Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

PubMed

Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

2015-04-01

Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

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

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.

Dose Relations between Goal Setting, Theory-Based Correlates of Goal Setting and Increases in Physical Activity during a Workplace Trial

ERIC Educational Resources Information Center

Dishman, Rod K.; Vandenberg, Robert J.; Motl, Robert W.; Wilson, Mark G.; DeJoy, David M.

2010-01-01

The effectiveness of an intervention depends on its dose and on moderators of dose, which usually are not studied. The purpose of the study is to determine whether goal setting and theory-based moderators of goal setting had dose relations with increases in goal-related physical activity during a successful workplace intervention. A…

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.

Comparative Proteomic Analysis of Liver Steatosis and Fibrosis after Oral Hepatotoxicant Administration in Sprague-Dawley Rats.

PubMed

McDyre, B Claire; AbdulHameed, Mohamed Diwan M; Permenter, Matthew G; Dennis, William E; Baer, Christine E; Koontz, Jason M; Boyle, Molly H; Wallqvist, Anders; Lewis, John A; Ippolito, Danielle L

2018-02-01

The past decade has seen an increase in the development and clinical use of biomarkers associated with histological features of liver disease. Here, we conduct a comparative histological and global proteomics analysis to identify coregulated modules of proteins in the progression of hepatic steatosis or fibrosis. We orally administered the reference chemicals bromobenzene (BB) or 4,4'-methylenedianiline (4,4'-MDA) to male Sprague-Dawley rats for either 1 single administration or 5 consecutive daily doses. Livers were preserved for histopathology and global proteomics assessment. Analysis of liver sections confirmed a dose- and time-dependent increase in frequency and severity of histopathological features indicative of lipid accumulation after BB or fibrosis after 4,4'-MDA. BB administration resulted in a dose-dependent increase in the frequency and severity of inflammation and vacuolation. 4,4'-MDA administration resulted in a dose-dependent increase in the frequency and severity of periportal collagen accumulation and inflammation. Pathway analysis identified a time-dependent enrichment of biological processes associated with steatogenic or fibrogenic initiating events, cellular functions, and toxicological states. Differentially expressed protein modules were consistent with the observed histology, placing physiologically linked protein networks into context of the disease process. This study demonstrates the potential for protein modules to provide mechanistic links between initiating events and histopathological outcomes.

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

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

Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, andmore » percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.« less

Low doses of glyphosate enhance growth, CO2 assimilation, stomatal conductance and transpiration in sugarcane and eucalyptus.

PubMed

Nascentes, Renan F; Carbonari, Caio A; Simões, Plinio S; Brunelli, Marcela C; Velini, Edivaldo D; Duke, Stephen O

2018-05-01

Sublethal doses of herbicides can enhance plant growth and stimulate other process, an effect known as hormesis. The magnitude of hormesis is dependent on the plant species, the herbicide and its dose, plant development stage and environmental parameters. Glyphosate hormesis is well established, but relatively little is known of the mechanism of this phenomenon. The objective of this study was to determine if low doses of glyphosate that cause growth stimulation in sugarcane and eucalyptus concomitantly stimulate CO 2 assimilation. Shoot dry weight in both species increased at both 40 and 60 days after application of 6.2 to 20.2 g a.e. ha -1 glyphosate. The level of enhanced shoot dry weight was 11 to 37%, depending on the time after treatment and the species. Concomitantly, CO 2 assimilation, stomatal conductance and transpiration were increased by glyphosate doses similar to those that caused growth increases. Glyphosate applied at low doses increased the dry weight of sugarcane and eucalyptus plants in all experiments. This hormetic effect was related to low dose effects on CO 2 assimilation rate, stomatal conductance and transpiration rate, indicating that low glyphosate doses enhance photosynthesis of plants. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

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.

Effects of irradiation source and dose level on quality characteristics of processed meat products

NASA Astrophysics Data System (ADS)

Ham, Youn-Kyung; Kim, Hyun-Wook; Hwang, Ko-Eun; Song, Dong-Heon; Kim, Yong-Jae; Choi, Yun-Sang; Song, Beom-Seok; Park, Jong-Heum; Kim, Cheon-Jei

2017-01-01

The effect of irradiation source (gamma-ray, electron-beam, and X-ray) and dose levels on the physicochemical, organoleptic and microbial properties of cooked beef patties and pork sausages was studied, during 10 days of storage at 30±1 °C. The processed meat products were irradiated at 0, 2.5, 5, 7.5, and 10 kGy by three different irradiation sources. The pH of cooked beef patties and pork sausages was unaffected by irradiation sources or their doses. The redness of beef patties linearly decreased with increasing dose level (P<0.05), obviously by e-beam irradiation compared to gamma-ray and X-ray (P<0.05). The redness of pork sausages was increased by gamma-ray irradiation, whereas it decreased by e-beam irradiation depending on absorbed dose level. No significant changes in overall acceptability were observed for pork sausages regardless of irradiation source (P>0.05), while gamma-ray irradiated beef patties showed significantly decreased overall acceptability in a dose-dependent manner (P<0.05). Lipid oxidation of samples was accelerated by irradiation depending on irradiation sources and dose levels during storage at 30 °C. E-beam reduced total aerobic bacteria of beef patties more effectively, while gamma-ray considerably decreased microbes in pork sausages as irradiation dose increased. The results of this study indicate that quality attributes of meat products, in particular color, lipid oxidation, and microbial properties are significantly influenced by the irradiation sources.

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.

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%.

The impact of the oxygen scavenger on the dose-rate dependence and dose sensitivity of MAGIC type polymer gels

NASA Astrophysics Data System (ADS)

Khan, Muzafar; Heilemann, Gerd; Kuess, Peter; Georg, Dietmar; Berg, Andreas

2018-03-01

Recent developments in radiation therapy aimed at more precise dose delivery along with higher dose gradients (dose painting) and more efficient dose delivery with higher dose rates e.g. flattening filter free (FFF) irradiation. Magnetic-resonance-imaging based polymer gel dosimetry offers 3D information for precise dose delivery techniques. Many of the proposed polymer gels have been reported to exhibit a dose response, measured as relaxation rate ΔR2(D), which is dose rate dependent. A lack of or a reduced dose-rate sensitivity is very important for dosimetric accuracy, especially with regard to the increasing clinical use of FFF irradiation protocols with LINACs at high dose rates. Some commonly used polymer gels are based on Methacrylic-Acid-Gel-Initiated-by-Copper (MAGIC). Here, we report on the dose sensitivity (ΔR2/ΔD) of MAGIC-type gels with different oxygen scavenger concentration for their specific dependence on the applied dose rate in order to improve the dosimetric performance, especially for high dose rates. A preclinical x-ray machine (‘Yxlon’, E  =  200 kV) was used for irradiation to cover a range of dose rates from low \\dot{D} min  =  0.6 Gy min-1 to high \\dot{D} max  =  18 Gy min-1. The dose response was evaluated using R2-imaging of the gel on a human high-field (7T) MR-scanner. The results indicate that all of the investigated dose rates had an impact on the dose response in polymer gel dosimeters, being strongest in the high dose region and less effective for low dose levels. The absolute dose rate dependence \\frac{(Δ R2/Δ D)}{Δ \\dot{D}} of the dose response in MAGIC-type gel is significantly reduced using higher concentrations of oxygen scavenger at the expense of reduced dose sensitivity. For quantitative dose evaluations the relative dose rate dependence of a polymer gel, normalized to its sensitivity is important. Based on this normalized sensitivity the dose rate sensitivity was reduced distinctly using an increased oxygen scavenger concentration with reference to standard MAGIC-type gel formulation at high dose rate levels. The proposed gel composition with high oxygen scavenger concentration exhibits a larger linear active dose response and might be used especially in FFF-radiation applications and preclinical dosimetry at high dose rates. We propose in general to use high dose rates for calibration and evaluation as the change in relative dose sensitivity is reduced at higher dose rates in all of the investigated gel types.

Stimulation of body weight increase and epiphyseal cartilage growth by insulin like growth factor

NASA Technical Reports Server (NTRS)

Ellis, S.

1981-01-01

The ability of insulin-like growth factor (IGF) to induce growth in hypophysectomized immature rats was tested by continuous infusion of the partially purified factor at daily doses of 6, 21, and 46 mU for an 8-day period. A dose-dependent growth of the proximal epiphyseal cartilage of the tibia and an associated stimulation of the primary spongiosa were produced by these amounts of IGF. The two highest doses of IGF also resulted in dose-dependent increases of body weight. Gel permeation of the sera at neutrality showed that the large-molecular-weight IGF binding protein was not induced by the infusion of IGF, whereas it ws generated in the sera of hypophysectomized rats that were infused with daily doses of 86 mU of human growth hormone.

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

High glucose impaired estrogen receptor alpha signaling via β-catenin in osteoblastic MC3T3-E1.

PubMed

Wang, Rui; Gao, Dong; Zhou, Yin; Chen, Lu; Luo, Bin; Yu, Yanrong; Li, Hao; Hu, Jiawei; Huang, Qiren; He, Ming; Peng, Weijie; Luo, Dan

2017-11-01

Diabetic Mellitus is a risk factor for osteoporosis. It has been suggested that altered estrogen or estrogen receptor α/β (ERα/β) signaling may be involved in diabetic osteoporosis. The present study is to investigate the effects of high glucose on ERα/β signaling in osteoblastic MC3T3-E1 and how the altered signaling of ERα/β affect osteoblastic bone formation. ERα/β signaling was demonstrated as ERα/β protein expression (Western Blotting) and ER transcription activity (Luciferase Reporter assays). Proliferation (WSK-1 assaying), differentiation (ALP staining) and mineralization (Alizalard Red staining) of MC3T3-E1 were examined to evaluate bone formation function. It has been found that high glucose increased ERα/β expression dose-dependently and time-dependently, but high glucose (33mM) decreased ERα transcription activity. 17β-estradiol increased the ERα/β expression dose-dependently in normal medium, but decreased the ERα/β expression dose-dependently in medium with high glucose (33mM). High glucose decreased bone formation and also decreased the osteogenic effects of 17β-estradiol (10 -8 M). High glucose decreased β-catenin expression dose-dependently and time-dependently. LiCl, an inhibitor of β-catenin degradation, decreased ERα expression but increased ERα transcription activity. When compared with high glucose treatment, LiCl (5mM) increased ALP activity and calcified nodes. Besides, high glucose also decreased the protein expression PI-3K, pAKT/AKT, GSK-3β. In conclusion, the present study suggested that high glucose may impair ERα transcription activity by inhibiting β-catenin signaling in osteoblastic MC3T3-E1, leading decreased bone formation ligand-dependently or ligand-independently. Copyright © 2017 Elsevier 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

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.

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.

Effects of Alcohol on Performance on a Distraction Task During Simulated Driving

PubMed Central

Allen, Allyssa J.; Meda, Shashwath A.; Skudlarski, Pawel; Calhoun, Vince; Astur, Robert; Ruopp, Kathryn C.; Pearlson, Godfrey D.

2009-01-01

Background Prior studies report that accidents involving intoxicated drivers are more likely to occur during performance of secondary tasks. We studied this phenomenon, using a dual-task paradigm, involving performance of a visual oddball (VO) task while driving in an alcohol challenge paradigm. Previous functional MRI (fMRI) studies of the VO task have shown activation in the anterior cingulate, hippocampus, and prefrontal cortex. Thus, we predicted dose-dependent decreases in activation of these areas during VO performance. Methods Forty healthy social drinkers were administered 3 different doses of alcohol, individually tailored to their gender and weight. Participants performed a VO task while operating a virtual reality driving simulator in a 3T fMRI scanner. Results Analysis showed a dose-dependent linear decrease in Blood Oxygen Level Dependent activation during task performance, primarily in hippocampus, anterior cingulate, and dorsolateral prefrontal areas, with the least activation occurring during the high dose. Behavioral analysis showed a dose-dependent linear increase in reaction time, with no effects associated with either correct hits or false alarms. In all dose conditions, driving speed decreased significantly after a VO stimulus. However, at the high dose this decrease was significantly less. Passenger-side line crossings significantly increased at the high dose. Conclusions These results suggest that driving impairment during secondary task performance may be associated with alcohol-related effects on the above brain regions, which are involved with attentional processing/decision-making. Drivers with high blood alcohol concentrations may be less able to orient or detect novel or sudden stimuli during driving. PMID:19183133

Deferasirox at therapeutic doses is associated with dose-dependent hypercalciuria.

PubMed

Wong, Phillip; Polkinghorne, Kevan; Kerr, Peter G; Doery, James C G; Gillespie, Matthew T; Larmour, I; Fuller, Peter J; Bowden, Donald K; Milat, Frances

2016-04-01

Deferasirox is an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies. Whilst initial long-term studies established the renal safety of deferasirox, there are now increasing reports of hypercalciuria and renal tubular dysfunction. In addition, urolithiasis with rapid loss of bone density in patients with β thalassemia major has been reported. We conducted a cross-sectional cohort study enrolling 152 adult patients comprising of β thalassemia major (81.5%), sickle cell disease (8%), thalassemia intermedia (2%), HbH disease (6.5%) and E/β thalassemia (2%). Cases were matched with normal control subjects on age, gender and serum creatinine. Iron chelator use was documented and urine calcium to creatinine ratios measured. At the time of analysis, 88.8% of patients were receiving deferasirox and 11.2% were on deferoxamine. Hypercalciuria was present in 91.9% of subjects on deferasirox in a positive dose-dependent relationship. This was not seen with subjects receiving deferoxamine. At a mean dose of 30.2±8.8mg/kg/day, deferasirox was associated with an almost 4 fold increase in urine calcium to creatinine ratio (UCa/Cr). Hypercalciuria was present at therapeutic doses of deferasirox in a dose-dependent manner and warrants further investigation and vigilance for osteoporosis, urolithiasis and other markers of renal dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Icosapent ethyl: Eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies.

PubMed

Bays, Harold E; Ballantyne, Christie M; Doyle, Ralph T; Juliano, Rebecca A; Philip, Sephy

2016-09-01

Icosapent ethyl is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved at a dose of 4g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500mg/dL) hypertriglyceridemia. This post-hoc exploratory analysis examined the relationship of icosapent ethyl dose with EPA concentrations in plasma and red blood cells (RBCs) across 3 clinical studies-a phase 1 pharmacokinetic study in healthy adult volunteers and 2 pivotal phase 3 studies (MARINE and ANCHOR) in adult patients with hypertriglyceridemia-and examined the relationship between EPA levels and TG-lowering effects in MARINE and ANCHOR. In all 3 studies, icosapent ethyl produced dose-dependent increases in the concentrations of EPA in plasma and RBCs. In both MARINE and ANCHOR, these dose-dependent EPA increases correlated with the degree of TG level lowering (all P<0.01). In patients with high TG levels (≥200mg/dL) and treated with icosapent ethyl 4g/day, the end-of-treatment plasma and RBC EPA concentrations were >170μg/mL and>70μg/mL, respectively. These studies support icosapent ethyl as producing predictable dose-dependent pharmacokinetics/pharmacodynamics, with TG level lowering dependent upon icosapent ethyl dose and EPA concentrations in plasma and RBCs. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Induction of sister chromatid exchanges and inhibition of cellular proliferation in vitro. I. Caffeine

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

Guglielmi, G.E.; Vogt, T.F.; Tice, R.R.

1982-01-01

While many agents have been examined for their ability to induce SCE's, complete dose-response information has often been lacking. We have reexamined the ability of one such compound - caffeine - to induce SCEs and also to inhibit cellular proliferation in human peripheral lymphocytes in vitro. An acute exposure to caffeine prior to the DNA synthetic period did not affect either SCE frequency or the rate of cellular proliferation. Chronic exposure to caffeine throughout the culture period lead to both a dose-dependent increase in SCEs (SCE/sub d/ or doubling dose = 2.4 mM; SCE/sub 10/ or the dose capable ofmore » inducing 10 SCE = 1.4 mM) and a dose-dependent inhibition of cellular proliferation (IC/sub 50/ or the 50% inhibition concentration = 2.6 mM). The relative proportion of first generation metaphase cells, an assessment of proliferative inhibiton, increased linearly with increasing caffeine concentrations. However, SCE frequency increased nonlinearly over the same range of caffeine concentrations. Examination of the ratio of nonsymmetrical to symmetrical SCEs in third generation metaphase cells indicated that caffeine induced SCEs in equal frequency in each of three successive generations. The dependency of SCE induction and cellular proliferative inhibition on caffeine's presence during the DNA synthetic period suggests that caffeine may act as an antimetabolite in normal human cells.« less

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

USDA-ARS?s Scientific Manuscript database

ABSTRACT Background: Enhanced n-3 intake benefit CVD risk reduction. Increasing consumption at a population level will be better addressed by dietary modification than through supplementation. However, limited data are available on the effect of increasing doses of fish intake on circulating level...

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.

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 and dose rate effects of whole-body proton-irradiation on lymphocyte blastogenesis and hematological variables: part II

NASA Technical Reports Server (NTRS)

Pecaut, Michael J.; Gridley, Daila S.; Smith, Anna L.; Nelson, Gregory A.

2002-01-01

The goal of part II of this study was to evaluate functional characteristics of leukocytes and circulating blood cell parameters after whole-body proton irradiation at varying doses and at low- and high-dose-rates (LDR and HDR, respectively). C57BL/6 mice (n=51) were irradiated and euthanized at 4 days post-exposure for assay. Significant radiation dose- (but not dose-rate-) dependent decreases were observed in splenocyte responses to T and B cell mitogens when compared to sham-irradiated controls (P<0.001). Spontaneous blastogenesis, also significantly dose-dependent, was increased in both blood and spleen (P<0.001). Red blood cell counts, hemoglobin concentration, and hematocrit were decreased in a dose-dependent manner (P<0.05), whereas thrombocyte numbers were only slightly affected. Comparison of proton- and gamma-irradiated groups (both receiving 3 Gy at HDR) showed a higher level of spontaneous blastogenesis in blood leukocytes and a lower splenocyte response to concanavalin A following proton irradiation (P<0.05). There were no dose rate effects. Collectively, the data demonstrate that the measurements in blood and spleen were largely dependent upon the total dose of proton radiation and that an 80-fold difference in the dose rate was not a significant factor. A difference, however, was found between protons and gamma-rays in the degree of change induced in some of the measurements.

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.

Inhibition of gamma-radiation induced DNA damage in plasmid pBR322 by TMG, a water-soluble derivative of vitamin E.

PubMed

Rajagopalan, Rema; Wani, Khalida; Huilgol, Nagaraj G; Kagiya, Tsutomu V; Nair, Cherupally K Krishnan

2002-06-01

Alpha-tocopherol monoglucoside (TMG), a water-soluble derivative of alpha-tocopherol, has been examined for its ability to protect DNA against radiation-induced strand breaks. Gamma radiation, up to a dose of 6 Gy (dose rate, 0.7 Gy/minute), induced a dose-dependent increase in single strand breaks (SSBs) in plasmid pBR322 DNA. TMG inhibited the formation of gamma-radiation induced DNA single strand breaks (SSBs) in a concentration-dependent manner; 500 microM of TMG protected the single strand breaks completely. It also protected thymine glycol formation induced by gamma-radiation in a dose-dependent manner, based on an estimation of thymine glycol by HPLC.

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

Time-dependent dissociation of cocaine dose–response effects on sucrose craving and locomotion

PubMed Central

Grimm, Jeffrey W.; Buse, Carl; Manaois, Meghan; Osincup, Dan; Fyall, Amber; Wells, Barbara

2010-01-01

In the present study, rats self-administered sucrose 6 h/day for 10 days. Separate groups of rats were then tested on day 1 or day 30 of forced abstinence. After they had responded to near extinction, rats were injected with either saline or cocaine (2.5, 5, 10, or 20 mg/kg intraperitoneal) and then allowed to respond to a sucrose-paired stimulus. Locomotor activity was assessed during testing. Rats pressed more during the extinction responding phase of testing on day 30 than on day 1 of forced abstinence, and this incubation of craving was accompanied by a time-dependent increase in locomotor activity. Compared with saline, cocaine increased responding for the sucrose-paired cue on day 1 of forced abstinence at the 5 mg/kg dose only. In contrast, responding on day 30 was increased at the 10 and 20 mg/kg doses. Locomotor activity increased dose-dependently at both forced-abstinence time points, suggesting a dissociation between cocaine-induced locomotion and cocaine-elevated responding for a sucrose-paired stimulus. These results also indicate that there are time-dependent changes in how cocaine affects sucrose craving. PMID:16495722

Genotoxicity of nanomaterials: DNA damage and micronuclei induced by carbon nanotubes and graphite nanofibres in human bronchial epithelial cells in vitro.

PubMed

Lindberg, Hanna K; Falck, Ghita C-M; Suhonen, Satu; Vippola, Minnamari; Vanhala, Esa; Catalán, Julia; Savolainen, Kai; Norppa, Hannu

2009-05-08

Despite the increasing industrial use of different nanomaterials, data on their genotoxicity are scant. In the present study, we examined the potential genotoxic effects of carbon nanotubes (CNTs; >50% single-walled, approximately 40% other CNTs; 1.1 nm x 0.5-100 microm; Sigma-Aldrich) and graphite nanofibres (GNFs; 95%; outer diameter 80-200 nm, inner diameter 30-50 nm, length 5-20 microm; Sigma-Aldrich) in vitro. Genotoxicity was assessed by the single cell gel electrophoresis (comet) assay and the micronucleus assay (cytokinesis-block method) in human bronchial epithelial BEAS 2B cells cultured for 24h, 48h, or 72h with various doses (1-100 microg/cm(2), corresponding to 3.8-380 microg/ml) of the carbon nanomaterials. In the comet assay, CNTs induced a dose-dependent increase in DNA damage at all treatment times, with a statistically significant effect starting at the lowest dose tested. GNFs increased DNA damage at all doses in the 24-h treatment, at two doses (40 and 100 microg/cm(2)) in the 48-h treatment (dose-dependent effect) and at four doses (lowest 10 microg/cm(2)) in the 72-h treatment. In the micronucleus assay, no increase in micronucleated cells was observed with either of the nanomaterials after the 24-h treatment or with CNTs after the 72-h treatment. The 48-h treatment caused a significant increase in micronucleated cells at three doses (lowest 10 microg/cm(2)) of CNTs and at two doses (5 and 10 microg/cm(2)) of GNFs. The 72-h treatment with GNFs increased micronucleated cells at four doses (lowest 10 microg/cm(2)). No dose-dependent effects were seen in the micronucleus assay. The presence of carbon nanomaterial on the microscopic slides disturbed the micronucleus analysis and made it impossible at levels higher than 20 microg/cm(2) of GNFs in the 24-h and 48-h treatments. In conclusion, our results suggest that both CNTs and GNFs are genotoxic in human bronchial epithelial BEAS 2B cells in vitro. This activity may be due to the fibrous nature of these carbon nanomaterials with a possible contribution by catalyst metals present in the materials-Co and Mo in CNTs (<5wt.%) and Fe (<3wt.%) in GNFs.

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.

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.

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.

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.

Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

NASA Technical Reports Server (NTRS)

Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Maennistoe, P. T.

1991-01-01

Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 microg/kg or about 2 percent of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5 percent and 1.5 percent, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33 percent and 16 percent, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine, and 3,4-dihydroxyphenvlacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However, dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceedimg 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

Effects of systemic carbidopa on dopamine synthesis in rat hypothalamus and striatum

NASA Technical Reports Server (NTRS)

Kaakkola, S.; Tuomainen, P.; Wurtman, R. J.; Mannisto, P. T.

1992-01-01

Significant concentrations of carbidopa (CD) were found in rat hypothalamus, striatum, and in striatal microdialysis efflux after intraperitoneal administration of the drug. Efflux levels peaked one hour after administration of 100 mg/kg at 0.37 micrograms/ml, or about 2% of serum levels. Concurrent CD levels in hypothalamus and striatum were about 2.5% and 1.5%, respectively, of corresponding serum levels. Levels of dopamine and its principal metabolites in striatal efflux were unaffected. The removal of the brain blood by saline perfusion decreased the striatal and hypothalamic CD concentrations only by 33% and 16%, respectively. In other rats receiving both CD and levodopa (LD), brain L-dopa, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels after one hour tended to be proportionate to LD dose. When the LD dose remained constant, increasing the CD dose dose-dependently enhanced L-dopa levels in the hypothalamus and striatum. However dopamine levels did not increase but, in contrast, decreased dose-dependently (although significantly only in the hypothalamus). CD also caused dose-dependent decrease in striatal 3-O-methyldopa (3-OMD) and in striatal and hypothalamic homovanillic acid (HVA), when the LD dose was 50 mg/kg. We conclude that, at doses exceeding 50 mg/kg, sufficient quantities of CD enter the brain to inhibit dopamine formation, especially in the hypothalamus. Moreover, high doses of LD/CD, both of which are themselves catechols, can inhibit the O-methylation of brain catecholamines formed from the LD.

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)

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.

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.

Extracting the normal lung dose-response curve from clinical DVH data: a possible role for low dose hyper-radiosensitivity, increased radioresistance

NASA Astrophysics Data System (ADS)

Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.

2015-09-01

In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence. Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP. Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (<20 Gy), a flat contribution from doses in the range ~20-40 Gy, then a further enhanced contribution from doses above 40 Gy. These features resemble the hyper-radiosensitivity / increased radioresistance (HRS/IRR) observed in some cell survival curves, which can be modeled using Joiner’s induced repair model. A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.

Thermoluminescent dosimetry in electron beams: energy dependence.

PubMed

Robar, V; Zankowski, C; Olivares Pla, M; Podgorsak, E B

1996-05-01

The response of thermoluminescent dosimeters to electron irradiations depends on the radiation dose, mean electron energy at the position of the dosimeter in phantom, and the size of the dosimeter. In this paper the semi-empirical expression proposed by Holt et al. [Phys. Med. Biol. 20, 559-570 (1975)] is combined with the calculated electron dose fraction to determine the thermoluminescent dosimetry (TLD) response as a function of the mean electron energy and the dosimeter size. The electron and photon dose fractions, defined as the relative contributions of electrons and bremsstrahlung photons to the total dose for a clinical electron beam, are calculated with Monte Carlo techniques using EGS4. Agreement between the calculated and measured TLD response is very good. We show that the considerable reduction in TLD response per unit dose at low electron energies, i.e., at large depths in phantom, is offset by an ever-increasing relative contribution of bremsstrahlung photons to the total dose of clinical electron beams. This renders the TLD sufficiently reliable for dose measurements over the entire electron depth dose distribution despite the dependence of the TLD response on electron beam energy.

EVALUATION OF CHITOSAN COAGULATION AS A SUSTAINABLE METHOD FOR POINT OF USE DRINKINGWATER TREATMENT IN DEVELOPING COUNTRIES

EPA Science Inventory

Chitosan A was found to remove up to 3.4 log₁₀ E. coli, a reduction of 99.96%. The removal was dose dependent; up to a point, removal of E. coli increases with increasing dose. Removal of E. coli ranged from 0% removal by a dose of 1g/L to...

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.

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

EPA Science Inventory

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

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.

Oxycodone physical dependence and its oral self-administration in C57BL/6J mice.

PubMed

Enga, Rachel M; Jackson, Asti; Damaj, M Imad; Beardsley, Patrick M

2016-10-15

Abuse of prescription opioids, such as oxycodone, has markedly increased in recent decades. While oxycodone's antinociceptive effects have been detailed in several preclinical reports, surprisingly few preclinical reports have elaborated its abuse-related effects. This is particularly surprising given that oxycodone has been in clinical use since 1917. In a novel oral operant self-administration procedure, C57BL/6J mice were trained to self-administer water before introducing increasing concentrations of oxycodone (0.056-1.0mg/ml) under post-prandial conditions during daily, 3-h test sessions. As the concentration of oxycodone increased, the numbers of deliveries first increased, then decreased in an inverted U-shape fashion characteristic of the patterns of other drugs self-administered during limited access conditions. After post-prandial conditions were removed, self-administration at the highest concentration was maintained suggesting oral oxycodone served as a positive reinforcer. In other mice, using a novel regimen of physical dependence, mice were administered increasing doses of oxycodone (9.0-33.0mg/kg, s.c.) over 9 days, challenged with naloxone (0.1-10.0mg/kg, s.c.), and then observed for 30min. Naloxone dose-dependently increased the observed number of somatic signs of withdrawal, suggesting physical dependence of oxycodone was induced under this regimen. This is the first report demonstrating induction of oral operant self-administration of oxycodone and dose-dependent precipitations of oxycodone withdrawal in C57BL/6J mice. The use of oral operant self-administration as well as the novel physical dependence regimen provides useful approaches to further examine the abuse- and dependence-related effects of this highly abused prescription opioid. Copyright © 2016 Elsevier B.V. All rights reserved.

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

Exposure to low UVA doses increases KatA and KatB catalase activities, and confers cross-protection against subsequent oxidative injuries in Pseudomonas aeruginosa.

PubMed

Pezzoni, Magdalena; Tribelli, Paula M; Pizarro, Ramón A; López, Nancy I; Costa, Cristina S

2016-05-01

Solar UVA radiation is one of the main environmental stress factors for Pseudomonas aeruginosa. Exposure to high UVA doses produces lethal effects by the action of the reactive oxygen species (ROS) it generates. P. aeruginosa has several enzymes, including KatA and KatB catalases, which provide detoxification of ROS. We have previously demonstrated that KatA is essential in defending P. aeruginosa against high UVA doses. In order to analyse the mechanisms involved in the adaptation of this micro-organism to UVA, we investigated the effect of exposure to low UVA doses on KatA and KatB activities, and the physiological consequences. Exposure to UVA induced total catalase activity; assays with non-denaturing polyacrylamide gels showed that both KatA and KatB activities were increased by radiation. This regulation occurred at the transcriptional level and depended, at least partly, on the increase in H2O2 levels. We demonstrated that exposure to low UVA produced a protective effect against subsequent lethal doses of UVA, sodium hypochlorite and H2O2. Protection against lethal UVA depends on katA, whilst protection against sodium hypochlorite depends on katB, demonstrating that different mechanisms are involved in the defence against these oxidative agents, although both genes can be involved in the global cellular response. Conversely, protection against lethal doses of H2O2 could depend on induction of both genes and/or (an)other defensive factor(s). A better understanding of the adaptive response of P. aeruginosa to UVA is relevant from an ecological standpoint and for improving disinfection strategies that employ UVA or solar irradiation.

Pb2+ Modulates Ca2+ Membrane Permeability In Paramecium

NASA Astrophysics Data System (ADS)

Bernal-Martínez, Juan; Ortega Soto, Arturo

2004-09-01

Intracellular recording experiments in current clamp configuration were done to evaluate whether Pb2+ modulates ionic membrane permeability in the fresh water Paramecium tetraurelia. It was found that Pb2+ triggers in a dose-dependent manner, a burst of spontaneous action potentials followed by a robust and sustained after hyper-polarization. In addition, Pb2+ increased the frequency of firing the spontaneous Ca2+-Action Potential and also, the duration of Ca2+-Action Potential, in a dose and reversibly-dependent manner. These results suggest that Pb2+ increases calcium membrane permeability of Paramecium and probably activates a calcium-dependent-potassium conductance in the ciliate.

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

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

Concentration rather than dose defines the local brain toxicity of agents that are effectively distributed by convection-enhanced delivery.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Kanamori, Masayuki; Sonoda, Yukihiko; Kumabe, Toshihiro; Tominaga, Teiji

2014-01-30

Convection-enhanced delivery (CED) has been developed as a potentially effective drug-delivery strategy into the central nervous system. In contrast to systemic intravenous administration, local delivery achieves high concentration and prolonged retention in the local tissue, with increased chance of local toxicity, especially with toxic agents such as chemotherapeutic agents. Therefore, the factors that affect local toxicity should be extensively studied. With the assumption that concentration-oriented evaluation of toxicity is important for local CED, we evaluated the appearance of local toxicity among different agents after delivery with CED and studied if it is dose dependent or concentration dependent. Local toxicity profile of chemotherapeutic agents delivered via CED indicates BCNU was dose-dependent, whereas that of ACNU was concentration-dependent. On the other hand, local toxicity for doxorubicin, which is not distributed effectively by CED, was dose-dependent. Local toxicity for PLD, which is extensively distributed by CED, was concentration-dependent. Traditional evaluation of drug induced toxicity was dose-oriented. This is true for systemic intravascular delivery. However, with local CED, toxicity of several drugs exacerbated in concentration-dependent manner. From our study, local toxicity of drugs that are likely to distribute effectively tended to be concentration-dependent. Concentration rather than dose may be more important for the toxicity of agents that are effectively distributed by CED. Concentration-oriented evaluation of toxicity is more important for CED. Copyright © 2013 Elsevier B.V. All rights reserved.

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.

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

Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats.

PubMed

Kotronoulas, Aristotelis; Pizarro, Nieves; Serra, Aida; Robledo, Patricia; Joglar, Jesús; Rubió, Laura; Hernaéz, Alvaro; Tormos, Carmen; Motilva, Ma José; Fitó, Montserrat; Covas, Maria-Isabel; Solà, Rosa; Farré, Magí; Saez, Guillermo; de la Torre, Rafael

2013-11-01

Hydroxytyrosol (HT), one of the major polyphenols present in olive oil, is known to possess a high antioxidant capacity. The aim of the present study was to investigate dose dependent (0, 1, 10 and 100 mg/kg) alterations in the metabolism of HT in rats since it has been reported that metabolites may contribute to biological effects. Special attention was paid to the activation of the semiquinone-quinone oxidative cycle and the formation of adducts with potential deleterious effects. Thus, we developed a novel analytical methodology to monitor the in vivo formation of the HT mercapturate, N-acetyl-5-S-cysteinyl-hydroxytyrosol in urine samples. Biomarkers of hepatic and renal toxicity were evaluated within the dose range tested. Following HT administration, dose-dependent effects were observed for the recovery of all the metabolites studied. At the lowest dose of 1 mg/kg, the glucuronidation pathway was the most relevant (25-30%), with lower recoveries for sulfation (14%), while at the highest dose of 100 mg/kg, sulfation was the most prevalent (75%). In addition, we report for the first time the formation of the mercapturate conjugate of HT in a dose-dependent manner. The biochemical data did not reveal significant toxic effects of HT at any of the doses studied. An increase in the GSH/GSSG ratio at the highest dose was observed indicating that the products of HT autoxidation are counteracted by glutathione, resulting in their detoxification. These results indicate that the metabolic disposition of HT is highly dependent on the dose ingested. Copyright © 2013. Published by Elsevier Ltd.

Immunostimulatory Activity of Opuntia ficus-indica var. Saboten Cladodes Fermented by Lactobacillus plantarum and Bacillus subtilis in RAW 264.7 Macrophages.

PubMed

Hwang, Joon-Ho; Lim, Sang-Bin

2017-02-01

To increase the functionality of Opuntia ficus-indica var. saboten cladodes, it was fermented by Lactobacillus plantarum and Bacillus subtilis. Eighty percent methanol extracts were investigated for their effects on nitric oxide (NO) production, cytokine secretion, nuclear factor-κB (NF-κB) activity, and mitogen-activated protein kinase (MAPK) phosphorylation in RAW 264.7 cells. Methanol extracts of L. plantarum culture medium (LPCME) and B. subtilis culture medium (BSCME) did not affect lipopolysaccharide (LPS)-induced NO production but, at 500 μg/mL, increased interferon (IFN)-γ-induced NO production by 55.2 and 66.5 μM, respectively, in RAW 264.7 cells. In RAW 264.7 cells not treated with LPS and IFN-γ, LPCME did not affect NO production, but BSCME increased NO production significantly in a dose-dependent manner. In addition, BSCME induced the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in RAW 264.7 cells in a dose-dependent manner. BSCME at 500 μg/mL increased TNF-α and IL-1β mRNA levels by 83.8% and 82.2%, respectively. BSCME increased NF-κB-dependent luciferase activity in a dose-dependent manner; 500 μg/mL BSCME increased activity 9.1-fold compared with the control. BSCME induced the phosphorylation of p38, c-JUN NH 2 -terminal protein kinase (JNK), and extracellular signal-regulated kinase (ERK) in a dose-dependent manner, but did not affect total ERK levels. In conclusion, BSCME exerted immunostimulatory effects, which were mediated by MAPK phosphorylation and NF-κB activation, resulting in increased TNF-α and IL-1β gene expression in RAW 264.7 macrophages. Therefore, BSCM shows promise for use as an immunostimulatory therapeutic.

Influence of serotonin and melatonin on some parameters of gastrointestinal activity.

PubMed

Bubenik, G A; Dhanvantari, S

1989-01-01

In vitro melatonin (M) reduced the tone of gut muscles and counteracted the tonic effect of serotonin (5-HT). In vivo 0.1 to 4 mg of 5-HT (contained in beeswax implants) decreased the food transit time (FTT) in a dose-dependent manner, but higher doses (5 and 6 mg) increased the FTT. Melatonin injected intraperitoneally into mice bearing 5-HT implants (2 mg per animal) blocked partly the serotonin effect and increased FTT by 50%; however, no dose-dependent effect was observed when doses between 0.01 and 1 mg were used. Surprisingly, M injected into intact mice decreased FTT to levels comparable to those observed in 5-HT implanted, M-treated mice. Again, this significant decrease was not dose-dependent between 0.02 and 1 mg. Although in vitro the maximal inhibition of serotonin-induced spasm was achieved when the M:5-HT ratio was 50-100:1, in vivo the effective ratio was about 1:1. This may indicate that part of M action on the gut movement is mediated by extraintestinal mechanisms. A hypothetical, counterbalancing system of M and 5-HT regulation of gut activity (similar to adrenaline-acetylcholine system) is proposed.

The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination[S

PubMed Central

Wang, Yuhuan; Liu, Xiaoxi; Pijut, Sonja S.; Li, Jianing; Horn, Jamie; Bradford, Emily M.; Leggas, Markos; Barrett, Terrence A.; Graf, Gregory A.

2015-01-01

Previous studies suggest an interdependent relationship between liver and intestine for cholesterol elimination from the body. We hypothesized that a combination of ursodiol (Urso) and ezetimibe (EZ) could increase biliary secretion and reduce cholesterol reabsorption, respectively, to promote cholesterol excretion. Treatment with Urso increased hepatic ABCG5 ABCG8 (G5G8) protein and both biliary and fecal sterols in a dose-dependent manner. To determine whether the drug combination (Urso-EZ) further increased cholesterol excretion, mice were treated with Urso alone or in combination with two doses of EZ. EZ produced an additive and dose-dependent increase in fecal neutral sterol (FNS) elimination in the presence of Urso. Finally, we sequentially treated wide-type and G5G8-deficient mice with Urso and Urso-EZ to determine the extent to which these effects were G5G8 dependent. Although biliary and FNS were invariably lower in G5G8 KO mice, the relative increase in FNS following treatment with Urso alone or the Urso-EZ combination was not affected by genotype. In conclusion, Urso increases G5G8, biliary cholesterol secretion, and FNS and acts additively with EZ to promote fecal sterol excretion. However, the stimulatory effect of these agents was not G5G8 dependent. PMID:25635125

Acute toxicity, biochemical and histopathological responses of endosulfan in Chanos chanos.

PubMed

Kumar, Neeraj; Ambasankar, K; Krishnani, K K; Gupta, S K; Bhushan, Shashi; Minhas, P S

2016-09-01

This study investigated 96h median lethal concentration of endosulfan (99%, pure α: β ratio of 7:3) by conducting static non-renewable acute toxicity bio-assay in Chanos chanos juvenile with average weight (110±5.65g). Further, the effect of different definitive doses (18.5, 19.5, 20.5, 21.5 and 22.5µg/L) of endosulfan on metabolic, heamato-immunoligcal and histopathological response were probed. Anti-oxidative enzymes CAT, SOD and GST showed significant (p<0.01) increase of activity in the liver, gill and brain during exposure to endosulfan in a dose and time dependent manner. The brain AChE activity showed significant (p<0.01) inhibition from 18.5 to 22.5µg/L exposure of endosulfan than the control group. LDH and MDH activity gradually increased with consequent increasing dose of endosulfan exposure in the liver, gill and brain. Similarly, ALT, AST and G6PDH activities in both liver and gill increased with consequent increases in the dose of endosulfan exposure. Immunological profile such as blood glucose and serum cortisol level significantly enhanced while respiratory burst activity declined with consequent increasing doses of endosulfan exposure. Histopathological alteration in the gill demonstrated curling of secondary lamellae, thickening of primary epithelium, shorting of secondary lamellae, epithelial hyperplasia, fusion of secondary lamellae, aneurism, and collapsed secondary lamellae due to dose dependent exposure of endosulfan. Liver histology illustrated cloudy swelling and necrosis with pyknotic nuclei to the moderate dose of endosulfan, whereas higher dose of endosulfan (21.5µg/L) displayed severe necrosis of hepatic cells. Overall results clearly indicate that acute exposure of endosulfan led to pronounced deleterious alterations on biochemical, heamato-immunological, and histopathological responses of C. chanos juvenile. Copyright © 2016 Elsevier Inc. All rights reserved.

Stimulatory effect of insulin on 5alpha-reductase type 1 (SRD5A1) expression through an Akt-dependent pathway in ovarian granulosa cells.

PubMed

Kayampilly, Pradeep P; Wanamaker, Brett L; Stewart, James A; Wagner, Carrie L; Menon, K M J

2010-10-01

Elevated levels of 5α-reduced androgens have been shown to be associated with hyperandrogenism and hyperinsulinemia, the leading causes of ovulatory dysfunction in women. 5α-Dihydrotestosterone reduces ovarian granulosa cell proliferation by inhibiting FSH-mediated mitogenic signaling pathways. The present study examined the effect of insulin on 5α-reductase, the enzyme that catalyses the conversion of androgens to their 5α-derivatives. Granulosa cells isolated from immature rat ovaries were cultured in serum-free, phenol red-free DMEM-F12 media and treated with different doses of insulin (0, 0.1, 1.0, and 10.0 μg/ml) for different time intervals up to 12 h. The expression of 5α-reductase type 1 mRNA, the predominant isoform found in granulosa cells, showed a significant (P<0.05) increase in response to the insulin treatment up to 12 h compared with control. The catalytic activity of 5α-reductase enzyme was also stimulated in a dose-depended manner (P<0.05). Inhibiting the Akt-dependent signaling pathway abolished the insulin-mediated increase in 5α-reductase mRNA expression, whereas inhibition of the ERK-dependent pathway had no effect. The dose-dependent increase in 5α-reductase mRNA expression as well as catalytic activity seen in response to insulin treatment was also demonstrated in the human granulosa cell line (KGN). In addition to increased mRNA expression, a dose-dependent increase in 5α-reductase protein expression in response to insulin was also seen in KGN cells, which corroborated well with that of mRNA expression. These results suggest that elevated levels of 5α-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5α-reductase in granulosa cells. The elevated levels of these metabolites, in turn, might adversely affect growth and proliferation of granulosa cells, thereby impairing follicle growth and ovulation.

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

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.

First-in-man-proof of concept study with molidustat: a novel selective oral HIF-prolyl hydroxylase inhibitor for the treatment of renal anaemia.

PubMed

Böttcher, M; Lentini, S; Arens, E R; Kaiser, A; van der Mey, D; Thuss, U; Kubitza, D; Wensing, G

2018-07-01

Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l -1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l -1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia. © 2018 The British Pharmacological Society.

Efficacy and Safety of the Glucagon Receptor Antagonist PF-06291874: A 12-Week, Randomized, Dose-Response Study in Patients With Type 2 Diabetes Mellitus on Background Metformin Therapy.

PubMed

Kazierad, David J; Chidsey, Kristin; Somayaji, Veena R; Bergman, Arthur J; Calle, Roberto A

2018-06-19

To conduct a dose-response assessment of the efficacy and safety of the glucagon receptor antagonist PF-06291874 in adults with type 2 diabetes (T2DM) receiving stable doses of metformin. This randomized, double-blind, statin-stratified, placebo-controlled, 4-arm, parallel-group study was conducted in patients with T2DM receiving background metformin. After an 8-week, non-metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF-06291874 (30, 60, or 100 mg once daily) for 12 weeks. Glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and safety endpoints were assessed at baseline and postbaseline. Dose-dependent mean reductions from baseline in HbA1c for PF-06291874 ranged from -0.67% (-7.29 mmol/mol) to -0.93% (-10.13 mmol/mol); and in FPG from -16.6 to -33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycemia was low and similar between groups receiving PF-06291874. Small, non-dose-dependent increases in LDL cholesterol (<10%) and blood pressure (BP; systolic BP>2 mmHg, diastolic BP>1 mmHg) were observed with PF-06291874. Modest non-dose-dependent median increases were observed across PF-06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6-48.7 U/L versus placebo) and aspartate aminotransferase (range, 33.3-36.6 U/L versus placebo) that were not associated with bilirubin changes. Small increases were observed for body weight (<0.5 kg) in each PF-06291874 group versus placebo. In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated, and had low risk of hypoglycemia. Small, non-dose-related increases in BP, lipids, and hepatic transaminases were observed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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.

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

EPA Science Inventory

Previous work has shown that a single oral administration of atrazine (ATR), a chlorotriazine herbicide, induces dose-dependent increases in plasma adrenocorticotropic hormone (ACTH) and serum corticosterone (CORT), with a NOEL equal to 5mg/kg. The mechanism for these effects ...

SU-E-T-159: Characteristics of Fiber-Optic Radiation Sensor for Proton Therapeutic Beam

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

Son, J; Kim, M; Hwang, U

Purpose: A fiber-optic radiation sensor using Cerenkov radiation has been widely studied for use as a dosimeter for proton therapeutic beam. Although the fiber-optic radiation sensor has already been investigated for proton therapeutic, it has been examined relatively little work for clinical therapeutic proton beams. In this study, we evaluated characteristics of a fiber-optic radiation sensor for clinical therapeutic proton beams. We experimentally evaluated dose-rate dependence, dose response and energy dependence for the proton beam. Methods: A fiber-optic radiation sensor was placed in a water phantom. Beams with energies of low, middle and high were used in the passively-scattered protonmore » therapeutic beam at the National Cancer Center in Korea. The sensor consists of two plastic optical fibers (POF). A reference POF and 2 cm longer POF were used to utilize the subtraction method for having sensitive volume. Each POF is optically coupled to the Multi-Anode Photo Multiplier Tube (MAPMT) and the MAPMT signals are processed using National Instruments Data Acquisition System (NI-DAQ). We were investigated dosimetric properties including dose-rate dependence, dose response and energy dependence. Results: We have successfully evaluated characteristics of a fiber optic radiation sensor using Cerenkov radiation. The fiber-optic radiation sensor showed the dose response linearity and low energy dependence. In addition, as the dose-rate was increased, Cerenkov radiation increased linearly. Conclusion: We evaluated the basic characteristics of the fiber optic radiation sensor, the dosimetry tool, to raise the quality of proton therapy. Based on the research, we developed a real time dosimetry system of the optic fiber to confirm the real time beam position and energy for therapeutic proton pencil beam.« less

Dosimetric Accuracy of a Dual Photon Energy Linac at Low Monitor Setting for Various Pulse Repetition Frequencies

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

Sharma, Anil Kumar; Supe, Sanjay S.; Anantha, N.

2015-01-15

Accuracy of dose delivery at low monitor unit setting is studied for a dual photon energy linear accelerator. Dose delivered per MU is found to be constant for both the photon beams for MU settings above 30. For lower MUs there is definite deviation from the calibrated value and the error is found to be increasing as fewer MUs are set for dose delivery. This dose/MU ratio at low MU setting is found to be dose-rate dependent, showing an increasing trend with pulse repetition frequency (PRF). Also, the dosimetric ratio is observed to be mode dependent; its value for anmore » 18 MV beam is almost double that observed in the case of a 6 MV beam at very low MU setting. The magnitude of this error should be determined for each energy so that appropriate corrections can be applied if very low MUs are to be used.« less

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

Effects of medetomidine on serum glucose in cattle calves.

PubMed

Tariq, Muhammad; Kalhoro, Amir Bukhsh; Sarwar, Mian Saeed; Khan, Hamayun; Ahmad, Shakoor; Hassan, Sayed Mubashir; Zahoor, Arshad

2016-05-01

An experimental study was carried out to compare physiological effects (serum glucose level) of medetomidine in Red Sindhi cattle calves at three different doses i.e. 8, 10 and 12µg/kg body weight intravenously. Medetomidine produced a dose dependent significant (P<0.01) increase in serum glucose level with a maximum increase observed at 30 minutes with 8µg/kg, 10μg/kg and 12μg/kg body weight respectively. Start of sedation, degree of sedation and total duration of sedation were all dose dependent and the values obtained were significantly (P<0.01) different from each other. It was observed that the sedation was rapid, deep and longer with the higher doses of medetomidine i.e. 12μg/kg. The results of the present study shows that medetomidine is a very effective and safest drug use as sedative for calves which in lower doses (8μg/kg) can be used as a pre-anesthetic and for restraining of the animal, while higher calculated doses (10μg/kg, 12μg/kg) can be used to execute the minor surgical procedures.

Caffeine as a model drug of dependence: recent developments in understanding caffeine withdrawal, the caffeine dependence syndrome, and caffeine negative reinforcement.

PubMed

Griffiths, R R; Chausmer, A L

2000-11-01

Caffeine is an excellent model compound for understanding drugs of abuse/dependence. The results of self-administration and choice studies in humans clearly demonstrate the reinforcing effects of low and moderate doses of caffeine. Caffeine reinforcement has been demonstrated in about 45% of normal subjects with histories of moderate and heavy caffeine use. Recent studies provide compelling evidence that caffeine physical dependence potentiates the reinforcing effects of caffeine through the mechanism of withdrawal symptom avoidance. Tolerance to the subjective and sleep-disrupting effects of caffeine in humans has been demonstrated. Physical dependence as reflected in a withdrawal syndrome in humans has been repeatedly demonstrated in adults and recently demonstrated in children. Withdrawal severity is an increasing function of caffeine maintenance dose, with withdrawal occurring at doses as low as 100 mg per day. Increased cerebral blood flow may be the physiological mechanism for caffeine withdrawal headache. Case studies in adults and adolescents clearly demonstrate that some individuals meet DSM-IV diagnostic criteria for a substance dependence syndrome on caffeine, including feeling compelled to continue caffeine use despite desires and recommendations to the contrary. Survey data suggest that 9% to 30% percent of caffeine consumers may be caffeine dependent according to DSM-IV criteria.

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.

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.

Dose-dependent effects of isoflurane and dobutamine on cardiovascular function in dogs with experimental mitral regurgitation.

PubMed

Goya, Seijirow; Wada, Tomoki; Shimada, Kazumi; Hirao, Daiki; Tanaka, Ryou

2018-04-18

To investigate the dose-dependent effects of isoflurane and dobutamine on haemodynamics in dogs with experimentally induced mitral valve insufficiency (MI). Experimental, dose-response study. Six healthy Beagle dogs. Dogs with surgically induced MI were anaesthetized once. First, anaesthesia was maintained at an end-tidal isoflurane concentration (Fe'Iso) 1.0% (ISO1.0) for 20 minutes. Then, dobutamine was infused successively at 2, 4, 8 and 12 μg kg -1 minute -1 (DOB2-12) for 10 minutes at each dose rate. Measurements were recorded at each stage. Dobutamine was discontinued and Fe'Iso was increased to 1.5% (ISO1.5) for 20 minutes. Dobutamine was administered similarly to ISO1.0, and cardiovascular variables were recorded. The same sequence was repeated for Fe'Iso 2.0% (ISO2.0). Aortic pressure (AoP) and left atrial pressure (LAP) were recorded by radiotelemetry. The combination method of the pressure-volume loop analysis and transoesophageal echocardiography was used to measure cardiovascular variables: end-systolic elastance (Ees), effective arterial elastance (Ea), Ea/Ees, forward stroke volume (FSV), heart rate (HR), and cardiac output (CO). High isoflurane concentration resulted in reduced Ees and increased Ea/Ees, which indicated low arterial pressure. High-dose dobutamine administration resulted in increased Ees and FSV at all isoflurane concentrations. In ISO1.5 and ISO2.0, HR was lower at DOB4 than baseline (BL) but increased at DOB12 compared with DOB4. CO increased at ≥ DOB8 compared with BL. In ISO1.5 and ISO2.0, systolic and mean AoP increased at ≥ DOB4 and ≥ DOB8, respectively. LAP did not change under all conditions. The dose-dependent hypotensive effect of isoflurane in MI dogs was mainly derived from the decrease in contractility. Dobutamine increased AoP without increasing LAP by increasing the contractility attenuated by isoflurane. Our findings may improve the cardiovascular management of dogs with MI undergoing general anaesthesia with isoflurane. Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Intracellular Networks of the PI3K/AKT and MAPK Pathways for Regulating Toxoplasma gondii-Induced IL-23 and IL-12 Production in Human THP-1 Cells

PubMed Central

Choi, In-Wook; Ismail, Hassan Ahmed Hassan Ahmed; Zhou, Wei; Cha, Guang-Ho; Zhou, Yu; Yuk, Jae-Min; Jo, Eun-Kyeong; Lee, Young-Ha

2015-01-01

Interleukin (IL)-23 and IL-12 are closely related in structure, and these cytokines regulate both innate and adaptive immunity. However, the precise signaling networks that regulate the production of each in Toxoplasma gondii-infected THP-1 monocytic cells, particularly the PI3K/AKT and MAPK signaling pathways, remain unknown. In the present study, T. gondii infection upregulated the expression of IL-23 and IL-12 in THP-1 cells, and both cytokines increased with parasite dose. IL-23 secretion was strongly inhibited by TLR2 monoclonal antibody (mAb) treatment in a dose-dependent manner and by TLR2 siRNA transfection, whereas IL-12 secretion was strongly inhibited by TLR4 mAb treatment dose-dependently and by TLR4 siRNA transfection. IL-23 production was dose-dependently inhibited by the PI3K inhibitors LY294002 and wortmannin, whereas IL-12 production increased dose-dependently. THP-1 cells exposed to live T. gondii tachyzoites underwent rapid p38 MAPK, ERK1/2 and JNK activation. IL-23 production was significantly upregulated by the p38 MAPK inhibitor SB203580 dose-dependently, whereas pretreatment with 10 μM SB203580 significantly downregulated IL-12 production. ERK1/2 inhibition by PD98059 was significantly downregulated IL-23 production but upregulated IL-12 production. JNK inhibition by SP600125 upregulated IL-23 production, but IL-12 production was significantly downregulated dose-dependently. T. gondii infection resulted in AKT activation, and AKT phosphorylation was inhibited dose-dependently after pretreatment with PI3K inhibitors. In T. gondii-infected THP-1 cells, ERK1/2 activation was regulated by PI3K; however, the phosphorylation of p38 MAPK and JNK was negatively modulated by the PI3K signaling pathway. Collectively, these results indicate that IL-23 production in T. gondii-infected THP-1 cells was regulated mainly by TLR2 and then by PI3K and ERK1/2; however, IL-12 production was mainly regulated by TLR4 and then by p38 MAPK and JNK. Our findings provide new insight concerning the intracellular networks of the PI3K/AKT and MAPK signaling cascades for regulating T. gondii-induced IL-23 and IL-12 secretion in human monocytic cells. PMID:26528819

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.

Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

PubMed Central

Cheng, Jia; Xiong, Zhe; Duffney, Lara J.; Wei, Jing; Liu, Aiyi; Liu, Sihang; Chen, Guo-Jun; Yan, Zhen

2014-01-01

Background Methylphenidate (MPH), a psychostimulant drug for the treatment of attention-deficit hyperactivity disorder (ADHD), produces the effects of increasing alertness and improving attention, while its misuse has been associated with an increased risk of aggression and psychosis. In this study, we sought to determine the molecular mechanism underlying the complex actions of MPH. Methods Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex (PFC) was measured. MPH-induced behavioral changes were also examined in parallel. Results We found that administration of low-dose (0.5 mg/kg) MPH selectively potentiated NMDAR-mediated excitatory synaptic currents (EPSCs) via adrenergic receptor activation, while the high-dose (10 mg/kg) MPH suppressed both NMDAR- and AMPAR-EPSCs. The dual effects of MPH on EPSCs were associated with bi-directional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated the PFC-mediated temporal order recognition memory (TORM) and attention, while animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of SNAP-25, a key SNARE proteins involved in NMDAR exocytosis, blocked the increase of NMDAR-EPSC by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and TORM via a mechanism dependent on SNAP-25. Conclusions Our results have provided a potential mechanism underlying the cognitive enhancing effects of low-dose MPH, as well as the psychosis-inducing effects of high-dose MPH. PMID:24832867

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.

Endothelial function across an oral contraceptive cycle in women using levonorgestrel and ethinyl estradiol.

PubMed

Torgrimson, Britta N; Meendering, Jessica R; Kaplan, Paul F; Minson, Christopher T

2007-06-01

Oral contraceptive pills (OCPs) are a popular contraception method. Currently, lower-dose ethinyl estradiol formulations are most commonly prescribed, although they have been linked to increased arterial vascular risk. The aim of this study was to investigate endothelial function in healthy young women using lower-dose ethinyl estradiol OCPs. We examined flow-mediated, endothelium-dependent and nitroglycerin-mediated, endothelium-independent vasodilation of the brachial artery, comparing two doses of ethinyl estradiol/levonorgestrel OCPs in 15 healthy young women on two study days: once during the active phase and once during the placebo phase of an OCP cycle. Group low dose (LD) (n=7) active pills contained 150 microg levonorgestrel/30 microg ethinyl estradiol versus Group very low dose (VLD) (n=8) with 100 microg levonorgestrel/20 microg ethinyl estradiol. Endothelium-dependent vasodilation was lower during the active phase in Group VLD (5.33 +/- 1.77% vs. 7.23 +/- 2.60%; P=0.024). This phase difference was not observed in Group LD (8.00 +/- 0.970% vs. 7.61 +/- 1.07%; P=0.647). Endothelium-independent vasodilation did not differ between phases in either group. Finally, we measured endothelium-dependent vasodilation in two additional women who received 10 microg of unopposed ethinyl estradiol. Endothelium-dependent vasodilation was increased by unopposed ethinyl estradiol compared with the placebo phase (10.88 +/- 2.34% vs. 6.97 +/- 1.83%). These results suggest that levonorgestrel may antagonize the activity of ethinyl estradiol. Thus both the progestin type and estradiol dose need to be considered when assessing arterial vascular risk of OCP use in women.

Caffeine and Migraine

MedlinePlus

... per week, for whatever reason, may lead to dependency and increased migraine frequency. For those who have ... given dose becomes less effective with repeated use. Dependency develops when the brain expects that an additional ...

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.

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.

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

EPA Science Inventory

Previous work has shown that a single oral administration of atrazine (ATR), a chlorotriazine herbicide, induces dose-dependent increases in plasma adrenocorticotropic hormone (ACTH) and serum corticosterone (CORT), with a LOEL of 12.5mg/kg. The mechanism for these effects is unk...

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.

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

Volotskova, O; Xu, A; Jozsef, G

Purpose: To investigate the response and dose rate dependence of a scintillation detector over a wide energy range. Methods: The energy dependence of W1 scintillation detector was tested with: 1) 50–225 keV beams generated by an animal irradiator, 2) a Leksell Gamma Knife Perfexion Co-60 source, 3) 6MV, 6FFF, 10FFF and 15MV photon beams, and 4) 6–20MeV electron beams from a linac. Calibrated linac beams were used to deliver 100 cGy to the detector at dmax in water under reference conditions. The gamma-knife measurement was performed in solid water (100 cGy with 16mm collimator). The low energy beams were calibratedmore » with an ion chamber in air (TG-61), and the scintillation detector was placed at the same location as the ionization chamber during calibration. For the linac photon and electron beams, dose rate dependence was tested for 100–2400 and 100–800 MU/min. Results: The scintillation detector demonstrated strong energy dependence in the range of 50–225keV. The measured values were lower than the delivered dose and increased as the energy increased. Therapeutic photon beams showed energy independence with variations less than 1%. Therapeutic electron beams displayed the same sensitivity of ∼2–3% at their corresponding dmax depths. The change in dose-rate of photon and electron beams within the therapeutic energy range did not affect detector output (<0.5%). Measurements acquired with the gamma knife showed that the output data agreed with the delivered dose up to 3%. Conclusion: W1 scintillation detector output has a strong energy dependence in the diagnostic and orthovoltage energy range. Therapeutic photon beams exhibited energy independence with no observable dose-rate dependence. This study may aid in the implementation of a scintillation detector in QA programs by providing energy calibration factors.« less

Anticonvulsant serotonergic and deep brain stimulation in anterior thalamus.

PubMed

Mirski, Marek A; Ziai, Wendy C; Chiang, Jason; Hinich, Melvin; Sherman, David

2009-01-01

Anterior thalamus (AN) has been shown to mediate seizures in both focal and generalized models. Specific regional increase in AN serotonergic activity was observed following AN-DBS in our pentylenetetrazol (PTZ) rodent model of acute seizures, and this increase may inhibit seizures and contribute to the mechanism of anticonvulsant DBS. Anesthetized rats with AN-directed dialysis cannula with scalp/depth EEG were infused with PTZ at 5.5mg/(kg min) until an EEG seizure occurred. Eight experimental groups of AN-dialysis infusion were evaluated: controls (dialysate-only), 10 and 100 microM serotonin 5-HT(7) agonist 5-carboxamidotryptamine (5-CT), 1, 10 and 100 microM serotonin antagonist methysergide (METH), AN-DBS, and 100 microM METH+AN-DBS. Latency for seizures in control animals was 3,120+/-770 s (S.D.); AN-DBS delayed onset to 5018+/-1100 (p<0.01). AN-directed 5-CT increased latency in dose-dependent fashion: 3890+/-430 and 4247+/-528 (p<0.05). Methysergide had an unexpected protective effect at low-dose (3908+/-550, p<0.05) but not at 100 microM (2687+/-1079). The anticonvulsant action of AN-DBS was blocked by prior dialysis using 100 microM METH. Surface EEG burst count and nonlinear analysis (H-Statistic) noted significant (p<0.05) increased pre-ictal epileptiform bursts in 5-CT, methysergide, but not DBS group compared to control. Increased serotonergic activity in AN raised PTZ seizure threshold, similar to DBS, but without preventing cortical bursting. 5-Carboxamidotryptamine, a 5-HT(7) agonist, demonstrated dose-dependent seizure inhibition. Methysergide proved to have an inverse, dose-dependent agonist property, antagonizing the action of AN-DBS at the highest dose. Anticonvulsant AN-DBS may in part act to selectively alter serotonin neurotransmission to raise seizure threshold.

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs.

PubMed

Perkins, Michael W; Pierre, Zdenka; Rezk, Peter; Sabnekar, Praveena; Kabra, Kareem; Chanda, Soma; Oguntayo, Samuel; Sciuto, Alfred M; Doctor, Bhupendra P; Nambiar, Madhusoodana P

2010-06-01

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m(3) concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m(3) soman survived, while animals exposed to 841, and 1121 mg/m(3) resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt(50) for soman determined by probit analysis was 827.2mg/m(3). A majority of the animals that died at 1121 mg/m(3) developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs. (c) 2010 Elsevier Inc. All rights reserved.

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

Perkins, Michael W.; Pierre, Zdenka; Rezk, Peter

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m{sup 3} concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m{sup 3} soman survived, while animals exposed to 841, and 1121 mg/m{sup 3} resulted in 38% and 13% survival,more » respectively. The microinstillation inhalation exposure LCt{sub 50} for soman determined by probit analysis was 827.2 mg/m{sup 3}. A majority of the animals that died at 1121 mg/m{sup 3} developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.« less

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

Dose and time-dependent effects of cyanide on thiosulfate sulfurtransferase, 3-mercaptopyruvate sulfurtransferase, and cystathionine λ-lyase activities.

PubMed

Singh, Poonam; Rao, Pooja; Bhattacharya, Rahul

2013-12-01

We assessed the dose-dependent effect of potassium cyanide (KCN) on thiosulfate sulfurtransferase (TST), 3-mercaptopyruvate sulfurtransferase (3-MPST), and cystathionine λ-lyase (CST) activities in mice. The time-dependent effect of 0.5 LD50 KCN on cyanide level and cytochrome c oxidase (CCO), TST, 3-MPST, and CST activities was also examined. Furthermore, TST, 3-MPST, and CST activities were measured in stored mice cadavers. Hepatic and renal TST activity increased by 0.5 LD50 KCN but diminished by ≥2.0 LD50. After 0.5 LD50 KCN, the elevated hepatic cyanide level was accompanied by increased TST, 3-MPST, and CST activities, and CCO inhibition. Elevated renal cyanide level was only accompanied by increased 3-MPST activity. No appreciable change in enzyme activities was observed in mice cadavers. The study concludes that high doses of cyanide exert saturating effects on its detoxification enzymes, indicating their exogenous use during cyanide poisoning. Also, these enzymes are not reliable markers of cyanide poisoning in autopsied samples. © 2013 Wiley Periodicals, Inc.

Peptidase inhibitors reduce opiate narcotic withdrawal signs, including seizure activity, in the rat.

PubMed

Pinsky, C; Dua, A K; LaBella, F S

1982-07-15

Narcotic withdrawal was precipitated by administration of naloxone in a low dose at 2 h after the final dose of morphine in a 9-day dependency-inducing schedule. Withdrawal was characterized by leaps, increased nocifensor activity and by cerebral cortical epileptiform activity, the latter not generally reported to be prominent in narcotic withdrawal. Single large doses of morphine did not provoke epileptiform activity at 2 h postinjection but did induce an acute opioid dependency wherein a moderately high dose of naloxone, ineffective in non-dependent rats, provoked upward leaping and electrocortical epileptiform activity. Pretreatment of the 9-day dependent rats with peptidase inhibitors, administered intracerebroventricularly, significantly reduced withdrawal severity including the epileptiform activity. We propose that peptidase inhibitors protect certain species of endogenous opioids and/or other neuropeptides that tend to suppress expression of the narcotic withdrawal syndrome. Furthermore, our findings suggest that epileptiform activity is a nascent form of cerebral activity hitherto largely unnoticed in narcotic withdrawal and that neuropeptides may be involved in certain epileptic states.

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.

Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone.

PubMed

Thygesen, Peter; Andersen, Henrik Sune; Behrens, Carsten; Fels, Johannes Josef; Nørskov-Lauritsen, Leif; Rischel, Christian; Johansen, Nils Langeland

2017-08-01

Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys. Pharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production. Pharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5-6h in rats, 10-12h in minipigs, and 17-20h in monkeys. Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3-4days in each dosing interval (p<0.001). The nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species. Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3-4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level. Copyright © 2017 Elsevier Ltd. All rights reserved.

Alprazolam use and dependence. A retrospective analysis of 30 cases of withdrawal.

PubMed Central

Dickinson, B; Rush, P A; Radcliffe, A B

1990-01-01

From 1986 to 1989, the Chemical Dependency Recovery Program at Kaiser Permanente Hospital, Fontana, California, admitted an increasing number of patients for alprazolam dependence. Severe withdrawal reactions and adverse consequences with use were reported in the literature. In this review of 30 cases of alprazolam dependence and subsequent withdrawal, there was a statistically significant increase in the number of patient hospital days, the subjective symptoms, and staff time spent with patients compared with those in alcoholic controls. Most patients with diagnosed alprazolam dependence used doses in the range recommended by the package information at the time of admission. Patients with low preadmission doses of 1 mg or less per day showed notable withdrawal symptoms. The average duration of use was 29.9 months, considerably longer than suggested effective ranges. Most patients (28) had a chemical dependence history before being placed on alprazolam therapy; 24 had a positive family history of chemical dependence; and 24 had previous or current psychiatric care. PMID:2349800

[Dose rate-dependent cellular and molecular effects of ionizing radiation].

PubMed

Przybyszewski, Waldemar M; Wideł, Maria; Szurko, Agnieszka; Maniakowski, Zbigniew

2008-09-11

The aim of radiation therapy is to kill tumor cells while minimizing damage to normal cells. The ultimate effect of radiation can be apoptotic or necrotic cell death as well as cytogenetic damage resulting in genetic instability and/or cell death. The destructive effects of radiation arise from direct and indirect ionization events leading to peroxidation of macromolecules, especially those present in lipid-rich membrane structures as well as chromatin lipids. Lipid peroxidative end-products may damage DNA and proteins. A characteristic feature of radiation-induced peroxidation is an inverse dose-rate effect (IDRE), defined as an increase in the degree of oxidation(at constant absorbed dose) accompanying a lower dose rate. On the other hand, a low dose rate can lead to the accumulation of cells in G2, the radiosensitive phase of the cell cycle since cell cycle control points are not sensitive to low dose rates. Radiation dose rate may potentially be the main factor improving radiotherapy efficacy as well as affecting the intensity of normal tissue and whole-body side effects. A better understanding of dose rate-dependent biological effects may lead to improved therapeutic intervention and limit normal tissue reaction. The study reviews basic biological effects that depend on the dose rate of ionizing radiation.

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.

NOTE: Investigating the potential of polymer gel dosimetry for interventional radiology: first results

NASA Astrophysics Data System (ADS)

Antoniou, P. E.; Bousbouras, P.; Sandaltzopoulos, R.; Kaldoudi, E.

2008-04-01

Complex interventional radiology (IR) procedures contribute an increasing percentage of the overall medical radiation exposure of the population making accurate dosimetry a challenge. Magnetic resonance (MR) based polymer gel dosimetry has been widely employed in complex dosimetric problems in radiotherapy. The aim of this note is to investigate the feasibility of normoxic gel dosimetry in IR. Dose response, energy dependence and dose rate dependence were investigated in irradiation set-ups relevant to IR for a particular normoxic gel, based on methacrylic acid (MAA) as the monomer and including tetrakis-hydroxy-methyl-phosphonium chloride (THPC) as antioxidant. The gel presents a linear dose response beyond a 25 cGy threshold. No significant energy dependence was observed in the useful range of interventional radiology (80-110 kVp). A linear correlation between the gel response and dose rate was observed in the range of dose rates relevant to IR (5-8 cGy min-1). These results demonstrate a reduction of gel sensitivity at very low dose rate levels. A possible explanation of this effect is suggested.

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.

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

Effects of T-2 Toxin on Pacific White Shrimp Litopenaeus vannamei: Growth, and Antioxidant Defenses and Capacity and Histopathology in the Hepatopancreas.

PubMed

Deng, Yijia; Wang, Yaling; Zhang, Xiaodi; Sun, Lijun; Wu, Chaojin; Shi, Qi; Wang, Rundong; Sun, Xiaodong; Bi, Siyuan; Gooneratne, Ravi

2017-03-01

Modified-masked T-2 toxin (mT-2) formed during metabolism in edible aquatic animals may go undetected by traditional analytical methods, thereby underestimating T-2 toxicity. The effects of T-2 on growth and antioxidant capacity and histopathological changes in the hepatopancreas were studied in Pacific white shrimp Litopenaeus vannamei exposed for 20 d to 0, 0.5, 1.2, 2.4, 4.8, and 12.2 mg/kg of T-2 in their feed. The concentration of mT-2 in the hepatopancreas was detected by liquid chromatography-tandem mass spectrophotometry before and after trifluoroacetic acid (TFA) treatment that converted mT-2 to free T-2. A dose-dependent increase in mT-2 concentration was observed in the hepatopancreas. Dietary exposure to T-2 significantly decreased (P < 0.05) shrimp growth and survival rate compared with the controls. The malondialdehyde (MDA) concentration was significantly increased in shrimp exposed to feed with ≥2.4 mg/kg T-2 (P < 0.05). The antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPx), total antioxidant capacity (T-AOC), and also glutathione (GSH) content increased in shrimp dosed with 2.4-4.8 mg/kg T-2 but declined at the highest dose (12.2 mg/kg), probably indicating an inability to cope with high concentrations of reactive oxygen species (ROS) as evident from a marked increase in MDA (P < 0.05) culminating in cellular toxicity. Histopathological changes in the hepatopancreas were dose dependent, with cell autophagy evident at the highest exposure dose. This is the first report in shrimp of a dose-dependent increase in ROS, SOD enzyme activity, and T-AOC at low T-2 exposures, and associated histopathological changes in the hepatopancreas, in response to dietary T-2. Received January 26, 2016; accepted October 9, 2016.

Adenosine A2A receptor deficiency attenuates the somnogenic effect of prostaglandin D2 in mice

PubMed Central

Zhang, Bin-jia; Huang, Zhi-li; Chen, Jiang-fan; Urade, Yoshihiro; Qu, Wei-min

2017-01-01

Prostaglandin D2 (PGD2) is one of the most potent endogenous sleep promoting substances. PGD2 activates the PGD2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD2-induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD2. The aim of this study was to determine the involvement of the adenosine A2A receptor (A2AR) in PGD2-induced sleep. We infused PGD2 into the lateral ventricle of WT and A2AR KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD2 infusion dose-dependently increased non-rapid eye movement (non-REM, NREM) sleep, which was 139.1%, 145.0% and 202.7% as large as that of vehicle-treated mice at doses of 10, 20 and 50 pmol/min, respectively. PGD2 infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD2 infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A2AR KO mice, however, PGD2 infusion at 10 pmol/min did not change the sleep profile, whereas higher doses at 20 and 50 pmol/min increased the NREM sleep during the 6-h PGD2 infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD2 infusion at 50 pmol/min significantly increased the episode number in both genotypes but only enhanced the episode duration in WT mice. The results demonstrate that PGD2-induced sleep in mice is mediated by both adenosine A2AR-dependent and -independent systems. PMID:28112177

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).

Cocoa consumption dose-dependently improves flow-mediated dilation and arterial stiffness decreasing blood pressure in healthy individuals.

PubMed

Grassi, Davide; Desideri, Giovambattista; Necozione, Stefano; di Giosia, Paolo; Barnabei, Remo; Allegaert, Leen; Bernaert, Herwig; Ferri, Claudio

2015-02-01

Cocoa flavonoids exert beneficial vascular effects and reduce the risk of cardiovascular morbidity and mortality. Nevertheless, the involved mechanisms have not been clarified and no study has yet focused on the dose-response effects. We aimed to investigate the effects of different doses of cocoa flavonoids on flow-mediated dilation (FMD), endothelin-1 (ET-1), pulse wave velocity (PWV), and SBP and DBP. According to a randomized, double-blind, controlled, cross-over design, 20 healthy volunteers (1.5% improvement in FMD in 20 individuals: 0.99 at alpha = 0.05) were assigned to receive either five treatments with daily intake of 10 g cocoa (0, 80, 200, 500 and 800 mg cocoa flavonoids/day) in five periods lasting 1 week each. Cocoa dose-dependently increased FMD from 6.2% (control) to 7.3, 7.6, 8.1 and 8.2% after the different flavonoid doses, respectively (P < 0.0001). Compared with the control, even 80  mg cocoa flavonoids per day increased FMD (P < 0.0001). Cocoa dose-dependently decreased PWV (P < 0.0001). Cocoa intake decreased office blood pressure (BP) (SBP: -4.8 ± 1.03  mmHg, P < 0.0001; DBP: -3.03 ± 1.07 mmHg, P = 0.0011). With respect to control, cocoa ingestion decreased 24-h (P = 0.05) and daytime (P = 0.038) SBP, and 24-h (P = 0.0064), daytime (P = 0.0088) and night-time (P = 0.0352) pulse pressure. Compared with the control, cocoa dose-dependently decreased ET-1 levels [from 17.1 (control) to 15.2, 14.5, 14.2 and 14.1 pg/ml, after the different flavonoid doses, respectively (P for treatment <0.05)]. Compared with the control, significant changes were observed for all doses of flavonoids (ET-1; P < 0.05). Our study showed for the first time that cocoa dose-dependently improved FMD and decreased PWV and ET-1 also by ameliorating office and monitored BP. Our findings are clinically relevant, suggesting cocoa, with very low calorie intake, might be reasonably incorporated into a dietary approach, representing a consistent tool in cardiovascular prevention.

Space-Time Dependent Transport, Activation, and Dose Rates for Radioactivated Fluids.

NASA Astrophysics Data System (ADS)

Gavazza, Sergio

Two methods are developed to calculate the space - and time-dependent mass transport of radionuclides, their production and decay, and the associated dose rates generated from the radioactivated fluids flowing through pipes. The work couples space- and time-dependent phenomena, treated as only space- or time-dependent in the open literature. The transport and activation methodology (TAM) is used to numerically calculate space- and time-dependent transport and activation of radionuclides in fluids flowing through pipes exposed to radiation fields, and volumetric radioactive sources created by radionuclide motions. The computer program Radionuclide Activation and Transport in Pipe (RNATPA1) performs the numerical calculations required in TAM. The gamma ray dose methodology (GAM) is used to numerically calculate space- and time-dependent gamma ray dose equivalent rates from the volumetric radioactive sources determined by TAM. The computer program Gamma Ray Dose Equivalent Rate (GRDOSER) performs the numerical calculations required in GAM. The scope of conditions considered by TAM and GAM herein include (a) laminar flow in straight pipe, (b)recirculating flow schemes, (c) time-independent fluid velocity distributions, (d) space-dependent monoenergetic neutron flux distribution, (e) space- and time-dependent activation process of a single parent nuclide and transport and decay of a single daughter radionuclide, and (f) assessment of space- and time-dependent gamma ray dose rates, outside the pipe, generated by the space- and time-dependent source term distributions inside of it. The methodologies, however, can be easily extended to include all the situations of interest for solving the phenomena addressed in this dissertation. A comparison is made from results obtained by the described calculational procedures with analytical expressions. The physics of the problems addressed by the new technique and the increased accuracy versus non -space and time-dependent methods are presented. The value of the methods is also discussed. It has been demonstrated that TAM and GAM can be used to enhance the understanding of the space- and time-dependent mass transport of radionuclides, their production and decay, and the associated dose rates related to radioactivated fluids flowing through pipes.

Increased sensitivity to apoptosis induced by methotrexate is mediated by Jun N-terminal kinase

PubMed Central

Spurlock, Charles F.; Aune, Zachary T.; Tossberg, John T.; Collins, Patrick L.; Aune, Jessica P.; Huston, Joseph W.; Crooke, Philip S.; Olsen, Nancy J.; Aune, Thomas M.

2011-01-01

Objective Low-dose methotrexate [MTX] is an effective therapy for rheumatoid arthritis yet its mechanism of action is incompletely understood. Here, we explored induction of apoptosis by MTX. Methods We employed flow cytometry to assess changes in levels of intracellular proteins, reactive oxygen species [ROS], and apoptosis.Quantitative polymerase chain reaction was usedtoassess changes in transcript levels of select target genes in response to MTX. Results MTX does not directly induce apoptosis but rather ‘primes’ cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways by a Jun N-terminal kinase [JNK]-dependent mechanism. Increased sensitivity to apoptosis is mediated, at least in part, by MTX-dependent production of reactive oxygen species, JNK activation and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocks these methotrexate-induced effects. Subjects with rheumatoid arthritis on low-dose MTX therapy express elevated levels of the JNK-target gene, JUN. Conclusions Our results support a model whereby methotrexate inhibits reduction of dihydrobiopterin to tetrahydrobiopterin resulting in increased production of ROS, increased JNK activity and increased sensitivity to apoptosis. The finding of increased JUN levels in subjects with RA taking low-dose MTX supports the notion that this pathway is activated by MTX, in vivo, and may contribute to efficacy of MTX in inflammatory disease. PMID:21618198

Safety and pharmacokinetics of the oral iron chelator SP-420 in β-thalassemia.

PubMed

Taher, Ali T; Saliba, Antoine N; Kuo, Kevin H; Giardina, Patricia J; Cohen, Alan R; Neufeld, Ellis J; Aydinok, Yesim; Kwiatkowski, Janet L; Jeglinski, Brenda I; Pietropaolo, Keith; Berk, Gregory; Viprakasit, Vip

2017-12-01

Our phase I, open-label, multi-center, dose-escalation study evaluated the pharmacokinetics (PK) of SP-420, a tridentate oral iron chelating agent of the desferrithiocin class, in patients with transfusion dependent β-thalassemia. SP-420 was administered as a single dose of 1.5 (n = 3), 3 (n = 3), 6 (n = 3), 12 (n = 3), and 24 (n = 6) mg/kg or as a twice-daily dose of 9 mg/kg (n = 6) over 14-28 days. There was a near dose-linear increase in the mean plasma SP-420 concentrations and in the mean values for C max and AUC 0-τ over the dose range evaluated. The median t max ranged from 0.5 to 2.25 h and was not dose dependent. The study was prematurely terminated by the sponsor due to renal adverse events (AE) including proteinuria, increase in serum creatinine, and one case of Fanconi syndrome. Other adverse effects included hypersensitivity reactions and gastrointestinal disturbances. Based on current dose administration, the renal AE observed outweighed the possible benefits from chelation therapy. However, additional studies assessing efficacy and safety of lower doses or less frequent dosing of SP-420 over longer durations with close monitoring would be necessary to better explain the findings of our study and characterize the safety of the study drug. © 2017 Wiley Periodicals, Inc.

Uncaria rhynchophylla induces angiogenesis in vitro and in vivo.

PubMed

Choi, Do-Young; Huh, Jeong-Eun; Lee, Jae-Dong; Cho, Eun-Mi; Baek, Yong-Hyeon; Yang, Ha-Ru; Cho, Yoon-Je; Kim, Kang-Il; Kim, Deog-Yoon; Park, Dong-Suk

2005-12-01

Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, and angiogenic factors and matrix protein interactions modulate this process. The aim of this study was to determine the angiogenic properties of Uncaria rhynchophylla. Uncaria rhynchophylla significantly enhanced human umbilical vein endothelial cells (HUVECs) proliferation in a dose-dependent manner. Neutralization of vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) by monoclonal antibody suppressed the Uncaria rhynchophylla stimulatory effect on proliferation. In addition, Uncaria rhynchophylla significantly increased chemotactic-migration on gelatin and tubular structures on Matrigel of HUVECs in a dose-dependent manner. Interestingly, Uncaria rhynchophylla dose-dependently increased VEGF, and bFGF gene expression and protein secretion of HUVEC. The angiogenic activity of Uncaria rhynchophylla was confirmed using an in vivo Matrigel angiogenesis model, showing promotion of blood vessel formation. These results suggest that Uncaria rhynchophylla could potentially used to accelerate vascular wound healing or to promote the growth of collateral blood vessel in ischemic tissues.

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.

Distinct DC subsets regulate adaptive Th1 and 2 responses during Trichuris muris infection.

PubMed

Demiri, M; Müller-Luda, K; Agace, W W; Svensson-Frej, M

2017-10-01

Low- and high-dose infections with the murine large intestinal nematode Trichuris muris are associated with induction of adaptive Th1 and Th2 responses, respectively, in mesenteric lymph nodes (MLN). Classical dendritic cells (cDC) accumulate in the large intestinal mucosa and MLN upon T. muris infection, yet their role in driving adaptive responses to infection remains largely unknown. We performed low- and high-dose T. muris infections of mice deficient in defined cDC subsets to investigate their role in induction of adaptive immune responses. Mice lacking IRF4-dependent cDC failed to clear a high-dose infection and displayed impaired Th2 responses. Conversely, mice lacking IRF8-dependent cDC cleared a low-dose infection and displayed an impaired Th1 response while increased production of Th2 cytokines. Finally, mice lacking both IRF4- and IRF8-dependent cDC were able to generate a Th2 response and clear a low-dose infection. Collectively, these results suggest that IRF4- and IRF8-dependent cDC act antagonistically during T. muris infection, and demonstrate that intestinal Th2 responses can be generated towards T. muris in the absence of IRF4-dependent cDC. © 2017 John Wiley & Sons Ltd.

Sibutramine-induced anorexia: potent, dose-dependent and behaviourally-selective profile in male rats.

PubMed

Tallett, A J; Blundell, J E; Rodgers, R J

2009-03-17

The serotonin and noradrenaline reuptake inhibitor sibutramine has been licensed as an anti-obesity treatment for more than a decade. However, while inhibitory effects on food intake and weight gain are well documented, surprisingly little published detail exists regarding its influence on feeding and related behaviours. The present study was therefore designed to assess the effects of acute sibutramine treatment on food intake, the behavioural satiety sequence (BSS) and post-treatment weight gain. Subjects were 10 non-deprived adult male Lister hooded rats, tested with 0.5-3.0 mg/kg sibutramine hydrochloride during 1-h DVD-recorded test sessions with palatable mash. Our results show that sibutramine dose-dependently reduced food intake, an effect significant at all doses tested. Ethological analysis revealed very few behavioural effects, except for a dose-dependent reduction in time spent feeding and an increase in the frequency of resting. Behavioural specificity was further supported by time-bin analysis which confirmed both the structural integrity and dose-dependent acceleration of the BSS. Single dosing with sibutramine (3.0 mg/kg) also suppressed daily weight gain over the 24-72 h period post-dosing. Current data support the conclusion that the acute anorectic and weight loss efficacy of sibutramine in adult male rats is not secondary to behavioural disruption but, instead, is due largely to an acceleration in behavioural satiety.

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.

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.

Gamma rays induce DNA damage and oxidative stress associated with impaired growth and reproduction in the copepod Tigriopus japonicus.

PubMed

Han, Jeonghoon; Won, Eun-Ji; Lee, Bo-Young; Hwang, Un-Ki; Kim, Il-Chan; Yim, Joung Han; Leung, Kenneth Mei Yee; Lee, Yong Sung; Lee, Jae-Seong

2014-07-01

Nuclear radioisotope accidents are potentially ecologically devastating due to their impact on marine organisms. To examine the effects of exposure of a marine organism to radioisotopes, we irradiated the intertidal copepod Tigriopus japonicus with several doses of gamma radiation and analyzed the effects on mortality, fecundity, and molting by assessing antioxidant enzyme activities and gene expression patterns. No mortality was observed at 96h, even in response to exposure to a high dose (800Gy) of radiation, but mortality rate was significantly increased 120h (5 days) after exposure to 600 or 800Gy gamma ray radiation. We observed a dose-dependent reduction in fecundity of ovigerous females; even the group irradiated with 50Gy showed a significant reduction in fecundity, suggesting that gamma rays are likely to have a population level effect. In addition, we observed growth retardation, particularly at the nauplius stage, in individuals after gamma irradiation. In fact, nauplii irradiated with more than 200Gy, though able to molt to copepodite stage 1, did not develop into adults. Upon gamma radiation, T. japonicus showed a dose-dependent increase in reactive oxygen species (ROS) levels, the activities of several antioxidant enzymes, and expression of double-stranded DNA break damage genes (e.g. DNA-PK, Ku70, Ku80). At a low level (sub-lethal dose) of gamma irradiation, we found dose-dependent upregulation of p53, implying cellular damage in T. japonicus in response to sub-lethal doses of gamma irradiation, suggesting that T. japonicus is not susceptible to sub-lethal doses of gamma irradiation. Additionally, antioxidant genes, phase II enzyme (e.g. GSTs), and cellular chaperone genes (e.g. Hsps) that are involved in cellular defense mechanisms also showed the same expression patterns for sublethal doses of gamma irradiation (50-200Gy). These findings indicate that sublethal doses of gamma radiation can induce oxidative stress-mediated DNA damage and increase the expression of antioxidant enzymes and proteins with chaperone-related functions, thereby significantly affecting life history parameters such as fecundity and molting in the copepod T. japonicus. Copyright © 2014 Elsevier B.V. All rights reserved.

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

Decreasing Irradiated Rat Lung Volume Changes Dose-Limiting Toxicity From Early to Late Effects

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

Veen, Sonja J. van der; Faber, Hette; Ghobadi, Ghazaleh

2016-01-01

Purpose: Technological developments in radiation therapy result in smaller irradiated volumes of normal tissue. Because the risk of radiation therapy-induced toxicity generally depends on irradiated volume, changing volume could change the dose-limiting toxicity of a treatment. Recently, in our rat model, we found that early radiation-induced lung dysfunction (RILD) was closely related to irradiated volume dependent vascular remodeling besides inflammation. The exact relationship between early and late RILD is still unknown. Therefore, in this preclinical study we investigated the dose-volume relationship of late RILD, assessed its dependence on early and late pathologies and studied if decreasing irradiated volume changed themore » dose-limiting toxicity. Methods and Materials: A volume of 25%, 32%, 50%, 63%, 88%, or 100% of the rat lung was irradiated using protons. Until 26 weeks after irradiation, respiratory rates were measured. Macrovascular remodeling, pulmonary inflammation, and fibrosis were assessed at 26 weeks after irradiation. For all endpoints dose-volume response curves were made. These results were compared to our previously published early lung effects. Results: Early vascular remodeling and inflammation correlated significantly with early RILD. Late RILD correlated with inflammation and fibrosis, but not with vascular remodeling. In contrast to the early effects, late vascular remodeling, inflammation and fibrosis showed a primarily dose but not volume dependence. Comparison of respiratory rate increases early and late after irradiation for the different dose-distributions indicated that with decreasing irradiated volumes, the dose-limiting toxicity changed from early to late RILD. Conclusions: In our rat model, different pathologies underlie early and late RILD with different dose-volume dependencies. Consequently, the dose-limiting toxicity changed from early to late dysfunction when the irradiated volume was reduced. In patients, early and late RILD are also due to different pathologies. As such, new radiation techniques reducing irradiated volume might change the dose-limiting toxicity of the radiation therapy treatment.« less

The reciprocity law concerning light dose relationships applied to BisGMA/TEGDMA photopolymers: theoretical analysis and experimental characterization.

PubMed

Wydra, James W; Cramer, Neil B; Stansbury, Jeffrey W; Bowman, Christopher N

2014-06-01

A model BisGMA/TEGDMA unfilled resin was utilized to investigate the effect of varied irradiation intensity on the photopolymerization kinetics and shrinkage stress evolution, as a means for evaluation of the reciprocity relationship. Functional group conversion was determined by FTIR spectroscopy and polymerization shrinkage stress was obtained by a tensometer. Samples were polymerized with UV light from an EXFO Acticure with 0.1wt% photoinitiator. A one-dimensional kinetic model was utilized to predict the conversion-dose relationship. As irradiation intensity increased, conversion decreased at a constant irradiation dose and the overall dose required to achieve full conversion increased. Methacrylate conversion ranged from 64±2% at 3mW/cm(2) to 78±1% at 24mW/cm(2) while the final shrinkage stress varied from 2.4±0.1MPa to 3.0±0.1MPa. The ultimate conversion and shrinkage stress levels achieved were dependent not only upon dose but also the irradiation intensity, in contrast to an idealized reciprocity relationship. A kinetic model was utilized to analyze this behavior and provide theoretical conversion profiles versus irradiation time and dose. Analysis of the experimental and modeling results demonstrated that the polymerization kinetics do not and should not be expected to follow the reciprocity law behavior. As irradiation intensity is increased, the overall dose required to achieve full conversion also increased. Further, the ultimate conversion and shrinkage stress that are achieved are not dependent only upon dose but rather upon the irradiation intensity and corresponding polymerization rate. Copyright © 2014 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Low-dose atorvastatin, losartan, and particularly their combination, provide cardiovascular protection in isolated rat heart and aorta.

PubMed

Lunder, Mojca; Ziberna, Lovro; Janić, Miodrag; Jerin, Aleš; Skitek, Milan; Sabovič, Mišo; Drevenšek, Gorazd

2013-03-01

Statins and angiotensin receptor blockers at therapeutic doses have beneficial cardiovascular effects, which can be applied for cardiovascular protection. We explored whether low doses of atorvastatin, losartan, and particularly their combination, possess important pleiotropic vasodilatory effects. Wistar rats were treated daily with low-dose atorvastatin (2 mg/kg, n = 15), low-dose losartan (5 mg/kg, n = 15), their combination (n = 15), or saline (n = 15). After 4, 6, or 8 weeks the animals were anesthetized, blood samples taken, and their hearts and thoracic aortas isolated. Two kinds of experiments were performed: the measurement of coronary flow rate after ischemia/reperfusion myocardial injury and endothelium-dependent relaxation of thoracic aorta. In both models, maximal vasodilation activity was obtained in rats treated for 6 weeks. In the ischemia/reperfusion myocardial injury model, coronary flow increased (atorvastatin or losartan 1.9-fold, P < 0.01; combination 2.4-fold, P < 0.001) compared with controls. In the thoracic aorta model, endothelium-dependent relaxation significantly increased only in the combination group compared with the control group (up to 1.4-fold; P < 0.01). Simultaneously, we detected increased anti-inflammatory activity and increased nitric oxide concentration, but no changes in lipids and blood pressure. In a rat model we showed important vasodilatory activity of low-dose atorvastatin, losartan, and particularly their combination. The effects of the low-dose combination were accompanied by, and probably at least partly achieved by, anti-inflammatory and nitric oxide pathways. Overall, these results could be valuable for the development of new vascular protective strategies focusing on a low-dose regimen of statins and sartans, and particularly their combination.

Promoting Abstinence from Cocaine and Heroin with a Methadone Dose Increase and a Novel Contingency

PubMed Central

Schmittner, John; Umbricht, Annie; Schroeder, Jennifer R.; Moolchan, Eric T.; Preston, Kenzie L.

2010-01-01

To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 X 3 (Dose X Contingency) factorial design in which dose assignment was double-blind. Participants were 252 heroin- and cocaine-abusing outpatients on methadone maintenance. They were randomly assigned to methadone dose (70 or 100 mg/day, double blind) and voucher condition (noncontingent, contingent on cocaine-negative urines, or “split”). The “split” contingency was a novel contingency that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both: the total value of incentives was “split” between drugs to contain costs. The main outcome measures were percentages of urine specimens negative for heroin, cocaine, and both simultaneously; these were monitored during a 5-week baseline of standard treatment (to determine study eligibility), a 12-week intervention, and a 10-week maintenance phase (to examine intervention effects in return-to-baseline conditions). DSM-IV criteria for ongoing drug dependence were assessed at study exit. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The Split 100mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose Noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased in the active intervention groups. For a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient; an increase in overall incentive amount may also be required. PMID:19101098

A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers.

PubMed

Kostic, Ana; King, Thomas Alexander; Yang, Feng; Chan, Kuo-Chen; Yancopoulos, George D; Gromada, Jesper; Harp, Joyce B

2018-02-01

Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial. Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose-lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges. REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC 0-90 minutes ) by 80% to 90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups. REGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown. © 2017 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

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.

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.

Stimulatory Effect of Insulin on 5α-Reductase Type 1 (SRD5A1) Expression through an Akt-Dependent Pathway in Ovarian Granulosa Cells

PubMed Central

Kayampilly, Pradeep P.; Wanamaker, Brett L.; Stewart, James A.; Wagner, Carrie L.; Menon, K. M. J.

2010-01-01

Elevated levels of 5α-reduced androgens have been shown to be associated with hyperandrogenism and hyperinsulinemia, the leading causes of ovulatory dysfunction in women. 5α-Dihydrotestosterone reduces ovarian granulosa cell proliferation by inhibiting FSH-mediated mitogenic signaling pathways. The present study examined the effect of insulin on 5α-reductase, the enzyme that catalyses the conversion of androgens to their 5α-derivatives. Granulosa cells isolated from immature rat ovaries were cultured in serum-free, phenol red-free DMEM-F12 media and treated with different doses of insulin (0, 0.1, 1.0, and 10.0 μg/ml) for different time intervals up to 12 h. The expression of 5α-reductase type 1 mRNA, the predominant isoform found in granulosa cells, showed a significant (P < 0.05) increase in response to the insulin treatment up to 12 h compared with control. The catalytic activity of 5α-reductase enzyme was also stimulated in a dose-depended manner (P < 0.05). Inhibiting the Akt-dependent signaling pathway abolished the insulin-mediated increase in 5α-reductase mRNA expression, whereas inhibition of the ERK-dependent pathway had no effect. The dose-dependent increase in 5α-reductase mRNA expression as well as catalytic activity seen in response to insulin treatment was also demonstrated in the human granulosa cell line (KGN). In addition to increased mRNA expression, a dose-dependent increase in 5α-reductase protein expression in response to insulin was also seen in KGN cells, which corroborated well with that of mRNA expression. These results suggest that elevated levels of 5α-reduced androgens seen in hyperinsulinemic conditions might be explained on the basis of a stimulatory effect of insulin on 5α-reductase in granulosa cells. The elevated levels of these metabolites, in turn, might adversely affect growth and proliferation of granulosa cells, thereby impairing follicle growth and ovulation. PMID:20810561

Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose

PubMed Central

Carlin, Lindsey E.; Hemann, Emily A.; Zacharias, Zeb R.; Heusel, Jonathan W.; Legge, Kevin L.

2018-01-01

Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections. PMID:29719539

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

Dose-dependent effects of wheel running on cocaine-seeking and prefrontal cortex Bdnf exon IV expression in rats.

PubMed

Peterson, Alexis B; Abel, Jean M; Lynch, Wendy J

2014-04-01

Physical activity, and specifically exercise, has shown promise as an intervention for drug addiction; however, the exercise conditions that produce the most efficacious response, as well as its underlying mechanism, are unknown. In this study, we examined the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking and associated changes in prefrontal cortex (PFC) brain-derived neurotrophic factor (Bdnf) exon IV expression, a marker of epigenetic regulation implicated in cocaine relapse and known to be regulated by exercise. Cocaine-seeking was assessed under a within-session extinction/cue-induced reinstatement procedure following extended access cocaine or saline self-administration (24-h/day, 4 discrete trials/h, 10 days, 1.5 mg/kg/infusion) and a 14-day abstinence period. During abstinence, rats had either locked or unlocked running wheel access for 1, 2, or 6 h/day. Bdnf exon IV expression was assessed using quantitative real-time polymerase chain reaction. Cocaine-seeking was highest under the locked wheel condition, and wheel running dose dependently attenuated this effect. Cocaine increased Bdnf exon IV expression, and wheel running dose dependently attenuated this increase, with complete blockade in rats given 6-h/day access. Notably, the efficacy of exercise was inversely associated with Bdnf exon IV expression, and both its efficacy and its effects on Bdnf exon IV expression were mimicked by treatment during abstinence with sodium butyrate, a histone deacetylase inhibitor that, like exercise, modulates gene transcription, including Bdnf exon IV expression. Taken together, these results indicate that the efficacy of exercise is dose dependent and likely mediated through epigenetic regulation of PFC Bdnf.

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

Pharmacokinetics of testosterone cream applied to scrotal skin.

PubMed

Iyer, R; Mok, S F; Savkovic, S; Turner, L; Fraser, G; Desai, R; Jayadev, V; Conway, A J; Handelsman, D J

2017-07-01

Scrotal skin is thin and has high steroid permeability, but the pharmacokinetics of testosterone via the scrotal skin route has not been studied in detail. The aim of this study was to define the pharmacokinetics of testosterone delivered via the scrotal skin route. The study was a single-center, three-phase cross-over pharmacokinetic study of three single doses (12.5, 25, 50 mg) of testosterone cream administered in random sequence on different days with at least 2 days between doses to healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate. Serum testosterone, DHT and estradiol concentrations were measured by liquid chromatograpy, mass spectrometry in extracts of serum taken before and for 16 h after administration of each of the three doses of testosterone cream to the scrotal skin. Testosterone administration onto the scrotal skin produced a swift (peak 1.9-2.8 h), dose-dependent (p < 0.0001) increase in serum testosterone with the 25 mg dose maintaining physiological levels for 16 h. Serum DHT displayed a time- (p < 0.0001), but not dose-dependent, increase in concentration reaching a peak concentration of 1.2 ng/mL (4.1 nm) at 4.9 h which was delayed by 2 h after peak serum testosterone. There were no significant changes in serum estradiol over time after testosterone administration. We conclude that testosterone administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route. © 2017 American Society of Andrology and European Academy of Andrology.

Radiation Pneumopathy in the Rat After Intravenous Application of {sup 188}Re-Labeled Microspheres

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

Liepe, Knut; Faulhaber, Diana; Wunderlich, Gerd

2011-10-01

Purpose: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ({sup 188}Re)-labeled microspheres in a rat model. Methods and Materials: {sup 188}Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 {+-} 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks.more » An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses. Results: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 {+-} 0.6 Gy and 20.4 {+-} 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component. Conclusions: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar.« less

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.

PubMed

Pasi, K John; Rangarajan, Savita; Georgiev, Pencho; Mant, Tim; Creagh, Michael D; Lissitchkov, Toshko; Bevan, David; Austin, Steve; Hay, Charles R; Hegemann, Inga; Kazmi, Rashid; Chowdary, Pratima; Gercheva-Kyuchukova, Liana; Mamonov, Vasily; Timofeeva, Margarita; Soh, Chang-Heok; Garg, Pushkal; Vaishnaw, Akshay; Akinc, Akin; Sørensen, Benny; Ragni, Margaret V

2017-08-31

Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).

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.

Arsenic disulfide induced apoptosis and concurrently promoted erythroid differentiation in cytokine-dependent myelodysplastic syndrome-progressed leukemia cell line F-36p with complex karyotype including monosomy 7.

PubMed

Hu, Xiao-mei; Tanaka, Sachiko; Onda, Kenji; Yuan, Bo; Toyoda, Hiroo; Ma, Rou; Liu, Feng; Hirano, Toshihiko

2014-05-01

Acute myeloid leukemia progressed from myelodysplastic syndrome (MDS/AML) is generally incurable with poor prognosis for complex karyotype including monosomy 7 (-7). Qinghuang Powder (, QHP), which includes Qing Dai (Indigo naturalis) and Xiong Huang (realgar) in the formula, is effective in treating MDS or MDS/AML even with the unfavorable karyotype, and its therapeutic efficacy could be enhanced by increasing the Xiong huang content in the formula, while Xiong huang contains > 90% arsenic disulfide (As2S2). F-36p cell line was established from a MDS/AML patient with complex karyotype including -7, and was in cytokine-dependent. The present study was to investigate the effects of As2S2 on F-36p cells. Cell proliferation was measured by an 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis was identified by Annexin V-staining. Cell viability was determined by a propidium iodide (PI) exclusion. Erythroid differentiation was evaluated by the expression of cell surface antigen CD235a (GpA). After treatment with As2S2 at concentrations of 0.5 to 16 μmol/L for 72 h, As2S2 inhibited the proliferation of F-36p cells. The 50% inhibitory concentrations (IC50) of As2S2 against the proliferation of F-36p cells was 6 μmol/L. The apoptotic cells significantly increased in a dose-dependent mannar (P<0.05). The cell viabilities were significantly inhibited by As2S2 dose-dependent in a dose-dependent manner (P<0.05). Significant increases of CD235a-positive cells were concurrently observed (P<0.05) also in a dose-dependent manner. As2S2 could inhibit proliferation and viability, induce apoptosis, and concurrently promote erythroid differentiation dose-dependently in F-36p cells. As2S2 can inhibit proliferation and viability, induce apoptosis, and concurrently promote erythroid differentiation in cytokine-dependent MDS-progressed human leukemia cell line F-36p with complex karyotype including -7. The data suggest that QHP and/or As2S2 could be a potential candidate in the treatment of MDS or MDS/AML even with unfavorable cytogenetics.

The Effect of Ingested Glucose Dose on the Suppression of Endogenous Glucose Production in Humans.

PubMed

Kowalski, Greg M; Moore, Samantha M; Hamley, Steven; Selathurai, Ahrathy; Bruce, Clinton R

2017-09-01

Insulin clamp studies have shown that the suppressive actions of insulin on endogenous glucose production (EGP) are markedly more sensitive than for stimulating glucose disposal ( R d ). However, clamp conditions do not adequately mimic postprandial physiological responses. Here, using the variable infusion dual-tracer approach, we used a threefold range of ingested glucose doses (25, 50, and 75 g) to investigate how physiological changes in plasma insulin influence EGP in healthy subjects. Remarkably, the glucose responses were similar for all doses tested, yet there was a dose-dependent increase in insulin secretion and plasma insulin levels. Nonetheless, EGP was suppressed with the same rapidity and magnitude (∼55%) across all doses. The progressive hyperinsulinemia, however, caused a dose-dependent increase in the estimated rates of R d , which likely accounts for the lack of a dose effect on plasma glucose excursions. This suggests that after glucose ingestion, the body preferentially permits a transient and optimal degree of postprandial hyperglycemia to efficiently enhance insulin-induced changes in glucose fluxes, thereby minimizing the demand for insulin secretion. This may represent an evolutionarily conserved mechanism that not only reduces the secretory burden on β-cells but also avoids the potential negative consequences of excessive insulin release into the systemic arterial circulation. © 2017 by the American Diabetes Association.

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.

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.

Skeletal response to corticosteroid deficiency and excess in growing male rats

NASA Technical Reports Server (NTRS)

Li, M.; Shen, Y.; Halloran, B. P.; Baumann, B. D.; Miller, K.; Wronski, T. J.

1996-01-01

The study was designed to investigate bone histomorphometric changes induced by corticosteroid deficiency and supplementation at different dose levels in the rat skeleton. Male rats were adrenalectomized (ADX) or sham-operated and divided into six groups. At 2 days after surgery, sham-operated control rats (CON + PLA) and one group of ADX rats (ADX + PLA) were implanted subcutaneously (s.c.) with placebo pellets. ADX rats in the remaining four groups (ADX + C25, ADX + C50, ADX + C100, and ADX + C300) were implanted sc with corticosterone pellets designed to release 25, 50, 100, or 300 mg of the hormone over a 60 day period. Each ADX rat was also implanted sc with an aldosterone pellet (2.5 mg) similarly designed to release its contents over the same time period. All rats were killed at 3 weeks after implantation of pellets. Terminal blood samples were collected for serum biochemistry and the proximal tibial metaphyses (PTM), tibial diaphyses, and first lumbar vertebrae (LV) were processed undecalcified for quantitative bone histomorphometry. A dose-dependent increase in serum corticosterone concentration was observed in ADX rats implanted with hormone pellets. In comparison to CON + PLA rats, ADX + PLA rats had lower cancellous bone volume associated with a stimulation in longitudinal bone growth, an increase in mineral apposition rate, and a trend for increased osteoclast and osteoblast surfaces in PTM. In contrast, cancellous bone of ADX + C25 rats was preserved at nearly the CON + PLA level. However, the higher doses of corticosterone increased cancellous bone mass, but decreased longitudinal bone growth and all indices of bone resorption and formation in a dose-dependent manner in PTM. Similar cancellous bone changes were observed in the LV of corticosterone-treated rats, with the exception of a lack of an hormonal effect on cancellous bone mass. In the tibial diaphysis, corticosterone inhibited periosteal bone formation in a dose-dependent manner, but did not affect cortical bone mass. The results indicate that corticosteroid deficiency induces cancellous osteopenia, whereas supplementation with a near physiologic dose of the hormone prevents this bone loss in ADX rats. Furthermore, corticosteroid excess inhibits bone growth and bone turnover in a dose-dependent manner, but does not induce cancellous osteopenia in growing male rats.

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.

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.

Low temperature neutron irradiation effects on microstructure and tensile properties of molybdenum

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

Li, Meimei; Eldrup, M.; Byun, Thak Sang

2008-01-01

Polycrystalline molybdenum was irradiated in the hydraulic tube facility at the High Flux Isotope Reactor to doses ranging from 7.2 x 10{sup -5} to 0.28 dpa at {approx} 80 C. As-irradiated microstructure was characterized by room-temperature electrical resistivity measurements, transmission electron microscopy (TEM) and positron annihilation spectroscopy (PAS). Tensile tests were carried out between -50 and 100 C over the strain rate range 1 x 10{sup -5} to 1 x 10{sup -2} s{sup -1}. Fractography was performed by scanning electron microscopy (SEM), and the deformation microstructure was examined by TEM after tensile testing. Irradiation-induced defects became visible by TEM atmore » {approx}0.001 dpa. Both their density and mean size increased with increasing dose. Submicroscopic three-dimensional cavities were detected by PAS even at {approx}0.0001 dpa. The cavity density increased with increasing dose, while their mean size and size distribution was relatively insensitive to neutron dose. It is suggested that the formation of visible dislocation loops was predominantly a nucleation and growth process, while in-cascade vacancy clustering may be significant in Mo. Neutron irradiation reduced the temperature and strain rate dependence of the yield stress, leading to radiation softening in Mo at lower doses. Irradiation had practically no influence on the magnitude and the temperature and strain rate dependence of the plastic instability stress.« less

Dose rate dependence for different dosimeters and detectors: TLD, OSL, EBT films, and diamond detectors.

PubMed

Karsch, L; Beyreuther, E; Burris-Mog, T; Kraft, S; Richter, C; Zeil, K; Pawelke, J

2012-05-01

The use of laser accelerators in radiation therapy can perhaps increase the low number of proton and ion therapy facilities in some years due to the low investment costs and small size. The laser-based acceleration technology leads to a very high peak dose rate of about 10(11) Gy∕s. A first dosimetric task is the evaluation of dose rate dependence of clinical dosimeters and other detectors. The measurements were done at ELBE, a superconductive linear electron accelerator which generates electron pulses with 5 ps length at 20 MeV. The different dose rates are reached by adjusting the number of electrons in one beam pulse. Three clinical dosimeters (TLD, OSL, and EBT radiochromic films) were irradiated with four different dose rates and nearly the same dose. A faraday cup, an integrating current transformer, and an ionization chamber were used to control the particle flux on the dosimeters. Furthermore two diamond detectors were tested. The dosimeters are dose rate independent up to 4●10(9) Gy∕s within 2% (OSL and TLD) and up to 15●10(9) Gy∕s within 5% (EBT films). The diamond detectors show strong dose rate dependence. TLD, OSL dosimeters, and EBT films are suitable for pulsed beams with a very high pulse dose rate like laser accelerated particle beams.

Dose rate dependence for different dosimeters and detectors: TLD, OSL, EBT films, and diamond detectors

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

Karsch, L.; Beyreuther, E.; Burris-Mog, T.

Purpose: The use of laser accelerators in radiation therapy can perhaps increase the low number of proton and ion therapy facilities in some years due to the low investment costs and small size. The laser-based acceleration technology leads to a very high peak dose rate of about 10{sup 11} Gy/s. A first dosimetric task is the evaluation of dose rate dependence of clinical dosimeters and other detectors. Methods: The measurements were done at ELBE, a superconductive linear electron accelerator which generates electron pulses with 5 ps length at 20 MeV. The different dose rates are reached by adjusting the numbermore » of electrons in one beam pulse. Three clinical dosimeters (TLD, OSL, and EBT radiochromic films) were irradiated with four different dose rates and nearly the same dose. A faraday cup, an integrating current transformer, and an ionization chamber were used to control the particle flux on the dosimeters. Furthermore two diamond detectors were tested. Results: The dosimeters are dose rate independent up to 410{sup 9} Gy/s within 2% (OSL and TLD) and up to 1510{sup 9} Gy/s within 5% (EBT films). The diamond detectors show strong dose rate dependence. Conclusions: TLD, OSL dosimeters, and EBT films are suitable for pulsed beams with a very high pulse dose rate like laser accelerated particle beams.« less

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

The Effect of Intra-articular Corticosteroids on Articular Cartilage

PubMed Central

Wernecke, Chloe; Braun, Hillary J.; Dragoo, Jason L.

2015-01-01

Background: Intra-articular (IA) corticosteroid therapy has been used for the treatment of inflammation and pain in the knee since the 1950s. Purpose: To review the current literature on the effects of IA corticosteroids on articular cartilage. Study Design: Systematic review. Methods: A MEDLINE and SCOPUS database search was performed, and studies were selected for basic science and clinical trial research on corticosteroids with direct outcome measures of cartilage health. Preliminary searches yielded 1929 articles, and final analysis includes 40 studies. Results: Methylprednisolone, dexamethasone, hydrocortisone, betamethasone, prednisolone, and triamcinolone were reported to display dose-dependent deleterious effects on cartilage morphology, histology, and viability in both in vitro and in vivo models. The beneficial animal in vivo effects of methylprednisolone, hydrocortisone, and triamcinolone occurred at low doses (usually <2-3 mg/dose or 8-12 mg/cumulative total dose in vivo), at which increased cell growth and recovery from damage was observed; the single human clinical trial indicated a beneficial effect of triamcinolone. However, at higher doses (>3 mg/dose or 18-24 mg/cumulative total dose in vivo), corticosteroids were associated with significant gross cartilage damage and chondrocyte toxicity. Dose and time dependency of corticosteroid chondrotoxicity was supported in the in vitro results, however, without clear dose thresholds. Conclusion: Corticosteroids have a time- and dose-dependent effect on articular cartilage, with beneficial effects occurring at low doses and durations and detrimental effects at high doses and durations. Clinically, beneficial effects are supported for IA administration, but the lowest efficacious dose should be used. PMID:26674652

[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.

Bioaccumulation and toxicity of selenium compounds in the green alga Scenedesmus quadricauda

PubMed Central

Umysová, Dáša; Vítová, Milada; Doušková, Irena; Bišová, Kateřina; Hlavová, Monika; Čížková, Mária; Machát, Jiří; Doucha, Jiří; Zachleder, Vilém

2009-01-01

Background Selenium is a trace element performing important biological functions in many organisms including humans. It usually affects organisms in a strictly dosage-dependent manner being essential at low and toxic at higher concentrations. The impact of selenium on mammalian and land plant cells has been quite extensively studied. Information about algal cells is rare despite of the fact that they could produce selenium enriched biomass for biotechnology purposes. Results We studied the impact of selenium compounds on the green chlorococcal alga Scenedesmus quadricauda. Both the dose and chemical forms of Se were critical factors in the cellular response. Se toxicity increased in cultures grown under sulfur deficient conditions. We selected three strains of Scenedesmus quadricauda specifically resistant to high concentrations of inorganic selenium added as selenite (Na2SeO3) – strain SeIV, selenate (Na2SeO4) – strain SeVI or both – strain SeIV+VI. The total amount of Se and selenomethionine in biomass increased with increasing concentration of Se in the culturing media. The selenomethionine made up 30–40% of the total Se in biomass. In both the wild type and Se-resistant strains, the activity of thioredoxin reductase, increased rapidly in the presence of the form of selenium for which the given algal strain was not resistant. Conclusion The selenium effect on the green alga Scenedesmus quadricauda was not only dose dependent, but the chemical form of the element was also crucial. With sulfur deficiency, the selenium toxicity increases, indicating interference of Se with sulfur metabolism. The amount of selenium and SeMet in algal biomass was dependent on both the type of compound and its dose. The activity of thioredoxin reductase was affected by selenium treatment in dose-dependent and toxic-dependent manner. The findings implied that the increase in TR activity in algal cells was a stress response to selenium cytotoxicity. Our study provides a new insight into the impact of selenium on green algae, especially with regard to its toxicity and bioaccumulation. PMID:19445666

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

PubMed

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

2016-08-01

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

Optimization of Monte Carlo dose calculations: The interface problem

NASA Astrophysics Data System (ADS)

Soudentas, Edward

1998-05-01

High energy photon beams are widely used for radiation treatment of deep-seated tumors. The human body contains many types of interfaces between dissimilar materials that affect dose distribution in radiation therapy. Experimentally, significant radiation dose perturbations has been observed at such interfaces. The EGS4 Monte Carlo code was used to calculate dose perturbations at boundaries between dissimilar materials (such as bone/water) for 60Co and 6 MeV linear accelerator beams using a UNIX workstation. A simple test of the reliability of a random number generator was also developed. A systematic study of the adjustable parameters in EGS4 was performed in order to minimize calculational artifacts at boundaries. Calculations of dose perturbations at boundaries between different materials showed that there is a 12% increase in dose at water/bone interface, and a 44% increase in dose at water/copper interface. with the increase mainly due to electrons produced in water and backscattered from the high atomic number material. The dependence of the dose increase on the atomic number was also investigated. The clinically important case of using two parallel opposed beams for radiation therapy was investigated where increased doses at boundaries has been observed. The Monte Carlo calculations can provide accurate dosimetry data under conditions of electronic non-equilibrium at tissue interfaces.

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.

Laboratory measures of methylphenidate effects in cocaine-dependent patients receiving treatment.

PubMed

Roache, J D; Grabowski, J; Schmitz, J M; Creson, D L; Rhoades, H M

2000-02-01

Two experiments examined the effects of methylphenidate in male and female patients enrolled in an outpatient treatment program for primary cocaine dependence. The first study was a component of a double-blind efficacy trial wherein 57 patients were first tested in a human laboratory for their initial responsiveness to medication. Patients were randomly assigned to receive either placebo or methylphenidate treatment and received their first dose in the human laboratory environment before continuing in outpatient treatment. Methylphenidate was given as a 20-mg sustained-release dose (twice daily) plus an additional 5-mg immediate-release dose combined with the morning dose. Methylphenidate increased heart rate and subjective ratings; however, the subjective effects were primarily of a "dysphoric" nature, and significant effects were limited to increases in anxiety, depression, and anger on the Profile of Mood States; shaky/jittery ratings on a visual analog scale; and dysphoria on the lysergic acid diethylamide (LSD) scale of the Addiction Research Center Inventory. Methylphenidate did not increase cocaine craving nor ratings suggesting abuse potential (i.e., Morphine-Benzedrine Group or drug-liking scores, etc.). None of the drug effects observed in the human laboratory was of clinical concern, and no subject was precluded from continuing in the outpatient study. After outpatient treatment completion, 12 patients were brought back into a second double-blind human laboratory study in which three doses (15, 30, and 60 mg) of immediate-release methylphenidate were administered in an ascending series preceded and followed by placebo. Methylphenidate produced dose-related increases in heart rate, subjective ratings of shaky/jittery, and LSD/dysphoria without significantly altering cocaine craving or stimulant euphoria ratings. These results suggest that stimulant substitution-type approaches to the treatment of cocaine dependence are not necessarily contraindicated because of cardiovascular toxicity or medication abuse potential. However, they also suggest that the subjective effects of methylphenidate may not be positive enough for an adequate replacement approach.

Amphetamine Exerts Dose-Dependent Changes in Prefrontal Cortex Attractor Dynamics during Working Memory

PubMed Central

Balaguer-Ballester, Emili; Seamans, Jeremy K.; Phillips, Anthony G.; Durstewitz, Daniel

2015-01-01

Modulation of neural activity by monoamine neurotransmitters is thought to play an essential role in shaping computational neurodynamics in the neocortex, especially in prefrontal regions. Computational theories propose that monoamines may exert bidirectional (concentration-dependent) effects on cognition by altering prefrontal cortical attractor dynamics according to an inverted U-shaped function. To date, this hypothesis has not been addressed directly, in part because of the absence of appropriate statistical methods required to assess attractor-like behavior in vivo. The present study used a combination of advanced multivariate statistical, time series analysis, and machine learning methods to assess dynamic changes in network activity from multiple single-unit recordings from the medial prefrontal cortex (mPFC) of rats while the animals performed a foraging task guided by working memory after pretreatment with different doses of d-amphetamine (AMPH), which increases monoamine efflux in the mPFC. A dose-dependent, bidirectional effect of AMPH on neural dynamics in the mPFC was observed. Specifically, a 1.0 mg/kg dose of AMPH accentuated separation between task-epoch-specific population states and convergence toward these states. In contrast, a 3.3 mg/kg dose diminished separation and convergence toward task-epoch-specific population states, which was paralleled by deficits in cognitive performance. These results support the computationally derived hypothesis that moderate increases in monoamine efflux would enhance attractor stability, whereas high frontal monoamine levels would severely diminish it. Furthermore, they are consistent with the proposed inverted U-shaped and concentration-dependent modulation of cortical efficiency by monoamines. PMID:26180194

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.

SPLICE VARIANT SPECIFIC UPREGULATIONOF CA+2/CALMODULIN DEPENDENT PROTEIN KINASE 1G BY PYRETHROID INSECTICIDES IN VIVO.

EPA Science Inventory

Pyrethroid insecticides induce neurotoxicity in mammals by interfering with ion channel function in excitable neuronal membranes. Previous work demonstrated dose-dependent increases in expression of Ca+2/calmodulin dependent protein kinase (Camk1g) mRNA following acute deltameth...

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.

A study of normoxic polymer gel using monomer 2-hydroxyethyl methacrylate (HEMA)

NASA Astrophysics Data System (ADS)

Ishak, Siti Atiqah; Mustafa, Iskandar Shahrim; Rahman, Azhar Abdul; Moktar, Mohd; Min, Ung Ngie

2015-04-01

The aim of this study is to determine the sensitivity of HEMA-polymer gel mixture consist of monomer 2-hydroxyethyl methacrylate (HEMA) with different types of composition. Several composition of HEMA-polymer gel were fabricated and the gels were irradiated with radiation dose between 10 cGy to 100cGy by using x-ray machine and 100 cGy to 1400 cGy by using 6 MV photon beam energy of linear accelerator. The degree of polymerization was evaluated by using magnetic resonance imaging (MRI) with dependence of R2-dose response. Polymer gel consists of cross-linker, anti-oxidant Tetrakis(Hydroxymethyl)phosphonium chloride solution (THPC) and oxygen scavenger hydroquinone shows a stable sensitivity with highest dose dependency. Besides, the results shows the stage polymerization consist of induction, propagation, termination, and chain transfer were dependence with type of chemical mixture and radiation dose. Thus, normoxic HEMA-polymer gel with the different gel formulations can have a better dose resolution and an appropriate recipe must be selected to increase of the sensitivity required and the stability of the dosimeter.

A study of normoxic polymer gel using monomer 2-hydroxyethyl methacrylate (HEMA)

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

Ishak, Siti Atiqah; Mustafa, Iskandar Shahrim; Rahman, Azhar Abdul

2015-04-24

The aim of this study is to determine the sensitivity of HEMA-polymer gel mixture consist of monomer 2-hydroxyethyl methacrylate (HEMA) with different types of composition. Several composition of HEMA-polymer gel were fabricated and the gels were irradiated with radiation dose between 10 cGy to 100cGy by using x-ray machine and 100 cGy to 1400 cGy by using 6 MV photon beam energy of linear accelerator. The degree of polymerization was evaluated by using magnetic resonance imaging (MRI) with dependence of R2-dose response. Polymer gel consists of cross-linker, anti-oxidant Tetrakis(Hydroxymethyl)phosphonium chloride solution (THPC) and oxygen scavenger hydroquinone shows a stable sensitivitymore » with highest dose dependency. Besides, the results shows the stage polymerization consist of induction, propagation, termination, and chain transfer were dependence with type of chemical mixture and radiation dose. Thus, normoxic HEMA-polymer gel with the different gel formulations can have a better dose resolution and an appropriate recipe must be selected to increase of the sensitivity required and the stability of the dosimeter.« less

Fundamental study on the characteristics of a radiophotoluminescence glass dosemeter with no energy compensation filter for measuring patient entrance doses in cardiac interventional procedures.

PubMed

Kato, Mamoru; Chida, Koichi; Moritake, Takashi; Koguchi, Yasuhiro; Sato, Tadaya; Oosaka, Hajime; Tosa, Tetsuo; Kadowaki, Ken

2014-12-01

Cardiac interventional procedures have been increasing year by year. However, radiation skin injuries have been still reported. There is a necessity to measure the patient entrance skin dose (ESD), but an accurate dose measurement method has not been established. To measure the ESD, a lot of radiophotoluminescence dosemeters (RPLDs) provide an accurate measurement of the direct actual ESD at the points they are arrayed. The purpose of this study was to examine the characteristics of RPLD to measure the ESD. As a result, X-ray permeable RPLD (with no tin filter) did not interfere with the percutaneous coronary intervention procedure. The RPLD also had good fundamental performance characteristics. Although the RPLD had a little energy dependence, it showed excellent dose and dose-rate linearity, and good angular dependence. In conclusion, by calibrating the energy dependence, RPLDs are useful dosemeter to measure the ESD in cardiac intervention. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cross-sectional and prospective relation of cannabis potency, dosing and smoking behaviour with cannabis dependence: an ecological study.

PubMed

van der Pol, Peggy; Liebregts, Nienke; Brunt, Tibor; van Amsterdam, Jan; de Graaf, Ron; Korf, Dirk J; van den Brink, Wim; van Laar, Margriet

2014-07-01

Increased delta-9-tetrahydrocannabinol (THC) concentrations in cannabis may lead to higher THC exposure, cannabis dependence and treatment need, but users may also adapt the actual intake of THC through reduced inhalation of THC containing smoke (titration). We investigated whether consumers of stronger cannabis use less cannabis per joint or inhale less smoke than those using less potent cannabis and whether these factors predict cannabis dependence severity. Heavy cannabis users (n = 98) brought their own cannabis, rolled a joint and smoked it ad libitum in a naturalistic setting. We analysed the content of the joint, its association with smoking behaviour and the cross-sectional and prospective (1.5-year follow-up) relations between smoking behaviour and cannabis dependence severity (total number of DSM-IV dependence symptoms). THC concentration in cannabis (range 1.10-24.70%) was correlated positively with cannabis dose per joint (b = 0.008, P = 0.01), but the resulting THC concentration per joint (range 0.24-15.72%) was associated negatively with inhalation volume (b = -0.05, P = 0.03). Smoking behaviour measures (number of puffs, inhaled volume, reduction of puff volume and puff duration while smoking) predicted follow-up dependence severity, independently of baseline dependence severity and monthly THC dose (number of joints × cannabis dose × cannabis THC concentration). Monthly THC dose only predicted follow-up dependence severity when unadjusted for baseline severity. Cannabis users titrate their delta-9-tetrahydrocannabinol intake by inhaling lower volumes of smoke when smoking strong joints, but this does not fully compensate for the higher cannabis doses per joint when using strong cannabis. Thus, users of more potent cannabis are generally exposed to more delta-9-tetrahydrocannabinol. Smoking behaviour appears to be a stronger predictor for cannabis dependence severity than monthly delta-9-tetrahydrocannabinol dose. © 2014 Society for the Study of Addiction.

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

PubMed Central

Liebman, Howard A.; Saleh, Mansoor N.; Bussel, James B.; Negrea, O. George; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2016-01-01

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066 PMID:27515248

Dose-dependent biodistribution of prenatal exposure to rutile-type titanium dioxide nanoparticles on mouse testis

NASA Astrophysics Data System (ADS)

Kubo-Irie, Miyoko; Uchida, Hiroki; Mastuzawa, Shotaro; Yoshida, Yasuko; Shinkai, Yusuke; Suzuki, Kenichiro; Yokota, Satoshi; Oshio, Shigeru; Takeda, Ken

2014-02-01

Titanium dioxide nanoparticles (nano-TiO2), believed to be inert and safe, are used in many products especially rutile-type in cosmetics. Detection, localization, and count of nanoparticles in tissue sections are of considerable current interest. Here, we evaluate the dose-dependent biodistribution of rutile-type nano-TiO2 exposure during pregnancy on offspring testes. Pregnant mice were subcutaneously injected five times with 0.1 ml of sequentially diluted of nano-TiO2 powder, 35 nm with primary diameter, suspensions (1, 10, 100, or 1,000 μg/ml), and received total doses of 0.5, 5, 50, and 500 μg, respectively. Prior to injection, the size distribution of nano-TiO2 was analyzed by dynamic light scattering measurement. The average diameter was increased in a dose-dependent manner. The most diluted concentration, 1 μg/ml suspension, contained small agglomerates averaging 193.3 ± 5.4 nm in diameter. The offspring testes were examined at 12 weeks postpartum. Individual particle analysis in testicular sections under scanning and transmission electron microscopy enabled us to understand the biodistribution. The correlation between nano-TiO2 doses injected to pregnant mice, and the number of agglomerates in the offspring testes was demonstrated to be dose-dependent by semiquantitative evaluation. However, the agglomerate size was below 200 nm in the testicular sections of all recipient groups, independent from the injected dose during pregnancy.

The energy dependence of the lateral dose response functions of detectors with various densities in photon-beam dosimetry.

PubMed

Looe, Hui Khee; Harder, Dietrich; Poppe, Björn

2017-02-07

The lateral dose response function is a general characteristic of the volume effect of a detector used for photon dosimetry in a water phantom. It serves as the convolution kernel transforming the true absorbed dose to water profile, which would be produced within the undisturbed water phantom, into the detector-measured signal profile. The shape of the lateral dose response function characterizes (i) the volume averaging attributable to the detector's size and (ii) the disturbance of the secondary electron field associated with the deviation of the electron density of the detector material from the surrounding water. In previous work, the characteristic dependence of the shape of the lateral dose response function upon the electron density of the detector material was studied for 6 MV photons by Monte Carlo simulation of a wall-less voxel-sized detector (Looe et al 2015 Phys. Med. Biol. 60 6585-07). This study is here continued for 60 Co gamma rays and 15 MV photons in comparison with 6 MV photons. It is found (1) that throughout these photon spectra the shapes of the lateral dose response functions are retaining their characteristic dependence on the detector's electron density, and (2) that their energy-dependent changes are only moderate. This appears as a practical advantage because the lateral dose response function can then be treated as practically invariant across a clinical photon beam in spite of the known changes of the photon spectrum with increasing distance from the beam axis.

The role of salsolinol in alcohol intake and withdrawal.

PubMed

Clow, A; Topham, A; Saunders, J B; Murray, R; Sandler, M

1985-01-01

We studied the urinary excretion of the tetrahydroisoquinoline (TIQ) salsolinol, formed from acetaldehyde and dopamine, in both severely and moderately dependent alcoholics during withdrawal from alcohol and subsequent challenge with an acute dose of alcohol and L-dopa, and compared these results with controls. Plasma acetaldehyde and alcohol levels in a sub-population of severely dependent withdrawn alcoholic and control subjects following an acute dose of alcohol were also determined. Salsolinol excretion during the first 4 days of alcohol withdrawal was variable but 10 out of 14 alcoholics showed an increasing trend from day 1 to day 3 and 4 of alcohol withdrawal. L-dopa administration raised salsolinol excretion in controls and withdrawn alcoholics to a uniform extent. Loading of the withdrawn alcoholics with an acute dose of alcohol did not cause an increase in urinary salsolinol concentration (despite increased plasma acetaldehyde). Indeed, 24 h following acute alcohol administration, salsolinol excretion rates were depressed in the alcoholics but not in the controls.

Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay.

PubMed

Waters, E K; Sigh, J; Friedrich, U; Hilden, I; Sørensen, B B

2017-09-01

Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentration-dependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. For the ex vivo spiking study, platelet-poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001-500 nm concizumab. For the multiple-dosing study, four healthy males received concizumab 250 μg kg -1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram ® system with 1 pm tissue factor. In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near-normal levels at concizumab concentrations >10 nm. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy. © 2017 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

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.

Delayed adverse effects of neonatal exposure to diethylstilbestrol and their dose dependency in female rats.

PubMed

Yoshida, Midori; Takahashi, Miwa; Inoue, Kaoru; Hayashi, Seigo; Maekawa, Akihiko; Nishikawa, Akiyoshi

2011-08-01

Neonatal exposure to estrogenic chemicals causes irreversible complex damage to the hypothalamus-pituitary-gonadal axis and reproductive system in females. Some lesions are noted after maturation as delayed adverse effects. We investigated the characteristics and dose dependence of delayed effects using female rats neonatally exposed to diethylstilbestrol (DES). Female Donryu rats were subcutaneously injected with a single dose of DES of 0 (control), 0.15, 1.5, 15, 150, or 1,500 µg/kg bw after birth. All except the lowest dose had estrogenic activity in a uterotrophic assay. All rats at 1500 µg/kg and some at 150 µg/kg showed abnormal morphologies in the genital tract, indicating they were androgenized before maturation. Although no morphological abnormalities were noted at 15 µg/kg or lower, onset of persistent estrus was significantly accelerated in the 1.5, 15, and 150 µg/kg groups with dose dependency, and the latest onset was from seventeen to twenty-one weeks of age at 1.5 µg/kg. The neonatal exposure to DES increased uterine adenocarcinoma development only at 150 µg/kg, although uterine anomalies were detected at 1,500 µg/kg. These results indicate that neonatal exposure to DES, which exerts estrogenic activity in vivo, induces delayed adverse effects in female rats in a dose-dependent manner. Early onset of persistent estrus appears to be the most sensitive parameter.

Risk Assessment in the 21st Century

EPA Science Inventory

For the past ~50 years, risk assessment depended almost exclusively on animal testing for hazard identification and dose-response assessment. Originally sound and effective, with increasing dependence on chemical tools and the number of chemicals in commerce, this traditional app...

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.

The Impact of Disulfiram Treatment on the Reinforcing Effects of Cocaine: A Randomized Clinical Trial

PubMed Central

Haile, Colin N.; De La Garza, Richard; Mahoney, James J.; Nielsen, David A.; Kosten, Thomas R.; Newton, Thomas F.

2012-01-01

Background Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users. Methods Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebo-controlled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05–16) and in the other cocaine (20 mg) or money. Results Participants chose cocaine more than saline under both disulfiram and placebo conditions (p<0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p<0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p<0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's<0.05–0.01). Conclusions Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research. Trial Registration Clinicaltrials.gov NCT00729300 PMID:23144826

Dose Comparisons for a Site-specific Representative Person Using the Age-dependent Dose Coefficients in CAP88-PC Version 4.

PubMed

Stagich, Brooke H; Moore, Kelsey R; Newton, Joseph R; Dixon, Kenneth L; Jannik, G Timothy

2017-04-01

Most U.S. Department of Energy (DOE) facilities with radiological airborne releases use the U.S. Environmental Protection Agency's (EPA) environmental dosimetry code CAP88-PC to demonstrate compliance with regulations in 40CFR61, subpart H [National Emission Standards for Hazardous Air Pollutants: Radiological (NESHAP)]. In 2015, EPA released Version 4 of CAP88-PC, which included significant modifications that improved usability and age-dependent dose coefficients and usage factors for six age groups (infant, 1 y, 5 y, 10 y, 15 y, and adult). However, EPA has not yet provided specific guidance on how to use these age-dependent factors. For demonstrating compliance with DOE public dose regulations, the Savannah River Site (SRS) recently changed from using the maximally exposed individual (MEI) concept (adult male) to the representative person concept (age- and gender-averaged reference person). In this study, dose comparisons are provided between the MEI and a SRS-specific representative person using the age-specific dose coefficients and usage factors in CAP88-PC V.4. Dose comparisons also are provided for each of the six age groups using five radionuclides of interest at SRS (tritium oxide, Cs, Sr, Pu, and I). In general, the total effective dose increases about 11% for the representative person as compared to the current NESHAP MEI because of the inclusion of the more radiosensitive age groups.

Characterization of the ultrasonic attenuation coefficient and its frequency dependence in a polymer gel dosimeter.

PubMed

Crescenti, Remo A; Bamber, Jeffrey C; Partridge, Mike; Bush, Nigel L; Webb, Steve

2007-11-21

Research on polymer-gel dosimetry has been driven by the need for three-dimensional dosimetry, and because alternative dosimeters are unsatisfactory or too slow for that task. Magnetic resonance tomography is currently the most well-developed technique for determining radiation-induced changes in polymer structure, but quick low-cost alternatives remain of significant interest. In previous work, ultrasound attenuation and speed of sound were found to change as a function of absorbed radiation dose in polymer-gel dosimeters, although the investigations were restricted to one ultrasound frequency. Here, the ultrasound attenuation coefficient mu in one polymer gel (MAGIC) was investigated as a function of radiation dose D and as a function of ultrasonic frequency f in a frequency range relevant for imaging dose distributions. The nonlinearity of the frequency dependence was characterized, fitting a power-law model mu = af(b); the fitting parameters were examined for potential use as additional dose readout parameters. In the observed relationship between the attenuation coefficient and dose, the slopes in a quasi-linear dose range from 0 to 30 Gy were found to vary with the gel batch but lie between 0.0222 and 0.0348 dB cm(-1) Gy(-1) at 2.3 MHz, between 0.0447 and 0.0608 dB cm(-1) Gy(-1) at 4.1 MHz and between 0.0663 and 0.0880 dB cm(-1) Gy(-1) at 6.0 MHz. The mean standard deviation of the slope for all samples and frequencies was 15.8%. The slope was greater at higher frequencies, but so were the intra-batch fluctuations and intra-sample standard deviations. Further investigations are required to overcome the observed variability, which was largely associated with the sample preparation technique, before it can be determined whether any frequency is superior to others in terms of accuracy and precision in dose determination. Nevertheless, lower frequencies will allow measurements through larger samples. The fit parameter a of the frequency dependence, describing the attenuation coefficient at 1 MHz, was found to be dose dependent, which is consistent with our expectations, as polymerization is known to be associated with increased absorption of ultrasound. No significant dose dependence was found for the fit parameter b, which describes the nonlinearity with frequency. This is consistent with the increased absorption being due to the introduction of new relaxation processes with characteristic frequencies similar to those of existing processes. The data presented here will help with optimizing the design of future 3D dose-imaging systems using ultrasound methods.

The thermoregulatory mechanism of melatonin-induced hypothermia in chicken.

PubMed

Rozenboim, I; Miara, L; Wolfenson, D

1998-01-01

The involvement of melatonin (Mel) in body temperature (Tb) regulation was studied in White Leghorn layers. In experiment 1, 35 hens were injected intraperitoneally with seven doses of Mel (0, 5, 10, 20, 40, 80, or 160 mg Mel/kg body wt) dissolved in ethanol. Within 1 h, Mel had caused a dose-dependent reduction in Tb. To eliminate a possible vehicle effect, 0, 80, and 160 mg/kg body wt Mel dissolved in N-methyl-2-pyrrolidone (NMP) was injected. NMP had no effect on Tb, with Mel again causing a dose-dependent hypothermia. In experiment 2 (n = 30), Mel injected before exposure of layers to heat reduced Tb and prevented heat-induced hyperthermia. Injection after heat stress had begun did not prevent hyperthermia. Under cold stress, Mel induced hypothermia, which was not observed in controls. In experiment 3 (n = 12), Mel injection reduced Tb and increased metatarsal and comb temperatures (but not feathered-skin temperature), respiratory rate, and evaporative water loss. Heart rate rose and then declined, and blood pressure increased 1 h after Mel injection. Heat production rose slightly during the first hour, then decreased in parallel to the Tb decline. We conclude that pharmacological doses of Mel induce hypothermia in hens by increasing nonevaporative skin heat losses and slightly increasing respiratory evaporation.

Somapacitan, a once-weekly reversible albumin-binding GH derivative, in children with GH deficiency: A randomized dose-escalation trial.

PubMed

Battelino, Tadej; Rasmussen, Michael Højby; De Schepper, Jean; Zuckerman-Levin, Nehama; Gucev, Zoran; Sävendahl, Lars

2017-10-01

To evaluate the safety, local tolerability, pharmacodynamics and pharmacokinetics of escalating single doses of once-weekly somapacitan, a reversible, albumin-binding GH derivative, vs once-daily GH in children with GH deficiency (GHD). Phase 1, randomized, open-label, active-controlled, dose-escalation trial (NCT01973244). Thirty-two prepubertal GH-treated children with GHD were sequentially randomized 3:1 within each of four cohorts to a single dose of somapacitan (0.02, 0.04, 0.08 and 0.16 mg/kg; n=6 each), or once-daily Norditropin ® SimpleXx ® (0.03 mg/kg; n=2 each) for 7 days. Pharmacokinetic and pharmacodynamic profiles were assessed. Adverse events were all mild, and there were no apparent treatment-dependent patterns in type or frequency. Four mild transient injection site reactions were reported in three of 24 children treated with somapacitan. No antisomapacitan/anti-human growth hormone (hGH) antibodies were detected. Mean serum concentrations of somapacitan increased in a dose-dependent but nonlinear manner: maximum concentration ranged from 21.8 ng/mL (0.02 mg/kg dose) to 458.4 ng/mL (0.16 mg/kg dose). IGF-I and IGFBP-3, and change from baseline in IGF-I standard deviation score (SDS) and IGFBP-3 SDS, increased dose dependently; greatest changes in SDS values were seen for 0.16 mg/kg. IGF-I SDS values were between -2 and +2 SDS, except for peak IGF-I SDS with 0.08 mg/kg somapacitan. Postdosing, IGF-I SDS remained above baseline levels for at least 1 week. Single doses of once-weekly somapacitan (0.02-0.16 mg/kg) were well tolerated in children with GHD, with IGF-I profiles supporting a once-weekly treatment profile. No clinically significant safety/tolerability signals or immunogenicity concerns were identified. © 2017 The Authors. Clinical Endocrinology Published by John Wiley & Sons Ltd.

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

Influence of vector dose on factor IX-specific T and B cell responses in muscle-directed gene therapy.

PubMed

Herzog, Roland W; Fields, Paul A; Arruda, Valder R; Brubaker, Jeff O; Armstrong, Elina; McClintock, Darryl; Bellinger, Dwight A; Couto, Linda B; Nichols, Timothy C; High, Katherine A

2002-07-20

Intramuscular injection of an adeno-associated virus (AAV) vector has resulted in vector dose-dependent, stable expression of canine factor IX (cF.IX) in hemophilia B dogs with an F.IX missense mutation (Herzog et al., Nat. Med. 1999;5:56-63). The use of a species-specific transgene allowed us to study risks and characteristics of antibody formation against the therapeutic transgene product. We analyzed seven dogs that had been injected at a single time point at multiple intramuscular sites with varying vector doses (dose per kilogram, dose per animal, dose per site). Comparison of individual animals suggests an increased likelihood of inhibitory anti-cF.IX (inhibitor) development with increased vector doses, with dose per site showing the strongest correlation with the risk of inhibitor formation. In six of seven animals, such immune responses were either absent or transient, and therefore did not prevent sustained systemic expression of cF.IX. Transient inhibitory/neutralizing anti-cF.IX responses occurred at vector doses of 2 x 10(12)/site, whereas a 6-fold higher dose resulted in a longer lasting, higher titer inhibitor. Anti-cF.IX was efficiently blocked in an eighth animal that was injected with a high vector dose per site, but in addition received transient immune suppression. Inhibitor formation was characterized by synthesis of two IgG subclasses and in vitro proliferation of lymphocytes to cF.IX antigen, indicating a helper T cell-dependent mechanism. Anti-cF.IX formation is likely influenced by the extent of local antigen presentation and may be avoided by limited vector doses or by transient immune modulation.

The Effect of Diagnostic Absorbed Doses from 131I on Human Thyrocytes in Vitro.

PubMed

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

2015-06-29

Administration of diagnostic activities of 131I, performed in order to detect thyroid remnants after surgery and/or thyroid cancer recurrence/metastases, may lead to reduction of iodine uptake. This phenomenon is called "thyroid stunning". We estimated radiation absorbed dose-dependent changes in genetic material, in particular in sodium iodide symporter (NIS) gene promoter, and NIS protein level in human thyrocytes (HT). We used unmodified HT isolated from patients subjected to thyroidectomy exposed to 131I in culture. The different 131I activities applied were calculated to result in absorbed doses of 5, 10, and 20 Gy. According to flow cytometry analysis and comet assay, 131I did not influence the HT viability in culture. Temporary increase of 8-oxo-dG concentration in HT directly after 24 h (p < 0.05) and increase in the number of AP-sites 72 h after termination of exposition to 20 Gy dose (p < 0.0001) were observed. The signs of dose-dependent DNA damage were not associated with essential changes in the NIS expression on mRNA and protein levels. Our observation constitutes a first attempt to evaluate the effect of the absorbed dose of 131I on HT. The results have not confirmed the theory that the "thyroid stunning" reduces the NIS protein synthesis.

Dietary Phytochemicals Promote Health by Enhancing Antioxidant Defence in a Pig Model.

PubMed

Selby-Pham, Sophie N B; Cottrell, Jeremy J; Dunshea, Frank R; Ng, Ken; Bennett, Louise E; Howell, Kate S

2017-07-14

Phytochemical-rich diets are protective against chronic diseases and mediate their protective effect by regulation of oxidative stress (OS). However, it is proposed that under some circumstances, phytochemicals can promote production of reactive oxygen species (ROS) in vitro, which might drive OS-mediated signalling. Here, we investigated the effects of administering single doses of extracts of red cabbage and grape skin to pigs. Blood samples taken at baseline and 30 min intervals for 4 hours following intake were analyzed by measures of antioxidant status in plasma, including Trolox equivalent antioxidant capacity (TEAC) and glutathione peroxidase (GPx) activity. In addition, dose-dependent production of hydrogen peroxide (H₂O₂) by the same extracts was measured in untreated commercial pig plasma in vitro. Plasma from treated pigs showed extract dose-dependent increases in non-enzymatic (plasma TEAC) and enzymatic (GPx) antioxidant capacities. Similarly, extract dose-dependent increases in H₂O₂ were observed in commercial pig plasma in vitro. The antioxidant responses to extracts by treated pigs were highly correlated with their respective yields of H₂O₂ production in vitro. These results support that dietary phytochemicals regulate OS via direct and indirect antioxidant mechanisms. The latter may be attributed to the ability to produce H₂O₂ and to thereby stimulate cellular antioxidant defence systems.

Effects of low dose treatment of tributyltin on the regulation of estrogen receptor functions in MCF-7 cells.

PubMed

Sharan, Shruti; Nikhil, Kumar; Roy, Partha

2013-06-01

Endocrine disrupting chemicals are the natural/synthetic compounds which mimic or inhibit the actions of endogenous hormones. Organotin compounds, such as tributyltin (TBT) are typical environmental contaminants and suspected endocrine-disrupting chemical. The present study evaluates the estrogenic potential of this compound in vitro in ER (+) breast adenocarcinoma, MCF-7 cell line. Our data showed that tributyltin chloride (TBTCl) had agonistic activities for estrogen receptor-α (ER-α). Its estrogenic potential was checked using cell proliferation assay, aromatase assay, transactivation assay, and protein expression analysis. Low dose treatment of TBTCl had a proliferative effect on MCF-7 cells and resulted in up-regulation of aromatase enzyme activity and enhanced estradiol production in MCF-7 cells. Immunofluorescence staining showed translocation of ER-α from cytoplasm to nucleus and increased expression of ER-α, 3β-HSD and aromatase on treatment with increasing doses of TBTCl. Further, to decipher the probable signaling pathways involved in its action, the MCF-7 cells were transfected with different pathway dependent luciferase reporter plasmids (CRE, SRE, NF-κB and AP1). A significant increase in CRE and SRE and decrease in NF-κB regulated pathway were observed (p<0.05). Our results thus showed that the activation of SRE by TBTCl may be due to ligand dependent ER-α activation of the MAPK pathway and increased phosphorylation of ERK. In summary, the present data suggests that low dose of tributyltin genomically and non-genomically augmented estrogen dependent signaling by targeting various pathways. Copyright © 2013 Elsevier Inc. All rights reserved.

Evaluation of the RBC Pig-a and PIGRET assays using single doses of hydroxyurea and melphalan in rats.

PubMed

Adachi, Hideki; Uematsu, Yasuaki; Yamada, Toru

2016-11-15

To evaluate the suitability of the rat Pig-a assay on reticulocytes (PIGRET assay) as a short-term test, red blood cell (RBC) Pig-a and PIGRET assays after single doses with hydroxyurea (HU) and melphalan (L-PAM) were conducted and the results of both assays were compared. HU was administered once orally to male SD rats at 250, 500 and 1000mg/kg, and both assays were conducted using peripheral blood withdrawn from the jugular vein at 1, 2 and 4 weeks after dosing. L-PAM was administered at 1.25, 2.5 and 5mg/kg in the same manner. L-PAM produced significant dose-dependent increases in mutant frequencies in the PIGRET assay after single oral doses, but did not produce dose-dependent increases in mutant frequencies in the RBC Pig-a assay. These results suggest that the PIGRET assay is more sensitive for the evaluation of the mutagenic potential of L-PAM than the RBC Pig-a assay. In contrast, HU, a clastogenic but not DNA-reactive compound, gave negative results in both assays. The results with these 2 chemicals indicate that the single-dose PIGRET assay in rats has the potential to properly detect DNA-reactive compounds that directly cause DNA damage in a short-term assay. Copyright © 2016 Elsevier B.V. All rights reserved.

Risk Assessment in the 21st Century - Conference Abstract

EPA Science Inventory

For the past ~50 years, risk assessment depended almost exclusively on animal testing for hazard identification and dose-response assessment. Originally sound and effective, with increasing dependence on chemical tools and the number of chemicals in commerce, this traditional ap...

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.

Memory effects of Aronia melanocarpa fruit juice in a passive avoidance test in rats.

PubMed

Valcheva-Kuzmanova, Stefka V; Eftimov, Miroslav Tz; Tashev, Roman E; Belcheva, Iren P; Belcheva, Stiliana P

2014-01-01

To study the effect of Aronia melanocarpa fruit juice on memory in male Wistar rats. The juice was administered orally for 7, 14, 21 and 30 days at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg. Memory was assessed in the one-way passive avoidance task (step through) which consisted of one training session and two retention tests (3 hours and 24 hours after training). The variables measured were the latency time to step into the dark compartment of the apparatus and the learning criterion (remaining in the illuminated compartment for at least 180 sec). Oral administration of Aronia melanocarpa fruit juice for 7 and 14 days resulted in a dose-dependent tendency to increase the latency time and the learning criterion compared to saline-treated controls but the effect failed to reach statistical significance. After 21 days of treatment, the juice dose-dependently prolonged the latency time at the retention tests, the effect being significant at doses of 5 ml/kg and 10 ml/kg. Applied for 30 days, the juice in all the tested doses increased significantly the latency time at the retention tests and the dose of 10 ml/kg significantly increased the percentage of rats reaching the learning criterion. These findings suggest that Aronia melanocarpa fruit juice could improve memory in rats. The effect is probably due to the polyphenolic ingredients of the juice which have been shown to be involved in learning and memory processes.

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.

MK-801 increases locomotor activity in a context-dependent manner in zebrafish.

PubMed

Tran, Steven; Muraleetharan, Arrujyan; Fulcher, Niveen; Chatterjee, Diptendu; Gerlai, Robert

2016-01-01

Zebrafish have become a popular animal model for behavioral neuroscience with an increasing number of studies examining the effects of pharmacological compounds targeting the brain. Exposure to MK-801, a non-competitive N-methyl-d-aspartate receptor antagonist has been shown to increase locomotor activity in zebrafish. However, others have failed to replicate this finding as several contradicting studies report no changes in locomotor activity following exposure to similar doses. In the current study we reconcile these behavioral reports by demonstrating that zebrafish do not exhibit changes in locomotor activity during exposure to non-sedative doses of MK-801. Interestingly, zebrafish do exhibit significant increases in locomotion if pre-treated with MK-801 followed by subsequent testing in a novel environment, which suggests the effects of MK-801 are context-dependent. In addition, we examine the potential role of the dopaminergic system in mediating MK-801's locomotor stimulant effect by quantifying the levels of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the brains of zebrafish following a 30 min exposure to 10 μM of MK-801 (the dose found to induce the largest increase in locomotor activity). Our findings indicate that the MK-801-induced increase in locomotor activity is not accompanied by changes in whole-brain levels of dopamine or DOPAC. Overall, our results suggest that MK-801's context-dependent locomotor stimulant effect may be independent of whole-brain dopaminergic activation. Copyright © 2015 Elsevier B.V. All rights reserved.

Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

PubMed

Harvey-Lewis, Colin; Perdrizet, Johnna; Franklin, Keith B J

2014-07-01

Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

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.

Effect of radiation processing on meat tenderisation

NASA Astrophysics Data System (ADS)

Kanatt, Sweetie R.; Chawla, S. P.; Sharma, Arun

2015-06-01

The effect of radiation processing (0, 2.5, 5 and 10 kGy) on the tenderness of three types of popularly consumed meat in India namely chicken, lamb and buffalo was investigated. In irradiated meat samples dose dependant reduction in water holding capacity, cooking yield and shear force was observed. Reduction in shear force upon radiation processing was more pronounced in buffalo meat. Protein and collagen solubility as well as TCA soluble protein content increased on irradiation. Radiation processing of meat samples resulted in some change in colour of meat. Results suggested that irradiation leads to dose dependant tenderization of meat. Radiation processing of meat at a dose of 2.5 kGy improved its texture and had acceptable odour.

The Effects of ELDRS at Ultra-Low Dose Rates

NASA Technical Reports Server (NTRS)

Chen, Dakai; Forney, James; Carts, Martin; Phan, Anthony; Pease, Ronald; Kruckmeyer, Kirby; Cox, Stephen; LaBel, Kenneth; Burns, Samuel; Albarian, Rafi;

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

Inhibition of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus.

PubMed

Chang, Hong-Bin; Chen, Bing-Huei

2015-01-01

The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 μg/mL), demethoxycurcumin (1,147.4 μg/mL), and bisdemethoxycurcumin (190.2 μg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 μg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells.

Inhibition of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus

PubMed Central

Chang, Hong-Bin; Chen, Bing-Huei

2015-01-01

The objectives of this study were to explore the inhibition mechanism of lung cancer cells A549 and H460 by curcuminoid extracts and nanoemulsions prepared from Curcuma longa Linnaeus. In addition, human bronchus epithelial cell line BEAS-2B (normal cell) was selected for comparison. A high-performance liquid chromatography (HPLC) method was developed to separate and quantify the various curcuminoids in C. longa extract, including curcumin (1,714.5 μg/mL), demethoxycurcumin (1,147.4 μg/mL), and bisdemethoxycurcumin (190.2 μg/mL). A high-stability nanoemulsion composed of Tween 80, water, and curcuminoid extract was prepared, with mean particle size being 12.6 nm. The cell cycle was retarded at G2/M for both the curcuminoid extract and nanoemulsion treatments; however, the inhibition pathway may be different. H460 cells were more susceptible to apoptosis than A549 cells for both curcuminoid extract and nanoemulsion treatments. Growth of BEAS-2B remained unaffected for both the curcuminoid extract and nanoemulsion treatments, with a concentration range from 1 to 4 μg/mL. Also, the activities of caspase-3, caspase-8, and caspase-9 followed a dose-dependent increase for both A549 and H460 cells for both the treatments, accompanied by a dose-dependent increase in cytochrome C expression and a dose-dependent decrease in CDK1 expression. Interestingly, a dose-dependent increase in cyclin B expression was shown for A549 cells for both the treatments, while a reversed trend was found for H460 cells. Both mitochondria and death receptor pathways may be responsible for apoptosis of both A549 and H460 cells. PMID:26345201

Dose validation of PhIP hair level as a biomarker of heterocyclic aromatic amines exposure: a feeding study

PubMed Central

Le Marchand, Loïc; Yonemori, Kim; White, Kami K.; Franke, Adrian A.; Wilkens, Lynne R.; Turesky, Robert J.

2016-01-01

Hair measurement of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a promising biomarker of exposure to this carcinogen formed in cooked meats. However, the dose relationship between normal range intake and hair levels and the modulating effects of CYP1A2 metabolism and hair melanin need to be evaluated. We conducted a randomized, cross-over feeding study among 41 non-smokers using ground beef cooked to two different levels of doneness, 5 days a week for 1 month. PhIP was measured by liquid chromatography/mass spectrometry in food (mean low dose = 0.72 µg/serving; mean high dose = 2.99 µg/serving), and change in PhIP hair level was evaluated. CYP1A2 activity was assessed in urine with the caffeine challenge test and head hair melanin was estimated by UV spectrophotometry. We observed a strong dose-dependent increase in hair PhIP levels. This increase was highly correlated with dose received (ρ = 0.68, P < 0.0001). CYP1A2 activity and normalizing for hair melanin did not modify the response to the intervention. Consumption of PhIP at doses similar to those in the American diet results in a marked dose-dependent accumulation of PhIP in hair. Hair PhIP levels may be used as a biomarker of dietary exposure in studies investigating disease risk. PMID:27207666

Time and dose-dependence evaluation of nitroheterocyclic drugs for improving efficacy following Trypanosoma cruzi infection: A pre-clinical study.

PubMed

Mazzeti, Ana Lia; Diniz, Lívia de F; Gonçalves, Karolina R; Nascimento, Alvaro F S; Spósito, Pollyanna A F; Mosqueira, Vanessa C F; Machado-Coelho, George L L; Ribeiro, Isabela; Bahia, Maria T

2018-02-01

Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3-10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term.

PubMed

de Zegher, Francis; Hokken-Koelega, Anita

2005-04-01

Approximately 3% of children are born small for gestational age (SGA), and approximately 10% of SGA children maintain a small body size throughout childhood and often into adult life. Among short SGA children, growth hormone (GH) therapy increases short-term growth in a dose-dependent manner; experience with long-term therapy is limited. To delineate the dose dependency of long-term height gain among short SGA children receiving GH therapy. We performed an epianalysis of the first adult height data for SGA children (n = 28) enrolled in 3 randomized trials comparing the growth-promoting efficacy of 2 continuous GH regimens (33 or 67 microg/kg per day for approximately 10 years, starting at approximately 5 years of age); in addition, we performed a meta-analysis of the adult height results published previously and those presented here. Epianalysis outcomes (n = 28) suggested that adult height increased more with a higher-dose regimen than with a lower-dose regimen. In the meta-analysis (n = 82), the higher-dose regimen was found to elicit a long-term height gain superior to that achieved with the lower-dose regimen by a mean of 0.4 SD (approximately 1 inch). Children who were shorter at the start of therapy experienced more long-term height gain. These findings confirm GH therapy as an effective and safe approach to reduce the adult height deficit that short SGA children otherwise face. In addition, the first meta-analysis indicated that height gain is less dose dependent over the long term than over the short term, at least within the dose range explored to date. For SGA children whose stature is not extremely short, current data support the use of a GH dose of approximately 33 microg/kg per day from start to adult height, particularly if treatment starts at a young age; shorter children (for example, height below -3 SD) might benefit from an approach in which short-term catch-up growth is achieved with a higher dose (> or =50 microg/kg per day) and long-term growth to adult height is ensured with a GH dose of approximately 33 mug/kg per day. Because GH-induced accelerations of height and weight gain evolve in parallel, the dose tapering from > or =50 microg/kg to approximately 33 microg/kg can be accomplished by simply maintaining the absolute GH dose (in micrograms) while the child gains weight (in kilograms). With this algorithm, more growth-responsive children taper their GH dose down to approximately 33 microg/kg per day more quickly.

Testosterone Dose Dependently Prevents Bone and Muscle Loss in Rodents after Spinal Cord Injury

PubMed Central

Conover, Christine F.; Beggs, Luke A.; Beck, Darren T.; Otzel, Dana M.; Balaez, Alexander; Combs, Sarah M.; Miller, Julie R.; Ye, Fan; Aguirre, J. Ignacio; Neuville, Kathleen G.; Williams, Alyssa A.; Conrad, Bryan P.; Gregory, Chris M.; Wronski, Thomas J.; Bose, Prodip K.; Borst, Stephen E.

2014-01-01

Abstract Androgen administration protects against musculoskeletal deficits in models of sex-steroid deficiency and injury/disuse. It remains unknown, however, whether testosterone prevents bone loss accompanying spinal cord injury (SCI), a condition that results in a near universal occurrence of osteoporosis. Our primary purpose was to determine whether testosterone-enanthate (TE) attenuates hindlimb bone loss in a rodent moderate/severe contusion SCI model. Forty (n=10/group), 14 week old male Sprague-Dawley rats were randomized to receive: (1) Sham surgery (T9 laminectomy), (2) moderate/severe (250 kdyne) SCI, (3) SCI+Low-dose TE (2.0 mg/week), or (4) SCI+High-dose TE (7.0 mg/week). Twenty-one days post-injury, SCI animals exhibited a 77–85% reduction in hindlimb cancellous bone volume at the distal femur (measured via μCT) and proximal tibia (measured via histomorphometry), characterized by a >70% reduction in trabecular number, 13–27% reduction in trabecular thickness, and increased trabecular separation. A 57% reduction in cancellous volumetric bone mineral density (vBMD) at the distal femur and a 20% reduction in vBMD at the femoral neck were also observed. TE dose dependently prevented hindlimb bone loss after SCI, with high-dose TE fully preserving cancellous bone structural characteristics and vBMD at all skeletal sites examined. Animals receiving SCI also exhibited a 35% reduction in hindlimb weight bearing (triceps surae) muscle mass and a 22% reduction in sublesional non-weight bearing (levator ani/bulbocavernosus [LABC]) muscle mass, and reduced prostate mass. Both TE doses fully preserved LABC mass, while only high-dose TE ameliorated hindlimb muscle losses. TE also dose dependently increased prostate mass. Our findings provide the first evidence indicating that high-dose TE fully prevents hindlimb cancellous bone loss and concomitantly ameliorates muscle loss after SCI, while low-dose TE produces much less profound musculoskeletal benefit. Testosterone-induced prostate enlargement, however, represents a potential barrier to the clinical implementation of high-dose TE as a means of preserving musculoskeletal tissue after SCI. PMID:24378197

The effect of a booster dose of quadrivalent or bivalent HPV vaccine when administered to girls previously vaccinated with two doses of quadrivalent HPV vaccine.

PubMed

Gilca, Vladimir; Sauvageau, Chantal; Boulianne, Nicole; De Serres, Gatson; Crajden, Mel; Ouakki, Manale; Trevisan, Andrea; Dionne, Marc

2015-01-01

This randomized, blinded study evaluated the immunogenicity and safety of a booster dose of Gardasil (qHPV) or Cervarix (bHPV) when administered to 12-13 year-old girls who were vaccinated at the age of 9-10 with 2 doses of qHPV (0-6 months). 366 out of 416 eligible girls participated in this follow-up study. Antibody titers were measured just before and one month post-booster. A Luminex Total IgG assay was used for antibody assessment and results are presented in Liminex Units (LU). Three years post-primary vaccination, 99-100% of subjects had detectable antibodies to 4HPV genotypes included in the qHPV with GMTs varying from 50 to 322 LU depending on genotype. After a booster dose of qHPV, a ≥4 fold increase of antibody titers to genotypes included in the vaccine was observed in 88-98% of subjects. Post-booster GMTs varied from 1666 to 4536 LU depending on genotype. These GMTs were 1.1 to 1.8-fold higher when compared to those observed one month post-second dose. After a booster of bHPV, a ≥4 fold increase of antibody titers to HPV16 and HPV18 was observed in 93-99% of subjects. The anti-HPV16 and HPV18 GMTs were 5458 and 2665 LU, respectively. These GMTs were 1.2 and 1.8 higher than those observed in the qHPV group (both P < 0.01). In bHPV group a 1.4-1.6-fold increase of antibody GMTs to HPV6 and HPV11was also observed (P < 0.001). The safety profile was acceptable for both vaccines. Both qHPV and bHPV increase antibody titers when given as a booster to girls previously vaccinated with 2 doses of qHPV. The magnitude of the immune response after booster is vaccine-dependent and has the same pattern as that reported after primary vaccination with qHPV or bHPV. When given as a booster, both vaccines have an acceptable safety profile. Longer follow-up studies are warranted to assess the need of booster doses.

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.

Disposition of inorganic mercury in pregnant rats and their offspring

PubMed Central

Oliveira, Cláudia S.; Joshee, Lucy; Zalups, Rudolfs K.; Pereira, Maria E.; Bridges, Christy C.

2015-01-01

Environmental toxicants such as methylmercury have been shown to negatively impact fetal health. Despite the prevalence of inorganic mercury (Hg2+) in the environment and the ability of methylmercury to biotransform into Hg2+, little is known about the ability of Hg2+ to cross the placenta into fetal tissues. Therefore, it is important to understand the handing and disposition of Hg2+ in the reproductive system. The purpose of the current study was to assess the disposition and transport of Hg2+ in placental and fetal tissues, and to test the hypothesis that acute renal injury in dams can alter the accumulation of Hg2+ in fetal tissues. Pregnant Wistar rats were injected intravenously with 0.5 or 2.5 μmol kg−1 HgCl2 for 6 or 48 h and the disposition of Hg2+ was measured. Accumulation of Hg2+ in the placenta was rapid and dose-dependent. Very little Hg2+ was eliminated during the initial 48 h after exposure. When dams were exposed to the low dose of HgCl2, fetal accumulation of Hg2+ increased between 6 h and 48 h, while at the higher dose, accumulation was similar at each time point. Within fetal organs, the greatest concentration of Hg2+ (nmol/g) was localized in the kidneys, followed by the liver and brain. A dose-dependent increase in the accumulation of Hg2+ in fetal organs was observed, suggesting that continued maternal exposure may lead to increased fetal exposure. Taken together, these data indicate that Hg2+ is capable of crossing the placenta and gaining access to fetal organs in a dose-dependent manner. PMID:26196528

Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans

PubMed Central

Lofwall, Michelle R.; Babalonis, Shanna; Nuzzo, Paul A.; Elayi, Samy Claude; Walsh, Sharon L.

2016-01-01

Background The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. Methods Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21 hours before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. Results Oxycodone produced prototypic opioid agonist effects (i.e., suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. Conclusion CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. PMID:27234658

Immunomodulatory effect of Moringa peregrina leaves, ex vivo and in vivo study

PubMed Central

Al-Oran, Sawsan Atallah; Hassuneh, Mona Rushdie; Al-Qaralleh, Haitham Naief; Rayyan, Walid Abu; Al-Thunibat, Osama Yosef; Mallah, Eyad; Abu-Rayyan, Ahmed; Salem, Shadi

2017-01-01

This study was conducted to assess the in vivo and ex vivo immunomodulatory effect of the ethanol leaves extract of Moringa peregrina in Balb/c mice. For this study, five groups of 5 Balb/c mice were given a single acute subtoxic oral dose of the ethanolic extract at 1.13, 11.30, 23.40 and 113.4 mg/kg and the immunomodulatory effect was assessed on the 6th day following the ingestion. In the (non-functional) assessment, the effect of the extract on the body weight, relative lymphoid organ weight, splenic cellularity and peripheral blood hematologic parameters were evaluated. While in the immunomodulation assessment (functional), we investigated the effect of the extract on the proliferative capacity of splenic lymphocytes and peripheral T and B lymphocytes using mitogen blastogenesis, mixed allogeneic MLR and IgM-Plaque forming cells assays. The ingestion of M. peregrina extract caused a significant increase in the body weight, weight and number of cells of spleen and lymph nodes of the treated mice. Furthermore, the count of RBCs, WBCs, platelets, hemoglobin concentration and PCV % were increased by the extract treatment in a dose-dependent manner. M. peregrina enhanced the proliferative responses of splenic lymphocytes for both T cell and B-cell mitogens. Likewise, the mixed lymphocyte reaction MLR assay has revealed a T-cell dependent proliferation enhancement in the extract treated mice. Moreover, the oral administration of M. peregrina leaves extracts significantly increased PFCs/106 splenocytes in a dose-dependent manner. In conclusion, subtoxic acute doses of M. peregrina extract demonstrated significant potential as an immunomodulatory agent even at the lowest dose of 1.13 mg/kg. PMID:29204086

Clinical application of the OneDose Patient Dosimetry System for total body irradiation.

PubMed

Best, S; Ralston, A; Suchowerska, N

2005-12-21

The OneDose Patient Dosimetry System (Sicel Technologies) is a new dosimeter based on metal oxide semiconductor field-effect transistor technology and designed for the in vivo measurement of patient dose during radiotherapy. In vivo dosimetry for total body irradiation (TBI) is challenging due to the extended treatment distance, low dose rates and beam spoilers. Phantom results confirm the suitability of the dosimeter for TBI in terms of inherent build-up, post-irradiation fading, accuracy, reproducibility, linearity and temperature dependence. Directional dependence is significant and should be taken into account. The OneDose dosimeters were also trialed in vivo for two TBI patients and the dose measured compared to conventional dosimeter measurements using an ionization chamber and thermoluminescent dosimeters (TLD), with agreement to within 2.2% and 3.9%, respectively. Phantom and patient results confirm that the OneDose patient dosimetry system is a practical and convenient alternative to TLDs for TBI in vivo dosimetry. For increased confidence in results with this dosimeter, we recommend that two dosimeters be used for each site of interest.

Low-dose γ-radiation-induced oxidative stress response in mouse brain and gut: regulation by NFκB-MnSOD cross-signaling.

PubMed

Veeraraghavan, Jamunarani; Natarajan, Mohan; Herman, Terence S; Aravindan, Natarajan

2011-01-10

Radiation-induced amplification of reactive oxygen species (ROS) may be a sensing mechanism for activation of signaling cascades that influence cell fate. However, the regulated intrinsic mechanisms and targets of low-dose ionizing radiation (LDIR) are still unclear. Accordingly, we investigated the effects of LDIR on NFκB signal transduction and manganese superoxide dismutase (SOD2) activity in mice brain and gut. LDIR resulted in both dose-dependent and persistent NFκB activation in gut and brain. QPCR displayed a dose- and tissue-dependent differential modulation of 88 signaling molecules. With stringent criteria, a total of 15 (2cGy), 43 (10cGy) and 19 (50cGy) genes were found to be commonly upregulated between brain and gut. SOD2 immunostaining showed a LDIR-dose dependent increase. Consistent with the NFκB results, we observed a persistent increase in SOD2 activity after LDIR. Moreover, muting of LDIR-induced NFκB attenuated SOD2 transactivation and cellular localization. These results imply that exposure of healthy tissues to LDIR results in induced NFκB and SOD2 activity and transcriptional activation of NFκB-signal transduction/target molecules. More importantly, the results suggest that NFκB initiates a feedback response through transcriptional activation of SOD2 that may play a key role in the LDIR-induced oxidative stress response and may control the switch that directs cell fate. 2010 Elsevier B.V. All rights reserved.

In vivo antioxidant activity of deacetylasperulosidic Acid in noni.

PubMed

Ma, De-Lu; Chen, Mai; Su, Chen X; West, Brett J

2013-01-01

Deacetylasperulosidic acid (DAA) is a major phytochemical constituent of Morinda citrifolia (noni) fruit. Noni juice has demonstrated antioxidant activity in vivo and in human trials. To evaluate the role of DAA in this antioxidant activity, Wistar rats were fed 0 (control group), 15, 30, or 60 mg/kg body weight per day for 7 days. Afterwards, serum malondialdehyde concentration and superoxide dismutase and glutathione peroxidase activities were measured and compared among groups. A dose-dependent reduction in malondialdehyde was evident as well as a dose-dependent increase in superoxide dismutase activity. DAA ingestion did not influence serum glutathione peroxidase activity. These results suggest that DAA contributes to the antioxidant activity of noni juice by increasing superoxide dismutase activity. The fact that malondialdehyde concentrations declined with increased DAA dose, despite the lack of glutathione peroxidase-inducing activity, suggests that DAA may also increase catalase activity. It has been previously reported that noni juice increases catalase activity in vivo but additional research is required to confirm the effect of DAA on catalase. Even so, the current findings do explain a possible mechanism of action for the antioxidant properties of noni juice that have been observed in human clinical trials.

In Vivo Antioxidant Activity of Deacetylasperulosidic Acid in Noni

PubMed Central

Ma, De-Lu; Chen, Mai; Su, Chen X.; West, Brett J.

2013-01-01

Deacetylasperulosidic acid (DAA) is a major phytochemical constituent of Morinda citrifolia (noni) fruit. Noni juice has demonstrated antioxidant activity in vivo and in human trials. To evaluate the role of DAA in this antioxidant activity, Wistar rats were fed 0 (control group), 15, 30, or 60 mg/kg body weight per day for 7 days. Afterwards, serum malondialdehyde concentration and superoxide dismutase and glutathione peroxidase activities were measured and compared among groups. A dose-dependent reduction in malondialdehyde was evident as well as a dose-dependent increase in superoxide dismutase activity. DAA ingestion did not influence serum glutathione peroxidase activity. These results suggest that DAA contributes to the antioxidant activity of noni juice by increasing superoxide dismutase activity. The fact that malondialdehyde concentrations declined with increased DAA dose, despite the lack of glutathione peroxidase-inducing activity, suggests that DAA may also increase catalase activity. It has been previously reported that noni juice increases catalase activity in vivo but additional research is required to confirm the effect of DAA on catalase. Even so, the current findings do explain a possible mechanism of action for the antioxidant properties of noni juice that have been observed in human clinical trials. PMID:24371540

Somatostatin increases glucocorticoid binding and signaling in macrophages by blocking the calpain-specific cleavage of Hsp 90.

PubMed

Bellocq, A; Doublier, S; Suberville, S; Perez, J; Escoubet, B; Fouqueray, B; Puyol, D R; Baud, L

1999-12-24

Somatostatin has direct anti-inflammatory actions and participates in the anti-inflammatory actions of glucocorticoids, but the mechanisms underlying this regulation remain poorly understood. The objective of this study was to evaluate whether somatostatin increases glucocorticoid responsiveness by up-regulating glucocorticoid receptor (GR) expression and signaling. Somatostatin promoted a time- and dose-dependent increase in [(3)H]dexamethasone binding to RAW 264.7 macrophages. Cell exposure to 10 nM somatostatin for 18 h promoted a 2-fold increase in the number of GR sites per cell without significant modification of the affinity. Analysis of GR heterocomplex components demonstrated that somatostatin increased the level of heat shock protein (Hsp) 90, whereas the level of GR remained almost unchanged. The increase in Hsp 90 was associated with a decrease in the cleavage of its carboxyl-terminal domain. Evidence for the involvement of calpain inhibition in this process was obtained by the demonstration that 1) somatostatin induced a dose-dependent decrease in calpain activity and 2) calpain inhibitors, calpain inhibitor I and calpeptin, both abolished the cleavage of Hsp 90 and induced a dose-dependent increase in [(3)H]dexamethasone binding. Increases in glucocorticoid binding after somatostatin treatment were associated with similar increases in the ability of GR to transactivate a minimal promoter containing two glucocorticoid response elements (GRE) and to interfere with the activation of nuclear factor-kappaB (NF-kappaB). Thus, the present findings indicate that somatostatin increases glucocorticoid binding and signaling by limiting the calpain-specific cleavage of GR-associated Hsp 90. This mechanism may represent a novel target for intervention to increase glucocorticoid responsiveness.

Normal tissue complication probability modelling of tissue fibrosis following breast radiotherapy

NASA Astrophysics Data System (ADS)

Alexander, M. A. R.; Brooks, W. A.; Blake, S. W.

2007-04-01

Cosmetic late effects of radiotherapy such as tissue fibrosis are increasingly regarded as being of importance. It is generally considered that the complication probability of a radiotherapy plan is dependent on the dose uniformity, and can be reduced by using better compensation to remove dose hotspots. This work aimed to model the effects of improved dose homogeneity on complication probability. The Lyman and relative seriality NTCP models were fitted to clinical fibrosis data for the breast collated from the literature. Breast outlines were obtained from a commercially available Rando phantom using the Osiris system. Multislice breast treatment plans were produced using a variety of compensation methods. Dose-volume histograms (DVHs) obtained for each treatment plan were reduced to simple numerical parameters using the equivalent uniform dose and effective volume DVH reduction methods. These parameters were input into the models to obtain complication probability predictions. The fitted model parameters were consistent with a parallel tissue architecture. Conventional clinical plans generally showed reducing complication probabilities with increasing compensation sophistication. Extremely homogenous plans representing idealized IMRT treatments showed increased complication probabilities compared to conventional planning methods, as a result of increased dose to areas receiving sub-prescription doses using conventional techniques.

Opioid Abstinence Reinforcement Delays Heroin Lapse during Buprenorphine Dose Tapering

ERIC Educational Resources Information Center

Greenwald, Mark K.

2008-01-01

A positive reinforcement contingency increased opioid abstinence during outpatient dose tapering (4, 2, then 0 mg/day during Weeks 1 through 3) in non-treatment-seeking heroin-dependent volunteers who had been maintained on buprenorphine (8 mg/day) during an inpatient research protocol. The control group (n = 12) received $4.00 for completing…

Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance.

PubMed

Preston, K L; Umbricht, A; Epstein, D H

2000-04-01

Although methadone maintenance is an effective therapy for heroin dependence, some patients continue to use heroin and may benefit from therapeutic modifications. This study evaluated a behavioral intervention, a pharmacological intervention, and a combination of both interventions. Throughout the study all patients received daily methadone hydrochloride maintenance (initially 50 mg/d orally) and weekly counseling. Following baseline treatment patients who continued to use heroin were randomly assigned to 1 of 4 interventions: (1) contingent vouchers for opiate-negative urine specimens (n = 29 patients); (2) methadone hydrochloride dose increase to 70 mg/d (n = 31 patients); (3) combined contingent vouchers and methadone dose increase (n = 32 patients); and (4) neither intervention (comparison standard; n = 28 patients). Methadone dose increases were double blind. Vouchers had monetary value and were exchangeable for goods and services. Groups not receiving contingent vouchers received matching vouchers independent of urine test results. Primary outcome measure was opiate-negative urine specimens (thrice weekly urinalysis). Contingent vouchers and a methadone dose increase each significantly increased the percentage of opiate-negative urine specimens during intervention. Contingent vouchers, with or without a methadone dose increase, increased the duration of sustained abstinence as assessed by urine screenings. Methadone dose increase, with or without contingent vouchers, reduced self-reported frequency of use and self-reported craving. In patients enrolled in a methadone-maintainence program who continued to use heroin, abstinence reinforcement and a methadone dose increase were each effective in reducing use. When combined, they did not dramatically enhance each other's effects on any 1 outcome measure, but they did seem to have complementary benefits.

Bacopa monnieri: An evaluation of antihyperglycemic and antinociceptive potential of methanolic extract of whole plants.

PubMed

Taznin, Inin; Mukti, Mohsina; Rahmatullah, Mohammed

2015-11-01

Antihyperglycemic and antinociceptive activity studies were carried out with methanolic extract of whole plants of Bacopa monnieri, respectively, through oral glucose tolerance test and gastric pain model induced by acetic acid in Swiss albino mice. In OGTT (oral glucose tolerance tests) conducted with glucose-challenged mice, the extract, administered at four doses of 50, 100, 200 and 400mg per kg body weight, dose-dependently and significantly inhibited the increase in serum glucose concentrations, respectively, by 33.3, 34.2, 42.1 and 44.2%. A standard antihyperglycemic drug, glibenclamide, when administered at a dose of 10mg per kg body weight, inhibited increase in serum glucose concentration by 50.7%. From the results, it can be concluded that the methanolic extract of the plant possess significant antihyperglycemic potential. In antinociceptive activity tests, administration of the extract at the aforementioned four doses also significantly and dose-dependently reduced the number of acetic acid-induced gastric constrictions in mice. The percent inhibitions in gastric constrictions were, respectively, 43.4, 46.6, 50.0, and 53.4 at the above four doses. A reference antinociceptive drug, aspirin, when administered at a dose of 200 mg per kg body weight, reduced the number of gastric constrictions by 40.0%. Thus the extract at even the lowest dose of 50 mg, demonstrated antinociceptive activity better than that of aspirin, and which activity was much more than aspirin at the other three higher doses tested. The results demonstrate that the plant can be an excellent candidate for further studies towards isolation of antihyperglycemic and pain-killing compounds.

Dose-dependent interaction between gemfibrozil and repaglinide in humans: strong inhibition of CYP2C8 with subtherapeutic gemfibrozil doses.

PubMed

Honkalammi, Johanna; Niemi, Mikko; Neuvonen, Pertti J; Backman, Janne T

2011-10-01

Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P < 0.001), and its peak concentration 1.4-, 1.7-, 2.1-, and 2.4-fold (P < 0.05), compared with placebo, respectively. Gemfibrozil pharmacokinetics was characterized by a slightly more than dose-proportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-repaglinide interaction could be mainly explained by gemfibrozil 1-O-β-glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic anion-transporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ∼50% inhibition of CYP2C8 already with a single 30-mg dose of gemfibrozil and >95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.

Effects of 2-deoxy-D-glucose administration on immune parameters in mice

NASA Technical Reports Server (NTRS)

Dreau, D.; Morton, D. S.; Foster, M.; Fowler, N.; Sonnenfeld, G.

1998-01-01

Physical exercise and diet alterations have been shown to affect immune parameters. Similar effects are also induced by the administration of the non-metabolizable glucose analog, 2-deoxy-D-glucose (2-DG). The current study was designed to characterize the effects of glucoprivation induced by 2-DG administration on leukocyte subset distribution and function. BDF1 mice (n = 8 per group) were injected intraperitoneally one or three times with 0, 500, 750, 1000 or 1500 mg/kg of 2-DG. Two hours after the last injection of 2-DG, immunological parameters were analyzed. A dose-dependent increase in plasma glucose concentrations of mice injected once with up to 1500 mg/kg of 2-DG was observed (p < 0.001). After either one or three injections of up to 1500 mg/kg of 2-DG, corticosterone levels, leukocyte counts in the spleen, and CD3+ cells in the thymus increased. In vitro proliferation of partially purified lymphocytes from the spleen in the presence of both concanavalin-A and lipopolysaccharide decreased in a dose dependent manner (p < 0.05). In addition, after three injections, the proportion of both thymocytes and splenocytes bearing alphabeta-TCR increased as the concentration of 2-DG increased (p < 0.01). These results demonstrate that 2-DG administration induced dose-dependent changes in both thymus and spleen cell distribution and function.

Pharmacokinetics of escin Ia in rats after intravenous administration.

PubMed

Wu, Xiu-Jun; Cui, Xiang-Yong; Tian, Lian-tian; Gao, Feng; Guan, Xin; Gu, Jing-Kai

2014-10-28

Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t₁/₂ was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg/kg after intravenous administration. Escin Ia is isomerized to isoescin Ia rapidly and extensively regardless of the doses. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

SU-E-J-06: Additional Imaging Guidance Dose to Patient Organs Resulting From X-Ray Tubes Used in CyberKnife Image Guidance System

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

Sullivan, A; Ding, G

Purpose: The use of image-guided radiation therapy (IGRT) has become increasingly common, but the additional radiation exposure resulting from repeated image guidance procedures raises concerns. Although there are many studies reporting imaging dose from different image guidance devices, imaging dose for the CyberKnife Robotic Radiosurgery System is not available. This study provides estimated organ doses resulting from image guidance procedures on the CyberKnife system. Methods: Commercially available Monte Carlo software, PCXMC, was used to calculate average organ doses resulting from x-ray tubes used in the CyberKnife system. There are seven imaging protocols with kVp ranging from 60 – 120 kVmore » and 15 mAs for treatment sites in the Cranium, Head and Neck, Thorax, and Abdomen. The output of each image protocol was measured at treatment isocenter. For each site and protocol, Adult body sizes ranging from anorexic to extremely obese were simulated since organ dose depends on patient size. Doses for all organs within the imaging field-of-view of each site were calculated for a single image acquisition from both of the orthogonal x-ray tubes. Results: Average organ doses were <1.0 mGy for every treatment site and imaging protocol. For a given organ, dose increases as kV increases or body size decreases. Higher doses are typically reported for skeletal components, such as the skull, ribs, or clavicles, than for softtissue organs. Typical organ doses due to a single exposure are estimated as 0.23 mGy to the brain, 0.29 mGy to the heart, 0.08 mGy to the kidneys, etc., depending on the imaging protocol and site. Conclusion: The organ doses vary with treatment site, imaging protocol and patient size. Although the organ dose from a single image acquisition resulting from two orthogonal beams is generally insignificant, the sum of repeated image acquisitions (>100) could reach 10–20 cGy for a typical treatment fraction.« less

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.

The total ozone and UV solar radiation over Stara Zagora, Bulgaria

NASA Astrophysics Data System (ADS)

Mendeva, B. D.; Gogosheva, Ts. N.; Petkov, B. H.; Krastev, D. G.

The results from direct ground-based solar UV irradiance measurements and the total ozone content (TOC) over Stara Zagora (42° 25'N, 25° 37'E), Bulgaria are presented. During the period 1999-2003 the TOC data show seasonal variations, typical for the middle latitudes - maximum in the spring and minimum in the autumn. The comparison between TOC ground-based data and Global Ozone Monitoring Experiment (GOME) satellite-borne ones shows a seasonal dependence of the differences between them. A strong negative relationship between the total ozone and the 305 nm wavelength irradiance was found. The dependence between the two variables is significant ( r = -0.62 ± 0.18) at 98% confidence level. The direct sun UV doses for some specific biological effects (erythema and eyes) are obtained. The estimation of the radiation amplification factor RAF shows that the ozone reduction by 1% increases the erythemal dose by 2.3%. The eye-damaging doses are more influenced by the TOC changes and in this case RAF = -2.7%. The amount of these biological doses depended on the solar altitude over the horizon. This dependence was not so strong when the total ozone content in the atmosphere was lower.

Beta-adrenergic and atrial natriuretic peptide interactions on human cardiovascular and metabolic regulation

PubMed Central

Birkenfeld, Andreas L.; Boschmann, Michael; Moro, Cedric; Adams, Frauke; Heusser, Karsten; Tank, Jens; Diedrich, André; Schroeder, Christoph; Franke, Gabi; Berlan, Michel; Luft, Friedrich C.; Lafontan, Max; Jordan, Jens

2006-01-01

Context Atrial natriuretic peptide (ANP) has well known cardiovascular effects and modifies lipid and carbohydrate metabolism in humans. Objective To determine the metabolic and cardiovascular interaction of beta-adrenergic receptors and ANP. Design Cross over study, conducted 2004–2005 Setting Academic clinical research center Patients Ten healthy, young, male subjects (BMI 24±1 kg/m2) Intervention We infused intravenously incremental ANP doses (6.25, 12.5, and 25 ng/kg/min) with and without propranolol (0.20 mg/kg in divided doses followed by 0.033 mg/kg/h infusion). Metabolism was monitored through venous blood sampling, intramuscular and subcutaneous microdialysis and indirect calorimetry. Cardiovascular changes where monitored by continuous ECG and beat-by-beat blood pressure recordings. Main outcome measures Venous NEFA, glycerol, glucose, insulin; microdialysate glucose, glycerol, lactate, pyruvate. Results ANP increased heart rate dose dependently. Beta-adrenergic receptor blockade abolished the response. ANP elicited a dose-dependent increase in serum non-esterified fatty acid and glycerol concentrations. The response was not suppressed with propranolol. Venous glucose and insulin concentrations increased with ANP, both, without or with propranolol. ANP induced lipid mobilization in subcutaneous adipose tissue. In skeletal muscle, microdialysate lactate increased while the lactate to pyruvate ratio decreased, both, with and without propranolol. Higher ANP doses increased lipid oxidation while energy expenditure remained unchanged. Propranolol tended to attenuate the increase in lipid oxidation. Conclusions Selected cardiovascular ANP effects are at least partly mediated by beta-adrenergic receptor stimulation. ANP induced changes in lipid mobilization and glycolysis are mediated by another mechanism, presumably stimulation of natriuretic peptide receptors whereas substrate oxidation might be modulated through adrenergic mechanisms. PMID:16984990

Effects of epidermal growth factor on bone formation and resorption in vivo

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

Marie, P.J.; Hott, M.; Perheentupa, J.

1990-02-01

The effects of mouse epidermal growth factor (EGF) on bone formation and resorption were examined in male mice. EGF administration (2-200 ng.g-1.day-1 ip for 7 days) induced a dose-dependent rise in plasma EGF levels that remained within physiological range. Histomorphometric analysis of caudal vertebrae showed that EGF (20 and 200 ng.g-1.day-1) reduced the endosteal matrix and mineral appositional rates after 5 days of treatment as measured by double (3H)proline labeling and double tetracycline labeling, respectively. This effect was transitory and was not observed after 7 days of EGF administration. EGF administered for 7 days induced a dose-dependent increase in themore » periosteal osteoblastic and tetracycline double-labeled surfaces. At high dosage (200 ng.g-1.day-1) EGF administration increased the osteoclastic surface and the number of acid phosphatase-stained osteoclasts, although plasma calcium remained normal. The results show that EGF administration at physiological doses induces distinct effects on endosteal and periosteal bone formation and that the effects are dependent on EGF dosage and duration of treatment. This study indicates that EGF at physiological dosage stimulates periosteal bone formation and increases endosteal bone resorption in the growing mouse.« less

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.

Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

PubMed

Melichar, Jan K; Hume, Susan P; Williams, Tim M; Daglish, Mark R C; Taylor, Lindsay G; Ahmad, Rabia; Malizia, Andrea L; Brooks, David J; Myles, Judith S; Lingford-Hughes, Anne; Nutt, David J

2005-01-01

Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

Dose Response of Endotoxin on Hepatocyte and Muscle Mitochondrial Respiration In Vitro

PubMed Central

Brandt, Sebastian; Porta, Francesca; Jakob, Stephan M.; Takala, Jukka; Djafarzadeh, Siamak

2015-01-01

Introduction. Results on mitochondrial dysfunction in sepsis are controversial. We aimed to assess effects of LPS at wide dose and time ranges on hepatocytes and isolated skeletal muscle mitochondria. Methods. Human hepatocellular carcinoma cells (HepG2) were exposed to placebo or LPS (0.1, 1, and 10 μg/mL) for 4, 8, 16, and 24 hours and primary human hepatocytes to 1 μg/mL LPS or placebo (4, 8, and 16 hours). Mitochondria from porcine skeletal muscle samples were exposed to increasing doses of LPS (0.1–100 μg/mg) for 2 and 4 hours. Respiration rates of intact and permeabilized cells and isolated mitochondria were measured by high-resolution respirometry. Results. In HepG2 cells, LPS reduced mitochondrial membrane potential and cellular ATP content but did not modify basal respiration. Stimulated complex II respiration was reduced time-dependently using 1 μg/mL LPS. In primary human hepatocytes, stimulated mitochondrial complex II respiration was reduced time-dependently using 1 μg/mL LPS. In isolated porcine skeletal muscle mitochondria, stimulated respiration decreased at high doses (50 and 100 μg/mL LPS). Conclusion. LPS reduced cellular ATP content of HepG2 cells, most likely as a result of the induced decrease in membrane potential. LPS decreased cellular and isolated mitochondrial respiration in a time-dependent, dose-dependent and complex-dependent manner. PMID:25649304

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

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

PubMed

Singer, Daniel E; Hellkamp, Anne S; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R; Piccini, Jonathan P; Hankey, Graeme J; Breithardt, Günter; Halperin, Jonathan L; Becker, Richard C; Hacke, Werner; Nessel, Christopher C; Mahaffey, Kenneth W; Fox, Keith A A; Califf, Robert M

2015-03-03

In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted. TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported. URL: ClinicalTrials.gov. Unique identifier: NCT00403767. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial

PubMed Central

Singer, Daniel E.; Hellkamp, Anne S.; Yuan, Zhong; Lokhnygina, Yuliya; Patel, Manesh R.; Piccini, Jonathan P.; Hankey, Graeme J.; Breithardt, Günter; Halperin, Jonathan L.; Becker, Richard C.; Hacke, Werner; Nessel, Christopher C.; Mahaffey, Kenneth W.; Fox, Keith A. A.; Califf, Robert M.

2015-01-01

Background In the ROCKET AF (Rivaroxaban–Once‐daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter‐INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow‐up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial. Methods and Results We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change–based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in‐range INRs (“corrections”) versus INRs that were out of range in the opposite direction (“overshoots”). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change–based approach, depending on assumptions. However, large inter‐regional differences in anticoagulation control persisted. Conclusions TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow‐up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change–based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter‐regional differences previously reported. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00403767. PMID:25736441

Baclofen for alcohol dependence: Relationships between baclofen and alcohol dosing and the occurrence of major sedation.

PubMed

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

2015-10-01

High-dose baclofen, i.e., 300 mg/d or more, has recently emerged as a strategy for treating alcohol dependence. The impact that the co-exposure of large amounts of alcohol and baclofen has on sedation is unclear. In a prospective cohort of 253 subjects with alcohol dependence, we collected daily alcohol and baclofen doses across the first year of baclofen treatment and the monthly maximum subjective sedation experienced by each patient (0-10 visual analog scale). For each patient-month, we determined the average weekly alcohol consumption (AWAC; standard-drinks/week) and the maximum daily dose of baclofen (DDB; mg/d). The occurrence of an episode of major sedation (EMS) during a patient-month was defined as a sedation score ≥7. The relationship between the EMS occurrence and the concurrent AWAC and DDB was investigated using a generalized estimating equation model. In total, 1528 patient-months were compiled (70 with an EMS). Univariate analyses demonstrated that the rate of patient-month to EMS increased gradually with AWAC (p<0.001), from 0.9% for AWAC=0 to 9.4% for AWAC >35. There was also a significant gradual risk for EMS associated with DDB (<0.001). Multivariate analysis demonstrated a significant interaction between DDB and AWAC on EMS risk (p=0.047). Each 20mg/d increase in DDB was associated with an OR of EMS in AWAC >35 of 1.22 (95%CI, 1.08-1.38) versus 1.11 (95%CI, 0.96-1.29) in AWAC=1-35, and 0.95 (95%CI, 0.76-1.19) in AWAC=0. The level of sedation observed in patients using baclofen for alcohol dependence appears to directly depend on the immediate doses of both the baclofen and the alcohol. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Hormonal regulation of phosphatidylcholine synthesis by reversible modulation of cytidylyltransferase.

PubMed Central

Kelly, K L; Gutierrez, G; Martin, A

1988-01-01

The effect of both lipolytic and antilipolytic hormones on the turnover of phosphatidylcholine in freshly isolated rat adipocytes was investigated. Treatment of adipocytes with agonists such as glucagon or isoprenaline that stimulate lipolysis through a cyclic AMP-dependent mechanism caused an increase in the incorporation of [Me-3H]choline into phosphatidylcholine. Pulse-chase studies indicated that the stimulation was due to an increase in the conversion of choline into phosphatidylcholine, which was both time- and dose-dependent. The stimulatory effect of isoprenaline was inhibited in a dose-dependent manner by oxytocin or insulin. Oxytocin inhibited the incorporation of [Me-3H]choline into phosphatidylcholine in both the presence and the absence of isoprenaline, whereas in the absence of isoprenaline insulin increased the incorporation of [Me-3H]choline into phosphatidylcholine. The effects of isoprenaline, oxytocin and insulin on the incorporation of [3H]choline into phosphatidylcholine were paralleled by changes in the activity of CTP:phosphocholine cytidylyltransferase. PMID:2849424

Vitamin K2 alleviates type 2 diabetes in rats by induction of osteocalcin gene expression.

PubMed

Hussein, Atef G; Mohamed, Randa H; Shalaby, Sally M; Abd El Motteleb, Dalia M

2018-03-01

The biological mechanisms behind the association between vitamin K (Vit K) and glucose metabolism are uncertain. We aimed to analyze the expression of insulin 1 (Ins 1), insulin 2 (Ins 2) and cyclin D2, the expression of adiponectin and UCP-1 . In addition, we aimed to estimate the doses of Vit K2 able to affect various aspects of glucose and energy metabolism in type 2 diabetes. Thirty adult male rats were allocated equally into five groups: control group, diabetes mellitus group, and groups 3, 4, and 5, which received Vit K 2 at three daily dose levels (10, 15, and 30 mg/kg, respectively) for 8 wk. At the end of the study, blood samples were collected to quantify total osteocalcin, fasting plasma glucose, fasting insulin, and relevant variables. The expression of OC, Ins 1, Ins 2, cyclin D2, adiponectin, UCP-1 genes was analyzed by real-time polymerase chain reaction. After administration of Vit K 2 , a dose-dependent decrease in fasting plasma glucose, hemoglobin A1c and homeostatic model assessment method insulin resistance, and a dose-dependent increase in fasting insulin and homeostatic model assessment method β cell function levels, when compared with diabetes mellitus rats, were detected. There was significant upregulation of OC, Ins 1, Ins 2, or cyclin D2 gene expression in the three treated groups in a dose-dependent manner when compared with the diabetic rats. However, expression of adiponectin and UCP-1 were significantly increased at the highest dose (30 mg/kg daily) only. Vit K 2 administration could improve glycemic status in type 2 diabetic rats by induction of OC gene expression. Osteocalcin could increase β-cell proliferation, energy expenditure, and adiponectin expression. Different concentrations of Vit K 2 were required to affect glucose metabolism and insulin sensitivity. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

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.

Different dose rate-dependent responses of human melanoma cells and fibroblasts to low dose fast neutrons.

PubMed

Dionet, Claude; Müller-Barthélémy, Melanie; Marceau, Geoffroy; Denis, Jean-Marc; Averbeck, Dietrich; Gueulette, John; Sapin, Vincent; Pereira, Bruno; Tchirkov, Andrei; Chautard, Emmanuel; Verrelle, Pierre

2016-09-01

To analyze the dose rate influence in hyper-radiosensitivity (HRS) of human melanoma cells to very low doses of fast neutrons and to compare to the behaviour of normal human skin fibroblasts. We explored different neutron dose rates as well as possible implication of DNA double-strand breaks (DSB), apoptosis, and energy-provider adenosine-triphosphate (ATP) levels during HRS. HRS in melanoma cells appears only at a very low dose rate (VLDR), while a high dose rate (HDR) induces an initial cell-radioresistance (ICRR). HRS does not seem to be due either to DSB or to apoptosis. Both phenomena (HRS and ICRR) appear to be related to ATP availability for triggering cell repair. Fibroblast survival after neutron irradiation is also dose rate-dependent but without HRS. Melanoma cells or fibroblasts exert their own survival behaviour at very low doses of neutrons, suggesting that in some cases there is a differential between cancer and normal cells radiation responses. Only the survival of fibroblasts at HDR fits the linear no-threshold model. This new insight into human cell responses to very low doses of neutrons, concerns natural radiations, surroundings of accelerators, proton-therapy devices, flights at high altitude. Furthermore, ATP inhibitors could increase HRS during high-linear energy transfer (high-LET) irradiation.

The flame-retardant BDE-99 dose-dependently affects viral replication in CVB3-infected mice.

PubMed

Lundgren, Magnus; Darnerud, Per Ola; Ilbäck, Nils-Gunnar

2013-06-01

The flame retardant component 2,2',4,4',5-penta-BDE (BDE-99) is found in the environment and in human tissues and fluids. In mice the common human coxsackievirus B3 (CVB3) infection has been shown to change the tissue distribution of BDE-99. We now investigate how CVB3 infection in mice affects liver uptake of (14)C at two doses of radiolabelled BDE-99, and whether increased tissue levels are related to changed virus replication and gene expression of the proinflammatory chemokine monocyte chemoattractant protein-1 (MCP-1). Mice were infected on day 0, orally treated either with 200μg or 20mg (14)C-BDE-99/kgbw on day 1, and euthanised on day 3. Serum and liver levels of (14)C-BDE-99, as well as virus levels and gene expressions of MCP-1 in the liver, were measured. In non-infected mice, there was a dose-dependent uptake of BDE-99 in both liver and serum, and in infected animals the liver BDE-99 levels was further increased. When comparing infected mice exposed to the two BDE-99 doses, the higher BDE dose resulted in increased virus amounts in the liver, and decreased infection-induced expression of MCP-1. Consequently, a high enough dose/tissue concentration of BDE-99 may result in a disturbed mobilisation of immune cells into infected tissues that could explain higher virus titres and a possibly altered clinical course of the disease. Moreover, the fact that CVB3 infection increased the BDE-99 levels in liver but not in serum may impair the risk assessment of polybrominated diphenyl ethers (PBDEs) in subclinical and clinically infected individuals, as serum levels is the common marker of exposure. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prostaglandins mediate the stimulatory effects of endothelin-1 on cAMP accumulation and inositol-1,4,5-trisphosphate production and contraction in cat iris sphincter.

PubMed

Yousufzai, S Y; Ye, Z; Abdel-Latif, A A

1995-12-01

We previously reported that in the iris sphincter smooth muscle, endothelin-1 (ET-1) activates both adenylyl cyclase and the phosphoinositide cascade and that the changes in the levels of cAMP and inositol-1,4,5-trisphosphate (IP3) produced are species specific. In the present study, we examined the mechanism of the ET-1 effects in cat iris sphincter. In general, we found that ET-1 (0.1 microM) increased prostaglandin E2 (PGE2) release by 156%, cAMP accumulation by 310%, IP3 production by 88% and induced contraction; that PGE2 increased cAMP accumulation, IP3 production and contraction; and that the effects of ET-1 are inhibited by indomethacin (Indo), suggesting that arachidonic acid metabolites may mediate the responses to the peptide. Kinetic studies revealed the following: (1) The effect of ET-1 on cAMP accumulation is rapid (within 30 sec), dose dependent (EC50 = 5.8 nM) and completely abolished by Indo (Ki = 0.16 microM), a cyclooxygenase inhibitor, but not by nordihydroguairetic acid, a lipoxygenase inhibitor, implying the involvement of PGs. (2) ET-1 dose-dependently evoked PGe2 release (EC50 = 1.8 nM), IP3 production (EC50 = 4.5 nM) and contraction (EC50 = 5 nM) and that all of these responses were inhibited by Indo. (3) PGE2 increased cAMP accumulation in a dose-dependent manner with an EC50 of 1.5 x 10(-7) M, and PGD2 and PGF2 alpha had little effect on the cyclic nucleotide. (4) PGE2 (1 microM), increased IP3 production by 55% and induced muscle contraction in a dose-dependent manner (EC50 = 40 nM). We conclude from these data that in cat iris sphincter PGs may mediate ET-1-induced cAMP accumulation, IP3 production and smooth muscle contraction.

Analgesic and antipyretic effects of Sansevieria trifasciata leaves.

PubMed

Anbu, Jeba Sunilson J; Jayaraj, P; Varatharajan, R; Thomas, John; Jisha, James; Muthappan, M

2009-07-03

The ethanol and water extracts of Sansevieria trifasciata leaves showed dose-dependent and significant (P < 0.05) increase in pain threshold in tail-immersion test. Moreover, both the extracts (100 - 200 mg/kg) exhibited a dose-dependent inhibition of writhing and also showed a significant (P < 0.001) inhibition of both phases of the formalin pain test. The ethanol extract (200 mg/kg) significantly (P < 0.01) reversed yeast-induced fever. Preliminary phytochemical screening of the extracts showed the presence of alkaloids, flavonoids, saponins, glycosides, terpenoids, tannins, proteins and carbohydrates.

Human stem cell-derived cardiomyocytes detect drug-mediated changes in action potentials and ion currents.

PubMed

Gibson, John K; Yue, Yimei; Bronson, Jared; Palmer, Cassie; Numann, Randy

2014-01-01

It has been proposed that proarrhythmia assessment for safety pharmacology testing includes the use of human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to detect drug-induced changes in cardiac electrophysiology. This study measured the actions of diverse agents on action potentials (AP) and ion currents recorded from hiPSC-CM. During AP experiments, the hiPSC-CM were paced at 1Hz during a baseline period, and when increasing concentrations of test compound were administered at 4-minute intervals. AP parameters, including duration (APD60 and APD90), resting membrane potential, rate of rise, and amplitude, were measured throughout the entire experiment. Voltage clamp experiments with E-4031 and nifedipine were similarly conducted. E-4031 produced a dose-dependent prolongation of cardiac action potential and blocked the hERG/IKr current with an IC50 of 17nM. At 3nM, dofetilide significantly increased APD90. Astemizole significantly increased APD60 and APD90 at 30nM. Terfenadine significantly increased APD90 at concentrations greater than 10nM. Fexofenadine, a metabolite of terfenadine, did not produce any electrophysiologic changes in cardiac action potentials. Flecainide produced a dose-dependent prolongation of the cardiac action potential at 1 and 3μM. Acute exposure to nifedipine significantly decreased APD60 and APD90 and produced a dose-dependent block of calcium current with an IC50 of 0.039μM. Verapamil first shortened APD60 and APD90 in a dose-dependent manner, until a compensating increase in APD90, presumably via hERG blockade, was observed at 1 and 3μM. Following a chronic exposure (20-24h) to clinically relevant levels of pentamidine, a significant increase in action potential duration was accompanied by early afterdepolarizations (EADs). These experiments show the ability of AP measured from hiPSC-CM to record the interactions of various ion channels via AP recording and avoid the limitations of using several single ion channel assays in a noncardiac tissue. Copyright © 2014 Elsevier Inc. All rights reserved.

Dose-dependent effects of hydrocortisone infusion on autobiographical memory recall

PubMed Central

Young, Kymberly; Drevets, Wayne C.; Schulkin, Jay; Erickson, Kristine

2011-01-01

The glucocorticoid hormone cortisol has been shown to impair episodic memory performance. The present study examined the effect of two doses of hydrocortisone (synthetic cortisol) administration on autobiographical memory retrieval. Healthy volunteers (n=66) were studied on two separate visits, during which they received placebo and either moderate-dose (0.15 mg/kg IV; n=33) or high-dose (0.45 mg/kg IV; n=33) hydrocortisone infusion. From 75 to 150 min post-infusion subjects performed an Autobiographical Memory Test and the California Verbal Learning Test (CVLT). The high-dose hydrocortisone administration reduced the percent of specific memories recalled (p = 0.04), increased the percent of categorical (nonspecific) memories recalled, and slowed response times for categorical memories (p <0.001), compared to placebo performance (p < 0.001). Under moderate-dose hydrocortisone the autobiographical memory performance did not change significantly with respect to percent of specific or categorical memories recalled or reaction times. Performance on the CVLT was not affected by hydrocortisone. These findings suggest that cortisol affects accessibility of autobiographical memories in a dose-dependent manner. Specifically, administration of hydrocortisone at doses analogous to those achieved under severe psychosocial stress impaired the specificity and speed of retrieval of autobiographical memories. PMID:21942435

Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans.

PubMed

Qureshi, Asaf A; Khan, Dilshad A; Silswal, Neerupma; Saleem, Shahid; Qureshi, Nilofer

2016-04-01

Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. δ-Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of δ-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (C max ). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto-based tocotrienols in healthy fed subjects. All four isomers (α-, β-, γ-, δ-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of δ-tocotrienol in 6 healthy fed subjects. All subjects (3/dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of α-,β-,γ-,δ-tocotrienols, and tocopherols in plasmas were quantified by HPLC. Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUCt 0- t 8 6621, 7450; AUCt 0-∞ 8688, 9633; AUMC t 0-∞ 52497, 57199; MRT 6.04, 5.93; C max 1444, 1592 (P<0.05), respectively, of δ-tocotrienol isomer. Moreover, both doses also resulted in plasmas T max 3.33-4 h; elimination half-life (t 1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h -1 ) 0.25, 0.17, respectively of δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol. This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that T max was 3-4 h for all isomers of tocotrienols and tocopherols except for α-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease.

SPECT-CT in routine clinical practice: increase in patient radiation dose compared with SPECT alone.

PubMed

Sharma, Punit; Sharma, Shekhar; Ballal, Sanjana; Bal, Chandrasekhar; Malhotra, Arun; Kumar, Rakesh

2012-09-01

To assess the patient radiation dose during routine clinical single-photon emission computed tomography-computed tomography (SPECT-CT) and measure the increase as compared with SPECT alone. Data pertaining to 357 consecutive patients who had undergone radioisotope imaging along with SPECT-CT of a selected volume were retrospectively evaluated. Dose of the injected radiopharmaceutical (MBq) was noted, and the effective dose (mSv) was calculated as per International Commission on Radiological Protection (ICRP) guidelines. The volume-weighted computed tomography dose index (CTDIvol) and dose length product of the CT were also assessed using standard phantoms. The effective dose (mSv) due to CT was calculated as the product of dose length product and a conversion factor depending on the region of investigation, using ICRP guidelines. The dose due to CT was compared among different investigations. The increase in effective dose was calculated as CT dose expressed as a percentage of radiopharmaceutical dose. The per-patient CT effective dose for different studies varied between 0.06 and 11.9 mSv. The mean CT effective dose was lowest for 99mTc-ethylene cysteine dimer brain SPECT-CT (0.9 ± 0.7) and highest for 99mTc-methylene diphosphonate bone SPECT-CT (4.2 ± 2.8). The increase in radiation dose (SPECT-CT vs. SPECT) varied widely (2.3-666.4% for 99mTc-tracers and 0.02-96.2% for 131I-tracers). However, the effective dose of CT in SPECT-CT was less than the values reported for conventional CT examinations of the same regions. Addition of CT to nuclear medicine imaging in the form of SPECT-CT increases the radiation dose to the patient, with the effective dose due to CT exceeding the effective dose of RP in many instances. Hence, appropriate utilization and optimization of the protocols of SPECT-CT is needed to maximize benefit to patients.

[The effect of hydra peptide morphogen on the levels of beta-endorphin and some blood and adrenal hormones in albino rats].

PubMed

Murzina, N B; Khomichuk, A Iu; Timoshin, S S; Obukhova, G G; Anosova, O A; Berezina, G P

1991-10-01

The influence of PMH on the level of beta-endorphin and some hormones of blood and adrenal glands was studied. The dose A (10 mkg/kg) and dose W (100 mkg/kg) of PMH were used in our experiments. Earlier it has been discovered, that PMH in such doses stimulated the processes of cell division in 24 hours since the moment of injection. The stimulation was dose-dependent. Within 24 hours PMH in A dose decreased the concentration of beta-endorphin in the blood 2.7-fold, ad in dose W increased it 2 times. The level of corticosterone in blood and adrenal glands after the injection of PMH in dose A exceeded the control data trustworthy in 4 and 24 hours since the moment of injection. In dose B in 4 hours 1.5-fold reduction of corticosterone concentration took place in the blood. Increase in epinephrine level in adrenal glands was observed after PMH administration in two doses. Content of T3 increased in 4 hours after PMH injection in dose B. The role of hormonal changes in stimulating cell division accompanied by PMH injection is discussed. The data received show that PMH influences directly proliferative processes.

The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval.

PubMed

Vollenweider, Franz X; Csomor, Philipp A; Knappe, Bernhard; Geyer, Mark A; Quednow, Boris B

2007-09-01

Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT(2A) receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT(2A) receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 microg/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120-2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

Comparative evaluation of Kodak EDR2 and XV2 films for verification of intensity modulated radiation therapy.

PubMed

Dogan, Nesrin; Leybovich, Leonid B; Sethi, Anil

2002-11-21

Film dosimetry provides a convenient tool to determine dose distributions, especially for verification of IMRT plans. However, the film response to radiation shows a significant dependence on depth, energy and field size that compromise the accuracy of measurements. Kodak's XV2 film has a low saturation dose (approximately 100 cGy) and, consequently, a relatively short region of linear dose-response. The recently introduced Kodak extended range EDR2 film was reported to have a linear dose-response region extending to 500 cGy. This increased dose range may be particularly useful in the verification of IMRT plans. In this work, the dependence of Kodak EDR2 film's response on the depth, field size and energy was evaluated and compared with Kodak XV2 film. Co-60, 6 MV, 10 MV and 18 MV beams were used. Field sizes were 2 x 2, 6 x 6, 10 x 10, 14 x 14, 18 x 18 and 24 x 24 cm2. Doses for XV2 and EDR2 films were 80 cGy and 300 cGy, respectively. Optical density was converted to dose using depth-corrected sensitometric (Hurter and Driffield, or H&D) curves. For each field size, XV2 and EDR2 depth-dose curves were compared with ion chamber depth-dose curves. Both films demonstrated similar (within 1%) field size dependence. The deviation from the ion chamber for both films was small forthe fields ranging from 2 x 2 to 10 x 10 cm2: < or =2% for 6, 10 and 18 MV beams. No deviation was observed for the Co-60 beam. As the field size increased to 24 x 24 cm2, the deviation became significant for both films: approximately 7.5% for Co-60, approximately 5% for 6 MV and 10 MV, and approximately 6% for 18 MV. During the verification of IMRT plans, EDR2 film showed a better agreement with the calculated dose distributions than the XV2 film.

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.

Monte Carlo investigation of the increased radiation deposition due to gold nanoparticles using kilovoltage and megavoltage photons in a 3D randomized cell model.

PubMed

Douglass, Michael; Bezak, Eva; Penfold, Scott

2013-07-01

Investigation of increased radiation dose deposition due to gold nanoparticles (GNPs) using a 3D computational cell model during x-ray radiotherapy. Two GNP simulation scenarios were set up in Geant4; a single 400 nm diameter gold cluster randomly positioned in the cytoplasm and a 300 nm gold layer around the nucleus of the cell. Using an 80 kVp photon beam, the effect of GNP on the dose deposition in five modeled regions of the cell including cytoplasm, membrane, and nucleus was simulated. Two Geant4 physics lists were tested: the default Livermore and custom built Livermore/DNA hybrid physics list. 10(6) particles were simulated at 840 cells in the simulation. Each cell was randomly placed with random orientation and a diameter varying between 9 and 13 μm. A mathematical algorithm was used to ensure that none of the 840 cells overlapped. The energy dependence of the GNP physical dose enhancement effect was calculated by simulating the dose deposition in the cells with two energy spectra of 80 kVp and 6 MV. The contribution from Auger electrons was investigated by comparing the two GNP simulation scenarios while activating and deactivating atomic de-excitation processes in Geant4. The physical dose enhancement ratio (DER) of GNP was calculated using the Monte Carlo model. The model has demonstrated that the DER depends on the amount of gold and the position of the gold cluster within the cell. Individual cell regions experienced statistically significant (p < 0.05) change in absorbed dose (DER between 1 and 10) depending on the type of gold geometry used. The DER resulting from gold clusters attached to the cell nucleus had the more significant effect of the two cases (DER ≈ 55). The DER value calculated at 6 MV was shown to be at least an order of magnitude smaller than the DER values calculated for the 80 kVp spectrum. Based on simulations, when 80 kVp photons are used, Auger electrons have a statistically insignificant (p < 0.05) effect on the overall dose increase in the cell. The low energy of the Auger electrons produced prevents them from propagating more than 250-500 nm from the gold cluster and, therefore, has a negligible effect on the overall dose increase due to GNP. The results presented in the current work show that the primary dose enhancement is due to the production of additional photoelectrons.

Alpha-amylase inhibitor, CS-1036 binds to serum amylase in a concentration-dependent and saturable manner.

PubMed

Honda, Tomohiro; Kaneno-Urasaki, Yoko; Ito, Takashi; Kimura, Takako; Matsushima, Nobuko; Okabe, Hiromi; Yamasaki, Atsushi; Izumi, Takashi

2014-03-01

(2R,3R,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidin-3-yl 4-O-(6-deoxy-β-D-glucopyranosyl)-α-D-glucopyranoside (CS-1036), which is an α-amylase inhibitor, exhibited biphasic and sustained elimination with a long t1/2 (18.4-30.0 hours) in rats and monkeys, but exhibited a short t1/2 (3.7-7.9 hours) in humans. To clarify the species differences in the t1/2, the plasma protein binding of CS-1036 was evaluated by ultrafiltration. A concentration-dependent and saturable plasma protein binding of CS-1036 was observed in rats and monkeys with the dissociation rate constant (KD) of 8.95 and 27.2 nM, and maximal binding capacity (Bmax) of 52.8 and 22.1 nM, respectively. By the assessments of the recombinant amylase and immunoprecipitation, the major binding protein of CS-1036 in rats was identified as salivary amylase (KD 5.64 nM). CS-1036 also showed concentration-dependent and saturable binding to human salivary and pancreatic amylase, with similar binding affinity in rats. However, the protein binding of CS-1036 was constant in human plasma (≤10.2%) due to the lower serum amylase level compared with rats and monkeys. From the calculation of the unbound fraction (fu) in plasma based on in vitro KD and Bmax, the dose-dependent increase in fu after oral administration is speculated to lead to a dose-dependent increase in total body clearance and a high area under the curve/dose at lower doses, such as 0.3 mg/kg in rats.

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.

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

Histamine-induced vasodilatation in the human forearm vasculature

PubMed Central

Sandilands, Euan A; Crowe, Jane; Cuthbert, Hayley; Jenkins, Paul J; Johnston, Neil R; Eddleston, Michael; Bateman, D Nicholas; Webb, David J

2013-01-01

Aim To investigate the mechanism of action of intra-arterial histamine in the human forearm vasculature. Methods Three studies were conducted to assess changes in forearm blood flow (FBF) using venous occlusion plethysmography in response to intra-brachial histamine. First, the dose–response was investigated by assessing FBF throughout a dose-escalating histamine infusion. Next, histamine was infused at a constant dose to assess acute tolerance. Finally, a four way, double-blind, randomized, placebo-controlled crossover study was conducted to assess FBF response to histamine in the presence of H1- and H2-receptor antagonists. Flare and itch were assessed in all studies. Results Histamine caused a dose-dependent increase in FBF, greatest with the highest dose (30 nmol min−1) infused [mean (SEM) infused arm vs. control: 26.8 (5.3) vs. 2.6 ml min−1 100 ml−1; P < 0.0001]. Dose-dependent flare and itch were demonstrated. Acute tolerance was not observed, with an increased FBF persisting throughout the infusion period. H2-receptor antagonism significantly reduced FBF (mean (95% CI) difference from placebo at 30 nmol min−1 histamine: −11.9 ml min−1 100 ml−1 (−4.0, −19.8), P < 0.0001) and flare (mean (95% CI) difference from placebo: −403.7 cm2 (−231.4, 576.0), P < 0.0001). No reduction in FBF or flare was observed in response to the H1-receptor antagonist. Itch was unaffected by the treatments. Histamine did not stimulate vascular release of tissue plasminogen activator or von Willebrand factor. Conclusion Histamine causes dose-dependent vasodilatation, flare and itch in the human forearm. H2-receptors are important in this process. Our results support further exploration of combined H1- and H2-receptor antagonist therapy in acute allergic syndromes. PMID:23488545

Dose-dependent effects and reversibility of the injuries caused by nandrolone decanoate in uterine tissue and fertility of rats.

PubMed

Belardin, Larissa Berloffa; Simão, Vinícius Augusto; Leite, Gabriel Adan Araújo; Chuffa, Luiz Gustavo de Almeida; Camargo, Isabel Cristina Cherici

2014-04-01

This study is the first to investigate the effects of different doses of nandrolone decanoate (ND) upon uterine tissue and fertility, and if the reproductive alterations can be restored after cessation of the treatment. Wistar female rats were treated with ND at doses of 1.87, 3.75, 7.5, and 15 mg/kg body weight, diluted in vehicle (n = 30/group), or received only mineral oil (control group, n = 45). The animals were divided into three periods of study: ND-treated receiving a daily subcutaneous injection for 15 consecutive days (1), and treatment with ND followed by 30-day recovery (2), and 60-day recovery (3). At the end of each period, five females per group were induced to death to histopathological analysis and the others were allowed to fertility evaluation (at 19th gestational day). Animals that received ND followed by 30-day recovery exhibited persistent diestrous and marked suppression of reproductive capacity. Conversely, after 60-day recovery, only lowest doses females (1.87 and 3.75 mg/kg) exhibited restoration of normal estrous cyclicity. Uterine weights were increased after ND treatment similarly to that of the controls after 60-day recovery. The ND-treated groups showed histopathological changes in the endometrium, myometrium, and perimetrium, and an increase in the thickness of both muscular and serous layers. Notably, the recovery of uterine tissue after ND treatment was dose- and period-dependent. We reported that administration of ND promoted damage in uterine tissue and fertility of rats, and the recovery periods were insufficient to restore all of the side effects caused by ND under a dose-dependent response. © 2014 Wiley Periodicals, Inc.

Increasing the Vegetable Intake Dose Is Associated with a Rise in Plasma Carotenoids without Modifying Oxidative Stress or Inflammation in Overweight or Obese Postmenopausal Women123

PubMed Central

Crane, Tracy E.; Kubota, Chieri; West, Julie L.; Kroggel, Mark A.; Wertheim, Betsy C.; Thomson, Cynthia A.

2011-01-01

The optimal amount of vegetable consumption required to reduce chronic disease risk is widely debated. Intervention trials evaluating biological activity of vegetables at various doses are limited. We conducted a 3-dose, crossover feeding trial to test the hypothesis that vegetable intake is associated in a dose-dependent manner with increased plasma carotenoids and subsequently reduced oxidative stress and inflammation in 49 overweight, postmenopausal women. Participants were assigned in random order to 2 (130 g), 5 (287 g), and 10 (614 g) daily servings of fresh, greenhouse-grown vegetables for 3-wk intervals with a 4-wk washout period between treatments. Plasma total carotenoids significantly increased from 1.63 to 2.07 μmol/L with a dose of 2 vegetable servings, from 1.49 to 2.84 μmol/L with a dose of 5 vegetable servings, and from 1.40 to 4.42 μmol/L with a dose of 10 vegetable servings (pre-post paired ttests, all P < 0.001). The change during each feeding period increased with each dose level (P < 0.001). Urine concentrations of 8-isoprostane F2α, hexanoyl lysine, and serum high sensitivity C-reactive protein were not affected by any administered vegetable dose. In this variable-dose vegetable study, a dose-response for plasma carotenoids was demonstrated without significant change in oxidative stress and inflammation in overweight, postmenopausal women. PMID:21865569

Evaluation of the Analgesic Activity of the Methanolic Stem Bark Extract of Dialium Guineense (Wild)

PubMed Central

Ezeja, MI; Omeh, YS; Ezeigbo, II; Ekechukwu, A

2011-01-01

Background: Dialium guineense is a medicinal plant used by some communities of Enugu-Ezike in Enugu State, Nigeria for treatment of fever, headache and other diverse ailments. Objectives: The present study evaluated the analgesic activity of the methanolic stem bark extract of the plant. Method: Acetic acid-induced abdominal constriction or writhing, tail immersion and hot plate analgesic models in albino Wistar mice were used for the study. Three test doses (250, 500, 1000 mg/kg body weight) of the extract were administered orally by gastric gavage. The activity was compared with a standard reference drug, acetylsalicylic acid (aspirin) (400 mg/kg) and negative control. The results were analysed by SPSS version 17 using ANOVA and Post Hoc Duncan. Result: In the acetic acid-induced writhing reflex model, D. guineense extract and the reference drug significantly (P =0.014 - 0.002) decreased the mean total number of abdominal constriction in the mice in a dose dependent fashion. The percentage inhibition of the abdominal constriction reflex was increased dose dependently from 0% in the negative control group to 71% at the highest dose of the extract (1000mg/kg). In the tail immersion model the extract at the dose of 1000 mg/kg significantly (P = 0. 048) increased the pain reaction time (PRT) while in hot plate model the extract and drug also significantly (P = 0.048 - 0.05) increased the mean PRT at the doses of 500 and 1000 mg/kg. The dose of 250 mg/kg showed no analgesic activity in tail immersion and hot plate models. Conclusion: Dialium guineense demonstrated significant analgesic activity that may be mediated through peripheral pain mechanism. PMID:23209955

Evaluation of the analgesic activity of the methanolic stem bark extract of dialium guineense (wild).

PubMed

Ezeja, Mi; Omeh, Ys; Ezeigbo, Ii; Ekechukwu, A

2011-01-01

Dialium guineense is a medicinal plant used by some communities of Enugu-Ezike in Enugu State, Nigeria for treatment of fever, headache and other diverse ailments. The present study evaluated the analgesic activity of the methanolic stem bark extract of the plant. Acetic acid-induced abdominal constriction or writhing, tail immersion and hot plate analgesic models in albino Wistar mice were used for the study. Three test doses (250, 500, 1000 mg/kg body weight) of the extract were administered orally by gastric gavage. The activity was compared with a standard reference drug, acetylsalicylic acid (aspirin) (400 mg/kg) and negative control. The results were analysed by SPSS version 17 using ANOVA and Post Hoc Duncan. In the acetic acid-induced writhing reflex model, D. guineense extract and the reference drug significantly (P =0.014 - 0.002) decreased the mean total number of abdominal constriction in the mice in a dose dependent fashion. The percentage inhibition of the abdominal constriction reflex was increased dose dependently from 0% in the negative control group to 71% at the highest dose of the extract (1000mg/kg). In the tail immersion model the extract at the dose of 1000 mg/kg significantly (P = 0. 048) increased the pain reaction time (PRT) while in hot plate model the extract and drug also significantly (P = 0.048 - 0.05) increased the mean PRT at the doses of 500 and 1000 mg/kg. The dose of 250 mg/kg showed no analgesic activity in tail immersion and hot plate models. Dialium guineense demonstrated significant analgesic activity that may be mediated through peripheral pain mechanism.

Increased prandial insulin secretion after administration of a single preprandial oral dose of repaglinide in patients with type 2 diabetes.

PubMed

Owens, D R; Luzio, S D; Ismail, I; Bayer, T

2000-04-01

To examine the dose-related pharmacodynamics and pharmacokinetics of a single preprandial oral dose of repaglinide in patients with type 2 diabetes. A total of 16 Caucasian men with type 2 diabetes participated in two placebo-controlled double-blind randomized cross-over studies. Patients were randomized to receive a single oral dose of repaglinide (0.5, 1.0, and 2.0 mg in study 1 and 4.0 mg in study 2) or placebo (both studies) administered 15 min before the first of two sequential identical standard meals (breakfast and lunch) that were 4 h apart. During each of the study days, which were 1 week apart, blood samples were taken at frequent intervals over a period of approximately 8 h for measurement of plasma glucose, insulin, C-peptide, and repaglinide concentrations. During the first meal period (0-240 min), administration of repaglinide reduced significantly the area under the curve (AUC) for glucose concentration and significantly increased the AUC for insulin levels, C-peptide levels, and the insulin secretion rate. These results, compared with those of administering placebo, were dose dependent and log linear. The effect of repaglinide administration on insulin secretion was most pronounced in the early prandial period. Within 30 min, it caused a relative increase in insulin secretion of up to 150%. During the second meal period (240-480 min), there was no difference between repaglinide and placebo administration in the AUC for glucose concentration, C-peptide concentration, and the estimated insulin secretion rate. A single dose of repaglinide (0.5-4.0 mg) before breakfast improves insulin secretion and reduces prandial hyperglycemia dose-dependently Administration of repaglinide had no effect on insulin secretion with the second meal, which was consumed 4 h after breakfast.

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

Overexpression of cerebral and hepatic cytochrome P450s alters behavioral activity of rat offspring following prenatal exposure to lindane

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

Johri, Ashu; Yadav, Sanjay; Dhawan, Alok

2007-12-15

Oral administration of different doses (0.0625, 0.125 or 0.25 mg/kg corresponding to 1/1400th, 1/700th or 1/350th of LD{sub 50}) of lindane to the pregnant Wistar rats from gestation days 5 to 21 were found to produce a dose-dependent increase in the activity of cytochrome P450 (CYP)-dependent 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD) and N-nitrosodimethylamine demethylase (NDMA-d) in brain and liver of offspring postnatally at 3 weeks. The increase in the activity of CYP monooxygenases was found to be associated with the increase in the mRNA and protein expression of xenobiotic metabolizing CYP1A, 2B and 2E1 isoenzymes in the brain and liver ofmore » offspring. Dose-dependent alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 3 weeks have suggested that increase in CYP activity may possibly lead to the formation of metabolites to the levels that may be sufficient to alter the behavioral activity of the offspring. Interestingly, the inductive effect on cerebral and hepatic CYPs was found to persist postnatally up to 6 weeks in the offspring at the relatively higher doses (0.125 and 0.25 mg/kg) of lindane and up to 9 weeks at the highest dose (0.25 mg/kg), though the magnitude of induction was less than that observed at 3 weeks. Alterations in the parameters of spontaneous locomotor activity in the offspring postnatally at 6 and 9 weeks, though significant only in the offspring at 3 and 6-week of age, have further indicated that due to the reduced activity of the CYPs during the ontogeny, lindane and its metabolites may not be effectively cleared from the brain. The data suggest that low dose prenatal exposure to the pesticide has the potential to produce overexpression of xenobiotic metabolizing CYPs in brain and liver of the offspring which may account for the behavioral changes observed in the offspring.« less

Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers.

PubMed

Jonkman, Kelly; Duma, Andreas; Olofsen, Erik; Henthorn, Thomas; van Velzen, Monique; Mooren, René; Siebers, Liesbeth; van den Beukel, Jojanneke; Aarts, Leon; Niesters, Marieke; Dahan, Albert

2017-10-01

Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

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

Molecular and cellular profiling of acute responses to total body radiation exposure in ovariectomized female cynomolgus macaques.

PubMed

DeBo, Ryne J; Register, Thomas C; Caudell, David L; Sempowski, Gregory D; Dugan, Gregory; Gray, Shauna; Owzar, Kouros; Jiang, Chen; Bourland, J Daniel; Chao, Nelson J; Cline, J Mark

2015-06-01

The threat of radiation exposure requires a mechanistic understanding of radiation-induced immune injury and recovery. The study objective was to evaluate responses to ionizing radiation in ovariectomized (surgically post-menopausal) female cynomolgus macaques. Animals received a single total-body irradiation (TBI) exposure at doses of 0, 2 or 5 Gy with scheduled necropsies at 5 days, 8 weeks and 24 weeks post-exposure. Blood and lymphoid tissues were evaluated for morphologic, cellular, and molecular responses. Irradiated animals developed symptoms of acute hematopoietic syndrome, and reductions in thymus weight, thymopoiesis, and bone marrow cellularity. Acute, transient increases in plasma monocyte chemoattractant protein 1 (MCP-1) were observed in 5 Gy animals along with dose-dependent alterations in messenger ribonucleic acid (mRNA) signatures in thymus, spleen, and lymph node. Expression of T cell markers was lower in thymus and spleen, while expression of macrophage marker CD68 (cluster of differentiation 68) was relatively elevated in lymphoid tissues from irradiated animals. Ovariectomized female macaques exposed to moderate doses of radiation experienced increased morbidity, including acute, dose-dependent alterations in systemic and tissue-specific biomarkers, and increased macrophage/T cell ratios. The effects on mortality exceeded expectations based on previous studies in males, warranting further investigation.

The Effect of Diagnostic Absorbed Doses from 131I on Human Thyrocytes in Vitro

PubMed Central

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

2015-01-01

Background: Administration of diagnostic activities of 131I, performed in order to detect thyroid remnants after surgery and/or thyroid cancer recurrence/metastases, may lead to reduction of iodine uptake. This phenomenon is called “thyroid stunning”. We estimated radiation absorbed dose-dependent changes in genetic material, in particular in sodium iodide symporter (NIS) gene promoter, and NIS protein level in human thyrocytes (HT). Materials and Methods: We used unmodified HT isolated from patients subjected to thyroidectomy exposed to 131I in culture. The different 131I activities applied were calculated to result in absorbed doses of 5, 10, and 20 Gy. Results: According to flow cytometry analysis and comet assay, 131I did not influence the HT viability in culture. Temporary increase of 8-oxo-dG concentration in HT directly after 24 h (p < 0.05) and increase in the number of AP-sites 72 h after termination of exposition to 20 Gy dose (p < 0.0001) were observed. The signs of dose-dependent DNA damage were not associated with essential changes in the NIS expression on mRNA and protein levels. Conclusions: Our observation constitutes a first attempt to evaluate the effect of the absorbed dose of 131I on HT. The results have not confirmed the theory that the “thyroid stunning” reduces the NIS protein synthesis. PMID:26132566

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

Fox, Donald A., E-mail: dafox@uh.edu; Department of Biology and Biochemistry, University of Houston, Houston, TX; Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, TX

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,more » {<=} 10, {approx} 25 and {approx} 40 {mu}g/dL, respectively, on PN10 and by PN30 all were {<=} 1 {mu}g/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. -- Highlights: Black-Right-Pointing-Pointer Peak [BPb] in control, low-, moderate- and high-dose newborn mice with gestational lead exposure: {<=} 1, {<=} 10, 25 and 40 {mu}g/dL Black-Right-Pointing-Pointer Gestational lead exposure dose-dependently decreased the number of TH-immunoreactive dopaminergic amacrine cells Black-Right-Pointing-Pointer Gestational lead exposure selectively decreased dopaminergic, but not GABAergic, glycinergic or cholinergic, amacrine cells Black-Right-Pointing-Pointer Gestational lead exposure dose-dependently decreased retinal dopamine content, its metabolites and dopamine utilization Black-Right-Pointing-Pointer A decrease in dopamine can alter ERG amplitudes, circadian rhythms, dark/light adaptation and spatial contrast sensitivity.« less

Comparison of effects of dose on image quality in digital breast tomosynthesis across multiple vendors

NASA Astrophysics Data System (ADS)

Zhao, Amy; Santana, Maira; Samei, Ehsan; Lo, Joseph

2017-03-01

In traditional radiography and computed tomography (CT), contrast is an important measure of image quality that, in theory, does not vary with dose. While increasing dose may increase the overall contrast-to-noise ratio (CNR), the contrast in an image should be primarily dependent on variation in tissue density and attenuation. We investigated the behavior of all three currently FDA-approved vendors' 3D DBT systems (Siemens, Hologic, and General Electric (GE)) using the Computerized Imaging Reference Systems (CIRS) Model 011A Breast Phantom and found that for both Siemens and Hologic systems, contrast increased with dose across multiple repeated trials. For these two systems, experimental CNR also appeared to increase above the expected CNR, which suggests that these systems seem to have introduced post-processing by manipulation of contrast, and thus DBT data cannot be used to reliably quantify tissue characteristics. Additional experimentation with both 2D mammography and 3D DBT systems from GE in addition to the previously mentioned vendors, however, suggested that this relationship is not true for all systems. An initial comparison of contrast vs. dose showed no relationship between contrast and dose for 2D mammography, with the contrast remaining relatively constant in the dose range of 33% of the automatic exposure control setting (AEC) to 300% AEC for all three vendors. The GE DBT system also did not exhibit increased contrast with increased dose, suggesting that the behavior of 3D DBT systems is vendor-specific.

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

ASSESSMENT OF THE RISK OF SOLAR ULTRAVIOLET RADIATION TO AMPHIBIANS. 1) DOSE-DEPENDENT INDUCTION OF HINDLIMB MALFORMATIONS IN THE NORTHERN LEOPARD FROG (RANA PIPIENS)

EPA Science Inventory

A number of environmental stressors have been hypothesized as responsible for seeming increases in limb malformations in several species of North American amphibians. The purpose of this study was to generate dose-response data suitable for assessing the potential role of solar u...

Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial.

PubMed

Quintana, D S; Westlye, L T; Hope, S; Nærland, T; Elvsåshagen, T; Dørum, E; Rustan, Ø; Valstad, M; Rezvaya, L; Lishaugen, H; Stensønes, E; Yaqub, S; Smerud, K T; Mahmoud, R A; Djupesland, P G; Andreassen, O A

2017-05-23

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η 2 =0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.

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.

A survey on anticancer effects of artemisinin, iron, miconazole, and butyric acid on 5637 (bladder cancer) and 4T1 (Breast cancer) cell lines.

PubMed

Shahbazfar, Amir Ali; Zare, Payman; Ranjbaran, Mehrdad; Tayefi-Nasrabadi, Hossein; Fakhri, Omid; Farshi, Yashar; Shadi, Sahar; Khoshkerdar, Afsaneh

2014-01-01

Anticancer properties of artemisinin and its derivatives have been shown in many experiments. Addition of butyric acid, miconazole, and iron to this traditional drug has been done in order to enhance its anticancer potency. Cell lines 5637 and 4T1, were cultivated and classified into 13 groups of three each. Different doses of artemisinin with constant doses of iron, miconazole and butyric acid, were added to the cultures. At the end of exposure pathological and enzymatic studies were performed. In four groups treated with different doses of artemisinin and iron, dose-dependent changes were observed. These changes included apoptosis and necrosis with dominance of apoptosis. The supernatant lactate dehydrogenase (LDH) level was increased in a dose-dependent manner, but there was no significant increase in the cell fraction of malonyldialdehyde (MDA) or LDH. In four other groups, which received miconazole, butyric acid and iron in addition to different doses of artemisinin, necrosis was more prominent than apoptosis, and the MDA level did not show any significant change, but LDH was increased. The groups treated with miconazole showed identical changes, with less severity compared to combination therapy groups. In butyric acid-treated groups, the only detectable changes were, mild cell swelling, few apoptosis, and rare necrosis. A combination therapy with artemisinin can be more effective against cancer cells than monotherapy with that. Butyric acid was not effective on cancer cells. Miconazole deviated the nature of cell death from apoptosis to necrosis and it must be used under caution.

Multichannel film dosimetry with nonuniformity correction.

PubMed

Micke, Andre; Lewis, David F; Yu, Xiang

2011-05-01

A new method to evaluate radiochromic film dosimetry data scanned in multiple color channels is presented. This work was undertaken to demonstrate that the multichannel method is fundamentally superior to the traditional single channel method. The multichannel method allows for the separation and removal of the nondose-dependent portions of a film image leaving a residual image that is dependent only on absorbed dose. Radiochromic films were exposed to 10 x 10 cm radiation fields (Co-60 and 6 MV) at doses up to about 300 cGy. The films were scanned in red-blue-green (RGB) format on a flatbed color scanner and measured to build calibration tables relating the absorbed dose to the response of the film in each of the color channels. Film images were converted to dose maps using two methods. The first method used the response from a single color channel and the second method used the response from all three color channels. The multichannel method allows for the separation of the scanned signal into one part that is dose-dependent and another part that is dose-independent and enables the correction of a variety of disturbances in the digitized image including nonuniformities in the active coating on the radiochromic film as well as scanner related artifacts. The fundamental mathematics of the two methods is described and the dose maps calculated from film images using the two methods are compared and analyzed. The multichannel dosimetry method was shown to be an effective way to separate out non-dose-dependent abnormalities from radiochromic dosimetry film images. The process was shown to remove disturbances in the scanned images caused by nonhomogeneity of the radiochromic film and artifacts caused by the scanner and to improve the integrity of the dose information. Multichannel dosimetry also reduces random noise in the dose images and mitigates scanner-related artifacts such as lateral position dependence. In providing an ability to calculate dose maps from data in all the color channels the multichannel method provides the ability to examine the agreement between the color channels. Furthermore, when using calibration data to convert RGB film images to dose using the new method, poor correspondence between the dose calculations for the three color channels provides an important indication that the this new technique enables easy indication in case the dose and calibration films are curve mismatched. The method permit compensation for thickness nonuniformities in the film, increases the signal to noise level, mitigates the lateral dose-dependency of flatbed scanners effect of the calculated dose map and extends the evaluable dose range to 10 cGy-100 Gy. Multichannel dosimetry with radiochromic film like Gafchromic EBT2 is shown to have significant advantages over single channel dosimetry. It is recommended that the dosimetry protocols described be implemented when using this radiochromic film to ensure the best data integrity and dosimetric accuracy.

Dietary Phytochemicals Promote Health by Enhancing Antioxidant Defence in a Pig Model

PubMed Central

Selby-Pham, Sophie N. B.; Cottrell, Jeremy J.; Ng, Ken

2017-01-01

Phytochemical-rich diets are protective against chronic diseases and mediate their protective effect by regulation of oxidative stress (OS). However, it is proposed that under some circumstances, phytochemicals can promote production of reactive oxygen species (ROS) in vitro, which might drive OS-mediated signalling. Here, we investigated the effects of administering single doses of extracts of red cabbage and grape skin to pigs. Blood samples taken at baseline and 30 min intervals for 4 hours following intake were analyzed by measures of antioxidant status in plasma, including Trolox equivalent antioxidant capacity (TEAC) and glutathione peroxidase (GPx) activity. In addition, dose-dependent production of hydrogen peroxide (H2O2) by the same extracts was measured in untreated commercial pig plasma in vitro. Plasma from treated pigs showed extract dose-dependent increases in non-enzymatic (plasma TEAC) and enzymatic (GPx) antioxidant capacities. Similarly, extract dose-dependent increases in H2O2 were observed in commercial pig plasma in vitro. The antioxidant responses to extracts by treated pigs were highly correlated with their respective yields of H2O2 production in vitro. These results support that dietary phytochemicals regulate OS via direct and indirect antioxidant mechanisms. The latter may be attributed to the ability to produce H2O2 and to thereby stimulate cellular antioxidant defence systems. PMID:28708113

[Effects of sinensetin on proliferation and apoptosis of human gastric cancer AGS cells].

PubMed

Dong, Yang; Ji, Guang; Cao, Aili; Shi, Jianrong; Shi, Hailian; Xie, Jianqun; Wu, Dazheng

2011-03-01

To study the effects and mechanisms of sinensetin on proliferation and apoptosis of human AGS gastric cancer cells. MTT assay was used to detect the growth inhibition rates of human AGS gastric cancer cells treated with sinsesectin in different concentrations and times. The cell cycle distribution was measured by flow cytometry. The apoptosis was examined by Annexin-FITC/PI staining and DNA fragment analysis. The apoptosis morphology was observed by inverted fluorescence microscope after Hoechst 33342 staining. The protein expressions of p21 and p53 were detected by western blot. MTT assay showed that sinensetin inhibited the growth of AGS gastric cancer cells in a dose- and time-dependent manner. Sinensetin blocked AGS cells in G2/ M and increased the apoptosis rates of AGS cells in a dose-dependent manner. DNA ladder was observed in cells treated with 60 micromol x L(-1) sinensetin for 48 h. The typical apoptotic morphological changes including cell nucleus shrinkage, chromatin condensation and apoptotic bodies were observed when treated with different dose of sinensetin. Western blot showed that sinensetin increased expressions of p53 and p21 in a dose-dependent manner. Sinensetin could inhibit human AGS gastric cancer cells proliferation and induce cell cycle block in G2/M phase and apoptosis. The up regulation of p53 and p21 protein might be one of the mechanisms.

SU-F-T-424: Mitigation of Increased Surface Dose When Treating Through A Carbon Fiber Couch Top

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

Johnson, E; Misgina, F

Purpose: To study the effect of the Varian carbon fiber couch top on surface dose for patients being treated using single PA beams in the supine position and to identify simple methods for surface dose reduction. Methods: Measurements of surface dose were obtained in Solid Water phantoms using both a parallel plate ionization chamber (PTW Advanced Markus) and EBT2 Radiochromic films for both 6 and 10MV photons. All measurements were referenced to a depth considered a typical for PA Spine fields. Techniques used to reduce the surface dose included introducing an air standoff using Styrofoam sheets to suspend the phantommore » surface above the couch top and by adding a thin high Z scattering foil on the table surface. Surface doses were evaluated for typical field sizes, standoff heights, and various scattering materials. Comparisons were made to the surface dose obtainable when treating through a Varian Mylar covered tennis racket style couch top. Results: Dependence on typical spine field sizes was relatively minor. Dependence on air gap was much more significant. Surface doses decreased exponentially with increases in air standoff distance. Surface doses were reduced by approximately 50% for an air gap of 10cm and 40% for a 15cm air gap. Surface doses were reduced by an additional 15% by the addition of a 1mm Tin scattering foil. Conclusion: Using simple techniques, it is possible to reduce the surface dose when treating single PA fields through the Varian carbon fiber couch top. Surface doses can be reduced to levels observed when treating though transparent Mylar tops by adding about 15 cm of air gap. Further reductions are possible by adding thin scattering foils, such as Tin or Lead, on the couch surface. This is a low cost approach to reduce surface dose when using the Varian carbon fiber couch top.« less

[Effect of the nonspecific biogenic stimulators pentoxyl and mumie on metabolic processes].

PubMed

Shvetskiĭ, A G; Vorob'eva, L M

1978-01-01

Unspecific biogenic stimulants (pentoxyl and mummie) accelerated metabolism of nucleic acids and protein in rat liver tissue. After the treatment with the stimulants the rate of lipolysis exceeded that of lipogenesis. Increase in content of lactate was similar if glycogen and glucose-6-phosphate were used as substrates of glycolysis, but it was stimulated 2-3-fold, when glucose was used; the phenomenon appears to be due to activation of hexokinase. As shown by polarographic measurements mitochondrial respiration was increased in all the metabolic states, but increased doses caused an inhibition of phosphorylation apparently due to functional overstrain of mitochondria. Increased doses of the stimulants accelerated also some other metabolic processes studied, but the effects were not dose-dependent. Pentoxyl and mummie apparently increased processes of protein and nuclei acid metabolism and stimulated the energy-providing reactions.

SU-E-T-491: Importance of Energy Dependent Protons Per MU Calibration Factors in IMPT Dose Calculations Using Monte Carlo Technique

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

Randeniya, S; Mirkovic, D; Titt, U

2014-06-01

Purpose: In intensity modulated proton therapy (IMPT), energy dependent, protons per monitor unit (MU) calibration factors are important parameters that determine absolute dose values from energy deposition data obtained from Monte Carlo (MC) simulations. Purpose of this study was to assess the sensitivity of MC-computed absolute dose distributions to the protons/MU calibration factors in IMPT. Methods: A “verification plan” (i.e., treatment beams applied individually to water phantom) of a head and neck patient plan was calculated using MC technique. The patient plan had three beams; one posterior-anterior (PA); two anterior oblique. Dose prescription was 66 Gy in 30 fractions. Ofmore » the total MUs, 58% was delivered in PA beam, 25% and 17% in other two. Energy deposition data obtained from the MC simulation were converted to Gy using energy dependent protons/MU calibrations factors obtained from two methods. First method is based on experimental measurements and MC simulations. Second is based on hand calculations, based on how many ion pairs were produced per proton in the dose monitor and how many ion pairs is equal to 1 MU (vendor recommended method). Dose distributions obtained from method one was compared with those from method two. Results: Average difference of 8% in protons/MU calibration factors between method one and two converted into 27 % difference in absolute dose values for PA beam; although dose distributions preserved the shape of 3D dose distribution qualitatively, they were different quantitatively. For two oblique beams, significant difference in absolute dose was not observed. Conclusion: Results demonstrate that protons/MU calibration factors can have a significant impact on absolute dose values in IMPT depending on the fraction of MUs delivered. When number of MUs increases the effect due to the calibration factors amplify. In determining protons/MU calibration factors, experimental method should be preferred in MC dose calculations. Research supported by National Cancer Institute grant P01CA021239.« less

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.

Dose validation of PhIP hair level as a biomarker of heterocyclic aromatic amines exposure: a feeding study.

PubMed

Le Marchand, Loïc; Yonemori, Kim; White, Kami K; Franke, Adrian A; Wilkens, Lynne R; Turesky, Robert J

2016-07-01

Hair measurement of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a promising biomarker of exposure to this carcinogen formed in cooked meats. However, the dose relationship between normal range intake and hair levels and the modulating effects of CYP1A2 metabolism and hair melanin need to be evaluated. We conducted a randomized, cross-over feeding study among 41 non-smokers using ground beef cooked to two different levels of doneness, 5 days a week for 1 month. PhIP was measured by liquid chromatography/mass spectrometry in food (mean low dose = 0.72 µg/serving; mean high dose = 2.99 µg/serving), and change in PhIP hair level was evaluated. CYP1A2 activity was assessed in urine with the caffeine challenge test and head hair melanin was estimated by UV spectrophotometry. We observed a strong dose-dependent increase in hair PhIP levels. This increase was highly correlated with dose received (ρ = 0.68, P < 0.0001). CYP1A2 activity and normalizing for hair melanin did not modify the response to the intervention. Consumption of PhIP at doses similar to those in the American diet results in a marked dose-dependent accumulation of PhIP in hair. Hair PhIP levels may be used as a biomarker of dietary exposure in studies investigating disease risk. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Abuse Liability and Reinforcing Efficacy of Oral Tramadol in Humans

PubMed Central

Babalonis, Shanna; Lofwall, Michelle R.; Nuzzo, Paul A.; Siegel, Anthony J.; Walsh, Sharon L.

2012-01-01

BACKGROUND Tramadol, a monoaminergic reuptake inhibitor, is hepatically metabolized to an opioid agonist (M1). This atypical analgesic is generally considered to have limited abuse liability. Recent reports of its abuse have increased in the U.S., leading to more stringent regulation in some states, but not nationally. The purpose of this study was to examine the relative abuse liability and reinforcing efficacy of tramadol in comparison to a high (oxycodone) and low efficacy (codeine) opioid agonist. METHODS Nine healthy, non-dependent prescription opioid abusers (6 male, 3 female) participated in this within-subject, randomized, double blind, placebo-controlled study. Participants completed 14 paired sessions (7 sample, 7 self-administration). During each sample session, an oral dose of tramadol (200, 400 mg), oxycodone (20, 40 mg), codeine (100, 200 mg) or placebo was administered, and a full array of abuse liability measures was collected. During self-administration sessions, volunteers were given the opportunity to work (via progressive ratio) for the sample dose or money. RESULTS All active doses were self-administered; placebo engendered no responding. The high doses of tramadol and oxycodone were readily self-administered (70%, 59% of available drug, respectively); lower doses and both codeine doses maintained intermediate levels of drug taking. All three drugs dose-dependently increased measures indicative of abuse liability, relative to placebo; however, the magnitude and time course of these and other pharmacodynamic effects varied qualitatively across drugs. CONCLUSIONS This study demonstrates that, like other mu opioids, higher doses of tramadol function as reinforcers in opioid abusers, providing new empirical data for regulatory evaluation. PMID:23098678

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.

Calcitriol accelerates vascular calcification irrespective of vitamin K status in a rat model of CKD with hyperphosphatemia and secondary hyperparathyroidism.

PubMed

McCabe, Kristin M; Zelt, Jason G; Kaufmann, Martin; Laverty, Kimberly; Ward, Emilie; Barron, Henry; Jones, Glenville; Adams, Michael A; Holden, Rachel M

2018-06-14

Patients with chronic kidney disease have a markedly increased risk for developing cardiovascular disease. Non-traditional risk factors, such as increased phosphate retention, and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol (1,25-(OH)2-D3) is a key transcriptional regulator of Matrix Gla protein (MGP), a vitamin K dependent protein that inhibits vascular calcification. The objective of this study was to determine if calcitriol treatment could inhibit the development of vascular calcification and if this inhibition was dependent on vitamin K status in a rat model of CKD. Rats were treated with dietary adenine (0.25%) to induce CKD, with either 0, 20 or 80 ng/kg of calcitriol with low or high dietary vitamin K1 (0.2 or 100 mg/kg) for 7 weeks. Calcitriol at both low (20 ng/kg) and moderate (80 ng/kg) doses increased the severity of vascular calcification and, contrary to our hypothesis, this was unaffected by high dietary vitamin K1. Calcitriol had a dose-dependent effect on: (i) lowering serum PTH, (ii) increasing serum calcium and (iii) increasing serum FGF-23. Calcitriol treatment significantly increased aortic expression of the calcification genes Runx2 and Pit-1. This data also implicates impaired vitamin D catabolism in CKD, which may contribute to the development of calcitriol toxicity and increased vascular calcification. The present findings demonstrate that in an adenine-induced rat model of CKD, calcitriol treatment at doses as low as 20 ng/kg can increase the severity of vascular calcification regardless of vitamin K status. The American Society for Pharmacology and Experimental Therapeutics.

Organometallic exposure dependence on organic–inorganic hybrid material formation in polyethylene terephthalate and polyamide 6 polymer fibers

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

Akyildiz, Halil I.; Jur, Jesse S., E-mail: jsjur@ncsu.edu

2015-03-15

The effect of exposure conditions and surface area on hybrid material formation during sequential vapor infiltrations of trimethylaluminum (TMA) into polyamide 6 (PA6) and polyethylene terephthalate (PET) fibers is investigated. Mass gain of the fabric samples after infiltration was examined to elucidate the reaction extent with increasing number of sequential TMA single exposures, defined as the times for a TMA dose and a hold period. An interdependent relationship between dosing time and holding time on the hybrid material formation is observed for TMA exposure PET, exhibited as a linear trend between the mass gain and total exposure (dose time ×more » hold time × number of sequential exposures). Deviation from this linear relationship is only observed under very long dose or hold times. In comparison, amount of hybrid material formed during sequential exposures to PA6 fibers is found to be highly dependent on amount of TMA dosed. Increasing the surface area of the fiber by altering its cross-sectional dimension is shown to have little on the reaction behavior but does allow for improved diffusion of the TMA into the fiber. This work allows for the projection of exposure parameters necessary for future high-throughput hybrid modifications to polymer materials.« less

In vitro comparison of the antiproliferative effects of rhenium-186 and rhenium-188 on human aortic endothelial cells.

PubMed

Sauter, Alexander; Arthasana, Daniel; Dittmann, Helmut; Pritzkow, Maren; Wiesinger, Benjamin; Schmehl, Joerg; Brechtel, Klaus; Bantleon, Rüdiger; Claussen, Claus; Kehlbach, Rainer

2011-08-01

Rhenium-186 ((186)Re) and rhenium-188 ((188)Re) are promising radionuclides for the inhibition of restenosis after percutaneous transluminal angioplasty or other vascular interventions. Until now the maximal dose tolerance of endothelial cells has not been clearly known. To characterize the effects of local irradiation treatment, human aortic endothelial cells (ECs) were incubated with different doses of (186)Re and (188)Re. Two days after plating, ECs received treatment for a period of 5 days. The total radiation doses applied were 1, 4, 8, 16, and 32 Gy. On days 1, 3, 5, 7, and 12 after initial rhenium incubation, cell growth, clonogenic activity, cell-cycle distribution, and cytoskeletal architecture were evaluated. From the first day on, a dose-dependent growth inhibition was observed. Cumulative doses of ≥32 Gy caused a weak colony formation and significant alterations in the cytoskeletal architecture. An increased fraction of cells in G2/M phase was seen for cumulative radiation doses of ≥16 Gy. Interestingly, there were no significant differences between (186)Re and (188)Re. Even for low dose rates of β particles a dose-dependent proliferation inhibition of ECs is seen. Doses beyond 32 Gy alter the cytoskeletal architecture with possibly endothelial dysfunction and late thrombosis.

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.

Antinociceptive and anti-inflammatory activity of the ethanolic extract of Cymbidium aloifolium (L.).

PubMed

Howlader, Md Amran; Alam, Mahmudul; Ahmed, Kh Tanvir; Khatun, Farjana; Apu, Apurba Sarker

2011-10-01

The ethanol leaf extract of Cymbidium aloifolium (L.) was evaluated for its analgesic and antiinflammatory activities. The extract, at the dose of 200 and 400 mg kg(-1) body weight, exerted the analgesic activity by observing the number of abdominal contractions and anti-inflammatory activity against Carrageenin induced paw edema in mice by measuring the paw volume. The ethanolic extract of Cymbidium aloifolium (L.) showed statistically significant (p < 0.05) reduction of percentage of writhing of 33.57 and 61.31% at 200 and 400 mg kg(-1) oral dose, respectively, when compared to negative control. The Ethanolic plant extract also showed significant (p < 0.05) dose dependent reduction of mean increase of formation of paw edema. The results of the experiment and its statistical analysis showed that the ethanolic plant extract had shown significant (p < 0.05) dose dependent analgesic and anti-inflammatory activities when compared to the control.

Mechanical properties of carbon steel depending on the rate of the dose build-up of nitrogen and argon ions

NASA Astrophysics Data System (ADS)

Vorob'ev, V. L.; Bykov, P. V.; Bayankin, V. Ya.; Shushkov, A. A.; Vakhrushev, A. V.

2014-08-01

The effect of pulsed irradiation with argons and nitrogen ions on the mechanical properties, morphology, and structure of the surface layers of carbon steel St3 (0.2% C, 0.4% Mn, 0.15% Si, and Fe for balance) has been investigated depending on the rate of dose build-up at an average ion current density of 10, 20, and 40 μA/cm2. It has been established that the fatigue life and microhardness of surface layers increase in the entire studied range of dose build-up rates. This seems to be due to the hardening of the surface layers, which resulted from the generation of radiation defects and the irradiation-dynamic effect of fast ions. The sample irradiated by argon ions at the lowest of the selected dose build-up rates j av = 10 μA/cm2 withstands the largest number of cycles to failure.

The effects of glucocorticoids on the inhibition of emotional information: A dose-response study.

PubMed

Taylor, Véronique A; Ellenbogen, Mark A; Washburn, Dustin; Joober, Ridha

2011-01-01

There is evidence that cortisol influences cognitive and affective processes such as selective attention and memory for emotional events, yet the effects of glucocorticoids on attentional inhibition in humans remain unknown. Consequently, this double-blind study examined dose-dependent effects of exogenous glucocorticoids on the inhibition of emotional information. Sixty-three university students (14 male, 49 female) ingested either a placebo pill or hydrocortisone (10mg or 40mg), and completed a negative priming task assessing the inhibition of pictures depicting angry, sad, and happy faces. The 10mg, but not the 40mg hydrocortisone dose elicited increased inhibition for angry faces relative to placebo. Thus, moderate glucocorticoid elevations may have adaptive effects on emotional information processing, whereas high glucocorticoid elevations appear to attenuate this effect, consistent with the view that there are dose-dependent effects of glucocorticoids on cognition. Copyright © 2010 Elsevier B.V. All rights reserved.

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans.

PubMed

Trammell, Samuel A J; Schmidt, Mark S; Weidemann, Benjamin J; Redpath, Philip; Jaksch, Frank; Dellinger, Ryan W; Li, Zhonggang; Abel, E Dale; Migaud, Marie E; Brenner, Charles

2016-10-10

Nicotinamide riboside (NR) is in wide use as an NAD + precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD + metabolism in humans. We report that human blood NAD + can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD + with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD + metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD + , is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD + repletion.

Protopine inhibits serotonin transporter and noradrenaline transporter and has the antidepressant-like effect in mice models.

PubMed

Xu, Lin-Feng; Chu, Wen-Jing; Qing, Xiao-Yun; Li, Sheng; Wang, Xue-Song; Qing, Guo-Wei; Fei, Jian; Guo, Li-He

2006-06-01

The protopine isolated from a Chinese herb Dactylicapnos scandens Hutch was identified as an inhibitor of both serotonin transporter and noradrenaline transporter in vitro assays. 5-hydroxy-DL-tryptophan(5-HTP)-induced head twitch response (HTR) and tail suspension test were adopted to study whether protopine has anti-depression effect in mice using reference antidepressant fluoxetine and desipramine as positive controls. In HTR test, protopine at doses of 5, 10, 20 mg/kg dose dependently increase the number of 5-HTP-induced HTR. Protopine at doses of 3.75 mg/kg, 7.5 mg/kg and 30 mg/kg also produces a dose-dependent reduction in immobility in the tail suspension test. The present results open up new possibilities for the use of protopine in the treatment of mood disorders, such as mild and moderate states of depression.

Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single ventricle physiology

PubMed Central

Buckley, Erin M.; Naim, Maryam Y.; Lynch, Jennifer M.; Goff, Donna A.; Schwab, Peter J.; Diaz, Laura K.; Nicolson, Susan C.; Montenegro, Lisa M.; Lavin, Natasha A.; Durduran, Turgut; Spray, Thomas L.; Gaynor, J. William; Putt, Mary E.; Yodh, A.G.; Fogel, Mark A.; Licht, Daniel J.

2013-01-01

Background Sodium bicarbonate (NaHCO3) is a common treatment for metabolic acidemia, however little definitive information exists regarding its treatment efficacy and cerebral hemodynamic effects. This pilot observational study quantifies relative changes in cerebral blood flow (rCBF) and oxy and deoxy-hemoglobin concentrations (ΔHbO2 and ΔHb) due to bolus administration of NaHCO3 in patients with mild base deficits. Methods Infants and children with hypoplastic left heart syndrome (HLHS) were recruited prior to cardiac surgery. NaHCO3 was given as needed for treatment of base deficit. Diffuse optical spectroscopies were employed for 15 minutes post-injection to non-invasively monitor ΔHb, ΔHbO2 and rCBF relative to baseline prior to NaHCO3 administration. Results Twenty-two anesthetized and mechanically ventilated HLHS patients (1 day to 4 years old) received a median (interquartile range) dose of 1.1 (0.8, 1.8) mEq/kg NaHCO3 administered intravenously over 10–20 seconds to treat a base deficit of −4 (−6, −3) mEq/l. NaHCO3 caused significant dose-dependent increases in rCBF, however population averaged ΔHb or Δ4HbO2 compared to controls were not significant. Conclusions Dose-dependent increases in cerebral blood flow (CBF) caused by bolus NaHCO3 are an important consideration in vulnerable populations wherein risk of rapid CBF fluctuations does not outweigh the benefit of treating a base deficit. PMID:23403802

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.

Dosimetric distribution of the surroundings of different dental crowns and implants during LINAC photon irradiation

NASA Astrophysics Data System (ADS)

Chang, Kwo-Ping; Lin, Wei-Ting; Shiau, An-Cheng; Chie, Yu-Huang

2014-11-01

In radiotherapy of the head and neck, metal dentures or implants will increase the risk of complications such as mucositis and osteoradionecrosis. The aim of this study is to explore the back scatter effect of commercially available dental metal alloys on the mucosa and bone under 6 MV LINAC irradiation. The Monte Carlo method has been employed to calculate the dose distribution in the heterogeneous media of the designed oral phantom based on the oral cavity geometry. Backscatter dose increases up to a maximum of 53%, and is primarily dependent on the physical density and electron density of the metal crown alloy. Ceramic metal crowns have been quantified to increase backscatter dose up to 10% on mucosa. Ceramic serves as an inherent shield of mucosa. The backscatter dose will be greater for a small field size if the tumor is located at a deeper region. Titanium implants will increase the backscatter dose by 13% to bone but will not affect the mucosa. QC-20 (polystyrene resin) is recommended as a shield material (3 mm) to eliminate the backscatter dose on mucosa due to the high density metals.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

PubMed

Foegh, Marie; Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Mishell, Daniel R

2013-02-01

The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women. Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women. AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women. Copyright © 2013 Elsevier Inc. All rights reserved.

(+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') increases social interaction in rats.

PubMed

Morley, K C; McGregor, I S

2000-11-10

A series of experiments administered a low dose range (0, 1.25, 2.5 and 5 mg/kg) of (+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') to rats and assessed them in a variety of standard tests of anxiety. These tests included the emergence and elevated plus-maze tests, social interaction, cat odor avoidance and footshock-induced ultrasonic vocalizations. MDMA increased anxiety-related behaviours in the emergence and elevated plus-maze tests at all dose levels. A 5 mg/kg dose of MDMA also significantly reduced the time spent in close proximity to an anxiogenic cat odor stimulus. The 5 mg/kg dose also significantly reduced footshock-induced ultrasonic vocalizations. In the social interaction test, MDMA decreased aggressive behaviours at all doses tested, while the highest dose (5 mg/kg) also significantly increased the duration of social interaction. These results indicate that MDMA has both anxiogenic and anxiolytic effects depending upon the test situation employed. The facilitation of social interaction produced by MDMA in rats concurs with human experience of MDMA as a uniquely prosocial drug.

Calculated organ doses from selected prostate treatment plans using Monte Carlo simulations and an anatomically realistic computational phantom

PubMed Central

Bednarz, Bryan; Hancox, Cindy; Xu, X George

2012-01-01

There is growing concern about radiation-induced second cancers associated with radiation treatments. Particular attention has been focused on the risk to patients treated with intensity-modulated radiation therapy (IMRT) due primarily to increased monitor units. To address this concern we have combined a detailed medical linear accelerator model of the Varian Clinac 2100 C with anatomically realistic computational phantoms to calculate organ doses from selected treatment plans. This paper describes the application to calculate organ-averaged equivalent doses using a computational phantom for three different treatments of prostate cancer: a 4-field box treatment, the same box treatment plus a 6-field 3D-CRT boost treatment and a 7-field IMRT treatment. The equivalent doses per MU to those organs that have shown a predilection for second cancers were compared between the different treatment techniques. In addition, the dependence of photon and neutron equivalent doses on gantry angle and energy was investigated. The results indicate that the box treatment plus 6-field boost delivered the highest intermediate- and low-level photon doses per treatment MU to the patient primarily due to the elevated patient scatter contribution as a result of an increase in integral dose delivered by this treatment. In most organs the contribution of neutron dose to the total equivalent dose for the 3D-CRT treatments was less than the contribution of photon dose, except for the lung, esophagus, thyroid and brain. The total equivalent dose per MU to each organ was calculated by summing the photon and neutron dose contributions. For all organs non-adjacent to the primary beam, the equivalent doses per MU from the IMRT treatment were less than the doses from the 3D-CRT treatments. This is due to the increase in the integral dose and the added neutron dose to these organs from the 18 MV treatments. However, depending on the application technique and optimization used, the required MU values for IMRT treatments can be two to three times greater than 3D CRT. Therefore, the total equivalent dose in most organs would be higher from the IMRT treatment compared to the box treatment and comparable to the organ doses from the box treatment plus the 6-field boost. This is the first time when organ dose data for an adult male patient of the ICRP reference anatomy have been calculated and documented. The tools presented in this paper can be used to estimate the second cancer risk to patients undergoing radiation treatment. PMID:19671968

Calculated organ doses from selected prostate treatment plans using Monte Carlo simulations and an anatomically realistic computational phantom

NASA Astrophysics Data System (ADS)

Bednarz, Bryan; Hancox, Cindy; Xu, X. George

2009-09-01

There is growing concern about radiation-induced second cancers associated with radiation treatments. Particular attention has been focused on the risk to patients treated with intensity-modulated radiation therapy (IMRT) due primarily to increased monitor units. To address this concern we have combined a detailed medical linear accelerator model of the Varian Clinac 2100 C with anatomically realistic computational phantoms to calculate organ doses from selected treatment plans. This paper describes the application to calculate organ-averaged equivalent doses using a computational phantom for three different treatments of prostate cancer: a 4-field box treatment, the same box treatment plus a 6-field 3D-CRT boost treatment and a 7-field IMRT treatment. The equivalent doses per MU to those organs that have shown a predilection for second cancers were compared between the different treatment techniques. In addition, the dependence of photon and neutron equivalent doses on gantry angle and energy was investigated. The results indicate that the box treatment plus 6-field boost delivered the highest intermediate- and low-level photon doses per treatment MU to the patient primarily due to the elevated patient scatter contribution as a result of an increase in integral dose delivered by this treatment. In most organs the contribution of neutron dose to the total equivalent dose for the 3D-CRT treatments was less than the contribution of photon dose, except for the lung, esophagus, thyroid and brain. The total equivalent dose per MU to each organ was calculated by summing the photon and neutron dose contributions. For all organs non-adjacent to the primary beam, the equivalent doses per MU from the IMRT treatment were less than the doses from the 3D-CRT treatments. This is due to the increase in the integral dose and the added neutron dose to these organs from the 18 MV treatments. However, depending on the application technique and optimization used, the required MU values for IMRT treatments can be two to three times greater than 3D CRT. Therefore, the total equivalent dose in most organs would be higher from the IMRT treatment compared to the box treatment and comparable to the organ doses from the box treatment plus the 6-field boost. This is the first time when organ dose data for an adult male patient of the ICRP reference anatomy have been calculated and documented. The tools presented in this paper can be used to estimate the second cancer risk to patients undergoing radiation treatment.

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.

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.

Errors introduced by dose scaling for relative dosimetry

PubMed Central

Watanabe, Yoichi; Hayashi, Naoki

2012-01-01

Some dosimeters require a relationship between detector signal and delivered dose. The relationship (characteristic curve or calibration equation) usually depends on the environment under which the dosimeters are manufactured or stored. To compensate for the difference in radiation response among different batches of dosimeters, the measured dose can be scaled by normalizing the measured dose to a specific dose. Such a procedure, often called “relative dosimetry”, allows us to skip the time‐consuming production of a calibration curve for each irradiation. In this study, the magnitudes of errors due to the dose scaling procedure were evaluated by using the characteristic curves of BANG3 polymer gel dosimeter, radiographic EDR2 films, and GAFCHROMIC EBT2 films. Several sets of calibration data were obtained for each type of dosimeters, and a calibration equation of one set of data was used to estimate doses of the other dosimeters from different batches. The scaled doses were then compared with expected doses, which were obtained by using the true calibration equation specific to each batch. In general, the magnitude of errors increased with increasing deviation of the dose scaling factor from unity. Also, the errors strongly depended on the difference in the shape of the true and reference calibration curves. For example, for the BANG3 polymer gel, of which the characteristic curve can be approximated with a linear equation, the error for a batch requiring a dose scaling factor of 0.87 was larger than the errors for other batches requiring smaller magnitudes of dose scaling, or scaling factors of 0.93 or 1.02. The characteristic curves of EDR2 and EBT2 films required nonlinear equations. With those dosimeters, errors larger than 5% were commonly observed in the dose ranges of below 50% and above 150% of the normalization dose. In conclusion, the dose scaling for relative dosimetry introduces large errors in the measured doses when a large dose scaling is applied, and this procedure should be applied with special care. PACS numbers: 87.56.Da, 06.20.Dk, 06.20.fb PMID:22955658

Contrasting effects of low versus high ascorbate doses on blood pressure responses to oral nitrite in L-NAME-induced hypertension.

PubMed

Pinheiro, Lucas C; Ferreira, Graziele C; Vilalva, Kelvin H; Toledo, José C; Tanus-Santos, Jose E

2018-04-01

Nitrite reduces blood pressure (BP) in both clinical and experimental hypertension. This effect is attributable to the formation of nitric oxide (NO) and other NO-related species, which may be improved by ascorbate or other antioxidants. However, the BP responses to oral nitrite result, at least in part, of increased gastric S-nitrosothiol formation. This study tested the hypothesis that ascorbate may destroy S-nitrosothiols and therefore not all doses of ascorbate enhance the BP responses to oral nitrite. We assessed the BP responses to oral sodim nitrite (0.2 mmol/kg) in L-NAME hypertensive rats pretreated with ascorbate (0, 0.02, 0.2, or 2 mmol/kg). Plasma and gastric wall concentrations of nitrite and nitroso compounds concentrations were determined using an ozone-based reductive chemiluminescence assay. Nitrate concentrations were determined using the Griess reaction. Free thiol concentrations were determined by a colorimetric assay. The BP responses to nitrite exhibited a bell-shape profile as they were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated BP responses. In parallel with BP responses, nitrite-induced increases in plasma nitrite and RSNO species were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated them. Similar experiments were carried out with an equimolar dose of S-nitrosogluthathione. Ascorbate dose-dependently impaired the BP responses to S-nitrosogluthathione, and the corresponding increases in plasma RSNO, but not in plasma nitrite concentrations. This is the first study to show that while ascorbate dose-dependently impairs the BP responses to oral S-nitrosogluthathione, there are contrasting effects when low versus high ascorbate doses are compared with respect to its effects on the blood pressure responses to oral nitrite administration. Our findings may have special implications to patients taking ascorbate, as high doses of this vitamin may impair protective mechanisms associated with nitrite or nitrate from dietary sources. Copyright © 2018 Elsevier Inc. All rights reserved.

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

PubMed

Rush, C R; Baker, R W; Rowlett, J K

2000-02-01

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5-15.0 mg), triazolam (0.0625-0.3750 mg), pentobarbital (25-150 mg), caffeine (100-600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines.

Detomidine reduces isoflurane anesthetic requirement (MAC) in horses.

PubMed

Steffey, Eugene P; Pascoe, Peter J

2002-10-01

To quantitate the dose- and time-related magnitude of the anesthetic sparing effect of, and selected physiological responses to detomidine during isoflurane anesthesia in horses. Randomized cross-over study. Three, healthy, young adult horses weighing 485 ± 14 kg. Horses were anesthetized on two occasions to determine the minimum alveolar concentration (MAC) of isoflurane in O 2 and then to measure the anesthetic sparing effect (time-related MAC reduction) following IV detomidine (0.03 and 0.06 mg kg -1 ). Selected common measures of cardiopulmonary function, blood glucose and urinary output were also recorded. Isoflurane MAC was 1.44 ± 0.07% (mean ± SEM). This was reduced by 42.8 ± 5.4% and 44.8 ± 3.0% at 83 ± 23 and 125 ± 36 minutes, respectively, following 0.03 and 0.06 mg kg -1 , detomidine. The MAC reduction was detomidine dose- and time-dependent. There was a tendency for mild cardiovascular and respiratory depression, especially following the higher detomidine dose. Detomidine increased both blood glucose and urine flow; the magnitude of these changes was time- and dose-dependent CONCLUSIONS: Detomidine reduces anesthetic requirement for isoflurane and increases blood glucose concentration and urine flow in horses. These changes were dose- and time-related. The results imply potent anesthetic sparing actions by detomidine. The detomidine-related increased urine flow should be considered in designing anesthetic protocols for individual horses. Copyright © 2002 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

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.

Characterization of a new transmission detector for patient individualized online plan verification and its influence on 6MV X-ray beam characteristics.

PubMed

Thoelking, Johannes; Sekar, Yuvaraj; Fleckenstein, Jens; Lohr, Frank; Wenz, Frederik; Wertz, Hansjoerg

2016-09-01

Online verification and 3D dose reconstruction on daily patient anatomy have the potential to improve treatment delivery, accuracy and safety. One possible implementation is to recalculate dose based on online fluence measurements with a transmission detector (TD) attached to the linac. This study provides a detailed analysis of the influence of a new TD on treatment beam characteristics. The influence of the new TD on surface dose was evaluated by measurements with an Advanced Markus Chamber (Adv-MC) in the build-up region. Based on Monte Carlo simulations, correction factors were determined to scale down the over-response of the Adv-MC close to the surface. To analyze the effects beyond dmax percentage depth dose (PDD), lateral profiles and transmission measurements were performed. All measurements were carried out for various field sizes and different SSDs. Additionally, 5 IMRT-plans (head & neck, prostate, thorax) and 2 manually created test cases (3×3cm(2) fields with different dose levels, sweeping gap) were measured to investigate the influence of the TD on clinical treatment plans. To investigate the performance of the TD, dose linearity as well as dose rate dependency measurements were performed. With the TD inside the beam an increase in surface dose was observed depending on SSD and field size (maximum of +11%, SSD = 80cm, field size = 30×30cm(2)). Beyond dmax the influence of the TD on PDDs was below 1%. The measurements showed that the transmission factor depends slightly on the field size (0.893-0.921 for 5×5cm(2) to 30×30cm(2)). However, the evaluation of clinical IMRT-plans measured with and without the TD showed good agreement after using a single transmission factor (γ(2%/2mm) > 97%, δ±3% >95%). Furthermore, the response of TD was found to be linear and dose rate independent (maximum difference <0.5% compared to reference measurements). When placed in the path of the beam, the TD introduced a slight, clinically acceptable increase of the skin dose even for larger field sizes and smaller SSDs and the influence of the detector on the dose beyond dmax as well as on clinical IMRT-plans was negligible. Since there was no dose rate dependency and the response was linear, the device is therefore suitable for clinical use. Only its absorption has to be compensated during treatment planning, either by the use of a single transmission factor or by including the TD in the incident beam model. Copyright © 2015. Published by Elsevier GmbH.

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.

Prediction of Drug-Drug Interactions with Crizotinib as the CYP3A Substrate Using a Physiologically Based Pharmacokinetic Model.

PubMed

Yamazaki, Shinji; Johnson, Theodore R; Smith, Bill J

2015-10-01

An orally available multiple tyrosine kinase inhibitor, crizotinib (Xalkori), is a CYP3A substrate, moderate time-dependent inhibitor, and weak inducer. The main objectives of the present study were to: 1) develop and refine a physiologically based pharmacokinetic (PBPK) model of crizotinib on the basis of clinical single- and multiple-dose results, 2) verify the crizotinib PBPK model from crizotinib single-dose drug-drug interaction (DDI) results with multiple-dose coadministration of ketoconazole or rifampin, and 3) apply the crizotinib PBPK model to predict crizotinib multiple-dose DDI outcomes. We also focused on gaining insights into the underlying mechanisms mediating crizotinib DDIs using a dynamic PBPK model, the Simcyp population-based simulator. First, PBPK model-predicted crizotinib exposures adequately matched clinically observed results in the single- and multiple-dose studies. Second, the model-predicted crizotinib exposures sufficiently matched clinically observed results in the crizotinib single-dose DDI studies with ketoconazole or rifampin, resulting in the reasonably predicted fold-increases in crizotinib exposures. Finally, the predicted fold-increases in crizotinib exposures in the multiple-dose DDI studies were roughly comparable to those in the single-dose DDI studies, suggesting that the effects of crizotinib CYP3A time-dependent inhibition (net inhibition) on the multiple-dose DDI outcomes would be negligible. Therefore, crizotinib dose-adjustment in the multiple-dose DDI studies could be made on the basis of currently available single-dose results. Overall, we believe that the crizotinib PBPK model developed, refined, and verified in the present study would adequately predict crizotinib oral exposures in other clinical studies, such as DDIs with weak/moderate CYP3A inhibitors/inducers and drug-disease interactions in patients with hepatic or renal impairment. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Poster — Thur Eve — 48: Dosimetric dependence on bone backscatter in orthovoltage radiotherapy: A Monte Carlo photon fluence spectral study

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

Chow, J; Grigor, G

This study investigated dosimetric impact due to the bone backscatter in orthovoltage radiotherapy. Monte Carlo simulations were used to calculate depth doses and photon fluence spectra using the EGSnrc-based code. Inhomogeneous bone phantom containing a thin water layer (1–3 mm) on top of a bone (1 cm) to mimic the treatment sites of forehead, chest wall and kneecap was irradiated by the 220 kVp photon beam produced by the Gulmay D3225 x-ray machine. Percentage depth doses and photon energy spectra were determined using Monte Carlo simulations. Results of percentage depth doses showed that the maximum bone dose was about 210–230%more » larger than the surface dose in the phantoms with different water thicknesses. Surface dose was found to be increased from 2.3 to 3.5%, when the distance between the phantom surface and bone was increased from 1 to 3 mm. This increase of surface dose on top of a bone was due to the increase of photon fluence intensity, resulting from the bone backscatter in the energy range of 30 – 120 keV, when the water thickness was increased. This was also supported by the increase of the intensity of the photon energy spectral curves at the phantom and bone surface as the water thickness was increased. It is concluded that if the bone inhomogeneity during the dose prescription in the sites of forehead, chest wall and kneecap with soft tissue thickness = 1–3 mm is not considered, there would be an uncertainty in the dose delivery.« less

Alcohol Attenuates Load-related Activation During a Working Memory Task: Relation to Level of Response to Alcohol

PubMed Central

Paulus, Martin P.; Tapert, Susan F.; Pulido, Carmen; Schuckit, Marc A.

2008-01-01

Background A low level of response to alcohol is a major risk factor for the development of alcohol dependence, but neural correlates of this marker are unclear. Method Ten healthy volunteers were classified by median split on level of response to alcohol and underwent 2 sessions of functional magnetic resonance imaging following ingestion of a moderate dose of alcohol and a placebo. The blood oxygen level–dependent activation to an event-related visual working memory test was examined. Results The subjects exhibited longer response latencies and more errors as a function of increasing working memory load and showed a load-dependent increase in activation in dorsolateral prefrontal cortex, posterior parietal cortex, and visual cortex. Alcohol did not affect performance (errors or response latency), but attenuated the working memory load–dependent activation in the dorsolateral prefrontal cortex. During the placebo condition, individuals with a low level of response to alcohol showed greater activation in dorsolateral prefrontal cortex and posterior parietal cortex than those with a high level of response to alcohol. During the alcohol condition, groups showed similar attenuation of load-dependent brain activation in these regions. Conclusion Low-level responders relative to high-level responders exhibited an increased working memory load–dependent activation in dorsolateral prefrontal cortex and posterior parietal cortex when not exposed to alcohol. This increase in brain response was attenuated in low-level responders after ingesting a moderate dose of alcohol. PMID:16899039

Testosterone influences spatial strategy preferences among adult male rats

PubMed Central

Spritzer, Mark D.; Fox, Elliott C.; Larsen, Gregory D.; Batson, Christopher G.; Wagner, Benjamin A.; Maher, Jack

2013-01-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats’ strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. PMID:23597827

Testosterone influences spatial strategy preferences among adult male rats.

PubMed

Spritzer, Mark D; Fox, Elliott C; Larsen, Gregory D; Batson, Christopher G; Wagner, Benjamin A; Maher, Jack

2013-05-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats' strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. Copyright © 2013 Elsevier Inc. All rights reserved.

Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia.

PubMed

Clarke, Zoe L; Moat, Stuart J; Miller, Alastair L; Randall, Michael D; Lewis, Malcolm J; Lang, Derek

2006-12-03

The exact mechanism(s) by which hyperhomocysteinaemia promotes vascular disease remains unclear. Moreover, recent evidence suggests that the beneficial effect of folic acid on endothelial function is independent of homocysteine-lowering. In the present study the effect of a low (400 microg/70 kg/day) and high (5 mg/70 kg/day) dose folic acid supplement on endothelium-dependent relaxation in the isolated perfused mesenteric bed of heterozygous cystathionine beta-synthase deficient mice was investigated. Elevated total plasma homocysteine and impaired relaxation responses to methacholine were observed in heterozygous mice. In the presence of N(G)-nitro-L-arginine methyl ester relaxation responses in wild-type tissues were reduced, but in heterozygous tissues were abolished. Clotrimazole and 18alpha-glycyrrhetinic acid, both inhibitors of non-nitric oxide/non-prostanoid-induced endothelium-dependent relaxation, reduced responses to methacholine in wild-type but not heterozygous tissues. The combination of N(G)-nitro-L-arginine methyl ester and either clotrimazole or 18alpha-glycyrrhetinic acid completely inhibited relaxation responses in wild-type tissues. Both low and high dose folic acid increased plasma folate, reduced total plasma homocysteine and reversed endothelial dysfunction in heterozygous mice. A greater increase in plasma folate in the high dose group was accompanied by a more significant effect on endothelial function. In the presence of N(G)-nitro-L-arginine methyl ester, a significant residual relaxation response was evident in tissues from low and high dose folic acid treated heterozygous mice. These data suggest that the impaired mesenteric relaxation in heterozygous mice is largely due to loss of the non-nitric oxide/non-prostanoid component. While low dose folic acid may restore this response in a homocysteine-dependent manner, the higher dose has an additional effect on nitric oxide-mediated relaxation that would appear to be independent of homocysteine lowering.

Effects of ultrafine diesel exhaust particles on oxidative stress generation and dopamine metabolism in PC-12 cells.

PubMed

Kim, Yong-Dae; Lantz-McPeak, Susan M; Ali, Syed F; Kleinman, Michael T; Choi, Young-Sook; Kim, Heon

2014-05-01

A major constituent of urban air pollution is diesel exhaust, a complex mixture of gases, chemicals, and particles. Recent evidence suggests that exposure to air pollution can increase the risk of a fatal stroke, cause cerebrovascular damage, and induce neuroinflammation and oxidative stress that may trigger neurodegenerative diseases, such as Parkinson's disease. The specific aim of this study was to determine whether ultrafine diesel exhaust particles (DEPs), the particle component of exhaust from diesel engines, can induce oxidative stress and effect dopamine metabolism in PC-12 cells. After 24 h exposure to DEPs of 200 nm or smaller, cell viability, ROS and nitric oxide (NO(2)) generation, and levels of dopamine (DA) and its metabolites, (dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)), were evaluated. Results indicated cell viability was not significantly changed by DEP exposure. However, ROS showed dramatic dose-dependent changes after DEP exposure (2.4 fold increase compared to control at 200 μg/mL). NO(2) levels were also dose-dependently increased after DEP exposure. Although not in a dose-dependent manner, upon DEP exposure, intracellular DA levels were increased while DOPAC and HVA levels decreased when compared to control. Results suggest that ultrafine DEPs lead to dopamine accumulation in the cytoplasm of PC-12 cells, possibly contributing to ROS formation. Further studies are warranted to elucidate this mechanism. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.

Tizanidine

MedlinePlus

... and gradually increase your dose, depending on your response to this medication.Do not stop taking tizanidine without talking to your doctor. If you suddenly stop taking tizanidine, your heart may beat faster and you may have increased blood pressure or tightness in your muscles. Your doctor will ...

Dose-response analysis of testosterone replacement therapy in patients with female to male gender identity disorder.

PubMed

Nakamura, Aya; Watanabe, Masami; Sugimoto, Morito; Sako, Tomoko; Mahmood, Sabina; Kaku, Haruki; Nasu, Yasutomo; Ishii, Kazushi; Nagai, Atsushi; Kumon, Hiromi

2013-01-01

Gender identity disorder (GID) is a conflict between a person's actual physical gender and the one they identify him or herself with. Testosterone is the key agent in the medical treatment of female to male GID patients. We conducted a dose-response analysis of testosterone replacement therapy (TRT) in 138 patients to determine the onset of the therapeutic effects. The TRT consisted of intramuscular injection of testosterone enanthate and patients were divided into three groups; 250 mg every two weeks, 250 mg every three weeks and 125 mg every two weeks. The onset of deepening of voice, increase in facial hair and cessation of menses was evaluated in each group. At one month after the start of TRT, the onset of these physical changes was more prevalent in the group receiving the higher dose of testosterone, and there were dose-dependent effects observed between the three treatment groups. On the other hand, at six months after the start of TRT, most of the patients had achieved treatment responses and there were no dose-dependent effects with regard to the percentage of patients with therapeutic effects. No significant side effects were observed in any of the treatment groups. We demonstrated that the early onset of the treatment effects of TRT is dose-dependent, but within six months of starting TRT, all three doses were highly effective. Current study provides useful information to determine the initial dose of TRT and to suggest possible changes that should be made in the continuous dosage for long term TRT.

Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.

Amphetamine increases schedule-induced drinking reduced by negative punishment procedures.

PubMed

Pérez-Padilla, Angeles; Pellón, Ricardo

2003-05-01

d-Amphetamine has been reported to increase schedule-induced drinking punished by lick-dependent signalled delays in food delivery. This might reflect a drug-behaviour interaction dependent on the type of punisher, because no such effect has been found when drinking was reduced by lick-contingent electric shocks. However, the anti-punishment effect of amphetamine could be mediated by other behavioural processes, such as a loss of discriminative control or an increase in the value of delayed reinforcers. To test the effects of d-amphetamine on the acquisition and maintenance of schedule-induced drinking reduced by unsignalled delays in food delivery. Rats received 10-s unsignalled delays initiated by each lick after polydipsia was induced by a fixed-time 30-s food reinforcement schedule or from the outset of the experiment. Yoked-control rats received these same delays but independently of their own behaviour. d-Amphetamine (0.1-3.0 mg/kg) was then tested IP. d-Amphetamine dose-dependently increased and then decreased punished schedule-induced drinking. The drug led to dose-dependent reductions when the delays were not contingent or when they were applied from the outset of training. These results support the contention that d-amphetamine has an increasing effect on schedule-induced drinking that has been previously reduced by a negative punishment procedure. This effect cannot be attributed to other potentially involved processes, and therefore support the idea that drug effects on punished behaviour depend on punishment being delays in food or shock deliveries.

Age-dependent differences in nicotine reward and withdrawal in female mice.

PubMed

Kota, D; Martin, B R; Damaj, M I

2008-06-01

Adolescent smoking is an increasing epidemic in the US. Research has shown that the commencement of smoking at a young age increases addiction and decreases the probability of successful cessation; however, limited work has focused on nicotine dependence in the female. The goal of the present study was to identify the biological and behavioral factors that may contribute to nicotine's increased abuse liability in female adolescents using animal models of nicotine dependence. Early adolescent (PND 28) and adult (PND 70) female mice were compared in various aspects of nicotine dependence using reward and withdrawal models following sub-chronic nicotine exposure. Furthermore, in vivo acute sensitivity and tolerance to nicotine were examined. In the conditioned place preference model, adolescents demonstrated a significant preference at 0.5 mg/kg nicotine, an inactive dose in adults. Adults found higher doses (0.7 and 1.0 mg/kg) of nicotine to elicit rewarding effects. Furthermore, adolescents displayed increased physical, but not affective, withdrawal signs in three models. Upon acute exposure to nicotine, adolescent mice showed increased sensitivity in an analgesic measure as well as hypothermia. After chronic nicotine exposure, both adults and adolescents displayed tolerance to nicotine with adolescents having a lower degree of tolerance to changes in body temperature. These data indicate that differences in nicotine's rewarding and aversive effects may contribute to variations in certain components of nicotine dependence between adult and adolescent female mice. Furthermore, this implies that smoking cessation therapies may not be equally effective across all ages.

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.

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

Dose-dependent effects of alpha-naphthylisothiocyanate disconnect biliary fibrosis from hepatocellular necrosis.

PubMed

Joshi, Nikita; Ray, Jessica L; Kopec, Anna K; Luyendyk, James P

2017-01-01

Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice. © 2016 Wiley Periodicals, Inc.

Observations on personnel dosimetry for radiotherapy personnel operating high-energy LINACs.

PubMed

Glasgow, G P; Eichling, J; Yoder, R C

1986-06-01

A series of measurements were conducted to determine the cause of a sudden increase in personnel radiation exposures. One objective of the measurements was to determine if the increases were related to changing from film dosimeters exchanged monthly to TLD-100 dosimeters exchanged quarterly. While small increases were observed in the dose equivalents of most employees, the dose equivalents of personnel operating medical electron linear accelerators with energies greater than 20 MV doubled coincidentally with the change in the personnel dosimeter program. The measurements indicated a small thermal neutron radiation component around the accelerators operated by these personnel. This component caused the doses measured with the TLD-100 dosimeters to be overstated. Therefore, the increase in these personnel dose equivalents was not due to changes in work habits or radiation environments. Either film or TLD-700 dosimeters would be suitable for personnel monitoring around high-energy linear accelerators. The final choice would depend on economics and personal preference.

Dose-Dependent Effects of Alpha-Naphthylisothiocyanate Disconnect Biliary Fibrosis from Hepatocellular Necrosis

PubMed Central

Joshi, Nikita; Ray, Jessica L.; Kopec, Anna K.; Luyendyk, James P.

2017-01-01

Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well-characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice. PMID:27605088

Implication of cyclin-dependent kinase 5 in the development of psychological dependence on and behavioral sensitization to morphine.

PubMed

Narita, Minoru; Shibasaki, Masahiro; Nagumo, Yasuyuki; Narita, Michiko; Yajima, Yoshinori; Suzuki, Tsutomu

2005-06-01

In the present study, we investigated the role of cyclin-dependent kinase 5 (cdk5) in the brain dynamics changed by repeated in vivo treatment with morphine. The level of phosphorylated-cdk5 was significantly increased in the cingulate cortex of mice showing the morphine-induced rewarding effect. Under these conditions, roscovitine, a cdk5 inhibitor, given intracerebroventricularly (i.c.v.) caused a dose-dependent and significant inhibition of the morphine-induced rewarding effect. In addition, the dose-response effect of the morphine-induced rewarding effect was dramatically attenuated in cdk5 heterozygous (+/-) knockout mice. Furthermore, the development of behavioral sensitization by intermittent administration of morphine was virtually abolished in cdk5 (+/-) mice. These findings suggest that the induction and/or activation of cdk5 are implicated in the development of psychological dependence on morphine.

Calcium signals and caspase-12 participated in paraoxon-induced apoptosis in EL4 cells.

PubMed

Li, Lan; Cao, Zhiheng; Jia, Pengfei; Wang, Ziren

2010-04-01

In order to investigate whether calcium signals participate in paraoxon (POX)-induced apoptosis in EL4 cells, real-time laser scanning confocal microscopy (LSCM) was used to detect Ca(2+) changes during the POX application. Apoptotic rates of EL4 cells and caspase-12 expression were also evaluated. POX (1-10nM) increased intracellular calcium concentration ([Ca(2+)]i) in EL4 cells in a dose-dependent manner at early stage (0-2h) of POX application, and apoptotic rates of EL4 cells after treatment with POX for 16h were also increased in a dose-dependent manner. Pre-treatment with EGTA, heparin or procaine attenuated POX-induced [Ca(2+)]i elevation and apoptosis. Additionally, POX up-regulated caspase-12 expression in a dose-dependent manner, and pre-treatment with EGTA, heparin or procaine significantly inhibited POX-induced increase of caspase-12 expression. Our results suggested that POX induced [Ca(2+)]i elevation in EL4 cells at the early stage of POX-induced apoptosis, which might involve Ca(2+) efflux from the endoplasmic reticulum (ER) and Ca(2+) influx from extracellular medium. Calcium signals and caspase-12 were important upstream messengers in POX-induced apoptosis in EL4 cells. The ER-associated pathway possibly operated in this apoptosis. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

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.

Desensitization of atriopeptin stimulated accumulation and extrusion of cyclic GMP from a kidney epithelial cell line (MDCK).

PubMed

Woods, M; Houslay, M D

1991-02-01

Atriopeptin caused dose- (EC50 ca. 2 x 10(-8) M) and time-dependent increases in the intracellular concentration of cyclic GMP in the MDCK kidney epithelial cell line; an effect potentiated by the phosphodiesterase inhibitor, IBMX. The atriopeptin-catalysed increase in cyclic GMP was transient and reached a maximum some 10-20 min after challenge of cells with atriopeptin. The basis for the transience of this increase was shown to be due to the desensitization of guanylate cyclase coupled with extrusion of cyclic GMP from the cells and the degradation of cyclic GMP by phosphodiesterase activity. Atriopeptin-catalysed extrusion of cyclic GMP was time- and dose-(EC50 ca. 1.5 x 10(-8) M) dependent and was inhibited by probenecid but not by high external cyclic GMP concentrations. The extrusion process underwent apparent desensitization as did guanylate cyclase with similar half lives (T1/2 of ca. 20 min). Desensitization was dose-dependent upon atriopeptin and did not appear to be mediated by elevated cyclic GMP concentrations as pre-incubation with 8-bromo cyclic GMP did not cause desensitization and the half-times for desensitization were similar whether or not IBMX was present. The majority of the cyclic nucleotide phosphodiesterase activity was found in the cytosol fraction of the cells and could be separated into two cyclic AMP specific forms and two cyclic GMP preferring forms.

Alpha2-adrenoceptor modulation of long-term potentiation elicited in vivo in rat occipital cortex.

PubMed

Mondaca, Mauricio; Hernández, Alejandro; Pérez, Hernán; Valladares, Luis; Sierralta, Walter; Fernández, Victor; Soto-Moyano, Rubén

2004-09-24

Pretreatment with the alpha(2)-adrenoceptor agonist clonidine (31.25, 62.5, or 125 microg/kg, i.p.) dose-dependently reduced long-term potentiation (LTP) elicited in vivo in the occipital cortex of anesthetized rats, whereas pretreatment with the alpha(2)-adrenoceptor antagonist yohimbine (0.133, 0.4, or 1.2 mg/kg, i.p.) increased neocortical LTP in a dose-dependent fashion. These effects could be related to the reported disruptive and facilitatory actions induced on memory formation by pretreatment with alpha(2)-adrenoceptor agonists and antagonists, respectively.

Enhanced Medial Collateral Ligament Healing using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

PubMed Central

Saether, Erin E.; Chamberlain, Connie S.; Leiferman, Ellen M.; Kondratko-Mittnacht, Jaclyn R.; Li, Wan Ju; Brickson, Stacey L.; Vanderby, Ray

2013-01-01

Mesenchymal stem cells (MSCs) have potential therapeutic applications for musculoskeletal injuries due to their ability to differentiate into several tissue cell types and modulate immune and inflammatory responses. These immune-modulatory properties were examined in vivo during early stage rat medial collateral ligament healing. Two different cell doses (low dose 1×106 or high dose 4×106 MSCs) were administered at the time of injury and compared with normal ligament healing at days 5 and 14 post-injury. At both times, the high dose MSC group demonstrated a significant decrease in M2 macrophages compared to controls. At day 14, fewer M1 macrophages were detected in the low dose group compared to the high dose group. These results, along with significant changes in procollagen I, proliferating cells, and endothelialization suggest that MSCs can alter the cellular response during healing in a dose-dependent manner. The higher dose ligaments also had increased expression of several pro-inflammatory cytokines at day 5 (IL-1β, IFNγ, IL-2) and increased expression of IL-12 at day 14. Mechanical testing at day 14 revealed increased failure strength and stiffness in low dose ligaments compared to controls. Based on these improved mechanical properties, MSCs enhanced functional healing when applied at a lower dose. Different doses of MSCs uniquely affected the cellular response and cytokine expression in healing ligaments. Interestingly, the lower dose of cells proved to be most effective in improving functional properties. PMID:24174129

Systemic SMAD7 Gene Therapy Increases Striated Muscle Mass and Enhances Exercise Capacity in a Dose-Dependent Manner.

PubMed

Maricelli, Joseph W; Bishaw, Yemeserach M; Wang, Bo; Du, Min; Rodgers, Buel D

2018-03-01

Striated muscle wasting occurs with a variety of disease indications, contributing to mortality and compromising life quality. Recent studies indicate that the recombinant adeno-associated virus (serotype 6) Smad7 gene therapeutic, AVGN7, enhances skeletal and cardiac muscle mass and prevents cancer-induced wasting of both tissues. This is accomplished by attenuating ActRIIb intracellular signaling and, as a result, the physiological actions of myostatin and other ActRIIb ligands. AVGN7 also enhances isolated skeletal muscle twitch force, but is unknown to improve systemic muscle function similarly, especially exercise capacity. A 2-month-long dose-escalation study was therefore conducted using 5 × 10 11 , 1 × 10 12 , and 5 × 10 12 vg/mouse and different tests of systemic muscle function. Body mass, skeletal muscle mass, heart mass, and forelimb grip strength were all increased in a dose-dependent manner, as was the fiber cross-sectional area of tibialis anterior muscles. Maximal oxygen consumption (VO 2 max), a measure of metabolic rate, was similarly enhanced during forced treadmill running, and although the total distance traveled was only elevated by the highest dose, all doses reduced the energy expenditure rate compared to control mice injected with an empty vector. Such improvements in VO 2 max are consistent with physiological cardiac hypertrophy, which is highly beneficial and a normal adaptive response to exercise. This was particularly evident at the lowest dose tested, which had minimal significant effects on skeletal muscle mass and/or function, but increased heart weight and exercise capacity. These results together suggest that AVGN7 enhances striated muscle mass and systemic muscle function. They also define minimally effective and optimal doses for future preclinical trials and toxicology studies and in turn will aid in establishing dose ranges for clinical trials.

Circulating Cytokine/Chemokine Concentrations Respond to Ionizing Radiation Doses but not Radiation Dose Rates: Granulocyte-Colony Stimulating Factor and Interleukin-18.

PubMed

Kiang, Juliann G; Smith, Joan T; Hegge, Sara R; Ossetrova, Natalia I

2018-06-01

Exposure to ionizing radiation is a crucial life-threatening factor in nuclear and radiological incidents. It is known that ionizing radiation affects cytokine/chemokine concentrations in the blood of B6D2F1 mice. It is not clear whether radiation dose rates would vary the physiological response. Therefore, in this study we utilized data from two experiments using B6D2F1 female mice exposed to six different dose rates ranging from low to high rates. In one experiment, mice received a total dose of 8 Gy (LD 0/30 ) of 60 Co gamma radiation at four dose rates: 0.04, 0.15, 0.30 and 0.47 Gy/min. Blood samples from mice were collected at 24 and 48 h postirradiation for cytokine/chemokine measurements, including interleukin (IL)-1β, IL-6, IL-10, keratinocyte cytokine (KC), IL-12p70, IL-15, IL-17A, IL-18, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage (GM)-CSF, macrophage (M)-CSF, monokine induced by gamma interferon (MIG), tumor necrosis factor (TNF)-α, fibroblast growth factor (FGF)-basic, vascular endothelial growth factor (VEGF) and platelet-derived growth factor basic (PDGF-bb). At 24 h after ionizing irradiation at dose rate of 0.04 Gy/min, significant increases were observed only in G-CSF and M-CSF ( P < 0.05). At 0.15 Gy/min, IL-10, IL-17A, G-CSF and GM-CSF concentrations were increased. At 0.3 Gy/min, IL-15, IL-18, G-CSF, GM-CSF, M-CSF, MCP-1, MIP-2, MIG, FGF-basic, VEGF and PDGF-bb were significantly elevated ( P < 0.05). At 0.47 Gy/min, IL-6, KC, IL-10, MCP-1, G-CSF, GM-CSF and M-CSF were significantly increased. At 48 h postirradiation, all cytokines/chemokines except MCP-1 returned to or were below their baselines, suggesting these increases are transient at LD 0/30 irradiation. Of note, there is a limitation on day 2 because cytokines/chemokines are either at or below their baselines. Other parameters such as fms-like tyrosine kinase receptor-3 ligand (Flt-3 ligand) concentrations and lymphocyte counts, which have proven to be unaffected by radiation dose rates, can be used instead for assessing the radiation dose. However, in a separate radiation dose and time-course experiment, increases in IL-18 and G-CSF depended on the radiation doses but showed no significant differences between 0.58 and 1.94 Gy/min ( P > 0.05) at 3 and 6 Gy but not 12 Gy. G-CSF continued to increase up to day 7, whereas IL-18 increased on day 4 and remained above baseline level on day 7. Therefore, time after irradiation at different doses should be taken into consideration. To our knowledge, these results are the first to suggest that ionizing radiation, even at a very low-dose-rate (0.04 Gy/min), induces circulating G-CSF increases but not others for selected time points; radiation-induced increases in IL-18 at radiation dose rates between 0.15 and 1.94 Gy/min are also not in a radiation dose-rate-dependent manner. C-CSF, lymphocyte counts and circulating Flt-3 ligand should be explored further as possible biomarkers of radiation exposure at early time points. IL-18 is also worthy of further study as a potential biomarker at later time points.

Gabapentin treatment for alcohol dependence: a randomized clinical trial.

PubMed

Mason, Barbara J; Quello, Susan; Goodell, Vivian; Shadan, Farhad; Kyle, Mark; Begovic, Adnan

2014-01-01

Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics. To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid-modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner. A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital. Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling. Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study. RESULTS Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups. Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence. clinicaltrials.gov Identifier: NCT00391716.

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.

Evaluation of the reinforcing and subjective effects of heroin in combination with dextromethorphan and quinidine

PubMed Central

Vosburg, Suzanne K.; Sullivan, Maria A.; Comer, Sandra D.

2015-01-01

Objective Studies have suggested that the N-methyl-d-aspartate antagonist dextromethorphan may be useful in the treatment of opioid dependence. Design This double-blinded, placebo-controlled inpatient study evaluated the effects of 0, 30, and 60 mg of dextromethorphan and quinidine (DMQ) on the reinforcing and subjective effects of heroin in recently detoxified heroin abusers. Participants Nine heroin-dependent participants were admitted and then detoxified from heroin over the course of several days. Interventions Participants were subsequently stabilized on 0, 30, or 60 mg of DMQ. Each dose of DMQ was administered for two consecutive weeks, and the effects of heroin (0, 12.5, and 50 mg) were studied under each DMQ maintenance dose condition. DMQ and heroin dose were administered in random order both within and between participants. Results Planned comparisons revealed statistically significant increases in progressive ratio breakpoint values and positive subjective ratings as a function of heroin dose. There were no consistent changes in any of the responses as a function of DMQ maintenance dose, other than a modest reduction in craving. Conclusions In summary, results from this study suggest that maintenance on dextromethorphan in combination with quinidine has a limited role in the treatment of opioid dependence. PMID:22320027

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study.

PubMed

Morain, P; Robin, J L; De Nanteuil, G; Jochemsen, R; Heidet, V; Guez, D

2000-10-01

The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5-2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t(1/2)) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events.

Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings.

PubMed

Noel, Gary J; Goodman, Daniel B; Chien, Shuchean; Solanki, Bhavna; Padmanabhan, Mukund; Natarajan, Jaya

2004-05-01

A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value, particularly with drugs that might influence HR.

Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol.

PubMed

Matsui, Sumika; Yasui, Toshiyuki; Kasai, Kana; Keyama, Kaoru; Yoshida, Kanako; Kato, Takeshi; Uemura, Hirokazu; Kuwahara, Akira; Matsuzaki, Toshiya; Irahara, Minoru

2017-07-01

Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 μg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 μg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans

PubMed Central

Qureshi, Asaf A; Khan, Dilshad A; Silswal, Neerupma; Saleem, Shahid; Qureshi, Nilofer

2016-01-01

Background Tocotrienols has been known to lower serum lipid parameters below 500 mg/d, while increase lipid parameters at higher dose of 750 mg/d. δ-Tocotrienol has a novel inflammatory property of concentration-dependent inhibition and activation. Therefore, inhibition (anti-inflammatory) property of tocotrienols at low doses is useful for cardiovascular disease, whereas, activation (pro-inflammatory) property using high dose is found effective for treatments of various types of cancer. We have recently described plasma bioavailability of 125 mg/d, 250 mg/d and 500 mg/d doses of δ-tocotrienol in healthy fed subjects, which showed dose-dependent increases in area under the curve (AUC) and maximum concentration (Cmax). Hence, in the current study, higher doses of tocotrienols have used to analyze its effect on plasma pharmacokinetic parameters. Aims To evaluate the safety and bioavailability of higher doses (750 mg and 1000 mg) of annatto-based tocotrienols in healthy fed subjects. All four isomers (α-, β-, γ-, δ-) of tocols (tocotrienols and tocopherols) present in the plasmas of subjects were quantified and analyzed for various pharmacokinetic parameters. Study design An open-label, randomized study was performed to analyze pharmacokinetics and bioavailability of δ-tocotrienol in 6 healthy fed subjects. All subjects (3/dose) were randomly assigned to one of each dose of 750 mg or 1000 mg. Blood samples were collected at 0, 1, 2, 4, 6, 8 h intervals and all isomers of α-,β-,γ-,δ-tocotrienols, and tocopherols in plasmas were quantified by HPLC. Results Oral administration of 750 and 1000 mg/d of tocotrienols resulted in dose-dependent increases in plasmas (ng/ml) AUCt0-t8 6621, 7450; AUCt0-∞ 8688, 9633; AUMC t0-∞ 52497, 57199; MRT 6.04, 5.93; Cmax 1444, 1592 (P<0.05), respectively, of δ-tocotrienol isomer. Moreover, both doses also resulted in plasmas Tmax 3.33–4 h; elimination half-life (t1/2 h) 2.74, 2.68; time of clearance (Cl-T, l/h) 0.086, 0.078; volume of distribution (Vd/f, mg/h) 0.34, 0.30; and elimination rate constant (ke; h-1) 0.25, 0.17, respectively of δ- tocotrienol isomer. Similar results of these parameters were reported for γ-tocotrienol, β- tocotrienol, α-tocotrienol, δ-tocopherol, γ-tocopherol, and β-tocopherol, except for α- tocopherol. Conclusions This study has described pharmacokinetics using higher doses of 750 mg/d and 1000 mg/d of δ-tocotrienol. These results confirmed earlier findings that Tmax was 3-4 h for all isomers of tocotrienols and tocopherols except for α-tocopherol (6 h). These higher doses of tocotrienols were found safe in humans and may be useful for treatments of various types of cancer, diabetes, and Alzheimer's disease. PMID:27493840

Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults

PubMed Central

Feehan, Robert P.; Kunselman, Allen R.; Preston, Amy G.; Miller, Debra L.; Lott, Mary E. J.

2011-01-01

An inverse relation exists between intake of flavonoid-rich foods, such as cocoa, and cardiovascular-related mortality. Favorable effects of flavonoids on the endothelium may underlie these associations. We performed a randomized, double-blind, placebo-controlled study to test the hypothesis that acute cocoa ingestion dose dependently increases endothelium-dependent vasodilation, as measured by an increase in brachial artery flow-mediated dilation (FMD), in healthy older adults. Measurements were obtained before (preingestion) and after (1- and 2-h postingestion) ingestion of 0 (placebo), 2, 5, 13, and 26 g of cocoa in 23 adults (63 ± 2 yr old, mean ± SE). Changes in brachial artery FMD 1- and 2-h postingestion compared with preingestion were used to determine the effects of cocoa. FMD was unchanged 1 (Δ−0.3 ± 0.2%)- and 2-h (Δ0.1 ± 0.1%) after placebo (0 g cocoa). In contrast, FMD increased both 1-h postingestion (2 g cocoa Δ0.0 ± 0.2%, 5 g cocoa Δ0.8 ± 0.3%, 13 g cocoa Δ1.0 ± 0.3%, and 26 g cocoa Δ1.6 ± 0.3%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) and 2-h postingestion (2 g cocoa Δ0.5 ± 0.3%, 5 g cocoa Δ1.0 ± 0.3%, 13 g cocoa Δ1.4 ± 0.2%, and 26 g cocoa Δ2.5 ± 0.4%: P < 0.05 compared with placebo for 5, 13, and 26 g cocoa) on the other study days. A serum marker of cocoa ingestion (total epicatechin) correlated with increased FMD 1- and 2-h postingestion (r = 0.44–0.48; both P < 0.05). Collectively, these results indicate that acute cocoa ingestion dose dependently increases brachial artery FMD in healthy older humans. These responses may help to explain associations between flavonoid intake and cardiovascular-related mortality in humans. PMID:21903881

Dose relations between goal setting, theory-based correlates of goal setting and increases in physical activity during a workplace trial.

PubMed

Dishman, Rod K; Vandenberg, Robert J; Motl, Robert W; Wilson, Mark G; DeJoy, David M

2010-08-01

The effectiveness of an intervention depends on its dose and on moderators of dose, which usually are not studied. The purpose of the study is to determine whether goal setting and theory-based moderators of goal setting had dose relations with increases in goal-related physical activity during a successful workplace intervention. A group-randomized 12-week intervention that included personal goal setting was implemented in fall 2005, with a multiracial/ethnic sample of employees at 16 geographically diverse worksites. Here, we examined dose-related variables in the cohort of participants (N = 664) from the 8 worksites randomized to the intervention. Participants in the intervention exceeded 9000 daily pedometer steps and 300 weekly minutes of moderate-to-vigorous physical activity (MVPA) during the last 6 weeks of the study, which approximated or exceeded current public health guidelines. Linear growth modeling indicated that participants who set higher goals and sustained higher levels of self-efficacy, commitment and intention about attaining their goals had greater increases in pedometer steps and MVPA. The relation between change in participants' satisfaction with current physical activity and increases in physical activity was mediated by increases in self-set goals. The results show a dose relation of increased physical activity with changes in goal setting, satisfaction, self-efficacy, commitment and intention, consistent with goal-setting theory.

Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.

PubMed

Dellinger, Ryan W; Santos, Santiago Roel; Morris, Mark; Evans, Mal; Alminana, Dan; Guarente, Leonard; Marcotulli, Eric

2017-01-01

NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD +) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X). All subjects took their blinded supplement daily for eight weeks. Analysis of NAD + in whole blood demonstrated that NRPT significantly increases the concentration of NAD + in a dose-dependent manner. NAD + levels increased by approximately 40% in the NRPT 1X group and approximately 90% in the NRPT 2X group after 4 weeks as compared to placebo and baseline. Furthermore, this significant increase in NAD + levels was sustained throughout the entire 8-week trial. NAD + levels did not increase for the placebo group during the trial. No serious adverse events were reported in this study. This study shows that a repeat dose of NRPT is a safe and effective way to increase NAD + levels sustainably.

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.

Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway.

PubMed

Leem, Kang-Hyun; Kim, Myung-Gyou; Hahm, Young-Tae; Kim, Hye Kyung

2016-12-09

Opuntia ficus-indica var. saboten (OFS) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, detailed mechanisms underlying hypoglycemic effects remain unclear. In this study, the mechanism underlying the hypoglycemic activity of OFS was evaluated using in vitro and in vivo systems. OFS treatment inhibited α-glucosidase activity and intestinal glucose absorption assessed by Na⁺-dependent glucose uptake using brush border membrane vesicles. AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle, and p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. In the present study, OFS dose-dependently increased glucose uptake in L6 muscle cells. The AMPK and p38 MAPK phosphorylations were stimulated by OFS, and inhibitors of AMPK (compound C ) and p38 MAPK (SB203580) abolished the effects of OFS. Furthermore, OFS increased glucose transporter 4 (GLUT4) translocation to the plasma membrane. OFS administration (1 g/kg and 2 g/kg body weight) in db/db mice dose-dependently ameliorated hyperglycemia, hyperinsulinemia, and glucose tolerance. Insulin resistance assessed by homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index were also dose-dependently improved with OFS treatment. OFS administration improved pancreatic function through increased β-cell mass in db/db mice. These findings suggest that OFS acts by inhibiting glucose absorption from the intestine and enhancing glucose uptake from insulin-sensitive muscle cells through the AMPK/p38 MAPK signaling pathway.

Hypoglycemic Effect of Opuntia ficus-indica var. saboten Is Due to Enhanced Peripheral Glucose Uptake through Activation of AMPK/p38 MAPK Pathway

PubMed Central

Leem, Kang-Hyun; Kim, Myung-Gyou; Hahm, Young-Tae; Kim, Hye Kyung

2016-01-01

Opuntia ficus-indica var. saboten (OFS) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, detailed mechanisms underlying hypoglycemic effects remain unclear. In this study, the mechanism underlying the hypoglycemic activity of OFS was evaluated using in vitro and in vivo systems. OFS treatment inhibited α-glucosidase activity and intestinal glucose absorption assessed by Na+-dependent glucose uptake using brush border membrane vesicles. AMP-activated protein kinase (AMPK) is widely recognized as an important regulator of glucose transport in skeletal muscle, and p38 mitogen-activated protein kinase (MAPK) has been proposed to be a component of AMPK-mediated signaling. In the present study, OFS dose-dependently increased glucose uptake in L6 muscle cells. The AMPK and p38 MAPK phosphorylations were stimulated by OFS, and inhibitors of AMPK (compound C) and p38 MAPK (SB203580) abolished the effects of OFS. Furthermore, OFS increased glucose transporter 4 (GLUT4) translocation to the plasma membrane. OFS administration (1 g/kg and 2 g/kg body weight) in db/db mice dose-dependently ameliorated hyperglycemia, hyperinsulinemia, and glucose tolerance. Insulin resistance assessed by homeostasis model assessment of insulin resistance and quantitative insulin sensitivity check index were also dose-dependently improved with OFS treatment. OFS administration improved pancreatic function through increased β-cell mass in db/db mice. These findings suggest that OFS acts by inhibiting glucose absorption from the intestine and enhancing glucose uptake from insulin-sensitive muscle cells through the AMPK/p38 MAPK signaling pathway. PMID:27941667

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

Nusrat, Humza; Pang, Geordi; Ahmad, Syed

Purpose: In radiotherapy, the amount of radiation delivered is determined by optimizing the amount of absorbed dose to the tumor. Dose does not always correlate well with the actual biological effects of radiation. This work seeks to validate the LET-dependence of doped plastic scintillators for use in a radiation beam quality (LET) detector. Methods: The LET spectrum ([Φ]) can be resolved knowing the measured signals of uniquely LET-dependent detectors, [S], and the response of each LET-dependent detector to specific LETs ([R]), through the relation [Φ]=[S][R]{sup −1}. Plastic scintillator response is intrinsically LET dependent and can be varied via doping. Initialmore » prototype consists of plastic scintillator and glass taper coupled to an optical fiber; components are housed in black acrylic, reducing effect of ambient light. In order to determine [R], the light response matrix, GEANT4.10.1 Monte Carlo (MC) was used. To validate MC, measurements were done using high energy electrons (9,12,15MeV) and orthovoltage x-rays (100,250kV); scintillator signal was normalized to dose measured simultaneously. Results: Stopping power was varied by changing particle type/energy; measurements indicated that as stopping power increased from 1.9 to 6.6MeV/cm, detector response increased by 263% (+/−29.2%) for 5%Pb-doped scintillator (155% in MC); 52% (+/−7.8%) increase observed when undoped scintillator was used (49% in MC). 5%Pb-doped discrepancy (100kV x-rays) is being investigated. Conclusions: This work validates that doping effects LET/energy response of scintillators; an effect that can be utilized for construction of an LET detector.« less

DOSE-DEPENDENT DISTRIBUTION AND ELIMINATION OF CIS- AND TRANS-PERMETHRIN IN THE RAT

EPA Science Inventory

Pyrethroids are neurotoxic insecticides used in a variety of agricultural and household activities. Due to the phase-out of organophosphate pesticides, use of pyrethroids has increased. The potential for increased human exposure to pyrethroids has prompted pharmacokinetic resea...

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.

Precipitate resolution in an electron irradiated ni-si alloy

NASA Astrophysics Data System (ADS)

Watanabe, H.; Muroga, T.; Yoshida, N.; Kitajima, K.

1988-09-01

Precipitate resolution processes in a Ni-12.6 at% Si alloy under electron irradiation have been observed by means of HVEM. Above 400°C, growth and resolution of Ni 3Si precipitates were observed simultaneously. The detail stereoscopic observation showed that the precipitates close to free surfaces grew, while those in the middle of a specimen dissolved. The critical dose when the precipitates start to shrink increases with increasing the depth. This depth dependence of the precipitate behavior under irradiation has a close relation with the formation of surface precipitates and the growth of solute depleted zone beneath them. The temperature and dose dependence of the resolution rate showed that the precipitates in the solute depleted zone dissolved by the interface controlled process of radiation-enhanced diffusion.

Supraspinal and spinal effects of L-trans-PDC, an inhibitor of glutamate transporter, on the micturition reflex in rats.

PubMed

Honda, Masashi; Yoshimura, Naoki; Hikita, Katsuya; Hinata, Nobuyuki; Muraoka, Kuniyasu; Saito, Motoaki; Chancellor, Michael B; Takenaka, Atsushi

2013-09-01

Glutamate is a major excitatory transmitter in the central nervous system, controlling lower urinary tract function. Five types of glutamate transporters such as GLAST (EAAT1), GLT-1 (EAAT2), EAAC-1 (EAAT3), EAAT4, and EAAT5 have been cloned so far. In the current study we tested whether L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), a non-selective inhibitor of glutamate transporters that increases endogenous glutamate concentration, can affect the micturition reflex in urethane anesthetized rats. Continuous cystometrograms (CMG, 0.04 ml/min infusion rate) were performed in two groups of urethane-anesthetized rats. A group of 18 rats was used for intrathecal administration of 1-10 µg of L-trans-PDC via an intrathecal catheter. In the second group of 18 rats, 1-10 µg of L-trans-PDC were administered intracerebroventricularly via a catheter inserted into the lateral ventricle. Micturition parameters were recorded and compared before and after drug administration. Intrathecal administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. Intracerebroventricular administration of L-trans-PDC at 1, 3, and 10 µg (n = 6 per dose) also increased intercontraction intervals in dose dependent fashion, but did not affect postvoid residual or basal pressure at any doses tested. The current results show that, in urethane-anesthetized rats, suppression of glutamate transporters by L-trans-PDC has an inhibitory effect on the micturition reflex at supraspinal and spinal sites, possibly via activation of glutamate-mediated inhibitory pathways. Copyright © 2012 Wiley Periodicals, Inc.

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.

Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.

PubMed

Madelain, Vincent; Guedj, Jérémie; Mentré, France; Nguyen, Thi Huyen Tram; Jacquot, Frédéric; Oestereich, Lisa; Kadota, Takumi; Yamada, Koichi; Taburet, Anne-Marie; de Lamballerie, Xavier; Raoul, Hervé

2017-01-01

Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC 50 ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC 50 for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses. Copyright © 2016 American Society for Microbiology.

Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

PubMed

Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

2015-03-01

Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days. Copyright © 2015 Elsevier B.V. All rights reserved.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects.

PubMed

Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

2014-12-01

The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. © 2014 The British Pharmacological Society.

Pharmacokinetics and pharmacodynamics of the cathepsin S inhibitor, LY3000328, in healthy subjects

PubMed Central

Payne, Christopher D; Deeg, Mark A; Chan, Melanie; Tan, Lai Hock; LaBell, Elizabeth Smith; Shen, Tong; DeBrota, David J

2014-01-01

Aim The aim of this study was to assess the safety and tolerability, pharmacokinetics and pharmacodynamics of LY3000328 when administered as single escalating doses to healthy volunteers. Methods This was a phase 1, placebo-controlled, dose escalation study with LY3000328 in 21 healthy male volunteers. Subjects were administered escalating LY3000328 doses up to 300 mg with food in this single dose study. Blood samples were collected at set times post-dose for the assessment of LY3000328 pharmacokinetics and the measurement of cathepsin S (CatS) activity, CatS mass and calculated CatS specific activity. Results All doses of LY3000328 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of LY3000328 was measured ex vivo showing a biphasic response to LY3000328, where CatS activity declines, then returns to baseline, and then increases to a level above baseline. CatS mass was also assessed post-dose which increased in a dose-dependent manner, and continued to increase after LY3000328 had been cleared from the body. CatS specific activity was additionally calculated to normalize CatS activity for changes in CatS mass. This demonstrated the increase in CatS activity was attributable to the increase in CatS mass detected in plasma. Conclusion A specific inhibitor of CatS which is cleared quickly from plasma may produce a transient decrease in plasma CatS activity which is followed by a more prolonged increase in plasma CatS mass which may have implications for the future clinical development of inhibitors of CatS. PMID:25039273

Dose-dependent effects of homologous seminal plasma on motility and kinematic characteristics of post-thaw stallion epididymal spermatozoa.

PubMed

Neuhauser, S; Dörfel, S; Handler, J

2015-05-01

Preservation of epididymal spermatozoa is important to save genetic material of endangered species and breeds, or in case of unexpected injury, which will end the breeding career of valuable sires. Seminal plasma (SP) influences sperm quality in a dose-dependent manner and its addition to preserved semen immediately before insemination may be beneficial for sperm fertility. Increased plasma membrane stability of epididymal spermatozoa reduces freezing injury of cells, and the addition of SP after freezing and thawing might have activating and protecting effects on spermatozoa within the female genital tract. In this study, epididymal spermatozoa were harvested by retrograde flush of the epididymal cauda immediately after routine castration and frozen. Seminal plasma was collected from other six stallions. Homologous SP (SP from the same species, but from a different animal) was added to frozen-thawed epididymal spermatozoa at concentrations of 0, 5, 20, 50 and 80% SP. Addition of SP increased sperm motility and influenced kinematic values in a dose-dependent manner (p < 0.05). Motility improved at concentrations of 20 and 50% SP, but did not further increase at 80% SP. There was no difference in sperm motility among SP from six different donor stallions regardless of the concentrations of SP (p > 0.05). Total and progressive motility of ten frozen-thawed epididymal spermatozoa samples collected from different stallions after dilution with extender and 5, 20, 50 or 80% SP differed significantly (p < 0.05). In conclusion, addition of homologous SP to frozen-thawed stallion epididymal spermatozoa immediately improved motility in a dose-dependent manner regardless of semen quality of SP donor stallions. This might positively influence fertility when SP is added before insemination. Moreover, there seems to be a threshold level of SP concentration for optimal improvement of sperm motility. © 2015 American Society of Andrology and European Academy of Andrology.

Doxycycline shows dose-dependent changes in hernia repair strength after mesh repair.

PubMed

Tharappel, Job C; Harris, Jennifer W; Zwischenberger, Brittany A; Levy, Salomon M; Puleo, David A; Roth, J Scott

2016-05-01

Ventral hernia is a commonly occurring surgical problem. Our earlier studies have shown that a 30 mg/kg dose of doxycycline can significantly impact the strength of polypropylene (PP) mesh in a rat hernia repair model at 6 and 12 weeks. The objective of the present study was to investigate the dose dependence of doxycycline treatment on hernia repair strengths in rats. Fifty-six Sprague-Dawley rats underwent hernia repair with either PP mesh (n = 28) or sutures only (primary; n = 28); both groups were further divided into four doxycycline groups of seven animals each: control (0 mg/kg), low (3 mg/kg), medium (10 mg/kg), and high (30 mg/kg). One day before hernia repair surgery, animals received doxycycline doses by gavage and continued receiving daily until euthanasia. After 8 weeks, rats were euthanized and tissue samples from hernia repaired area were collected and analyzed for tensile strength using a tensiometer (Instron, Canton, MA, USA), while MMPs 2, 3, and 9, and collagen type 1 and 3 were analyzed by western blotting. In mesh-repaired animals, medium and high doxycycline dose repaired mesh fascia interface (MFI) showed significant increase in tensile strength when compared to control. In the primary repaired animals, there was no significant difference in MFI tensile strength in any dose group. In medium-dose MFI, there was a significant reduction in MMPs 2, 3, and 9. In this animal group, MFI showed significant increase in collagen 1 and significant reduction in collagen type 3 when compared to control. It is possible to improve the strength of mesh-repaired tissue by administering a significantly lower dose of the drug, which has implications for translation of the findings.

Studies on the bronchodilator, tremorogenic, cardiovascular and hypokalaemic effects of fenoterol dry powder in asthma.

PubMed Central

Bauer, K G; Kaik, B; Sertl, K; Kaik, G A

1993-01-01

1. The airway and tremor response and cardiovascular and hypokalaemic effects of single and cumulative doses of fenoterol given by dry powder capsules (DPC) and by metered dose inhaler (MDI) were studied in asthmatics in two randomized, crossover trials. 2. Single doses of fenoterol DPC and MDI (0.2 mg, 0.4 mg), investigated in 24 subjects, produced similar, dose-dependent increases in FEV1. Fenoterol DPC caused less tremor response and less hypokalaemic effects than fenoterol MDI. 3. Cumulative doses of fenoterol DPC and MDI (0.2, 0.6, 1.4, 3.0, 6.2 mg), investigated in 12 subjects, produced a comparable bronchodilatation (mean maximum increase in FEV1 was 0.53 +/- 0.06/0.52 +/- 0.081 for DPC/MDI) and a similar, dose-dependent rise in heart rate (35 +/- 3.81/41 +/- 2.25 beats min(-1)). The rise in tremor and the fall in plasma potassium were smaller after DPC than after MDI. The mean maximum changes were 51.58 +/- 6.41/95.83 +/- 6.75 cm s(-2) for tremor and -0.68 +/- 0.09/-0.96 +/- 0.10 mmol l(-1) for potassium. 4. Our findings may result from a difference in the pharmacokinetics of the dry powder and the aerosol formulation, particularly differences in distribution and absorption. 5. In conclusion, fenoterol DPC used in low therapeutic doses (0.2,0.4 mg), is preferable to the MDI. Fenoterol DPC used as rescue medication in high cumulative doses, do not suggest a greater safety margin than the MDI and the same restrictions should be considered for the fenoterol dry powder formulation as suggested for the MDI. PMID:12959305

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.

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

Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose

PubMed Central

Marciani, L; Garsed, K C; Hoad, C L; Fields, A; Fordham, I; Pritchard, S E; Placidi, E; Murray, K; Chaddock, G; Costigan, C; Lam, C; Jalanka-Tuovinen, J; De Vos, W M; Gowland, P A; Spiller, R C

2014-01-01

Background Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo-colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing. Methods Twelve HVs received a split dose (1 L the evening before and 1 L on the study day) and another 12 HVs a single dose (2 L on the main study day) of PEG electrolyte. They underwent MRI scans, completed symptom questionnaires, and provided stool samples. Outcomes included small bowel water content, ascending colon motility index, and regional colonic volumes. Key Results Small bowel water content increased fourfold from baseline after ingesting both split (p = 0.0010) and single dose (p = 0.0005). The total colonic volume increase from baseline was smaller for the split dose at 35 ± 8% than for the single dose at 102 ± 27%, p = 0.0332. The ascending colon motility index after treatment was twofold higher for the single dose group (p = 0.0103). Conclusions & Inferences Ingestion of 1 and 2 L PEG electrolyte solution caused a rapid increase in the small bowel and colonic volumes and a robust rise in colonic motility. The increase in both volumes and motility was dose dependent. Such a challenge, being well-tolerated, could be a useful way of assessing colonic motility in future studies. PMID:25060551

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose.

PubMed

Bola, R Aaron; Kiyatkin, Eugene A

2017-11-01

Here we examined how intravenous heroin at a dose that maintains self-administration (0.1 mg/kg) affects brain temperature homeostasis in freely moving rats under conditions that seek to mimic some aspects of human drug use. When administered under standard laboratory conditions (quiet rest at 22 °C ambient temperature), heroin induced moderate temperature increases (1.0-1.5 °C) in the nucleus accumbens (NAc), a critical structure of the brain motivation-reinforcement circuit. By simultaneously recording temperatures in the temporal muscle and skin, we demonstrate that the hyperthermic effects of heroin results primarily from inhibition of heat loss due to strong and prolonged skin vasoconstriction. Heroin-induced brain temperature increases were enhanced during behavioral activation (i.e., social interaction) and in a moderately warm environment (29 °C). By calculating the "net" effects of the drug in these two conditions, we found that this enhancement results from the summation of the hyperthermic effects of heroin with similar effects induced by either social interaction or a warmer environment. When the dose of heroin was increased (to 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg), brain temperature showed a biphasic down-up response. The initial temperature decrease was dose-dependent and resulted from a transient inhibition of intra-brain heat production coupled with increased heat loss via skin surfaces-the effects typically induced by general anesthetics. These initial inhibitory effects induced by large-dose heroin injections could be related to profound CNS depression-the most serious health complications typical of heroin overdose in humans. Published by Elsevier Ltd.

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.

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.

Endothelium-dependent desensitization to angiotensin II in rabbit aorta: the mechanisms involved.

PubMed

Jerez, S; de Bruno, M P; Coviello, A

2001-06-01

The aim of this study was to characterize the role of the endothelium in angiotensin II-desensitization and its mechanisms of action. Rabbit aortic rings were exposed to increasing doses of angiotensin II (Ang II, 10(-9) to 2.5 x 10(-6)) to generate two cumulative dose-response curves (CDRC I and II). A 50-min interval separated CDRC I and II. Desensitization was observed at all doses in unrubbed aortic tissue and at lower doses in rubbed aortic tissue. Tachyphylaxis was greater in arteries with endothelium. Treatment of intact rings with L-N(G)-nitroarginine methyl ester (L-NAME, 10(-4) M) did not prevent this phenomenon. However, indomethacin (10(-5) M) and miconazol (10(-6) M) attenuated Ang II-desensitization. Treatment of unrubbed rings with nifedipine (10(-6) M) and cromakalim (10(-6) M) inhibited the effect of indomethacin. To confirm the involvement of K+ channels, unrubbed and rubbed aortic rings were treated with the K(Ca2+) blockers apamin (10(-7) M), tetraethylammonium (TEA, 10(-3) M), and iberiotoxin (10(-8) M), and the K(ATP) blocker glibenclamide (10(-5) M). In both arteries apamin, TEA, and glibenclamide abolished the tachyphylaxis without changes in the maximal response. Iberiotoxin diminished Ang II-desensitization in rubbed but not unrubbed arteries. Results from this study suggest that Ang II-desensitization involves endothelium-dependent and -independent mechanisms. Endothelium-dependent desensitization could be mediated by a cyclooxygenase-cytochrome P450 product, which could act by increasing K(Ca2+) channel activity.

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.

Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3.

PubMed

Harris, Ruth B S; Desai, Bhavna N

2016-12-01

Previous studies have shown that very low-dose infusions of leptin into the third or the fourth ventricle alone have little effect on energy balance, but simultaneous low-dose infusions cause rapid weight loss and increased phosphorylation of STAT3 (p-STAT3) in hypothalamic sites that express leptin receptors. Other studies show that injecting high doses of leptin into the fourth ventricle inhibits food intake and weight gain. Therefore, we tested whether fourth-ventricle leptin infusions that cause weight loss are associated with increased leptin signaling in the hypothalamus. In a dose response study 14-day infusions of increasing doses of leptin showed significant hypophagia, weight loss, and increased hypothalamic p-STAT3 in rats receiving at least 0.9 μg leptin/day. In a second study 0.6 μg leptin/day transiently inhibited food intake and reduced carcass fat, but had no significant effect on energy expenditure. In a final study, we identified the localization of STAT3 activation in the hypothalamus of rats receiving 0, 0.3, or 1.2 μg leptin/day. The high dose of leptin, which caused weight loss in the first experiment, increased p-STAT3 in the ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus. The low dose that increased brown fat UCP1 but did not affect body composition in the first experiment had little effect on hypothalamic p-STAT3. We propose that hindbrain leptin increases the precision of control of energy balance by lowering the threshold for leptin signaling in the forebrain. Further studies are needed to directly test this hypothesis. Copyright © 2016 the American Physiological Society.

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

Dietary Selenium as a Modulator of PCB 126–Induced Hepatotoxicity in Male Sprague-Dawley Rats

PubMed Central

Lai, Ian K.; Chai, Yingtao; Simmons, Donald; Watson, Walter H.; Tan, Rommel; Haschek, Wanda M.; Wang, Kai; Wang, Bingxuan; Ludewig, Gabriele; Robertson, Larry W.

2011-01-01

Homeostasis of selenium (Se), a critical antioxidant incorporated into amino acids and enzymes, is disrupted by exposure to aryl hydrocarbon receptor (AhR) agonists. Here we examined the importance of dietary Se in preventing the toxicity of the most toxic polychlorinated biphenyl congener, 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), a potent AhR agonist. Male Sprague-Dawley rats were fed a modified AIN-93 diet with differing dietary Se levels (0.02, 0.2, and 2 ppm). Following 3 weeks of acclimatization, rats from each dietary group were given a single ip injection of corn oil (vehicle), 0.2, 1, or 5 μmol/kg body weight PCB 126, followed 2 weeks later by euthanasia. PCB exposure caused dose-dependent increases in liver weight and at the highest PCB 126 dose decreases in whole body weight gains. Hepatic cytochrome P-450 (CYP1A1) activity was significantly increased even at the lowest dose of PCB 126, indicating potent AhR activation. PCB exposure diminished hepatic Se levels in a dose-dependent manner, and this was accompanied by diminished Se-dependent glutathione peroxidase activity. Both these effects were partially mitigated by Se supplementation. Conversely, thioredoxin (Trx) reductase activity and Trx oxidation state, although significantly diminished in the lowest dietary Se groups, were not affected by PCB exposure. In addition, PCB 126–induced changes in hepatic copper, iron, manganese, and zinc were observed. These results demonstrate that supplemental dietary Se was not able to completely prevent the toxicity caused by PCB 126 but was able to increase moderately the levels of several key antioxidants, thereby maintaining them roughly at normal levels. PMID:21865291

Combination of Nigella sativa with Glycyrrhiza glabra and Zingiber officinale augments their protective effects on doxorubicin-induced toxicity in h9c2 cells.

PubMed

Hosseini, Azar; Shafiee-Nick, Reza; Mousavi, Seyed Hadi

2014-12-01

The use of doxorubicin (DOX) is limited by its dose-dependent cardio toxicity in which reactive Oxygen Species (ROS) play an important role in the pathological process. The aim of this study was to evaluate the protective effect of three medicinal plants, Nigella sativa (N), Glycyrrhiza glabra (G) and Zingiber officinale (Z), and their combination (NGZ), against DOX-induced apoptosis and death in H9c2 cells. The cells were incubated with different concentrations of each extract or NGZ for 4 hr which continued in the presence or absence of 5µM doxorubicin for 24 hr. Cell viability and the apoptotic rate were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) and propidium iodide (PI) staining assays, respectively. The level of ROS and lipid peroxidation were measured by fluorimetric methods. Treatment with doxorubicin increased ROS generation, enhanced malondialdehyde (MDA) formation, and induced apoptosis. Co-treatment of the cells with each herb extract increased viability of cells dose-dependently with a maximum protection effect of about 30%, and their potencies were N>G>Z. The combination of the threshold dose of each extract (NGZ) produced a similar effect, which was increased dose-dependently to a maximum protection of 70%. These effects were correlated with the effects of NGZ on ROS and MDA. All of the extracts have some protective effects against DOX-induced toxicity in cardiomyocytes with similar efficacies, but with different potencies. However, NGZ produced much higher protective effect via reducing oxidative stress and inhibiting of apoptotic induction processes. Further investigations are needed to determine the effects of NGZ on DOX chemotherapy.

Combination of Nigella sativa with Glycyrrhiza glabra and Zingiber officinale augments their protective effects on doxorubicin-induced toxicity in h9c2 cells

PubMed Central

Hosseini, Azar; Shafiee-Nick, Reza; Mousavi, Seyed Hadi

2014-01-01

Objective(s): The use of doxorubicin (DOX) is limited by its dose-dependent cardio toxicity in which reactive Oxygen Species (ROS) play an important role in the pathological process. The aim of this study was to evaluate the protective effect of three medicinal plants, Nigella sativa (N), Glycyrrhiza glabra (G) and Zingiber officinale (Z), and their combination (NGZ), against DOX-induced apoptosis and death in H9c2 cells. Materials and Methods: The cells were incubated with different concentrations of each extract or NGZ for 4 hr which continued in the presence or absence of 5µM doxorubicin for 24 hr. Cell viability and the apoptotic rate were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) and propidium iodide (PI) staining assays, respectively. The level of ROS and lipid peroxidation were measured by fluorimetric methods. Results: Treatment with doxorubicin increased ROS generation, enhanced malondialdehyde (MDA) formation, and induced apoptosis. Co-treatment of the cells with each herb extract increased viability of cells dose-dependently with a maximum protection effect of about 30%, and their potencies were N>G>Z. The combination of the threshold dose of each extract (NGZ) produced a similar effect, which was increased dose-dependently to a maximum protection of 70%. These effects were correlated with the effects of NGZ on ROS and MDA. Conclusion: All of the extracts have some protective effects against DOX-induced toxicity in cardiomyocytes with similar efficacies, but with different potencies. However, NGZ produced much higher protective effect via reducing oxidative stress and inhibiting of apoptotic induction processes. Further investigations are needed to determine the effects of NGZ on DOX chemotherapy. PMID:25859303

Radiation-induced alterations in synaptic neurotransmission of dentate granule cells depend on the dose and species of charged particles.

PubMed

Marty, V N; Vlkolinsky, R; Minassian, N; Cohen, T; Nelson, G A; Spigelman, I

2014-12-01

The evaluation of potential health risks associated with neuronal exposure to space radiation is critical for future long duration space travel. The purpose of this study was to evaluate and compare the effects of low-dose proton and high-energy charged particle (HZE) radiation on electrophysiological parameters of the granule cells in the dentate gyrus (DG) of the hippocampus and its associated functional consequences. We examined excitatory and inhibitory neurotransmission in DG granule cells (DGCs) in dorsal hippocampal slices from male C57BL/6 mice at 3 months after whole body irradiation with accelerated proton, silicon or iron particles. Multielectrode arrays were used to investigate evoked field synaptic potentials, an extracellular measurement of synaptic excitability in the perforant path to DG synaptic pathway. Whole-cell patch clamp recordings were used to measure miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in DGCs. Exposure to proton radiation increased synaptic excitability and produced dose-dependent decreases in amplitude and charge transfer of mIPSCs, without affecting the expression of γ-aminobutyric acid type A receptor α2, β3 and γ2 subunits determined by Western blotting. Exposure to silicon radiation had no significant effects on synaptic excitability, mEPSCs or mIPSCs of DGCs. Exposure to iron radiation had no effect on synaptic excitability and mIPSCs, but significantly increased mEPSC frequency at 1 Gy, without changes in mEPSC kinetics, suggesting a presynaptic mechanism. Overall, the data suggest that proton and HZE exposure results in radiation dose- and species-dependent long-lasting alterations in synaptic neurotransmission, which could cause radiation-induced impairment of hippocampal-dependent cognitive functions.

Aluminium oxide nanoparticles induced morphological changes, cytotoxicity and oxidative stress in Chinook salmon (CHSE-214) cells.

PubMed

Srikanth, Koigoora; Mahajan, Amit; Pereira, Eduarda; Duarte, Armando Costa; Venkateswara Rao, Janapala

2015-10-01

Aluminium oxide nanoparticles (Al2 O3 NPs) are increasingly used in diverse applications that has raised concern about their safety. Recent studies suggested that Al2 O3 NPs induced oxidative stress may be the cause of toxicity in algae, Ceriodaphnia dubia, Caenorhabditis elegans and Danio rerio. However, there is paucity on the toxicity of Al2 O3 NPs on fish cell lines. The current study was aimed to investigate Al2 O3 NPs induced cytotoxicity, oxidative stress and morphological abnormality of Chinnok salmon cells (CHSE-214). A dose-dependent decline in cell viability was observed in CHSE-214 cells exposed to Al2 O3 NPs. Oxidative stress induced by Al2 O3 NPs in CHSE-214 cells has resulted in the significant reduction of superoxide dismutase, catalase and glutathione in a dose-dependent manner. However, a significant increase in glutathione sulfo-transferase and lipid peroxidation was observed in CHSE-214 cells exposed to Al2 O3 NPs in a dose-dependent manner. Significant morphological changes in CHSE-214 cells were observed when exposed to Al2 O3 NPs at 6, 12 and 24 h. The cells started to detach and appear spherical at 6 h followed by loss of cellular contents resulting in the shrinking of the cells. At 24 h, the cells started to disintegrate and resulted in cell death. Our data demonstrate that Al2 O3 NPs induce cytotoxicity and oxidative stress in a dose-dependent manner in CHSE-214 cells. Thus, our current work may serve as a base-line study for future evaluation of toxicity studies using CHSE-214 cells. Copyright © 2015 John Wiley & Sons, Ltd.

[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.

Effect of stress at dosing on organophosphate and heavy metal toxicity

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

Jortner, Bernard S.

2008-11-15

This paper reviews recent studies assessing the effect of well-defined, severe, transient stress at dosing on two classical models of toxicity. These are the acute (anticholinesterase) toxicity seen following exposure to the organophosphate insecticide chlorpyrifos, and the nephrotoxicity elicited by the heavy metal depleted uranium, in rats. Stress was induced by periods of restraint and forced swimming in days to weeks preceding toxicant exposure. Forced swimming was far more stressful, as measured by marked, if transient, elevation of plasma corticosterone. This form of stress was administered immediately prior to administration of chlorpyrifos or depleted uranium. Chlorpyrifos (single 60 mg/kg subcutaneously)more » elicited marked inhibition of brain acetylcholinesterase 4-day post-dosing. Depleted uranium (single intramuscular doses of 0.1, 0.3 or 1.0 mg/kg uranium) elicited dose-dependent increase in kidney concentration of the metal, with associated injury to proximal tubular epithelium and increases in serum blood urea nitrogen and creatinine during the 30-day post-dosing period. Stress at dosing had no effect on these toxicologic endpoints.« less

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.

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.

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

Development of a translational model to screen medications for cocaine use disorder I: Choice between cocaine and food in rhesus monkeys.

PubMed

Johnson, Amy R; Banks, Matthew L; Blough, Bruce E; Lile, Joshua A; Nicholson, Katherine L; Negus, S Stevens

2016-08-01

Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial "sample" trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine "choice" trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. Preference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32-3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. These results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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

Thioridazine dose-related effects on biomechanical force platform measures of sway in young and old men.

PubMed

Liu, Y J; Stagni, G; Walden, J G; Shepherd, A M; Lichtenstein, M J

1998-04-01

Thioridazine (TDZ) is associated with an increased risk of falls. The purpose of this study was to determine whether (1) thioridazine increases Biomechanics Force Platform (BFP) measures of sway in a dose-related manner, (2) there is a difference in sway between young and old men, (3) there is a correlation between sway and orthostatic changes in BP and HR. Seven younger (aged 20-42) and five older (aged 70-76) healthy male volunteers received, in a randomized order double-blind design, a single oral dose of 0, 25, and 50 mg of TDZ on three separate days at least 7 days apart and 75 mg on the fourth day of the study. Sway and blood pressure were measured for 24 hours. A general clinical research center. Biomechanics force platform measures of postural sway were measured as the movement of the center of pressure. The elliptical area (EA) and average velocity (AV) were calculated with eyes open and eyes closed. Blood pressure and heart rate were measured for 5 minutes supine and 5 minutes standing. Thioridazine increases BFP sway in a dose-dependent manner. EA increased from 0.56 (SD = .51) cm2 for placebo to 0.88 (SD = 1.09) cm2 for 75 mg TDZ. AV increased from 1.07 (SD = .27) cm/sec, placebo, to 1.43 (SD = .55) cm/sec, 75 mg TDZ. Older men swayed more than younger men. Changes followed the expected time course for TDZ. EA and AV were associated with HR and BP, e.g., SBP versus ln(EA) and ln(AV) (r = -0.21 and r = -0.22, respectively; P < .0001). Thioridazine increases validated measures of fall risk dose dependently in young and old men. This may explain the effects of neuroleptic drugs on fall risk in older people.

Myricetin and Quercetin Are Naturally-Occurring Co-substrates of Cyclooxygenases In Vivo1

PubMed Central

Bai, Hyoung-Woo; Zhu, Bao T.

2009-01-01

Bioflavonoids are ubiquitously present in the plant kingdom, and some of them are presently being sold as healthy dietary supplements around the world. Recently, it was shown that some of the dietary polyphenols were strong stimulators of the catalytic activity of cyclooxygenase I and II, resulting in increased formation of certain prostaglandin (PG) products in vitro and also in intact cells in culture. In the present study, we investigated the effect of two representative dietary compounds, quercetin and myricetin, on plasma and tissue levels of several PG products in normal Sprague-Dawley rats. We found that these two dietary bioflavonoids could strongly stimulate the formation of PG products in vivo in a time-dependent manner, and the stimulatory effect of these two bioflavonoids was dose-dependent with a unique biphasic pattern. At lower doses (<0.3 mg/kg b.w.), they strongly stimulated the formation of PGE2, but at higher doses (>0.3 mg/kg b.w.), there was a dose-dependent reduction of the stimulatory effect. These results provide support for the hypothesis that some of the bioflavonoids are naturally-occurring physiological co-substrates for the cyclooxygenases in vivo. PMID:19897347

Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

PubMed

Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

2015-01-01

Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.

Hydrocortisone and dexamethasone dose-dependently stabilize mast cells derived from rat peritoneum.

PubMed

Mori, Tomohiro; Abe, Nozomu; Saito, Kazutomo; Toyama, Hiroaki; Endo, Yasuhiro; Ejima, Yutaka; Yamauchi, Masanori; Goto, Mariko; Mushiake, Hajime; Kazama, Itsuro

2016-12-01

Besides their anti-inflammatory properties, corticosteroid drugs exert anti-allergic effects. Exocytosis of mast cells is electrophysiologically detected as the increase in the whole-cell membrane capacitance (Cm). Therefore, the lack of such increase after exposure to the drugs suggests their mast cell-stabilizing effects. We examined the effects of 1, 10, 100 and 200μM hydrocortisone or dexamethasone on the degranulation from rat peritoneal mast cells. Employing the whole-cell patch-clamp recording technique, we also tested their effects on the Cm during exocytosis. At relatively lower concentrations (1, 10μM), both hydrocortisone and dexamethasone did not significantly affect the degranulation from mast cells and the increase in the Cm induced by GTP-γ-S. Nevertheless, at higher doses (100, 200μM), these drugs inhibited the degranulation from mast cells and markedly suppressed the GTP-γ-S-induced increase in the Cm. Our results provided electrophysiological evidence for the first time that corticosteroid drugs, such as hydrocortisone and dexamethasone, inhibited the exocytotic process of mast cells in a dose-dependent manner. The mast cell-stabilizing effects of these drugs may be attributable to their "non-genomic" action, by which they exert rapid anti-allergic effects. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion.

PubMed

Shigemura, Yasutaka; Kubomura, Daiki; Sato, Yoshio; Sato, Kenji

2014-09-15

The presence of hydroxyproline (Hyp)-containing peptides in human blood after collagen hydrolysate ingestion is believed to exert beneficial effects on human health. To estimate the effective beneficial dose of these peptides, we examined the relationship between ingested dose and food-derived Hyp levels in human plasma. Healthy volunteers (n=4) ingested 30.8, 153.8 and 384.6 mg per kg body weight of collagen hydrolysate. The average plasma concentration of Hyp-containing peptides was dose-dependent, reaching maximum levels of 6.43, 20.17 and 32.84 nmol/ml following ingestion of 30.8, 153.8 and 384.6-mg doses of collagen hydrolysate, respectively. Ingesting over 153.8 mg of collagen hydrolysate significantly increased the average concentrations of the free and peptide forms of Hyp in plasma. The Hyp absorption limit was not reached with ingestion of as much as 384.6 mg of collagen hydrolysate. These finding suggest that ingestion of less than 30.8 mg of collagen hydrolysate is not effective for health benefits. Copyright © 2014 Elsevier Ltd. All rights reserved.

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

Effect of dexamethasone on expression of glucocorticoid receptor in human monocyte cell line THP-1.

PubMed

Li, Bo; Bai, Xiangjun; Wanh, Haiping

2006-01-01

The effect of dexamethasone with different concentrations and different stimulating periods on the expression of glucocorticoid receptors (GRalpha, GRbeta) protein was investigated in human monocyte cell line THP-1. The cultured human monocyte line THP-1 cells were stimulated by dexamethasone with different concentrations and different periods. The expression of GRalpha and GRbeta protein was detected by Western blotting. The results showed that the expression of GRalpha and GRbeta was detected in the THP-1 cells. The quantity of GRalpha expression was reduced by dexamethasone under the same concentration with the prolongation of the stimulating periods. The quantity of GRbeta expression was increased by dexamethasone treatment in a time- and dose-dependent manner. It was concluded that dexamethasone stimulation time-dependently reduced the GRalpha expression in THP-1 cells. Dexamethasone stimulation time- and dose-dependently increased the GRbeta expression in THP-1 cells. The expression of GRalpha and GRbeta was regulated by glucocorticoid.

Effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells (MSCs) in vitro.

PubMed

Lu, Yi-Qun; Lu, Yan; Li, Hui-Juan; Cheng, Xing-Bo

2012-10-01

This study aims to explore the effect of advanced glycosylation end products (AGEs) on proliferation of human bone marrow mesenchymal stem cells in vitro and the underlying mechanism. Bone marrow cell proliferation was determined by WST-8 assay using Cell Counting Kit-8 under the intervention of AGEs. In addition, the content of maldondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were also measured. The proliferation activity of mesenchymal stem cells (MSCs) was significantly inhibited when AGEs were added to culture medium, and this effect was dose-dependent and time-dependent. As the concentration of AGEs-bovine serum albumin increased, the content of intracellular MDA was significantly increased, but the activity of SOD in cell homogenates was significantly suppressed, which also showed a dose-dependent manner. AGEs could significantly inhibit the proliferation of MSCs in vitro by improving the oxidative stress in MSCs and breaking the homeostasis of intracellular environment.

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.

Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial

PubMed Central

Quintana, D S; Westlye, L T; Hope, S; Nærland, T; Elvsåshagen, T; Dørum, E; Rustan, Ø; Valstad, M; Rezvaya, L; Lishaugen, H; Stensønes, E; Yaqub, S; Smerud, K T; Mahmoud, R A; Djupesland, P G; Andreassen, O A

2017-01-01

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin’s dose–response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η2=0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure. PMID:28534875

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.

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

Ultraviolet-B radiation increases serum 25-hydroxyvitamin D levels: the effect of UVB dose and skin color.

PubMed

Armas, Laura A G; Dowell, Susan; Akhter, Mohammed; Duthuluru, Sowjanya; Huerter, Christopher; Hollis, Bruce W; Lund, Richard; Heaney, Robert P

2007-10-01

Ultraviolet (UV)-B light increases vitamin D levels, but the dose response and the effect of skin pigmentation have not been well characterized. We sought to define the relationship between UVB exposure and 25-hydroxyvitamin D (25-OH-D) concentrations as a function of skin pigmentation. Seventy two participants with various skin tones had 90% of their skin exposed to UVB light (20-80 mJ/cm2) 3 times a week for 4 weeks. Serum 25-OH-D was measured weekly. Eighty percent of the variation in treatment response was explained by UVB dose and skin tone. Therapeutically important changes in 25-OH-D were achieved with minimal tanning. Four weeks was not long enough to reach a steady state at the higher dose rates. The response of 25-OH-D levels to UVB light is dependent on skin pigmentation and the amount of UVB given, and useful increases in vitamin D status can be achieved by defined UVB doses small enough to produce only minimal tanning.

Micronucleus induction in Vicia faba roots. Part 1. Absence of dose-rate, fractionation, and oxygen effect at low doses of low LET radiations.

PubMed

Marshall, I; Bianchi, M

1983-08-01

Micronucleus indication in Vicia faba roots has been evaluated after irradiation with 60Co gamma-rays. The dependence of the damage on dose, dose rate, fractionation, and oxygen has been studied. The best fit to the experimental data in the dose region between 7 and 190 cGy is represented, for single-dose exposures, by a linear + quadratic relationship. In the low-dose region, between 7 and 20 cGy, where the linear dose dependence is dominant, no dose-rate, fractionation, or oxygen effect could be observed. These effects were, however, present in the high-dose region, where the quadratic dependence is dominant.

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

Comparison of high MRI T1 signals with manganese concentration in brains of cynomolgus monkeys after 8 months of stainless steel welding-fume exposure.

PubMed

Park, Jung Duck; Chung, Yong Hyun; Kim, Choong Yong; Ha, Chang Soo; Yang, Seoung Oh; Khang, Hyun Soo; Yu, In Kyu; Cheong, Hae Kwan; Lee, Jong Seong; Song, Chang-Woo; Kwon, Il Hoon; Han, Jeong Hee; Sung, Jae Hyuck; Heo, Jeong Doo; Choi, Byung Sun; Im, Ruth; Jeong, Jayoung; Yu, Il Je

2007-09-01

Several pharmacokinetic studies on inhalation exposure to manganese (Mn) have already demonstrated that Mn readily accumulates in the olfactory and brain regions. However, a shortening of the magnetic resonance imaging (MRI) T1 relaxation time or high T1 signal intensity in specific sites of the brain, including the globus pallidus and subcortical frontal white matter, as indicative of tissue manganese accumulation has not yet been clearly established for certain durations of known doses of welding-fume exposure in experimental animals. Accordingly, to investigate the movement of manganese after welding-fume exposure, six cynomolgus monkeys were acclimated and assigned to three dose groups: unexposed, low dose (31 mg/m(3) total suspended particulate [TSP], 0.9 mg/m(3) of Mn), and high dose (62 mg/m(3) TSP, 1.95 mg/m(3) of Mn) of total suspended particulate. The primates were exposed to manual metal arc stainless steel (MMA-SS) welding fumes for 2 h per day in an inhalation chamber system equipped with an automatic fume generator. Magnetic resonance imaging (MRI) studies were conducted before the initiation of exposure and thereafter every month. The tissue Mn concentrations were then measured after a plateau was reached regarding the shortening of the MRI T1 relaxation time. A dose-dependent increase in the Mn concentration was found in the lungs, while noticeable increases in the Mn concentrations were found in certain tissues, such as the liver, kidneys, and testes. Slight increases in the Mn concentrations were found in the caudate, putamen, frontal lobe, and substantia nigra, while a dose-dependent noticeable increase was only found in the globus pallidus. Therefore, the present results indicated that a shortening of the MRI T1 relaxation time corresponded well with the Mn concentration in the globus pallidus after prolonged welding-fume exposure.

Betahistine exerts a dose-dependent effect on cochlear stria vascularis blood flow in guinea pigs in vivo.

PubMed

Ihler, Fritz; Bertlich, Mattis; Sharaf, Kariem; Strieth, Sebastian; Strupp, Michael; Canis, Martin

2012-01-01

Betahistine is a histamine H(1)-receptor agonist and H(3)-receptor antagonist that is administered to treat Menière's disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of betahistine. When betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933-1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Menière's disease. Our data suggest that the improved effects of higher doses of betahistine in the treatment of Menière's disease might be due to a corresponding increase of cochlear blood flow.

Betahistine Exerts a Dose-Dependent Effect on Cochlear Stria Vascularis Blood Flow in Guinea Pigs In Vivo

PubMed Central

Ihler, Fritz; Bertlich, Mattis; Sharaf, Kariem; Strieth, Sebastian

2012-01-01

Objective Betahistine is a histamine H1-receptor agonist and H3-receptor antagonist that is administered to treat Menière’s disease. Despite widespread use, its pharmacological mode of action has not been entirely elucidated. This study investigated the effect of betahistine on guinea pigs at dosages corresponding to clinically used doses for cochlear microcirculation. Methods Thirty healthy Dunkin-Hartley guinea pigs were randomly assigned to five groups to receive betahistine dihydrochloride in a dose of 1,000 mg/kg b. w. (milligram per kilogram body weight), 0.100 mg/kg b. w., 0.010 mg/kg b. w., 0.001 mg/kg b. w. in NaCl 0.9% or NaCl 0.9% alone as placebo. Cochlear blood flow and mean arterial pressure were continuously monitored by intravital fluorescence microscopy and invasive blood pressure measurements 3 minutes before and 15 minutes after administration of betahistine. Results When betahistine was administered in a dose of 1.000 mg/kg b. w. cochlear blood flow was increased to a peak value of 1.340 arbitrary units (SD: 0.246; range: 0.933–1.546 arb. units) compared to baseline (p<0.05; Two Way Repeated Measures ANOVA/Bonferroni t-test). The lowest dosage of 0.001 mg/kg b. w. betahistine or NaCl 0.9% had the same effect as placebo. Nonlinear regression revealed that there was a sigmoid correlation between increase in blood flow and dosages. Conclusions Betahistine has a dose-dependent effect on the increase of blood flow in cochlear capillaries. The effects of the dosage range of betahistine on cochlear microcirculation corresponded well to clinically used single dosages to treat Menière’s disease. Our data suggest that the improved effects of higher doses of betahistine in the treatment of Menière’s disease might be due to a corresponding increase of cochlear blood flow. PMID:22745706

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.

Increased γ-H2A.X intensity in response to chronic medium-dose-rate γ-ray irradiation.

PubMed

Sugihara, Takashi; Murano, Hayato; Tanaka, Kimio

2012-01-01

The molecular mechanisms of DNA repair following chronic medium-dose-rate (MDR) γ-ray-induced damage remain largely unknown. We used a cell function imager to quantitatively measure the fluorescence intensity of γ-H2A.X foci in MDR (0.015 Gy/h and 0.06 Gy/h) or high-dose-rate (HDR) (54 Gy/h) γ-ray irradiated embryonic fibroblasts derived from DNA-dependent protein kinase mutated mice (scid/scid mouse embryonic fibroblasts (scid/scid MEFs)). The obtained results are as follows: (1) Automatic measurement of the intensity of radiation-induced γ-H2A.X foci by the cell function imager provides more accurate results compared to manual counting of γ-H2A.X foci. (2) In high-dose-rate (HDR) irradiation, γ-H2A.X foci with high fluorescence intensity were observed at 1 h after irradiation in both scid/scid and wild-type MEFs. These foci were gradually reduced through de-phosphorylation at 24 h or 72 h after irradiation. Furthermore, the fluorescence intensity at 24 h increased to a significantly greater extent in scid/scid MEFs than in wild-type MEFs in the G(1) phase, although no significant difference was observed in G(2)/M-phase MEFs, suggesting that DNA-PKcs might be associated with non-homologous-end-joining-dependent DNA repair in the G(1) phase following HDR γ-ray irradiation. (3) The intensity of γ-H2A.X foci for continuous MDR (0.06 Gy/h and 0.015 Gy/h) irradiation increased significantly and in a dose-dependent fashion. Furthermore, unlike HDR-irradiated scid/scid MEFs, the intensity of γ-H2A.X foci in MDR-irradiated scid/scid MEFs showed no significant increase in the G(1) phase at 24 h, indicating that DNA repair systems using proteins other than DNA-PKcs might induce cell functioning that are subjected to MDR γ-ray irradiation. Our results indicate that the mechanism of phosphorylation or de-phosphorylation of γ-H2A.X foci induced by chronic MDR γ-ray irradiation might be different from those induced by HDR γ-ray irradiation.

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.

Naloxone reversal of buprenorphine-induced respiratory depression.

PubMed

van Dorp, Eveline; Yassen, Ashraf; Sarton, Elise; Romberg, Raymonda; Olofsen, Erik; Teppema, Luc; Danhof, Meindert; Dahan, Albert

2006-07-01

The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression. Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

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.

Improvement of attention with amphetamine in low- and high-performing rats.

PubMed

Turner, Karly M; Burne, Thomas H J

2016-09-01

Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25 mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. Acute low dose amphetamine (0.1 and 0.25 mg/kg) improved accuracy, while the highest dose (1.25 mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents.

High-dose buprenorphine: perioperative precautions and management strategies.

PubMed

Roberts, D M; Meyer-Witting, M

2005-02-01

Buprenorphine has been in clinical use in anaesthesia for several decades. Recently, the high-dose sublingual formulation (Subutex, Reckitt Benckiser, Slough, U.K.) has been increasingly used as maintenance therapy in opioid dependence, as an alternative to methadone and other pharmacological therapies. Buprenorphine has unique pharmacological properties making it well suited for use as a maintenance therapy in opioid dependence. However, these same properties may cause difficulty in the perioperative management of pain. Buprenorphine is a partial opioid agonist, attenuating the effects of supplemental illicit or therapeutic opioid agonists. As a result of its high receptor affinity, supplemental opioids do not readily displace buprenorphine from the opioid receptor in standard doses. High-dose buprenorphine has an extended duration of action that prolongs both of these effects. The perioperative management of patients stabilized on high-dose buprenorphine and undergoing surgery requires consideration of the likely analgesic requirements. Where possible the buprenorphine should be continued. Pain management should focus on maximizing non-opioid analgesia, local anaesthesia and non-pharmacological techniques. Where pain may not be adequately relieved by these methods, the addition of a full opioid agonist such as fentanyl or morphine at appropriate doses should be considered, accompanied by close monitoring in a high dependency unit. In situations where this regimen is unlikely to be effective, preoperative conversion to morphine or methadone may be an option. Where available, liaison with a hospital-based alcohol and drug service should always be considered.

Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways.

PubMed

Dong, Yang; Cao, Aili; Shi, Jianrong; Yin, Peihao; Wang, Li; Ji, Guang; Xie, Jianqun; Wu, Dazheng

2014-04-01

Tangeretin, a natural polymethoxyflavone present in citrus peel oil, is known to have anticancer activities in breast cancer, colorectal carcinoma and lung carcinoma, yet, the underlying mechanisms of tangeretin in human gastric cancer AGS cells have not been investigated to date. In the present study, the apoptotic mechanisms of tangeretin in AGS cells were explored. It was observed that tangeretin increased the apoptotic rates of AGS cells following treatment with tangeretin for 48 h in a dose-dependent manner by Annexin V-FITC and PI double staining. In addition, characteristic apoptotic morphology such as nuclear shrinkage and apoptotic bodies was observed after Hoechst 33258 staining. Flow cytometric assay showed that treatment of AGS cells with tangeretin decreased the mitochondrial membrane potential (MMP) in a dose-dependent manner, which indicated that mitochondrial dysfunction was involved in the tangeretin-induced apoptosis. Caspase-3, -8 and -9 activities were increased by tangeretin in a dose-dependent manner. Western blotting showed that the protein levels of pro-apoptotic proteins including cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax, Bid, tBid, p53, p21/cip1, Fas and FasL were significantly upregulated by tangeretin. In addition, PFT-α (a p53 inhibitor) reduced the apoptotic rates and the expression of p53, p21, caspase-3 and caspase-9 induced by tangeretin, indicating that tangeretin-induced apoptosis was p53-dependent. In conclusion, these results suggest that tangeretin induces the apoptosis of AGS cells mainly through p53-dependent mitochondrial dysfunction and the Fas/FasL-mediated extrinsic pathway.

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions

PubMed Central

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A.; Trofimov, Alexei

2013-01-01

Purpose: Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. Methods: For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. Results: IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. Conclusions: In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled. PMID:23635256

Maximizing the biological effect of proton dose delivered with scanned beams via inhomogeneous daily dose distributions.

PubMed

Zeng, Chuan; Giantsoudi, Drosoula; Grassberger, Clemens; Goldberg, Saveli; Niemierko, Andrzej; Paganetti, Harald; Efstathiou, Jason A; Trofimov, Alexei

2013-05-01

Biological effect of radiation can be enhanced with hypofractionation, localized dose escalation, and, in particle therapy, with optimized distribution of linear energy transfer (LET). The authors describe a method to construct inhomogeneous fractional dose (IFD) distributions, and evaluate the potential gain in the therapeutic effect from their delivery in proton therapy delivered by pencil beam scanning. For 13 cases of prostate cancer, the authors considered hypofractionated courses of 60 Gy delivered in 20 fractions. (All doses denoted in Gy include the proton's mean relative biological effectiveness (RBE) of 1.1.) Two types of plans were optimized using two opposed lateral beams to deliver a uniform dose of 3 Gy per fraction to the target by scanning: (1) in conventional full-target plans (FTP), each beam irradiated the entire gland, (2) in split-target plans (STP), beams irradiated only the respective proximal hemispheres (prostate split sagittally). Inverse planning yielded intensity maps, in which discrete position control points of the scanned beam (spots) were assigned optimized intensity values. FTP plans preferentially required a higher intensity of spots in the distal part of the target, while STP, by design, employed proximal spots. To evaluate the utility of IFD delivery, IFD plans were generated by rearranging the spot intensities from FTP or STP intensity maps, separately as well as combined using a variety of mixing weights. IFD courses were designed so that, in alternating fractions, one of the hemispheres of the prostate would receive a dose boost and the other receive a lower dose, while the total physical dose from the IFD course was roughly uniform across the prostate. IFD plans were normalized so that the equivalent uniform dose (EUD) of rectum and bladder did not increase, compared to the baseline FTP plan, which irradiated the prostate uniformly in every fraction. An EUD-based model was then applied to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). To assess potential local RBE variations, LET distributions were calculated with Monte Carlo, and compared for different plans. The results were assessed in terms of their sensitivity to uncertainties in model parameters and delivery. IFD courses included equal number of fractions boosting either hemisphere, thus, the combined physical dose was close to uniform throughout the prostate. However, for the entire course, the prostate EUD in IFD was higher than in conventional FTP by up to 14%, corresponding to the estimated increase in TCP to 96% from 88%. The extent of gain depended on the mixing factor, i.e., relative weights used to combine FTP and STP spot weights. Increased weighting of STP typically yielded a higher target EUD, but also led to increased sensitivity of dose to variations in the proton's range. Rectal and bladder EUD were same or lower (per normalization), and the NTCP for both remained below 1%. The LET distributions in IFD also depended strongly on the mixing weights: plans using higher weight of STP spots yielded higher LET, indicating a potentially higher local RBE. In proton therapy delivered by pencil beam scanning, improved therapeutic outcome can potentially be expected with delivery of IFD distributions, while administering the prescribed quasi-uniform dose to the target over the entire course. The biological effectiveness of IFD may be further enhanced by optimizing the LET distributions. IFD distributions are characterized by a dose gradient located in proximity of the prostate's midplane, thus, the fidelity of delivery would depend crucially on the precision with which the proton range could be controlled.

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

Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

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

Yoon, Jeongyeon; Ryoo, Sungwoo, E-mail: ryoosw08@kangwon.ac.kr

2013-06-07

Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS)more » mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner.« less

Prophylaxis of thromboembolism in bariatric surgery with parnaparin.

PubMed

Forestieri, Pietro; Quarto, Gennaro; De Caterina, Maurizio; Cuocolo, Alberto; Pilone, Vincenzo; Formato, Antonio; Ruocco, Aldo; Ferrari, Patrizio

2007-12-01

There are limited data on appropriate dosing of low-molecular-weight heparins (LMWHs) for venous thromboembolism (VTE) prophylaxis in bariatric surgery. The primary objective of this preliminary study was to evaluate the preoperative effects of increasing doses of the LMWH parnaparin on coagulation in severely obese patients undergoing bariatric surgery. Severely obese patients (BMI > 50 kg/m(2)) were administered three increasing single doses of parnaparin (3200, 4250, and 6400 IU) on the three consecutive days leading up to biliointestinal bypass surgery. Activated partial thromboplastin time (APTT), anti-factor IIa and anti-factor Xa levels were measured 1 h before and 4 h after dosing. The highest dose (6400 IU/day) was continued from the day of surgery until day 30 (recovery period). Intermittent pneumatic compression and stockings were applied during surgery and the recovery period, respectively. Lower limb echoDoppler and phleboscintigraphy, and pulmonary scintigraphy were used for VTE detection. Ten patients (mean BMI 52.4 kg/m(2)) were recruited into this study. During the preoperative dosing phase, parnaparin dose-dependently prolonged APTT, with the 6400 IU dose significantly prolonging APTT versus the lower doses. Meanwhile, anti-factor Xa and anti-factor IIa activity was increased by the 4250 and 6400 IU doses. After surgery, one patient with heparin resistance experienced pulmonary embolization. No bleeding complications were observed. The dose-response data reported in this preliminary study suggest that parnaparin doses of 4250 and 6400 IU may provide effective prophylaxis for VTE in patients undergoing bariatric surgery. However, given the small number of patients, larger, well-controlled trials are required to confirm these findings.

Dose and elasticity of demand for self-administered cocaine in rats.

PubMed

Kearns, David N; Silberberg, Alan

2016-04-01

The present experiment tested whether the elasticity of demand for self-administered cocaine in rats is dose-dependent. Subjects lever pressed for three different doses of intravenous cocaine - 0.11, 0.33, and 1.0 mg/kg/infusion - on a demand procedure where the number of lever presses required per infusion increased within a session. The main finding was that demand for the 0.11 mg/kg dose was more elastic than it was for the two larger doses. There was no difference in demand elasticity between the 0.33 and 1.0 mg/kg doses. These results parallel findings previously reported in monkeys. The present study also demonstrated that a within-session procedure can be used to generate reliable demand curves.

Antioxidant and anticancer activity of Artemisia princeps var. orientalis extract in HepG2 and Hep3B hepatocellular carcinoma cells

PubMed Central

Choi, Eun-Jeong

2013-01-01

Objective 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. Methods 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. Results 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. Conclusions These results indicate the potential role of APME as an antioxidant and anticancerigen agent in hepatocarcinoma cell lines. PMID:24255577

Kilovoltage Imaging Doses in the Radiotherapy of Pediatric Cancer Patients

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

Deng Jun, E-mail: jun.deng@yale.edu; Chen Zhe; Roberts, Kenneth B.

Purpose: To investigate doses induced by kilovoltage cone-beam computed tomography (kVCBCT) to pediatric cancer patients undergoing radiotherapy, as well as strategies for dose reduction. Methods and Materials: An EGS4 Monte Carlo code was used to calculate three-dimensional dose deposition due to kVCBCT on 4 pediatric cancer patients. Absorbed doses to various organs were analyzed for both half-fan and full-fan modes. Clinical conditions, such as distance from organ at risk (OAR) to CBCT field border, kV peak energy, and testicular shielding, were studied. Results: The mean doses induced by one CBCT scan operated at 125 kV in half-fan mode to testes,more » liver, kidneys, femoral heads, spinal cord, brain, eyes, lens, and optical nerves were 2.9, 4.7, 7.7, 10.5, 8.8, 7.6, 7.7, 7.8, and 7.2 cGy, respectively. Increasing the distances from OARs to CBCT field border greatly reduced the doses to OARs, ranging from 33% reduction for spinal cord to 2300% reduction for testes. As photon beam energy increased from 60 to 125 kV, the dose increase due to kVCBCT ranged from 170% for lens to 460% for brain and spinal cord. A testicular shielding made of 1-cm cerrobend could reduce CBCT doses down to 31%, 51%, 68%, and 82%, respectively, for 60, 80, 100, and 125 kV when the testes lay within the CBCT field. Conclusions: Generally speaking, kVCBCT deposits much larger doses to critical structures in children than in adults, usually by a factor of 2 to 3. Increasing the distances from OARs to CBCT field border greatly reduces doses to OARs. Depending on OARs, kVCBCT-induced doses increase linearly or exponentially with photon beam energy. Testicular shielding works more efficiently at lower kV energies. On the basis of our study, it is essential to choose an appropriate scanning protocol when kVCBCT is applied to pediatric cancer patients routinely.« less

Cow's milk increases the activities of human nuclear receptors peroxisome proliferator-activated receptors alpha and delta and retinoid X receptor alpha involved in the regulation of energy homeostasis, obesity, and inflammation.

PubMed

Suhara, W; Koide, H; Okuzawa, T; Hayashi, D; Hashimoto, T; Kojo, H

2009-09-01

The nuclear peroxisome proliferator-activated receptors (PPAR) have been shown to play crucial roles in regulating energy homeostasis including lipid and carbohydrate metabolism, inflammatory responses, and cell proliferation, differentiation, and survival. Because PPAR agonists have the potential to prevent or ameliorate diseases such as hyperlipidemia, diabetes, atherosclerosis, and obesity, we have explored new natural agonists for PPAR. For this purpose, cow's milk was tested for agonistic activity toward human PPAR subtypes using a reporter gene assay. Milk increased human PPARalpha activity in a dose-dependent manner with a 3.2-fold increase at 0.5% (vol/vol). It also enhanced human PPARdelta activity in a dose-dependent manner with an 11.5-fold increase at 0.5%. However, it only slightly affected human PPARgamma activity. Ice cream, butter, and yogurt also increased the activities of PPARalpha and PPARdelta, whereas vegetable cream affected activity of PPARdelta but not PPARalpha. Skim milk enhanced the activity of PPAR to a lesser degree than regular milk. Milk and fresh cream increased the activity of human retinoid X receptor (RXR)alpha as well as PPARalpha and PPARdelta, whereas neither affected vitamin D3 receptor, estrogen receptors alpha and beta, or thyroid receptors alpha and beta. Both milk and fresh cream were shown by quantitative real-time PCR to increase the quantity of mRNA for uncoupling protein 2 (UCP2), an energy expenditure gene, in a dose-dependent manner. The increase in UCP2 mRNA was found to be reduced by treatment with PPARdelta-short interfering (si)RNA. This study unambiguously clarified at the cellular level that cow's milk increased the activities of human PPARalpha, PPARdelta, and RXRalpha. The possible role in enhancing the activities of PPARalpha, PPARdelta, and RXRalpha, and the health benefits of cow's milk were discussed.

A Randomized Trial of Vitamin D3 Supplementation in Children: Dose-Response Effects on Vitamin D Metabolites and Calcium Absorption

PubMed Central

Laing, E. M.; Hill Gallant, K. M.; Hall, D. B.; McCabe, G. P.; Hausman, D. B.; Martin, B. R.; Warden, S. J.; Peacock, M.; Weaver, C. M.

2013-01-01

Context: Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D3 in healthy children are unknown. Objective: Our objective was to examine the dose-response effects of supplemental vitamin D3 on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes. Design: Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D3 (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope 44Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption. Results: The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from −10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)2D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D. Conclusion: Large increases in serum 25(OH)D with vitamin D3 supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children. PMID:24092833

Acute effects of quercetin-3-O-glucoside on endothelial function and blood pressure: a randomized dose-response study.

PubMed

Bondonno, Nicola P; Bondonno, Catherine P; Rich, Lisa; Mas, Emilie; Shinde, Sujata; Ward, Natalie C; Hodgson, Jonathan M; Croft, Kevin D

2016-07-01

Epidemiologic studies have suggested that a flavonoid-rich diet can reduce the risk of developing cardiovascular disease. Certain flavonoids, in particular quercetin, have been shown to ameliorate endothelial dysfunction and reduce blood pressure (BP), possibly by increasing the bioavailability of the potent vasodilator nitric oxide (NO). Several studies have indicated that improvements in measures of cardiovascular health do not occur linearly, but rather, plateau or decrease with an increasing dose of flavonoids. We determined whether the acute administration of increasing doses of a common quercetin glycoside (quercetin-3-O-glucoside) improves endothelial function and reduces BP in a dose-dependent manner. We also explored whether any effects were correlated with changes in plasma NO production. A randomized, controlled, crossover study was performed in 15 healthy volunteers who each completed 5 visits with a minimum washout period of 1 wk between testing days. Participants received each of the following 5 interventions in a random order: 1) 0, 2) 50, 3) 100, 4) 200, or 5) 400 mg quercetin-3-O-glucoside. Endothelial function and BP were assessed before and 60 min after intervention. A blood sample was taken before and 90 min after intervention for the analysis of plasma nitrate and nitrite as markers of NO production as well as of plasma quercetin metabolites. Although we observed a significant correlation between the dose of quercetin-3-O-glucoside and plasma concentrations of total quercetin (R(2) = 0.52, P < 0.001) and isorhamnetin (R(2) = 0.12, P = 0.005), we showed no improvements in endothelial function or BP and no changes in NO production after any dose. From these results, we conclude that there are no acute changes in BP or the NO-mediated endothelium-dependent relaxation of the brachial artery with doses of quercetin ranging from 50 to 400 mg in healthy men and women. This trial was registered at www.anzctr.org.au as ACTRN12615001338550. © 2016 American Society for Nutrition.

A randomized trial of vitamin D₃ supplementation in children: dose-response effects on vitamin D metabolites and calcium absorption.

PubMed

Lewis, R D; Laing, E M; Hill Gallant, K M; Hall, D B; McCabe, G P; Hausman, D B; Martin, B R; Warden, S J; Peacock, M; Weaver, C M

2013-12-01

Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D₃ in healthy children are unknown. Our objective was to examine the dose-response effects of supplemental vitamin D₃ on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes. Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D₃ (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)₂D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope ⁴⁴Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption. The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from -10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)₂D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D. Large increases in serum 25(OH)D with vitamin D₃ supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children.

Age-related respiratory responses to substance P in normal sheep.

PubMed

Corcoran, B M; Haigh, A L

1993-01-01

The in vivo effects of substance P (SP) on respiratory parameters in four different age groups of sheep were examined. Intravenous SP (10(-8) to 5 x 10(-6) mol kg-1 bodyweight) caused a dose-dependent reduction in dynamic compliance and increase in respiratory resistance in all four groups. The bronchoconstrictor response was age-related, with the greatest response occurring in the youngest age group (four to six months). In the oldest group (over four years) there was minimal bronchomotor response to SP, but a dose-dependent apnoea was present. These findings indicate that there is an age-related alteration in the respiratory response to SP in sheep.

The effect of locally delivered recombinant human bone morphogenetic protein-2 with hydroxyapatite/tri-calcium phosphate on the biomechanical properties of bone in diabetes-related osteoporosis.

PubMed

Liporace, Frank A; Breitbart, Eric A; Yoon, Richard S; Doyle, Erin; Paglia, David N; Lin, Sheldon

2015-06-01

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is particularly effective in improving osteogenesis in patients with diminished bone healing capabilities, such as individuals with type 1 diabetes mellitus (T1DM) who have impaired bone healing capabilities and increased risk of developing osteoporosis. This study measured the effects of rhBMP-2 treatment on osteogenesis by observing the dose-dependent effect of localized delivery of rhBMP-2 on biomechanical parameters of bone using a hydroxyapatite/tri-calcium phosphate (HA/TCP) carrier in a T1DM-related osteoporosis animal model. Two different doses of rhBMP-2 (LD low dose, HD high dose) with a HA/TCP carrier were injected into the femoral intramedullary canal of rats with T1DM-related osteoporosis. Two more diabetic rat groups were injected with saline alone and with HA/TCP carrier alone. Radiographs and micro-computed tomography were utilized for qualitative assessment of bone mineral density (BMD). Biomechanical testing occurred at 4- and 8-week time points; parameters tested included torque to failure, torsional rigidity, shear stress, and shear modulus. At the 4-week time point, the LD and HD groups both exhibited significantly higher BMD than controls; at the 8-week time point, the HD group exhibited significantly higher BMD than controls. Biomechanical testing revealed dose-dependent, higher trends in all parameters tested at the 4- and 8-week time points, with minimal significant differences. Groups treated with rhBMP-2 demonstrated improved bone mineral density at both 4 and 8 weeks compared to control saline groups, in addition to strong trends towards improvement of intrinsic and extrinsic biomechanical properties when compared to control groups. Data revealed trends toward dose-dependent increases in peak torque, torsional rigidity, shear stress, and shear modulus 4 weeks after rhBMP-2 treatment. Not applicable.

Delta-9-tetrahydrocannabinol (THC) affects forelimb motor map expression but has little effect on skilled and unskilled behavior.

PubMed

Scullion, K; Guy, A R; Singleton, A; Spanswick, S C; Hill, M N; Teskey, G C

2016-04-05

It has previously been shown in rats that acute administration of delta-9-tetrahydrocannabinol (THC) exerts a dose-dependent effect on simple locomotor activity, with low doses of THC causing hyper-locomotion and high doses causing hypo-locomotion. However the effect of acute THC administration on cortical movement representations (motor maps) and skilled learned movements is completely unknown. It is important to determine the effects of THC on motor maps and skilled learned behaviors because behaviors like driving place people at a heightened risk. Three doses of THC were used in the current study: 0.2mg/kg, 1.0mg/kg and 2.5mg/kg representing the approximate range of the low to high levels of available THC one would consume from recreational use of cannabis. Acute peripheral administration of THC to drug naïve rats resulted in dose-dependent alterations in motor map expression using high resolution short duration intracortical microstimulation (SD-ICMS). THC at 0.2mg/kg decreased movement thresholds and increased motor map size, while 1.0mg/kg had the opposite effect, and 2.5mg/kg had an even more dramatic effect. Deriving complex movement maps using long duration (LD)-ICMS at 1.0mg/kg resulted in fewer complex movements. Dosages of 1.0mg/kg and 2.5mg/kg THC reduced the number of reach attempts but did not affect percentage of success or the kinetics of reaching on the single pellet skilled reaching task. Rats that received 2.5mg/kg THC did show an increase in latency of forelimb removal on the bar task, while dose-dependent effects of THC on unskilled locomotor activity using the rotorod and horizontal ladder tasks were not observed. Rats may be employing compensatory strategies after receiving THC, which may account for the robust changes in motor map expression but moderate effects on behavior. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Peripheral organ doses from radiotherapy for heterotopic ossification of non-hip joints: is there a risk for radiation-induced malignancies?

PubMed

Berris, Theocharis; Mazonakis, Michalis; Kachris, Stefanos; Damilakis, John

2014-05-01

Radiotherapy, used for heterotopic ossification (HO) management, may increase radiation risk to patients. This study aimed to determine the peripheral dose to radiosensitive organs and the associated cancer risks due to radiotherapy of HO in common non-hip joints. A Monte Carlo model of a medical linear accelerator combined with a mathematical phantom representing an average adult patient were employed to simulate radiotherapy for HO with standard AP and PA fields in the regions of shoulder, elbow and knee. Radiation dose to all out-of-field radiosensitive organs defined by the International Commission on Radiological Protection was calculated. Cancer induction risk was estimated using organ-specific risk coefficients. Organ dose change with increased field dimensions was also evaluated. Radiation therapy for HO with a 7 Gy target dose in the sites of shoulder, elbow and knee, resulted in the following equivalent organ dose ranges of 0.85-62 mSv, 0.28-1.6 mSv and 0.04-1.6 mSv, respectively. Respective ranges for cancer risk were 0-5.1, 0-0.6 and 0-1.3 cases per 10(4) persons. Increasing the field size caused an average increase of peripheral doses by 15-20%. Individual organ dose increase depends upon the primary treatment site and the distance between organ of interest and treatment volume. Relatively increased risks of more than 1 case per 10,000 patients were found for skin, breast and thyroid malignancies after treatment in the region of shoulder and for skin cancer following elbow irradiation. The estimated risk for inducing any other malignant disease ranges from negligible to low. Copyright © 2013 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

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.

Pharmacokinetics of heparin and related polysaccharides

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

Boneu, B.; Dol, F.; Caranobe, C.

1989-01-01

The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activitymore » present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where /sup 125/I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses.« less

Hypothyroidism after Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

PubMed

Inskip, Peter D; Veiga, Lene H S; Brenner, Alina V; Sigurdson, Alice J; Ostroumova, Evgenia; Chow, Eric J; Stovall, Marilyn; Smith, Susan A; Weathers, Rita E; Leisenring, Wendy; Robison, Leslie L; Armstrong, Gregory T; Sklar, Charles A; Lubin, Jay H

2018-05-15

While thyroid cancer risks from exposure to ionizing radiation early in life are well characterized quantitatively, the association of radiation with nonmalignant, functional thyroid disorders has been less studied. Here, we report on a risk analysis study of hypothyroidism with radiation dose to the thyroid gland and the hypothalamic-pituitary axis among survivors of childhood cancer. Utilizing data from the Childhood Cancer Survivor Study, a cohort of 14,364 five-year survivors of childhood cancer diagnosed at 26 hospitals in the U.S. and Canada between 1970 and 1986 and followed through 2009, the occurrence of hypothyroidism was ascertained among 12,015 survivors through serial questionnaires. Radiation doses to the thyroid gland and pituitary gland were estimated from radiotherapy records. Binary outcome regression was used to estimate prevalence odds ratios for hypothyroidism at five years from diagnosis of childhood cancer and Poisson regression to model incidence rate ratios (RR) after the first five years. A total of 1,193 cases of hypothyroidism were observed, 777 (65%) of which occurred five or more years after cancer diagnosis. The cumulative proportion affected with hypothyroidism (prevalence at five years after cancer diagnosis plus incidence through 30 years after cancer diagnosis) was highest among five-year survivors of Hodgkin lymphoma (32.3%; 95% CI: 29.5-34.9) and cancers of the central nervous system (17.7%; 95% CI: 15.2-20.4). The incidence rate was significantly associated with radiation dose to the thyroid and pituitary. The joint association of hypothyroidism with thyroid and pituitary dose was sub-additive for pituitary doses greater than 16 Gy. In particular, a very strong thyroid radiation dose dependence at low-to-moderate pituitary/hypothalamic doses was diminished at high pituitary doses. Radiation-related risks were higher in males than females and inversely associated with age at exposure and time since exposure but remained elevated more than 25 years after exposure. Our findings indicated that hypothyroidism was significantly associated with treatment with bleomycin (RR = 3.4; 95% CI: 1.6-7.3) and the alkylating agents cyclohexyl-chloroethyl-nitrosourea (CCNU) (RR = 3.0; 95% CI: 1.5-5.3) and cyclophosphamide (RR = 1.3; 95% CI: 1.0-1.8), with a significant dose response for CCNU ( P < 0.01). The risk of hypothyroidism among childhood cancer survivors treated with radiation depends both on direct, dose-dependent radiation-induced damage to the thyroid gland and on dose-dependent indirect effects secondary to irradiation of the hypothalamic-pituitary axis. The dose-response relationship for each site depends on dose to the other. Radiation-related risk persists for more than 25 years after treatment. Treatment with certain chemotherapy agents may increase the risk of hypothyroidism.

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.

BMP-2 up-regulates PTEN expression and induces apoptosis of pulmonary artery smooth muscle cells under hypoxia.

PubMed

Pi, Weifeng; Guo, Xuejun; Su, Liping; Xu, Weiguo

2012-01-01

To investigate the role of bone morphogenetic protein 2 (BMP-2) in regulation of phosphatase and tensin homologue deleted on chromosome ten (PTEN) and apoptosis of pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Normal human PASMCs were cultured in growth medium (GM) and treated with BMP-2 from 5-80 ng/ml under hypoxia (5% CO(2)+94% N(2)+1% O(2)) for 72 hours. Gene expression of PTEN, AKT-1 and AKT-2 were determined by quantitative RT-PCR (QRT-PCR). Protein expression levels of PTEN, AKT and phosph-AKT (pAKT) were determined. Apoptosis of PASMCs were determined by measuring activities of caspases-3, -8 and -9. siRNA-smad-4, bpV(HOpic) (PTEN inhibitor) and GW9662 (PPARγ antagonist) were used to determine the signalling pathways. Proliferation of PASMCs showed dose dependence of BMP-2, the lowest proliferation rate was achieved at 60 ng/ml concentration under hypoxia (82.2±2.8%). BMP-2 increased PTEN gene expression level, while AKT-1 and AKT-2 did not change. Consistently, the PTEN protein expression also showed dose dependence of BMP-2. AKT activity significantly reduced in BMP-2 treated PASMCs. Increased activities of caspase-3, -8 and -9 of PASMCs were found after cultured with BMP-2. PTEN expression remained unchanged when Smad-4 expression was inhibited by siRNA-Smad-4. bpV(HOpic) and GW9662 (PPARγ inhibitor) inhibited PTEN protein expression and recovered PASMCs proliferation rate. BMP-2 increased PTEN expression under hypoxia in a dose dependent pattern. BMP-2 reduced AKT activity and increased caspase activity of PASMCs under hypoxia. The increased PTEN expression may be mediated through PPARγ signalling pathway, instead of BMP/Smad signalling pathway.

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.

Ozone Inhalation Leads to a Dose-Dependent Increase of Cytogenetic Damage in Human Lymphocytes

PubMed Central

Holland, Nina; Davé, Veronica; Venkat, Subha; Wong, Hofer; Donde, Aneesh; Balmes, John R; Arjomandi, Mehrdad

2014-01-01

Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we employed a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than 1 MN per cell (P < 0.0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments. PMID:25451016

Bioactive compounds from crocodile (Crocodylus siamensis) white blood cells induced apoptotic cell death in hela cells.

PubMed

Patathananone, Supawadee; Thammasirirak, Sompong; Daduang, Jureerut; Chung, Jing Gung; Temsiripong, Yosapong; Daduang, Sakda

2016-08-01

Crocodile (Crocodylus siamensis) white blood cell extracts (WBCex) were examined for anticancer activity in HeLa cell lines using the MTT assay. The percentage viability of HeLa cells significantly deceased after treatment with WBCex in a dose- and time-dependent manner. The IC50 dose was suggested to be approximately 225 μg/mL protein. Apoptotic cell death occurred in a time-dependent manner based on investigation by flow cytometry using annexin V-FITC and PI staining. DAPI nucleic acid staining indicated increased chromatin condensation. Caspase-3, -8 and -9 activities also increased, suggesting the induction of the caspase-dependent apoptotic pathway. Furthermore, the mitochondrial membrane potential (ΔΨm ) of HeLa cells was lost as a result of increasing levels of Bax and reduced levels of Bcl-2, Bcl-XL, Bcl-Xs, and XIAP. The decreased ΔΨm led to the release of cytochrome c and the activation of caspase-9 and -3. Apoptosis-inducing factor translocated into the nuclei, and endonuclease G (Endo G) was released from the mitochondria. These results suggest that anticancer agents in WBCex can induce apoptosis in HeLa cells via both caspase-dependent and -independent pathways. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 986-997, 2016. © 2015 Wiley Periodicals, Inc.

[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.

Prevalence of bisphosphonate-related osteonecrosis of the jaw-like lesions is increased in a chemotherapeutic dose-dependent manner in mice.

PubMed

Kuroshima, Shinichiro; Sasaki, Muneteru; Nakajima, Kazunori; Tamaki, Saki; Hayano, Hiroki; Sawase, Takashi

2018-07-01

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) worsens oral health-related quality of life. Most BRONJ occurs in multiple myeloma or metastatic breast cancer patients treated with bisphosphonate/chemotherapeutic combination therapies. Cyclophosphamide (CY), an alkylating chemotherapeutic drug, is used to treat multiple myeloma, although its use has been recently reduced. The aim of this study was to clarify the effects of CY dose on tooth extraction socket healing when CY is used with or without bisphosphonate in mice. Low-dose CY (50 mg/kg; CY-L), moderate-dose CY (100 mg/kg; CY-M), high-dose CY (150 mg/kg; CY-H), and bisphosphonate [Zometa (ZA): 0.05 mg/kg] were administered for 7 weeks. Each dose of CY and ZA in combination was also administered for 7 weeks. Both maxillary first molars were extracted at 3 weeks after the initiation of drug administration. Euthanasia was performed at 4 weeks post-extraction. Gross wound healing, microcomputed tomography analysis, histomorphometry, and immunohistochemistry were used to quantitatively evaluate osseous and soft tissue wound healing of tooth extraction sockets. ZA monotherapy induced no BRONJ-like lesions in mice. CY monotherapy rarely induced open wounds, though delayed osseous wound healing occurred in a CY dose-dependent manner. In contrast, CY/ZA combination therapy prevalently induced BRONJ-like lesions with compromised osseous and soft tissue healing in a CY dose-dependent manner. Interestingly, anti-angiogenesis was noted regardless of CY dose and ZA administration, even though only CY-M/ZA and CY-H/ZA combination therapies induced BRONJ-like lesions. Our findings suggest that high-dose CY may be associated with the development of BRONJ following tooth extraction only when CY is used together with ZA. In addition to anti-angiogenesis, other factors may contribute to the pathoetiology of BRONJ. Copyright © 2018 Elsevier Inc. All rights reserved.

Influence of ACTG4-7-PGP (Semax) on Morphofunctional State of Hepatocytes in Chronic Emotional and Painful Stress.

PubMed

Ivanov, A V; Bobyntsev, I I; Shepeleva, O M; Kryukov, A A; Andreeva, L A; Myasoedov, N F

2017-05-01

We studied the effect of intraperitoneal administration of peptide ACTG 4-7 -PGP to male Wistar rats in doses of 5, 50, 150, and 450 μg/kg on the morphofunctional state of hepatocytes in chronic emotional and painful stress. A dose-dependent stress-limiting effect of the peptide was observed: it normalized the protein synthesis function of the liver and serum activity of ALT. The anticytolytic effect of the peptide increased with increasing its dose against the background of the increase in the relative number of multinucleated and multinucleolated cells and deceleration of the recovery of serum protein concentration. The decrease of hepatocyte cytolysis against the background of more intense morphological signs of protein synthesis processes attests to activation of reparative processes in the liver parenchyma via enhanced constitutional synthesis of protein.

Force properties of skinned cardiac muscle following increasing volumes of aerobic exercise in rats.

PubMed

Boldt, Kevin Rudi; Rios, Jaqueline Lourdes; Joumaa, Venus; Herzog, Walter

2018-05-03

The positive effects of chronic endurance exercise training on health and performance have been well documented. These positive effects have been evaluated primarily at the structural level, and work has begun to evaluate mechanical adaptations of the myocardium. However, it remains poorly understood how the volume of exercise training affects cardiac adaptation. In order to gain some understanding, we subjected three-month-old Sprague-Dawley rats (N=23) to treadmill running for eleven weeks at one of three exercise volumes (moderate, high, and extra high). Following training, hearts were excised and mechanical testing was completed on skinned trabecular fiber bundles. Performance on a maximal fitness test was dose-dependent upon training volume, where greater levels of training led to greater performance. No differences were observed between animals from any group for active stress production. Heart mass and passive stress increases in a dose-dependent manner for animals in the control, moderate, and high duration groups. However, hearts from animals in the extra high duration group presented with inhibited responses for heart mass and passive stress, despite performing greatest on a graded treadmill fitness test. These results suggest that heart mass and passive stress adapt in a dose-dependent manner, until exercise becomes excessive and adaptation is inhibited. Our findings are in agreement with the beneficial role exercise has in cardiac adaptation. However, excessive exercise comes with risks of maladaptation which must be weighed against the desire to increase performance.

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.

Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

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

Smetanina, Mariya A., E-mail: maria.smetanina@gmail.com; Laboratory of Gene Expression Control, Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, prospekt Lavrentyeva 10, Novosibirsk 630090; Group of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, prospekt Lavrentyeva 8, Novosibirsk 630090

2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepaticmore » mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car{sup -/-}) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car{sup -/-} livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor. - Highlights: > The azo dye and mouse carcinogen OAT is a very effective mCAR activator. > OAT increases mCAR transactivation in a dose-dependent manner. > OAT CAR-dependently increases the expression of a specific subset of CAR target genes. > OAT induces an unexpectedly deferred, but CAR-dependent hepatocyte proliferation.« less

Asbestos-induced endothelial cell activation and injury. Demonstration of fiber phagocytosis and oxidant-dependent toxicity.

PubMed

Garcia, J G; Gray, L D; Dodson, R F; Callahan, K S

1988-10-01

Vascular endothelial cell injury is important in the development of a variety of chronic interstitial lung disorders. However, the involvement of such injury in the inflammatory response associated with the inhalation of asbestos fibers is unclear and the mechanism of asbestos fiber cytotoxicity remains unknown. In the present study, human umbilical vein endothelial cells were challenged with amosite asbestos and several parameters of cellular function were examined. Electron microscopic examination revealed that endothelial cell exposure to asbestos resulted in active phagocytosis of these particulates. Biochemical evidence of dose-dependent asbestos-mediated endothelial cell activation was indicated by increased metabolism of arachidonic acid. For example, amosite asbestos (500 micrograms/ml) produced a ninefold increase in prostacyclin (PGI2) levels over those levels in non-exposed cells. Incubation of human endothelial cells with asbestos fibers induced specific 51Cr release in both a dose- and time-dependent fashion indicative of cellular injury. Injury induced by amosite asbestos was not significantly attenuated by treatment of the endothelial cell monolayer with either the iron chelator deferoxamine, which prevents hydroxyl radical (.OH) formation, or by the superoxide anion (O2-) scavenger, superoxide dismutase. However, significant dose-dependent protection was observed with the hydrogen peroxide (H2O2) scavenger, catalase. Chelation of elemental iron present within amosite asbestos fibers by deferoxamine produced a 33% reduction in asbestos cytotoxicity, suggesting a potential role for hydroxyl radical-mediated injury via the iron-catalyzed Haber-Weiss reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced Sensitivity to Attenuation of Conditioned Reinstatement by the mGluR2/3 Agonist LY379268 and Increased Functional Activity of mGluR2/3 in Rats with a History of Ethanol Dependence

PubMed Central

Kufahl, Peter R; Martin-Fardon, Rémi; Weiss, Friedbert

2011-01-01

Recent findings implicate group II metabotropic glutamate receptors (mGluR2/3) in the reinforcing and dependence-inducing actions of ethanol and identify these receptors as treatment targets for alcoholism. Here, we investigated the effects of mGLuR2/3 activation on conditioned reinstatement in rats with different ethanol-dependence histories and examined dependence-associated changes in the functional activity of mGluR2/3. Following ethanol self-administration training and conditioning procedures, rats were made ethanol dependent, using ethanol vapor inhalation, under three conditions: a single intoxication and withdrawal episode (SW), repeated cycles of intoxication and withdrawal (RW), or no intoxication (CTRL). At 1 week after removal from ethanol vapor, self-administration resumed until stable baseline performance was reached, followed by extinction of operant responding and reinstatement tests. Post-withdrawal self-administration was increased in the RW group, but all groups showed conditioned reinstatement. The mGluR2/3 agonist LY379268 dose -dependently reduced reinstatement in all groups, but was more effective at low doses in the SW and RW groups. The highest dose of LY379268 tested reduced spontaneous locomotor activity and operant responding maintained by a non-drug reinforcer, without differences among groups. The heightened sensitivity to the effects of LY379268 in rats with an ethanol-dependence history was therefore specific to behavior motivated by ethanol-related stimuli. Both the SW and RW groups showed elevated [35S]GTPγS binding in the central nucleus of the amygdala (CeA) and bed nucleus of stria terminalis (BNST), relative to the CTRL group. The findings implicate changes in mGluR2/3 functional activity as a factor in ethanol dependence and support treatment target potential of mGlu2/3 receptors for craving and relapse prevention. PMID:21881571

Characteristics of an OSLD in the diagnostic energy range.

PubMed

Al-Senan, Rani M; Hatab, Mustapha R

2011-07-01

Optically stimulated luminescence (OSL) dosimetry has been recently introduced in radiation therapy as a potential alternative to the thermoluminescent dosimeter (TLD) system. The aim of this study was to investigate the feasibility of using OSL point dosimeters in the energy range used in diagnostic imaging. NanoDot OSL dosimeters (OSLDs) were used in this study, which started with testing the homogeneity of a new packet of nanoDots. Reproducibility and the effect of optical treatment (bleaching) were then examined, followed by an investigation of the effect of accumulated dose on the OSLD indicated doses. OSLD linearity, angular dependence, and energy dependence were also studied. Furthermore, comparison with LiF:Mg,Ti TLD chips using standard CT dose phantoms at 80 and 120 kVp settings was performed. Batch homogeneity showed a coefficient of variation of <5%. Single-irradiation measurements with bleaching after each OSL readout was found to be associated with a 3.3% reproducibility (one standard deviation measured with a 8 mGy test dose), and no systematic change in OSLDs sensitivity could be noted from measurement to measurement. In contrast, the multiple-irradiation readout without bleaching in between measurements was found to be associated with an uncertainty (using a 6 mGy test dose) that systematically increased with accumulated dose, reaching 42% at 82 mGy. Good linearity was shown by nanoDots under general x-ray, CT, and mammography units with an R2 > 0.99. The angular dependence test showed a drop of approximately 70% in the OSLD response at 90 degrees in mammography (25 kVp). With the general radiography unit, the maximum drop was 40% at 80 kVp and 20% at 120 kVp, and it was only 10% with CT at both 80 and 120 kVp. The energy dependence study showed a range of ion chamber-to-OSLDs ratios between 0.81 and 1.56, at the energies investigated (29-62 keV). A paired t-test for comparing the OSLDs and TLDs showed no significant variation (p > 0.1). OSLDs exhibited good batch homogeneity (<5%) and reproducibility (3.3%), as well as a linear response. In addition, they showed no statistically significant difference with TLDs in CT measurements (p > 0.1). However, high uncertainty (42%) in the dose estimate was found as a result of relatively high accumulated dose. Furthermore, nanoDots showed high angular dependence (up to 70%) in low kVp techniques. Energy dependence of about 60% was found, and correction factors were suggested for the range of energies investigated. Therefore, if angular and energy dependences are taken into consideration and the uncertainty associated with accumulated dose is avoided, OSLDs (nanoDots) can be suitable for use as point dosimeters in diagnostic settings.

Antihyperalgesic effects of ProTx-II, a Nav1.7 antagonist, and A803467, a Nav1.8 antagonist, in diabetic mice.

PubMed

Tanaka, Ken-Ichiro; Sekino, Shota; Ikegami, Megumi; Ikeda, Hiroko; Kamei, Junzo

2015-01-01

The present study investigated the effects of intrathecal administration of ProTx-II (tarantula venom peptide) and A803467 (5-[4-chloro-phenyl]-furan-2-carboxylic acid [3,5-dimethoxy-phenyl]-amide), selective Nav1.7 and Nav1.8 antagonists, respectively, on thermal hyperalgesia in a painful diabetic neuropathy model of mice. Intrathecal administration of ProTx-II at doses from 0.04 to 4 ng to diabetic mice dose-dependently and significantly increased the tail-flick latency. Intrathecal administration of A803467 at doses from 10 to 100 ng to diabetic mice also dose-dependently and significantly increased the tail-flick latency. However, intrathecal administration of either ProTx-II (4 ng) or A803467 (100 ng) had no effect on the tail-flick latency in nondiabetic mice. The expression of either the Nav1.7 or Nav1.8 sodium channel protein in the dorsal root ganglion in diabetic mice was not different from that in nondiabetic mice. The present results suggest that ProTx-II and A803467, highly selective blockers of Nav1.7 and Nav1.8 sodium channels, respectively, in the spinal cord, can have antihyperalgesic effects in diabetic mice.

Somatostatin inhibits cholecystokinin-induced pancreatic protein secretion via cholinergic pathways.

PubMed

Brodish, R J; Kuvshinoff, B W; McFadden, D W; Fink, A S

1995-05-01

Although somatostatin is a potent inhibitor of pancreatic exocrine secretion in vivo, its mechanism of action remains unclear. The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion was studied in conscious dogs. Chronic pancreatic fistulae were created in six mongrel dogs, and a second group of six dogs also underwent complete pancreatic denervation. The pancreatic responses to graded doses of cholecystokinin (12.5-200 ng/kg/h) and bethanechol (57-916 micrograms/kg/h), both alone and during background infusion of somatostatin-14 (800 pm/kg/h), were determined in all dogs. The cholecystokinin dose-response with a somatostatin-14 background was then repeated with the addition of atropine (10 micrograms/kg/h). In both groups of animals, cholecystokinin elicited a dose-dependent increase in pancreatic protein secretion that was inhibited significantly by somatostatin-14. Regardless of the status of extrapancreatic nerves, atropine further inhibited cholecystokinin-induced protein secretion beyond that evoked by somatostatin-14. In both innervated and denervated animals, cholinergic stimulation with bethanechol elicited a dose-dependent increase in pancreatic protein secretion that was unaffected by somatostatin-14. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Somatostatin-14 appears to inhibit cholecystokinin-induced pancreatic secretion by an intrapancreatic cholinergic mechanism.

RANTES: a new prostaglandin dependent endogenous pyrogen in the rat.

PubMed

Tavares, E; Miñano, F J

2000-09-01

Fever, a hallmark of disease, is a highly complex process initiated by the action of a number of endogenous pyrogens on the thermosensitive cells of the brain. We describe the activity of RANTES, a chemotactic cytokine, as intrinsically pyrogenic in the rat, when it is delivered directly to the thermosensitive region of the rat's anterior hypothalamic, pre-optic area (AH/POA). RANTES, microinjected into the AH/POA in a dose of 1, 5, 10, 15, 25 or 50 pg, produces an immediate and intense dose-related fever following injection. Increasing the dose to 100 pg did not result in a further increase in the febrile response. No significant change in body temperature was produced by heat-inactivated RANTES. The intrahypothalamic injection of antibodies against RANTES (2.0 microg, 15 min prior to RANTES) significantly blocked the fever induced by this chemokine. Pretreatment with ibuprofen blocked the fever induced by RANTES. In order of potency, the magnitude of the febrile response induced by RANTES was greater than that produced with equipotent doses of either macrophage inflammatory protein-1beta or interleukin-6. The results thus demonstrate that RANTES is the most potent endopyrogen discovered thus far and exerts its action directly on pyrogen-sensitive cells of the AH/POA through a prostaglandin-dependent pathway.

Programmed Cell Death in the Honey Bee (Apis mellifera) (Hymenoptera: Apidae) Worker Brain Induced by Imidacloprid.

PubMed

Wu, Yan-Yan; Zhou, Ting; Wang, Qiang; Dai, Ping-Li; Xu, Shu-Fa; Jia, Hui-Ru; Wang, Xing

2015-08-01

Honey bees are at an unavoidable risk of exposure to neonicotinoid pesticides, which are used worldwide. Compared with the well-studied roles of these pesticides in nontarget site (including midgut, ovary, or salivary glands), little has been reported in the target sites, the brain. In the current study, laboratory-reared adult worker honey bees (Apis mellifera L.) were treated with sublethal doses of imidacloprid. Neuronal apoptosis was detected using the TUNEL technique for DNA labeling. We observed significantly increased apoptotic markers in dose- and time-dependent manners in brains of bees exposed to imidacloprid. Neuronal activated caspase-3 and mRNA levels of caspase-1, as detected by immunofluorescence and real-time quantitative PCR, respectively, were significantly increased, suggesting that sublethal doses of imidacloprid may induce the caspase-dependent apoptotic pathway. Additionally, the overlap of apoptosis and autophagy in neurons was confirmed by transmission electron microscopy. It further suggests that a relationship exists between neurotoxicity and behavioral changes induced by sublethal doses of imidacloprid, and that there is a need to determine reasonable limits for imidacloprid application in the field to protect pollinators. © The Authors 2015. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dietary proanthocyanidins boost hepatic NAD(+) metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats.

PubMed

Aragonès, Gerard; Suárez, Manuel; Ardid-Ruiz, Andrea; Vinaixa, Maria; Rodríguez, Miguel A; Correig, Xavier; Arola, Lluís; Bladé, Cinta

2016-04-22

Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD(+)) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD(+) precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD(+). Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD(+) availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD(+) levels.

Dietary proanthocyanidins boost hepatic NAD+ metabolism and SIRT1 expression and activity in a dose-dependent manner in healthy rats

PubMed Central

Aragonès, Gerard; Suárez, Manuel; Ardid-Ruiz, Andrea; Vinaixa, Maria; Rodríguez, Miguel A.; Correig, Xavier; Arola, Lluís; Bladé, Cinta

2016-01-01

Proanthocyanidins (PACs) have been reported to modulate multiple targets by simultaneously controlling many pivotal metabolic pathways in the liver. However, the precise mechanism of PAC action on the regulation of the genes that control hepatic metabolism remains to be clarified. Accordingly, we used a metabolomic approach combining both nuclear magnetic resonance and mass spectrometry analysis to evaluate the changes induced by different doses of grape-seed PACs in the liver of healthy rats. Here, we report that PACs significantly increased the hepatic nicotinamide adenine dinucleotide (NAD+) content in a dose-dependent manner by specifically modulating the hepatic concentrations of the major NAD+ precursors as well as the mRNA levels of the genes that encode the enzymes involved in the cellular metabolism of NAD+. Notably, Sirtuin 1 (Sirt1) gene expression was also significantly up-regulated in a dose-response pattern. The increase in both the NAD+ availability and Sirt1 mRNA levels, in turn, resulted in the hepatic activation of SIRT1, which was significantly associated with improved protection against hepatic triglyceride accumulation. Our data clearly indicates that PAC consumption could be a valid tool to enhance hepatic SIRT1 activity through the modulation of NAD+ levels. PMID:27102823

Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats.

PubMed

Ozyigit, Filiz; Kucuk, Aysegul; Akcer, Sezer; Tosun, Murat; Kocak, Fatma Emel; Kocak, Cengiz; Kocak, Ahmet; Metineren, Hasan; Genc, Osman

2015-08-26

Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (p<0.01), levels of MDA, NO, and inducible nitric oxide synthase (iNOS) positive cells (p<0.01, p<0.05, respectively), and increased SOD, GPx, and CAT activities (p<0.001, p<0.01, p<0.05, respectively) compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (p<0.01, p<0.05, p<0.001) and MDA and NO levels (p<0.05, p<0.01) and decreased SOD, GPx, and CAT activities (p<0.05) compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.

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.

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.

Intranasal Administration of a Therapeutic HIV Vaccine (Vacc-4x) Induces Dose-Dependent Systemic and Mucosal Immune Responses in a Randomized Controlled Trial

PubMed Central

Brekke, Kristin; Lind, Andreas; Holm-Hansen, Carol; Haugen, Inger Lise; Sørensen, Birger; Sommerfelt, Maja; Kvale, Dag

2014-01-01

Background Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant. Methods Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β. Results Vacc-4x proliferative T cell responses increased only among the vaccinated (p≤0.031). The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037) and developed larger DTH (p = 0.005) than the adjuvant group. Rectal (distal) Vacc-4x IgA and IgG antibodies also increased (p = 0.043) in this group. In contrast, the high dose generated higher nasal (local) Vacc-4x IgA (p = 0.028) and serum IgG (p = 0.030) antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = −0.82, p<0.001) and high regulation (r = 0.61, p = 0.010) at baseline. Conclusion Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation. Trial Registration ClinicalTrials.gov NCT01473810 PMID:25398137

Cytogenetic Reconstruction of Gamma-Ray Doses Delivered to Atomic Bomb Survivors: Dealing with Wide Distributions of Photon Energies and Contributions from Hematopoietic Stem/Progenitor Cells.

PubMed

Nakamura, Nori; Hirai, Yuko; Kodama, Yoshiaki; Hamasaki, Kanya; Cullings, Harry M; Cordova, Kismet A; Awa, Akio

2017-10-01

Retrospective estimation of the doses received by atomic bomb (A-bomb) survivors by cytogenetic methods has been hindered by two factors: One is that the photon energies released from the bomb were widely distributed, and since the aberration yield varies depending on the energy, the use of monoenergetic 60 Co gamma radiation to construct a calibration curve may bias the estimate. The second problem is the increasing proportion of newly formed lymphocytes entering into the lymphocyte pool with increasing time intervals since the exposures. These new cells are derived from irradiated precursor/stem cells whose radiosensitivity may differ from that of blood lymphocytes. To overcome these problems, radiation doses to tooth enamel were estimated using the electron spin resonance (ESR; or EPR, electron paramagnetic resonance) method and compared with the cytogenetically estimated doses from the same survivors. The ESR method is only weakly dependent on the photon energy and independent of the years elapsed since an exposure. Both ESR and cytogenetic doses were estimated from 107 survivors. The latter estimates were made by assuming that although a part of the cells examined could be lymphoid stem or precursor cells at the time of exposure, all the cells had the same radiosensitivity as blood lymphocytes, and that the A-bomb gamma-ray spectrum was the same as that of the 60 Co gamma rays. Subsequently, ESR and cytogenetic endpoints were used to estimate the kerma doses using individual DS02R1 information on shielding conditions. The results showed that the two sets of kerma doses were in close agreement, indicating that perhaps no correction is needed in estimating atomic bomb gamma-ray doses from the cytogenetically estimated 60 Co gamma-ray equivalent doses. The present results will make it possible to directly compare cytogenetic doses with the physically estimated doses of the survivors, which would pave the way for testing whether or not there are any systematic trends or factors affecting physically estimated doses.

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).

Quantification of damage due to low-dose radiation exposure in mice: construction and application of a biodosimetric model using mRNA indicators in circulating white blood cells

PubMed Central

Ishihara, Hiroshi; Tanaka, Izumi; Yakumaru, Haruko; Tanaka, Mika; Yokochi, Kazuko; Fukutsu, Kumiko; Tajima, Katsushi; Nishimura, Mayumi; Shimada, Yoshiya; Akashi, Makoto

2016-01-01

Biodosimetry, the measurement of radiation damage in a biologic sample, is a reliable tool for increasing the accuracy of dose estimation. Although established chromosome analyses are suitable for estimating the absorbed dose after high-dose irradiation, biodosimetric methodology to measure damage following low-dose exposure is underdeveloped. RNA analysis of circulating blood containing radiation-sensitive cells is a candidate biodosimetry method. Here we quantified RNA from a small amount of blood isolated from mice following low-dose body irradiation (<0.5 Gy) aimed at developing biodosimetric tools for situations that are difficult to study in humans. By focusing on radiation-sensitive undifferentiated cells in the blood based on Myc RNA expression, we quantified the relative levels of RNA for DNA damage-induced (DDI) genes, such as Bax, Bbc3 and Cdkn1a. The RNA ratios of DDI genes/Myc in the blood increased in a dose-dependent manner 4 h after whole-body irradiation at doses ranging from 0.1 to 0.5 Gy (air-kerma) of X-rays, regardless of whether the mice were in an active or resting state. The RNA ratios were significantly increased after 0.014 Gy (air-kerma) of single X-ray irradiation. The RNA ratios were directly proportional to the absorbed doses in water ranging from 0.1 to 0.5 Gy, based on gamma-irradiation from 137Cs. Four hours after continuous irradiation with gamma-rays or by internal contamination with a beta-emitter, the increased RNA ratios resembled those following single irradiation. These findings indicate that the RNA status can be utilized as a biodosimetric tool to estimate low-dose radiation when focusing on undifferentiated cells in blood. PMID:26589759

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.

Pharmacodynamic and pharmacokinetic profile of S 17092, a new orally active prolyl endopeptidase inhibitor, in elderly healthy volunteers. A phase I study

PubMed Central

Morain, P; Robin, J L; De Nanteuil, G; Jochemsen, R; Heidet, V; Guez, D

2000-01-01

Aims The aim of this study was to characterize the pharmacodynamics and the pharmacokinetics of S 17092, a new orally active prolyl endopeptidase inhibitor following single and repeated administration in elderly healthy volunteers. Methods This was a double-blind, randomized, placebo-controlled, single and multiple dose study in elderly healthy male and female volunteers (n = 36). Four doses were investigated in sequential order: 100, 400, 800 and 1200 mg. Each dose was administered orally once a day in single administration and then, after a 1 week washout period, during 7 days. Pharmacodynamics were assessed by measurement of plasmatic prolyl endopeptidase (PEP) activity, quantitative electroencephalogram (EEG) and psychometric tests. S 17092 concentrations in plasma were quantified by high performance liquid chromatography with tandem mass spectrometric detection. Results PEP activity in plasma was dose-dependently inhibited both after administration of a single dose and after repeated doses of S 17092. The mean maximal inhibition was obtained within 0.5–2 h after dosing, while inhibition lasted at least 12 h after dose administration. S 17092 appeared to be a centrally active substance as it induced statistically significant modifications in EEG compared with placebo. S 17092 at 100 mg exerted an acute increase in alpha band following single administration at 4 h and 8 h postdosing. When administered repeatedly over 7 days S 17092 did not appear to induce significant lasting central nervous system (CNS) effects. In psychometric tests, response times in the numeric working memory were significantly reduced compared with placebo, following the 800 mg dose. There were some beneficial residual effects of the 1200 mg dose on day 13: delayed word recall and word recognition sensitivity improved compared with the declines noted under placebo. Maximum measured concentration (Cmax) and area under the curve (AUC) parameters increased in proportion to the dose. The terminal half-life (t½) values ranged between 9 and 31 h on day 1 and between 7 and 18 h on day 14. A high interindividual variability was observed at all dose levels. S 17092 was well tolerated with no clinically significant changes in laboratory or physical parameters observed at any dose. Conclusions S 17092 had a potent, dose-dependent inhibitory effect on plasmatic PEP, increased alpha band EEG at the 100 mg dose and improved performance in two verbal memory tests at the 1200 mg dose while there were disruption to the vigilance task. The results obtained in elderly healthy subjects indicated that S 17092 is suitable for once-daily dosing without any serious adverse events. PMID:11012558

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 genotoxicity and subclinical toxicity of Agaricus blazei Murrill in the Ames test and in histopathological and biochemical analysis.

PubMed

Chang, Jin-Biou; Lu, Hsu-Feng; Liao, Nien-Chieh; Lee, Ching-Sung; Yeh, Ming-Yang; Liu, Chi-Ming; Chung, Ming-Teng; Man-Kuan, Au; Lin, Jen-Jyh; Wu, Ming-Fang; Chung, Jing-Gung

2012-01-01

This study was conducted in order to assess the safety and tolerability of Agaricus blazei Murrill (ABM) in general toxicological studies by Ames tests in vitro and in 28-day feeding toxicity experiments. There were no dose-dependent increases or decreases in the number of revertant colonies both with and without metabolic activation in Ames tests. Doses of 10, 5 and 0.1 mg/per mouse of ABM daily were administered by oral gavage to mice (n=10) for 28 days. The effects on clinical observations, clinical pathology, and histopathology were evaluated. There were no significant changes in the brain, heart, kidney, liver, spleen, adrenal gland, testes or ovaries visually. With increasing doses, male and female treated mice did not show any gradual elevation of serum concentration in any of the nine items we examined, except for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in females. The AST levels of the treatment by medium or high dose and the ALT levels of the treatment by high dose in females were abnormal in comparison to those of the baseline control group, with significant differences. On studying the histological changes in mice, tissue sections of negative control and experimental groups exhibited no apparent pathological alterations. In summary, the Ames test, pathology determinations, biochemical analysis and routine blood parameters were all normal, except for AST and ALT in females. Results showed that the statistical differences observed in one sex were not observed in the other and were not dose dependent.

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

Ward, W.F.; Molteni, A.; Ts'ao, C.H.

The angiotensin converting enzyme inhibitor captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats. The present study determined whether captopril also reduces collagen (hydroxyproline) accumulation in the lungs of rats sacrificed 2 months after a range of single doses (0-30 Gy) of 60Co gamma rays to the right hemithorax. Captopril was administered in the feed at a regimen of 0, 25, or 50 mg/kg/day continuously after irradiation. Mast cell counts also were obtained from lungs of all animals exposed to 30 Gy. In rats receiving no captopril, there was a radiation dose-dependent increase in right lung hydroxyproline (HP) content and inmore » HP concentration per g wet weight. Captopril produced a drug dose-dependent suppression in this radiation-induced HP accumulation. At a dose of 50 mg/kg/d, captopril reduced the slope of the radiation dose response curve for lung HP content by a factor of 1.7, and completely prevented the increase in HP concentration. At an isoeffect level of 550 micrograms HP per right superior lobe, this dose of captopril exhibited a DRF of 1.7 +/- 0.2. In rats exposed to 30 Gy, moreover, the number of mast cells per mm2 of alveolar cross-sectional surface area decreased from 105 +/- 8 to 100 +/- 7 and 59 +/- 5 in the groups given 0, 25 or 50 mg/kg/d of captopril, respectively, (vs none in sham-irradiated rats). These data are the first to demonstrate that the ACE inhibitor captopril might provide a novel intervention in the pathogenesis of radiation fibrosis.« less

Paradox effects of binge drinking on response inhibition processes depending on mental workload.

PubMed

Stock, Ann-Kathrin; Riegler, Lea; Chmielewski, Witold X; Beste, Christian

2016-06-01

Binge drinking is an increasing problem in Western societies, but we are still only beginning to unravel the effects of binge drinking on a cognitive level. While common sense suggests that all cognitive functions are compromised during high-dose ethanol intoxication, several studies suggest that the effects might instead be rather specific. Moreover, some results suggest that the degrees of automaticity and complexity of cognitive operations during response control modulate effects of binge drinking. However, this has not been tested in detail. In the current study, we therefore parametrically modulate cognitive/"mental" workload during response inhibition and examine the effects of high-dose ethanol intoxication (~1.1 ‰) in n = 18 male participants. The results suggest that detrimental effects of high-dose ethanol intoxication strongly depend on the complexity of processes involved in response inhibition. The results revealed strong effects (η (2) = .495) and are in line with findings showing that even high doses of ethanol have very specific effects on a cognitive level. Opposed to common sense, more complex cognitive operations seem to be less affected by a high-dose ethanol intoxication. Complementing this, high-dose ethanol intoxication is increasingly detrimental for action control, as stronger automated response tendencies are in charge and need to be controlled. Binge-like ethanol intoxication may take a heavier toll on cognitive control processes than on automated responses/response tendencies. Therefore, ethanol effects are more pronounced in supposedly "easier" control conditions because those facilitate the formation of automated response tendencies.

A novel and selective sodium-glucose cotransporter-2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus.

PubMed

Ikeda, S; Takano, Y; Cynshi, O; Tanaka, R; Christ, A D; Boerlin, V; Beyer, U; Beck, A; Ciorciaro, C; Meyer, M; Kadowaki, T

2015-10-01

To assess the efficacy, safety and tolerability of different doses of tofogliflozin, a novel, highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). In a 12-week, multicentre, multinational, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study, patients with inadequate glycaemic control from diet and exercise alone, or from diet and exercise plus a stable dose of metformin, were randomized to one of five doses of tofogliflozin (2.5, 5, 10, 20, or 40 mg) or placebo. The primary efficacy endpoint was absolute change at week 12 from baseline in glycated haemoglobin (HbA1c), minus the change in the placebo group. Statistically significant dose-dependent reductions in HbA1c were shown in all treated groups except the 2.5-mg dose group, with a maximum reduction of 0.56% (placebo-subtracted) at the 40-mg dose, along with increased urinary glucose excretion. Metformin treatment had no substantial influence on tofogliflozin efficacy. Dose-dependent reductions in fasting plasma glucose and body weight were observed, and glucose intolerance was improved, with a trend towards blood pressure reduction. Slight increases were observed for mean ketone bodies with no abnormal change in ketone body ratio. No deaths or treatment-related serious adverse events were reported. The incidence of adverse events was similar in the placebo (37.9%) to that in the tofogliflozin group (35.9-46.3%). Withdrawal because of adverse events was rare (≤2 patients per treatment group), with similar rates of withdrawal in the placebo and tofogliflozin groups. A once-daily dose of tofogliflozin for 12 weeks was an effective, safe and well-tolerated treatment for T2DM. © 2015 John Wiley & Sons Ltd.

Individual exposures to drinking water trihalomethanes, low birth weight and small for gestational age risk: a prospective Kaunas cohort study.

PubMed

Grazuleviciene, Regina; Nieuwenhuijsen, Mark J; Vencloviene, Jone; Kostopoulou-Karadanelli, Maria; Krasner, Stuart W; Danileviciute, Asta; Balcius, Gediminas; Kapustinskiene, Violeta

2011-04-19

Evidence for an association between exposure during pregnancy to trihalomethanes (THMs) in drinking water and impaired fetal growth is still inconsistent and inconclusive, in particular, for various exposure routes. We examined the relationship of individual exposures to THMs in drinking water on low birth weight (LBW), small for gestational age (SGA), and birth weight (BW) in singleton births. We conducted a cohort study of 4,161 pregnant women in Kaunas (Lithuania), using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, to estimate an internal dose of THM. We used regression analysis to evaluate the relationship between internal THM dose and birth outcomes, adjusting for family status, education, smoking, alcohol consumption, body mass index, blood pressure, ethnic group, previous preterm, infant gender, and birth year. The estimated internal dose of THMs ranged from 0.0025 to 2.40 mg/d. We found dose-response relationships for the entire pregnancy and trimester-specific THM and chloroform internal dose and risk for LBW and a reduction in BW. The adjusted odds ratio for third tertile vs. first tertile chloroform internal dose of entire pregnancy was 2.17, 95% CI 1.19-3.98 for LBW; the OR per every 0.1 μg/d increase in chloroform internal dose was 1.10, 95% CI 1.01-1.19. Chloroform internal dose was associated with a slightly increased risk of SGA (OR 1.19, 95% CI 0.87-1.63 and OR 1.22, 95% CI 0.89-1.68, respectively, for second and third tertile of third trimester); the risk increased by 4% per every 0.1 μg/d increase in chloroform internal dose (OR 1.04, 95% CI 1.00-1.09). THM internal dose in pregnancy varies substantially across individuals, and depends on both water THM levels and water use habits. Increased internal dose may affect fetal growth.

A bone marrow toxicity model for 223Ra alpha-emitter radiopharmaceutical therapy

NASA Astrophysics Data System (ADS)

Hobbs, Robert F.; Song, Hong; Watchman, Christopher J.; Bolch, Wesley E.; Aksnes, Anne-Kirsti; Ramdahl, Thomas; Flux, Glenn D.; Sgouros, George

2012-05-01

Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.

Individual exposures to drinking water trihalomethanes, low birth weight and small for gestational age risk: a prospective Kaunas cohort study

PubMed Central

2011-01-01

Background Evidence for an association between exposure during pregnancy to trihalomethanes (THMs) in drinking water and impaired fetal growth is still inconsistent and inconclusive, in particular, for various exposure routes. We examined the relationship of individual exposures to THMs in drinking water on low birth weight (LBW), small for gestational age (SGA), and birth weight (BW) in singleton births. Methods We conducted a cohort study of 4,161 pregnant women in Kaunas (Lithuania), using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, to estimate an internal dose of THM. We used regression analysis to evaluate the relationship between internal THM dose and birth outcomes, adjusting for family status, education, smoking, alcohol consumption, body mass index, blood pressure, ethnic group, previous preterm, infant gender, and birth year. Results The estimated internal dose of THMs ranged from 0.0025 to 2.40 mg/d. We found dose-response relationships for the entire pregnancy and trimester-specific THM and chloroform internal dose and risk for LBW and a reduction in BW. The adjusted odds ratio for third tertile vs. first tertile chloroform internal dose of entire pregnancy was 2.17, 95% CI 1.19-3.98 for LBW; the OR per every 0.1 μg/d increase in chloroform internal dose was 1.10, 95% CI 1.01-1.19. Chloroform internal dose was associated with a slightly increased risk of SGA (OR 1.19, 95% CI 0.87-1.63 and OR 1.22, 95% CI 0.89-1.68, respectively, for second and third tertile of third trimester); the risk increased by 4% per every 0.1 μg/d increase in chloroform internal dose (OR 1.04, 95% CI 1.00-1.09). Conclusions THM internal dose in pregnancy varies substantially across individuals, and depends on both water THM levels and water use habits. Increased internal dose may affect fetal growth. PMID:21501533

The irradiation hardening of Ni-Mo-Cr and Ni-W-Cr alloy under Xe26+ ion irradiation

NASA Astrophysics Data System (ADS)

Chen, Huaican; Hai, Yang; Liu, Renduo; Jiang, Li; Ye, Xiang-xi; Li, Jianjian; Xue, Wandong; Wang, Wanxia; Tang, Ming; Yan, Long; Yin, Wen; Zhou, Xingtai

2018-04-01

The irradiation hardening of Ni-Mo-Cr and Ni-W-Cr alloy was investigated. 7 MeV Xe26+ ion irradiation was performed at room temperature and 650 °C with peak damage dose from 0.05 to 10 dpa. With the increase of damage dose, the hardness of Ni-Mo-Cr and Ni-W-Cr alloy increases, and reaches saturation at damage dose ≥1 dpa. Moreover, the damage dose dependence of hardness in both alloys can be described by the Makin and Minter's equation, where the effective critical volume of obstacles can be used to represent irradiation hardening resistance of the alloys. Our results also show that Ni-W-Cr alloy has better irradiation hardening resistance than Ni-Mo-Cr alloy. This is ascribed to the fact that the W, instead of Mo in the alloy, can suppress the formation of defects under ion irradiation.

Continuing evaluation of bipolar linear devices for total dose bias dependency and ELDRS effects

NASA Technical Reports Server (NTRS)

McClure, Steven S.; Gorelick, Jerry L.; Yui, Candice; Rax, Bernard G.; Wiedeman, Michael D.

2003-01-01

We present results of continuing efforts to evaluate total dose bias dependency and ELDRS effects in bipolar linear microcircuits. Several devices were evaluated, each exhibiting moderate to significant bias and/or dose rate dependency.

Quantification of rat retinal growth and vascular population changes after single and split doses of proton irradiation: translational study using stereology methods

NASA Technical Reports Server (NTRS)

Mao, Xiao W.; Archambeau, John O.; Kubinova, Lucie; Boyle, Soames; Petersen, Georgia; Grove, Roger; Nelson, G. A. (Principal Investigator)

2003-01-01

This study quantified architectural and population changes in the rat retinal vasculature after proton irradiation using stereology. A 100 MeV conformal proton beam delivered 8, 14, 20 and 28 Gy as single and split doses to the whole eye. The vascular networks were prepared from retinal digests. Stereological methods were used to obtain the area of the retina and unbiased estimates of microvessel/artery/vein endothelial, pericyte and smooth muscle population, and vessel length. The retinal area increased progressively in the unirradiated, age-matched controls and in the retinas irradiated with 8 and 14 Gy, indicating uniform progressive retinal growth. No growth occurred after 20 and 28 Gy. Regression analysis of total endothelial cell number in all vessels (arteries, veins and capillaries) after irradiation documented a progressive time- and dose-dependent cell loss occurring over 15 to 24 months. The difference from controls was significant (P<0.01) after 28 Gy given in single and split doses and after 20 Gy given as a split dose (P<0.05). Total vessel length in microvessel was significantly shortened at 20 and 28 Gy compared to that of controls (P<0.05). No evident dose recovery was observed in the endothelial populations after split doses. At 10 Gy, the rate of endothelial cell loss, a dose parameter used to characterize the time- and dose-dependent loss of the endothelial population, was doubled.

Symptom relief in Parkinson disease by safinamide: Biochemical and clinical evidence of efficacy beyond MAO-B inhibition.

PubMed

Stocchi, F; Vacca, L; Grassini, P; De Pandis, M F; Battaglia, G; Cattaneo, C; Fariello, R G

2006-10-10

In an open pilot study, doses of safinamide (100, 150, and 200 mg once a day, higher than previously tested) were administered to 13 parkinsonian patients along with a stable dose of dopamine (DA) agonist, causing a significant progressive improvement in motor performance as evaluated by the Unified Parkinson Disease Rating Scale (UPDRS) part III over an 8-week period (4.2 points; P < 0.001). In association with levodopa, the same doses of safinamide in another group of patients (N = 11) induced a significant decrease in motor fluctuations (UPDRS part IV, 2.1 points; P < 0.001), accompanied by a dose-proportional increase of the levodopa AUC, up to 77% from baseline. Because MAO-B was fully inhibited (95%) at all doses tested, we suggest that these biochemical and symptomatic dose-dependent effects must be related to additional mechanisms of action, such as inhibition of glutamate release, increased dopamine release, or inhibition of dopamine re-uptake. These hypotheses are under investigation and will pursue confirmation in controlled clinical trials.

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

Safety and tolerability of omecamtiv mecarbil during exercise in patients with ischemic cardiomyopathy and angina.

PubMed

Greenberg, Barry H; Chou, Willis; Saikali, Khalil G; Escandón, Rafael; Lee, Jacqueline H; Chen, Michael M; Treshkur, Tatyana; Megreladze, Irakli; Wasserman, Scott M; Eisenberg, Paul; Malik, Fady I; Wolff, Andrew A; Shaburishvili, Tamaz

2015-01-01

The goal of this study was to assess the safety and tolerability of omecamtiv mecarbil treatment during symptom-limited exercise in patients with ischemic cardiomyopathy and angina. These patients may have increased vulnerability to prolongation of the systolic ejection time. Omecamtiv mecarbil is a selective cardiac myosin activator that augments cardiac contractility in patients with systolic heart failure through a dose-dependent increase in systolic ejection time. In this double-blind, placebo-controlled study, patients with chronic heart failure were randomized 2:1 to receive omecamtiv mecarbil or placebo in 2 sequential cohorts of escalating doses designed to achieve plasma concentrations previously shown to increase systolic function. Patients underwent 2 symptom-limited exercise treadmill tests (ETTs) at baseline (ETT1 and ETT2) and again before the end of a 20-h infusion of omecamtiv mecarbil (ETT3). The primary pre-defined safety endpoint (i.e., the proportion of patients who stopped ETT3 because of angina at a stage earlier than baseline) was observed in 1 patient receiving placebo and none receiving omecamtiv mecarbil. No dose-dependent differences emerged in the proportion of patients stopping ETT3 for any reason or in the pattern of adverse events. Doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise in these study patients with ischemic cardiomyopathy and angina. There was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population. (Pharmacokinetics [PK] and Tolerability of Intravenous [IV] and Oral CK-1827452 in Patients With Ischemic Cardiomyopathy and Angina; NCT00682565). Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Inflammatory biomarkers of sulfur mustard analog 2-chloroethyl ethyl sulfide-induced skin injury in SKH-1 hairless mice.

PubMed

Tewari-Singh, Neera; Rana, Sumeet; Gu, Mallikarjuna; Pal, Arttatrana; Orlicky, David J; White, Carl W; Agarwal, Rajesh

2009-03-01

Sulfur mustard (HD) is an alkylating and cytotoxic chemical warfare agent, which inflicts severe skin toxicity and an inflammatory response. Effective medical countermeasures against HD-caused skin toxicity are lacking due to limited knowledge of related mechanisms, which is mainly attributed to the requirement of more applicable and efficient animal skin toxicity models. Using a less toxic analog of HD, chloroethyl ethyl sulfide (CEES), we identified quantifiable inflammatory biomarkers of CEES-induced skin injury in dose- (0.05-2 mg) and time- (3-168 h) response experiments, and developed a CEES-induced skin toxicity SKH-1 hairless mouse model. Topical CEES treatment at high doses caused a significant dose-dependent increase in skin bi-fold thickness indicating edema. Histopathological evaluation of CEES-treated skin sections revealed increases in epidermal and dermal thickness, number of pyknotic basal keratinocytes, dermal capillaries, neutrophils, macrophages, mast cells, and desquamation of epidermis. CEES-induced dose-dependent increases in epidermal cell apoptosis and basal cell proliferation were demonstrated by the terminal deoxynucleotidyl transferase (tdt)-mediated dUTP-biotin nick end labeling and proliferative cell nuclear antigen stainings, respectively. Following an increase in the mast cells, myeloperoxidase activity in the inflamed skin peaked at 24 h after CEES exposure coinciding with neutrophil infiltration. F4/80 staining of skin integuments revealed an increase in the number of macrophages after 24 h of CEES exposure. In conclusion, these results establish CEES-induced quantifiable inflammatory biomarkers in a more applicable and efficient SKH-1 hairless mouse model, which could be valuable for agent efficacy studies to develop potential prophylactic and therapeutic interventions for HD-induced skin toxicity.

Tamoxifen mutagenesis and carcinogenesis in livers of lambda/lacI transgenic rats: selective influence of phenobarbital promotion.

PubMed

Styles, J A; Davies, R; Fenwick, S; Walker, J; White, I N; Smith, L L

2001-01-10

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to female lambda/lacI transgenic rats caused a 4-fold increase in mutation frequency (MF) at the lacI gene locus in the livers of dosed animals compared with controls. After cessation of dosing, the MF showed a further increase with time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of similarly treated animals resulted in no increase in mutation frequency compared with TAM alone. Treatment with phenobarbital or TAM+phenobarbital resulted in time-dependent increases in liver weight compared with the corresponding controls. There was an increase in cell proliferation in the phenobarbital and TAM+phenobarbital groups, and at 24 weeks in the TAM dosed animals compared with controls. There was also a progressive increase in the number of GST-P expressing foci in the livers of TAM and TAM + phenobarbital rats compared with controls. The induction of cell proliferation and GSTP foci in the rat liver by phenobarbital is consistent with its ability to promote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regarded as being representative of the rat genome in general (albeit that the gene is bacterial) the above observations suggest that promotion by tamoxifen confers selective advantage on mutated genes at loci that contribute to the tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation.

Buprenorphine does not aggravate ischemic neuronal injury in experimental focal cerebral ischemia.

PubMed

Yulug, Burak; Cam, Ertugrul; Yildiz, Aysegul; Kilic, Ertugrul

2007-01-01

Buprenorphine has been increasingly used as maintenance therapy in opioid dependence as an alternative to methadone and other pharmacological therapies. However, available data suggest increased risk of cerebrovascular events in opioid-dependent patients. Therefore, an opioid that provides safety with regard to neurological function should be considered by opioid-dependent patients. The evidence for the in vitro neurotoxic effects of buprenorphine is rapidly increasing. In order to clarify whether buprenorphine is also neurotoxic under the condition of cerebral ischemia in vivo, we applied an acute dose of buprenorphine in a transient model of focal cerebral ischemia in rats. Our study provides preclinical evidence for the usage of buprenorphine during the postoperative period following ischemic events as well as for the maintenance therapy of opioid-dependent patients wherein the risk of cerebrovascular events is increased.

Inhaled nitric oxide in acute respiratory distress syndrome with and without septic shock requiring norepinephrine administration: a dose–response study

PubMed Central

Mourgeon, Eric; Puybasset, Louis; Law-Koune, Jean-Dominique; Lu, Qin; Abdennour, Lamine; Gallart, Lluis; Malassine, Patrick; Rao, GS Umamaheswara; Cluzel, Philippe; Bennani, Abdelhai; Coriat, Pierre; Rouby, Jean-Jacques

1997-01-01

Background: The aim of this prospective study was to assess whether the presence of septic shock could influence the dose response to inhaled nitric oxide (NO) in NO-responding patients with adult respiratory distress syndrome (ARDS). Results: Eight patients with ARDS and without septic shock (PaO2 = 95 ± 16 mmHg, PEEP = 0, FiO2 = 1.0), and eight patients with ARDS and septic shock (PaO2 = 88 ± 11 mmHg, PEEP = 0, FiO2 = 1.0) receiving exclusively norepinephrine were studied. All responded to 15 ppm inhaled NO with an increase in PaO2 of at least 40 mmHg, at FiO2 1.0 and PEEP 10 cmH2O. Inspiratory intratracheal NO concentrations were recorded continuously using a fast response time chemiluminescence apparatus. Seven inspiratory NO concentrations were randomly administered: 0.15, 0.45, 1.5, 4.5, 15, 45 and 150 ppm. In both groups, NO induced a dose-dependent decrease in mean pulmonary artery pressure (MPAP), pulmonary vascular resistance index (PVRI), and venous admixture (QVA/QT), and a dose-dependent increase in PaO2/FiO2 (P ≤ 0.012). Dose-response of MPAP and PVRI were similar in both groups with a plateau effect at 4.5 ppm. Dose-response of PaO2/FiO2 was influenced by the presence of septic shock. No plateau effect was observed in patients with septic shock and PaO2/FiO2 increased by 173 ± 37% at 150 ppm. In patients without septic shock, an 82 ± 26% increase in PaO2/FiO2 was observed with a plateau effect obtained at 15 ppm. In both groups, dose-response curves demonstrated a marked interindividual variability and in five patients pulmonary vascular effect and improvement in arterial oxygenation were dissociated. Conclusion: For similar NOinduced decreases in MPAP and PVRI in both groups, the increase in arterial oxygenation was more marked in patients with septic shock. PMID:11056694

Pharmacological characterisation of a new oral GH secretagogue, NN703.

PubMed

Hansen, B S; Raun, K; Nielsen, K K; Johansen, P B; Hansen, T K; Peschke, B; Lau, J; Andersen, P H; Ankersen, M

1999-08-01

NN703 is a novel orally active GH secretagogue (GHS) derived from ipamorelin. NN703 stimulates GH release from rat pituitary cells in a dose-dependent manner with a potency and efficacy similar to that of GHRP-6. The effect is inhibited by known GHS antagonists, but not by a GH-releasing hormone antagonist. Binding of (35)S-MK677 to the human type 1A GHS receptor (GHS-R 1A) stably expressed on BHK cells was inhibited by GHRP-6 and MK677 as expected. NN703 was also able to inhibit the binding of (35)S-MK677. However, the observed K(i) value was lower than expected, as based on the observed potencies regarding GH release from rat pituitary cells. Similarly, the effect of NN703 on the GHS-R 1A-induced inositol phosphate turnover in these cells showed a lower potency, when compared with GHRP-6 and MK677, than that observed in rat pituitary cells. The effect of i.v. administration of NN703 on GH and cortisol release was studied in swine. The potency and efficacy of NN703 on GH release were determined to be 155+/-23 nmol/kg and 91+/-7 ng GH/ml plasma respectively. A 50% increase of cortisol, compared with basal levels, was observed for all the tested doses of NN703, but no dose-dependency was shown. The effect of NN703 on GH release after i. v. and oral dosing in beagle dogs was studied. NN703 dose-dependently increased the GH release after oral administration. At the highest dose (20 micromol/kg), a 35-fold increase in peak GH concentration was observed (49.5+/-17.8 ng/ml, mean+/-s.e.m.). After a single i.v. dose of 1 micromol/kg the peak GH plasma concentration was elevated to 38.5+/-19.6 ng/ml (mean+/-s.e.m.) approximately 30 min after dosing and returned to basal level after 360 min. The oral bioavailability was 30%. The plasma half-life of NN703 was 4.1+/-0.4 h. A long-term biological effect of NN703 was demonstrated in a rat study, where the body weight gain was measured during a 14-day once daily oral challenge with 100 micromol/kg. The body weight gain was significantly increased after 14 days as compared with a vehicle-treated group. In summary, we here describe an orally active and GH specific secretagogue, NN703. This compound acts through a similar mechanism as GHRP-6, but has a different receptor pharmacology. NN703 induced GH release in both swine and dogs after i.v. and/or p.o. administration, had a high degree of GH specificity in swine and significantly increased the body weight gain in rats.

Field-size dependence of doses of therapeutic carbon beams.

PubMed

Kusano, Yohsuke; Kanai, Tatsuaki; Yonai, Shunsuke; Komori, Masataka; Ikeda, Noritoshi; Tachikawa, Yuji; Ito, Atsushi; Uchida, Hirohisa

2007-10-01

To estimate the physical dose at the center of spread-out Bragg peaks (SOBP) for various conditions of the irradiation system, a semiempirical approach was applied. The dose at the center of the SOBP depends on the field size because of large-angle scattering particles in the water phantom. For a small field of 5 x 5 cm2, the dose was reduced to 99.2%, 97.5%, and 96.5% of the dose used for the open field in the case of 290, 350, and 400 MeV/n carbon beams, respectively. Based on the three-Gaussian form of the lateral dose distributions of the carbon pencil beam, which has previously been shown to be effective for describing scattered carbon beams, we reconstructed the dose distributions of the SOBP beam. The reconstructed lateral dose distribution reproduced the measured lateral dose distributions very well. The field-size dependencies calculated using the reconstructed lateral dose distribution of the therapeutic carbon beam agreed with the measured dose dependency very well. The reconstructed beam was also used for irregularly shaped fields. The resultant dose distribution agreed with the measured dose distribution. The reconstructed beams were found to be applicable to the treatment-planning system.

The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats.

PubMed

Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

2016-01-01

In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system - the thymus and the spleen. The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen-dependent manner.

Discriminative and Reinforcing Stimulus Effects of Nicotine, Cocaine, and Cocaine + Nicotine Combinations in Rhesus Monkeys

PubMed Central

Mello, Nancy K.; Newman, Jennifer L.

2011-01-01

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was two-fold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine’s discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. PMID:21480727