed a dose-and-time-dependent manner, its mechanism may involve cell apoptosis induction, which was associated with the activation of caspase-8, caspase-9, and caspase-3 protein and the down-regulation of p-AKT and NF-κB protein expression.

GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra.

PubMed

Engberg, G; Kling-Petersen, T; Nissbrandt, H

1993-11-01

Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB-receptor agonist baclofen (1-16 mg/kg) was associated with a dose-dependent regularization of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16-32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). The GABAA-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a decreased regularity. The NMDA receptor antagonist MK 801 (0.4-3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3-10 min) did neither promote nor prevent the regularization of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst firing activity on these neurons.

Improvements to image quality using hybrid and model-based iterative reconstructions: a phantom study.

PubMed

Aurumskjöld, Marie-Louise; Ydström, Kristina; Tingberg, Anders; Söderberg, Marcus

2017-01-01

The number of computed tomography (CT) examinations is increasing and leading to an increase in total patient exposure. It is therefore important to optimize CT scan imaging conditions in order to reduce the radiation dose. The introduction of iterative reconstruction methods has enabled an improvement in image quality and a reduction in radiation dose. To investigate how image quality depends on reconstruction method and to discuss patient dose reduction resulting from the use of hybrid and model-based iterative reconstruction. An image quality phantom (Catphan® 600) and an anthropomorphic torso phantom were examined on a Philips Brilliance iCT. The image quality was evaluated in terms of CT numbers, noise, noise power spectra (NPS), contrast-to-noise ratio (CNR), low-contrast resolution, and spatial resolution for different scan parameters and dose levels. The images were reconstructed using filtered back projection (FBP) and different settings of hybrid (iDose 4 ) and model-based (IMR) iterative reconstruction methods. iDose 4 decreased the noise by 15-45% compared with FBP depending on the level of iDose 4 . The IMR reduced the noise even further, by 60-75% compared to FBP. The results are independent of dose. The NPS showed changes in the noise distribution for different reconstruction methods. The low-contrast resolution and CNR were improved with iDose 4 , and the improvement was even greater with IMR. There is great potential to reduce noise and thereby improve image quality by using hybrid or, in particular, model-based iterative reconstruction methods, or to lower radiation dose and maintain image quality. © The Foundation Acta Radiologica 2016.

Dose-dependent effects of vitamin 1,25(OH)2D3 on oxidative stress and apoptosis.

PubMed

Cakici, Cagri; Yigitbasi, Turkan; Ayla, Sule; Karimkhani, Hadi; Bayramoglu, Feyza; Yigit, Pakize; Kilic, Ertugrul; Emekli, Nesrin

2018-02-08

Background The purpose of this study is to examine the dose-dependent effects of vitamin 1,25(OH)2D3 on apoptosis and oxidative stress. Methods In this study, 50 male Balb/c mice were used as control and experiment groups. The mice were divided into 5 groups each consisting of 10 mice. Calcitriol was intraperitoneally administered as low dose, medium dose, medium-high dose and high dose vitamin D groups (at 0.5, 1, 5 and 10 μg/kg, respectively), for three times a week during 14 days. At the end of the study, annexin V was measured by enzyme-linked immunosorbent assay method, and total antioxidant capacity and total oxidant status values were measured by colorimetric method in serum. Hematoxylin eosin staining was performed in liver tissues and periodic acid schiff staining was performed in kidney tissues. Results While comparing the results of medium-high dose (5 μg/kg) and high dose (10 μg/kg) vitamin D administration to that of the control group, it was observed that serum antioxidant status and annexin V levels decreased and glomerular mesenchial matrix ratio increased in kidney (p<0.05). In addition to these findings, in the group receiving high dose vitamin D (10 μg/kg), it was observed that the damage to the liver increased together with the the oxidative stress index values (p<0.05). Conclusions As a result, this study was the first in the literature to report that use of high-dose vitamin D (10 μg/kg) results in oxidant effect, rather than being an antioxidant, and causes severe histopathological toxicity in the liver and kidney.

Antioxidant and anticancer activity of Artemisia princeps var. orientalis extract in HepG2 and Hep3B hepatocellular carcinoma cells.

PubMed

Choi, Eun-Jeong; Kim, Gun-Hee

2013-10-01

The aim of the present study was to investigate antioxidant and the anticancerigen activity of a methanol extract from Artemisia princeps var. orientalis (APME), a well-known traditional herbal medicine in Asia, in hepatocellular cancer cells. To evaluate the antioxidant activity of APME, reactive oxygen species (ROS) and the antioxidant enzymes, superoxide dismutase (SOD) and catalase were investigated in HepG2 cells exposed to APME (5, 100, and 200 µg/mL) for 72 h. Then, to evaluate the anticancer activity of APME, we investigated the proliferation and apoptosis induction of HepG2 and Hep3B cells exposed to APME (1-200 µg/mL) for 24, 48, and 72 h. APME dose-dependently reduced the generation of ROS in the presence of H2O2 compared with control cells. Furthermore, it increased catalase and SOD activity. Moreover, APME inhibited cell proliferation in a dose- and time-dependent manner, but at concentrations lower than 100 µg/mL, the inhibition was less dose-dependent than time-dependent. HepG2 and Hep3B cells exposed to 5, 100, and 200 µg/mL APME for 72 h underwent cell cycle arrest and apoptosis. Exposure to APME resulted in a significant increase in the number of cells in G1 phase and a decrease in the G2/M phase cell population. In addition, APME induced P53 expression of HepG2 cells in a dose-dependent manner, and played a role in the downregulation of Bcl-2 and upregulation of Bax in both HepG2 and Hep3B cells. These results indicate the potential role of APME as an antioxidant and anticancerigen agent in hepatocarcinoma cell lines.

In utero exposure to di(n)butyl phthalate reduces testicular testosterone and testis size in a dose-dependent manner in Harlan Sprague Dawley fetal rats

EPA Science Inventory

Phthalate esters are widely used to impart flexibility to plastics (e.g. plastic medical devices and children’s toys) as well as other uses in health and beauty products and some pharmaceuticals. Certain phthalate esters cause reproductive malformations and decrease androgen-dep...

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

PubMed Central

Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-01-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day. PMID:25874036

Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs.

PubMed

Nam, Chunja; Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

2015-03-01

Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Dong U., E-mail: lee.dong@gene.com

Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models.more » While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure.« less

Evaluation of buprenorphine dosage adequacy in opioid receptor agonist substitution therapy for heroin dependence: first use of the BUprenorphine-naloxone Dosage Adequacy eVAluation (BUDAVA) questionnaire.

PubMed

D'Amore, Antonio; Romano, Filomena; Biancolillo, Vincenzo; Lauro, Guglielmo; Armenante, Ciro; Pizzirusso, Anna; Del Tufo, Salvatore; Ruoppolo, Ciro; Auriemma, Francesco; Cassese, Francesco; Oliva, Patrizia; Amato, Patrizia

2012-07-01

The dosing of opioid receptor agonist medications adequately and on an individual basis is crucial in the pharmacotherapy of opioid dependence. Clinical tools that are able to measure dose appropriateness are sorely needed. The recently developed and validated Opiate Dosage Adequacy Scale (ODAS) comprehensively evaluates the main outcomes relevant for methadone dose optimization, namely relapse, cross-tolerance, objective and subjective withdrawal symptoms, craving and overdose. Based on the ODAS, we developed a new assessment tool (BUprenorphine-naloxone Dosage Adequacy eVAluation [BUDAVA]) for evaluating dosage adequacy in patients in treatment with buprenorphine-naloxone. The main goal of this observational study was to explore whether the BUDAVA questionnaire could be used to assess buprenorphine-based, long-term substitution therapy for heroin addiction. The study included heroin-dependent patients who had been in treatment with buprenorphine-naloxone for at least 3 months. Patients (n = 196) were recruited from 11 drug abuse treatment centres in Italy. Dosage adequacy was assessed with the BUDAVA questionnaire. Patients classified as inadequately treated had their dosage modified. After 1 week, they were again administered the questionnaire to assess the adequacy of the new dosage. The buprenorphine-naloxone dosage was found to be inadequate in 61 of the 196 patients. In 13 patients, the treatment scored as inadequate only in the subjective withdrawal symptoms item of the questionnaire and therefore no dosage adjustment was made in the 2 weeks that have characterized this work. The remaining 48 inadequately treated patients had their dosage modified (42 dose increases and six dose decreases). After 1 week on the modified dosage, in 24 of these patients the new regimen was found by the assessment with the questionnaire to be adequate. These preliminary results suggest that the BUDAVA questionnaire may be useful for guiding buprenorphine-naloxone maintenance dose adjustments in heroin-dependent patients.

Supplementation with Hualian No. 4 wild bitter gourd (Momordica charantia Linn. var. abbreviata ser.) extract increases anti-fatigue activities and enhances exercise performance in mice

PubMed Central

HSIAO, Chien-Yu; CHEN, Yi-Ming; HSU, Yi-Ju; HUANG, Chi-Chang; SUNG, Hsin-Ching; CHEN, Sheng-Shih

2017-01-01

Hualian No. 4 wild bitter gourd (WBG) is a specific vegetable cultivated by the Hualien District Agricultural Research and Extension Station in Taiwan. WBG is commonly consumed as a vegetable and used as a popular folk medicine. However, few studies have demonstrated the effects of WBG supplementation on exercise performance, physical fatigue and the biochemical profile. The purpose of this study was to evaluate the potential beneficial effects of WBG extract on fatigue and ergogenic functions following physiological challenge. Three groups of male ICR mice (n=8 per group) were orally administered 0, 1 or 2.5 g/kg/day of WBG for 4 weeks. They were respectively designated the vehicle, WBG-1X and WBG-2.5X groups. WBG significantly decreased body weight (BW) and epididymal fat pad (EFP) weight. Concerning physical performance, WBG supplementation dose-dependently increased grip strength and endurance swimming time. Concerning anti-fatigue activity, WBG decreased levels of serum lactate, ammonia, creatine kinase and blood urea nitrogen, and economized glucose metabolism after acute exercise challenge. Glycogen in the liver and gastrocnemius muscle dose-dependently increased with WBG treatment. Concerning the biochemical profile, WBG treatment significantly decreased alanine aminotransferase (ALT), blood urea nitrogen (BUN) and urea acid (UA), and increased total protein (TP). Therefore, 4-week supplementation with WBG may decrease white adipose weight, enhance energy economy, increase glycogen storage to enhance exercise performance and reduce fatigue. PMID:28458274

Interactions between scopolamine and muscarinic cholinergic agonists or cholinesterase inhibitors on spatial alternation performance in rats.

PubMed

Shannon, H E; Bemis, K G; Hendrix, J C; Ward, J S

1990-12-01

The effects on working memory of the muscarinic cholinergic agonists oxotremorine, arecoline, RS86 and pilocarpine, and the cholinesterase inhibitors physostigmine and tetrahydroaminoacadine were investigated in male F344 rats. Working memory was assessed by behavior maintained under a spatial alternation schedule of food presentation in which the interval between trials was varied from 2 to 32 sec. Under control conditions the percentage of correct responses decreased as the retention interval was varied from 2 to 32 sec. Administered alone the cholinergic agonists oxotremorine (0.01-0.1 mg/kg), arecoline (3-30 mg/kg), RS86 (0.3-3 mg/kg) and pilocarpine (0.3-3.0 mg/kg), and the cholinesterase inhibitors physostigmine (0.01-0.1 mg/kg) and tetrahydroaminoacridine (0.3-3.0 mg/kg) either had no effect on or produced dose-related deficits in working memory and decreases in response rates. The muscarinic antagonist scopolamine (0.1 mg/kg) produced retention interval-dependent decreases in the percentage of correct responding and rates of responding. The cholinergic agonists and tetrahydroaminoacridine failed to reverse the effects of scopolamine. However, physostigmine produced a dose-dependent reversal of the working-memory deficits and response-rate decreasing effects of scopolamine. The present results are consistent with the interpretation that drugs which primarily enhance M2 muscarinic cholinergic transmission are ineffective in enhancing working memory or in reversing scopolamine-induced deficits in working memory.

Effects of neuropeptides and capsaicin on the canine tracheal vasculature in vivo.

PubMed

Salonen, R O; Webber, S E; Widdicombe, J G

1988-12-01

1. The nonadrenergic, noncholinergic nervous system may control the airway vasculature via various neuropeptides. We have perfused the cranial tracheal arteries of the anaesthetized dog and investigated the effects of neuropeptides and capsaicin (which is supposed to release neuropeptides from sensory nerve endings) on the tracheal vasculature by injecting them locally into the perfusion system. 2. Neurokinin A (NKA, 0.02-20 pmol), calcitonin gene-related peptide (CGRP, 2-200 pmol) and peptide histidine isoleucine (PHI, 0.02-2 nmol) dose-dependently decreased tracheal vascular resistance (Rtv). NKA was 10 and 100 times more potent than CGRP and PHI, respectively. The duration of the response to CGRP was greatly prolonged with larger doses. Galanin (0.2-2 nmol) had no appreciable effect on Rtv. 3. Neuropeptide Y (NPY 0.02-2 nmol) and bombesin (0.02-10 nmol) dose-dependently increased Rtv. However, the dose-response curve for bombesin was bell-shaped suggesting the development of tachyphylaxis with larger doses. In smaller doses, bombesin was twice as potent as NPY. The duration of the response to NPY was prolonged with larger doses. 4. With the exception of PHI no neuropeptide altered tracheal smooth muscle tone; PHI (1 and 2 nmol) caused small dilatations of the trachea. 5. The effects of capsaicin (2-100 nmol) were complex. Usually, the vascular response had two dose-dependent phases: a rapid vasoconstriction followed by a small, longer-lasting vasodilatation. The tracheal smooth muscle response was usually biphasic, a contraction followed by a relaxation. 6. According to previous and present data, the order of potency of the neuropeptides on the canine tracheal vasculature is for the vasodilators : NKA > vasoactive intestinal peptide (VIP) > CGRP > substance P > PHI, and for the vasoconstrictors: bombesin > NPY. The longer-acting neuropeptides (VIP, CGRP and NPY) may be more important than the shorter-acting neuropeptides (substance P, NKA, PHI and bombesin) as regulators of the airway wall blood flow.

Decreased Phototoxic Effects of TiO₂ Nanoparticles in Consortium of Bacterial Isolates from Domestic Waste Water

PubMed Central

Mathur, Ankita; Kumari, Jyoti; Parashar, Abhinav; T., Lavanya; Chandrasekaran, N.; Mukherjee, Amitava

2015-01-01

This study is aimed to explore the toxicity of TiO2 nanoparticles at low concentrations (0.25, 0.50 & 1.00 μg/ml); on five bacterial isolates and their consortium in waste water medium both in dark and UVA conditions. To critically examine the toxic effects of nanoparticles and the response mechanism(s) offered by microbes, several aspects were monitored viz. cell viability, ROS generation, SOD activity, membrane permeability, EPS release and biofilm formation. A dose and time dependent loss in viability was observed for treated isolates and the consortium. At the highest dose, after 24h, oxidative stress was examined which conclusively showed more ROS generation & cell permeability and less SOD activity in single isolates as compared to the consortium. As a defense mechanism, EPS release was enhanced in case of the consortium against the single isolates, and was observed to be dose dependent. Similar results were noticed for biofilm formation, which substantially increased at highest dose of nanoparticle exposure. Concluding, the consortium showed more resistance against the toxic effects of the TiO2 nanoparticles compared to the individual isolates. PMID:26496250

Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury

PubMed Central

Zhu, Andy Z. X.; Johnson, Mike; Yu, Shaoxia; Moriya, Yuu; Ebihara, Takuya; Csizmadia, Vilmos; Grieves, Jessica; Paton, Martin; Liao, Mingxiang; Gemski, Christopher; Pan, Liping; Vakilynejad, Majid; Dragan, Yvonne P.; Chowdhury, Swapan K.; Kirby, Patrick J.

2017-01-01

Abstract Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs. PMID:28108665

Bronchodilatory and Anti-Inflammatory Effects of ASM-024, a Nicotinic Receptor Ligand, Developed for the Treatment of Asthma

PubMed Central

Assayag, Evelyne Israël; Beaulieu, Marie-Josée; Cormier, Yvon

2014-01-01

Conventional asthma and COPD treatments include the use of bronchodilators, mainly β2-adrenergic agonists, muscarinic receptor antagonists and corticosteroids or leukotriene antagonists as anti-inflammatory agents. These active drugs are administered either separately or given as a fixed-dose combination medication into a single inhaler. ASM-024, a homopiperazinium compound, derived from the structural modification of diphenylmethylpiperazinium (DMPP), has been developed to offer an alternative mechanism of action that could provide symptomatic control through combined anti-inflammatory and bronchodilator properties in a single entity. A dose-dependent inhibition of cellular inflammation in bronchoalveolar lavage fluid was observed in ovalbumin-sensitized mice, subsequently treated for 3 days by nose-only exposure with aerosolized ASM-024 at doses up to 3.8 mg/kg (ED50 = 0.03 mg/kg). The methacholine ED250 values indicated that airway hyperresponsivenness (AHR) to methacholine decreased following ASM-024 administration by inhalation at a dose of 1.5 mg/kg, with a value of 0.145±0.032 mg/kg for ASM 024-treated group as compared to 0.088±0.023 mg/kg for untreated mice. In in vitro isometric studies, ASM-024 elicited dose-dependent relaxation of isolated mouse tracheal, human, and dog bronchial preparations contracted with methacholine and guinea pig tracheas contracted with histamine. ASM-024 showed also a dose and time dependant protective effect on methacholine-induced contraction. Overall, with its combined anti-inflammatory, bronchodilating and bronchoprotective properties, ASM-024 may represent a new class of drugs with a novel pharmacological approach that could prove useful for the chronic maintenance treatment of asthma and, possibly, COPD. PMID:24465890

Bronchodilatory and anti-inflammatory effects of ASM-024, a nicotinic receptor ligand, developed for the treatment of asthma.

PubMed

Assayag, Evelyne Israël; Beaulieu, Marie-Josée; Cormier, Yvon

2014-01-01

Conventional asthma and COPD treatments include the use of bronchodilators, mainly β2-adrenergic agonists, muscarinic receptor antagonists and corticosteroids or leukotriene antagonists as anti-inflammatory agents. These active drugs are administered either separately or given as a fixed-dose combination medication into a single inhaler. ASM-024, a homopiperazinium compound, derived from the structural modification of diphenylmethylpiperazinium (DMPP), has been developed to offer an alternative mechanism of action that could provide symptomatic control through combined anti-inflammatory and bronchodilator properties in a single entity. A dose-dependent inhibition of cellular inflammation in bronchoalveolar lavage fluid was observed in ovalbumin-sensitized mice, subsequently treated for 3 days by nose-only exposure with aerosolized ASM-024 at doses up to 3.8 mg/kg (ED50 = 0.03 mg/kg). The methacholine ED250 values indicated that airway hyperresponsivenness (AHR) to methacholine decreased following ASM-024 administration by inhalation at a dose of 1.5 mg/kg, with a value of 0.145 ± 0.032 mg/kg for ASM 024-treated group as compared to 0.088 ± 0.023 mg/kg for untreated mice. In in vitro isometric studies, ASM-024 elicited dose-dependent relaxation of isolated mouse tracheal, human, and dog bronchial preparations contracted with methacholine and guinea pig tracheas contracted with histamine. ASM-024 showed also a dose and time dependant protective effect on methacholine-induced contraction. Overall, with its combined anti-inflammatory, bronchodilating and bronchoprotective properties, ASM-024 may represent a new class of drugs with a novel pharmacological approach that could prove useful for the chronic maintenance treatment of asthma and, possibly, COPD.

The peripheral quantitative computed tomographic and densitometric analysis of skeletal tissue in male Wistar rats after chromium sulfate treatment.

PubMed

Bieńko, Marek; Radzki, Radosław Piotr; Wolski, Dariusz

2017-09-21

This study evaluates the effects of three different doses of chromium sulphate on bone density and the tomographic parameters of skeletal tissue of rats. The experiment was performed on 40 male Wistar rats which received, by gavage, during 90 days, a chromium sulphate in either a daily dose of 400, 600 or 800 µg/kg BW. At the end of experiment, the rats were scanned using the densitometry method (DXA) to determine the bone mineral density, bone mineral content of total skeleton and vertebral column (L2-L4) and parameters of body composition (Lean Mass and Fat Mass). The isolated femora were scanned using peripheral a quantitative computed tomography method (pQCT) for a separate analysis of the trabecular and cortical bone tissue. The ultimate strength, work to ultimate and the Young modulus of femora was also investigated by the three-point bending test. The negative impact of chromium was observed in relation to bone tissue. All doses significantly decreased total skeleton density and mineral content, and also had impact upon the isolated femora and vertebral column. Trabecular volumetric bone mineral density and trabecular bone mineral content measured by pQCT in distal femur metaphysis were significantly lower in the experimental groups than in the control. Higher doses of chromium also significantly decreased values of ultimate strength and Young modulus in the investigated femora. The results of the experiment demonstrate that chromium sulphate is dose dependent, and exerts a disadvantageous effect on the skeleton, as it decreases bone density and resistance.

Short-term estradiol replacement in postmenopausal women selectively mutes somatostatin's dose-dependent inhibition of fasting growth hormone secretion.

PubMed

Bray, M J; Vick, T M; Shah, N; Anderson, S M; Rice, L W; Iranmanesh, A; Evans, W S; Veldhuis, J D

2001-07-01

How estradiol stimulates pulsatile GH secretion in the human is not well understood. Here, we test the clinical hypothesis that estradiol stimulates GH secretion, in part, by opposing somatostatin's inhibition of GH release. To this end, 13 estrogen-withdrawn postmenopausal women received placebo or 1 mg micronized estradiol-17beta orally, twice daily for 14 days, in a prospectively randomized, patient-blinded, within-subject cross-over design. For each intervention, the dose-dependent suppressive actions of somatostatin were evaluated by infusing 0 (saline), 3, 10, 30, 100, or 300 microg/1.73 m(2).h somatostatin-14 continuously, iv, for 3 h, on separate mornings, in the fasting state, 48 h apart. Blood was sampled at 10-min intervals for 2 h before, for 3 h concurrently with, and for 1 h after each infusion. Serum GH concentrations were quantitated in an ultrasensitive chemiluminescence-based assay (detection threshold, 0.005 microg/L). In the estrogen-deficient milieu, constant iv somatostatin infusions inhibited steady-state serum GH concentrations (valley mean during the last 60 min of the infusion interval) in a dose-dependent manner (P < 10(-4) interventional effect). Maximally effective doses of somatostatin reduced the latter by 89 +/- 6.1% (mean +/- SEM) below the subject-specific preinfusion baseline. Estrogen administration increased the serum estradiol concentration from 12 +/- 1 to 245 +/- 35 pg/mL [42 +/- 4 to 920 +/- 110 pmol/L] (P < 10(-4)); decreased serum concentrations of LH (P = 0.018), FSH (P < 10(-4)), and insulin-like growth factor-I (P = 0.003); and elevated the fasting (6-h mean) serum GH concentration from 0.41 +/- 0.07 to 0.87 +/- 0.27 (P = 0.011). Estradiol supplementation did not alter somatostatin's maximal suppression of GH by 89 +/- 4.7% (P < 10(-4) below subject-specific preinfusion baseline), thus signifying unchanging somatostatin efficacy. In contrast, estradiol replacement significantly elevated the half-maximally inhibitory dose of infused somatostatin by 13.5-fold, from 0.43 (0.38-0.48, 95% group statistical confidence intervals) (placebo) to 6.0 (5.2-7.0) (estradiol) microg/1.73 m(2)/h (P < 10(-4)), denoting muting of somatostatin's inhibitory potency. The latter inference was confirmed by a concomitant 4-fold decrease in the exponential steepness of the somatostatin inhibitory dose-response function; viz., mean 1.42 (1.49 to 1.33) (placebo) vs. 0.34 (0.62 to 0.26) (estradiol) slope units (P < 10(-4)). The foregoing effects were specific, because estrogen did not alter somatostatin's dose-dependent enhancement (P < 10(-4)) of the orderliness of GH release patterns, as quantitated via the approximate entropy regularity statistic. In summary, short-term replacement of estradiol to midfollicular phase levels in postmenopausal women selectively reduces the potency, but not the efficacy, of somatostatin's dose-dependent inhibition of GH release. Estrogen supplementation does not modify somatostatin's reciprocal enhancement of the quantifiable orderliness (approximate entropy) of the GH secretory process. Accordingly, we postulate that estradiol can facilitate pulsatile GH secretion, in part, by opposing the repressive actions of somatostatin.

Low Doses of Curcuma longa Modulates Cell Migration and Cell-Cell Adhesion.

PubMed

de Campos, Paloma Santos; Matte, Bibiana Franzen; Diel, Leonardo Francisco; Jesus, Luciano Henrique; Bernardi, Lisiane; Alves, Alessandro Menna; Rados, Pantelis Varvaki; Lamers, Marcelo Lazzaron

2017-09-01

Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC. Curcumin (2 μM) decreased cell proliferation in cell lines with mesenchymal characteristics, while cell death was detected only at 50 μM. We observed that highly migratory cells showed a decrease on migration speed and directionality when treated with 2 or 5 μM of curcumin (50% and 40%, respectively, p < 0.05). Using spheroids, we observed that curcumin dose dependently decreased cell-cell adhesion, especially on tumor-derived spheroids. Also, in a xenograft model with patient-derived OSCC cells, the administration of curcumin decreased tumor growth and aggressiveness when compared with untreated tumors, indicating the potential antitumor effect in oral cancer. These results suggest that lower doses of curcumin can influence several steps involved in tumorigenesis, including migration properties, suggesting a possible use in cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Inhibition of glycogen synthase kinase-3beta downregulates total tau proteins in cultured neurons and its reversal by the blockade of protein phosphatase-2A.

PubMed

Martin, Ludovic; Magnaudeix, Amandine; Esclaire, Françoise; Yardin, Catherine; Terro, Faraj

2009-02-03

In tauopathies such as Alzheimer's disease (AD), the molecular mechanisms of tau protein aggregation into neurofibrillary tangles (NFTs) and their contribution to neurodegeneration remain not understood. It was recently demonstrated that tau, regardless of its aggregation, might represent a key mediator of neurodegeneration. Therefore, reduction of tau levels might represent a mechanism of neuroprotection. Glycogen synthase kinase-3beta (GSK3beta) and protein phosphatase-2A (PP2A) are key enzymes involved in the regulation of tau phosphorylation, and have been suggested to be involved in the abnormal tau phosphorylation and aggregation in AD. Connections between PP2A and GSK3beta signaling have been reported. We have previously demonstrated that exposure of cultured cortical neurons to lithium decreased tau protein expression and provided neuroprotection against Abeta. Since lithium is not a specific inhibitor of GSK3beta (ID50=2.0 mM), whether or not the lithium-induced tau decrease involves GSK3beta remained to be determined. For that purpose, cultured cortical neurons were exposed to 6-bromo-indirubin-3'-oxime (6-BIO), a more selective and potent GSK3beta inhibitor (ID50=1.5 microM) or to lithium. Analysis of tau levels and phosphorylation by western-blot assays showed that lithium and 6-BIO dose-dependently decreased both tau protein levels and tau phosphorylation. Conversely, inhibition of cyclin-dependent kinase-5 (CDK5) by roscovitine decreased phosphorylated tau but failed to alter tau protein levels. These data indicate that GSK3beta might be selectively involved in the regulation of tau protein levels. Moreover, inhibition of PP2A by okadaic acid, but not that of PP2B (protein phosphatase-2B)/calcineurin by FK506, dose-dependently reversed lithium-induced tau decrease. These data indicate that GSK3beta regulates both tau phosphorylation and total tau levels through PP2A.

Toxicity of dietary Heliotropium dolosum seed to broiler chickens.

PubMed

Eröksüz, Y; Eröksüz, H; Ozer, H; Canatan, H; Yaman, I; Cevik, A

2001-12-01

Five groups of 20 female broiler chicks were fed different levels of dehulled Heliotropium dolosum seed (w/w%; 0.0, 1.0, 3.0, 5.0 or 10.0%) from 10 to 52 d of age. In all doses the seed caused decreases in daily feed intake, weight gain, and feed efficiency, and biochemical findings, severity of pathologic changes, and mortality rate increased in a dose-dependent manner. Acute toxicity was observed in livers of chicks fed 10% seed. Other test groups had chronic changes. Livers had massive to submassive necrosis, hepatic megalocytosis, bile duct proliferation, fatty change, and periportal fibrosis. Biochemical evaluations revealed hypoalbuminemia, hypoprotienemia and increased ALP activity and billuribin. The seed of Heliotropium dolosum produced biochemical and specific pathologic changes in broiler chicks, as well as decreased food intake and feed efficiency. Higher seed levels induced more pronounced changes.

Effect of lithium chloride and antineoplastic drugs on survival and cell cycle of androgen-dependent prostate cancer LNCap cells

PubMed Central

Azimian-Zavareh, Vajihe; Hossein, Ghamartaj; Janzamin, Ehsan

2012-01-01

Objective: Glycogen synthase kinase-3β (GSK-3β) has been reported to be required for androgen receptor (AR) activity. This study sought to determine the usefulness of lithium chloride (LiCl) as a highly selective inhibitor of GSK-3β to increase the sensitivity of LNCap cells to doxorubicin (Dox), etoposide (Eto), and vinblastine (Vin) drugs. Materials and Methods: Thiazolyl Blue Tetrazolium Blue (MTT) assay was used to determine the cytotoxic effect to LiCl alone or in combination with low dose and IC50 doses of drugs. Subsequently, cell cycle analysis was performed by using flow cytometry. Results: LiCl showed cytotoxic effect in a dose- and time-dependent manner (P<0.001). Both Dox (100 or 280 nM) and Vin IC50 (5 nM) doses caused G2/M-phase arrest (P<0.001) compared with control. However, low dose (10 μM) or IC50 (70 μM) Eto doses showed G2/M or S-phase arrests, respectively (P<0.001). Combination of low dose or IC50 dose of Eto with LiCl showed increased apoptosis as revealed by high percent of cells in SubG1 (P<0.05, P<0.01, respectively). Moreover, Eto (10 μM) led to decreased percent of cells in G2/M phase when combined with LiCl (P<0.05). Conclusion: This study showed that LiCl increases apoptosis of (LNCap) Lymph Node Carcinoma of the Prostate cells in the presence of Eto, which is S- and G2-phase-specific drug. PMID:23248400

Fluence-to-absorbed-dose conversion coefficients for neutron beams from 0.001 eV to 100 GeV calculated for a set of pregnant female and fetus models

NASA Astrophysics Data System (ADS)

Taranenko, Valery; Xu, X. George

2008-03-01

Protection of fetuses against external neutron exposure is an important task. This paper reports a set of absorbed dose conversion coefficients for fetal and maternal organs for external neutron beams using the RPI-P pregnant female models and the MCNPX code. The newly developed pregnant female models represent an adult female with a fetus including its brain and skeleton at the end of each trimester. The organ masses were adjusted to match the reference values within 1%. For the 3 mm cubic voxel size, the models consist of 10-15 million voxels for 35 organs. External monoenergetic neutron beams of six standard configurations (AP, PA, LLAT, RLAT, ROT and ISO) and source energies 0.001 eV-100 GeV were considered. The results are compared with previous data that are based on simplified anatomical models. The differences in dose depend on source geometry, energy and gestation periods: from 20% up to 140% for the whole fetus, and up to 100% for the fetal brain. Anatomical differences are primarily responsible for the discrepancies in the organ doses. For the first time, the dependence of mother organ doses upon anatomical changes during pregnancy was studied. A maximum of 220% increase in dose was observed for the placenta in the nine months model compared to three months, whereas dose to the pancreas, small and large intestines decreases by 60% for the AP source for the same models. Tabulated dose conversion coefficients for the fetus and 27 maternal organs are provided.

Dose-Dependent Cortical Thinning After Partial Brain Irradiation in High-Grade Glioma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karunamuni, Roshan; Bartsch, Hauke; White, Nathan S.

Purpose: Radiation-induced cognitive deficits may be mediated by tissue damage to cortical regions. Volumetric changes in cortex can be reliably measured using high-resolution magnetic resonance imaging (MRI). We used these methods to study the association between radiation therapy (RT) dose and change in cortical thickness in high-grade glioma (HGG) patients. Methods and Materials: We performed a voxel-wise analysis of MRI from 15 HGG patients who underwent fractionated partial brain RT. Three-dimensional MRI was acquired pre- and 1 year post RT. Cortex was parceled with well-validated segmentation software. Surgical cavities were censored. Each cortical voxel was assigned a change in cortical thicknessmore » between time points, RT dose value, and neuroanatomic label by lobe. Effects of dose, neuroanatomic location, age, and chemotherapy on cortical thickness were tested using linear mixed effects (LME) modeling. Results: Cortical atrophy was seen after 1 year post RT with greater effects at higher doses. Estimates from LME modeling showed that cortical thickness decreased by −0.0033 mm (P<.001) for every 1-Gy increase in RT dose. Temporal and limbic cortex exhibited the largest changes in cortical thickness per Gy compared to that in other regions (P<.001). Age and chemotherapy were not significantly associated with change in cortical thickness. Conclusions: We found dose-dependent thinning of the cerebral cortex, with varying neuroanatomical regional sensitivity, 1 year after fractionated partial brain RT. The magnitude of thinning parallels 1-year atrophy rates seen in neurodegenerative diseases and may contribute to cognitive decline following high-dose RT.« less

Pulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling

PubMed Central

Nurkiewicz, Timothy R.; Porter, Dale W.; Hubbs, Ann F.; Stone, Samuel; Chen, Bean T.; Frazer, David G.; Boegehold, Matthew A.; Castranova, Vincent

2009-01-01

We have shown that pulmonary nanoparticle exposure impairs endothelium dependent dilation in systemic arterioles. However, the mechanism(s) through which this effect occurs is/are unclear. The purpose of this study was to identify alterations in the production of reactive species and endogenous nitric oxide (NO) after nanoparticle exposure, and determine the relative contribution of hemoproteins and oxidative enzymes in this process. Sprague-Dawley rats were exposed to fine TiO2 (primary particle diameter ∼1 μm) and TiO2 nanoparticles (primary particle diameter ∼21 nm) via aerosol inhalation at depositions of 4–90 μg per rat. As in previous intravital experiments in the spinotrapezius muscle, dose-dependent arteriolar dilations were produced by intraluminal infusions of the calcium ionophore A23187. Nanoparticle exposure robustly attenuated these endothelium-dependent responses. However, this attenuation was not due to altered microvascular smooth muscle NO sensitivity because nanoparticle exposure did not alter arteriolar dilations in response to local sodium nitroprusside iontophoresis. Nanoparticle exposure significantly increased microvascular oxidative stress by ∼60%, and also elevated nitrosative stress fourfold. These reactive stresses coincided with a decreased NO production in a particle deposition dose-dependent manner. Radical scavenging, or inhibition of either myeloperoxidase or nicotinamide adenine dinucleotide phosphate oxidase (reduced) oxidase partially restored NO production as well as normal microvascular function. These results indicate that in conjunction with microvascular dysfunction, nanoparticle exposure also decreases NO bioavailability through at least two functionally distinct mechanisms that may mutually increase local reactive species. PMID:19270016

Apoptosis of murine melanoma B16-BL6 cells induced by quercetin targeting mitochondria, inhibiting expression of PKC-alpha and translocating PKC-delta.

PubMed

Zhang, Xian-Ming; Chen, Jia; Xia, Yu-Gui; Xu, Qiang

2005-03-01

In our previous study, quercetin was found to induce apoptosis of murine melanoma B16-BL6 cells. The cellular and molecular mechanism of quercetin-induced apoptosis was investigated in the present study. Nuclear morphology was determined by fluorescence microscopy. DNA fragmentation was analyzed by electrophoresis and quantified by the diphenylamine method. The transmembrane potential of mitochondria was measured by flow cytometry. Bcl-2, Bcl-X(L), PKC-alpha, PKC-beta, and PKC-delta were detected by Western blotting. Caspase activity was determined spectrophotometrically. Quercetin induced the condensation of nuclei of B16-BL6 cells in a dose-dependent pattern as visualized by Hoechst 33258 and propidium iodide dying. Phorbol 12-myristate 13-acetate (PMA), a PKC activator, significantly enhanced apoptosis induced by quercetin, while doxorubicin, a PKC inhibitor, markedly decreased it. Both PMA and doxorubicin showed a consistent effect on the fragmentation of nuclear DNA caused by various dosages of quercetin. Quercetin dose-dependently led to loss of the mitochondrial membrane potential, which was also significantly reinforced or antagonized by PMA and doxorubicin, respectively. Moreover, PMA showed reinforcement, while doxorubicin showed significant antagonization, of the quercetin-mediated decrease in the expression of Bcl-2. Quercetin promoted caspase-3 activity in a dose-dependent manner, which was also regulated by PMA and doxorubicin with a pattern similar to that seen in their effect on apoptosis, mitochondrial membrane potential and Bcl-2 expression, but none of these were directly affected by PMA and doxorubicin. Free fatty acid and chlorpromazine, a PKC activator and inhibitor, respectively, did not interfere with these effects of quercetin. B16-BL6 cells expressed PKC-alpha, PKC-beta, and PKC-delta. Quercetin dose-dependently inhibited the expression of PKC-alpha but not that of PKC-beta and PKC-delta. Doxorubicin almost completely blocked the effect of quercetin on the expression of PKC-alpha. Quercetin was also involved in the translocation of PKC-delta from the cytosol to the nucleus. PMA enhanced the effect of quercetin on the translocation of PKC-delta. These results indicate that quercetin induced apoptosis of murine melanoma B16-BL6 cells by injuring their mitochondria, increasing the activity of caspase-3, inhibiting the expression of Bcl-2 and PKC-alpha, and inducing the translocation of PKC-delta. Doxorubicin inhibited these effects of quercetin by blocking the decreased expression of PKC-alpha induced by quercetin while PMA increased these effects by enhancing the translocation of PKC-delta induced by quercetin.

[Effect of bemithyl on sexual behavior and spermatogenesis in rats].

PubMed

Bugaeva, L I; Spasov, A A; Kuzubova, E A

2006-01-01

Bemithyl produced different influence on the sexual behavior (pairing motivation) and spermatogenesis in rats, depending on the dose and duration of drug administration. A three-day administration of bemithyl (20 and 200 mg/kg, p.o.) stimulated the sexual activity and spermatogenesis in male rats irrespective of the drug dose. The chronic administration of bemithyl over a period of 60 days led to a decrease in the male sexual activity and spermatogenesis index. This behavior can be related to the drug influence on the hypothalamus/pituitary structures responsible for the male rat generative function.

Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPAR{alpha} deterioration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takahashi, Kyoko; Department of Nephrology Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621; Kamijo, Yuji, E-mail: yujibeat@shinshu-u.ac.jp

2011-05-01

Development of a preventive strategy against tubular damage associated with proteinuria is of great importance. Recently, free fatty acid (FFA) toxicities accompanying proteinuria were found to be a main cause of tubular damage, which was aggravated by insufficiency of peroxisome proliferator-activated receptor alpha (PPAR{alpha}), suggesting the benefit of PPAR{alpha} activation. However, an earlier study using a murine acute tubular injury model, FFA-overload nephropathy, demonstrated that high-dose treatment of PPAR{alpha} agonist (0.5% clofibrate diet) aggravated the tubular damage as a consequence of excess serum accumulation of clofibrate metabolites due to decreased kidney elimination. To induce the renoprotective effects of PPAR{alpha} agonistsmore » without drug accumulation, we tried a pretreatment study using low-dose clofibrate (0.1% clofibrate diet) using the same murine model. Low-dose clofibrate pretreatment prevented acute tubular injuries without accumulation of its metabolites. The tubular protective effects appeared to be associated with the counteraction of PPAR{alpha} deterioration, resulting in the decrease of FFAs influx to the kidney, maintenance of fatty acid oxidation, diminution of intracellular accumulation of undigested FFAs, and attenuation of disease developmental factors including oxidative stress, apoptosis, and NF{kappa}B activation. These effects are common to other fibrates and dependent on PPAR{alpha} function. Interestingly, however, clofibrate pretreatment also exerted PPAR{alpha}-independent tubular toxicities in PPAR{alpha}-null mice with FFA-overload nephropathy. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-independent tubular toxicities. This delicate balance seems to be easily affected by the drug dose. It will be important to establish the appropriate dosage of fibrates for treatment against kidney disease and to develop a novel PPAR{alpha} activator that has a steady serum concentration regardless of kidney dysfunction. - Graphical Abstract: Massive proteinuria introduces free fatty acid toxicity to proximal tubular epithelial cells (PTECs). PPAR{alpha} activationvia clofibrate pretreatment maintains fatty acid catabolism and attenuates oxidative stress, apoptosis, and NF{kappa}B activation, resulting in protection of PTECs. The favorable properties of fibrates are evident when PPAR{alpha}-dependent tubular protective effects outweigh their PPAR{alpha}-independent tubular toxicities. Display Omitted Highlights: > Clofibrate pretreatment protects against acute FFA-induced tubular toxicity. > PPAR{alpha} activation decreases FFA influx and maintains fatty acid catabolism. > PPAR{alpha} activation attenuates oxidative stress, apoptosis, and NF{kappa}B activation. > Protective effects must outweigh PPAR{alpha}-independent tubular toxicities of fibrates.« less

Evidence for a possible neurotransmitter/neuromodulator role of tyramine on the locust oviducts.

PubMed

Donini, Andrew; Lange, Angela B

2004-04-01

Visualization of the tyraminergic innervation of the oviducts was demonstrated by immunohistochemistry, and the presence of tyramine was confirmed using high-performance liquid chromatography coupled to electrochemical detection. Oviducts incubated in high-potassium saline released tyramine in a calcium-dependent manner. Stimulation of the oviducal nerves also resulted in tyramine release, suggesting that tyramine might function as a neurotransmitter/neuromodulator at the locust oviducts. Tyramine decreased the basal tension, and also attenuated proctolin-induced contractions in a dose-dependent manner over a range of doses between 10(-7) and 10(-4) M. Low concentrations of tyramine attenuated forskolin-stimulated cyclic AMP levels in a dose-dependent manner. This effect was not blocked by yohimbine. High concentrations of tyramine increased basal cyclic AMP levels of locust oviducts in a dose-dependent manner; however, the increases in cyclic AMP were only evident at the highest concentrations tested, 5 x 10(-5) and 10(-4) M tyramine. The tyramine-induced increase in cyclic AMP shared a similar pharmacological profile with the octopamine-induced increase in cyclic AMP. Tyramine increased the amplitude of excitatory junction potentials at low concentrations while hyperpolarizing the membrane potential by 2-5 mV. A further increase in the amplitude of the excitatory junction potentials and the occurrence of an active response was seen upon washing tyramine from the preparation. These results suggest that tyramine can activate at least three different endogenous receptors on the locust oviducts a putative tyramine receptor at low concentrations, a different tyramine receptor to inhibit muscle contraction, and an octopamine receptor at high concentrations.

Influence of phantom materials on the energy dependence of LiF:Mg,Ti thermoluminescent dosimeters exposed to 20-300 kV narrow x-ray spectra, 137Cs and 60Co photons.

PubMed

Massillon-J L, G; Cabrera-Santiago, A; Minniti, R; O'Brien, M; Soares, C G

2014-08-07

LiF:Mg,Ti, are widely used to estimate absorbed-dose received by patients during diagnostic or medical treatment. Conveniently, measurements are usually made in plastic phantoms. However, experimental conditions vary from one group to another and consequently, a lack of consensus data exists for the energy dependence of thermoluminescent (TL) response. This work investigated the energy dependence of TLD-100 TL-response and the effect of irradiating the dosimeters in different phantom materials for a broad range of energy photons in an attempt to understand the parameters that affect the discrepancies reported by various research groups. TLD-100s were exposed to 20-300 kV narrow x-ray spectra, (137)Cs and (60)Co photons. Measurements were performed in air, PMMA, wt1, polystyrene and TLDS as surrounding material. Total air-kerma values delivered were between 50 and 150 mGy for x-rays and 50 mGy for (137)Cs and (60)Co beams; each dosimeter was irradiated individually. Relative response, R, defined as the TL-response per air-kerma and relative efficiency, RE, described as the TL-response per absorbed-dose (obtained through Monte Carlo (MC) and analytically) were used to describe the TL-response. Both R and RE are normalized to the responses in a (60)Co beam. The results indicate that the use of different phantom materials affects the TL-response and this response varies with energy and material type. MC simulations reproduced qualitatively the experimental data: a) R increases, reaches a maximum at ~25 keV and decreases; b) RE decreases, down to a minimum at ~60 keV, increases to a maximum at ~150 keV and after decreases. Independent of the phantom materials, RE strongly depends on how the absorbed dose is evaluated and the discrepancies between RE evaluated analytically and by MC simulation are around 4% and 18%, dependent on the photon energy. The comparison between our results and that reported in the literature suggests that the discrepancy observed between different research groups appears to be most likely related to supralinearity effect, phantom materials, difference on the energy-spectra and geometry conditions during each experiment rather than parameters such as heating-rate or annealing procedure, which was supported by MC simulation. From the results obtained in this work and the strict analysis performed, we can conclude that for clinical applications of TLD-100, special attention must be taken when published data are used to convert TL calibration curve from (60)Co to low-energy photons. Otherwise, this can lead to incorrect results when later used to measure absorbed dose in human tissue.

Monte Carlo simulation and film dosimetry for electron therapy in vicinity of a titanium mesh

PubMed Central

Rostampour, Masoumeh; Roayaei, Mahnaz

2014-01-01

Titanium (Ti) mesh plates are used as a bone replacement in brain tumor surgeries. In the case of radiotherapy, these plates might interfere with the beam path. The purpose of this study is to evaluate the effect of titanium mesh on the dose distribution of electron fields. Simulations were performed using Monte Carlo BEAMnrc and DOSXYZnrc codes for 6 and 10 MeV electron beams. In Monte Carlo simulation, the shape of the titanium mesh was simulated. The simulated titanium mesh was considered as the one which is used in head and neck surgery with a thickness of 0.055 cm. First, by simulation, the percentage depth dose was obtained while the titanium mesh was present, and these values were then compared with the depth dose of homogeneous phantom with no titanium mesh. In the experimental measurements, the values of depth dose with titanium mesh and without titanium mesh in various depths were measured. The experiments were performed using a RW3 phantom with GAFCHROMIC EBT2 film. The results of experimental measurements were compared with values of depth dose obtained by simulation. In Monte Carlo simulation, as well as experimental measurements, for the voxels immediately beyond the titanium mesh, the change of the dose were evaluated. For this purpose the ratio of the dose for the case with titanium to the case without titanium was calculated as a function of titanium depth. For the voxels before the titanium mesh there was always an increase of the dose up to 13% with respect to the same voxel with no titanium mesh. This is because of the increased back scattering effect of the titanium mesh. The results also showed that for the voxel right beyond the titanium mesh, there is an increased or decreased dose to soft tissues, depending on the depth of the titanium mesh. For the regions before the depth of maximum dose, there is an increase of the dose up to 10% compared to the dose of the same depth in homogeneous phantom. Beyond the depth of maximum dose, there was a 16% decrease in dose. For both 6 and 10 MeV, before the titanium mesh, there was always an increase in dose. If titanium mesh is placed in buildup region, it causes an increase of the dose and could lead to overdose of the adjacent tissue, whereas if titanium mesh is placed beyond the buildup region, it would lead to a decrease in dose compared to the homogenous tissue. PACS number: 87.53.Bn PMID:25207397

Space radiation-associated lung injury in a murine model.

PubMed

Christofidou-Solomidou, Melpo; Pietrofesa, Ralph A; Arguiri, Evguenia; Schweitzer, Kelly S; Berdyshev, Evgeny V; McCarthy, Maureen; Corbitt, Astrid; Alwood, Joshua S; Yu, Yongjia; Globus, Ruth K; Solomides, Charalambos C; Ullrich, Robert L; Petrache, Irina

2015-03-01

Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space-relevant radiation (SR) on the lung. C3H mice were exposed to (137)Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u (56)Fe ions, or 350 MeV/u (28)Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high-energy (56)Fe or (28)Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions. Copyright © 2015 the American Physiological Society.

Effects of milrinone and epinephrine or dopamine on biventricular function and hemodynamics in an animal model with right ventricular failure after pulmonary artery banding.

PubMed

Hyldebrandt, Janus Adler; Sivén, Eleonora; Agger, Peter; Frederiksen, Christian Alcaraz; Heiberg, Johan; Wemmelund, Kristian Borup; Ravn, Hanne Berg

2015-07-01

Right ventricular (RV) failure due to chronic pressure overload is a main determinant of outcome in congenital heart disease. Medical management is challenging because not only contractility but also the interventricular relationship is important for increasing cardiac output. This study evaluated the effect of milrinone alone and in combination with epinephrine or dopamine on hemodynamics, ventricular performance, and the interventricular relationship. RV failure was induced in 21 Danish landrace pigs by pulmonary artery banding. After 10 wk, animals were reexamined using biventricular pressure-volume conductance catheters. The maximum pressure in the RV increased by 113% (P < 0.0001) and end-diastolic volume by 43% (P < 0.002), while left ventricular (LV) pressure simultaneously decreased (P = 0.006). Concomitantly, mean arterial pressure (MAP; -16%, P = 0.01), cardiac index (CI; -23%, P < 0.0001), and mixed venous oxygen saturation (SvO2 ; -40%, P < 0.0001) decreased. Milrinone increased CI (11%, P = 0.008) and heart rate (HR; 21%, P < 0.0001). Stroke volume index (SVI) decreased (7%, P = 0.03), although RV contractility was improved. The addition of either epinephrine or dopamine further increased CI and HR in a dose-dependent manner but without any significant differences between the two interventions. A more pronounced increase in biventricular contractility was observed in the dopamine-treated animals. LV volume was reduced in both the dopamine and epinephrine groups with increasing doses In the failing pressure overloaded RV, milrinone improved CI and increased contractility. Albeit additional dose-dependent effects of both epinephrine and dopamine on CI and contractility, neither of the interventions improved SVI due to reduced filling of the LV. Copyright © 2015 the American Physiological Society.

Liquid Medication Dosing Errors in Children: Role of Provider Counseling Strategies

PubMed Central

Yin, H. Shonna; Dreyer, Benard P.; Moreira, Hannah A.; van Schaick, Linda; Rodriguez, Luis; Boettger, Susanne; Mendelsohn, Alan L.

2014-01-01

Objective To examine the degree to which recommended provider counseling strategies, including advanced communication techniques and dosing instrument provision, are associated with reductions in parent liquid medication dosing errors. Methods Cross-sectional analysis of baseline data on provider communication and dosing instrument provision from a study of a health literacy intervention to reduce medication errors. Parents whose children (<9 years) were seen in two urban public hospital pediatric emergency departments (EDs) and were prescribed daily dose liquid medications self-reported whether they received counseling about their child’s medication, including advanced strategies (teachback, drawings/pictures, demonstration, showback) and receipt of a dosing instrument. Primary dependent variable: observed dosing error (>20% deviation from prescribed). Multivariate logistic regression analyses performed, controlling for: parent age, language, country, ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease status; site. Results Of 287 parents, 41.1% made dosing errors. Advanced counseling and instrument provision in the ED were reported by 33.1% and 19.2%, respectively; 15.0% reported both. Advanced counseling and instrument provision in the ED were associated with decreased errors (30.5 vs. 46.4%, p=0.01; 21.8 vs. 45.7%, p=0.001). In adjusted analyses, ED advanced counseling in combination with instrument provision was associated with a decreased odds of error compared to receiving neither (AOR 0.3; 95% CI 0.1–0.7); advanced counseling alone and instrument alone were not significantly associated with odds of error. Conclusion Provider use of advanced counseling strategies and dosing instrument provision may be especially effective in reducing errors when used together. PMID:24767779

Multileaf collimator tongue-and-groove effect on depth and off-axis doses: A comparison of treatment planning data with measurements and Monte Carlo calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Hee Jung; Department of Biomedical Engineering, Seoul National University, Seoul; Department of Radiation Oncology, Soonchunhyang University Hospital, Seoul

2015-01-01

To investigate how accurately treatment planning systems (TPSs) account for the tongue-and-groove (TG) effect, Monte Carlo (MC) simulations and radiochromic film (RCF) measurements were performed for comparison with TPS results. Two commercial TPSs computed the TG effect for Varian Millennium 120 multileaf collimator (MLC). The TG effect on off-axis dose profile at 3 depths of solid water was estimated as the maximum depth and the full width at half maximum (FWHM) of the dose dip at an interleaf position. When compared with the off-axis dose of open field, the maximum depth of the dose dip for MC and RCF rangedmore » from 10.1% to 20.6%; the maximum depth of the dose dip gradually decreased by up to 8.7% with increasing depths of 1.5 to 10 cm and also by up to 4.1% with increasing off-axis distances of 0 to 13 cm. However, TPS results showed at most a 2.7% decrease for the same depth range and a negligible variation for the same off-axis distances. The FWHM of the dose dip was approximately 0.19 cm for MC and 0.17 cm for RCF, but 0.30 cm for Eclipse TPS and 0.45 cm for Pinnacle TPS. Accordingly, the integrated value of TG dose dip for TPS was larger than that for MC and RCF and almost invariant along the depths and off-axis distances. We concluded that the TG dependence on depth and off-axis doses shown in the MC and RCF results could not be appropriately modeled by the TPS versions in this study.« less

Liquid medication dosing errors in children: role of provider counseling strategies.

PubMed

Yin, H Shonna; Dreyer, Benard P; Moreira, Hannah A; van Schaick, Linda; Rodriguez, Luis; Boettger, Susanne; Mendelsohn, Alan L

2014-01-01

To examine the degree to which recommended provider counseling strategies, including advanced communication techniques and dosing instrument provision, are associated with reductions in parent liquid medication dosing errors. Cross-sectional analysis of baseline data on provider communication and dosing instrument provision from a study of a health literacy intervention to reduce medication errors. Parents whose children (<9 years) were seen in 2 urban public hospital pediatric emergency departments (EDs) and were prescribed daily dose liquid medications self-reported whether they received counseling about their child's medication, including advanced strategies (teachback, drawings/pictures, demonstration, showback) and receipt of a dosing instrument. The primary dependent variable was observed dosing error (>20% deviation from prescribed). Multivariate logistic regression analyses were performed, controlling for parent age, language, country, ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease status; and site. Of 287 parents, 41.1% made dosing errors. Advanced counseling and instrument provision in the ED were reported by 33.1% and 19.2%, respectively; 15.0% reported both. Advanced counseling and instrument provision in the ED were associated with decreased errors (30.5 vs. 46.4%, P = .01; 21.8 vs. 45.7%, P = .001). In adjusted analyses, ED advanced counseling in combination with instrument provision was associated with a decreased odds of error compared to receiving neither (adjusted odds ratio 0.3; 95% confidence interval 0.1-0.7); advanced counseling alone and instrument alone were not significantly associated with odds of error. Provider use of advanced counseling strategies and dosing instrument provision may be especially effective in reducing errors when used together. Copyright © 2014 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy.

PubMed

Fellows, Patricia; Price, Jessica; Martin, Shannon; Metcalfe, Karen; Krile, Robert; Barnewall, Roy; Hart, Mary Kate; Lockman, Hank

2015-09-01

The efficacy of a recombinant plague vaccine (rF1V) was evaluated in cynomolgus macaques (CMs) to establish the relationship among vaccine doses, antibody titers, and survival following an aerosol challenge with a lethal dose of Yersinia pestis strain Colorado 92. CMs were vaccinated with a range of rF1V doses on a three-dose schedule (days 0, 56, and 121) to provide a range of survival outcomes. The humoral immune response following vaccination was evaluated with anti-rF1, anti-rV, and anti-rF1V bridge enzyme-linked immunosorbent assays (ELISAs). Animals were challenged via aerosol exposure on day 149. Vaccine doses and antibody responses were each significantly associated with the probability of CM survival (P < 0.0001). Vaccination also decreased signs of pneumonic plague in a dose-dependent manner. There were statistically significant correlations between the vaccine dose and the time to onset of fever (P < 0.0001), the time from onset of fever to death (P < 0.0001), the time to onset of elevated respiratory rate (P = 0.0003), and the time to onset of decreased activity (P = 0.0251) postinfection in animals exhibiting these clinical signs. Delays in the onset of these clinical signs of disease were associated with larger doses of rF1V. Immunization with ≥ 12 μg of rF1V resulted in 100% CM survival. Since both the vaccine dose and anti-rF1V antibody titers correlate with survival, rF1V bridge ELISA titers can be used as a correlate of protection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Equivalence in Dose Fall-Off for Isocentric and Nonisocentric Intracranial Treatment Modalities and Its Impact on Dose Fractionation Schemes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma Lijun, E-mail: lijunma@radonc.ucsf.ed; Sahgal, Arjun; Descovich, Martina

2010-03-01

Purpose: To investigate whether dose fall-off characteristics would be significantly different among intracranial radiosurgery modalities and the influence of these characteristics on fractionation schemes in terms of normal tissue sparing. Methods and Materials: An analytic model was developed to measure dose fall-off characteristics near the target independent of treatment modalities. Variations in the peripheral dose fall-off characteristics were then examined and compared for intracranial tumors treated with Gamma Knife, Cyberknife, or Novalis LINAC-based system. Equivalent uniform biologic effective dose (EUBED) for the normal brain tissue was calculated. Functional dependence of the normal brain EUBED on varying numbers of fractions (1more » to 30) was studied for the three modalities. Results: The derived model fitted remarkably well for all the cases (R{sup 2} > 0.99). No statistically significant differences in the dose fall-off relationships were found between the three modalities. Based on the extent of variations in the dose fall-off curves, normal brain EUBED was found to decrease with increasing number of fractions for the targets, with alpha/beta ranging from 10 to 20. This decrease was most pronounced for hypofractionated treatments with fewer than 10 fractions. Additionally, EUBED was found to increase slightly with increasing number of fractions for targets with alpha/beta ranging from 2 to 5. Conclusion: Nearly identical dose fall-off characteristics were found for the Gamma Knife, Cyberknife, and Novalis systems. Based on EUBED calculations, normal brain sparing was found to favor hypofractionated treatments for fast-growing tumors with alpha/beta ranging from 10 to 20 and single fraction treatment for abnormal tissues with low alpha/beta values such as alpha/beta = 2.« less

The effects of small field dosimetry on the biological models used in evaluating IMRT dose distributions

NASA Astrophysics Data System (ADS)

Cardarelli, Gene A.

The primary goal in radiation oncology is to deliver lethal radiation doses to tumors, while minimizing dose to normal tissue. IMRT has the capability to increase the dose to the targets and decrease the dose to normal tissue, increasing local control, decrease toxicity and allow for effective dose escalation. This advanced technology does present complex dose distributions that are not easily verified. Furthermore, the dose inhomogeneity caused by non-uniform dose distributions seen in IMRT treatments has caused the development of biological models attempting to characterize the dose-volume effect in the response of organized tissues to radiation. Dosimetry of small fields can be quite challenging when measuring dose distributions for high-energy X-ray beams used in IMRT. The proper modeling of these small field distributions is essential in reproducing accurate dose for IMRT. This evaluation was conducted to quantify the effects of small field dosimetry on IMRT plan dose distributions and the effects on four biological model parameters. The four biological models evaluated were: (1) the generalized Equivalent Uniform Dose (gEUD), (2) the Tumor Control Probability (TCP), (3) the Normal Tissue Complication Probability (NTCP) and (4) the Probability of uncomplicated Tumor Control (P+). These models are used to estimate local control, survival, complications and uncomplicated tumor control. This investigation compares three distinct small field dose algorithms. Dose algorithms were created using film, small ion chamber, and a combination of ion chamber measurements and small field fitting parameters. Due to the nature of uncertainties in small field dosimetry and the dependence of biological models on dose volume information, this examination quantifies the effects of small field dosimetry techniques on radiobiological models and recommends pathways to reduce the errors in using these models to evaluate IMRT dose distributions. This study demonstrates the importance of valid physical dose modeling prior to the use of biological modeling. The success of using biological function data, such as hypoxia, in clinical IMRT planning will greatly benefit from the results of this study.

High dose-per-pulse electron beam dosimetry - A model to correct for the ion recombination in the Advanced Markus ionization chamber.

PubMed

Petersson, Kristoffer; Jaccard, Maud; Germond, Jean-François; Buchillier, Thierry; Bochud, François; Bourhis, Jean; Vozenin, Marie-Catherine; Bailat, Claude

2017-03-01

The purpose of this work was to establish an empirical model of the ion recombination in the Advanced Markus ionization chamber for measurements in high dose rate/dose-per-pulse electron beams. In addition, we compared the observed ion recombination to calculations using the standard Boag two-voltage-analysis method, the more general theoretical Boag models, and the semiempirical general equation presented by Burns and McEwen. Two independent methods were used to investigate the ion recombination: (a) Varying the grid tension of the linear accelerator (linac) gun (controls the linac output) and measuring the relative effect the grid tension has on the chamber response at different source-to-surface distances (SSD). (b) Performing simultaneous dose measurements and comparing the dose-response, in beams with varying dose rate/dose-per-pulse, with the chamber together with dose rate/dose-per-pulse independent Gafchromic™ EBT3 film. Three individual Advanced Markus chambers were used for the measurements with both methods. All measurements were performed in electron beams with varying mean dose rate, dose rate within pulse, and dose-per-pulse (10 -2  ≤ mean dose rate ≤ 10 3 Gy/s, 10 2  ≤ mean dose rate within pulse ≤ 10 7  Gy/s, 10 -4  ≤ dose-per-pulse ≤ 10 1  Gy), which was achieved by independently varying the linac gun grid tension, and the SSD. The results demonstrate how the ion collection efficiency of the chamber decreased as the dose-per-pulse increased, and that the ion recombination was dependent on the dose-per-pulse rather than the dose rate, a behavior predicted by Boag theory. The general theoretical Boag models agreed well with the data over the entire investigated dose-per-pulse range, but only for a low polarizing chamber voltage (50 V). However, the two-voltage-analysis method and the Burns & McEwen equation only agreed with the data at low dose-per-pulse values (≤ 10 -2 and ≤ 10 -1  Gy, respectively). An empirical model of the ion recombination in the chamber was found by fitting a logistic function to the data. The ion collection efficiency of the Advanced Markus ionization chamber decreases for measurements in electron beams with increasingly higher dose-per-pulse. However, this chamber is still functional for dose measurements in beams with dose-per-pulse values up toward and above 10 Gy, if the ion recombination is taken into account. Our results show that existing models give a less-than-accurate description of the observed ion recombination. This motivates the use of the presented empirical model for measurements with the Advanced Markus chamber in high dose-per-pulse electron beams, as it enables accurate absorbed dose measurements (uncertainty estimation: 2.8-4.0%, k = 1). The model depends on the dose-per-pulse in the beam, and it is also influenced by the polarizing chamber voltage, with increasing ion recombination with a lowering of the voltage. © 2017 American Association of Physicists in Medicine.

The dose-dependent effects of chronic iron overload on the production of oxygen free radicals and vitamin E concentrations in the liver of a murine model.

PubMed

McCullough, Karey D; Bartfay, Wally J

2007-04-01

Genetic disorders of iron metabolism such as primary and secondary hemochromatosis affect thousands of individuals worldwide and are major causes of liver dysfunction, morbidity, and mortality. Although the exact mechanism of hepatic injury associated with these genetic disorders is not fully understood, the propagation of excess concentrations of iron-catalyzed oxygen free radicals (OFRs) may play a role. The authors hypothesized that chronic iron burden would result in dose-dependent (a) increases in hepatic iron stores, (b) increases in hepatic OFR-mediated hepatic cellular injury as quantified by the cytotoxic aldehydes malondialdehyde (MDA) and hexanal, and (c) decreases in protective antioxidant reserve status as quantified by plasma vitamin E (alpha-tocopherol) levels in a murine model. Twenty B(6)D(2)F1 male mice were randomized to the (a) saline control (0.05 mL intraperiotoneal [i.p.]/mouse/day, n = 5), (b) 100 mg total iron burden (n = 5), (c) 200 mg total iron burden (n = 5), or (d) 400 mg total iron burden (n = 5) group. Iron burden was achieved by daily injections of iron dextran (Imferon, 0.05 mL i.p./mouse/day). In comparison to control mice and in support of the hypothesis, the authors observed significant dose-dependent increases in total hepatic iron burden (p < .001) with corresponding increases in MDA and hexanal concentrations (p < .001) and decreases in the protective plasma antioxidant vitamin E (p < .001). These findings suggest that iron-catalyzed OFR-mediated damage may play a role in damaging the liver in chronic states of iron burden.

KML001 Induces Apoptosis and Autophagic Cell Death in Prostate Cancer Cells via Oxidative Stress Pathway

PubMed Central

You, Dalsan; Kim, Yunlim; Jang, Myoung Jin; Lee, Chunwoo; Jeong, In Gab; Cho, Yong Mee; Hwang, Jung Jin; Hong, Jun Hyuk; Ahn, Hanjong; Kim, Choung-Soo

2015-01-01

We investigated the effects of KML001 (NaAsO2, sodium metaarsenite, Kominox), an orally bioavailable arsenic compound, on the growth and death of human prostate cancer cells and its mechanism of action. Growth inhibition was assessed by cytotoxicity assays in the presence or absence of inhibitor of apoptosis, inhibitor of autophagy or antioxidant N-Acetyl-L-cysteine to study mechanism of cell death induced by KML001 in PC3, DU145 and LNCaP prostate cancer cell lines. Electron microscopy, flow cytometry and Western blotting were used to study apoptotic and autophagic mechanisms. The DU145 xenograft model was used to determine the efficacy of KML001 in vivo. KML001 decreased the viability of cells and increased the percentage of annexin V-positive cells dose-dependently in prostate cancer cells, and LNCaP cells were more sensitive to KML001 than PC3 or DU145 cells. Electron microscopy revealed typical apoptotic characters and autophagic vacuoles in cells treated with KML001. Exposure to KML001 in prostate cancer cells induced apoptosis and autophagy in a time- and dose-dependent manner. KML001 induced dose-dependent accumulation of reactive oxygen species, and scavenging the reactive oxygen species with N-Acetyl-L-cysteine reduced LC3 and cleaved poly (ADP-ribose) polymerase. KML001 significantly inhibited tumor growth in the DU145 xenograft model. In addition, significant decrease of proliferation and significant increases of apoptosis and autophagy were observed in KML001-treated tumors than in vehicle-treated tumors. Exposure of human prostate cancer cells to KML001 induced both apoptosis and autophagic cell death via oxidative stress pathway. And KML001 had an antiproliferative effect on DU145 cells in xenograft mice. PMID:26352139

KML001 Induces Apoptosis and Autophagic Cell Death in Prostate Cancer Cells via Oxidative Stress Pathway.

PubMed

You, Dalsan; Kim, Yunlim; Jang, Myoung Jin; Lee, Chunwoo; Jeong, In Gab; Cho, Yong Mee; Hwang, Jung Jin; Hong, Jun Hyuk; Ahn, Hanjong; Kim, Choung-Soo

2015-01-01

We investigated the effects of KML001 (NaAsO2, sodium metaarsenite, Kominox), an orally bioavailable arsenic compound, on the growth and death of human prostate cancer cells and its mechanism of action. Growth inhibition was assessed by cytotoxicity assays in the presence or absence of inhibitor of apoptosis, inhibitor of autophagy or antioxidant N-Acetyl-L-cysteine to study mechanism of cell death induced by KML001 in PC3, DU145 and LNCaP prostate cancer cell lines. Electron microscopy, flow cytometry and Western blotting were used to study apoptotic and autophagic mechanisms. The DU145 xenograft model was used to determine the efficacy of KML001 in vivo. KML001 decreased the viability of cells and increased the percentage of annexin V-positive cells dose-dependently in prostate cancer cells, and LNCaP cells were more sensitive to KML001 than PC3 or DU145 cells. Electron microscopy revealed typical apoptotic characters and autophagic vacuoles in cells treated with KML001. Exposure to KML001 in prostate cancer cells induced apoptosis and autophagy in a time- and dose-dependent manner. KML001 induced dose-dependent accumulation of reactive oxygen species, and scavenging the reactive oxygen species with N-Acetyl-L-cysteine reduced LC3 and cleaved poly (ADP-ribose) polymerase. KML001 significantly inhibited tumor growth in the DU145 xenograft model. In addition, significant decrease of proliferation and significant increases of apoptosis and autophagy were observed in KML001-treated tumors than in vehicle-treated tumors. Exposure of human prostate cancer cells to KML001 induced both apoptosis and autophagic cell death via oxidative stress pathway. And KML001 had an antiproliferative effect on DU145 cells in xenograft mice.

A meta-analysis of the effects of Lactobacillus buchneri on the fermentation and aerobic stability of corn and grass and small-grain silages.

PubMed

Kleinschmit, D H; Kung, L

2006-10-01

The results of adding Lactobacillus buchneri to silages from 43 experiments in 23 sources reporting standard errors were summarized using meta-analysis. The effects of inoculation were summarized by type of crop (corn or grass and small grains) and the treatments were classified into the following categories: 1) untreated silage with nothing applied (LB0), 2) silage treated with L. buchneri at < or = 100,000 cfu/g of fresh forage (LB1), and 3) silage treated with L. buchneri at > 100,000 cfu/g (LB2). In both types of crops, inoculation with L. buchneri decreased concentrations of lactic acid, and this response was dose-dependent in corn but not in grass and small-grain silages. Treatment with L. buchneri markedly increased the concentrations of acetic acid in both crops in a dose-dependent manner. The numbers of yeasts were lower in silages treated with LB1 and further decreased in silages treated with LB2 compared with untreated silages. Untreated corn silage spoiled after 25 h of exposure to air but corn silage treated with LB1 did not spoil until 35 h, and this stability was further enhanced to 503 h with LB2. In grass and small-grain silages, yeasts were nearly undetectable; however, inoculation improved aerobic stability in a dose-dependent manner (206, 226, and 245 h for LB0, LB1, and LB2, respectively). The recovery of DM after ensiling was lower for LB2 (94.5%) when compared with LB0 (95.5%) in corn silage and was lower for both LB1 (94.8%) and LB2 (95.3%) when compared with LB0 (96.6%) in grass and small-grain silages.