Musculoskeletal imaging with a prototype photon-counting detector.

PubMed

Gruber, M; Homolka, P; Chmeissani, M; Uffmann, M; Pretterklieber, M; Kainberger, F

2012-01-01

To test a digital imaging X-ray device based on the direct capture of X-ray photons with pixel detectors, which are coupled with photon-counting readout electronics. The chip consists of a matrix of 256 × 256 pixels with a pixel pitch of 55 μm. A monolithic image of 11.2 cm × 7 cm was obtained by the consecutive displacement approach. Images of embalmed anatomical specimens of eight human hands were obtained at four different dose levels (skin dose 2.4, 6, 12, 25 μGy) with the new detector, as well as with a flat-panel detector. The overall rating scores for the evaluated anatomical regions ranged from 5.23 at the lowest dose level, 6.32 at approximately 6 μGy, 6.70 at 12 μGy, to 6.99 at the highest dose level with the photon-counting system. The corresponding rating scores for the flat-panel detector were 3.84, 5.39, 6.64, and 7.34. When images obtained at the same dose were compared, the new system outperformed the conventional DR system at the two lowest dose levels. At the higher dose levels, there were no significant differences between the two systems. The photon-counting detector has great potential to obtain musculoskeletal images of excellent quality at very low dose levels.

Predictors of Rectal Tolerance Observed in a Dose-Escalated Phase 1-2 Trial of Stereotactic Body Radiation Therapy for Prostate Cancer

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

Kim, D.W. Nathan; Cho, L. Chinsoo; Straka, Christopher

2014-07-01

Purpose: To convey the occurrence of isolated cases of severe rectal toxicity at the highest dose level tested in 5-fraction stereotactic body radiation therapy (SBRT) for localized prostate cancer; and to rationally test potential causal mechanisms to guide future studies and experiments to aid in mitigating or altogether avoiding such severe bowel injury. Methods and Materials: Clinical and treatment planning data were analyzed from 91 patients enrolled from 2006 to 2011 on a dose-escalation (45, 47.5, and 50 Gy in 5 fractions) phase 1/2 clinical study of SBRT for localized prostate cancer. Results: At the highest dose level, 6.6% ofmore » patients treated (6 of 91) developed high-grade rectal toxicity, 5 of whom required colostomy. Grade 3+ delayed rectal toxicity was strongly correlated with volume of rectal wall receiving 50 Gy >3 cm{sup 3} (P<.0001), and treatment of >35% circumference of rectal wall to 39 Gy (P=.003). Grade 2+ acute rectal toxicity was significantly correlated with treatment of >50% circumference of rectal wall to 24 Gy (P=.010). Conclusion: Caution is advised when considering high-dose SBRT for treatment of tumors near bowel structures, including prostate cancer. Threshold dose constraints developed from physiologic principles are defined, and if respected can minimize risk of severe rectal toxicity.« less

[The radiological situation before and after Chernobyl disaster].

PubMed

Leoniak, Marcin; Zonenberg, Anna; Zarzycki, Wiesław

2006-01-01

The nuclear reactor accident, which occurred on 26 April 1986 at Chernobyl, has been one of the greatest ecological disasters in human history. In our study we discussed the most recent data on the accident, and the natural and synthetic sources of radiation. According to the recent data, the air at Chernobyl had been contaminated with about 5300 PBq radionuclide activity (excluding rare gases), including 1760 PBq (131)I and 85 PBq (137)Cs. The highest radiation received by the liquidators (0.8-16 Gy), lower doses were received by the population which was evacuated or inhabited the contaminated areas (in which the level of (137)Cs activity deposited in the earth was 37 kBq/m(2)). In the European countries the highest mean radiation dose per year for the whole body in the first year after the accident was in Bulgaria (760 microSv), Austria (670 microSv) and Greece (590 microSv), while the lowest radiation dose was observed in Portugal (1.8 microSv) and Spain (4.2 microSv). In Poland the mean effective equivalent dose resulting from Chernobyl accident was 932 microSv and is close to the limited dose permitted in Poland, equalling 1 mSv/year. The highest radiation dose to thyroid was received by inhabitants of the states previously known as Bielskopodlaskie, Nowosadeckie and the north-east region of Poland. Lowest dose was received by inhabitants of the areas previously known as Slupski and Rzeszowski.

Maternal and developmental toxicity of ayahuasca in Wistar rats.

PubMed

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

2010-06-01

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

Oral hypoglycemic activity of culinary-medicinal mushrooms Pleurotus ostreatus and P. cystidiosus (higher basidiomycetes) in normal and alloxan-induced diabetic Wistar rats.

PubMed

Jayasuriya, W J A B; Suresh, T S; Abeytunga, D; Fernando, G H; Wanigatunga, C A

2012-01-01

This study investigates the oral hypoglycemic activity of Pleurotus ostreatus (P.o.) and P. cystidiosus (P.c.) mushrooms on normal and alloxan-induced diabetic Wistar rats. Different doses (250, 500, 750, 1000, and 1250 mg/kg/body weight) of suspensions of freeze-dried and powdered (SFDP) P.o. and P.c. were administered to normal rats, and postprandial serum glucose levels were measured. Optimal time of activity was investigated using the dose 500 mg/kg. Hypoglycemic effect of a single dose of SFDP P.o. and P.c. (500 mg/kg) were investigated using diabetic male and female rats at different stages of estrous cycle and compared with metformin and glibenclamide. Chronic hypoglycemic activity of SFDP P.o. and P.c. (500 mg/kg) was studied using serum glucose levels and glycosylated hemoglobin levels. Maximally effective dose of SFDP P.o. and P.c. was 500 mg/kg. The highest reduction in the serum glucose level was observed 120 minutes after administration of mushrooms. A single dose of P.o. and P.c. significantly (P < 0.05) reduced the serum glucose levels of male diabetic rats. The hypoglycemic activity in female rats was highest in proestrous stage. The hypoglycemic effect of P.o. and P.c. is comparable with metformin and glibenclamide. Daily single administrations of P.o. and P.c. to diabetic rats exert apparent control on the homeostasis of blood glucose. SFDP P.o. and P.c. possessed marked and significant oral hypoglycemic activity. This study suggests the consumption of P.o. and P.c. mushrooms might bring health benefits to mankind as it shows hypoglycemic activity in rats.

Mebendazole paste as an anthelmintic in random source research cats.

PubMed

Bradley, R E; Peters, L J

1982-10-01

Mebendazole paste, administered per os daily for 3 days, at dose levels of 22 mg/kg and 33 mg/kg was highly effective in removing Ancylostoma tubaeforme from naturally infected cats. The 22 mg/kg dose gave the highest efficacy (95.5% critical and 98% controlled). The same product at 11 mg/kg, 22 mg/kg, or 33 mg/kg was 100% effective in removing Toxocara cati from naturally infected cats. Both 11 mg/kg and 22 mg/kg dose levels were highly efficacious against the common tapeworm, Dipylidium caninum. No toxic side effects or clinical illness were observed in any of the cats used in this study.

In vivo antimalarial activity of crude extracts and solvent fractions of leaves of Strychnos mitis in Plasmodium berghei infected mice.

PubMed

Fentahun, Selamawit; Makonnen, Eyasu; Awas, Tesfaye; Giday, Mirutse

2017-01-05

Malaria is a major public health problem in the world which is responsible for death of millions particularly in sub-Saharan Africa. Today, the control of malaria has become gradually more complex due to the spread of drug-resistant parasites. Medicinal plants are the unquestionable source of effective antimalarials. The present study aimed to evaluate antiplasmodial activity and acute toxicity of the plant Strychnos mitis in Plasmodium berghei infected mice. Standard procedures were employed to investigate acute toxicity and 4-day suppressive effect of crude aqueous and hydro-methanolic extracts of the leaves of Strychnos mitis against P. berghei in Swiss albino mice. Water, n-hexane and chloroform fractions, obtained from crude hydro-methanolic extract, were also tested for their suppressive effect against P. berghei. All crude extracts revealed no obvious acute toxicity in mice up to the highest dose administered (2000 mg/kg). All crude and solvent fractions of the leaves of Strychnos mitis inhibited parasitaemia significantly (p < 0.01). At the highest dose of 600 mg/kg, both aqueous and hydro-methanolic extracts demonstrated higher performance with 95.5 and 93.97% parasitaemia suppression, respectively. All doses of crude extracts and fractions of leaves of Strychnos mitis prolonged survival time of infected mice dose dependently. The highest two doses of the crude aqueous and hydro-methanolic extracts, and chloroform and aqueous fractions prevented weight loss in a dose dependent manner. Whereas, all doses of n-hexane fraction prevented loss of body weight but not in a dose dependent manner. The crude aqueous extract at the doses of 400 mg/kg and 600 mg/kg and hydro-methanolic extract at all dose levels significantly (p < 0.01) prevented packed cell volume reduction. Crude aqueous extract at a dose of 600 mg/kg and hydro-methanolic extract at all dose levels significantly prevented temperature reduction. Phytochemical screening of the crude aqueous and hydro-methanolic extracts revealed the presence of alkaloids, anthraquinones, glycosides, terpenoids, saponins, tannins and phenols. The results of this study provide support the traditional therapeutic use of Strychnos mitis for treatment of malaria. However, further in-depth study is needed to evaluate the potential of the plant towards the development of new antimalarial agent.

Estimation of 1945 to 1957 food consumption. Hanford Environmental Dose Reconstruction Project: Draft

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

Anderson, D.M.; Bates, D.J.; Marsh, T.L.

This report details the methods used and the results of the study on the estimated historic levels of food consumption by individuals in the Hanford Environmental Dose Reconstruction (HEDR) study area from 1945--1957. This period includes the time of highest releases from Hanford and is the period for which data are being collected in the Hanford Thyroid Disease Study. These estimates provide the food-consumption inputs for the HEDR database of individual diets. This database will be an input file in the Hanford Environmental Dose Reconstruction Integrated Code (HEDRIC) computer model that will be used to calculate the radiation dose. Themore » report focuses on fresh milk, eggs, lettuce, and spinach. These foods were chosen because they have been found to be significant contributors to radiation dose based on the Technical Steering Panel dose decision level.« less

Estimation of 1945 to 1957 food consumption. Hanford Environmental Dose Reconstruction Project

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

Anderson, D.M.; Bates, D.J.; Marsh, T.L.

This report details the methods used and the results of the study on the estimated historic levels of food consumption by individuals in the Hanford Environmental Dose Reconstruction (HEDR) study area from 1945--1957. This period includes the time of highest releases from Hanford and is the period for which data are being collected in the Hanford Thyroid Disease Study. These estimates provide the food-consumption inputs for the HEDR database of individual diets. This database will be an input file in the Hanford Environmental Dose Reconstruction Integrated Code (HEDRIC) computer model that will be used to calculate the radiation dose. Themore » report focuses on fresh milk, eggs, lettuce, and spinach. These foods were chosen because they have been found to be significant contributors to radiation dose based on the Technical Steering Panel dose decision level.« less

[Personal dose monitoring of radiation workers in medical institutions at the municipal level and below in a city from 2011 to 2014].

PubMed

Wang, C; Mo, S F; Zhang, J B; Li, J R; Huang, R L; Tan, H Y

2017-08-20

Objective: To determine the personal dose level of radiation workers in medical institutions at the municipal level and below in a city, and to provide a scientific support for strengthening the radiation protection in the city's medical institutions. Methods: Information of the successful applicants for the "Radiation Worker Permit" from 174 medical institutions at the municipal level and below was collected from October 1, 2011 to December 31, 2014. The annual effective dose was calculated based on the personal dose monitoring report, and indicators including sex, permit application time, hospital level, type of occupational radiation, length of radiation work, blood test, and micronucleated lymphocyte rate were analyzed. Results: Of the 1 143 radiation worker permit applications submitted by medical institutions the municipal level and below in this city from 2011 to 2014, 1 123 provided at least one personal dose monitoring report. The annual effective dose of the radiation workers was 0-4.76 mSv (mean 0.31±0.40 mSv) , and the collective annual effective dose was 351.96 mSv. The annual effective dose was significantly different between radiation workers with different times of permit application, hospital levels, and types of occupational radiation ( P <0.05) . Interventional radiology workers had the highest annual effective dose (0.63 mSv) , and annual effective dose was significantly different between interventional radiology workers with different lengths of radiation work ( H =10.812, P <0.05) . Conclusion: The personal radiation dose of radiation workers in medical institutions at the municipal level and below in this city is maintained at a relatively low level, suggesting that the occupational environment is relatively safe for these workers. However, more focus should be placed on clinical interventional radiology workers.

Patient doses from chest radiography in Victoria.

PubMed

Cardillo, I; Boal, T J; Einsiedel, P F

1997-06-01

This survey examines doses from PA chest radiography at radiology practices, private hospitals and public hospitals throughout metropolitan and country Victoria. Data were collected from 111 individual X-ray units at 86 different practices. Entrance skin doses in air were measured for exposure factors used by the centre for a 23 cm thick male chest. A CDRH LucA1 chest phantom was used when making these measurements. About half of the centres used grid technique and half used non-grid technique. There was a factor of greater than 10 difference in the entrance dose delivered between the highest dose centre and the lowest dose centre for non-grid centres; and a factor of about 5 for centres using grids. Factors contributing to the high doses recorded at some centres were identified. Guidance levels for chest radiography based on the third quartile value of the entrance doses from this survey have been recommended and compared with guidance levels recommended in other countries.

Embryotoxicity of orally administered chromium in mice: exposure during the period of organogenesis.

PubMed

Junaid, M; Murthy, R C; Saxena, D K

1996-03-01

Administration of chromium (VI)(250, 500 and 750 ppm as potassium dichromate) via drinking water during organogenesis (days 6-14 of gestation) in mice revealed embryo- and fetotoxic effects. Reduced fetal weight, retarded fetal development, number of fetuses (live and dead) per mother and high incidences of dead fetuses and resorptions in treated mothers in the highest dosed group were evident. No significant gross structural abnormalities were observed in any of the fetuses of chromium (VI)-treated mothers. Significant incidences of reduced ossification were found in the highest dosed group. Chromium levels were increased in a dose-dependent manner in maternal blood, placenta and fetuses. The present study suggests a risk to the developing embryo if the mother is exposed to a sufficiently high concentration of chromium (VI) through drinking water during the period of organogenesis.

Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study.

PubMed

Nakamura, M; Ishii, A; Nakahara, D

1998-05-22

In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

Estimation of 1945 to 1957 food consumption

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

Anderson, D.M.; Bates, D.J.; Marsh, T.L.

This report details the methods used and the results of the study on the estimated historic levels of food consumption by individuals in the Hanford Environmental Dose Reconstruction (HEDR) study area from 1945--1957. This period includes the time of highest releases from Hanford and is the period for which data are being collected in the Hanford Thyroid Disease Study. These estimates provide the food-consumption inputs for the HEDR database of individual diets. This database will be an input file in the Hanford Environmental Dose Reconstruction Integrated Code (HEDRIC) computer model that will be used to calculate the radiation dose. Themore » report focuses on fresh milk, eggs, lettuce, and spinach. These foods were chosen because they have been found to be significant contributors to radiation dose based on the Technical Steering Panel dose decision level.« less

Extracellular domain shedding influences specific tumor uptake and organ distribution of the EGFR PET tracer 89Zr-imgatuzumab.

PubMed

Pool, Martin; Kol, Arjan; Lub-de Hooge, Marjolijn N; Gerdes, Christian A; de Jong, Steven; de Vries, Elisabeth G E; Terwisscha van Scheltinga, Anton G T

2016-10-18

Preclinical positron emission tomography (PET) imaging revealed a mismatch between in vivo epidermal growth factor receptor (EGFR) expression and EGFR antibody tracer tumor uptake. Shed EGFR ectodomain (sEGFR), which is present in cancer patient sera, can potentially bind tracer and therefore influence tracer kinetics. To optimize EGFR-PET, we examined the influence of sEGFR levels on tracer kinetics and tumor uptake of EGFR monoclonal antibody 89Zr-imgatuzumab in varying xenograft models. Human cancer cell lines A431 (EGFR overexpressing, epidermoid), A549 and H441 (both EGFR medium expressing, non-small cell lung cancer) were xenografted in mice. Xenografted mice received 10, 25 or 160 μg 89Zr-imgatuzumab, co-injected with equal doses 111In-IgG control. MicroPET scans were made 24, 72 and 144 h post injection, followed by biodistribution analysis. sEGFR levels in liver and plasma samples were determined by ELISA. 89Zr-imgatuzumab uptake in A431 tumors was highest (29.8 ± 5.4 %ID/g) in the 160 μg dose group. Contrary, highest uptake in A549 and H441 tumors was found at the lowest (10 μg) 89Zr-imgatuzumab dose. High 89Zr-imgatuzumab liver accumulation was found in A431 xenografted mice, which decreased with antibody dose increments. 89Zr-imgatuzumab liver uptake in A549 and H441 xenografted mice was low at all doses. sEGFR levels in liver and plasma of A431 bearing mice were up to 1000-fold higher than levels found in A549, H441 and non-tumor xenografted mice. 89Zr-imgatuzumab effectively visualizes EGFR-expressing tumors. High sEGFR levels can redirect 89Zr-imgatuzumab to the liver, in which case tumor visualization can be improved by increasing tracer antibody dose.

Developmental neurotoxicity of Propylthiouracil (PTU) in rats: Relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes

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

Axelstad, Marta; Hansen, Pernille Reimar; Boberg, Julie

2008-10-01

Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation daymore » (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T{sub 4}) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T{sub 4} during development. This supports the hypothesis that decreased T{sub 4} may be a relevant predictor for long-lasting developmental neurotoxicity.« less

Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes.

PubMed

Axelstad, Marta; Hansen, Pernille Reimar; Boberg, Julie; Bonnichsen, Mia; Nellemann, Christine; Lund, Søren Peter; Hougaard, Karin Sørig; Hass, Ulla

2008-10-01

Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation day (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T(4)) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T(4) during development. This supports the hypothesis that decreased T(4) may be a relevant predictor for long-lasting developmental neurotoxicity.

Enantioselective bioaccumulation of diniconazole in Tenebrio molitor larvae.

PubMed

Liu, Chen; LV, Xiao Tian; Zhu, Wen Xue; QU, Hao Yang; Gao, Yong Xin; Guo, Bao Yuan; Wang, Hui Li

2013-12-01

The enantioselective bioaccumulation of diniconazole in Tenebrio molitor Linne larva was investigated with liquid chromatography tandem mass spectrometry based on the ChiralcelOD-3R[cellulose tri-(3,5-dimethylphenyl carbamate)] column. In this study we documented the effects of dietary supplementation with wheat bran contaminated by racemic diniconazole at two dose levels of 20 mg kg(-1) and 2 mg kg(-1) (dry weight) in Tenebrio molitor. The results showed that both doses of diniconazole were taken up by Tenebrio molitor rapidly in the first few days, the concentrations of R-enantiomer and S-enantiomer at high doses reached the highest level of 0.55 mg kg(-1) and 0.48 mg kg(-1) , respectively, on the 1(st) d, and the concentrations of them obtained a maxima of 0.129 mg kg(-1) and 0.128 mg kg(-1) at low dose, respectively, on the 3(rd) d, which means that the concentration of diniconazole was proportional to the time of achieving the highest accumulated level. It afterwards attained equilibrium after a sharp decline at both 20 mg kg(-1) and 2 mg kg(-1) of diniconazole. The determination results from the feces of Tenebrio molitor demonstrated that the extraction recovery (ER) values of the high dose group were higher than that of the low dose group and the values were all above 1; therefore, it could be inferred that enantiomerization existed in Tenebrio molitor. Additionally, the biota accumulation factor was used to evaluate the bioaccumulation of diniconazole enantiomers, showing that the bioaccumulation of diniconazole in Tenebrio molitor was enantioselective with preferential accumulation of S-enantiomer. © 2013 Wiley Periodicals, Inc.

Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies.

PubMed

Jiang, Xiubo; Zhang, Dongfeng; Jiang, Wenjie

2014-02-01

Coffee and caffeine have been linked to type 2 diabetes mellitus (T2DM). A dose-response meta-analysis of prospective studies was conducted to assess the association between coffee and caffeine intake and T2DM incidence. Pertinent studies were identified by a search of PubMed and EMBASE. The fixed- or random-effect pooled measure was selected based on between-study heterogeneity. Dose-response relationship was assessed by restricted cubic spline. Compared with the lowest level, the pooled relative risk (95 % CI) of T2DM was 0.71 (0.67-0.76) for the highest level of coffee intake (26 articles involving 50,595 T2DM cases and 1,096,647 participants), 0.79 (0.69-0.91) for the highest level of decaffeinated coffee intake (10 articles involving 29,165 T2DM cases and 491,485 participants) and 0.70 (0.65-0.75) for the highest level of caffeine intake (6 articles involving 9,302 T2DM cases and 321,960 participants). The association of coffee, decaffeinated coffee and caffeine intake with T2DM incidence was stronger for women than that for men. A stronger association of coffee intake with T2DM incidence was found for non-smokers and subjects with body mass index <25 kg/m(2). Dose-response analysis suggested that incidence of T2DM decreased by 12 % [0.88 (0.86-0.90)] for every 2 cups/day increment in coffee intake, 11 % [0.89 (0.82-0.98)] for every 2 cups/day increment in decaffeinated coffee intake and 14 % [0.86 (0.82-0.91)] for every 200 mg/day increment in caffeine intake. Coffee and caffeine intake might significantly reduce the incidence of T2DM.

Occupational exposure to acrylamide in closed system production plants: air levels and biomonitoring.

PubMed

Moorman, William J; Reutman, Susan S; Shaw, Peter B; Blade, Leo Michael; Marlow, David; Vesper, Hubert; Clark, John C; Schrader, Steven M

2012-01-01

The aim of this study was to evaluate biomarkers of acrylamide exposure, including hemoglobin adducts and urinary metabolites in acrylamide production workers. Biomarkers are integrated measures of the internal dose, and it is total acrylamide dose from all routes and sources that may present health risks. Workers from three companies were studied. Workers potentially exposed to acrylamide monomer wore personal breathing-zone air samplers. Air samples and surface-wipe samples were collected and analyzed for acrylamide. General-area air samples were collected in chemical processing units and control rooms. Hemoglobin adducts were isolated from ethylenediamine teraacetic acid (EDTA)-whole blood, and adducts of acrylamide and glycidamide, at the N-terminal valines of hemoglobin, were cleaved from the protein chain by use of a modified Edman reaction. Full work-shift, personal breathing zone, and general-area air samples were collected and analyzed for particulate and acrylamide monomer vapor. The highest general-area concentration of acrylamide vapor was 350 μg/cm(3) in monomer production. Personal breathing zone and general-area concentrations of acrylamide vapor were found to be highest in monomer production operations, and lower levels were in the polymer production operations. Adduct levels varied widely among workers, with the highest in workers in the monomer and polymer production areas. The acrylamide adduct range was 15-1884 pmol/g; glycidamide adducts ranged from 17.8 to 1376 p/mol/g. The highest acrylamide and glycidamide adduct levels were found among monomer production process operators. The primary urinary metabolite N-acetyl-S-(2-carbamoylethyl) cysteine (NACEC) ranged from the limit of detection to 15.4 μg/ml. Correlation of workplace exposure and sentinel health effects is needed to determine and control safe levels of exposure for regulatory standards.

Dose-response effects of Lepidium meyenii (Maca) aqueous extract on testicular function and weight of different organs in adult rats.

PubMed

Chung, Francisco; Rubio, Julio; Gonzales, Carla; Gasco, Manuel; Gonzales, Gustavo F

2005-04-08

Lepidium meyenii (Brassicaceae) known as Maca grows exclusively between 4000 and 4500 m over the sea level in the Peruvian central Andes. The dried hypocotyls of Maca are traditionally used as food and for its supposed fertility-enhancing properties. A dose-response study was performed to determine the effect of 7 days oral administration of an aqueous lyophilized extract of Maca at 0.01-5 g/kg (corresponding to 0.022-11 g dry hypocotyls of Maca/kg) on body and different organ weights, stages of the seminiferous tubules, epididymal sperm count and motility, and serum testosterone and estradiol levels in rats. In doses up to 5 g extract/kg, no toxicity was observed. Almost all organ weights were similar in controls and in the Maca extract-treated groups. Seminal vesicles weight was significantly reduced at 0.01 and 0.10 g extract/kg. Maca increased in length of stages VII-VIII of the seminiferous tubules in a dose-response fashion, with highest response at 1.0 g/kg, while caput/corpus epididymal sperm count increased at the 1.0 g dose. Cauda epididymal sperm count, sperm motility, and serum estradiol level were not affected at any of the doses studied. Serum testosterone was lower at 0.10 g extract/kg. Low-seminal vesicle weights correlated with low-serum testosterone levels (R2=0.33; P<0.0001) and low-testosterone/estradiol ratio (R2=0.35; P<0.0001). Increase in epididymal sperm count was related to lengths of stages VII-VIII. Highest effect on stages VII-VIII of the seminiferous tubules was observed at 1.0 g Maca aqueous extract/kg. The present study demonstrated that Maca extract in doses up to 5 g/kg (equivalent to the intake of 770 g hypocotyls in a man of 70 kg) was safe and that higher effect on reproductive parameters was elicited with a dose of 1 g extract/kg corresponding to 2.2 g dry Maca hypocotyls/kg.

Impact of Long-Term Serum Platinum Concentrations on Neuro- and Ototoxicity in Cisplatin-Treated Survivors of Testicular Cancer

PubMed Central

Sprauten, Mette; Darrah, Thomas H.; Peterson, Derick R.; Campbell, M. Ellen; Hannigan, Robyn E.; Cvancarova, Milada; Beard, Clair; Haugnes, Hege S.; Fosså, Sophie D.; Oldenburg, Jan; Travis, Lois B.

2012-01-01

Purpose Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its impact on NTX has not been evaluated. Patients and Methods In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, “not at all”; 1, “a little”; 2, “quite a bit”; or 3, “very much.” Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age. Results At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio [OR], 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses. Conclusion Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose. PMID:22184390

Correlation between levels of 2, 5-hexanedione and pyrrole adducts in tissues of rats exposure to n-hexane for 5-days.

PubMed

Yin, Hongyin; Guo, Ying; Zeng, Tao; Zhao, Xiulan; Xie, Keqin

2013-01-01

The formation of pyrrole adducts might be responsible for peripheral nerve injury caused by n-hexane. The internal dose of pyrrole adducts would supply more information for the neurotoxicity of n-hexane. The current study was designed to investigate the tissue distributions of 2, 5-hexanedione (2,5-HD) and pyrrole adducts in rats exposed to n-hexane, and analyze the correlation between pyrrole adducts and 2,5-HD in tissues. Male Wistar rats were given daily dose of 500,1000, 2000, 4000 mg/kg bw n-hexane by gavage for 5 days. The rats were sacrificed 24 hours after the last administration. The levels of 2, 5-hexanedione and pyrrole adducts in tissues were measured by gas chromatography and Ehrlich's reagent, respectively. The correlations between 2, 5-hexanedione and pyrrole adducts were analyzed by linear regression. Dose-dependent effects were observed between the dosage of n-hexane and 2, 5-hexanedione, and pyrrole adducts in tissues. The highest level of 2, 5-hexanedione was found in urine and the lowest in sciatic nerve, while the highest level of pyrrole adducts was seen in liver and the lowest in serum. There were significant correlations among the free 2, 5-hexanedione, total 2, 5-hexanedione and pyrrole adducts within the same tissues. Pyrrole adducts in serum showed the most significant correlation with free 2, 5-hexanedione or pyrrole adducts in tissues. The findings suggested that pyrrole adducts in serum might be a better indicator for the internal dose of free 2, 5-hexanedione and pyrrole adducts in tissues.

Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

PubMed

Fukushima, Shoji; Gi, Min; Kakehashi, Anna; Wanibuchi, Hideki; Matsumoto, Michiharu

2016-05-01

Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Optimal and safe standard doses of midazolam and propofol to achieve patient and doctor satisfaction with dental treatment: A prospective cohort study

PubMed Central

Nonaka, Mutsumi; Nishimura, Akiko; Gotoh, Kinuko; Oka, Shuichirou; Iijima, Takehiko

2017-01-01

Background The incidences of morbidity and mortality caused by pharmacosedation for dental treatment have not yet reached zero. Adverse events are related to inappropriate respiratory management, mostly originating from an overdose of sedatives. Since sedation is utilized for the satisfaction of both the dentist and the patient, the optimal dose should be minimized to prevent adverse events. We attempted to define the optimal doses of midazolam and propofol required to achieve high levels of patient and dentist satisfaction. Methods One thousand dental patients, including those undergoing third molar extractions, were enrolled in this study. A dose of 1 mg of midazolam was administered at 1-minute intervals until adequate sedation was achieved. Propofol was then infused continuously to maintain the sedation level. Both the patients and the dentists were subsequently interviewed and asked to complete a questionnaire. A multivariate logistic regression analysis was used to examine the factors that contributed to patient and dentist satisfaction. Results The peak midazolam dose resulting in the highest percentage of patient satisfaction was 3 mg. Both a lower dose and a higher dose reduced patient satisfaction. Patient satisfaction increased with an increasing dosage of propofol up until 4 mg/kg/hr, reaching a peak of 78.6%. The peak midazolam dose resulting in the highest percentage of dentist satisfaction (78.8%) was 2 mg. Incremental propofol doses reduced dentist satisfaction, in contrast to their effect on patient satisfaction. The strongest independent predictors of patient satisfaction and dentist satisfaction were no intraoperative memory (OR, 5.073; 95% CI, 3.532–7.287; P<0.001) and unintentional movements by the patient (OR, 0.035; 95% CI, 0.012–0.104; P<0.001), respectively. No serious adverse events were reported. Conclusion We found that 3 mg of midazolam and 3 mg/kg/hr of propofol may be the optimal doses for maximizing both patient and dentist satisfaction. Although this level of sedation is relatively light, memory loss and an absence of unintentional patient movements can be expected without adverse events. PMID:28182732

Modulatory effects of naringin on hepatic key enzymes of carbohydrate metabolism in high-fat diet/low-dose streptozotocin-induced diabetes in rats.

PubMed

Pari, Leelavinothan; Chandramohan, Ramasamy

2017-07-01

We evaluated the modulatory effects of naringin on altered hepatic key enzymes of carbohydrate metabolism in high-fat diet/low-dose streptozotocin-induced diabetic rats. Oral treatment of naringin at a doses of 20, 40 and 80 mg/kg body weight to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, blood glycosylated hemoglobin and increase in the levels of plasma insulin and blood hemoglobin. The altered activities of the hepatic key enzymes of carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase, glycogen phosphorylase and glycogen content of diabetic rats were significantly reverted to near normal levels by the treatment of naringin in a dose-dependent manner. Naringin at a dose of 80 mg/kg body weight showed the highest significant effect than the other two doses (20 and 40 mg/kg). Further, immunohistochemical observation of pancreas revealed that naringin-treated diabetic rats showed the increased number of insulin immunoreactive β-cells, which confirmed the biochemical findings. These findings revealed that naringin has potential antihyperglycemic activity in high-fat diet/low-dose streptozotocin-induced diabetic rats.

Occupational exposure due to naturally occurring radionuclide material in granite quarry industry.

PubMed

Ademola, J A

2012-02-01

The potential occupational exposure in granite quarry industry due to the presence of naturally occurring radioactive material (NORM) has been investigated. The activity concentrations of (40)K, (226)Ra and (232)Th were determined using gamma-ray spectroscopy method. The annual effective dose of workers through different exposure pathways was determined by model calculations. The total annual effective dose varied from 21.48 to 33.69 μSv y(-1). Inhalation dose contributes the highest to the total effective dose. The results obtained were much lower than the intervention exemption levels (1.0 mSv y(-1)) given in the International Commission on Radiological Protection Publication 82.

High-dose HOOK effect in urinary DcR2 assay in patients with chronic kidney disease.

PubMed

Chen, Jia; Chen, Ke-Hong; Wang, Li-Ming; Zhang, Wei-Wei; Feng, Lei; Dai, Huan-Zi; He, Ya-Ni

2018-06-05

Urinary DcR2 (uDcR2) is a biomarker for the early detection the tubulointerstitial injury (TII) in patients with chronic kidney disease (CKD), but the high-dose hook effect may lead to falsely low or even negative results when using an enzyme-linked immunosorbent assay (ELISA). This study aimed to investigate if the high-dose hook effect exists with ELISA testing, and to uncover a potential approach for reducing this effect. 72 CKD patients were recruited and categorized into four groups based on TII scores. uDcR2 was measured in undiluted and serially diluted (two-, four-, eight- and 16-fold dilutions) urine using an ELISA kit. The results from the assay were normalized to urinary creatinine. We evaluated the correlation between uDcR2/cre levels at different dilutions and renal histological parameters. Receiver operating characteristic (ROC) curves were generated to examine the value of uDcR2/cre for predicting TII. uDcR2/cre levels in the undiluted urine were significantly higher in patients with CKD than those in the control. However, higher TII scores did not yield higher levels of uDcR2/cre in the undiluted urine. After serial dilution, uDcR2/cre levels were highest with the four-fold dilution. A positive correlation was found between uDcR2/cre levels at different dilutions and TII scores, with the highest correlation coefficient and the largest AUC being observed at the four-fold dilution. The high-dose hook effect was apparent during ELISA testing of uDcR2 in CKD patients, yet dilution of the urine samples neutralized this effect. However, the use of a four-fold dilution of urine for uDcR2/cre testing may eliminate the high-dose hook effect and make it possible to effectively monitor the severity of TII in CKD patients. Copyright © 2018. Published by Elsevier Inc.

Effect of variations in the redox potential of Gleysol on barium mobility and absorption in rice plants.

PubMed

Magalhães, Marcio Osvaldo Lima; Sobrinho, Nelson Moura Brasil do Amaral; Zonta, Everaldo; de Carvalho, Michel Miranda; Tolón-Becerra, Alfredo

2012-09-01

Two assays were designed to obtain information about the influence of redox potential variations on barium mobility and bioavailability in soil. One assay was undertaken in leaching columns, and the other was conducted in pots cultivated with rice (Oryza sativa) using soil samples collected from the surface of Gleysol in both assays. Three doses of barium (100,300 mg kg(-1) and 3000 mg kg(-1)-soil dry weight) and two redox potential values (oxidizing and reducing) were evaluated. During the incubation period, the redox potential (Eh) was monitored in columns and pots until values of -250 mV were reached. After the incubation period, geochemical partitioning was conducted on the barium using the European Communities Bureau of Reference (BCR) method. Rainfall of 200 mm d(-1) was simulated in the columns and in the planting of rice seedlings in the pots. The results of the geochemical partitioning demonstrated that the condition of reduction favors increased barium concentrations in the more labile chemical forms and decreased levels in the chemical forms related to oxides. The highest barium concentrations in leached extracts (3.36 mg L(-1)) were observed at the highest dose and condition of reduction at approximately five times above the drinking water standard. The high concentrations of barium in the soil did not affect plant dry matter production. The highest levels and accumulation of barium in roots, leaves, and grains of rice were found at the highest dose and condition of reduction. These results demonstrate that reduction leads to solubilization of barium sulfate, thereby favoring greater mobility and bioavailability of this element. Copyright © 2012 Elsevier Ltd. All rights reserved.

Comparison of Life-Stage-Dependent Internal Dosimetry for Bisphenol A, Ethinyl Estradiol, a Reference Estrogen, and Endogenous Estradiol to Test an Estrogenic Mode of Action in Sprague Dawley Rats

PubMed Central

Churchwell, Mona I.; Camacho, Luísa; Vanlandingham, Michelle M.; Twaddle, Nathan C.; Sepehr, Estatira; Delclos, K. Barry; Fisher, Jeffrey W.; Doerge, Daniel R.

2014-01-01

Bisphenol A (BPA) was administered by gavage (2.5–300,000 μg/kg body weight (bw)/day) to pregnant Sprague Dawley dams, newborn pups, and continuing into adulthood. Aglycone (i.e., unconjugated and active) and conjugated (i.e., inactive) BPA were evaluated by liquid chromatography electrospray tandem mass spectrometry (LC-ES/MS/MS) in serum to better interpret toxicological endpoints measured in the study. Ethinyl estradiol (EE2, 0.5 and 5 μg/kg bw/day) and the endogenous hormones, 17β-estradiol (E2) and testosterone, were similarly evaluated. Mean BPA aglycone levels in vehicle and naïve control rat serum (0.02–0.5 ng/ml) indicated sample processing artifact, consistent with literature reports of a propensity for postexposure blood contamination by BPA. Direct measurements of BPA-glucuronide in vehicle and naïve control serum (2–10nM) indicated unintentional exposure and metabolism at levels similar to those produced by 2.5 μg/kg bw/day BPA (7–10nM), despite careful attention to potential BPA inputs (diet, drinking water, vehicle, cages, bedding, and dust) and rigorous dosing solution certification and delivery. The source of this exposure could not be identified, but interpretation of the toxicological effects, observed only at the highest BPA doses, was not compromised. Internal exposures to BPA and EE2 aglycones were highest in young rats. When maximal serum concentrations from the two highest BPA doses and both EE2 doses were compared with concurrent levels of endogenous E2, the ERα binding equivalents were similar to or above those of endogenous E2 in male and female rats of all ages tested. Such evaluations of estrogenic internal dosimetry and comprehensive evaluation of contamination impact should aid in extrapolating risks from human BPA exposures. PMID:24496641

Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones, plasma glucose and brain c-fos induction.

PubMed

Rotllant, David; Ons, Sheila; Carrasco, Javier; Armario, Antonio

2002-08-01

Metyrapone, a 11-beta steroid hydroxylase inhibitor that blocks stress-induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstantial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well-characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose-dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos-like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone-induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose-response study of metyrapone-induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.

Mercury Reduces Avian Reproductive Success and Imposes Selection: An Experimental Study with Adult- or Lifetime-Exposure in Zebra Finch

PubMed Central

Varian-Ramos, Claire W.; Swaddle, John P.; Cristol, Daniel A.

2014-01-01

Mercury is a global pollutant that biomagnifies in food webs, placing wildlife at risk of reduced reproductive fitness and survival. Songbirds are the most diverse branch of the avian evolutionary tree; many are suffering persistent and serious population declines and we know that songbirds are frequently exposed to mercury pollution. Our objective was to determine the effects of environmentally relevant doses of mercury on reproductive success of songbirds exposed throughout their lives or only as adults. The two modes of exposure simulated philopatric species versus dispersive species, and are particularly relevant because of the heightened mercury-sensitivity of developing nervous systems. We performed a dosing study with dietary methylmercury in a model songbird species, the zebra finch (Taeniopygia guttata), at doses from 0.3 – 2.4 parts per million. Birds were exposed to mercury either as adults only or throughout their lives. All doses of mercury reduced reproductive success, with the lowest dose reducing the number of independent offspring produced in one year by 16% and the highest dose, representing approximately half the lethal dose for this species, causing a 50% reduction. While mercury did not affect clutch size or survivorship, it had the most consistent effect on the proportion of chicks that fledged from the nest, regardless of mode of exposure. Among birds exposed as adults, mercury caused a steep increase in the latency to re-nest after loss of a clutch. Birds exposed for their entire lifetimes, which were necessarily the offspring of dosed parents, had up to 50% lower reproductive success than adult-exposed birds at low doses of methylmercury, but increased reproductive success at high doses, suggesting selection for mercury tolerance at the highest level of exposure. Our results indicate that mercury levels in prey items at contaminated sites pose a significant threat to populations of songbirds through reduced reproductive success. PMID:24759822

Evaluation of acute and sub-acute toxicity of Pinus eldarica bark extract in Wistar rats

PubMed Central

Ghadirkhomi, Akram; Safaeian, Leila; Zolfaghari, Behzad; Agha Ghazvini, Mohammad Reza; Rezaei, Parisa

2016-01-01

Objective: Pinus eldarica (P. eldarica) is one of the most common pines in Iran which has various bioactive constituents and different uses in traditional medicine. Since there is no documented evidence for P. eldarica safety, the acute and sub-acute oral toxicities of hydroalcoholic extract of P. eldarica bark were investigated in male and female Wistar rats in this study. Materials and Methods: In the acute study, a single dose of extract (2000 mg/kg) was orally administered and animals were monitored for 7 days. In the sub-acute study, repeated doses (125, 250 and 500 mg/kg/day) of the extract were administered for 28 days and biochemical, hematological and histopathological parameters were evaluated. Results: Our results showed no sign of toxicity and no mortality after single or repeated administration of P. eldarica. The median lethal dose (LD50) of P. eldarica was determined to be higher than 2000 mg/kg. The mean body weight and most of the biochemical and hematological parameters showed normal levels. There were only significant decreases in serum triglyceride levels at the doses of 250 and 500 mg/kg of the extract in male rats (p<0.05 and p<0.01, respectively) and in monocyte counts at the highest dose of the extract in both male and female rats (p<0.05). Mild inflammation was also found in histological examination of kidney and liver tissues at the highest dose of extract. Conclusion: Oral administration of the hydroalcoholic extract of P. eldarica bark may be considered as relatively non-toxic particularly at the doses of 125 and 250 mg/kg. PMID:27761426

In vivo anti-psoriatic activity, biodistribution, sub-acute and sub-chronic toxicity studies of orally administered methotrexate loaded chitin nanogel in comparison with methotrexate tablet.

PubMed

Panonnummal, Rajitha; Jayakumar, R; Anjaneyan, Gopikrishnan; Sabitha, M

2018-04-15

The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5.143 mg/kg dose, followed by MTX tablet and are lowest in MCNG at 2.715 mg/kg dose. MCNG at the highest dose of 5.143 mg/kg caused liver, lung and kidney toxicities on sub acute toxicity studies and MTX tablet was found to be toxic on liver and lung on sub chronic toxicity studies. MCNG 2.715 mg/kg was found to be safe on both sub acute and sub chronic administrations, suggesting that it can provide sufficient serum and tissue level of methotrexate necessary to clear psoriatic lesions, without inducing systemic toxicity and expected to be a better alternative for orally administered conventional methotrexate tablet for patients who need systemic medications for psoriasis. Copyright © 2018. Published by Elsevier B.V.

GMP-grade α-TEA lysine salt: a 28-Day oral toxicity and toxicokinetic study with a 28-Day recovery period in Beagle dogs.

PubMed

Guerrouahen, Bella S; Hahn, Tobias; Alderman, Zefora; Curti, Brendan; Urba, Walter; Akporiaye, Emmanuel T

2016-03-08

Alpha-tocopheryloxyacetic acid (α-TEA) is a semi-synthetic derivative of naturally occurring vitamin E (alpha-tocopherol) that can be delivered via an oral route. Preclinical in vitro and in vivo data demonstrated that α-TEA is a potent anti-tumor agent with a safe toxicity profile in mice. We report a comprehensive study to evaluate the toxokinetics of good manufacturing practice (GMP)-grade α-TEA in dogs after daily oral administration for 28 days, followed by a 28-day recovery period. Male and female beagle dogs received capsules of α-TEA Lysine Salt at doses of 100, 300, 1500 mg/kg/day. α-TEA plasma levels were determined by high-performance liquid chromatography (HPLC) with mass spectrometric detection. During the treatment, animals were observe for clinical signs, food consumption, body weight, and subjected to ophthalmoscopic, and electrocardiographic assessments. At the end of the dosing period, blood was taken and toxicokinetic analyses and histopathology assessments were performed when animals were necropsied. Our findings showed that there was no α-TEA-related mortality or moribundity. At the highest dose, increases in white blood cells and fibrinogen levels were observed. These levels returned to normal at the end of the recovery period. Histopathological evaluation of major organs revealed no significant lesions related to α-TEA-treatment. We demonstrate that for designing clinical trials in patients, the highest non-severely toxic dose (HNSTD) of α-TEA is 1500 mg/kg/day in Beagle dogs and this data informed the design of dose-escalation studies of α-TEA in patients with advanced cancer.

Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

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

Laham, S.; Szabo, J.; Long, G.

The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0more » g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.« less

Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS)

PubMed Central

Diamond, David M.

2004-01-01

Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people. PMID:19330152

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

Batal, Mohamed; Département de Toxicologie et Risques Chimiques, Unité de Brûlure Chimique, Institut de Recherche Biomédicale des Armées, Antenne de La Tronche, BP87, F-38702 La Tronche Cedex; Boudry, Isabelle

Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, andmore » liver of SKH-1 mice cutaneously exposed to 2, 6 and 60 mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target. - Highlights: • Sulphur mustard reaches internal organs after skin exposure • Adducts are detected in the DNA of internal organs • Brain is the organ with the highest level of DNA damage • The barrier function of skin is lost at high dose of sulphur mustard • DNA adducts persist in organs for 2 or 3 weeks.« less

Radiation exposure to nuclear medicine staffs during 18F-FDG PET/CT procedures at Ramathibodi Hospital

NASA Astrophysics Data System (ADS)

Donmoon, T.; Chamroonrat, W.; Tuntawiroon, M.

2016-03-01

The aim of this study is to estimate the whole body and finger radiation doses per study received by nuclear medicine staff involved in dispensing, administration of 18F-FDG and interacting with radioactive patients during PET/CT imaging procedures in a PET/CT facility. The whole-body doses received by radiopharmacists, technologists and nurses were measured by electronic dosimeter and the finger doses by ring dosimeter during a period of 4 months. In 70 PET/CT studies, the mean whole-body dose per study to radiopharmacist, technologist, and nurse were 1.07±0.09, 1.77±0.46, μSv, and not detectable respectively. The mean finger doses per study received by radiopharmacist, technologist, and nurse were 265.65±107.55, 4.84±1.08 and 19.22±2.59 μSv, respectively. The average time in contact with 18F-FDG was 5.88±0.03, 39.06±1.89 and 1.21±0.02 minutes per study for radiopharmacist, technologist and nurse respectively. Technologists received highest mean effective whole- body dose per study and radiopharmacist received the highest finger dose per study. When compared with the ICRP dose limit, each individual worker can work with many more 18F- FDG PET/CT studies for a whole year without exceeding the occupational dose limits. This study confirmed that low levels of radiation does are received by our medical personnel involved in 18F-FDG PET/CT procedures.

Evaluation of clinical hypothyroidism risk due to irradiation of thyroid and pituitary glands in radiotherapy of nasopharyngeal cancer patients.

PubMed

Lin, Zhixiong; Wang, Xiaoyan; Xie, Wenjia; Yang, Zhining; Che, Kaijun; Wu, Vincent W C

2013-12-01

Radiation-induced thyroid dysfunction after radiotherapy for nasopharyngeal cancer (NPC) has been reported. This study investigated the radiation effects of the thyroid and pituitary glands on thyroid function after radiotherapy for NPC. Sixty-five NPC patients treated with radiotherapy were recruited. Baseline thyroid hormone levels comprising free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) were taken before treatment and at 3, 6, 12 and 18 months. A seven-beam intensity-modulated radiotherapy plan was generated for each patient. Thyroid and pituitary gland dose volume histograms were generated, dividing the patients into four groups: high (>50 Gy) thyroid and pituitary doses (HTHP group); high thyroid and low pituitary doses (HTLP group); low thyroid and high pituitary doses; and low thyroid and pituitary doses. Incidence of hypothyroidism was analysed. Twenty-two (34%) and 17 patients (26%) received high mean thyroid and pituitary doses, respectively. At 18 months, 23.1% of patients manifested various types of hypothyroidism. The HTHP group showed the highest incidence (83.3%) of hypothyroidism, followed by the HTLP group (50%). NPC patients with high thyroid and pituitary gland doses carried the highest risk of abnormal thyroid physiology. The dose to the thyroid was more influential than the pituitary dose at 18 months after radiotherapy, and therefore more attention should be given to the thyroid gland in radiotherapy planning. © 2013 The Royal Australian and New Zealand College of Radiologists.

Association between physical activity and risk of nonalcoholic fatty liver disease: a meta-analysis.

PubMed

Qiu, Shanhu; Cai, Xue; Sun, Zilin; Li, Ling; Zügel, Martina; Steinacker, Jürgen Michael; Schumann, Uwe

2017-09-01

Increased physical activity (PA) is a key element in the management of patients with nonalcoholic fatty liver disease (NAFLD); however, its association with NAFLD risk has not been systematically assessed. This meta-analysis of observational studies was to quantify this association with dose-response analysis. Electronic databases were searched to January 2017 for studies of adults reporting the risk of NAFLD in relation to PA with cohort or case-control designs. Studies that reported sex-specific data were included as separate studies. The overall risk estimates were pooled using a random-effects model, and the dose-response analysis was conducted to shape the quantitative relationship. A total of 6 cohort studies from 5 articles with 32,657 incident NAFLD cases from 142,781 participants, and 4 case-control studies from 3 articles with 382 NAFLD cases and 302 controls were included. Compared with the lowest PA level, the highest PA level was associated with a risk reduction of NAFLD in cohort [RR (risk ratio) 0.79, 95% CI (confidence interval) 0.71-0.89] and case-control studies [OR (odds ratio) 0.43, 95% CI 0.27-0.68]. For cohort studies, both highest and moderate PA levels were superior to the light one in lowering NAFLD risk ( p for interaction = 0.006 and 0.02, respectively), and there was a log-linear dose-response association ( p for nonlinearity = 0.10) between PA and NAFLD risk [RR 0.82 (95% CI 0.73-0.91) for every 500 metabolic equivalent (MET)-minutes/week increment in PA]. Increased PA may lead to a reduced risk of NAFLD in a dose-dependent manner, and the current guideline-recommended minimum PA level that approximates to 500 MET-minutes/week is able to moderately reduce the NAFLD risk.

Correlation between Levels of 2, 5-Hexanedione and Pyrrole Adducts in Tissues of Rats Exposure to n-Hexane for 5-Days

PubMed Central

Yin, Hongyin; Guo, Ying; Zeng, Tao; Zhao, Xiulan; Xie, Keqin

2013-01-01

Background The formation of pyrrole adducts might be responsible for peripheral nerve injury caused by n-hexane. The internal dose of pyrrole adducts would supply more information for the neurotoxicity of n-hexane. The current study was designed to investigate the tissue distributions of 2, 5-hexanedione (2,5-HD) and pyrrole adducts in rats exposed to n-hexane, and analyze the correlation between pyrrole adducts and 2,5-HD in tissues. Methods Male Wistar rats were given daily dose of 500,1000, 2000, 4000 mg/kg bw n-hexane by gavage for 5 days. The rats were sacrificed 24 hours after the last administration. The levels of 2, 5-hexanedione and pyrrole adducts in tissues were measured by gas chromatography and Ehrlich’s reagent, respectively. The correlations between 2, 5-hexanedione and pyrrole adducts were analyzed by linear regression Results Dose-dependent effects were observed between the dosage of n-hexane and 2, 5-hexanedione, and pyrrole adducts in tissues. The highest level of 2, 5-hexanedione was found in urine and the lowest in sciatic nerve, while the highest level of pyrrole adducts was seen in liver and the lowest in serum. There were significant correlations among the free 2, 5-hexanedione, total 2, 5-hexanedione and pyrrole adducts within the same tissues. Pyrrole adducts in serum showed the most significant correlation with free 2, 5-hexanedione or pyrrole adducts in tissues. Conclusion The findings suggested that pyrrole adducts in serum might be a better indicator for the internal dose of free 2, 5-hexanedione and pyrrole adducts in tissues. PMID:24098756

Dissociation of a ferric maltol complex and its subsequent metabolism during absorption across the small intestine of the rat.

PubMed Central

Barrand, M. A.; Callingham, B. A.; Dobbin, P.; Hider, R. C.

1991-01-01

1. The fate and disposition of [59Fe]-ferric [3H]-maltol after intravenous administration were investigated in anaesthetized rats. Immediate dissociation of ferric iron from maltol took place in the circulation even with high doses of ferric maltol (containing 1 mg elemental iron). In plasma samples withdrawn within 1 min of injection and subjected to gel filtration, 59Fe eluted with the high molecular weight proteins whilst the tritium was associated with low molecular weight material. 2. The rates of elimination of 59Fe and of tritium from the plasma and their ultimate fate were very different. The half life for 59Fe in the plasma was around 70 min and 59Fe appeared mainly in the bone marrow and liver. There was an initial rapid exit of tritium from the plasma with a half life of around 12 min. This was followed either by a plateau or by a rise in tritium levels, involving entry of maltol metabolites into the circulation. These metabolites could be recovered in the urine. 3. Entry of 59Fe and of tritium into the blood plasma after intraduodenal administration of [59Fe]-ferric [3H]-maltol was also very different. At low doses of ferric maltol (containing 100 micrograms elemental iron), the tritium appeared in the plasma in highest amounts within seconds and then decreased whilst there was a slow rise in 59Fe levels. At higher doses of ferric maltol (containing 7 mg elemental iron), levels of 59Fe in the plasma were highest at 5 min and then fell whereas tritium levels rose steadily. Mucosal processing of 59Fe prevented further entry of iron at high dose into the circulation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1364845

IL-33 stimulates expression of the GPR84 (EX33) fatty acid receptor gene and of cytokine and chemokine genes in human adipocytes.

PubMed

Zaibi, Mohamed S; Kępczyńska, Małgorzata A; Harikumar, Parvathy; Alomar, Suliman Y; Trayhurn, Paul

2018-05-15

Expression of GPCR fatty acid sensor/receptor genes in adipocytes is modulated by inflammatory mediators, particularly IL-1β. In this study we examined whether the IL-1 gene superfamily member, IL-33, also regulates expression of the fatty acid receptor genes in adipocytes. Human fat cells, differentiated from preadipocytes, were incubated with IL-33 at three different dose levels for 3 or 24 h and mRNA measured by qPCR. Treatment with IL-33 induced a dose-dependent increase in GPR84 mRNA at 3 h, the level with the highest dose being 13.7-fold greater than in controls. Stimulation of GPR84 expression was transitory; the mRNA level was not elevated at 24 h. In contrast to GPR84, IL-33 had no effect on GPR120 expression. IL-33 markedly stimulated expression of the IL1B, CCL2, IL6, CXCL2 and CSF3 genes, but there was no effect on ADIPOQ expression. The largest effect was on CSF3, the mRNA level of which increased 183-fold over controls at 3 h with the highest dose of IL-33; there was a parallel increase in the secretion of G-CSF protein into the medium. It is concluded that in human adipocytes IL-33, which is synthesised in adipose tissue, has a strong stimulatory effect on the expression of cytokine and chemokine genes, particularly CSF3, and on the expression of GPR84, a pro-inflammatory fatty acid receptor. Copyright © 2018 Elsevier Ltd. All rights reserved.

Preclinical toxicity profile of oral bilastine.

PubMed

Lucero, María Luisa; Arteche, Joseba K; Sommer, E W; Casadesus, Agustín

2012-06-01

As part of the bilastine development program, and as mandated by regulatory authorities, several studies were performed with oral bilastine in different animal species to evaluate its toxicity profile. Toxicokinetic analyses conducted in tandem to evaluate systemic exposure, gender differences, and dose proportionality in the different animal species indicated that animals were systemically exposed to bilastine during treatment. Repeated-dose toxicity studies in beagle dogs (52 weeks) and in rats and mice (13 weeks) showed that bilastine at doses up to 2,000 mg/kg/day was not associated with any mortality, ocular effects, or nodules/masses. Likewise, no bilastine-associated neoplastic lesions were observed in rats and mice after 104 weeks of treatment with bilastine at doses up to 2,000 mg/kg/day. In general, bilastine-related clinical signs, body-weight changes, food consumption, clinical chemistry, haematology, and macro- and microscopic findings were of low order and reversible, with effects present only at the highest doses administered. Bilastine (up to 1,000 mg/kg/day) was well tolerated in pregnant/lactating rats and in their offspring and subsequent generations. With respect to effects on embryofoetal development in rabbits, bilastine at 400 mg/kg/day (the highest dose evaluated) was assessed to be the no observed adverse effects level. Overall, bilastine demonstrated a favorable toxicity profile in all animal models investigated and at higher doses than the corresponding recommended daily human dosage.

Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.

PubMed

Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas; Rosthøj, Susanne; Nersting, Jacob

2015-05-01

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

Safety of fluralaner chewable tablets (BravectoTM), a novel systemic antiparasitic drug, in dogs after oral administration

PubMed Central

2014-01-01

Background Fluralaner is a novel systemic insecticide and acaricide that provides long acting efficacy in dogs after a single oral treatment. This study investigated the safety of oral administration of fluralaner in chewable tablets to dogs at the highest recommended treatment dose and at multiples of this dose. Methods Thirty-two (16 male and 16 female) healthy 8-week old Beagle dogs weighing 2.0 - 3.6 kg at first administration were included in the study. Fluralaner was administered on three occasions at 8-week intervals at doses of up to 56, 168, and 280 mg fluralaner/kg body weight, equivalent to 1, 3, and 5 times the highest recommended treatment dose of fluralaner; sham dosed dogs served as controls. During the study, all dogs were clinically observed, and their health was carefully monitored including body weight development, food consumption and measurement of hematology, coagulation, clinical chemistry (including measurement of levels of ACTH and C-reactive protein) and urinalysis. Following euthanasia of the dogs, complete gross post mortem examination, including organ weight determination, and histopathological examination of multiple tissues were conducted. Results There were no clinical findings related to fluralaner treatment. Statistically significant differences between the treated groups and the control group were observed for some clinical pathology parameters and organ weights; none of these findings were considered to be of clinical relevance. Conclusions Oral administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-week intervals is well tolerated and has a safety margin of more than five in healthy dogs eight weeks of age or older and weighing at least 2 kg. PMID:24606886

Fourth ventricular thyrotropin induces satiety and increases body temperature in rats.

PubMed

Smedh, Ulrika; Scott, Karen A; Moran, Timothy H

2018-05-01

Besides its well-known action to stimulate thyroid hormone release, thyrotropin mRNA is expressed within the brain, and thyrotropin and its receptor have been shown to be present in brain areas that control feeding and gastrointestinal function. Here, the hypothesis that thyrotropin acts on receptors in the hindbrain to alter food intake and/or gastric function was tested. Fourth ventricular injections of thyrotropin (0.06, 0.60, and 6.00 µg) were given to rats with chronic intracerebroventricular cannulas aimed at the fourth ventricle. Thyrotropin produced an acute reduction of sucrose intake (30 min). The highest dose of thyrotropin caused inhibition of overnight solid food intake (22 h). In contrast, subcutaneous administration of corresponding thyrotropin doses had no effect on nutrient intake. The highest effective dose of fourth ventricular thyrotropin (6 µg) did not produce a conditioned flavor avoidance in a standardized two-bottle test, nor did it affect water intake or gastric emptying of glucose. Thyrotropin injected in the fourth ventricle produced a small but significant increase in rectal temperature and lowered plasma levels of tri-iodothyronin but did not affect plasma levels of thyroxine. In addition, there was a tendency toward a reduction in blood glucose 2 h after fourth ventricular thyrotropin injection ( P = 0.056). In conclusion, fourth ventricular thyrotropin specifically inhibits food intake, increases core temperature, and lowers plasma levels of tri-iodothyronin but does not affect gastromotor function.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis.

PubMed

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra/rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept [corrected]. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs.

Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis

PubMed Central

Tvete, Ingunn Fride; Natvig, Bent; Gåsemyr, Jørund; Meland, Nils; Røine, Marianne; Klemp, Marianne

2015-01-01

Rheumatoid arthritis patients have been treated with disease modifying anti-rheumatic drugs (DMARDs) and the newer biologic drugs. We sought to compare and rank the biologics with respect to efficacy. We performed a literature search identifying 54 publications encompassing 9 biologics. We conducted a multiple treatment comparison regression analysis letting the number experiencing a 50% improvement on the ACR score be dependent upon dose level and disease duration for assessing the comparable relative effect between biologics and placebo or DMARD. The analysis embraced all treatment and comparator arms over all publications. Hence, all measured effects of any biologic agent contributed to the comparison of all biologic agents relative to each other either given alone or combined with DMARD. We found the drug effect to be dependent on dose level, but not on disease duration, and the impact of a high versus low dose level was the same for all drugs (higher doses indicated a higher frequency of ACR50 scores). The ranking of the drugs when given without DMARD was certolizumab (ranked highest), etanercept, tocilizumab/ abatacept and adalimumab. The ranking of the drugs when given with DMARD was certolizumab (ranked highest), tocilizumab, anakinra, rituximab, golimumab/ infliximab/ abatacept, adalimumab/ etanercept. Still, all drugs were effective. All biologic agents were effective compared to placebo, with certolizumab the most effective and adalimumab (without DMARD treatment) and adalimumab/ etanercept (combined with DMARD treatment) the least effective. The drugs were in general more effective, except for etanercept, when given together with DMARDs. PMID:26356639

Out-of-field doses and neutron dose equivalents for electron beams from modern Varian and Elekta linear accelerators.

PubMed

Cardenas, Carlos E; Nitsch, Paige L; Kudchadker, Rajat J; Howell, Rebecca M; Kry, Stephen F

2016-07-08

Out-of-field doses from radiotherapy can cause harmful side effects or eventually lead to secondary cancers. Scattered doses outside the applicator field, neutron source strength values, and neutron dose equivalents have not been broadly investigated for high-energy electron beams. To better understand the extent of these exposures, we measured out-of-field dose characteristics of electron applicators for high-energy electron beams on two Varian 21iXs, a Varian TrueBeam, and an Elekta Versa HD operating at various energy levels. Out-of-field dose profiles and percent depth-dose curves were measured in a Wellhofer water phantom using a Farmer ion chamber. Neutron dose was assessed using a combination of moderator buckets and gold activation foils placed on the treatment couch at various locations in the patient plane on both the Varian 21iX and Elekta Versa HD linear accelerators. Our findings showed that out-of-field electron doses were highest for the highest electron energies. These doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. The Elekta linear accelerator had higher electron out-of-field doses than the Varian units examined, and the Elekta dose profiles exhibited a second dose peak about 20 to 30 cm from central-axis, which was found to be higher than typical out-of-field doses from photon beams. Electron doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. With respect to neutron dosimetry, Q values and neutron dose equivalents increased with electron beam energy. Neutron contamination from electron beams was found to be much lower than that from photon beams. Even though the neutron dose equivalent for electron beams represented a small portion of neutron doses observed under photon beams, neutron doses from electron beams may need to be considered for special cases.

Variation of radiation level and radionuclide enrichment in high background area.

PubMed

Shetty, P K; Narayana, Y

2010-12-01

Significantly high radiation level and radionuclide concentration along Quilon beach area of coastal Kerala have been reported by several investigators. Detailed gamma radiation level survey was carried out using a portable scintillometer. Detailed studies on radionuclides concentration in different environmental matrices of high background areas were undertaken in the coastal areas of Karunagapalli, Kayankulam, Chavara, Neendakara and Kollam to study the distribution and enrichment of the radionuclides in the region. The absorbed gamma dose rates in air in high background area are in the range 43-17,400nGyh⁻¹. Gamma radiation level is found to be maximum at a distance of 20m from the sea waterline in all beaches. The soil samples collected from different locations were analysed for primordial radionuclides by gamma spectrometry. The activity of primordial radionuclides was determined for the different size fractions of soil to study the enrichment pattern. The highest activity of (232)Th and (226)Ra was found to be enriched in 125-63μ size fraction. The preferential accumulation of (40)K was found in <63μ fraction. The minimum (232)Th activity was 30.2Bqkg⁻¹, found in 1000-500μ particle size fraction at Kollam and maximum activity of 3250.4Bqkg⁻¹ was observed in grains of size 125-63μ at Neendakara. The lowest (226)Ra activity observed was 33.9Bqkg⁻¹ at Neendakara in grains of size 1000-500μ and the highest activity observed was 482.6Bqkg⁻¹ in grains of size 125-63μ in Neendakara. The highest (40)K activity found was 1923Bqkg⁻¹ in grains of size <63μ for a sample collected from Neendakara. A good correlation was observed between computed dose and measured dose in air. The correlation between (232)Th and (226)Ra was also moderately high. The results of these investigations are presented and discussed in this paper. Copyright © 2010 Elsevier Ltd. All rights reserved.

Patterns of prednisone use during pregnancy in women with rheumatoid arthritis: Daily and cumulative dose.

PubMed

Palmsten, Kristin; Rolland, Matthieu; Hebert, Mary F; Clowse, Megan E B; Schatz, Michael; Xu, Ronghui; Chambers, Christina D

2018-04-01

To characterize prednisone use in pregnant women with rheumatoid arthritis using individual-level heat-maps and clustering individual trajectories of prednisone dose, and to evaluate the association between prednisone dose trajectory groups and gestational length. This study included pregnant women with rheumatoid arthritis who enrolled in the MotherToBaby Autoimmune Diseases in Pregnancy Study (2003-2014) before gestational week 20 and reported prednisone use without another oral glucocorticoid during pregnancy (n = 254). Information on medication use and pregnancy outcomes was collected by telephone interview plus by medical record review. Prednisone daily dose and cumulative dose were plotted by gestational day using a heat map for each individual. K-means clustering was used to cluster individual trajectories of prednisone dose into groups. The associations between trajectory group and demographics, disease severity measured by the Health Assessment Questionnaire at enrollment, and gestational length were evaluated. Women used prednisone 3 to 292 days during pregnancy, with daily doses ranging from <1 to 60 mg. Total cumulative dose ranged from 8 to 6225 mg. Disease severity, non-biologic disease modifying anti-rheumatic drug use, and gestational length varied significantly by trajectory group. After adjusting for disease severity, non-biologic disease modifying anti-rheumatic drug use, and other covariates, the highest vs lowest daily dose trajectory group was associated with reduced gestational age at delivery (β: -2.3 weeks (95%: -3.4, -1.3)), as was the highest vs lowest cumulative dose trajectory group (β: -2.6 weeks (95%: -3.6, -1.5)). In pregnant women with rheumatoid arthritis, patterns of higher prednisone dose were associated with shorter gestational length compared with lower dose. Copyright © 2018 John Wiley & Sons, Ltd.

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

Sun, Li-Min, E-mail: limin.sun@yahoo.com; Huang, Chih-Jen; Faculty of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan

Acute skin reaction during adjuvant radiotherapy for breast cancer is an inevitable process, and its severity is related to the skin dose. A high–skin dose area can be speculated based on the isodose distribution shown on a treatment planning. To determine whether treatment planning can reflect high–skin dose location, 80 patients were collected and their skin doses in different areas were measured using a thermoluminescent dosimeter to locate the highest–skin dose area in each patient. We determined whether the skin dose is consistent with the highest-dose area estimated by the treatment planning of the same patient. The χ{sup 2} andmore » Fisher exact tests revealed that these 2 methods yielded more consistent results when the highest-dose spots were located in the axillary and breast areas but not in the inframammary area. We suggest that skin doses shown on the treatment planning might be a reliable and simple alternative method for estimating the highest skin doses in some areas.« less

Subacute toxicity of the mycotoxin cyclopiazonic acid.

PubMed

van Rensburg, S J

1984-12-01

Cyclopiazonic acid (CA) is known to contaminate processed foods, maize and peanuts. Since previously available toxicity data were limited to the effects of single doses, Wistar-derived rats were given weekly doses of 0, 12 or 21 mg CA/kg body weight in 1 N-sodium bicarbonate, using a dosage volume of 2.5 ml/kg body weight, and subgroups of eight were killed 1 wk after doses 2, 5, 9 and 14. Males on the highest dose level showed mild growth retardation initially and 25% died suddenly during wk 4. No abnormal signs were observed in the surviving males or in any of the females throughout the 15 wk of the experiment. CA induced mild cellular degenerative changes in the myocardium and in several other organs where ballooning of nuclei, especially in ductal epithelia, was also characteristic. The changes were only weakly related to dose level, sex and the number of doses given. The findings suggest that CA is probably a metabolic inhibitor requiring considerable concentrations to exert toxicity. The limited data currently available do not elicit concern in terms of human risk or warrant any particular control procedures.

Assessment of relative potential for Legionella species or surrogates inhalation exposure from common water uses.

PubMed

Hines, Stephanie A; Chappie, Daniel J; Lordo, Robert A; Miller, Brian D; Janke, Robert J; Lindquist, H Alan; Fox, Kim R; Ernst, Hiba S; Taft, Sarah C

2014-06-01

The Legionella species have been identified as important waterborne pathogens in terms of disease morbidity and mortality. Microbial exposure assessment is a tool that can be utilized to assess the potential of Legionella species inhalation exposure from common water uses. The screening-level exposure assessment presented in this paper developed emission factors to model aerosolization, quantitatively assessed inhalation exposures of aerosolized Legionella species or Legionella species surrogates while evaluating two generalized levels of assumed water concentrations, and developed a relative ranking of six common in-home uses of water for potential Legionella species inhalation exposure. Considerable variability in the calculated exposure dose was identified between the six identified exposure pathways, with the doses differing by over five orders of magnitude in each of the evaluated exposure scenarios. The assessment of exposure pathways that have been epidemiologically associated with legionellosis transmission (ultrasonic and cool mist humidifiers) produced higher estimated inhalation exposure doses than pathways where epidemiological evidence of transmission has been less strong (faucet and shower) or absent (toilets and therapy pool). With consideration of the large uncertainties inherent in the exposure assessment process used, a relative ranking of exposure pathways from highest to lowest exposure doses was produced using culture-based measurement data and the assumption of constant water concentration across exposure pathways. In this ranking, the ultrasonic and cool mist humidifier exposure pathways were estimated to produce the highest exposure doses, followed by the shower and faucet exposure pathways, and then the toilet and therapy pool exposure pathways. Published by Elsevier Ltd.

Population Pharmacokinetics of Enoxaparin in Pediatric Patients.

PubMed

Moffett, Brady S; Lee-Kim, YoungNa; Galati, Marianne; Mahoney, Donald; Shah, Mona D; Teruya, Jun; Yee, Donald

2018-02-01

There are no studies evaluating the pharmacokinetics of enoxaparin in the hospitalized pediatric patient population. To characterize the pharmacokinetics of enoxaparin in pediatric patients. A retrospective review of inpatients 1 to 18 years of age admitted to our institution who received enoxaparin with anti-factor Xa activity level monitoring was performed. Demographic variables, enoxaparin dosing, and anti-factor Xa activity levels were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. Simulation (n = 10 000) was performed to determine the percentage who achieved targeted anti-Xa levels at various doses. A total of 853 patients (male 52.1%, median age = 12.2 years; interquartile range [IQR] = 4.6-15.8 years) received a mean enoxaparin dose of 0.86 ± 0.31 mg/kg/dose. A median of 3 (IQR = 1-5) anti-factor Xa levels were sampled at 4.4 ± 1.3 hours after a dose, with a mean anti-factor Xa level of 0.52 ± 0.23 U/mL. A 1-compartment model best fit the data, and significant covariates included allometrically scaled weight, serum creatinine, and hematocrit on clearance, and platelets on volume of distribution. Simulations were run for patients both without and with reduced kidney function (creatinine clearance of ≤30 mL/min/1.73 m 2 ). A dose of 1 mg/kg/dose every 12 hours had the highest probability (72.3%) of achieving an anti-Xa level within the target range (0.5-1 U/mL), whereas a dose reduction of ~30% achieved the same result in patients with reduced kidney function. Pediatric patients should initially be dosed at 1-mg/kg/dose subcutaneously every 12 hours for treatment of thromboembolism followed by anti-Xa activity monitoring. Dose reductions of ~30% for creatinine clearance ≤30 mL/min/1.73 m 2 are required.

Stress, Chemical Defense Agents and Cholinergic Receptors

DTIC Science & Technology

1989-11-30

reasons: I) Bused on the observations of Dam et al. (1982), i.e., low-dose oxotremorine activation of cerebral glucose utilization in cortical layers IVNb...QNB Lower: Localization of the binding of 2.0 nM ( H]- Oxotremorine -M The highest levels of binding for both radioligands are observed in the cerebral

Acute and Short-Term Inhalation Toxicity Study of FT Fuel

DTIC Science & Technology

2011-02-01

Nasopharyngeal duct goblet cell hypertrophy/hyperplasia is evident in both sexes of rats exposed to the two highest doses of jet fuel. 47 Distribution A...findings in lung, nose and liver and, in male rats, kidneys. Inflammatory foci were evident in the lungs of both sexes of rat exposed to the two...highest doses of jet fuel. Olfactory epithelial degeneration was evident in both sexes of rats exposed to the two highest doses of jet fuel. An

Ingestion dose from 238U, 232Th, 226Ra, 40K and 137Cs in cereals, pulses and drinking water to adult population in a high background radiation area, Odisha, India.

PubMed

Lenka, Pradyumna; Sahoo, S K; Mohapatra, S; Patra, A C; Dubey, J S; Vidyasagar, D; Tripathi, R M; Puranik, V D

2013-03-01

A natural high background radiation area is located in Chhatrapur, Odisha in the eastern part of India. The inhabitants of this area are exposed to external radiation levels higher than the global average background values, due to the presence of uranium, thorium and its decay products in the monazite sands bearing placer deposits in its beaches. The concentrations of (232)Th, (238)U, (226)Ra, (40)K and (137)Cs were determined in cereals (rice and wheat), pulses and drinking water consumed by the population residing around this region and the corresponding annual ingestion dose was calculated. The annual ingestion doses from cereals, pulses and drinking water varied in the range of 109.4-936.8, 10.2-307.5 and 0.5-2.8 µSv y(-1), respectively. The estimated total annual average effective dose due to the ingestion of these radionuclides in cereals, pulses and drinking water was 530 µSv y(-1). The ingestion dose from cereals was the highest mainly due to a high consumption rate. The highest contribution of dose was found to be from (226)Ra for cereals and drinking water and (40)K was the major dose contributor from the intake of pulses. The contribution of man-made radionuclide (137)Cs to the total dose was found to be minimum. (226)Ra was found to be the largest contributor to ingestion dose from all sources.

Tafenoquine is not neurotoxic following supertherapeutic dosing in rats.

PubMed

Dow, Geoffrey S; Brown, Tracey; Reid, Mark; Smith, Bryan; Toovey, Stephen

Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7-8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumors including medulloblastoma

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

Merchant, Thomas E.; Kiehna, Erin N.; Li Chenghong

2006-05-01

Purpose: Model the effects of radiation dosimetry on IQ among pediatric patients with central nervous system (CNS) tumors. Methods and Materials: Pediatric patients with CNS embryonal tumors (n = 39) were prospectively evaluated with serial cognitive testing, before and after treatment with postoperative, risk-adapted craniospinal irradiation (CSI) and conformal primary-site irradiation, followed by chemotherapy. Differential dose-volume data for 5 brain volumes (total brain, supratentorial brain, infratentorial brain, and left and right temporal lobes) were correlated with IQ after surgery and at follow-up by use of linear regression. Results: When the dose distribution was partitioned into 2 levels, both had amore » significantly negative effect on longitudinal IQ across all 5 brain volumes. When the dose distribution was partitioned into 3 levels (low, medium, and high), exposure to the supratentorial brain appeared to have the most significant impact. For most models, each Gy of exposure had a similar effect on IQ decline, regardless of dose level. Conclusions: Our results suggest that radiation dosimetry data from 5 brain volumes can be used to predict decline in longitudinal IQ. Despite measures to reduce radiation dose and treatment volume, the volume that receives the highest dose continues to have the greatest effect, which supports current volume-reduction efforts.« less

A phase I trial of intraperitoneal GEN-1, an IL-12 plasmid formulated with PEG-PEI-cholesterol lipopolymer, administered with pegylated liposomal doxorubicin in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers: An NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Thaker, Premal H.; Brady, William E.; Lankes, Heather A.; Odunsi, Kunle; Bradley, William H.; Moore, Kathleen N.; Muller, Carolyn Y.; Anwer, Khursheed; Schilder, Russell J.; Alvarez, Ronald D.; Fracasso, Paula M.

2017-01-01

Objective The study’s purpose was to assess safety and efficacy of escalating doses of weekly GEN-1 with pegylated liposomal doxorubicin (PLD) in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancers (EOC). Methods Patients had persistent or recurrent platinum-resistant EOC. The trial was a standard 3 + 3 phase I dose escalation design with patients receiving intravenous PLD 40 mg/m2 (dose level 1 and 2) or 50 mg/m2 (dose level 3) every 28 days and intraperitoneal GEN-1 at 24 mg/m2 (dose level 1) or 36 mg/m2 (dose level 2 and 3) on days 1, 8, 15, and 22 of a 28 day cycle. Cycles were repeated every 28 days until disease progression. Patients were monitored for toxicity, clinical efficacy, and evidence of systemic and intraperitoneal immunologic effect. Results Sixteen evaluable patients received a median of 4 cycles (range 1–8). No dose limiting toxicities were found. The adverse side effects were 4 grade 3 anemia, 2 grade 3 abdominal pain, 7 grade 3 neutropenia, and 2 grade 4 neutropenia. A clinical benefit of 57.1% (PR = 21.4%; SD = 35.7%) was found in the 14 patients with measurable disease. The highest number of partial responses (28.6%) and stable disease (57.1%) were found at dose level 3. The maximum tolerated dose was not reached. Increases in IL-12, IFN-γ, and TNF-α levels were found in peritoneal fluid following GEN-1 treatment. Conclusions GEN-1 in combination with PLD has encouraging clinical benefit and biological activity in recurrent or persistent EOC and warrants further investigation with escalating doses of GEN-1. PMID:28802766

Bone cancer occurrence among beagles given 239Pu as young adults.

PubMed

Lloyd, R D; Taylor, G N; Angus, W; Bruenger, F W; Miller, S C

1993-01-01

The occurrence of skeletal malignancies has been documented among 234 young adult beagles given single intravenous injections of monomeric 239Pu citrate. Occurrence has also been documented among 132 comparable control group animals surviving the minimum latent time period of 2.79 y for radiation-induced bone cancer, who were maintained for lifespan observation. Injected amounts ranged from about 0.02-106 kBq kg-1 body mass with factors of 2 or 3 between dose levels. There were 84 radiographically apparent bone tumors in 76 plutonium-injected dogs and one tumor in a control group dog. Most of these were osteosarcomas except for seven chondrosarcomas, one liposarcoma, and one plasma cell myeloma of bone. The relationship between percent of dogs at any dose level with bone malignancy and average skeletal dose at the presumed time of tumor initiation of 1 y before death appeared to be linear below about 1.3 Gy average skeletal dose. The observed data can be approximated by the expression A = 0.76 + 75 D, where A = percent of dogs with bone cancer at any dose level, D = average skeletal dose in Gy (for doses up to 1.3 Gy) at tumor initiation, and 0.76 represents the percent tumor response in the control animals not given plutonium. Similar analysis of our corresponding data for beagles given 226Ra, excluding the two highest dose levels (approximately 100% occurrence), yielded the expression A = 0.76 + 4.7 D, where D = the average skeletal dose in Gy (for doses up to 20 Gy) at 1 y before death. The ratio of coefficients indicates the effectiveness for bone cancer induction of 239Pu relative to 226Ra, or [(75 +/- 22.5)(4.7 +/- 0.47)-1] = 16 +/- 5 for a single, brief intake of either nuclide into blood.

Estrogen hormone level of prepubertal female rat treated with Calliandra calothyrsus ethanolic leaf extract

NASA Astrophysics Data System (ADS)

Setyawati, I.; Wiratmini, N. I.; Narayani, I.

2018-03-01

This research examined the phytoestrogen potential of Calliandra calothyrsus leaf extract in prepubertal female rat (Rattus norvegicus). Sixty weaned female rats (21 days old) were divided into five groups i.e. control (K), negative control which was given 0.5% Na CMC suspension (KN) and treatment groups which were given with C. calothyrsus ethanolic leaf extract doses 25 mg/kg bw (P1), 50 mg/kg bw (P2) and 75 mg/kg bw (P3). The treatment suspension was administered 0.5 mL/rat/day by gavage for 28 days, started at the age of 21st days old. The rats were sacrificed and the blood samples were collected from 4 rats / group at the age of 28th, 42nd and 56th days old, each. The concentration of estrogen hormone levels were measured from blood serum by ELISA kit and were read at 450 nm wavelength with an ELISA Spectrophotometer. Data was analyzed statistically by General Linear Model with 95% of confidence. The result showed that rat’s body weight decreased significantly with the higher doses and the longer the treatment of C. calothyrsus leaf extract due to the anti-nutritive activity of calliandra tannins. The estrogen hormone level was significantly increased at the highest dose. The highest estrogen levels were found in the group of female rats which were given the exctract of 75 mg/kg bw until the age of 42nd days. This results showed that there was a phytoestrogen potential in the C. calothyrsus leaf extract.

Toxicity of glyphosate as Glypro and LI700 to red-eared slider (trachemys scripta elegans) embryos and early hatchlings.

PubMed

Sparling, Donald W; Matson, Cole; Bickham, John; Doelling-Brown, Paige

2006-10-01

More than 8.2 billion ha of cropland, gardens, and forests are treated with the herbicide glyphosate each year. Whereas the toxicity of glyphosate and associated adjuvants has been measured in other vertebrates, few, if any, studies have looked at their effects in reptiles. In some instances, management of turtle habitat requires control of successional stages through application of herbicides. Adults and juvenile turtles may be exposed directly, whereas embryos may contact the chemicals through the soil. In the present study, we exposed eggs of red-eared sliders (Trachemys scripta elegans) to single applications of herbicide ranging from 0 to 11,206 ppm wet weight of glyphosate in Glypro and 0 to 678 ppm of the surfactant, LI700. Hatching success at the highest concentration was significantly lower (73%) than in other treatments (80-100%). At hatch, turtles at the highest concentration weighed less than those at other concentrations. During a 14-d holding period, we observed dose-response relationships in the ability of hatchlings to right themselves when turned on their backs. At the end of the holding period, hatchlings at the highest dose level were still lighter, and somatic indices were lower, than those in other treatments. Genetic damage, as measured by flow cytometry, increased with treatment concentration except for the highest dose. We conclude that because of the high concentrations needed to produce effects and the protection offered by several centimeters of soil or sediment, glyphosate with LI700 poses low levels of risk to red-eared slider embryos under normal field operations with regards to the endpoints measured in the present study. Carelessness in handling glyphosate or failure to follow label directions may produce adverse effects. There also is a risk that the health of turtle embryos may be affected in ways not measured in the present study.

Assessment of dose rate to terrestrial biota in the area around coal fired power plant applying ERICA tool and RESRAD BIOTA code.

PubMed

Ćujić, Mirjana; Dragović, Snežana

2018-08-01

This paper presents the environmental radiation risk assessment based on two software program approaches ERICA Tool (version 1.2) and RESRAD BIOTA (version 1.5) to estimate dose rates to terrestrial biota in the area around the largest coal fired power plant in Serbia. For dose rate assessment software's default reference animals and plants and the best estimated values of activity concentrations of 238 U, 234 U, 234 Th, 232 Th, 230 Th, 226 Ra, 210 Pb, 210 Po, 137 Cs in soil were used. Both approaches revealed the highest contribution to the internal dose rate due to 226 Ra and 210 Po, while 137 Cs contributed the most to the external dose rate. In the investigated area total dose rate to biota derived using ERICA Tool ranged from 0.3 to 14.4 μGy h -1 . The natural radionuclides exhibited significantly higher contribution to the total dose rate than the artificial one. In the investigated area, only dose rate for lichens and bryophytes exceeded ERICA Tool screening value of total dose rate of 10 μGy h -1 suggested as confident that environmental risks are negligible. The assessed total dose rates for reference animals and plants using RESRAD BIOTA were found to be 7 and 3 μGy h -1 , respectively. In RESRAD BIOTA - Level 3, 10 species (Lumbricus terrestris, Rana lessonae, Sciurus vulgaris, Anas platyrhynchos, Lepus europaeus, Vulpes vulpes, Capreolus capreolus, Suss crofa, Quercu srobur, Tilia spp.) representative for the study area were modeled. Among them the highest total dose rate (4.5 μGy h -1 ) was obtained for large mammals. Differences in the predicted dose rates to biota using the two software programs are the consequence of the difference in the values of transfer parameters used to calculate activity concentrations in biota. Doses of ionizing radiation estimated in this study will not exhibit deterministic effects at the population level. Thus, the obtained results indicate no significant radiation impact of coal fired power plant operation on terrestrial biota. This paper confirms the use ERICA Tool and RESRAD BIOTA softwares as flexible and effective means of radiation impact assessment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Altitudinal characteristics of atmospheric deposition of aerosols in mountainous regions: Lessons from the Fukushima Daiichi Nuclear Power Station accident.

PubMed

Sanada, Yukihisa; Katata, Genki; Kaneyasu, Naoki; Nakanishi, Chika; Urabe, Yoshimi; Nishizawa, Yukiyasu

2018-03-15

To understand the formation process of radiologically contaminated areas in eastern Japan caused by the Fukushima Daiichi Nuclear Power Station (FDNPS) accident, the deposition mechanisms over complex topography are the key factors to be investigated. To characterize the atmospheric deposition processes of radionuclides over complex mountainous topography, we investigated the altitudinal distributions of the radiocesium deposited during the accident. In five selected areas, altitudinal characteristics of the air dose rates observed using airborne surveys were analyzed. To examine the deposition mechanisms, we supplementarily used vertical profiles of radiocesium deposition in each area calculated in the latest atmospheric dispersion model. In southern Iwate, the vertical profile of the observed air dose rate was uniform regardless of altitude. In western Tochigi, the areas with the highest levels of contamination were characteristically distributed in the middle of the mountains, while in southern Fukushima, the areas with the highest contamination levels were enhanced near the summits of mountains. In central Fukushima, high air dose rates were limited to the bottoms of basin-like valley. In the region northwest of FDNPS, the air dose rate was the highest at the bottom of valley topography and decreased gradually with altitude. The simulation results showed that calculated wet deposition and observed vertical profiles of total deposition were similar in areas of southern Iwate and northwest of FDNPS qualitatively, suggesting that the dominant deposition mechanism was wet deposition. In contrast, the atmospheric dispersion model failed to reproduce either the timing of precipitation events or vertical profiles of radiocesium deposition in three other areas. Although it was difficult to elucidate the deposition mechanisms in these areas due to uncertainties of the present model results, potential mechanisms such as cloud water deposition were still proposed based on circumstantial evidences of limited meteorological data during the early stage of the accident. Copyright © 2017 Elsevier B.V. All rights reserved.

National survey on the natural radioactivity and 222Rn exhalation rate of building materials in The Netherlands.

PubMed

de Jong, P; van Dijk, W; van der Graaf, E R; de Groot, T J H

2006-09-01

The present study reports on results of a nation-wide survey on the natural radioactivity concentrations and Rn exhalation rates of the prevailing building materials in the Netherlands. In total 100 samples were taken and analyzed for the activity concentrations of Ra, Ra, Th, and K and for their Rn exhalation rate. The sampled materials consisted of gypsum products, aerated concrete, sand-lime and clay bricks, mortars and concrete, representing about 95% of the stony building materials used in the construction of Dutch homes. The laboratory analyses were performed according to two well-documented standard procedures, the interlaboratory reproducibility of which is found to be within 5% on average. The highest radionuclide concentrations were found in a porous inner wall brick to which fly ash was added. The second highest were clay bricks with average Ra and Ra levels around 40 Bq kg. Concrete and mortar show the highest exhalation rates with a fairly broad range of 1 to 13 microBq (kg s). Low natural radioactivity levels are associated with either natural gypsum (products) or gypsum from flue gas desulphurization units, and low exhalation rates with clay bricks. To evaluate the radiological impact the radioactivity concentrations in each sample were combined into a so-called dose factor, representing the absorbed dose rate in a room with a floor, walls and ceiling of 20 cm of the material in question. For that purpose, calculations with the computer codes MCNP, Marmer and MicroShield on the specific absorbed dose rates were incorporated in the paper. The results of these codes corresponded within 6% and average values were calculated at 0.90, 1.10, and 0.080 nGy h per Bq kg for the U series, the Th series, and K, respectively. Model calculations on the external dose rate, based on the incidence of the various building materials in 1,336 living rooms, are in accordance with measured data.

High-level dietary cadmium exposure is associated with global DNA hypermethylation in the gastropod hepatopancreas

PubMed Central

Popescu, Cristina; Draghici, George A.; Andrica, Florina-Maria; Privistirescu, Ionela A.; Gergen, Iosif I.; Stöger, Reinhard

2017-01-01

5-methylcytosine (5mC) is a key epigenetic mark which influences gene expression and phenotype. In vertebrates, this epigenetic mark is sensitive to Cd exposure, but there is no information linking such an event with changes in global 5mC levels in terrestrial gastropods despite their importance as excellentecotoxicological bioindicators of metal contamination. Therefore, we first evaluated total 5mC content in DNA of the hepatopancreas of adult Cantareus aspersus with the aim to determine whether this epigenetic mark is responsive to Cd exposure. The experiment was conducted under laboratory conditions and involved a continuous exposure, multiple dose- and time-point (14, 28, and 56 days) study design. Hepatopancreas cadmium levels were measured using Flame Atomic Absorption Spectrometry and the percentage of 5-mC in samples using an ELISA-based colorimetric assay. Snail death rates were also assessed. Our results, for the first time, reveal the presence of 5mC in C. aspersus and provide evidence for Cd-induced changes in global 5mC levels in DNA of gastropods and mollusks. Although less sensitive than tissue accumulation, DNA methylation levels responded in a dose- and time-dependent manner to dietary cadmium, with exposure dose having a much stronger effect than exposure duration. An obvious trend of increasing 5mC levels was observed starting at 28 days of exposure to the second highest dose and this trend persisted at the two highest treatments for close to one month, when the experiment was terminated after 56 days. Moreover, a strong association was identified between Cd concentrations in the hepatopancreas and DNA methylation levels in this organ. These data indicate an overall trend towards DNA hypermethylation with elevated Cd exposure. No consistent lethal effect was observed, irrespective of time point and Cd-dosage. Overall, our findings suggest that the total 5mC content in DNA of the hepatopancreas of land snails is responsive to sublethal Cd exposure and give new insights into invertebrate environmental epigenetics. PMID:28877233

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2010 CFR

2010-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2013 CFR

2013-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2014 CFR

2014-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2012 CFR

2012-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

40 CFR 798.6560 - Subchronic delayed neuro-toxicity of organophosphorus substances.

Code of Federal Regulations, 2011 CFR

2011-07-01

... employed. (2) Number of animals. Ten hens should be used for each treatment and control group. (3) Control group—(i) General. A concurrent control group should be used. This group should be treated in a manner... control group(s). The highest dose level should result in toxic effects, preferably delayed neurotoxicity...

Study of runaway electrons using dosimetry of hard x-ray radiations in Damavand tokamak

NASA Astrophysics Data System (ADS)

Rasouli, C.; Pourshahab, B.; Hosseini Pooya, S. M.; Orouji, T.; Rasouli, H.

2014-05-01

In this work several studies have been conducted on hard x-ray emissions of Damavand tokamak based on radiation dosimetry using the Thermoluminescence method. The goal was to understand interactions of runaway electrons with plasma particles, vessel wall, and plasma facing components. Total of 354 GR-200 (LiF:Mg,Cu,P) thermoluminescence dosimeter (TLD) crystals have been placed on 118 points - three TLDs per point - to map hard x-ray radiation doses on the exterior of the vacuum vessel. Results show two distinctive levels of x-ray radiations doses on the exterior of the vessel. The low-dose area on which measured dose is about 0.5 mSv/shot. In the low-dose area there is no particular component inside the vessel. On the contrary, on high-dose area of the vessel, x-ray radiations dose exceeds 30 mSv/shot. The high-dose area coincides with the position of limiters, magnetic probe ducts, and vacuum vessel intersections. Among the high-dose areas, the highest level of dose is measured in the position of the limiter, which could be due to its direct contact with the plasma column and with runaway electrons. Direct collisions of runaway electrons with the vessel wall and plasma facing components make a major contribution for production of hard x-ray photons in Damavand tokamak.

Study of runaway electrons using dosimetry of hard x-ray radiations in Damavand tokamak.

PubMed

Rasouli, C; Pourshahab, B; Hosseini Pooya, S M; Orouji, T; Rasouli, H

2014-05-01

In this work several studies have been conducted on hard x-ray emissions of Damavand tokamak based on radiation dosimetry using the Thermoluminescence method. The goal was to understand interactions of runaway electrons with plasma particles, vessel wall, and plasma facing components. Total of 354 GR-200 (LiF:Mg,Cu,P) thermoluminescence dosimeter (TLD) crystals have been placed on 118 points--three TLDs per point--to map hard x-ray radiation doses on the exterior of the vacuum vessel. Results show two distinctive levels of x-ray radiations doses on the exterior of the vessel. The low-dose area on which measured dose is about 0.5 mSv/shot. In the low-dose area there is no particular component inside the vessel. On the contrary, on high-dose area of the vessel, x-ray radiations dose exceeds 30 mSv/shot. The high-dose area coincides with the position of limiters, magnetic probe ducts, and vacuum vessel intersections. Among the high-dose areas, the highest level of dose is measured in the position of the limiter, which could be due to its direct contact with the plasma column and with runaway electrons. Direct collisions of runaway electrons with the vessel wall and plasma facing components make a major contribution for production of hard x-ray photons in Damavand tokamak.

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.

PubMed

Hernández-Plata, Everardo; Quiroz-Compeán, Fátima; Ramírez-Garcia, Gonzalo; Barrientos, Eunice Yáñez; Rodríguez-Morales, Nadia M; Flores, Alberto; Wrobel, Katarzina; Wrobel, Kazimierz; Méndez, Isabel; Díaz-Muñoz, Mauricio; Robles, Juvencio; Martínez-Alfaro, Minerva

2015-03-04

Melatonin, a hormone known for its effects on free radical scavenging and antioxidant activity, can reduce lead toxicity in vivo and in vitro.We examined the effects of melatonin on lead bio-distribution. Rats were intraperitoneally injected with lead acetate (10, 15 or 20mg/kg/day) with or without melatonin (10mg/kg/day) daily for 10 days. In rats intoxicated with the highest lead doses, those treated with melatonin had lower lead levels in blood and higher levels in urine and feces than those treated with lead alone, suggesting that melatonin increases lead excretion. To explore the mechanism underlying this effect, we first assessed whether lead/melatonin complexes were formed directly. Electronic density functional (DFT) calculations showed that a lead/melatonin complex is energetically feasible; however, UV spectroscopy and NMR analysis showed no evidence of such complexes. Next, we examined the liver mRNA levels of metallothioneins (MT) 1 and 2. Melatonin cotreatment increased the MT2 mRNA expression in the liver of rats that received the highest doses of lead. The potential effects of MTs on the tissue distribution and excretion of lead are not well understood. This is the first report to suggest that melatonin directly affects lead levels in organisms exposed to subacute lead intoxication. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Antihyperglycemic activities of leaves of three edible fruit plants (Averrhoa carambola, Ficus hispida and Syzygium samarangense) of Bangladesh.

PubMed

Shahreen, Shejuty; Banik, Joyanta; Hafiz, Abdul; Rahman, Shahnaz; Zaman, Anahita Tanzia; Shoyeb, Md Abu; Chowdhury, Majeedul H; Rahmatullah, Mohammed

2012-01-01

Averrhoa carambola L. (Oxalidaceae), Ficus hispida L.f. (Moraceae), and Syzygium samarangense (Blume) Merr. & L.M. Perry (Myrtaceae) are three common plants in Bangladesh, the fruits of which are edible. The leaves and fruits of A. carambola and F. hispida are used by folk medicinal practitioners for treatment of diabetes, while the leaves of S. samarangense are used for treatment of cold, itches, and waist pain. Since scientific studies are absent on the antihyperglycemic effects of the leaves of the three plants, it was the objective of the present study to evaluate the antihyperglycemic potential of methanolic extract of leaves of the plants in oral glucose tolerance tests carried out with glucose-loaded mice. The extracts at different doses were administered one hour prior to glucose administration and blood glucose level was measured after two hours of glucose administration (p.o.) using glucose oxidase method. Significant oral hypoglycemic activity was found with the extracts of leaves of all three plants tested. The fall in serum glucose levels were dose-dependent for every individual plant, being highest at the highest dose tested of 400 mg extract per kg body weight. At this dose, the extracts of A. carambola, F. hispida, and S. samarangense caused, respectively, 34.1, 22.7, and 59.3% reductions in serum glucose levels when compared to control animals. The standard antihyperglycemic drug, glibenclamide, caused a 57.3% reduction in serum glucose levels versus control. Among the three plants evaluated, the methanolic extract of leaves of S. samarangense proved to be the most potent in demonstrating antihyperglycemic effects. The result validates the folk medicinal uses of A. carambola and F. hispida in the treatment of diabetes, and indicates that the leaves of S. samarangense can also possibly be used for amelioration of diabetes-induced hyperglycemia.

A Bayesian Dose-finding Design for Oncology Clinical Trials of Combinational Biological Agents

PubMed Central

Cai, Chunyan; Yuan, Ying; Ji, Yuan

2013-01-01

Treating patients with novel biological agents is becoming a leading trend in oncology. Unlike cytotoxic agents, for which efficacy and toxicity monotonically increase with dose, biological agents may exhibit non-monotonic patterns in their dose-response relationships. Using a trial with two biological agents as an example, we propose a dose-finding design to identify the biologically optimal dose combination (BODC), which is defined as the dose combination of the two agents with the highest efficacy and tolerable toxicity. A change-point model is used to reflect the fact that the dose-toxicity surface of the combinational agents may plateau at higher dose levels, and a flexible logistic model is proposed to accommodate the possible non-monotonic pattern for the dose-efficacy relationship. During the trial, we continuously update the posterior estimates of toxicity and efficacy and assign patients to the most appropriate dose combination. We propose a novel dose-finding algorithm to encourage sufficient exploration of untried dose combinations in the two-dimensional space. Extensive simulation studies show that the proposed design has desirable operating characteristics in identifying the BODC under various patterns of dose-toxicity and dose-efficacy relationships. PMID:24511160

Monitoring of perchlorate in diverse foods and its estimated dietary exposure for Korea populations.

PubMed

Lee, Ji-Woo; Oh, Sung-Hee; Oh, Jeong-Eun

2012-12-01

The perchlorate concentrations in various Korean food samples were monitored, and 663 samples belonging to 39 kinds of food were analyzed. The analysis results revealed that dairy products contain the highest average concentration of 6.34 μg/kg and high detection frequency of over 85%. Fruit and vegetables showed the next highest perchlorate concentration with an average of 6.17 μg/kg. Especially, with its average concentration of 39.9 μg/kg, spinach showed the highest perchlorate level among all target food samples studied. Tomato was followed by spinach, which showed a high perchlorate average concentration of 19.8 μg/kg, and over 7 μg/kg was detected in ham and sausage (avg. 7.31 μg/kg) and in instant noodles (avg. 7.58 μg/kg). Less than 2 μg/kg was detected in fishes, meats and beverages. The exposure dose of perchlorate in Korean by food intake was calculated on the basis of the analyzed perchlorate levels in this study. The daily perchlorate dose to which Korean adults are exposed is 0.04 μg/kg bw/day, which is lower than the RfD (0.7 μg/kg bw/day) value suggested by US NAS. This result indicates that Korean people's current exposure to perchlorate from domestic food consumption is evaluated as safe. Copyright © 2012 Elsevier B.V. All rights reserved.

Modeling adverse event counts in phase I clinical trials of a cytotoxic agent.

PubMed

Muenz, Daniel G; Braun, Thomas M; Taylor, Jeremy Mg

2018-05-01

Background/Aims The goal of phase I clinical trials for cytotoxic agents is to find the maximum dose with an acceptable risk of severe toxicity. The most common designs for these dose-finding trials use a binary outcome indicating whether a patient had a dose-limiting toxicity. However, a patient may experience multiple toxicities, with each toxicity assigned an ordinal severity score. The binary response is then obtained by dichotomizing a patient's richer set of data. We contribute to the growing literature on new models to exploit this richer toxicity data, with the goal of improving the efficiency in estimating the maximum tolerated dose. Methods We develop three new, related models that make use of the total number of dose-limiting and low-level toxicities a patient experiences. We use these models to estimate the probability of having at least one dose-limiting toxicity as a function of dose. In a simulation study, we evaluate how often our models select the true maximum tolerated dose, and we compare our models with the continual reassessment method, which uses binary data. Results Across a variety of simulation settings, we find that our models compare well against the continual reassessment method in terms of selecting the true optimal dose. In particular, one of our models which uses dose-limiting and low-level toxicity counts beats or ties the other models, including the continual reassessment method, in all scenarios except the one in which the true optimal dose is the highest dose available. We also find that our models, when not selecting the true optimal dose, tend to err by picking lower, safer doses, while the continual reassessment method errs more toward toxic doses. Conclusion Using dose-limiting and low-level toxicity counts, which are easily obtained from data already routinely collected, is a promising way to improve the efficiency in finding the true maximum tolerated dose in phase I trials.

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)

Milnacipran affects mouse impulsive, aggressive, and depressive-like behaviors in a distinct dose-dependent manner.

PubMed

Tsutsui-Kimura, Iku; Ohmura, Yu; Yoshida, Takayuki; Yoshioka, Mitsuhiro

2017-07-01

Serotonin/noradrenaline reuptake inhibitors (SNRIs) are widely used for the treatment for major depressive disorder, but these drugs induce several side effects including increased aggression and impulsivity, which are risk factors for substance abuse, criminal involvement, and suicide. To address this issue, milnacipran (0, 3, 10, or 30 mg/kg), an SNRI and antidepressant, was intraperitoneally administered to mice prior to the 3-choice serial reaction time task, resident-intruder test, and forced swimming test to measure impulsive, aggressive, and depressive-like behaviors, respectively. A milnacipran dose of 10 mg/kg suppressed all behaviors, which was accompanied by increased dopamine and serotonin levels in the medial prefrontal cortex (mPFC) but not in the nucleus accumbens (NAc). Although the most effective dose for depressive-like behavior was 30 mg/kg, the highest dose increased aggressive behavior and unaffected impulsive behavior. Increased dopamine levels in the NAc could be responsible for the effects. In addition, the mice basal impulsivity was negatively correlated with the latency to the first agonistic behavior. Thus, the optimal dose range of milnacipran is narrower than previously thought. Finding drugs that increase serotonin and dopamine levels in the mPFC without affecting dopamine levels in the NAc is a potential strategy for developing novel antidepressants. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Efficacy of an extract from garlic, Allium sativum, against infection with the furunculosis bacterium, Aeromonas salmonicida, in rainbow trout, Oncorhynchus mykiss

USGS Publications Warehouse

Breyer, Kate E.; Getchell, Rodman G.; Cornwell, Emily R.; Wooster, Gregory A.; Ketola, H. George; Bowser, Paul R.

2015-01-01

Juvenile rainbow trout, Oncorhynchus mykiss, were fed diets containing 0, 0.5, 1.0, and 2.0% of a garlic extract, challenged with a modified 50% lethal dose of Aeromonas salmonicida and monitored for 28 d. There were significant increases in survival of trout fed 0.5 and 1.0% garlic extract as compared to the control and 2.0% garlic extract groups. A target animal safety study was performed at varying increments using the target dose of 0.5% garlic extract at 0× (0% garlic extract), 1× (0.5% garlic extract), 3× (1.5% garlic extract), and 5× (2.5% garlic extract) for 3× (6 wk) the duration of the original study. There was a significant increase in the level of circulating lymphocytes and a significant decrease in the level of circulating monocytes. The latter correlated to an increased level of pigment-containing macrophage centers within the renal tissue as garlic extract dosing increased, denoting a potential deleterious inflammatory effect as macrophage infiltration became severe at the highest dose. These studies suggest that feeding low-dose (0.5% or 1.0%) garlic extract improves survivability in rainbow trout when challenged with A. salmonicida and appears safe; however, higher levels do not appear to be effective and may cause deleterious effects on health.

A Comprehensive Toxicological Safety Assessment of an Extract of Olea Europaea L. Leaves (Bonolive™).

PubMed

Clewell, Amy E; Béres, Erzsébet; Vértesi, Adél; Glávits, Róbert; Hirka, Gábor; Endres, John R; Murbach, Timothy S; Szakonyiné, Ilona Pasics

2016-01-01

A battery of toxicological studies was conducted to investigate the genotoxicity and repeated-dose oral toxicity of Bonolive™, a proprietary water-soluble extract of the leaves of the olive tree (Olea europaea L.), in accordance with internationally accepted protocols. There was no evidence of mutagenicity in a bacterial reverse mutation test and in an vitro mammalian chromosomal aberration test nor was any genotoxic activity observed in an in vivo mouse micronucleus test at concentrations up to the limit dose of 2000 mg/kg bw/d. Bonolive™ did not cause mortality or toxic effects in Crl:(WI)BR Wistar rats in a 90-day repeated-dose oral toxicity study at doses of 360, 600, and 1000 mg/kg bw/d. The no observed adverse effect level in the 90-day study was 1000 mg/kg bw/d for both male and female rats, the highest dose tested. © The Author(s) 2015.

Benzo(a)pyrene-induced cytochrome p4501A expression of four freshwater fishes (Oryzias latipes, Danio rerio, Cyprinus carpio, and Zacco platypus).

PubMed

Lee, Jin Wuk; Yoon, Hong-Gil; Lee, Sung Kyu

2015-05-01

Oryzias latipes, Danio rerio, Cyprinus carpio, and Zacco platypus are useful indicator species for CYP1A biomarker studies; however, comparative studies have not been performed. To compare susceptibility, dose- and time-dependent CYP1A induction at the mRNA and protein levels in response to benzo(a)pyrene (BaP) exposure was analyzed. At the mRNA level, a statistically significant difference was found among the four species; however, such was not observed at the protein level. C. carpio showed the highest CYP1A induction level and the steepest slope in the dose-response curve. To assess susceptibility, the difference in CYP1A mRNA induction among species must be considered, and C. carpio was the most sensitive species of the four evaluated in terms of CYP1A expression. Copyright © 2015 Elsevier B.V. All rights reserved.

[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.

Tributyltin potentiates 3,3',4,4',5-pentachlorobiphenyl-induced cytochrome P-4501A-related activity.

PubMed

DeLong, G T; Rice, C D

1997-06-06

Induction of cytochrome P-4501A protein and induction of related enzyme activity are hallmark physiological responses following exposure to planar halogenated aromatic hydrocarbons (HAHs) such as 3,3',4,4',5-pentachlorobiphenyl (PCB 126; PeCB). Environments contaminated by HAHs are often contaminated by mixtures of anthropogenic contaminants, including organometallic compounds. Both HAHs and organometallics easily bioconcentrate and bioaccumulate in aquatic food chains that may ultimately be linked to humans through seafood consumption. Tributyltin (TBT), a marine biocide, has been detected in many aquatic environments due to its primary use as a marine antifoulant agent. Exposure to TBT, as well as several PCBs, has been associated with immunotoxicity, neurotoxicity, and endocrine disruption. Recently TBT has been shown to inhibit cytochrome P-4501A activity in vitro, but information concerning these effects in vivo and in combination with classical inducers of P-4501A, such PeCB, is lacking. We exposed female B6C3F1 mice to 0.01, 0.1, and 1.0 mg/kg PeCB, TBT, or both in combination, with corn oil (CO) serving as a carrier control. Cytochrome P-4501A protein levels and related benzo[a]pyrene hydroxylation (BaP-OHase) activity were measured following a single acute intraperitoneal (ip) dose or seven daily injections. Body, thymus, and liver weights were used to monitor general physiological responses following exposure. P-4501A levels and BaP-OHase activity were significantly elevated in mice exposed to PeCB alone. This effect was enhanced by coexposure to low levels of TBT; PeCB-induced P-4501A-related activity was potentiated at the low range of each. The highest dose of TBT, however, inhibited these activities when given in combination with PeCB. Thymic atrophy was evident only in mice exposed daily to 0:1 and 1.0 mg/kg PeCB alone, or to a combination of the lowest and highest dose of PeCB and TBT, respectively. Because environmental levels of TBT are not expected to be as high as the highest level used in our toxicological studies, we conclude that environmental exposure to TBT may potentiate, rather than inhibit, the activity of environmental levels of HAHs that are associated with P-4501A induction.

Concentration of 3H in ground water and estimation of committed effective dose due to ground water ingestion in some places in the Maharashtra state, India.

PubMed

Reddy, P J; Bhade, S P D; Kolekar, R V; Singh, Rajvir; Pradeepkumar, K S

2014-01-01

The measurement of tritium in environmental samples requires highest possible sensitivity. In the present study, the authors have optimised the counting window for the analysis of (3)H in environmental samples using the recently installed Ultra Low Level Quantulus 1220 Liquid Scintillation Counting at BARC to improve the detection limit of the system. The optimised counting window corresponding to the highest figure of merit of 883.8 was found to be 20-162 channels. Different brands of packaged drinking waters were analysed to select a blank that would define the system background. The minimum detectable activity (MDA) achieved was 1.5 Bq l(-1) for a total counting time of 500 min. The concentration of tritium in well and bore well water samples collected from the villages of Pune, villages located at 1.8 km from Tarapur Atomic Power Station, Kolhapur and Ratnagiri, was analysed. The activity concentration ranged from 0.55 to 3.66 Bq l(-1). The associated age-dependant dose from water ingestion in the study area was estimated. The effective committed dose recorded for different age classes is negligible compared with World Health Organization and US Environmental Protection Agency dose guidelines.

Diethylene glycol in health products sold over-the-counter and imported from Asian countries.

PubMed

Schier, Joshua G; Barr, Dana B; Li, Zheng; Wolkin, Amy F; Baker, Samuel E; Lewis, Lauren S; McGeehin, Michael A

2011-03-01

Diethylene glycol (DEG), a chemical that has been implicated in multiple medication-associated mass poisonings, can result in renal and neurological toxicity if ingested. Three previous such mass poisonings implicated Chinese manufacturers as the origin of contaminated ingredients. No literature exists on potential DEG or triethylene glycol (TEG), a related compound, contamination of health products imported from Asian countries to the USA. Our primary objective was to quantitatively assess the amount of DEG present in a convenience sampling of these health products. The study's secondary objectives were to: (1) evaluate for, and quantify TEG levels in these samples; (2) compare DEG and TEG levels in these products directly to levels in medications implicated in previous similar mass poisonings; and (3) to estimate DEG dose (in mg/kg) based on the manufacturer's instructions and compare these values to toxic doses from past mass poisonings and the literature. A quantitative assessment of DEG and TEG was performed in a convenience sampling of over-the-counter health products imported from Asian countries. Results were converted to volume to volume (v/v) % and compared with DEG levels in medications implicated in previous mass poisonings. Estimated doses (based on the manufacturer's instructions) of each product with detectable levels of DEG for a 70 kg adult were compared to toxic doses of DEG reported in the literature. Seventeen of 85 (20%) samples were not able to be analyzed for DEG or TEG due to technical reasons. Fifteen of 68 (22%) samples successfully tested had detectable levels of DEG (mean, 18.8 μg/ml; range, 0.791-110.1 μg/ml; and volume to volume (v/v) range, 0.00007-0.01%). Two of 68 (3%) samples had TEG levels of 12.8 and 20.2 μg/ml or 0.0012% and 0.0018% TEG v/v. The product with the highest DEG% by v/v was 810 times less than the product involved in the Panama DEG mass poisoning (8.1%). The lowest reported toxic dose from a past DEG mass poisoning (14 mg/kg) was more than 150 times higher than the highest daily dose estimated in our study (0.09 mg/kg). Sixty-eight of 85 (80%) samples were able to be successfully analyzed for DEG and TEG. DEG and TEG were detectable in 15/68 (22%) and 2/68 (3%) samples, respectively. Based on current standards, these levels probably do not represent an acute public health threat. Additional research focusing on why DEG is found in these products and on the minimum amount of DEG needed to result in toxicity is needed. © American College of Medical Toxicology 2010

Gamma Radiation Dose Rate in Air due to Terrestrial Radionuclides in Southern Brazil: Synthesis by Geological Units and Lithotypes Covered by the Serra do Mar Sul Aero-Geophysical Project

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

Bastos, Rodrigo O.; Appoloni, Carlos R.; Pinese, Jose P. P.

2008-08-07

The absorbed dose rates in air due to terrestrial radionuclides were estimated from aerial gamma spectrometric data for an area of 48,600 km{sup 2} in Southern Brazil. The source data was the Serra do Mar Sul Aero-Geophysical Project back-calibrated in a cooperative work among the Geological Survey of Brazil, the Geological Survey of Canada, and Paterson, Grant and Watson Ltd. The concentrations of eU (ppm), eTh (ppm) and K (%) were converted to dose rates in air (nGy{center_dot}h{sup -1}) by accounting for the contribution of each element's concentration. Regional variation was interpreted according to lithotypes and a synthesis was performedmore » according to the basic geological units present in the area. Higher values of total dose were estimated for felsic igneous and metamorphic rocks, with average values varying up to 119{+-}24 nGy{center_dot}h{sup -1}, obtained by Anitapolis syenite body. Sedimentary, metasedimentary and metamafic rocks presented the lower dose levels, and some beach deposits reached the lowest average total dose, 18.5{+-}8.2 nGy{center_dot}h{sup -1}. Thorium gives the main average contribution in all geological units, the highest value being reached by the nebulitic gneisses of Atuba Complex, 71{+-}23 nGy{center_dot}h{sup -1}. Potassium presents the lowest average contribution to dose rate in 53 of the 72 units analyzed, the highest contribution being obtained by intrusive alkaline bodies (28{+-}12 nGy{center_dot}h{sup -1}). The general pattern of geographic dose distribution respects well the hypotheses on geo-physicochemical behavior of radioactive elements.« less

Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.

PubMed

Zhao, Yan; Guo, Chenyang; Hu, Hongtao; Zheng, Lin; Ma, Junli; Jiang, Li; Zhao, Erjiang; Li, Hailiang

2017-02-07

Previously reported findings on the association between folate intake or serum folate levels and esophageal cancer risk have been inconsistent. This study aims to summarize the evidence regarding these relationships using a dose-response meta-analysis approach. We performed electronic searches of the Pubmed, Medline and Cochrane Library electronic databases to identify studies examining the effect of folate on the risk of esophageal cancer. Ultimately, 19 studies were included in the meta-analysis. Summary odds ratios (ORs) were estimated using a random effects model. A linear regression analysis of the natural logarithm of the OR was carried out to assess the possible dose-response relationship between folate intake and esophageal cancer risk. The pooled ORs for esophageal cancer in the highest vs. lowest levels of dietary folate intake and serum folate were 0.63 (95% CI: 0.56-0.71) and 0.71 (95% CI: 0.55-0.92), respectively. The dose-response meta-analysis indicated that a 100 μg/day increment in dietary folate intake reduced the estimate risk of esophageal cancer by 12%. These findings suggest that dietary and serum folate exert a protective effect against esophageal carcinogenesis.

Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats.

PubMed

Jay Murray, F; Tyl, Rochelle W; Sullivan, Frank M; Tiwary, Asheesh K; Carey, Sandra

2014-11-01

Molybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2μg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain. In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40mgMo/kgbw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40mgMo/kgbw/day, the highest dose tested. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Spatial interpolation of gamma dose in radioactive waste storage facility

NASA Astrophysics Data System (ADS)

Harun, Nazran; Fathi Sujan, Muhammad; Zaidi Ibrahim, Mohd

2018-01-01

External radiation measurement for a radioactive waste storage facility in Malaysian Nuclear Agency is a part of Class G License requirement under Atomic Licensing Energy Board (AELB). The objectives of this paper are to obtain the distribution of radiation dose, create dose database and generate dose map in the storage facility. The radiation dose measurement is important to fulfil the radiation protection requirement to ensure the safety of the workers. There are 118 sampling points that had been recorded in the storage facility. The highest and lowest reading for external radiation recorded is 651 microSv/hr and 0.648 microSv/hour respectively. The calculated annual dose shows the highest and lowest reading is 1302 mSv/year and 1.3 mSv/year while the highest and lowest effective dose reading is 260.4 mSv/year and 0.26 mSv/year. The result shows that the ALARA concept along time, distance and shield principles shall be adopted to ensure the dose for the workers is kept below the dose limit regulated by AELB which is 20 mSv/year for radiation workers. This study is important for the improvement of planning and the development of shielding design for the facility.

Evaluating toxicity of copper(II) oxide nanoparticles (CuO-NPs) through waterborne exposure to tilapia (Oreochromis mossambicus) by tissue accumulation, oxidative stress, histopathology, and genotoxicity.

PubMed

Shahzad, Khurram; Khan, Muhammad Naeem; Jabeen, Farhat; Kosour, Nasreen; Chaudhry, Abdul Shakoor; Sohail, Muhammad

2018-06-01

Metal oxide nanoparticles are widely used in industries, and peak level can be confirmed in their surroundings. In the present study, the sub-lethal effects of CuO-NPs from low to high concentration as 0.5 to 1.5 mg/L were observed in tilapia (Oreochromis mossambicus). Accumulation of copper from CuO-NPs was increased with the increase in doses, and maximum accumulation was found in the gill than liver and muscles. The increased lipid peroxidation level was observed in the gill as compared to liver, and the similar results were obtained in catalase and glutathione while superoxide dismutase level was higher in the liver than gills. In histological alterations, gill edema, curved tips, fusion of gill lamellae, and thickening of primary and secondary gill lamellae were observed. Necrosis and apoptosis with condensed nuclear bodies and pyknotic nuclei were observed in the liver at the highest dose concentration. In a genotoxic study, the highest value of % tail DNA and olive tail movement was observed with increasing concentrations. Copper oxide nanoparticles has greater potential to accumulate in the soft tissues, which may cause respiratory distress such as oxidative stress, induction of antioxidant defense by raising glutathione, organ pathology, and genotoxicity.

Insecticide Transfer Efficiency and Lethal Load in Argentine Ants

DOE PAGES

Hooper-Bui, L. M.; Kwok, E S.C.; Buchholz, B. A.; ...

2015-07-03

Trophallaxis between individual worker ants and the toxicant load in dead and live Argentine ants (Linepithema humile) in colonies exposed to fipronil and hydramethylnon experimental baits were examined using accelerator mass spectrometry (AMS). About 50% of the content of the crop containing trace levels of 14C-sucrose, 14C-hydramethylnon, and 14C-fipronil was shared between single donor and recipient ants. Dead workers and queens contained significantly more hydramethylnon (122.7 and 22.4 amol/μg ant, respectively) than did live workers and queens (96.3 and 10.4 amol/μg ant, respectively). Dead workers had significantly more fipronil (420.3 amol/μg ant) than did live workers (208.5 amol/μg ant), butmore » dead and live queens had equal fipronil levels (59.5 and 54.3 amol/μg ant, respectively). Moreover, the distribution of fipronil differed within the bodies of dead and live queens; the highest amounts of fipronil were recovered in the thorax of dead queens whereas live queens had the highest levels in the head. Resurgence of polygynous ant colonies treated with hydramethylnon baits may be explained by queen survival resulting from sublethal doses due to a slowing of trophallaxis throughout the colony. The bait strategies and dose levels for controlling insect pests need to be based on the specific toxicant properties and trophic strategies for targeting the entire colony.« less

Insecticide Transfer Efficiency and Lethal Load in Argentine Ants

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

Hooper-Bui, L. M.; Kwok, E S.C.; Buchholz, B. A.

Trophallaxis between individual worker ants and the toxicant load in dead and live Argentine ants (Linepithema humile) in colonies exposed to fipronil and hydramethylnon experimental baits were examined using accelerator mass spectrometry (AMS). About 50% of the content of the crop containing trace levels of 14C-sucrose, 14C-hydramethylnon, and 14C-fipronil was shared between single donor and recipient ants. Dead workers and queens contained significantly more hydramethylnon (122.7 and 22.4 amol/μg ant, respectively) than did live workers and queens (96.3 and 10.4 amol/μg ant, respectively). Dead workers had significantly more fipronil (420.3 amol/μg ant) than did live workers (208.5 amol/μg ant), butmore » dead and live queens had equal fipronil levels (59.5 and 54.3 amol/μg ant, respectively). Moreover, the distribution of fipronil differed within the bodies of dead and live queens; the highest amounts of fipronil were recovered in the thorax of dead queens whereas live queens had the highest levels in the head. Resurgence of polygynous ant colonies treated with hydramethylnon baits may be explained by queen survival resulting from sublethal doses due to a slowing of trophallaxis throughout the colony. The bait strategies and dose levels for controlling insect pests need to be based on the specific toxicant properties and trophic strategies for targeting the entire colony.« less

Assessment of doses to game animals in Finland.

PubMed

Vetikko, Virve; Kostiainen, Eila

2013-11-01

A study was carried out to assess the dose rates to game animals in Finland affected by the radioactive caesium deposition that occurred after the accident at the Chernobyl nuclear power plant in Ukraine in 1986. The aim of this assessment was to obtain new information on the dose rates to mammals and birds under Finnish conditions. Dose rates were calculated using the ERICA Assessment Tool developed within the EC 6th Framework Programme. The input data consisted of measured activity concentrations of (137)Cs and (134)Cs in soil and lake water samples and in flesh samples of selected animal species obtained for environmental monitoring. The study sites were located in the municipality of Lammi, Southern Finland, where the average (137)Cs deposition was 46.5 kBq m(-2) (1 October 1987). The study sites represented the areas receiving the highest deposition in Finland after the Chernobyl accident. The selected species included moose (Alces alces), arctic hare (Lepus timidus) and several bird species: black grouse (Tetrao tetrix), hazel hen (Bonasia bonasia), mallard (Anas platurhynchos), goldeneye (Bucephala clangula) and teal (Anas crecca). For moose, dose rates were calculated for the years 1986-1990 and for the 2000s. For all other species, maximal measured activity concentrations were used. The results showed that the dose rates to these species did not exceed the default screening level of 10 μGy h(-1) used as a protection criterion. The highest total dose rate (internal and external summed), 3.7 μGy h(-1), was observed for the arctic hare in 1986. Although the dose rate of 3.7 μGy h(-1) cannot be considered negligible given the uncertainties involved in predicting the dose rates, the possible harmful effects related to this dose rate are too small to be assessed based on current knowledge on the biological effects of low doses in mammals. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

PubMed

Khoza, Star; Moyo, Ishmael; Ncube, Denver

2017-01-01

Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels ( p = 0.0017) and AST levels ( p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment ( p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

Psychopharmacology of theobromine in healthy volunteers.

PubMed

Baggott, Matthew J; Childs, Emma; Hart, Amy B; de Bruin, Eveline; Palmer, Abraham A; Wilkinson, Joy E; de Wit, Harriet

2013-07-01

Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited. We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug's effects in relation to genes related to their target receptors, but few associations were detected. This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative.

Psychopharmacology of theobromine in healthy volunteers

PubMed Central

Baggott, Matthew J.; Childs, Emma; Hart, Amy B.; de Bruin, Eveline; Palmer, Abraham A.; Wilkinson, Joy E.; de Wit, Harriet

2013-01-01

Background Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, currently evidence for this is limited. Objectives We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Results Caffeine had the expected effects on mood including feelings of alertness, and cardiovascular parameters. Theobromine responses differed according to dose: it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses we also examined individual differences in the drugs' effects in relation to genes related to their target receptors, but few associations were detected. Conclusions This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes effects become negative. PMID:23420115

Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration

PubMed Central

Berkó, Szilvia; Szűcs, Kálmán F; Balázs, Boglárka; Csányi, Erzsébet; Varju, Gábor; Sztojkov-Ivanov, Anita; Budai-Szűcs, Mária; Bóta, Judit; Gáspár, Róbert

2016-01-01

Purpose Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. Methods The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Results Both intravenously and EP-administered neostigmine (0.2–66.7 μg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 μg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. Conclusion The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice. PMID:27274203

SU-E-T-573: Normal Tissue Dose Effect of Prescription Isodose Level Selection in Lung Stereotactic Body Radiation Therapy

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

Zhang, Q; Lei, Y; Zheng, D

Purpose: To evaluate dose fall-off in normal tissue for lung stereotactic body radiation therapy (SBRT) cases planned with different prescription isodose levels (IDLs), by calculating the dose dropping speed (DDS) in normal tissue on plans computed with both Pencil Beam (PB) and Monte-Carlo (MC) algorithms. Methods: The DDS was calculated on 32 plans for 8 lung SBRT patients. For each patient, 4 dynamic conformal arc plans were individually optimized for prescription isodose levels (IDL) ranging from 60% to 90% of the maximum dose with 10% increments to conformally cover the PTV. Eighty non-overlapping rind structures each of 1mm thickness weremore » created layer by layer from each PTV surface. The average dose in each rind was calculated and fitted with a double exponential function (DEF) of the distance from the PTV surface, which models the steep- and moderate-slope portions of the average dose curve in normal tissue. The parameter characterizing the steep portion of the average dose curve in the DEF quantifies the DDS in the immediate normal tissue receiving high dose. Provided that the prescription dose covers the whole PTV, a greater DDS indicates better normal tissue sparing. The DDS were compared among plans with different prescription IDLs, for plans computed with both PB and MC algorithms. Results: For all patients, the DDS was found to be the lowest for 90% prescription IDL and reached a highest plateau region for 60% or 70% prescription. The trend was the same for both PB and MC plans. Conclusion: Among the range of prescription IDLs accepted by lung SBRT RTOG protocols, prescriptions to 60% and 70% IDLs were found to provide best normal tissue sparing.« less

Expression of Genes Associated with DNA Damage Sensing in Human Fibroblasts Exposed to Low-dose-rate Gamma Rays

NASA Technical Reports Server (NTRS)

Zhang, Ye; Mehta, Satish; Hammond, Diane; Pierson, Duane; Jeevarajan, Antony; Cucinotta, Francis; Rohde, Larry; Wu, Honglu

2007-01-01

Understanding of the molecular response to low-dose and low-dose-rate radiation exposure is essential for the extrapolation of high-dose radiation risks to those at dose levels relevant to space and other environmental concerns. Most of the reported studies of gene expressions induced by low-dose or low-dose-rate radiation were carried out on exponentially growing cells. In the present study, we analyzed expressions of 84 genes associated with DNA damage sensing using real time PCR in human fibroblasts in mostly G1 phase of the cell cycle. The cells were exposed continuously to gamma rays at a dose rate of 0.8 cGy/hr for 1, 2, 6 or 24 hrs at 37 C throughout the exposure. The total RNA was isolated immediately after the exposure was terminated. Of the 84 genes, only a few showed significant changes of the expression level. Some of the genes (e.g. DDit3 and BTG2) were found to be up or down regulated only after a short period of exposure, while other genes (e.g. PRKDC) displayed a highest expression level at the 24 hr time point. The expression profiles for the exposed cells which had a smaller portion of G1 cells indicated more cell cycle signaling and DNA repair genes either up or down regulated. Interestingly, the panel of genes changed from radiation exposure in G1 cells is different from the panel in cells having less G1 arrest cells. The gene expression profile of the cells responding to low-dose-radiation insult apparently depends on the cell growth stage. The response pathway in G1 cells may differ from that in exponentially growing cells.

Teratology Studies on Lewisite and Sulfur Mustard Agents: Effects of Sulfur Mustard in Rats and Rabbits

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

Hackett, P. L.; Rommereim, R. L.; Burton, F. G.

1987-09-30

Sulfur mustard (HD) was administered to rats and rabbits by intragastric intubation. Rats were dosed daily from 6 through 15 days of gestation (dg) with 0. 0.5, 1.0 or 2.0 mg of HD/kg; rabbits were dosed with 0, 0.4, 0.6 or 0.8 mg/kg on 6 through 19 dg. Maternal animals were weighed periodically and, at necropsy, were examined for gross lesions of major organs and reproductive performance; live fetuses were weighed and examined for external, internal and skeletal defects. In rats, reductions in body weights were observed in maternal animals and their female fetuses at the lowest administered dose (0.5more » mg/kg), but the incidence of fetal malformations was not increased. In rabbits the highest administered dose (0.8 mg/kg) induced maternal mortality and depressed body weight measures but did not affect fetal development. These results suggest that orally administered HD is not teratogenic in rats and rabbits since fetal effects were observed only at dose levels that induced frank maternal toxicity. Estimations of dose ranges for "no observable effects levels" in rats and rabbits, respectively, were: < 0.5 and < 0.4 mg/kg in maternal animals and < 0.5 and > 0.8 mg/kg in their fetuses.« less

Organochlorine pesticides and polychlorinated biphenyls in fish from Lake Awassa in the Ethiopian Rift Valley: human health risks.

PubMed

Deribe, Ermias; Rosseland, Bjørn Olav; Borgstrøm, Reidar; Salbu, Brit; Gebremariam, Zinabu; Dadebo, Elias; Skipperud, Lindis; Eklo, Ole Martin

2014-08-01

Dietary intake of fish containing organic contaminants poses a potential threat to human health. In the present work, an assessment has been carried out to look at the human health risk associated with consumption of fish contaminated with organochlorine pesticides (OCPs) and polychlorinated biphenyles (PCBs) in certain fish species collected from Lake Hawassa, Ethiopia. The health risk assessment was made by comparing the concentrations of OCPs and PCBs in fish muscle tissues with reference doses given in the USEPA guidelines. Dichlorodiphenyltrichloroethanes (DDTs), endosulfans, PCBs and chloridanes were identified in fish species collected from Lake Hawassa. The most predominant pesticides were DDTs, with mean concentrations of ΣDDT ranging from 19 to 56 ng g(-1) wet weights. The highest concentrations of DDTs were found in Barbus intermedius, representing the highest trophic level. PCBs, DDT and endosulfan concentrations found in B. intermedius exceeded the reference dose for children between the ages of 0-1 year (with hazard index of above 1.0). Therefore, consumption of fish from a high trophic level (e.g. B. intermedius) from Lake Hawassa may pose a special health risk to children.

Deficiency of macro- and micronutrients induced by Lentinula edodes.

PubMed

Grotto, D; Gerenutti, M; Souza, V C O; Barbosa, F

2015-01-01

Mushroom Lentinula edodes has been widely studied therapeutically. However, there is no data regarding its daily intake level safety. Since L. edodes has many active compounds known to bind to metals, we evaluated macro and micronutrients in liver and kidney of healthy rats after subchronic exposure to L. edodes . Rats were divided into four groups, receiving water and L. edodes at 100, 400 and 800 mg/kg/day. The treatment lasted 30 days. Essential elements (Zn, Cu, Mg, Fe, Mn, Se, Co, Mo, and Li) were analyzed in an inductively coupled plasma mass spectrometer. Our results demonstrated a significant decrease in Cu, Fe, Mn and Co levels in liver of rats receiving L. edodes at the highest doses. In kidney, Mn, Mo and Li concentrations significantly dropped in the groups exposed to the highest doses. In this way, an important point is revealed concerning the food safety from L. edodes , once its chronic and high consumption could contribute to macro and micronutrients deficiency. Additionally, we speculate that the daily use of L. edodes could be unsuccessful for patients in mineral therapy besides being able to be unsafe for individuals with some propensity to mineral deficiency.

Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

PubMed Central

Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

2016-01-01

ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

Developmental Exposure to Perchlorate Alters Synaptic Transmission in Hippocampus of the Adult Rat

PubMed Central

Gilbert, Mary E.; Sui, Li

2008-01-01

Background Perchlorate is an environmental contaminant that blocks iodine uptake into the thyroid gland and reduces thyroid hormones. This action of perchlorate raises significant concern over its effects on brain development. Objectives The purpose of this study was to evaluate neurologic function in rats after developmental exposure to perchlorate. Methods Pregnant rats were exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning. Adult male offspring were evaluated on a series of behavioral tasks and neurophysiologic measures of synaptic function in the hippocampus. Results At the highest perchlorate dose, triiodothyronine (T3) and thyroxine (T4) were reduced in pups on postnatal day 21. T4 in dams was reduced relative to controls by 16%, 28%, and 60% in the 30-, 300-, and 1,000-ppm dose groups, respectively. Reductions in T4 were associated with increases in thyroid-stimulating hormone in the high-dose group. No changes were seen in serum T3. Perchlorate did not impair motor activity, spatial learning, or fear conditioning. However, significant reductions in baseline synaptic transmission were observed in hippocampal field potentials at all dose levels. Reductions in inhibitory function were evident at 300 and 1,000 ppm, and augmentations in long-term potentiation were observed in the population spike measure at the highest dose. Conclusions Dose-dependent deficits in hippocampal synaptic function were detectable with relatively minor perturbations of the thyroid axis, indicative of an irreversible impairment in synaptic transmission in response to developmental exposure to perchlorate. PMID:18560531

The pathology of americium 241.

PubMed

Nilsson, A; Broomé-Karlsson, A

1976-02-01

Male CBA-mice were injected intraperitoneally with different doses of 241Am-citrate (16, 8, 0.4, 0.2, 0.04 muCi/kg). The two highest doses were highly destructive of the haematopoietic tissues, testes and bone tissue. The highest frequency of induced tumours of the skeleton and haematopoietic tissue was found in the 8 muCi group. In the liver, adrenal glands, kidney and heart degenerative lesions were found mainly in the higher dose groups. In the lower dose groups degenerative lesions seemed to appear earlier and at a higher frequency than in the control group.

Uranium in drinking water: renal effects of long-term ingestion by an aboriginal community.

PubMed

Zamora, Maria L Limson; Zielinski, Jan M; Moodie, Gerry B; Falcomer, Renato A F; Hunt, Wendy C; Capello, Kevin

2009-01-01

The authors conducted a study of an aboriginal community to determine if kidney func-tion had been affected by the chronic ingestion of uranium in drinking water from the community's drilled wells. Uranium concentrations in drinking water varied from < 1 to 845 ppb. This nonin-vasive study relied on the measurement of a combination of urinary indicators of kidney function and markers for cell toxicity. In all, 54 individuals (12-73 years old) participated in the study. Correlation of uranium excreted in urine with bio-indicators at p

Dose-related gene expression changes in forebrain following acute, low-level chlorpyrifos exposure in neonatal rats

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

Ray, Anamika; Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078; Liu Jing

2010-10-15

Chlorpyrifos (CPF) is a widely used organophosphorus insecticide (OP) and putative developmental neurotoxicant in humans. The acute toxicity of CPF is elicited by acetylcholinesterase (AChE) inhibition. We characterized dose-related (0.1, 0.5, 1 and 2 mg/kg) gene expression profiles and changes in cell signaling pathways 24 h following acute CPF exposure in 7-day-old rats. Microarray experiments indicated that approximately 9% of the 44,000 genes were differentially expressed following either one of the four CPF dosages studied (546, 505, 522, and 3,066 genes with 0.1, 0.5, 1.0 and 2.0 mg/kg CPF). Genes were grouped according to dose-related expression patterns using K-means clusteringmore » while gene networks and canonical pathways were evaluated using Ingenuity Pathway Analysis (registered) . Twenty clusters were identified and differential expression of selected genes was verified by RT-PCR. The four largest clusters (each containing from 276 to 905 genes) constituted over 50% of all differentially expressed genes and exhibited up-regulation following exposure to the highest dosage (2 mg/kg CPF). The total number of gene networks affected by CPF also rose sharply with the highest dosage of CPF (18, 16, 18 and 50 with 0.1, 0.5, 1 and 2 mg/kg CPF). Forebrain cholinesterase (ChE) activity was significantly reduced (26%) only in the highest dosage group. Based on magnitude of dose-related changes in differentially expressed genes, relative numbers of gene clusters and signaling networks affected, and forebrain ChE inhibition only at 2 mg/kg CPF, we focused subsequent analyses on this treatment group. Six canonical pathways were identified that were significantly affected by 2 mg/kg CPF (MAPK, oxidative stress, NF{Kappa}B, mitochondrial dysfunction, arylhydrocarbon receptor and adrenergic receptor signaling). Evaluation of different cellular functions of the differentially expressed genes suggested changes related to olfactory receptors, cell adhesion/migration, synapse/synaptic transmission and transcription/translation. Nine genes were differentially affected in all four CPF dosing groups. We conclude that the most robust, consistent changes in differential gene expression in neonatal forebrain across a range of acute CPF dosages occurred at an exposure level associated with the classical marker of OP toxicity, AChE inhibition. Disruption of multiple cellular pathways, in particular cell adhesion, may contribute to the developmental neurotoxicity potential of this pesticide.« less

Effects of long-term corticosterone implants on growth and immune function in juvenile alligators, Alligator mississippiensis.

PubMed

Morici, L A; Elsey, R M; Lance, V A

1997-10-01

Sixty juvenile alligators were implanted subcutaneously with slow release pellets of corticosterone or placebo. Alligators were divided into five different groups such that each group received a different dose. A blood sample was taken prior to and 4 days after the implants were in place to measure hormone levels. Additional blood samples were collected at 1 month and 3 months. At 4 days corticosterone levels ranged from 3,400 ng/ml in the group treated with the high dose to 40 ng/ml in the group implanted with the low dose. The extremely high dose caused 40% mortality within 4 weeks. It was evident that the pellets did not release the hormone for the expected 90 days. Circulating levels of corticosterone were back to baseline levels by 3 months. Hormone levels achieved at 4 days were a reliable predictor of subsequent growth. Rate of growth was negatively correlated with plasma corticosterone at 4 days (r2 = 0.711) and at 1 month (r2 = 0.544) posttreatment. Differential white blood cell counts performed after 1 month of treatment showed a clear effect of the implant. Alligators treated with corticosterone had decreased percentages of lymphocytes, eosinophils, and basophils and had a higher heterophil/lymphocyte (H/L) ratio than the placebo group. Furthermore, histological examination of the spleen revealed a significant depletion of lymphoid cells in alligators treated with the highest dose of hormone. The results from this study demonstrate that exogenous corticosterone can mimic the effects of prolonged stress in juvenile alligators.

Evaluation of automatic exposure control system chamber for the dose optimization when examining pelvic in digital radiography.

PubMed

Kim, Sung-Chul; Lee, Hae-Kag; Lee, Yang-Sub; Cho, Jae-Hwan

2015-01-01

We found a way to optimize the image quality and reduce the exposure dose of patients through the proper activity combination of the automatic exposure control system chamber for the dose optimization when examining the pelvic anteroposterior side using the phantom of the human body standard model. We set 7 combinations of the chamber of automatic exposure control system. The effective dose was yielded by measuring five times for each according to the activity combination of the chamber for the dose measurement. Five radiologists with more than five years of experience evaluated the image through picture archiving and communication system using double blind test while classifying the 6 anatomical sites into 3-point level (improper, proper, perfect). When only one central chamber was activated, the effective dose was found to be the highest level, 0.287 mSv; and lowest when only the top left chamber was used, 0.165 mSv. After the subjective evaluation by five panel members on the pelvic image was completed, there was no statistically meaningful difference between the 7 chamber combinations, and all had good image quality. When testing the pelvic anteroposterior side with digital radiography, we were able to reduce the exposure dose of patients using the combination of the top right side of or the top two of the chamber.

Effects of a Single Dose of Parecoxib on Inflammatory Response and Ischemic Tubular Injury Caused by Hemorrhagic Shock in Rats.

PubMed

Takaku, Mariana; da Silva, Andre Carnevali; Iritsu, Nathalie Izumi; Vianna, Pedro Thadeu Galvao; Castiglia, Yara Marcondes Machado

2018-01-01

Parecoxib, a selective COX-2 inhibitor, is used to improve analgesia in postoperative procedures. Here we evaluated whether pretreatment with a single dose of parecoxib affects the function, cell injury, and inflammatory response of the kidney of rats subjected to acute hemorrhage. Inflammatory response was determined according to serum and renal tissue cytokine levels (IL-1 α , IL-1 β , IL-6, IL-10, and TNF- α ). Forty-four adult Wistar rats anesthetized with sevoflurane were randomized into four groups: placebo/no hemorrhage (Plc/NH); parecoxib/no hemorrhage (Pcx/NH); placebo/hemorrhage (Plc/H); and parecoxib/hemorrhage (Pcx/H). Pcx groups received a single dose of intravenous parecoxib while Plc groups received a single dose of placebo (isotonic saline). Animals in hemorrhage groups underwent bleeding of 30% of blood volume. Renal function and renal histology were then evaluated. Plc/H showed the highest serum levels of cytokines, suggesting that pretreatment with parecoxib reduced the inflammatory response in rats subjected to hemorrhage. No difference in tissue cytokine levels between groups was observed. Plc/H showed higher percentage of tubular dilation and degeneration, indicating that parecoxib inhibited tubular injury resulting from renal hypoperfusion. Our findings indicate that pretreatment with a single dose of parecoxib reduced the inflammatory response and tubular renal injury without altering renal function in rats undergoing acute hemorrhage.

Quercetin dose affects the fate of hepatic ischemia and reperfusion injury in rats: An experimental research.

PubMed

Uylaş, Mustafa Ufuk; Şahin, Adnan; Şahintürk, Varol; Alataş, İbrahim Özkan

2018-05-01

Quercetin found in fruits and vegetables has an antioxidative effect. We aimed to investigate the protective effects of quercetin according to different doses on hepatic and ischemia-reperfusion (I/R) injury. Fifty mature male Sprague-Dawley rats were randomly divided into five groups (n = 10 for each). All the animal groups underwent laparotomy. Group 1 rats served as a sham-operated group. Groups 2-5 underwent 1 h hepatic ischemia and were followed by 2 h reperfusion. Group 3-5 animals received an additional intraperitoneal dose of 25, 50 or 100 mg/kg quercetin respectively before I/R operation. Blood samples were collected for determining serum aspartate transaminase (AST), alanine transaminase (ALT) and malondialdehyde (MDA) levels. Also, liver tissue samples were taken for measuring of liver MDA concentration and for histopathology assessment. The highest levels of biochemical parameters were observed in group 2. In quercetin-treated groups, serum AST, ALT, MDA levels, and tissue MDA concentration were decreased as inversely with increasing quercetin dose. Microscopic evaluation revealed that most conspicuous histological improvement was observed in 50 mg/kg quercetin co-treated rats. 25 and 100 mg/kg quercetin co-treatment could not protect completely against hepatic I/R injury. Quercetin can be effective in preventing of hepatic I/R injury when the correct dose was used. Copyright © 2018. Published by Elsevier Ltd.

Work-related lesions of the supraspinatus tendon: a case-control study.

PubMed

Seidler, Andreas; Bolm-Audorff, Ulrich; Petereit-Haack, Gabriela; Ball, Elke; Klupp, Magdalena; Krauss, Noëlle; Elsner, Gine

2011-04-01

To examine the dose-response relationship between cumulative duration of work with highly elevated arms (work above shoulder level) as well as of manual material handling and ruptures of the supraspinatus tendon in a population-based case-control study. In 14 radiologic practices, we recruited 483 male patients aged 25-65 with radiographically confirmed partial (n = 385) or total (n = 98) supraspinatus tears associated with shoulder pain. A total of 300 male control subjects were recruited. Data were gathered in a structured personal interview. To calculate cumulative exposure, the self-reported duration of lifting/carrying of heavy loads (>20 kg) as well as the duration of work with highly elevated arms was added up over the entire working life. The results of our study support a dose-response relationship between cumulative duration of work with highly elevated arms and symptomatic supraspinatus tendon tears. For a cumulative duration of >3,195 h work above shoulder level, the risk of a supraspinatus tendon rupture is elevated to 2.0 (95% CI 1.1-3.5), adjusted for age, region, lifting/carrying of heavy loads, handheld vibration, apparatus gymnastics/shot put/javelin/hammer throwing/wrestling, and tennis. The cumulative duration of carrying/lifting of heavy loads also yields a positive dose-response relation with disease (independent from work above shoulder level and from handheld vibration), with an adjusted odds ratio of 1.8 (95% CI 1.0-3.2) in the highest exposure category (>77 h). We find an increased risk for subjects exposed to handheld vibration with an adjusted OR of 3.2 (95% CI 1.7-5.9) in the highest exposure category (16 years or more in the job with exposure), but a clear dose-response relationship is lacking. This study points to a potential etiologic role of long-term cumulative effects of work with highly elevated arms and heavy lifting/carrying on shoulder tendon disorders.

Effects of Chronic Exposure to an Environmentally Relevant Mixture of Brominated Flame Retardants on the Reproductive and Thyroid System in Adult Male Rats

PubMed Central

Ernest, Sheila R.; Wade, Michael G.; Lalancette, Claudia; Ma, Yi-Qian; Berger, Robert G.; Robaire, Bernard; Hales, Barbara F.

2012-01-01

Brominated flame retardants (BFRs) are incorporated into a wide variety of consumer products, are readily released into home and work environments, and are present in house dust. Studies using animal models have revealed that exposure to polybrominated diphenyl ethers (PBDEs) may impair adult male reproductive function and thyroid hormone physiology. Such studies have generally characterized the outcome of acute or chronic exposure to a single BFR technical mixture or congener but not the impact of environmentally relevant BFR mixtures. We tested whether exposure to the BFRs found in house dust would have an adverse impact on the adult male rat reproductive system and thyroid function. Adult male Sprague Dawley rats were exposed to a complex BFR mixture composed of three commercial brominated diphenyl ethers (52.1% DE-71, 0.4% DE-79, and 44.2% decaBDE-209) and hexabromocyclododecane (3.3%), formulated to mimic the relative congener levels in house dust. BFRs were delivered in the diet at target doses of 0, 0.02, 0.2, 2, or 20 mg/kg/day for 70 days. Compared with controls, males exposed to the highest dose of BFRs displayed a significant increase in the weights of the kidneys and liver, which was accompanied by induction of CYP1A and CYP2B P450 hepatic drug–metabolizing enzymes. BFR exposure did not affect reproductive organ weights, serum testosterone levels, testicular function, or sperm DNA integrity. The highest dose caused thyroid toxicity as indicated by decreased serum thyroxine (T4) and hypertrophy of the thyroid gland epithelium. At lower doses, the thickness of the thyroid gland epithelium was reduced, but no changes in hormone levels (T4 and thyroid-stimulating hormone) were observed. Thus, exposure to BFRs affected liver and thyroid physiology but not male reproductive parameters. PMID:22387749

Pharmacological evaluation for anticancer and immune activities of a novel polysaccharide isolated from Boletus speciosus Frost.

PubMed

Hou, Yiling; Ding, Xiang; Hou, Wanru; Song, Bo; Wang, Ting; Wang, Fang; Li, Jian; Zeng, Yichun; Zhong, Jie; Xu, Ting; Zhu, Hongqing

2014-04-01

The fungal polysaccharides have been revealed to exhibit a variety of biological activities, including antitumor, immune-stimulation and antioxidation activities. In the present study, the immune and anticancer activities of a novel polysaccharide, BSF-A, isolated from Boletus speciosus Frost was investigated. The inhibitory rate of S180 tumors in mice treated with 40 mg/kg BSF-A reached 62.449%, which was the highest rate from the three doses administered; this may be comparable to mannatide. The antitumor activity of BSF-A is commonly considered to be a consequence of the stimulation of the cell-mediated immune response, as it may significantly promote the macrophage cells in the dose range of 100-400 µg/ml in vitro. The levels of the cytokines, IL-6, IL-1β and TNF-α, and nitric oxide, induced by BSF-A treatment at varying concentrations in the macrophage cells were similar to the levels in the cells treated with lipopolysaccharide. There was weak expression of the TNF-α, IL-6, IL-1β and inducible nitric oxide synthase mRNA in the untreated macrophages, but this increased significantly in a dose-dependent manner in the BSF-A-treated cells. BSF-A also had a time- and dose-dependent effect on the growth inhibition of the Hep-2 cells, with the concentration of 400 µg/ml having the highest inhibitory rate. A quantitative PCR array analysis of the gene expression profiles indicated that BSF-A had anticancer activities that affected cell apoptosis in the Hep-2 cells. The results obtained in the present study indicated that the purified polysaccharide of Boletus speciosus Frost is a potential source of natural anticancer substances.

Pulmonary deposition modeling with airborne fiber exposure data: a study of workers manufacturing refractory ceramic fibers.

PubMed

Lentz, Thomas J; Rice, Carol H; Succop, Paul A; Lockey, James E; Dement, John M; LeMasters, Grace K

2003-04-01

Increasing production of refractory ceramic fiber (RCF), a synthetic vitreous material with industrial applications (e.g., kiln insulation), has created interest in potential respiratory effects of exposure to airborne fibers during manufacturing. An ongoing study of RCF manufacturing workers in the United States has indicated an association between cumulative fiber exposure and pleural plaques. Fiber sizing data, obtained from electron microscopy analyses of 118 air samples collected in three independent studies over a 20-year period (1976-1995), were used with a computer deposition model to estimate pulmonary dose of fibers of specified dimensions for 652 former and current RCF production workers. Separate dose correction factors reflecting differences in fiber dimensions in six uniform job title groups were used with data on airborne fiber concentration and employment duration to calculate cumulative dose estimates for each worker. From review of the literature, critical dimensions (diameter <0.4 microm, length <10 microm) were defined for fibers that may translocate to the parietal pleura. Each of three continuous exposure/dose metrics analyzed in separate logistic regression models was significantly related to plaques, even after adjusting for possible past asbestos exposure: cumulative fiber exposure, chi(2) = 15.2 (p < 0.01); cumulative pulmonary dose (all fibers), chi(2) = 14.6 (p < 0.01); cumulative pulmonary dose (critical dimension fibers), chi(2) = 12.4 (p < 0.01). Odds ratios (ORs) were calculated for levels of each metric. Increasing ORs were statistically significant for the two highest dose levels of critical dimension fibers (level three, OR = 11, 95%CI = [1.4, 98]; level four, OR = 25, 95%CI = [3.2, 190]). Similar associations existed for all metrics after adjustment for possible asbestos exposure. It was concluded that development of pleural plaques follows exposure- and dose-response patterns, and that airborne fibers in RCF manufacturing facilities include those with critical dimensions associated with pleural plaque formation. Analysis of additional air samples may improve estimates of the dose-response relationship.

THE HIGH BACKGROUND RADIATION AREA IN RAMSAR IRAN: GEOLOGY, NORM, BIOLOGY, LNT, AND POSSIBLE REGULATORY FUN

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

Karam, P. A.

2002-02-25

The city of Ramsar Iran hosts some of the highest natural radiation levels on earth, and over 2000 people are exposed to radiation doses ranging from 1 to 26 rem per year. Curiously, inhabitants of this region seem to have no greater incidence of cancer than those in neighboring areas of normal background radiation levels, and preliminary studies suggest their blood cells experience fewer induced chromosomal abnormalities when exposed to 150 rem ''challenge'' doses of radiation than do the blood cells of their neighbors. This paper will briefly describe the unique geology that gives Ramsar its extraordinarily high background radiationmore » levels. It will then summarize the studies performed to date and will conclude by suggesting ways to incorporate these findings (if they are borne out by further testing) into future radiation protection standards.« less

Protein phosphatases 2A as well as reactive oxygen species involved in tributyltin-induced apoptosis in mouse livers.

PubMed

Zhang, Yali; Chen, Yonggang; Sun, Lijun; Liang, Jing; Guo, Zonglou; Xu, Lihong

2014-02-01

Tributyltin (TBT), a highly toxic environmental contaminant, has been shown to induce caspase-3-dependent apoptosis in human amniotic cells through protein phosphatase 2A (PP2A) inhibition and consequent JNK activation. This in vivo study was undertaken to further verify the results derived from our previous in vitro study. Mice were orally dosed with 0, 10, 20, and 60 mg/kg of body weight TBT, and levels of PP2A, reactive oxygen species (ROS), mitogen-activated protein kinase (MAPK), Bax/Bcl-2, and caspase-3 were detected in the mouse livers. Apoptosis was also evaluated using the TUNEL assay. The results showed that PP2A activity was inhibited, ROS levels were elevated, and MAPKs including ERK, JNK, and p38 were activated in mouse livers treated with the highest dose of TBT. Additionally, the ratio of Bax/Bcl-2 was increased, caspase-3 was activated, and apoptosis in mouse livers could be detected in the highest dose group. Therefore, a possible signaling pathway in TBT-induced apoptosis in mouse livers involves PP2A inhibition and ROS elevation serving a pivotal function as upstream activators of MAPKs; activation of MAPKs in turn leads to an increase in the Bax/Bcl-2 ratio, ultimately leading to the activation of caspase-3. The results give a comprehensive and novel description of the mechanism of TBT-induced toxicity. Copyright © 2011 Wiley Periodicals, Inc., A Wiley Company.

Characteristics and outcomes of Italian patients from the observational, multicentre, hypopituitary control and complications study (HypoCCS) according to tertiles of growth hormone peak concentration following stimulation testing at study entry.

PubMed

Losa, Marco; Beck-Peccoz, Paolo; Aimaretti, Gianluca; Di Somma, Carolina; Ambrosio, Maria Rosaria; Ferone, Diego; Giampietro, Antonella; Corsello, Salvatore M; Poggi, Maurizio; Scaroni, Carla; Jia, Nan; Mossetto, Gilberto; Cannavò, Salvatore; Rochira, Vincenzo

2015-10-01

To determine whether characteristics and outcomes of Italian patients in the observational global Hypopituitary Control and Complication Study (HypoCCS) differed according to the degree of GH deficiency (GHD). Patients were grouped by tertiles of stimulated GH peak concentration at baseline (Group A lowest tertile, n = 342; Group B middle tertile, n = 345; Group C highest tertile, n = 338). Baseline demographics, lipid levels, body mass index categories and mean Framingham cardiovascular risk indexes were similar in the three groups and remained substantially unchanged over time, with no subsequent significant between-group differences (except mean levels of triglycerides increased in the highest tertile group). GHD was adult-onset for >75% of patients in all groups. The percentage of patients with multiple pituitary deficiencies was higher in Group A than in the other groups; isolated GHD was reported with highest frequency in Group C. Patients in Group A received the lowest mean starting dose of GH. Hyperlipidaemia at baseline was reported in 35·1%, 31·1% and 24·7% of patients in groups A, B and C, respectively (P = 0·029). Mean duration of GH treatment was 7·21, 5·45 and 4·96 years, respectively. The proportion of patients with adverse events did not differ significantly between groups, with a low prevalence over time of diabetes and cancer. In Italian patients from HypoCCS, the level of GH deficit did not influence changes over time in metabolic parameters or adverse event profile, despite differences in GHD severity at baseline and in the starting GH dose. © 2015 John Wiley & Sons Ltd.

Radiation enhanced modification of HDPE for medical applications.

PubMed

Suwanprateeb, J; Trongtong, P

2003-10-01

Comparison of gamma irradiation induced change in properties in terms of thermal and mechanical properties between two grades of HDPE and UHMWPE was carried out. It was found that the responses to irradiation of two grades of HDPE investigated were close whereas a difference in response was found between HDPE and UHMWPE. The irradiation dose that caused the lowest wear and highest hardness for UHMWPE was 500 kGy. When irradiation dose was above 500 kGy, no significant changes in wear and hardness properties were observed. The irradiation dose for HDPE, both 2208J and 7000F, that caused the wear resistance and hardness comparable to irradiated UHMWPE at 500 kGy was 1000 kGy. In addition, the dose of 750 kGy was needed for HDPE to achieve the similar level of wear resistance as non-irradiated UHMWPE. Copyright 2003 Kluwer Acadamic Publishers

Methylmercury in dried shark fins and shark fin soup from American restaurants.

PubMed

Nalluri, Deepthi; Baumann, Zofia; Abercrombie, Debra L; Chapman, Demian D; Hammerschmidt, Chad R; Fisher, Nicholas S

2014-10-15

Consumption of meat from large predatory sharks exposes human consumers to high levels of toxic monomethylmercury (MMHg). There also have been claims that shark fins, and hence the Asian delicacy shark fin soup, contain harmful levels of neurotoxic chemicals in combination with MMHg, although concentrations of MMHg in shark fins are unknown. We measured MMHg in dried, unprocessed fins (n=50) of 13 shark species that occur in the international trade of dried shark fins as well as 50 samples of shark fin soup prepared by restaurants from around the United States. Concentrations of MMHg in fins ranged from 9 to 1720 ng/g dry wt. MMHg in shark fin soup ranged from <0.01 to 34 ng/mL, with MMHg averaging 62 ± 7% of total Hg. The highest concentrations of MMHg and total Hg were observed in both fins and soup from large, high trophic level sharks such as hammerheads (Sphyrna spp.). Consumption of a 240 mL bowl of shark fin soup containing the average concentration of MMHg (4.6 ng/mL) would result in a dose of 1.1 μg MMHg, which is 16% of the U.S. EPA's reference dose (0.1 μg MMHg per 1 kg per day in adults) of 7.4 μg per day for a 74 kg person. If consumed, the soup containing the highest measured MMHg concentration would exceed the reference dose by 17%. While shark fin soup represents a potentially important source of MMHg to human consumers, other seafood products, particularly the flesh of apex marine predators, contain much higher MMHg concentrations and can result in substantially greater exposures of this contaminant for people. Copyright © 2014 Elsevier B.V. All rights reserved.

Effectiveness and efficiency of potassium fertilizer application to increase the production and quality of rice in entisols

NASA Astrophysics Data System (ADS)

Hartati, S.; Suryono; Purnomo, D.

2018-03-01

The study aimed to determine the appropriate dose of K-type fertilizer on the production and quality of IR-64 rice varieties in Entisols. The study was conducted on Entisols, Nglarang, Basin, Kebonarum, Klaten, Central Java, Indonesia. Randomized Complete Block Design (RCBD) was used with 2 factors and three replicates. Factor I: types of K fertilizer: KCl, ZK, and KNO3. Factor II: K fertilizer dose consists of four levels: 0, 50, 100 and 150 kg K2O ha-1. The results showed that the type of K fertilizer KCl, ZK, and KNO3 gave similar effect on growth and yield of rice variety IR 64 on Entisols. Dose of K fertilizer increased the growth and yield of rice but an increased dose provides improved meaningful results. K fertilizer with a dose of 50 kg ha-1 K2O is the most efficient, with the agronomic efficiency for dry grain highest yield of 13.6 kg/kg K2O achieved by ZK fertilizer.

Locomotor activating effects of cocaine and scopolamine combinations in rats: isobolographic analysis

PubMed Central

Thomsen, Morgane

2014-01-01

Muscarinic cholinergic receptors are receiving renewed interest as viable targets for treating various psychiatric disorders. Dopaminergic and muscarinic systems interact in complex ways. The goal of this study was to quantify the interaction of a systemically administered psychomotor stimulant and muscarinic antagonist at the behavioral level. Using isobolographic analysis of locomotor activity data, we assessed the effects of three cocaine/scopolamine mixtures in terms of deviation from simple dose addition (additivity), at four effect levels. All three mixtures produced some more-than-additive (synergistic) effects, as lower doses were needed to produce given effects relative to the calculated effect of additive doses. A mixture with comparable contributions from cocaine and scopolamine produced significantly more-than-additive effects at all but the lowest effect level examined. A mostly-cocaine mixture was more-than-additive at low effect levels only, while a mostly-scopolamine mixture produced effects more consistent with additivity, with only the highest effect level barely reaching significant synergism. Our study confirms and quantifies previous findings that suggested synergistic effects of stimulants and muscarinic antagonists. The synergism implies that cocaine and scopolamine stimulate locomotor activity through non-identical pathways, and was most pronounced for a mixture containing cocaine and scopolamine in comparable proportions. PMID:24769455

Ozone dose-response relationships for spring oilseed rape and broccoli

NASA Astrophysics Data System (ADS)

De Bock, Maarten; Op de Beeck, Maarten; De Temmerman, Ludwig; Guisez, Yves; Ceulemans, Reinhart; Vandermeiren, Karine

2011-03-01

Tropospheric ozone is an important air pollutant with known detrimental effects for several crops. Ozone effects on seed yield, oil percentage, oil yield and 1000 seed weight were examined for spring oilseed rape ( Brassica napus cv. Ability). For broccoli ( Brassica oleracea L. cv. Italica cv. Monaco) the effects on fresh marketable weight and total dry weight were studied. Current ozone levels were compared with an increase of 20 and 40 ppb during 8 h per day, over the entire growing season. Oilseed rape seed yield was negatively correlated with ozone dose indices calculated from emergence until harvest. This resulted in an R2 of 0.24 and 0.26 ( p < 0.001) for the accumulated hourly O 3 exposure over a threshold of 40 ppb (AOT40) and the phytotoxic ozone dose above a threshold of 6 nmol m -2 s -1 (POD 6) respectively. Estimated critical levels, above which 5% yield reduction is expected, were 3.7 ppm h and 4.4 mmol m -2 respectively. Our results also confirm that a threshold value of 6 nmol s -1 m -2 projected leaf area, as recommended for agricultural crops (UNECE, Mills, 2004), can indeed be applied for spring oilseed rape. The reduction of oilseed rape yield showed the highest correlation with the ozone uptake during the vegetative growth stage: when only the first 47 days after emergence were used to calculate POD 6, R2 values increased up to 0.476 or even 0.545 when the first 23 days were excluded. The highest ozone treatments, corresponding to the future ambient level by 2100 (IPCC, Meehl et al., 2007), led to a reduction of approximately 30% in oilseed rape seed yield in comparison to the current ozone concentrations. Oil percentage was also significantly reduced in response to ozone ( p < 0.001). As a consequence oil yield was even more severely affected by elevated ozone exposure compared to seed yield: critical levels for oil yield dropped to 3.2 ppm h and 3.9 mmol m -2. For broccoli the applied ozone doses had no effect on yield.

Extrapolating theoretical efficacy of inactivated influenza A/H5N1 virus vaccine from human immunogenicity studies

PubMed Central

Feldstein, Leora R.; Matrajt, Laura; Halloran, M. Elizabeth; Keitel, Wendy A.; Longini, Ira M.

2016-01-01

Influenza A virus subtype H5N1 has been a public health concern for almost 20 years due to its potential ability to become transmissible among humans. Phase I and II clinical trials have assessed safety, reactogenicity and immunogenicity of inactivated influenza A/H5N1 virus vaccines. A shortage of vaccine is likely to occur during the first months of a pandemic. Hence, determining whether to give one dose to more people or two doses to fewer people to best protect the population is essential. We use hemagglutination-inhibition antibody titers as an immune correlate for avian influenza vaccines. Using an established relationship to obtain a theoretical vaccine efficacy from immunogenicity data from thirteen arms of six phase I and phase II clinical trials of inactivated influenza A/H5N1 virus vaccines, we assessed: 1) the proportion of theoretical vaccine efficacy achieved after a single dose (defined as primary response level), and 2) whether theoretical efficacy increases after a second dose, with and without adjuvant. Participants receiving vaccine with AS03 adjuvant had higher primary response levels (range: 0.48–0.57) compared to participants receiving vaccine with MF59 adjuvant (range: 0.32–0.47), with no observed trends in primary response levels by antigen dosage. After the first and second doses, vaccine with AS03 at dosage levels 3.75, 7.5 and 15 mcg had the highest estimated theoretical vaccine efficacy: Dose 1) 45% (95%CI: 36–57%), 53% (95%CI: 42–63%) and 55% (95%CI: 44–64%), respectively and Dose 2) 93% (95%CI: 89–96%), 97% (95%CI: 95–98%) and 97% (95%CI: 96–100%), respectively. On average, the estimated theoretical vaccine efficacy of lower dose adjuvanted vaccines (AS03 and MF59) was 17% higher than that of higher dose unadjuvanted vaccines, suggesting that including an adjuvant is dose-sparing. These data indicate adjuvanted inactivated influenza A/H5N1 virus vaccine produces high theoretical efficacy after two doses to protect individuals against a potential avian influenza pandemic. PMID:27268778

Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration

PubMed Central

Gonçalves de Albuquerque, Cassiano Felippe; Burth, Patrícia; Younes Ibrahim, Mauricio; Garcia, Diogo Gomes; Bozza, Patrícia Torres; Castro Faria Neto, Hugo Caire; Castro Faria, Mauro Velho

2012-01-01

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets. PMID:22529526

Reduced plasma nonesterified fatty acid levels and the advent of an acute lung injury in mice after intravenous or enteral oleic acid administration.

PubMed

Gonçalves de Albuquerque, Cassiano Felippe; Burth, Patrícia; Younes Ibrahim, Mauricio; Garcia, Diogo Gomes; Bozza, Patrícia Torres; Castro Faria Neto, Hugo Caire; Castro Faria, Mauro Velho

2012-01-01

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets.

Microdose-induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

PubMed Central

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W.; Cimino, George D.; Tepper, Clifford G.; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-xian; Henderson, Paul T.

2017-01-01

We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry (AMS) in blood and tumor samples collected within 24 hours, and compared to subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [14C]carboplatin or [14C]gemcitabine and the resulting drug-DNA adduct levels were compared to tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. PMID:27903751

Digoxin: placental transfer, effects on the fetus, and therapeutic use in the newborn.

PubMed

Soyka, L F

1975-03-01

Digoxin rapidly crosses the placenta and reaches equilibrium, with maternal and fetal sera having equal concentrations. Virtually nothing is known about the effects of transplacentally administered digoxin on the fetus. Toxicity has been reported in the fetus of a woman ingesting a huge overdose of digitoxin; the same result would be anticipated with digoxin poisoning. Serum levels in pregnant women receiving the standard dose of 0.25 mg tend to be subnormal and certain patients may require a small increase in dose during the last trimester. While the full-term neonate appears to tolerate relatively high doses and the resultant high serum levels, there is no compelling evidence that such doses are necessary or even useful. Since toxicity can and does occur in neonates, especially during administration of loading (digitalizing) doses, it is recommended that maintenance doses of 0.01 mg per kg per day be used routinely. If the full inotropic effect is needed immediately, a loading dose of 0.03 mg per kg may be employed. Maintenance therapy is then begun on the following day. Without a loading dose cumulation occurs for about 3 days; after 5 or so days, serum levels will equal those found after use of a loading dose followed by maintenance therapy. Results of a single study suggest that the daily dose should be divided and given every 12 hours. After about 1 week of therapy, the serum level should be determined and the dose modified to maintain a serum level of 1 to 2 ng per ml. If the therapeutic effect is less than desired, a cautions increase in dose to as high as 0.02 mg per kg per day or to that dose which produces serum levels up to 3 ng per ml can be tried. Certain infants appear to tolerate serum levels of 3.5 to 4 ng per ml but such infants must be closely monitored. There are no data which indicate that a greater inotropic response will occur at these high serum levels, though this point has not been definitively investigated, and is the highest priority question for research. The intramuscular route should be researved for the unusual situation. Vomiting should be considered an early sign of toxicity and may act as a "safety valve." When adminstered in solution (as in the elixir or solution for intravenous use), oral digoxin is rapidly absorbed an an inotropic response is found within minutes, reaching a peak within hours, so that little is gained by parenteral administration. If an inotropic effect is urgently needed, intravenous administration of ouabain will give an immediate response.

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

Perchlorate disrupts embryonic androgen synthesis and reproductive development in threespine stickleback without changing whole-body levels of thyroid hormone

PubMed Central

Petersen, Ann M.; Dillon, Danielle; Bernhardt, Richard A.; Torunsky, Roberta; Postlethwait, John H.; von Hippel, Frank A.; Buck, C. Loren; Cresko, William A.

2014-01-01

Perchlorate, an environmental contaminant, disrupts normal functioning of the thyroid. We previously showed that perchlorate disrupts behavior and gonad development, and induces external morphological changes in a vertebrate model organism, the threespine stickleback. Whether perchlorate alters these phenotypes via a thyroid-mediated mechanism, and the extent to which the effects depend on dose, are unknown. To address these questions, we chronically exposed stickleback to control conditions and to three concentrations of perchlorate (10, 30 and 100 ppm) at various developmental stages from fertilization to reproductive maturity. Adults chronically exposed to perchlorate had increased numbers of thyroid follicles and decreased numbers of thyrocytes. Surprisingly, T4 and T3 levels in larval, juvenile, and adult whole fish chronically exposed to perchlorate did not differ from controls, except at the lowest perchlorate dose, suggesting a non-monotonic dose response curve. We found no detectable abnormalities in external phenotype at any dose of perchlorate, indicating that the increased number of thyroid follicles compensated for the disruptive effects of these doses. In contrast to external morphology, gonadal development was altered substantially, with the highest dose of perchlorate causing the largest effects. Perchlorate increased the number both of early stage ovarian follicles in females and of advanced spermatogenic stages in males. Perchlorate also disrupted embryonic androgen levels. We conclude that chronic perchlorate exposure may not result in lasting adult gross morphological changes but can produce lasting modifications to gonads when compensation of T3 and T4 levels occurs by thyroid follicle hyperplasia. Perchlorate may therefore affect vertebrate development via both thyroidal and non-thyroidal mechanisms. PMID:25448260

Pharmacokinetic profile of Mitoguazone (MGBG) in patients with AIDS related non-Hodgkin's lymphoma.

PubMed

Rizzo, J; Levine, A M; Weiss, G R; Pearce, T; Kraynak, M; Mueck, R; Smith, S; Von Hoff, D D; Kuhn, J G

1996-01-01

Mitoguazone is a unique chemotherapeutic agent whose activity is believed to result primarily from the competitive inhibition of S-adenosyl-methionine decarboxylase leading to a disruption in polyamine biosynthesis. Initial clinical trials demonstrated that the dose-limiting toxicities (mucositis and myelosuppression) of Mitoguazone were both dose and schedule dependent. Early pharmacokinetic studies of Mitoguazone in man revealed a prolonged half-life. Concurrent with a recent Phase II trial of Mitoguazone in patients with AIDS related non-Hodgkin's lymphoma, the single dose pharmacokinetics of Mitoguazone were characterized. Twelve patients received 600 mg/m2 of intravenous Mitoguazone over 30 minutes on an intermittent every 2 week schedule. Blood, urine, cerebrospinal fluid (CSF), pleural fluid and tissue samples were collected and analyzed by HPLC. Mitoguazone was cleared from the plasma triexponentially with a harmonic mean terminal half-life of 175 hours and a mean residence time of 192 hours. Peak plasma levels occurred immediately post-infusion, ranged from 6.47 to 42.8 micrograms/ml, and remained (for an extended period) well above the reported concentration for inhibition of polyamine biosynthesis. Plasma clearance averaged 4.73 l/hr/m2 with a relatively large apparent volume of distribution at steady-state of 1012 l/m2 indicating tissue sequestration. Renal excretion of unchanged Mitoguazone accounted for an average of 15.8% of the dose within 48 to 72 hours post-administration. Detectable levels of drug were present in random voided samples eight days post-dose. Mitoguazone levels in CSF ranged from 22 to 186 ng/ml post-dose with CSF/plasma ratios ranging from 0.6% to 7%. The pleural fluid/plasma ratio was approximately 1. Tissue levels of Mitoguazone were highest in the liver followed by lymph node, spleen and the brain.

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

Genotoxicity evaluation of buprofezin, petroleum oil and profenofos in somatic and germ cells of male mice.

PubMed

Fahmy, M A; Abdalla, E F

1998-01-01

The two pest control agents, buprofezin and petroleum oil (Super Royal), were tested to evaluate their potential mutagenicity, in comparison with the organophosphorus insecticide profenofos. Chromosomal aberration analysis was used in both somatic and germ cells of male mice. Single oral treatment at three different dose levels (1/16, 1/8 and 1/4 LD50) for each insecticide induced an increase in the percentage of chromosomal aberrations in bone-marrow cells 24 h post-treatment, indicating a dose-dependent relationship. The percentage of chromosomal aberrations reached 23 +/- 0.73, 10.5 +/- 0.64 and 15 +/- 1.4 after treatment with the highest tested dose of profenofos, buprofezin and Super Royal, respectively. Such percentages did not exceed the corresponding value of the positive control, mitomycin C (29.2 +/- 0.69). The percentage of chromosomal aberrations induced by the different doses of profenofos was still highly significant even after excluding gaps. The same trend of results was noticed only at the highest tested dose of buprofezin and Super Royal. With respect to germ cells, profenofos is also a potent inducer of chromosomal aberrations in 1ry spermatocytes, giving percentages of 14 +/- 1.3 and 19 +/- 1.6 at the two higher doses of 4.25 and 8.5 mg kg(-1) body wt., respectively. Buprofezin and Super Royal had no significant effect on mouse spermatocytes at the tested concentrations. The various types of induced aberrations were examined and recorded in both somatic and germ cells. In conclusion, the present investigation indicates that the two pest control agents buprofezin and Super Royal are relatively much safer compounds than the conventional organophosphorus insecticides.

Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose

PubMed Central

Harris, Andrew C.; Pentel, Paul R.; LeSage, Mark G.

2013-01-01

Rationale The ability of tobacco harm reduction strategies to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon and assessing the feasibility of harm reduction interventions. Objective To use an animal model of human compensatory smoking that involves a decrease in unit dose supporting nicotine self-administration (NSA) to examine potential contributors to individual differences in compensation. Methods Rats were trained for NSA during daily 23 hr sessions at a unit dose of 0.06 mg/kg/inf until responding was stable. The unit dose was then reduced to 0.03 mg/kg/inf for at least 10 sessions. Following reacquisition of NSA at the training dose and extinction, single-dose nicotine pharmacokinetic parameters were determined. Results Decreases in nicotine intake following dose reduction were proportionally less than the decrease in unit dose, indicating partial compensation. Compensatory increases in infusion rates were observed across the course of the 23 hr sessions. The magnitude of compensation differed considerably between rats. Rats exhibiting the highest baseline infusion rates exhibited the lowest levels of compensation. Nicotine pharmacokinetic parameters were not significantly correlated with compensation. Infusion rates immediately returned to pre-reduction levels when baseline conditions were restored. Conclusions These findings provide initial insights into correlates of individual differences in compensation following a reduction in nicotine unit dose. The present assay may be useful for characterizing mechanisms and potential consequences of the marked individual differences in compensatory smoking observed in humans. PMID:19475400

Effects of realistic doses of atrazine, metolachlor, and glyphosate on lipid peroxidation and diet-derived antioxidants in caged honey bees (Apis mellifera).

PubMed

Helmer, Stephanie Hedrei; Kerbaol, Anahi; Aras, Philippe; Jumarie, Catherine; Boily, Monique

2015-06-01

The decline in the population of pollinators is a worrying phenomenon worldwide. In North America, the extensive use of herbicides in maize and soya crops may affect the health of nontarget organisms like the honey bee. In this study, caged honey bees were exposed to realistic doses of atrazine, metolachlor, and glyphosate for 10 days via contaminated syrup. Peroxidation of lipids was evaluated using the thiobarbituric acid reactive substance (TBARS) test, and diet-derived antioxidants-carotenoids, all-trans-retinol (at-ROH) and α-tocopherol-were detected and quantified using reversed-phase HPLC techniques. Significant increases in syrup consumption were observed in honey bees exposed to metolachlor, and a lower TBARS value was recorded for the highest dose. No relationship was observed between the peroxidation of lipids and the levels of antioxidants. However, β-carotene, which was found to be the most abundant carotenoid, and at-ROH (derived from β-carotene) both decreased with increasing doses of atrazine and glyphosate. In contrast, metolachlor increased levels of at-ROH without any effects on β-carotene. These results show that the honey bee carotenoid-retinoid system may be altered by sublethal field-realistic doses of herbicides.

(+/-)-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.

Measuring Adolescent Human Papillomavirus Vaccine Coverage: A Match of Sexually Transmitted Disease Clinic and Immunization Registry Data.

PubMed

Pathela, Preeti; Jamison, Kelly; Papadouka, Vikki; Kabir, Rezaul; Markowitz, Lauri E; Dunne, Eileen F; Schillinger, Julia A

2016-12-01

Human papillomavirus (HPV) vaccine is recommended for adolescents. By the end of 2013, 64% of female and 40% of male New York City residents aged 13-18 years had received ≥1 HPV vaccine dose. Adolescents attending sexually transmitted disease (STD) clinics are at high risk for HPV exposure and could benefit from vaccination. Our objective was to estimate HPV vaccination coverage for this population. We matched records of New York City's STD clinic patients aged 13-18 years during 2010-2013 with the Citywide Immunization Registry. We assessed HPV vaccine initiation (≥1 dose) and series completion (≥3 doses among those who initiated) as of clinic visit date and by patient demographics. We compared receipt of ≥1 dose for HPV, tetanus-diphtheria-acellular pertussis, and meningococcal conjugate vaccine. Eighty-two percent of clinic attendees (13,505/16,364) had records in the Citywide Immunization Registry. Receipt of ≥1 HPV dose increased during 2010-2013 (females: 57.6%-69.7%; males: 1.5%-36.3%). Among females, ≥1-dose coverage was lowest among whites (53.4%) and highest among Hispanics (73.3%); among males, ≥1-dose coverage was lowest among whites (6.9%) and highest among Asians (20.9%). Series completion averaged 57.7% (females) and 28.0% (males), with little variation by race/ethnicity or poverty level. Receipt of ≥1 dose was 59.7% for HPV, 82% for tetanus-diphtheria-acellular pertussis, and 76% for meningococcal conjugate vaccines. HPV vaccine initiation and completion were low among adolescent STD clinic patients; coverage was lower compared with other recommended vaccines. STD clinics may be good venues for delivering HPV vaccine, thereby enhancing efforts to improve HPV vaccination. Copyright © 2016 Society for Adolescent Health and Medicine. All rights reserved.

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

PubMed

Izzotti, Alberto; Larghero, Patrizia; Longobardi, Mariagrazia; Cartiglia, Cristina; Camoirano, Anna; Steele, Vernon E; De Flora, Silvio

2011-12-01

Our previous studies demonstrated that exposure to cigarette smoke (CS), either mainstream or environmental, results in a remarkable downregulation of microRNA expression in the lung of both mice and rats. The goals of the present study were to evaluate the dose responsiveness to CS and the persistence of microRNA alterations after smoking cessation. ICR (CD-1) neonatal mice were exposed whole-body to mainstream CS, at the doses of 119, 292, 438, and 631mg/m(3) of total particulate matter. Exposure started within 12h after birth and continued daily for 4 weeks. The levels of bulky DNA adducts and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) were measured by (32)P postlabeling procedures, and the expression of 697 mouse microRNAs was analyzed by microarray. The highest CS dose was lethal. Exposure to CS caused a dose-dependent increase of DNA alterations. DNA adducts and, even more sharply, 8-oxodGuo were reverted 1 and 4 weeks after smoking cessation. Exposure to CS resulted in an evident dysregulation of microRNA expression profiles, mainly in the sense of downregulation. The two lowest doses were not particularly effective, while the highest nonlethal dose produced extensive microRNA alterations. The expression of most downregulated microRNAs, including among others 7 members of the let-7 family, was restored one week after smoking cessation. However, the recovery was incomplete for a limited array of microRNAs, including mir-34b, mir-345, mir-421, mir-450b, mir-466, and mir-469. Thus, it appears that microRNAs mainly behave as biomarkers of effect and that exposure to high-dose, lasting for an adequate period of time, is needed to trigger the CS-related carcinogenesis process in the experimental animal model used. Copyright © 2011 Elsevier B.V. All rights reserved.

Short-term effects of T-2 toxin or deoxynivalenol on lipid peroxidation and the glutathione system in common carp.

PubMed

Pelyhe, Csilla; Kövesi, Benjámin; Zándoki, Erika; Kovács, Balázs; Szabó-Fodor, Judit; Mézes, Miklós; Balogh, Krisztián

2016-12-01

The purpose of this study was to investigate the short-term effects of a single oral dose of T-2 and HT-2 toxin at 0.15, 0.33 and 1.82 mg kg -1 body weight, or deoxynivalenol (DON) and 15-acetyl-DON at 0.13, 0.31 and 1.75 mg kg -1 body weight in common carp. Conjugated dienes and trienes (the early markers of lipid peroxidation) were elevated in all DON-treated groups at the 16th hour, while thiobarbituric acid reactive substances (TBARS; termination marker) were increased at the highest dose of DON at the 16th and 24th hours. T-2 toxin did not cause changes in these parameters. Glutathione content and glutathione peroxidase activity showed higher levels at the 16th hour as the effect of both mycotoxins. The expression of glutathione peroxidase (GPx4) genes (gpx4a and gpx4b) revealed a dual response. Downregulation was observed at the 8th hour, followed by an induction at the 16th hour, at the lowest dose of both mycotoxins. Higher doses revealed long-drawn emergence and an elevation was observed only at the 24th hour. However, at the lowest and highest doses of DON or T-2 toxin the changes in gene expression were delayed, which may be related to the low oxidative stress response, as suggested by the expression profiles of the nrf2, keap1, gpx4a and gpx4b genes.

A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer.

PubMed

Flaig, Thomas W; Glodé, Michael; Gustafson, Daniel; van Bokhoven, Adrie; Tao, Yuzhen; Wilson, Shandra; Su, Lih-Jen; Li, Yuan; Harrison, Gail; Agarwal, Rajesh; Crawford, E David; Lucia, M Scott; Pollak, Michael

2010-06-01

Silibinin is a polyphenolic flavonolignan derived from milk thistle (Silybum marianium) with anti-oxidant properties. The purpose of the current trial was to determine the tissue and blood effects of high-dose silybin-phytosome in prostate cancer patients. Subjects with localized prostate cancer planning for a prostatectomy were eligible to enroll. Six patients received 13 g of silybin-phytosome daily with six additional participants serving as control subjects. Patients in the treatment arm received silybin-phytosome for 14-31 days (mean was 20 days) prior to surgery. Silibinin blood levels were measured 1 hr after the first silybin-phytosome dose with a mean value of 19.7 microM. Trough silibinin levels were assessed at the end of the trial with an average concentration of 1.2 microM. In contrast to the high peak levels of silibinin observed in blood, the highest silibinin level observed in the harvested prostate tissue was 496.6 pmol/g. There were no significant differences noted in baseline and post-treatment blood levels of IGF-I and IGFBP-3. One of the treated patients developed a grade 4 post-operative thromboembolic event. The other observed toxicities in the treatment group were mild: four subjects had diarrhea and one had asymptomatic grade 2 hyperbilirubinemia which was transient. High-dose oral silybin-phytosome achieves high blood concentrations transiently, but low levels of silibinin are seen in prostate tissue. Silibinin's lack of tissue penetration may be explained by its short half-life, the brief duration of therapy in this study or an active process removing silibinin from the prostate.

Nonclinical Safety and Toxicokinetics of MnTnBuOE-2-PyP5+ (BMX-001).

PubMed

Gad, Shayne Cox; Sullivan, Dexter W; Spasojevic, Ivan; Mujer, Cesar V; Spainhour, Charles B; Crapo, James D

2016-07-01

BMX-001, a manganese porphyrin that has anti-inflammatory, antioxidant, and antitumor properties, is being developed as a potential therapeutic for high-grade glioma (HGG) and head and neck (H&N) cancer. An IND has been opened for BMX-001 in the treatment of HGG (NCT02655601) and another is in preparation for H&N. The safety of BMX-001 has been evaluated in a battery of nonclinical Good Laboratory Practice (GLP)-compliant studies. Systemic toxicity has been evaluated using the intended cGMP product administered subcutaneously for periods of up to 5 weeks in both the mouse and the monkey and included toxicokinetic evaluations to characterize systemic exposure and tissue distribution and clearance of BMX-001. In additional GLP studies, BMX-001 was not irritating to the skin or eye and caused no changes in cardiac rate or rhythm or blood pressure. Mixed results for genotoxicity were seen with the weight of evidence indicating that BMX-001 poses no genotoxic risk in humans. In systemic mouse and monkey studies, loading/maintenance dose no observed adverse effect levels were 12/2 mg/kg/dose and 6/2 mg/kg/dose, respectively, with maintenance doses administered every 3 days after the initial loading dose. Systemic data were used to determine a Food and Drug Administration-approved safe starting dose for the initial clinical study in patients with HGG. BMX-001 was detected in analyzed tissues, including the brain, persisting well past the short plasma clearance period. The highest levels of BMX-001 were seen in the liver and kidneys, with amounts in these tissues returning to close to undetectable levels after a 2-week cessation of dosing. © The Author(s) 2016.

[Effect of beta-ecdysterone in competitive cultures of Drosophila melanogaster].

PubMed

Botella, L M; Ménsua, J L

1987-03-01

High levels of beta-ecdysterone (more than 1 microgram/ml) have been shown to decrease larva-adult viability and to speed up developmental times when supplied to the media in crowding cultures. The highest doses (100 micrograms/ml) of ecdysterone suppresses almost completely the phenomenon of larval stop in the third instar of development, first reported by our laboratory in overcrowded situations. Thus, one may deduce that stopped larvae could have low levels of ecdysone, and perhaps these are the ultimate physiological cause of their arrested development before the critical larva-pupa molt.

Risk assessment of skin lightening cosmetics containing hydroquinone.

PubMed

Matsumoto, Mariko; Todo, Hiroaki; Akiyama, Takumi; Hirata-Koizumi, Mutsuko; Sugibayashi, Kenji; Ikarashi, Yoshiaki; Ono, Atsushi; Hirose, Akihiko; Yokoyama, Kazuhito

2016-11-01

Following reports on potential risks of hydroquinone (HQ), HQ for skin lightening has been banned or restricted in Europe and the US. In contrast, HQ is not listed as a prohibited or limited ingredient for cosmetic use in Japan, and many HQ cosmetics are sold without restriction. To assess the risk of systemic effects of HQ, we examined the rat skin permeation rates of four HQ (0.3%, 1.0%, 2.6%, and 3.3%) cosmetics. The permeation coefficients ranged from 1.2 × 10 -9 to 3.1 × 10 -7  cm/s, with the highest value superior than the HQ aqueous solution (1.6 × 10 -7  cm/s). After dermal application of the HQ cosmetics to rats, HQ in plasma was detected only in the treatment by highest coefficient cosmetic. Absorbed HQ levels treated with this highest coefficient cosmetic in humans were estimated by numerical methods, and we calculated the margin of exposure (MOE) for the estimated dose (0.017 mg/kg-bw/day in proper use) to a benchmark dose for rat renal tubule adenomas. The MOE of 559 is judged to be in a range safe for the consumer. However, further consideration may be required for regulation of cosmetic ingredients. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential response of two cell lines sequentially irradiated with low X-ray doses.

PubMed

Güerci, A M; Dulout, F N; Grillo, C A; Seoane, A I

2005-05-01

An experiment was designed to compare the effect of repeated low doses of X-rays in two different cell lines: one transformed, epithelial like and aneuploid Chinese hamster ovary K-1 (CHO-K1); the other originated from a human primary culture, fibroblast, diploid and non-transformed, MRC-5. CHO and MRC-5 cells were cultured for 14 or eight passages, respectively. Irradiation was performed once per passage when cells were in the quiescent state (90 - 95% in G1/G0). Cells were exposed to 10.0 mSv X-ray doses. Ionizing radiation did not induce apoptosis or necrosis in the exposed CHO cell population. Significant increases of low-level damaged cells (degrees 1 and 2) were found for the 14 cycles of radiation when compared with controls, except for the first irradiation cycle. No significant increases in the frequency of cells with severe damage were observed. The frequency of MRC-5 cells with low-level damage increased significantly when compared with controls for radiation cycles seven and eight. Significant increases of apoptosis, necrosis and severe damage were found only for the highest dose. Transformed and non-transformed cell types responded differently to direct and indirect damage using low-dose repeat exposures to ionizing radiation. Though more investigation is needed to understand the mechanisms of radiation effects in chronic low-dose-exposed cell populations, cellular type should be taken into account in the design of in vitro experiments for understanding low-dose-irradiation effects.

In vitro dermal disposition of abamectin (avermectin B(1)) in livestock.

PubMed

Baynes, Ronald E

2004-06-01

Many avermectins are approved for topical application in domestic animals. However, extralabel use may result in significant dermal absorption and consequently the potential for adverse effects or violative residues. The primary aim of this study was to assess dermal disposition of abamectin in vitro in bovine, caprine, ovine, and porcine skin dosed in 100% isopropanol, commercial alcohol-based (Ivomec), or oil-based (Eprinex) formulations. Skin sections were perfused in a flow-through diffusion cell system for 8 h, and the disposition of radiolabel abamectin was determined from perfusate and skin samples. Abamectin absorption ranged from 0.09% to 0.20% dose and there were no significant differences between formulations in each species. Isopropanol significantly increased skin deposition in all species when compared to the oil formulation. Absorption was significantly greater in bovine skin than in porcine skin for the isopropanol-containing formulations, but there were no significant species differences for the oil formulation. While significant levels (11.69-50.23% dose) remained on the skin surface, the highest levels deposited in viable skin were observed in caprine skin (28.09% dose) and the lowest levels were in porcine skin (1.50% dose) which could lead to systemic absorption. In summary, these 8-h experiments demonstrated that the alcohol-based formulations compared to oil-based formulations enhanced abamectin absorption and skin deposition in several animal species, and this effect is more likely to be observed in ruminant species than in porcine species.

Pharmacokinetics and metabolism of all-trans- and 13-cis-retinoic acid in pulmonary emphysema patients.

PubMed

Muindi, Josephia R; Roth, Michael D; Wise, Robert A; Connett, John E; O'Connor, George T; Ramsdell, Joe W; Schluger, Neil W; Romkes, Marjorie; Branch, Robert A; Sciurba, Frank C

2008-01-01

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow-up, plasma ATRA C(max) was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C(max) (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r2 = -0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.

Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity.

PubMed

Mennenga, Sarah E; Gerson, Julia E; Koebele, Stephanie V; Kingston, Melissa L; Tsang, Candy W S; Engler-Chiurazzi, Elizabeth B; Baxter, Leslie C; Bimonte-Nelson, Heather A

2015-04-01

Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high injection doses of EE reduced the number of ChAt-immunoreactive cells in the basal forebrain, and cell population estimates in the vertical/diagonal bands negatively correlated with working memory errors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dose-response of women's health-related quality of life (HRQoL) and life satisfaction to physical activity.

PubMed

Eime, Rochelle; Harvey, Jack; Payne, Warren

2014-02-01

To examine the dose-response relationship between health related quality of life (HRQoL) and life satisfaction (outcomes) and duration of recreational physical activity (exposure). Further, to explore whether these relationships depend on type of physical activity (PA). 793 Australian rural-living women self-reported on duration of recreational PA; HRQoL via SF-36 Mental Component Summary (MCS) and Physical Component Summary (PCS); and a life satisfaction scale. ANOVAs and ANCOVAs investigated differences in outcomes (MCS, PCS, and life satisfaction) between tertiles of exposure to recreational PA, and types of PA (club sport, gymnasium, walking), with adjustment for potential confounders. A significant positive dose-response relationship was found between PCS and level of PA. Furthermore, this relationship depended on type of PA, with club-sport participants recording higher PCS than non-club-sport participants in all but the highest tertile of exposure. Life satisfaction and MCS were not significantly related to level of PA. Physical health was positively associated with level of recreational PA, with club sport participation contributing greater benefits at low to moderate exposures than participation in gymnasium or walking activities.

Effectiveness of Reducing P Fertilizer and Adding Fish Pond Mud Waste on Growth and Yield of Soybean in Peatland

NASA Astrophysics Data System (ADS)

Asie, Erina Riak; Rumbang, Nyahu; Winarti, Sih; Sinaga, Soaloon

2018-02-01

The objective of the study was to assess the effectiveness of P fertilizer reduction and the addition of fish pond sludge waste on the growth and yield of soybean crop in peatland. Research used Complete Randomized Design factorial with two factors. The first factor was the reduction of P fertilizer from the dose of 150 kg.ha-1 consisting of 4 levels, namely P0: 100% (2.944 g/polybag), P1: 75% (2.208 g/polybag), P2: 50% (1.472 g/polybag), and P3: 25% (0.736 g/polybag). The second factor was the addition of fish pond mud waste (L) from the dose of 15 ton.ha-1 consisting of 4 levels, namely L0: 25% (73.595 g/polybag), L1: 50% (147.19 g/polybag), L2: 75% (220.78 g/polybag), and L3: 100% (294.38 g/polybag). Each treatment combination was replicated 3 times to obtain 48 experimental units. The results showed that (1) fish pond mud waste was effective to reduce the use of P fertilizer, (2) the reduction of P fertilizer up to 50% from recommendation dosage by addition of fish pond sludge waste at 75% dose of 15 ton/ha was the best combination due to providing the best plant growth and the highest P concentration of plant tissue. The highest number of pods and weight of seed obtained in the combination were 60.33 pods/plant and 7.30 g/plant, respectively.

Effects of pre- and postnatal exposure to the UV-filter Octyl Methoxycinnamate (OMC) on the reproductive, auditory and neurological development of rat offspring

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

Axelstad, Marta, E-mail: maap@food.dtu.dk; Boberg, Julie; Hougaard, Karin Sorig

Octyl Methoxycinnamate (OMC) is a frequently used UV-filter in sunscreens and other cosmetics. The aim of the present study was to address the potential endocrine disrupting properties of OMC, and to investigate how OMC induced changes in thyroid hormone levels would be related to the neurological development of treated offspring. Groups of 14-18 pregnant Wistar rats were dosed with 0, 500, 750 or 1000 mg OMC/kg bw/day during gestation and lactation. Serum thyroxine (T{sub 4}), testosterone, estradiol and progesterone levels were measured in dams and offspring. Anogenital distance, nipple retention, postnatal growth and timing of sexual maturation were assessed. Onmore » postnatal day 16, gene expression in prostate and testes, and weight and histopathology of the thyroid gland, liver, adrenals, prostate, testes, epididymis and ovaries were measured. After weaning, offspring were evaluated in a battery of behavioral and neurophysiological tests, including tests of activity, startle response, cognitive and auditory function. In adult animals, reproductive organ weights and semen quality were investigated. Thyroxine (T{sub 4}) levels showed a very marked decrease during the dosing period in all dosed dams, but were less severely affected in the offspring. On postnatal day 16, high dose male offspring showed reduced relative prostate and testis weights, and a dose-dependent decrease in testosterone levels. In OMC exposed female offspring, motor activity levels were decreased, while low and high dose males showed improved spatial learning abilities. The observed behavioral changes were probably not mediated solely by early T{sub 4} deficiencies, as the observed effects differed from those seen in other studies of developmental hypothyroxinemia. At eight months of age, sperm counts were reduced in all three OMC-dosed groups, and prostate weights were reduced in the highest dose group. Taken together, these results indicate that perinatal OMC-exposure can affect both the reproductive and neurological development of rat offspring, which may be a cause of concern, as humans are systematically exposed to the compound through usage of sunscreens and other cosmetics.« less

Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) n.e. Brown.

PubMed

do Vale, T Gurgel; Furtado, E Couto; Santos, J G; Viana, G S B

2002-12-01

Citral, myrcene and limonene (100 and 200 mg/kg body wt., i.p.), constituents of essential oils from Lippia alba chemotypes, decreased not only the number of crossings but also numbers for rearing and grooming, as measured by the open-field test in mice. Although muscle relaxation detected by the rota rod test was seen only at the highest doses of citral (200 mg/kg body wt.) and myrcene (100 and 200 mg/kg body wt.), this effect was observed even at the lowest dose of limonene (50 mg/kg body wt.). Also, citral and myrcene (100 and 200 mg/kg body wt.) increased barbiturate sleeping time as compared to control. Limonene was also effective at the highest dose, and although citral did not increase the onset of sleep, it increased the duration of sleep, which is indicative of a potentiation of sleeping time. Citral (100 and 200 mg/kg body wt.) increased 2.3 and 3.5 times, respectively, the barbiturate sleeping time in mice. Similar effects were observed for myrcene and limonene at the highest dose (200 mg/kg body wt.) which increased the sleeping time around 2.6 times. In the elevated-plus maze, no effect was detected with citral up to 25 mg/kg body wt., while at a high dose it decreased by 46% the number of entries in the open arms. A smaller but significant effect was detected with limonene (5 mg/kg body wt.). While myrcene (10 mg/kg body wt.) decreased only by 22% the number of entries in the open arms, this parameter was decreased by 48% at the highest dose. Our study showed that citral, limonene and myrcene presented sedative as well as motor relaxant effects. Although only at the highest dose, they also produced a potentiation of the pentobarbital-induced sleeping time in mice, which was more intense in the presence of citral. In addition, neither of them showed an anxiolytic effect, but rather a slight anxiogenic type of effect at the higher doses.

Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation

PubMed Central

Angle, Brittany M.; Do, Rylee Phuong; Ponzi, Davide; Stahlhut, Richard W.; Drury, Bertram E.; Nagel, Susan C.; Welshons, Wade V.; Besch-Williford, Cynthia L; Palanza, Paola; Parmigiani, Stefano; vom Saal, Frederick S.; Taylor, Julia A.

2013-01-01

Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000 μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0–24h),we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose–response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes. PMID:23892310

Radiation doses to members of the public near to Sellafield, Cumbria, from liquid discharges 1952-98.

PubMed

Jackson, D; Lambers, B; Gray, J

2000-06-01

Liquid wastes containing low levels of radioactivity have been discharged to the Irish Sea from the nuclear fuel reprocessing site at Sellafield since operations began in the early 1950s, and monitoring of radioactivity in foodstuffs has been undertaken over many years. Based on the best available monitoring data, supplemented by modelled values where necessary, doses to local critical groups have been reassessed using the most recent dosimetry. Contemporary habits data have been used where available, again supplemented by assumed habits where necessary. During the 1950s and 1960s the highest doses were received by individuals consuming Cumbrian Porphyra as laverbread, and peak doses around 0.8 to 1.0 mSv year(-1) have been estimated. During the 1970s and 1980s the critical exposure group switched to consumers of local fish and shellfish, with peak doses possibly reaching 2.5 to 3.0 mSv year(-1). Latterly, doses to all marine-related groups have declined to less than 150 to 200 microSv year(-1). At all times, doses have been within the appropriate limits set for members of the public.

Radioactive contamination of arthropods from different trophic levels in hilly and mountainous areas after the Fukushima Daiichi nuclear power plant accident.

PubMed

Tanaka, Sota; Hatakeyama, Kaho; Takahashi, Sentaro; Adati, Tarô

2016-11-01

In order to understand the influence of the Fukushima Daiichi nuclear power plant accident on the ecosystem in hilly and mountainous areas of Fukushima Prefecture, chronological changes in the levels of radiocesium in arthropod species were investigated. From 2012 to 2014, arthropods from different trophic levels were sampled and the air radiation dose rates at the sampling sites were analyzed. The air radiation dose rates showed a significant and constant reduction over the 2 years at the sampling sites in Fukushima. The median radiocesium concentration ( 134 Cs +  137 Cs) detected in the rice grasshopper, Oxya yezoensis, and the Emma field cricket, Teleogryllus emma, dropped continuously to 0.080 and 0.078 Bq/g fresh weight, respectively, in 2014. In contrast, no significant reduction in radioactive contamination was observed in the Jorô spider, Nephila clavata, in which the level remained at 0.204 Bq/g in 2014. A significant positive correlation between radiocesium concentration and the air radiation dose rate was observed in the rice grasshopper, the Emma field cricket and the Jorô spider. The highest correlation coefficient (ρ = 0.946) was measured in the grasshopper. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Efficiency of various vitamin doses for polyhypovitaminosis correction in rats.

PubMed

Kodentsova, V M; Vrzhesinskaya, O A; Beketova, N A; Kosheleva, O V; Sokol'nikov, A A

2014-09-01

A 5-fold decrease of the content of vitamin mixture in the ration and exclusion of vitamin E from this mixture over 4 weeks led to a significant growth delay in rats initially weighing 58.1±0.5 g, but was inessential for the growth rates of animals weighing 107.1±1.1 g. The decrease in the levels of vitamins A and B2 in the liver and of 25-hydroxyvitamin D in the plasma of younger rats was more significant, this indicating their higher sensitivity to alimentary vitamin deficit. The increase in vitamin content in the ration to 100% over 5 days led to a significant body weight increment but did not restore vitamin levels in the liver, restoring, however, plasma levels of vitamins E and 25-hydroxyvitamin D. Addition of 50% vitamin content of the vitamin mixture for controls to vitamin-deficient rations of older rats for 2 weeks improved the levels of vitamins B1 and B2, but was virtually inessential for the liver content of vitamins A and E. High dose (158-200%) vitamins in animals of both age groups repaired the deficit of all vitamins, except vitamin A, despite the fact that its doses were the highest. These results validate long-term vitamin consumption for repair of their deficit.

[Association between urinary polycyclic aromatic hydrocarbon metabolites and elevated serum uric acid levels in coke oven workers].

PubMed

Deng, Siyun; Deng, Qifei; Hu, Die; Li, Jun; Zhu, Xiaoyan; Guo, Huan; Wu, Tangchun

2014-06-01

To analyze the relationship between metabolites of polycyclic aromatic hydrocarbons (PAHs) and serum uric acid levels in coke oven workers and to provide new clues to the pathogenic mechanism of PAHs. A total of 1302 coke oven workers were divided into four groups, namely control group and low-, intermediate-, and high-dose exposure groups. The concentrations of ambient PAHs at each workplace were determined by high-performance liquid chromatography. The detailed information on the occupational history and health of workers was collected by questionnaire survey and physical examination, and so were their blood and urine samples. Serum uric acid and creatinine levels were measured using a Hitachi 7020 automatic biochemical analyzer. Ten urinary PAH metabolites were detected by gas chromatography-mass spectrometry. Serum uric acid levels were the highest in the high-dose exposure group, followed by the intermediate- and low-dose exposure groups, and were the lowest in the control group. There were significant correlations between serum uric acid levels and the quartiles of 1-hydroxynaphthalene and 1-hydroxyphenanthrene (P < 0.05). After adjustment for PAH metabolite-related relationship, only urinary 1-hydroxyphenanthrene was significantly correlated with serum uric acid levels (P = 0.001). After adjustment for confounding factors and using the 1st quartile of 1-hydroxyphenanthrene as a reference, the odds ratio for hyperuricemia in subjects with the 2nd, 3rd, and 4th quartiles of 1-hydroxyphenanthrene were 1.55, 1.57, and 2.35, respectively. Urinary 1-hydroxyphenanthrene is associated with a dose-response increase in serum uric acid levels in coke oven workers, and exposure to phenanthrene in PAHs may be a risk factor for hyperuricemia.

Precision-Cut Liver Slices of Salmo salar as a tool to investigate the oxidative impact of CYP1A-mediated PCB 126 and 3-methylcholanthrene metabolism.

PubMed

Lemaire, Benjamin; Beck, Michaël; Jaspart, Mélanie; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean-Pierre; Rees, Jean-François

2011-02-01

Fish isolated cell systems have long been used to predict in vivo toxicity of man-made chemicals. In present study, we tested the suitability of Precision-Cut Liver Slices (PCLS) as an alternative to these models that allows the evaluation of a global tissue response to toxicants, to investigate oxidative stress response to cytochrome P450 1A (CYP1A) induction in fish liver. PCLS of Salmo salar were exposed for 21 h to increasing doses of 3-methylcholanthrene (3-MC) and Polychlorobiphenyl 126 (PCB 126). 3-MC (25 μM) strongly induced CYP1A transcription. In dose-response analysis (25-100 μM), EROD activity was strongly increased at intermediate 3-MC concentrations. We found the counter-intuitive decline of EROD at the highest 3-MC doses to result from reversible competition with ethoxyresorufin. No increases of H(2)O(2) production, antioxidant enzymes activities or oxidative damage to lipids were found with 3-MC treatments. PCLS subjected to PCB 126 (2-200 nM) showed increased contamination levels and a parallel increased CYP1A mRNA synthesis and EROD activity. H(2)O(2) production tended to increase but no oxidative damage to lipids was found. As antioxidant enzymes activities declined at the highest PCB 126 dose, it is suggested that longer incubation periods could be required to generate oxidative stress in PCLS. Copyright © 2010 Elsevier Ltd. All rights reserved.

TH-AB-207A-04: Assessment of Patients’ Cumulative Effective Dose From CT Examinations

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

Bostani, M; Cagnon, C; Sepahdari, A

Purpose: The Joint Commission requires institutions to consider patient’s age and recent imaging exams when deciding on the most appropriate type of imaging exam. Additionally, knowing patient’s imaging history can help prevent duplicate scans. Radiation dose management software affords new opportunities to identify and utilize patients with high cumulative doses as one proxy for subsequent review of imaging history and opportunities in avoiding redundant exams. Methods: Using dose management software (Radimetrics, Bayer Healthcare) a total of 72073 CT examinations performed from Jan 2015 to Jan 2016 were examined to categorize patients with a cumulative effective dose of 100 mSv andmore » above. This threshold was selected based on epidemiological studies on populations exposed to radiation, which demonstrate a statistical increase of cancer risk at doses above 100 mSv. Histories of patients with highest cumulative dose and highest number of exams were further investigated by a Radiologist for appropriateness of recurrent studies and potential opportunities for reduction. Results: Out of 34762 patients, 927 (2.7%) were identified with a cumulative dose of 100 mSv and above. The highest cumulative dose (842 mSv) belonged to an oncology patient who underwent 2 diagnostic exams and 9 interventional ablative CT guided procedures. The patient with highest number of exams (56 counts) and cumulative dose of 170 mSv was a 17 year old trauma patient. An imaging history review of these two patients did not suggest any superfluous scans. Conclusion: Our limited pilot study suggests that recurrent CT exams for patients with oncologic or severe trauma history may be warranted and appropriate. As a result, for future studies we will be focusing on high dose patient cohorts not associated with oncology or severe trauma. Additionally, the review process itself has suggested areas for potential improvement in patient care, including improved documentation and Radiologist involvement in patient management. Dr. McNitt-Gray’s disclosures: Institutional research agreement, Siemens Healthcare; Past recipient, research grant support, Siemens Healthcare; Consultant, Toshiba America Medical Systems; Consultant, Samsung Electronics.« less

Applicator-guided volumetric-modulated arc therapy for low-risk endometrial cancer

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

Cilla, Savino, E-mail: savinocilla@gmail.com; Macchia, Gabriella; Sabatino, Domenico

2013-04-01

The aim of this study was to report the feasibility of volumetric-modulated arc therapy (VMAT) in the postoperative irradiation of the vaginal vault. Moreover, the VMAT technique was compared with 3D conformal radiotherapy (3D-CRT) and fixed-field intensity-modulated radiotherapy (IMRT), in terms of target coverage and organs at risk sparing. The number of monitor units and the delivery time were analyzed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a 2D array of ionization chambers. Twelve patients with endometrial carcinoma who underwent radical hystero-adenexectomy and fixed-field IMRT treatments were retrospectively included in thismore » analysis; for each patient, plans were compared in terms of dose-volume histograms, homogeneity index, and conformity indexes. All techniques met the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformity at all dose levels. VMAT resulted in significant reduction of rectal and bladder volumes irradiated at all dose levels compared with 3D-CRT. No significant differences were found with respect to IMRT. Moreover, a significant improvement of the dose conformity was reached by VMAT technique not only at the 95% dose level (0.74 vs. 0.67 and 0.62) but also at 50% and 75% levels of dose prescription. In addition, VMAT plans showed a significant reduction of monitor units by nearly 28% with respect to IMRT, and reduced treatment time from 11 to <3 minutes for a single 6-Gy fraction. In conclusion, VMAT plans can be planned and carried out with high quality and efficiency for the irradiation of vaginal vault alone, providing similar or better sparing of organs at risk to fixed-field IMRT and resulting in the most efficient treatment option. VMAT is currently our standard approach for radiotherapy of low-risk endometrial cancer.« less

Evaluation on radiation protection aspect and radiological risk at Mukim Belanja repository

NASA Astrophysics Data System (ADS)

Azmi, Siti Nur Aisyah; Kenoh, Hamiza; Majid, Amran Ab.

2016-01-01

Asian Rare Earth (ARE) is a locally incorporated company that operated a mineral processing operation to extract rare earth element. ARE has received much attention from the public since the beginning of their operation until the work of decommissioning and decontamination of the plant. Due to the existence of Naturally Occurring Radioactive Material (NORM) in the residue, the decommissioning and disposal was done by the company in collaboration with the Perak State Government and the Atomic Energy Licensing Board (AELB). The main objective of this study is to review the level of compliance of the existing Radiation Protection Regulations enforced by AELB particularly in the achievement of allowed exposure dose limit. The next objective was to study the impact of the construction of the Mukim Belanja Repository to workers and public. This study was conducted by analyzing documents that were issued and conducting the area monitoring using a Geiger Muller detector (GM) and Sodium Iodide (NaI(Tl)) survey meters. The measurements were made at 5 cm and 1 m from the ground surface at 27 measurement stations. The external doses measured were within the background levels of the surrounding area. The annual effective dose using the highest reading at 5 cm and 1 m from ground surface by GM detector was calculated to be 1.36 mSv/year and 1.21 mSv/year respectively. Whereas the annual effective dose using the highest reading at 5 cm and 1 m from ground surface by using NaI(Tl) detector was calculated to be 3.31 mSv/year and 2.83 mSv/year respectively. The calculated cancer risks from the study showed that the risk is small compared with the risks derived from natural radiation based on global annual radiation dose to humans. This study therefore indicated that the repository is able to constrain the dose exposure from the disposed NORM waste. The study also revealed that the construction of the repository has complied with all the rules and regulations subjected to it. The exposed dose received by the radiation and the public workers during the construction of the repository were below the annual limit i.e. 20 mSv/year and 1mSv/year respectively.

Evaluation on radiation protection aspect and radiological risk at Mukim Belanja repository

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

Azmi, Siti Nur Aisyah, E-mail: nuclear.aisyahazmi@gmail.com; Kenoh, Hamiza; Majid, Amran Ab.

2016-01-22

Asian Rare Earth (ARE) is a locally incorporated company that operated a mineral processing operation to extract rare earth element. ARE has received much attention from the public since the beginning of their operation until the work of decommissioning and decontamination of the plant. Due to the existence of Naturally Occurring Radioactive Material (NORM) in the residue, the decommissioning and disposal was done by the company in collaboration with the Perak State Government and the Atomic Energy Licensing Board (AELB). The main objective of this study is to review the level of compliance of the existing Radiation Protection Regulations enforcedmore » by AELB particularly in the achievement of allowed exposure dose limit. The next objective was to study the impact of the construction of the Mukim Belanja Repository to workers and public. This study was conducted by analyzing documents that were issued and conducting the area monitoring using a Geiger Muller detector (GM) and Sodium Iodide (NaI(Tl)) survey meters. The measurements were made at 5 cm and 1 m from the ground surface at 27 measurement stations. The external doses measured were within the background levels of the surrounding area. The annual effective dose using the highest reading at 5 cm and 1 m from ground surface by GM detector was calculated to be 1.36 mSv/year and 1.21 mSv/year respectively. Whereas the annual effective dose using the highest reading at 5 cm and 1 m from ground surface by using NaI(Tl) detector was calculated to be 3.31 mSv/year and 2.83 mSv/year respectively. The calculated cancer risks from the study showed that the risk is small compared with the risks derived from natural radiation based on global annual radiation dose to humans. This study therefore indicated that the repository is able to constrain the dose exposure from the disposed NORM waste. The study also revealed that the construction of the repository has complied with all the rules and regulations subjected to it. The exposed dose received by the radiation and the public workers during the construction of the repository were below the annual limit i.e. 20 mSv/year and 1mSv/year respectively.« less

Ships' Ballast Water Treatment by Chlorination Can Generate Toxic Trihalomethanes.

PubMed

Hernandez, Marco R; Ismail, Nargis; Drouillard, Ken G; MacIsaac, Hugh J

2017-08-01

The International Maritime Organization (IMO) will enforce a new abundance-based performance standard for ballast water in September, 2017. Strong oxidants, like chlorine, have been proposed as a method for achieving this standard. However chlorine treatment of ballast water can produce hazardous trihalomethanes. We assessed maximum trihalomethane production from one chlorine dose for three types of ballast water (fresh, brackish and marine) and three levels of total organic carbon (TOC) concentration (natural, filtered, enhanced). While the current standard test considers a 5 day voyage, there is a high possibility of shorter trips and sudden change of plans that will release treated waters in the environment. Water source and TOC significantly affected trihalomethane production, with the highest amounts generated in brackish waters and enhanced TOC concentration. The concentration of brominated trihalomethanes increased from background levels and was highest in brackish water, followed by marine and fresh water.

Noise Exposure Assessment in a Dental School

PubMed Central

Kaimook, Wandee; Tantisarasart, Ratchada; Sooksamear, Puwanai; Chayaphum, Satith; Kongkamol, Chanon; Srisintorn, Wisarut; Phakthongsuk, Pitchaya

2011-01-01

Objectives This cross-sectional study was performed in the Dental School of Prince of Songkla University to ascertain noise exposure of dentists, dental assistants, and laboratory technicians. A noise spectral analysis was taken to illustrate the spectra of dental devices. Methods A noise evaluation was performed to measure the noise level at dental clinics and one dental laboratory from May to December 2010. Noise spectral data of dental devices were taken during dental practices at the dental services clinic and at the dental laboratory. A noise dosimeter was set following the Occupational Safety and Health Administration criteria and then attached to the subjects' collar to record personal noise dose exposure during working periods. Results The peaks of the noise spectrum of dental instruments were at 1,000, 4,000, and 8,000 Hz which depended on the type of instrument. The differences in working areas and job positions had an influence on the level of noise exposure (p < 0.01). Noise measurement in the personal hearing zone found that the laboratory technicians were exposed to the highest impulsive noise levels (137.1 dBC). The dentists and dental assistants who worked at a pedodontic clinic had the highest percent noise dose (4.60 ± 3.59%). In the working areas, the 8-hour time-weighted average of noise levels ranged between 49.7-58.1 dBA while the noisiest working area was the dental laboratory. Conclusion Dental personnel are exposed to noise intensities lower than occupational exposure limits. Therefore, these dental personnel may not experience a noise-induced hearing loss. PMID:22953219

Noise exposure assessment in a dental school.

PubMed

Choosong, Thitiworn; Kaimook, Wandee; Tantisarasart, Ratchada; Sooksamear, Puwanai; Chayaphum, Satith; Kongkamol, Chanon; Srisintorn, Wisarut; Phakthongsuk, Pitchaya

2011-12-01

This cross-sectional study was performed in the Dental School of Prince of Songkla University to ascertain noise exposure of dentists, dental assistants, and laboratory technicians. A noise spectral analysis was taken to illustrate the spectra of dental devices. A noise evaluation was performed to measure the noise level at dental clinics and one dental laboratory from May to December 2010. Noise spectral data of dental devices were taken during dental practices at the dental services clinic and at the dental laboratory. A noise dosimeter was set following the Occupational Safety and Health Administration criteria and then attached to the subjects' collar to record personal noise dose exposure during working periods. The peaks of the noise spectrum of dental instruments were at 1,000, 4,000, and 8,000 Hz which depended on the type of instrument. The differences in working areas and job positions had an influence on the level of noise exposure (p < 0.01). Noise measurement in the personal hearing zone found that the laboratory technicians were exposed to the highest impulsive noise levels (137.1 dBC). The dentists and dental assistants who worked at a pedodontic clinic had the highest percent noise dose (4.60 ± 3.59%). In the working areas, the 8-hour time-weighted average of noise levels ranged between 49.7-58.1 dBA while the noisiest working area was the dental laboratory. Dental personnel are exposed to noise intensities lower than occupational exposure limits. Therefore, these dental personnel may not experience a noise-induced hearing loss.

Residue depletion of tilmicosin in chicken tissues.

PubMed

Zhang, Yue; Jiang, Haiyang; Jin, Xingjun; Shen, Zhangqi; Shen, Jianzhong; Fu, Caixia; Guo, Junlin

2004-05-05

A high-performance liquid chromatography (HPLC) method with detection at 290 nm was modified and validated for the determination of tilmicosin residues in broiler chicken tissues. The limits of detection (LOD) of the method were 0.01 microg/g for muscle and 0.025 microg/g for liver and kidney. Average recoveries ranged from 80.4 to 88.3%. Relative standard deviation values ranged from 5.2 to 12.1%. Residue depletion of tilmicosin in broiler chickens was examined after dosing over a 5-day period by incorporation of the drug into drinking water at 37.5 and 75.0 mg/L. Tilmicosin concentrations in liver and kidney were highest on day 3 of medication and on day 5 in muscle, in both low- and high-dose groups. The residue levels in both groups were significantly higher in liver than in kidney or muscle. A minimum withdrawal time of 9 days was indicated for residue levels in muscle, liver, and kidney tissues below the maximum residue level (MRL).

Subacute intramuscular toxicity of the acetylcholinesterase reactivating agent Hi-6 in rats and dogs. (Reannouncement with new availability information)

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

Levine, B.S.; Tomlinson, M.J.

1993-12-31

Studies herein describe the toxicity of HI-6 in Sprague-Dawley rats and Beagle dogs following i.m. injection for 14 days. Dose levels were 0, 50, 150, and 450 mg/kg/day for 10 rats/sex/dose and 0, 35, 70, and 140 mg/kg/day for 4 dogs/sex/dose. Three rats at the high dose, 2 males and 1 female, died prior to scheduled sacrifice. Reduced weight gain, decreased activity, tremors, hunched posture,and poor grooming were seen in high dose survivors. Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities at the mid and high doses suggested hepatotoxicity, although liver weights and histology were normal. Hematology parameters weremore » unaffected except for slight, dose-related increases of platelets in both sexes. Injection site inflammation was seen; however, serum creatine kinase activity was not altered. In dogs, slight weight loss, vomiting, salivation, and diarrhea occurred at the high dose, but no deaths were observed at any of the doses. As with rats, dose-related increases in ALT and AST activities occurred at the mid and high doses, and were, in this case, accompanied at the high dose by hepatomegaly and hepatocellular vacuolization. Cardiotoxicity was evidenced by increased relative heart weights and subtle ECG changes, the latter of which occurred almost exclusively at the highest dose. Injection site inflammation, which was accompanied by dose-related elevations in serum CK-MM2 activity, was also observed.« less

Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia.

PubMed

Akdim, Fatima; Visser, Maartje E; Tribble, Diane L; Baker, Brenda F; Stroes, Erik S G; Yu, Rosie; Flaim, Joann D; Su, John; Stein, Evan A; Kastelein, John J P

2010-05-15

A randomized, double-blind, placebo-controlled, dose-escalation study was conducted to examine the efficacy and safety of mipomersen (ISIS 301012), an antisense inhibitor of apolipoprotein B, when added to conventional lipid-lowering therapy for patients with heterozygous familial hypercholesterolemia. A total of 44 patients were enrolled and were separated into 4 cohorts, with doses ranging from 50 to 300 mg (4:1 active treatment/placebo ratio). Patients received 8 doses subcutaneously during a 6-week treatment period. Patients assigned to the 300-mg dose continued for an additional 7 weeks with once-per-week dosing. The primary efficacy end point was the percentage of change from baseline to week 7 in low-density lipoprotein (LDL) cholesterol. Safety was assessed using the laboratory test results and according to the incidence, severity, and relation of adverse events to drug dose. Mipomersen produced significant reductions in LDL cholesterol and other atherogenic apolipoprotein B-containing lipoproteins. After 6 weeks of treatment, the LDL cholesterol level was reduced by 21% from baseline in the 200-mg/week dose group (p <0.05) and 34% from baseline in the 300-mg/week dose group (p <0.01), with a concomitant reduction in apolipoprotein B of 23% (p <0.05) and 33% (p <0.01), respectively. Injection site reactions were the most common adverse event. Elevations in liver transaminase levels (> or =3 times the upper limit of normal) occurred in 4 (11%) of 36 patients assigned to active treatment; 3 of these patients were in the highest dose group. In conclusion, mipomersen has an incremental LDL cholesterol lowering effect when added to conventional lipid-lowering therapy. Copyright 2010 Elsevier Inc. All rights reserved.

Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats.

PubMed

Rodd, Zachary A; Bell, Richard L; Oster, Scott M; Toalston, Jamie E; Pommer, Tylene J; McBride, William J; Murphy, James M

2010-05-01

Several studies indicated the involvement of serotonin-3 ([5-hydroxy tryptamine] 5-HT(3)) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT(3) receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers (Coulbourn Instruments, Allentown, PA) were used to examine the effects of seven consecutive bilateral microinfusions of ICS 205-930 (ICS), a 5-HT(3) receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (vol/vol) ethanol self-administration. P rats readily acquired ethanol self-administration by the fourth session. The three highest doses (0.125, 0.25, and 1.25 microg) of ICS prevented acquisition of ethanol self-administration. During the acquisition postinjection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the three highest doses (0.75, 1.0, and 1.25 microg) of ICS significantly increased responding on the ethanol lever; after the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Microinfusion of ICS into the posterior VTA did not alter the low responding on the water lever and did not alter saccharin (0.0125% wt/v) self-administration. Microinfusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT(3) receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration and/or repeated treatments with a 5-HT(3) receptor antagonist may alter neuronal circuitry within the posterior VTA. 2010 Elsevier Inc. All rights reserved.

The role of sex steroids in forming anxiety states in female mice.

PubMed

Galeeva, A Yu; Tuohimaa, P; Shalyapina, V G

2003-05-01

Natural fluctuations in sex hormones during the ovarian cycle have enormous influences on ongoing psychological status in the female body. We report here studies of the effects of exogenous sex steroids on anxiety levels in female mice, as evaluated in the elevated cross maze test. Female NMRI mice were subjected to bilateral oophorectomy and one week later received s.c. injections of solvent (sesame oil, controls) or estradiol benzoate for 7 days, either alone or with an additional dose of progesterone on day 7. Elevated maze tests performed 6 h later showed that animals given progesterone had the highest levels of anxiety and the highest levels of grooming reactions as compared with the other groups. Immunohistochemical analysis of the distribution of progesterone receptors in different parts of the brain demonstrated significant increases in the numbers of immunopositive cells after injections of estradiol benzoate alone, with further increases after progesterone injections. Thus, the data obtained here suggest that the genomic effects of sex steroids are important, as they appear to be involved in non-sexual forms of behavior, particularly the level of anxiety.

Di-(2-ethylhexyl) phthalate and mono-(2-ethylhexyl) phthalate inhibit growth and reduce estradiol levels of antral follicles in vitro

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

Gupta, Rupesh K., E-mail: drrupesh@illinois.ed; Singh, Jeffery M., E-mail: jsingh20@illinois.ed; Leslie, Tracie C., E-mail: tleslie2@illinois.ed

2010-01-15

Any insult that affects survival of ovarian antral follicles can cause abnormal estradiol production and fertility problems. Phthalate esters (PEs) are plasticizers used in a wide range of consumer and industrial products. Exposure to these chemicals has been linked to reduced fertility in humans and animal models. Di-(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP) decrease serum estradiol levels and aromatase (Arom) expression, prolong estrous cycles, and cause anovulation in animal and culture models. These observations suggest PEs directly target antral follicles. We therefore tested the hypothesis that DEHP (1-100 mug/ml) and MEHP (0.1-10 mug/ml) directly inhibit antral follicular growth andmore » estradiol production. Antral follicles from adult mice were cultured with DEHP or MEHP, and/or estradiol for 96 h. During culture, follicle size was measured every 24 h as a measurement of follicle growth. After culture, media were collected for measurement of estradiol levels and follicles were subjected to measurement of cylin-D-2 (Ccnd2), cyclin-dependant-kinase-4 (Cdk4), and Arom. We found that DEHP and MEHP inhibited growth of follicles and decreased estradiol production compared to controls at the highest doses. DEHP and MEHP also decreased mRNA expression of Ccnd2, Cdk4, and Arom at the highest dose. Addition of estradiol to the culture medium prevented the follicles from DEHP- and MEHP-induced inhibition of growth, reduction in estradiol levels, and decreased Ccnd2 and Cdk4 expression. Collectively, our results indicate that DEHP and MEHP may directly inhibit antral follicle growth via a mechanism that partially includes reduction in levels of estradiol production and decreased expression of cell cycle regulators.« less

Microstructural characterization and density change of 304 stainless steel reflector blocks after long-term irradiation in EBR-II

NASA Astrophysics Data System (ADS)

Huang, Y.; Wiezorek, J. M. K.; Garner, F. A.; Freyer, P. D.; Okita, T.; Sagisaka, M.; Isobe, Y.; Allen, T. R.

2015-10-01

While thin reactor structural components such as cladding and ducts do not experience significant gradients in dpa rate, gamma heating rate, temperature or stress, thick components can develop strong local variations in void swelling and irradiation creep in response to gradients in these variables. In this study we conducted microstructural investigations by transmission electron microscopy of two 52 mm thick 304-type stainless steel hex-blocks irradiated for 12 years in the EBR-II reactor with accumulated doses ranging from ∼0.4 to 33 dpa. Spatial variations in the populations of voids, precipitates, Frank loops and dislocation lines have been determined for 304 stainless steel sections exposed to different temperatures, different dpa levels and at different dpa rates, demonstrating the existence of spatial gradients in the resulting void swelling. The microstructural measurements compare very well with complementary density change measurements regarding void swelling gradients in the 304 stainless steel hex-block components. The TEM studies revealed that the original cold-worked-state microstructure of the unirradiated blocks was completely erased by irradiation, replaced by high densities of interstitial Frank loops, voids and carbide precipitates at both the lowest and highest doses. At large dose levels the amount of volumetric void swelling correlated directly with the gamma heating gradient-related temperature increase (e.g. for 28 dpa, ∼2% swelling at 418 °C and ∼2.9% swelling at 448 °C). Under approximately iso-thermal local conditions, volumetric void swelling was found to increase with dose level (e.g. ∼0.2% swelling at 0.4 dpa, ∼0.5% swelling at 4 dpa and ∼2% swelling at 28 dpa). Carbide precipitate formation levels were found to be relatively independent of both dpa level and temperature and induced a measurable densification. Void swelling was dominant at the higher dose levels and caused measurable decreases in density. Void swelling at the lowest doses was larger than might be expected based on the dpa level, an observation in agreement with earlier studies showing that the onset of void swelling is accelerated by decreasing dpa rates.

A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers.

PubMed

Chi, K N; Yu, E Y; Jacobs, C; Bazov, J; Kollmannsberger, C; Higano, C S; Mukherjee, S D; Gleave, M E; Stewart, P S; Hotte, S J

2016-06-01

Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. NCT00487786. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Effect of peptide YY on gastric, pancreatic, and biliary function in humans.

PubMed

Adrian, T E; Savage, A P; Sagor, G R; Allen, J M; Bacarese-Hamilton, A J; Tatemoto, K; Polak, J M; Bloom, S R

1985-09-01

The effect of peptide YY (PYY) on gastric and pancreatico-biliary secretion was studied in humans. Peptide YY was infused into groups of 6 healthy volunteers at doses of 0.59, 0.20, and 0.064 pmol X kg-1 X min-1. The two higher doses caused a significant suppression of gastric acid and pepsin output during background stimulation with pentagastrin. The middle dose of PYY (0.20 pmol X kg-1 X min-1) that increased plasma PYY levels by 27 +/- 2 pM caused a 90% +/- 18% (mean +/- SEM; p less than 0.001) reduction in the incremental gastric volume response to pentagastrin. Similarly this dose of PYY caused a substantial inhibition of the acid (77% +/- 14%; p less than 0.005) and pepsin (96% +/- 22%; p less than 0.01) response to pentagastrin; in 2 subjects, pepsin output fell to below basal levels. In contrast, the highest dose of PYY (0.62 pmol X kg-1 X min-1) had no significant influence on duodenal juice volume, output of bicarbonate, trypsin, or bilirubin during low dose stimulation with secretin (0.25 pmol X kg-1 X min-1) and cholecystokinin-8 (0.15 pmol X kg-1 X min-1). Thus PYY concentrations in the circulation similar to those seen after the ingestion of food cause a marked reduction in gastric secretion. This peptide should therefore be considered as one of the possible candidates for the classical enterogastrone.

A single institution study of radiation dose received from CT imaging: A comparison to Malaysian NDRL

NASA Astrophysics Data System (ADS)

Osman, N. D.; Shamsuri, S. B. M.; Tan, Y. W.; Razali, M. A. S. M.; Isa, S. M.

2017-05-01

Advancement of CT technology has led to an increase in CT scanning as it improves the diagnosis. However, it is important to assess health risk of patients associated with ionising radiation received from CT. This study evaluated current dose distributions at Advanced Medical and Dental Institute (AMDI), Malaysia and was used to establish Local Diagnostic Reference Level (LDRL). Dose indicators such as CT Dose Index (CTDIvol and CTDIw) and Dose-Length Product (DLP) were gathered for all routine CT examinations performed at the Imaging Unit, AMDI from January 2015 to June 2016. The first and third quartile values for each dose indicator were determined. A total of 364 CT studies were performed during that period with the highest number of cases being Thorax-Abdomen-Pelvis (TAP) study (57% of total study). The CTDIw ranged between 2.0 mGy to 23.4 mGy per procedure. DLP values were ranged between 94 mGy.cm to 1687 mGy.cm. The local dose data was compared with the national DRL to monitor the current CT practice at AMDI and LDRL will be established from the calculated third quartile values of dose distribution. From the results, some of the local dose values exceeded the Malaysian and further evaluation is important to ensure the dose optimisation for patients.

A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats.

PubMed

Neven, Ellen; De Schutter, Tineke M; Dams, Geert; Gundlach, Kristina; Steppan, Sonja; Büchel, Janine; Passlick-Deetjen, Jutta; D'Haese, Patrick C; Behets, Geert J

2014-01-01

The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.

Dose-dependent DNA adduct formation by cinnamaldehyde and other food-borne α,β-unsaturated aldehydes predicted by physiologically based in silico modelling.

PubMed

Kiwamoto, R; Ploeg, D; Rietjens, I M C M; Punt, A

2016-03-01

Genotoxicity of α,β-unsaturated aldehydes shown in vitro raises a concern for the use of the aldehydes as food flavourings, while at low dose exposures the formation of DNA adducts may be prevented by detoxification. Unlike many α,β-unsaturated aldehydes for which in vivo data are absent, cinnamaldehyde was shown to be not genotoxic or carcinogenic in vivo. The present study aimed at comparing dose-dependent DNA adduct formation by cinnamaldehyde and 18 acyclic food-borne α,β-unsaturated aldehydes using physiologically based kinetic/dynamic (PBK/D) modelling. In rats, cinnamaldehyde was predicted to induce higher DNA adducts levels than 6 out of the 18 α,β-unsaturated aldehydes, indicating that these 6 aldehydes may also test negative in vivo. At the highest cinnamaldehyde dose that tested negative in vivo, cinnamaldehyde was predicted to form at least three orders of magnitude higher levels of DNA adducts than the 18 aldehydes at their respective estimated daily intake. These results suggest that for all the 18 α,β-unsaturated aldehydes DNA adduct formation at doses relevant for human dietary exposure may not raise a concern. The present study illustrates a possible use of physiologically based in silico modelling to facilitate a science-based comparison and read-across on the possible risks posed by DNA reactive agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Image processing techniques revealing the relationship between the field-measured ambient gamma dose equivalent rate and geological conditions at a granitic area, Velence Mountains, Hungary

NASA Astrophysics Data System (ADS)

Beltran Torres, Silvana; Petrik, Attila; Zsuzsanna Szabó, Katalin; Jordan, Gyozo; Szabó, Csaba

2017-04-01

In order to estimate the annual dose that the public receive from natural radioactivity, the identification of the potential risk areas is required which, in turn, necessitates understanding the relationship between the spatial distribution of natural radioactivity and the geogenic risk factors (e.g., rock types, dykes, faults, soil conditions, etc.). A detailed spatial analysis of ambient gamma dose equivalent rate was performed in the western side of Velence Mountains, the largest outcropped granitic area in Hungary. In order to assess the role of local geology in the spatial distribution of ambient gamma dose rates, field measurements were carried out at ground level at 300 sites along a 250 m x 250 m regular grid in a total surface of 14.7 km2. Digital image processing methods were applied to identify anomalies, heterogeneities and spatial patterns in the measured gamma dose rates, including local maxima and minima determination, digital cross sections, gradient magnitude and gradient direction, second derivative profile curvature, local variability, lineament density, 2D autocorrelation and directional variogram analyses. Statistical inference showed that different gamma dose rate levels are associated with the rock types (i.e., Carboniferous granite, Pleistocene colluvial, proluvial, deluvial sediments and talus, and Pannonian sand and pebble), with the highest level on the Carboniferous granite including outlying values. Moreover, digital image processing revealed that linear gamma dose rate spatial features are parallel to the SW-NE dyke system and possibly to the NW-SE main fractures. The results of this study underline the importance of understanding the role of geogenic risk factors influencing the ambient gamma dose rate received by public. The study also demonstrates the power of the image processing techniques for the identification of spatial pattern in field-measured geogenic radiation.

Relationship of antioxidant and oxidative stress markers in different organs following copper toxicity in a rat model

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

Kumar, Vijay; Kalita, Jayantee, E-mail: jayanteek@yahoo.com; Bora, Himangsu K.

Copper (Cu) at a higher level becomes toxic and it can catalyze the formation of highly reactive hydroxyl radical. We report the vulnerability of liver, kidney and brain to different dose of copper sulfate (CuSO{sub 4}) induced oxidative stress at different time duration. Fifty-four male Wistar rats (weight range = 205 ± 10 g) were equally divided into three groups. CuSO{sub 4} was administered orally to the experimental groups (Group-II and III) up to 90 days in a dose of 100 and 200 mg/Kg body weight per day. Saline water was given to the control group (Group-I). At the endmore » of 30, 60 and 90 days of administration, neurobehavioral studies were done and six rats from each group were sacrificed. Their liver, kidney and brain tissues were subjected for Cu, glutathione (GSH), malondialdehyde (MDA) and total antioxidant capacity (TAC) assay. Blood urea nitrogen (BUN), serum creatinine, bilirubin and transaminases were measured. GSH, TAC and MDA levels were correlated with the markers of respective organ dysfunction. Administration of CuSO{sub 4} resulted in increased free Cu and MDA level, and decrease GSH and TAC levels in group-II and III compared with group-I. In experimental groups, the reduction in TAC and GSH levels was maximum in liver tissue followed by brain and kidney; whereas increase in MDA level was highest in liver followed by brain and kidney at 30, 60 and 90 days. TAC and GSH levels in the liver inversely correlated with serum transaminases and bilirubin, and tissue free Cu, and positively correlated with MDA levels. Free Cu level in kidney tissue and BUN inversely correlated with TAC and GSH, and positively with MDA level. Grip-strength, rotarod and Y-maze findings were inversely correlated with brain free Cu and MDA levels and positively with GSH and TAC levels. The oxidative stress was highest in liver followed by brain and kidney after oral CuSO{sub 4} exposure in a rat model. These levels correlated with the respective organ dysfunction and tissue free Cu concentration. - Highlights: • Oral dosing of CuSO{sub 4} leads to oxidative stress in liver, brain and kidney. • Liver has maximum oxidative stress followed by brain and kidney. • Oxidative stress correlated with the respective organ dysfunction and tissue Cu concentration.« less

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

DOE PAGES

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; ...

2016-11-30

Here, we report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice weremore » dosed with [ 14C]carboplatin or [ 14C]gemcitabine and the resulting drug–DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug–DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug–DNA adducts as predictive biomarkers.« less

Microdose-Induced Drug–DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice

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

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong

Here, we report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice weremore » dosed with [ 14C]carboplatin or [ 14C]gemcitabine and the resulting drug–DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug–DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug–DNA adducts as predictive biomarkers.« less

Effects of sub-lethal exposure of rats to the herbicide glyphosate in drinking water: glutathione transferase enzyme activities, levels of reduced glutathione and lipid peroxidation in liver, kidneys and small intestine.

PubMed

Larsen, K; Najle, R; Lifschitz, A; Virkel, G

2012-11-01

Glyphosate (GLP), the active ingredient of many weed killing formulations, is a broad spectrum herbicide compound. Wistar rats were exposed during 30 or 90 days to the highest level (0.7 mg/L) of GLP allowed in water for human consumption (US EPA, 2011) and a 10-fold higher concentration (7 mg/L). The low levels of exposure to the herbicide did not produce histomorphological changes. The production of TBARS was similar or tended to be lower compared to control animals not exposed to the herbicide. In rats exposed to GLP, increased levels of reduced glutathione (GSH) and enhanced glutathione peroxidase (GPx) activity may act as a protective mechanism against possible detrimental effects of the herbicide. Overall, this work showed certain biochemical modifications, even at 3-20-fold lower doses of GLP than the oral reference dose of 2mg/kg/day (US EPA, 1993). The toxicological significance of these findings remains to be clarified. Copyright © 2012 Elsevier B.V. All rights reserved.

Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice.

PubMed

Zimmermann, Maike; Wang, Si-Si; Zhang, Hongyong; Lin, Tzu-Yin; Malfatti, Michael; Haack, Kurt; Ognibene, Ted; Yang, Hongyuan; Airhart, Susan; Turteltaub, Kenneth W; Cimino, George D; Tepper, Clifford G; Drakaki, Alexandra; Chamie, Karim; de Vere White, Ralph; Pan, Chong-Xian; Henderson, Paul T

2017-02-01

We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [ 14 C]carboplatin (1% of the therapeutic dose). Carboplatin-DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibility that another drug in the regimen could cause a response. The mice were dosed with [ 14 C]carboplatin or [ 14 C]gemcitabine and the resulting drug-DNA adduct levels were compared with tumor response to chemotherapy. At least one of the drugs had to induce high drug-DNA adduct levels or create a synergistic increase in overall adducts to prompt a corresponding therapeutic response, demonstrating proof-of-principle for drug-DNA adducts as predictive biomarkers. Mol Cancer Ther; 16(2); 376-87. ©2016 AACR. ©2016 American Association for Cancer Research.

Concordance of transcriptional and apical benchmark dose levels for conazole-induced liver effects in mice.

PubMed

Bhat, Virunya S; Hester, Susan D; Nesnow, Stephen; Eastmond, David A

2013-11-01

The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode-of-action determinations and improves quantitative risk assessments. Previous global expression profiling identified a 330-probe cluster differentially expressed and commonly responsive to 3 hepatotumorigenic conazoles (cyproconazole, epoxiconazole, and propiconazole) at 30 days. Extended to 2 more conazoles (triadimefon and myclobutanil), the present assessment encompasses 4 tumorigenic and 1 nontumorigenic conazole. Transcriptional benchmark dose levels (BMDL(T)) were estimated for a subset of the cluster with dose-responsive behavior and a ≥ 5-fold increase or decrease in signal intensity at the highest dose. These genes primarily encompassed CAR/RXR activation, P450 metabolism, liver hypertrophy- glutathione depletion, LPS/IL-1-mediated inhibition of RXR, and NRF2-mediated oxidative stress pathways. Median BMDL(T) estimates from the subset were concordant (within a factor of 2.4) with apical benchmark doses (BMDL(A)) for increased liver weight at 30 days for the 5 conazoles. The 30-day median BMDL(T) estimates were within one-half order of magnitude of the chronic BMDLA for hepatocellular tumors. Potency differences seen in the dose-responsive transcription of certain phase II metabolism, bile acid detoxification, and lipid oxidation genes mirrored each conazole's tumorigenic potency. The 30-day BMDL(T) corresponded to tumorigenic potency on a milligram per kilogram day basis with cyproconazole > epoxiconazole > propiconazole > triadimefon > myclobutanil (nontumorigenic). These results support the utility of measuring short-term gene expression changes to inform quantitative risk assessments from long-term exposures.

Use of rivastigmine transdermal patch in the treatment of Alzheimer's disease.

PubMed

Winblad, Bengt; Machado, João Carlos

2008-12-01

Cholinesterase inhibitors such as rivastigmine and donepezil exhibit a dose-response relationship, with higher doses of the drugs demonstrating greater efficacy. Transdermal patches provide smooth continuous drug delivery, with the potential to offer efficacious levels of drug exposure while avoiding the peaks and troughs associated with side effects. As a small, lipophilic and hydrophilic molecule, rivastigmine (C14H22N2O2) is chemically well-suited to transdermal delivery. The technology underlying the rivastigmine patch allows it to be discreetly small and thin. The target dose 9.5 mg/24 h rivastigmine patch has a diameter of just 3.5 cm and a surface area of 10 cm2. A large randomized controlled trial has demonstrated that the target dose 9.5 mg/24 h rivastigmine patch provided similar efficacy to the highest rivastigmine capsule doses, yet with three times fewer reports of nausea and vomiting. Thus, the rivastigmine patch enables quick and easy access to high dose efficacy. The skin tolerability profile is good, and the patch has demonstrated excellent adhesion. The apparent success of rivastigmine patch, in terms of clinical utility and patient acceptability, suggests that it may mark the next generation of dementia treatment.

Measurement of soil contamination by radionuclides due to the Fukushima Dai-ichi Nuclear Power Plant accident and associated estimated cumulative external dose estimation.

PubMed

Endo, S; Kimura, S; Takatsuji, T; Nanasawa, K; Imanaka, T; Shizuma, K

2012-09-01

Soil sampling was carried out at an early stage of the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. Samples were taken from areas around FDNPP, at four locations northwest of FDNPP, at four schools and in four cities, including Fukushima City. Radioactive contaminants in soil samples were identified and measured by using a Ge detector and included (129 m)Te, (129)Te, (131)I, (132)Te, (132)I, (134)Cs, (136)Cs, (137)Cs, (140)Ba and (140)La. The highest soil depositions were measured to the northwest of FDNPP. From this soil deposition data, variations in dose rates over time and the cumulative external doses at the locations for 3 months and 1y after deposition were estimated. At locations northwest of FDNPP, the external dose rate at 3 months after deposition was 4.8-98 μSv/h and the cumulative dose for 1 y was 51 to 1.0 × 10(3)mSv; the highest values were at Futaba Yamada. At the four schools, which were used as evacuation shelters, and in the four urban cities, the external dose rate at 3 months after deposition ranged from 0.03 to 3.8μSv/h and the cumulative doses for 1 y ranged from 3 to 40 mSv. The cumulative dose at Fukushima Niihama Park was estimated as the highest in the four cities. The estimated external dose rates and cumulative doses show that careful countermeasures and remediation will be needed as a result of the accident, and detailed measurements of radionuclide deposition densities in soil will be important input data to conduct these activities. Copyright © 2011 Elsevier Ltd. All rights reserved.

A dose-range study assessing immunogenicity and safety of one dose of a new candidate meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate (MenACWY-TT) vaccine administered in the second year of life and in young children.

PubMed

Knuf, M; Kieninger-Baum, D; Habermehl, P; Muttonen, P; Maurer, H; Vink, P; Poolman, J; Boutriau, D

2010-01-08

Meningococcal disease incidence is highest in young children, yet a tetravalent conjugate vaccine is currently not available for this age group. This study evaluated a single dose of four different ACWY-TT conjugate vaccine formulations in 240 toddlers (12-14 months) and 268 children (3-5 years) compared to licensed age-appropriate control vaccines. In toddlers, rSBA-MenC GMTs for the selected formulation were statistically higher than after monovalent-MenC-conjugate vaccine. In children, rSBA-GMTs against each serogroup were statistically higher than after tetravalent polysaccharide vaccine. The safety profile was comparable to licensed controls. The new ACWY-TT conjugate vaccine promises high seroprotection levels against meningococcal disease from 1 year of age.

Protective effect of natural honey against acetic acid-induced colitis in rats.

PubMed

Mahgoub, A A; el-Medany, A H; Hagar, H H; Sabah, D M

2002-01-01

The protective effects of natural honey against acetic acid-induced colitis were investigated in rats. Honey and glucose, fructose, sucrose, maltose mixture were administered, orally and rectally, daily for a period of 4 days. Induction of colitis was done on the third day using 3% acetic acid. Animals were killed on day 4 two hours after administration of the dose and colonic biopsies were taken for macroscopic scoring, histopathological and biochemical studies. Honey dose-dependently afforded protection against acetic acid-induced colonic damage. There was almost 100% protection with the highest dose (5 g/kg) used while glucose, fructose, sucrose, maltose mixture produced no significant protective effect. Also, honey prevented the depletion of the antioxidant enzymes reduced glutathione and catalase and restored the lipid peroxide malondialdehyde towards normal levels. Further studies are required to explore the active ingredients responsible for the antioxidant effect of honey and its therapeutic potential in humans.

Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration

PubMed Central

2014-01-01

Background Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies. Methods Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment. Results No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose. Conclusions Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration. PMID:24602342

Systemic effects in naïve mice injected with immunomodulatory lectin ArtinM

PubMed Central

Oliveira Brito, Patrícia Kellen Martins; Gonçalves, Thiago Eleutério; Fernandes, Fabrício Freitas; Miguel, Camila Botelho; Rodrigues, Wellington Francisco; Lazo Chica, Javier Emílio; Roque-Barreira, Maria Cristina

2017-01-01

Toll-like receptors (TLR) contain N-glycans, which are important glycotargets for plant lectins, to induce immunomodulation. The lectin ArtinM obtained from Artocarpus heterophyllus interacts with TLR2 N-glycans to stimulate IL-12 production by antigen-presenting cells and to drive the immune response toward the Th1 axis, conferring resistance against intracellular pathogens. This immunomodulatory effect was demonstrated by subcutaneously injecting (s.c.) ArtinM (0.5 μg) in infected mice. In this study, we evaluated the systemic implications of ArtinM administration in naïve BALB/c mice. The mice were s.c. injected twice (7 days interval) with ArtinM (0.5, 1.0, 2.5, or 5.0 μg), LPS (positive control), or PBS (negative control) and euthanized after three days. None of the ArtinM-injected mice exhibited change in body weight, whereas the relative mass of the heart and lungs diminished in mice injected with the highest ArtinM dose (5.0 μg). Few and discrete inflammatory foci were detected in the heart, lung, and liver of mice receiving ArtinM at doses ≥2.5 μg. Moreover, the highest dose of ArtinM was associated with increased serum levels of creatine kinase MB isoenzyme (CK-MB) and globulins as well as an augmented presence of neutrophils in the heart and lung. IL-12, IFN-γ, TNF-α, and IL-10 measurements in the liver, kidney, spleen, heart, and lung homogenates revealed decreased IL-10 level in the heart and lung of mice injected with 5.0 μg ArtinM. We also found an augmented frequency of T helper and B cells in the spleen of all ArtinM-injected naïve mice, whereas the relative expressions of T-bet, GATA-3, and ROR-γt were similar to those in PBS-injected animals. Our study demonstrates that s.c. injection of high doses of ArtinM in naïve mice promotes mild inflammatory lesions and that a low immunomodulatory dose is innocuous to naïve mice. PMID:29084277

Radiation dose to Malaysian infants from natural radionuclides via consumption of powdered milk

NASA Astrophysics Data System (ADS)

Uwatse, Onosohwo Bemigho; Olatunji, Michael Adekunle; Khandaker, Mayeen Uddin; Amin, Yusoff Mohd.

2015-04-01

Milk is the basic food stuff for the infants because they generally consume more milk on a daily basis as its minerals and proteins are essential for their growth and development, therefore, it is very important to assess the natural radioactivity levels and the associated dose in the widely consumed powered infant's milk. As a result, 14 brands of infant's powdered milk were collected from different supermarkets around Selangor, Malaysia and analysed for 226Ra, 232Th and 40K activities. The obtained mean activity of 226Ra, 232Th and 40K are 3.05±1.84, 2.55±2.48 and 99.1±69.5 Bqkg-1, respectively. Among the analysed milk samples, the brand from Philippines (Lactogen) showed low level of radioactivity while Singaporean brand (S26 SMA Gold) showed the highest. The estimated mean annual effective doses due to the ingestion of natural radionuclides in the sampled milk are 635 and 111 µSv for infant ≤ 1y and infant 1-2y, respectively. The obtained dose value does not yet pose any significant radiological hazards to the population under investigation comparing with the 1.0 mSvy-1 recommended by ICRP for all ages.

Sub-Chronic Oral Exposure to Iridium (III) Chloride Hydrate in Female Wistar Rats: Distribution and Excretion of the Metal

PubMed Central

Iavicoli, Ivo; Fontana, Luca; Bergamaschi, Antonio; Conti, Marcelo Enrique; Pino, Anna; Mattei, Daniela; Bocca, Beatrice; Alimonti, Alessandro

2012-01-01

Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure. PMID:22942873

Key parameters and practices controlling pesticide degradation efficiency of biobed substrates.

PubMed

Karanasios, Evangelos; Karpouzas, Dimitrios G; Tsiropoulos, Nikolaos G

2012-01-01

We studied the contribution of each of the components of a compost-based biomixture (BX), commonly used in Europe, on pesticide degradation. The impact of other key parameters including pesticide dose, temperature and repeated applications on the degradation of eight pesticides, applied as a mixture, in a BX and a peat-based biomixture (OBX) was compared and contrasted to their degradation in soil. Incubation studies showed that straw was essential in maintaining a high pesticide degradation capacity of the biomixture, whereas compost, when mixed with soil, retarded pesticide degradation. The highest rates of degradation were shown in the biomixture composed of soil/compost/straw suggesting that all three components are essential for maximum biobed performance. Increasing doses prolonged the persistence of most pesticides with biomixtures showing a higher tolerance to high pesticide dose levels compared to soil. Increasing the incubation temperature from 15 °C to 25 °C resulted in lower t(1/2) values, with biomixtures performing better than soil at the lower temperature. Repeated applications led to a decrease in the degradation rates of most pesticides in all the substrates, with the exception of iprodione and metalaxyl. Overall, our results stress the ability of biomixtures to perform better than soil under unfavorable conditions and extreme pesticide dose levels. Copyright © Taylor & Francis Group, LLC

Estimating radiation risk induced by CT screening for Korean population

NASA Astrophysics Data System (ADS)

Yang, Won Seok; Yang, Hye Jeong; Min, Byung In

2017-02-01

The purposes of this study are to estimate the radiation risks induced by chest/abdomen computed tomography (CT) screening for healthcare and to determine the cancer risk level of the Korean population compared to other populations. We used an ImPACT CT Patient Dosimetry Calculator to compute the organ effective dose induced by CT screening (chest, low-dose chest, abdomen/pelvis, and chest/abdomen/pelvis CT). A risk model was applied using principles based on the BEIR VII Report in order to estimate the lifetime attributable risk (LAR) using the Korean Life Table 2010. In addition, several countries including Hong Kong, the United States (U.S.), and the United Kingdom, were selected for comparison. Herein, each population exposed radiation dose of 100 mSv was classified according to country, gender and age. For each CT screening the total organ effective dose calculated by ImPACT was 6.2, 1.5, 5.2 and 11.4 mSv, respectively. In the case of Korean female LAR, it was similar to Hong Kong female but lower than those of U.S. and U.K. females, except for those in their twenties. The LAR of Korean males was the highest for all types of CT screening. However, the difference of the risk level was negligible because of the quite low value.

The novelty-seeking phenotype modulates the long-lasting effects of adolescent MDMA exposure.

PubMed

Rodríguez-Arias, Marta; Vaccaro, Sonia; Arenas, M Carmen; Aguilar, María A; Miñarro, José

2015-03-15

Exposure to drugs such as ethanol or cocaine during adolescence induces alterations in the central nervous system that are modulated by the novelty-seeking trait. Our aim was to evaluate the influence of this trait on the long-term effects of MDMA administration during adolescence on spontaneous behavior and conditioned rewarding effects in adulthood. Adolescent mice were classified as high or low novelty seekers (HNS or LNS) according to the hole-board test and received either MDMA (0, 10 or 20mg/kg PND 33-42) or saline. Three weeks later, having entered adulthood (PND>68), one set of mice performed the elevated plus maze and social interaction tests, while another set performed the conditioning place preference (CPP) test induced by cocaine-(1mg/kg) or MDMA-(1mg/kg). Only HNS mice treated with MDMA during adolescence acquired CPP in adulthood with a non-effective dose of cocaine or MDMA. Although it did not produce changes in motor activity, exposure to MDMA during adolescence was associated with more aggressive behaviors (threat and attack) and increased social contacts in HNS mice, while an anxiolytic effect was noted in LNS mice pre-treated with the highest dose of MDMA (20mg/kg). Administration of MDMA (10 or 20mg/kg) induced a decrease in DA levels in the striatum in LNS mice only and lower striatal serotonin levels in mice treated with the highest MDMA dose. Our findings show that adolescent MDMA exposure results in higher sensitivity to the conditioned reinforcing properties of MDMA and cocaine in adult HNS mice, which suggests that the relationship between exposure to MDMA in adolescence and a higher probability of substance is a feature of high novelty seekers only. Copyright © 2015. Published by Elsevier Inc.

Comparing paediatric intravenous phenytoin doses using physiologically based pharmacokinetic (PBPK) modelling software.

PubMed

Batchelor, Hannah; Appleton, Richard; Hawcutt, Daniel B

2015-12-01

To use a physiologically based pharmacokinetic (PBPK) modelling system to predict the serum levels achieved by two different intravenous loading doses of phenytoin. A phenytoin pharmacokinetic model was used in the Simcyp population-based ADME simulator, simulating 100 children age 2-10 years receiving intravenous phenytoin (18 and 20mg/kg). Visual checks were used to evaluate the predictive performance of the candidate model. Loading with doses of 18 mg/kg, blood levels were sub-therapeutic in 22/100 (concentration at 2h post infusion (C2h) <10 μg/mL), therapeutic in 62/100 (C2h 10-20 μg/mL), and supra-therapeutic in 16/100 (C2h>20 μg/mL). Loading with 20mg/kg, the percentages were 15, 59, and 26, respectively. Increasing from 18 to 20 mg/kg increased the mean C2h from 16.0 to 17.9 μg/mL, and the mean AUC from 145 to 162 μg/mL/h. A C2h>30 μg/mL was predicted in 4% and 8% of children in the 18 and 20 mg/kg doses, with 3% predicted to have a C2h>40 μg/mL following either dose. For maintenance doses, a 1st dose of 2.5 or 5mg/kg (intravenous) given at 12h (after either 18 or 20 mg/kg loading) gives the highest percentages of 10-20 μg/mL serum concentrations. For sub-therapeutic concentrations following intravenous loading (20 mg/kg), a 1st maintenance dose (intravenous) of 10mg/kg will achieve therapeutic concentrations in 93%. Use of PBPK modelling suggests that children receiving the 20 mg/kg intravenous loading dose are at slightly increased risk of supra-therapeutic blood levels. Ideally, therapeutic drug monitoring is required to monitor serum concentrations, although the dose regime suggested by the BNFc appear appropriate. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT.

PubMed

Doss, Mohan; Zhang, James J; Bélanger, Marie-José; Stubbs, James B; Hostetler, Eric D; Alpaugh, Katherine; Kolb, Hartmuth C; Yu, Jian Q

2010-12-01

F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans. Successive whole-body PET/CT scans were done after the injection of F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software. The bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 μGy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 μSv/MBq from monkey data and 27±2 μSv/MBq from human data. Bladder, kidneys, and liver have the highest uptake of injected F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of F-HX4 is comparable with that of other F-based imaging agents.

miR-26b enhances radiosensitivity of hepatocellular carcinoma cells by targeting EphA2.

PubMed

Jin, Qiao; Li, Xiang Jun; Cao, Pei Guo

2016-08-01

Although low-dose radiotherapy (RT) that involves low collateral damage is more suitable for hepatocellular carcinoma (HCC) than traditional high-dose RT, but to achieve satisfactory therapeutic effect with low-dose RT, it is necessary to sensitize HCC cells to irradiation. This study was aimed to determine whether radiosensitivity of HCC cells can be enhanced using miR-26b by targeting erythropoietin producing human hepatocelluar A2 (EphA2). The levels of miR-26b and EphA2 expression in multiple HCC cell lines were assessed by qPCR and western blotting, respectively, and compared with those in a hepatic cell line. HCC 97H cells were transfected with miR-26b mimics, EphA2-ShRNA or EphA2 over-expression vector before exposure to low-dose irradiation. Different degrees of miR-26b down-regulation and EphA2 up-regulation were observed in all HCC cell lines, among which the HCC 97H cell line expressed the lowest level of miR-26b and highest level of EphA2. EphA2 was verified as the target of miR-26b by dual luciferase reporter assay. HCC 97H cells transfected with miR-26b mimics or EphA2-ShRNA reduced the expression of EphA2 protein, with significantly lower cell proliferation rate and cell invasion ability and higher apoptosis rate in response to low-dose irradiation than those in the non-transfected cells. These results were reversed after EphA2 was overexpressed by transfection with the EphA2 overexpression vector. Co-transfection with miR-26b mimics and EphA2 overexpression vector barely altered EphA2 expression level and cell response to low-dose irradiation. These data suggest that miR-26b enhances radiosensitivity of HCC 97H cells by targeting EphA2 protein.

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.

Induction of DNA-strand breaks after X-irradiation in murine bone cells of various differentiation capacities

NASA Astrophysics Data System (ADS)

Lau, Patrick; Hellweg, Christine E.; Kirchner, Simone; Baumstark-Khan, Christa

During longterm space missions, astronauts suffer from the loss of minerals especially from weightbearing bones due to prolonged sojourn under microgravity. In addition to weightlessness, exposure to cosmic ionization radiation is another space related factor endangering health and productivity of astronauts. In order to elucidate changes in bone cell metabolism induced by ionizing radiation, ground-based bone cell models have been developed. The differentiation level of the bone cells may influence their radiation sensitivity. Therefore, our cell model comprises a collection of immortalized murine pre-osteoblast, osteoblast and osteocyte cell lines representing discrete stages of differentiation: the subclones 4 and 24 of the osteoblast cell line MC3T3-E1, the osteoblast cell line OCT-1 and the osteocyte cell line MLO-Y4 display varying potential to produce mineralized bone matrix upon incubation with ascorbic acid and β-glycerophosphate (osteogenic medium). The MLO-Y4 cells showed the highest and subclone 24 the lowest proliferation rate. The most intense von Kossa reaction after culture in osteogenic medium was observed in subclone 4, indicating mineralized bone matrix. The bone cell markers alkaline phosphatase and osteocalcin were determined to further characterize the differentiation stage. All cell lines expressed osteocalcin, as determined by reverse transcriptase polymerase chain reaction. The activity of alkaline phosphatase was highest in the cell line OCT-1 and very low in MLO-Y4 and S4. The peculiarity of the markers suggests a characterization of OCT-1 and S24 as preosteoblast, S4 as (mature) osteoblast, and MLO-Y4 as osteocyte. Survival after exposure to X-rays was determined using the colony forming ability test. The resulting dose-effect relationships revealed normal radiation sensitivity (compared to human fibroblasts). Cell clone specific variations (subclones 4 and 24) in the radiation sensitivity may be due to the differentiation level. The survival curve of MLO-Y4 shows a broad shoulder, suggesting a high repair capacity or a high DNA damage or misrepair tolerance. The quantitative acquisition of DNA-strand breaks was performed by fluorescent analysis of DNA unwinding and revealed a high level of DNA damage immediately after X-irradiation, which increases dose dependently. In conclusion, the cell line with the highest differentiation level (MLO-Y4) displays lower radiation sensitivity, regarding the shoulder width of the dose-effect curve, compared to the less differentiated osteoblast cell lines.

A pragmatic approach to determine the optimal kVp in cone beam CT: balancing contrast-to-noise ratio and radiation dose

PubMed Central

Silkosessak, O; Jacobs, R; Bogaerts, R; Bosmans, H; Panmekiate, S

2014-01-01

Objectives: To determine the optimal kVp setting for a particular cone beam CT (CBCT) device by maximizing technical image quality at a fixed radiation dose. Methods: The 3D Accuitomo 170 (J. Morita Mfg. Corp., Kyoto, Japan) CBCT was used. The radiation dose as a function of kVp was measured in a cylindrical polymethyl methacrylate (PMMA) phantom using a small-volume ion chamber. Contrast-to-noise ratio (CNR) was measured using a PMMA phantom containing four materials (air, aluminium, polytetrafluoroethylene and low-density polyethylene), which was scanned using 180 combinations of kVp/mA, ranging from 60/1 to 90/8. The CNR was measured for each material using PMMA as background material. The pure effect of kVp and mAs on the CNR values was analysed. Using a polynomial fit for CNR as a function of mA for each kVp value, the optimal kVp was determined at five dose levels. Results: Absorbed doses ranged between 0.034 mGy mAs−1 (14 × 10 cm, 60 kVp) and 0.108 mGy mAs−1 (14 × 10 cm, 90 kVp). The relation between kVp and dose was quasilinear (R2 > 0.99). The effect of mA and kVp on CNR could be modelled using a second-degree polynomial. At a fixed dose, there was a tendency for higher CNR values at increasing kVp values, especially at low dose levels. A dose reduction through mA was more efficient than an equivalent reduction through kVp in terms of image quality deterioration. Conclusions: For the investigated CBCT model, the most optimal contrast at a fixed dose was found at the highest available kVp setting. There is great potential for dose reduction through mA with a minimal loss in image quality. PMID:24708447

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response.

PubMed

Manno, Catherine S; Pierce, Glenn F; Arruda, Valder R; Glader, Bertil; Ragni, Margaret; Rasko, John J; Rasko, John; Ozelo, Margareth C; Hoots, Keith; Blatt, Philip; Konkle, Barbara; Dake, Michael; Kaye, Robin; Razavi, Mahmood; Zajko, Albert; Zehnder, James; Rustagi, Pradip K; Nakai, Hiroyuki; Chew, Amy; Leonard, Debra; Wright, J Fraser; Lessard, Ruth R; Sommer, Jürg M; Tigges, Michael; Sabatino, Denise; Luk, Alvin; Jiang, Haiyan; Mingozzi, Federico; Couto, Linda; Ertl, Hildegund C; High, Katherine A; Kay, Mark A

2006-03-01

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression.

Management of background pain and anxiety in critically burned children requiring protracted mechanical ventilation.

PubMed

Sheridan, R; Stoddard, F; Querzoli, E

2001-01-01

Optimal control of pain and anxiety is an elusive but important goal in children with protracted critical illness. This review represents an effort to document the doses of background medication required to achieve this goal in a group of children managed under a pain and anxiety protocol that adjusts background infusions to comfort. The course of children with wounds involving at least 10% of the body surface and coincident respiratory failure requiring mechanical ventilation for more than 7 days managed 1 Jan 97 to 31 Dec 98 was reviewed. A pain and anxiety protocol was used, including background infusions of morphine and midazolam adjusted to comfort. These 28 children had a mean (+/- standard deviation) age of 5.3 +/- 4.6 years, wound size of 48.3 +/- 28.4%, and were intubated for 25.0 +/- 23.9 days. Neuromuscular blocking drugs were administered for 65 of 447 (14.5%) ventilator days. To maintain comfort, drugs were required at doses substantially above standard dosing schemes. The highest daily background infusion of morphine sulfate averaged 0.40 mg/kg/hr +/- 0.24 mg/kg/hr (usual starting dose was 0.05 to 0.1 mg/kg/hr) and was reached 14.1 +/- 12.8 days after admission. The highest daily background infusion of midazolam averaged 0.15 +/- 0.07 mg/kg/hr (usual starting dose was 0.04 mg/kg/hr) and was reached 14.0 +/- 3.8 days after admission. Morphine infusions at extubation averaged 0.22 +/- 0.17 mg/kg/hr and midazolam infusions 0.10 +/- 0.12 mg/kg/hr. All children survived to discharge and there was no perceived morbidity related to these high doses of medication. Children with serious burns and respiratory failure will require high doses of background opiates and benzodiazepines to remain comfortable, because they develop drug tolerance during protracted critical illness. Infusions can be continued at a reduced dose through extubation, do not result in addiction or other apparent morbidity if adjusted to desired level of comfort, and may contribute to a reduced incidence of treatment-related stress disorders.

Enhanced UV-B radiation during pupal stage reduce body mass and fat content, while increasing deformities, mortality and cell death in female adults of solitary bee Osmia bicornis.

PubMed

Wasielewski, Oskar; Wojciechowicz, Tatiana; Giejdasz, Karol; Krishnan, Natraj

2015-08-01

The effects of enhanced UV-B radiation on the oogenesis and morpho-anatomical characteristics of the European solitary red mason bee Osmia bicornis L. (Hymenoptera: Megachilidae) were tested under laboratory conditions. Cocooned females in the pupal stage were exposed directly to different doses (0, 9.24, 12.32, and 24.64 kJ/m(2) /d) of artificial UV-B. Our experiments revealed that enhanced UV-B radiation can reduce body mass and fat body content, cause deformities and increase mortality. Following UV exposure at all 3 different doses, the body mass of bees was all significantly reduced compared to the control, with the highest UV dose causing the largest reduction. Similarly, following UV-B radiation, in treated groups the fat body index decreased and the fat body index was the lowest in the group receiving the highest dose of UV radiation. Mortality and morphological deformities, between untreated and exposed females varied considerably and increased with the dose of UV-B radiation. Morphological deformities were mainly manifested in the wings and mouthparts, and occurred more frequently with an increased dose of UV. Cell death was quantified by the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay (DNA fragmentation) during early stages of oogenesis of O. bicornis females. The bees, after UV-B exposure exhibited more germarium cells with fragmented DNA. The TUNEL test indicated that in germarium, low doses of UV-B poorly induced the cell death during early development. However, exposure to moderate UV-B dose increased programmed cell death. In females treated with the highest dose of UV-B the vast majority of germarium cells were TUNEL-positive. © 2014 Institute of Zoology, Chinese Academy of Sciences.

Inhalation dose due to radon, thoron, and progenies in dwellings of a hill station.

PubMed

Sivakumar, R

2017-02-01

The general public spends a major portion of their time in an indoor environment and hence receives a considerable amount of radiation. Knowledge about indoor radiation is important in order to arrive at the actual effective dose received by residents. The indoor radon, thoron, and progeny concentrations observed in the present study were found to vary with seasons of a given year. The highest and lowest indoor average radon, thoron, and progeny levels were observed during winter and summer seasons, respectively. The concentrations of indoor radon, thoron, and progenies were found to vary with the type of houses. The highest 222 Rn, 220 Rn, and progeny concentrations were observed in mud houses and the lowest values were recorded in wooden houses. The indoor 222 Rn concentration correlated well with concentration of its grandparent 238 U in underlying soil with a correlation coefficient of 0.87. The correlation between indoor 220 Rn and 232 Th in the underlying soil was found to be 0.64. The estimated effective doses received by the general public in the present study due to indoor radon and thoron were 1.49 ± 0.49 and 1.30 ± 0.53 mSv/year, respectively. The annual effective doses due to radon and thoron progenies were estimated as 0.76 ± 0.27 and 0.47 ± 0.23 mSv/year, respectively. The contributions from 222 Rn, 220 Rn, and corresponding progenies to the annual effective doses received were 37, 32, 19, and 12%, respectively. The general public living in the study area receives an inhalation dose of 4.02 mSv/year due to indoor radon, thoron, and progenies, which were found to be less than the action limit of ICRP 2009.

Maternal treatment with a high dose of CpG ODN during gestation alters fetal craniofacial and distal limb development in C57BL/6 mice.

PubMed

Prater, M Renee; Johnson, Victor J; Germolec, Dori R; Luster, Michael I; Holladay, Steven D

2006-01-16

Synthetic oligodeoxynucleotides (ODN) containing CpG motifs, characteristic of bacterial DNA, are currently being evaluated as vaccine adjuvants for inducing protective immunity. Recently, there is increasing pressure to vaccinate pregnant women against maternally transmitted diseases including AIDS and tetanus, as well as against potential bio-weapons such as anthrax. CpG vaccines are effective because they trigger transient increases in T(H)1 cytokine production. Recent literature suggests, however, that a shift toward a T(H)1 cytokine profile during pregnancy may increase the risk of fetal morphologic defects. On this basis, we hypothesized that exposure to CpG motifs during pregnancy could result in T(H)1 inflammation leading to adverse effects on fetal development. To address this hypothesis, pregnant C57BL/6 mice were injected with CpG ODN (0-300 microg/dam) and maternal and fetal outcomes were determined. Injection of dams with the highest dose of CpG ODN resulted in markedly increased fetal resorptions and craniofacial/limb defects, while lower doses had little, if any effects. Histological examination of placentas revealed cellular necrosis with mixed inflammation and calcification in the spongiotrophoblast layer and dysregulation of labyrinthine vascular development. Concomitant elevations in maternal serum cytokine levels were observed including interleukin (IL)-2, IL-10 and IL-12. Treatment with 300 microg of non-CpG ODN did not cause any adverse effects. The 300 microg dose of CpG ODN used in the present study is 30-fold higher than the highest dose that has been administered to humans during clinical trials. These results suggest that the induction of T(H)1 cytokines during pregnancy by CpG motifs may potentially increase the risk of fetal loss and morphologic defects in mice, at least at high doses, and support the need for further investigation of teratogenesis that may result from exposure to vaccine adjuvants designed to produce T(H)1 cytokine profile shifts.

Safety of {sup 90}Y Radioembolization in Patients Who Have Undergone Previous External Beam Radiation Therapy

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

Lam, Marnix G.E.H.; Department of Radiology and Nuclear Medicine, University Medical Center Utrecht; Abdelmaksoud, Mohamed H.K.

2013-10-01

Purpose: Previous external beam radiation therapy (EBRT) is theoretically contraindicated for yttrium-90 ({sup 90}Y) radioembolization (RE) because the liver has a lifetime tolerance to radiation before becoming vulnerable to radiation-induced liver disease. We analyzed the safety of RE as salvage treatment in patients who had previously undergone EBRT. Methods and Materials: Between June 2004 and December 2010, a total of 31 patients who had previously undergone EBRT were treated with RE. Three-dimensional treatment planning with dose–volume histogram (DVH) analysis of the liver was used to calculate the EBRT liver dose. Liver-related toxicities including RE-induced liver disease (REILD) were reviewed andmore » classified according to Common Terminology Criteria for Adverse Events version 4.02. Results: The mean EBRT and RE liver doses were 4.40 Gy (range, 0-23.13 Gy) and 57.9 Gy (range, 27.0-125.9 Gy), respectively. Patients who experienced hepatotoxicity (≥grade2; n=12) had higher EBRT mean liver doses (7.96 ± 8.55 Gy vs 1.62 ± 3.39 Gy; P=.037), the only independent predictor in multivariate analysis. DVH analysis showed that the fraction of liver exposed to ≥30 Gy (V30) was the strongest predictor of hepatotoxicity (10.14% ± 12.75% vs 0.84% ± 3.24%; P=.006). All patients with V30 >13% experienced hepatotoxicity. Fatal REILD (n=2) occurred at the 2 highest EBRT mean liver doses (20.9 Gy and 23.1 Gy) but also at the highest cumulative liver doses (91.8 Gy and 149 Gy). Conclusions: Prior exposure of the liver to EBRT may lead to increased liver toxicity after RE treatment, depending on fractional liver exposure and dose level. The V30 was the strongest predictor of toxicity. RE appears to be safe for the treatment of hepatic malignancies only in patients who have had limited hepatic exposure to prior EBRT.« less

Simulation of major space particles toward selected materials in a near-equatorial low earth orbit

NASA Astrophysics Data System (ADS)

Suparta, Wayan; Zulkeple, Siti Katrina

2017-05-01

A low earth orbit near the equator (LEO-NEqO) is exposed to the highest energies from galactic cosmic rays (GCR) and from trapped protons with a wide range of energies. Moreover, GCR fluxes were seen to be the highest in 2009 to 2010 when communication belonging to the RazakSAT-1 satellite was believed to have been lost. Hence, this study aimed to determine the influence of the space environment toward the operation of LEO-NEqO satellites by investigating the behavior of major space particles toward satellite materials. The space environment was referred to GCR protons and trapped protons. Their fluxes were obtained from the Space Environment Information System (SPENVIS) and their tracks were simulated through three materials using a simulation program called Geometry and Tracking (Geant4). The materials included aluminum (Al), gallium arsenide (GaAs) and silicon (Si). Then the total ionizing dose (TID) and non-ionizing dose (NIEL) were calculated for a three-year period. Simulations showed that GCR traveled at longer tracks and produced more secondary radiation than trapped protons. Al turned out to receive the lowest total dose, while GaAs showed to be susceptible toward GCR than Si. However, trapped protons contributed the most in spacecraft doses where Si received the highest doses. Finally, the comparison between two Geant4 programs revealed the estimated doses differed at <18%.

Reproductive responses of male Brandt's voles ( Lasiopodomys brandtii) to 6-methoxybenzoxazolinone (6-MBOA) under short photoperiod

NASA Astrophysics Data System (ADS)

Dai, Xin; Jiang, Lian Yu; Han, Mei; Ye, Man Hong; Wang, Ai Qin; Wei, Wan Hong; Yang, Sheng Mei

2016-04-01

The plant secondary metabolite 6-methoxybenzoxazolinone (6-MBOA) can stimulate and enhance animal reproduction. This compound has been successfully detected in Leymus chinensis, which is the main diet of Brandt's voles. The aim of this study was to investigate the effect of different 6-MBOA doses on the reproductive physiology of male Brandt's voles under a short photoperiod. The results showed that 6-MBOA administration increased relative testis weight, regardless of the dose, but it had little effect on the body mass. Low and middle doses of 6-MBOA increased the concentrations of luteinizing hormone and testosterone in the serum and the mRNA levels of StAR and CYP11a1 in the testes. However, 6-MBOA did not cause any significant increase in the mRNA levels of KiSS-1, GPR54, and GnRH compared to those in the control group. The mRNA level of KiSS-1 in the arcuate nucleus (ARC) was higher than that in the anteroventral periventricular nucleus (AVPV). Collectively, our results demonstrated that the number of KiSS-1-expressing neurons located in the ARC was the highest, and that 6-MBOA, which might modulate the reproductive activity along the hypothalamic-pituitary-gonadal axis, had a dose-dependent stimulatory effect on the reproductive activity of Brandt's voles under a short photoperiod. Our study provided insights into the mechanism of 6-MBOA action and the factors influencing the onset of reproduction in Brandt's voles.

Reproductive responses of male Brandt's voles (Lasiopodomys brandtii) to 6-methoxybenzoxazolinone (6-MBOA) under short photoperiod.

PubMed

Dai, Xin; Jiang, Lian Yu; Han, Mei; Ye, Man Hong; Wang, Ai Qin; Wei, Wan Hong; Yang, Sheng Mei

2016-04-01

The plant secondary metabolite 6-methoxybenzoxazolinone (6-MBOA) can stimulate and enhance animal reproduction. This compound has been successfully detected in Leymus chinensis, which is the main diet of Brandt's voles. The aim of this study was to investigate the effect of different 6-MBOA doses on the reproductive physiology of male Brandt's voles under a short photoperiod. The results showed that 6-MBOA administration increased relative testis weight, regardless of the dose, but it had little effect on the body mass. Low and middle doses of 6-MBOA increased the concentrations of luteinizing hormone and testosterone in the serum and the mRNA levels of StAR and CYP11a1 in the testes. However, 6-MBOA did not cause any significant increase in the mRNA levels of KiSS-1, GPR54, and GnRH compared to those in the control group. The mRNA level of KiSS-1 in the arcuate nucleus (ARC) was higher than that in the anteroventral periventricular nucleus (AVPV). Collectively, our results demonstrated that the number of KiSS-1-expressing neurons located in the ARC was the highest, and that 6-MBOA, which might modulate the reproductive activity along the hypothalamic-pituitary-gonadal axis, had a dose-dependent stimulatory effect on the reproductive activity of Brandt's voles under a short photoperiod. Our study provided insights into the mechanism of 6-MBOA action and the factors influencing the onset of reproduction in Brandt's voles.

Maternal vitamin D status during pregnancy and risk of childhood asthma: A meta-analysis of prospective studies.

PubMed

Song, Huihui; Yang, Lei; Jia, Chongqi

2017-05-01

Mounting evidence suggests that maternal vitamin D status during pregnancy may be associated with development of childhood asthma, but the results are still inconsistent. A dose-response meta-analysis was performed to quantitatively summarize evidence on the association of maternal vitamin D status during pregnancy with the risk of childhood asthma. A systematic search was conducted to identify all studies assessing the association of maternal 25-hydroxyvitamin D (25(OH)D) during pregnancy with risk of childhood asthma. The fixed or random-effect model was selected based on the heterogeneity test among studies. Nonlinear dose-response relationship was assessed by restricted cubic spline model. Fifteen prospective studies with 12 758 participants and 1795 cases were included in the meta-analysis. The pooled relative risk of childhood asthma comparing the highest versus lowest category of maternal 25(OH)D levels was 0.87 (95% confidence interval, CI, 0.75-1.02). For dose-response analysis, evidence of a U-shaped relationship was found between maternal 25(OH)D levels and risk of childhood asthma (P nonlinearity = 0.02), with the lowest risk at approximately 70 nmol/L of 25(OH)D. This dose-response meta-analysis suggested a U-shaped relationship between maternal blood 25(OH)D levels and risk of childhood asthma. Further studies are needed to confirm the association. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Prospective iterative trial of proteasome inhibitor-based desensitization.

PubMed

Woodle, E S; Shields, A R; Ejaz, N S; Sadaka, B; Girnita, A; Walsh, R C; Alloway, R R; Brailey, P; Cardi, M A; Abu Jawdeh, B G; Roy-Chaudhury, P; Govil, A; Mogilishetty, G

2015-01-01

A prospective iterative trial of proteasome inhibitor (PI)-based therapy for reducing HLA antibody (Ab) levels was conducted in five phases differing in bortezomib dosing density and plasmapheresis timing. Phases included 1 or 2 bortezomib cycles (1.3 mg/m(2) × 6-8 doses), one rituximab dose and plasmapheresis. HLA Abs were measured by solid phase and flow cytometry (FCM) assays. Immunodominant Ab (iAb) was defined as highest HLA Ab level. Forty-four patients received 52 desensitization courses (7 patients enrolled in multiple phases): Phase 1 (n = 20), Phase 2 (n = 12), Phase 3 (n = 10), Phase 4 (n = 5), Phase 5 (n = 5). iAb reductions were observed in 38 of 44 (86%) patients and persisted up to 10 months. In Phase 1, a 51.5% iAb reduction was observed at 28 days with bortezomib alone. iAb reductions increased with higher bortezomib dosing densities and included class I, II, and public antigens (HLA DRβ3, HLA DRβ4 and HLA DRβ5). FCM median channel shifts decreased in 11/11 (100%) patients by a mean of 103 ± 54 mean channel shifts (log scale). Nineteen out of 44 patients (43.2%) were transplanted with low acute rejection rates (18.8%) and de novo DSA formation (12.5%). In conclusion, PI-based desensitization consistently and durably reduces HLA Ab levels providing an alternative to intravenous immune globulin-based desensitization. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits.

PubMed

Bonham, A C; Kott, K S; Ravi, K; Kappagoda, C T; Joad, J P

1996-05-15

1. This study tested the hypothesis that substance P stimulates rapidly adapting receptors (RARs), contributes to the increase in RAR activity produced by mild pulmonary congestion, and evokes an augmented response from RARs when combined with near-threshold levels of pulmonary congestion. 2. RAR activity, peak tracheal pressure, arterial blood pressure and left atrial pressure were measured in paralysed, anaesthetized and ventilated rabbits. Substance P was given i.v. in one-half log incremental doses to a maximum of 3 micrograms kg-1. Mild pulmonary congestion was produced by inflating a balloon in the left atrium to increase left atrial pressure by 5 mmHg. Near-threshold levels of pulmonary congestion were produced by increasing left atrial pressure by 2 mmHg. 3. Substance P produced dose-dependent increases in RAR activity. The highest dose given increased the activity from 1.3 +/- 0.5 to 11.0 +/- 3.1 impulses bin-1. Increases in left atrial pressure of 5 mmHg increased RAR activity from 3.8 +/- 1.4 to 14.7 +/- 3.9 impulses bin-1. Blockade of NK1 receptors with CP 96345 significantly attenuated RAR responses to substance P and to mild pulmonary congestion. 4. Doses of substance P, which alone had no effect, stimulated the RARs when delivered during near-threshold levels of pulmonary congestion. 5. The findings suggest that substance P augments the stimulatory effect of mild pulmonary congestion on RAR activity, most probably by enhancing hydraulically induced microvascular leak.

Parastar insecticide induced changes in reproductive parameters and testicular oxidative stress biomarkers in Wistar male rats.

PubMed

Nantia, Edouard Akono; Kada, Antoine S; Manfo, Faustin Pt; Tangu, Nehemiah N; Mbifung, Kaghou M; Mbouobda, Desire H; Kenfack, Augustave

2018-07-01

Parastar is an insecticide formulation of lambda-cyhalothrin and imidacloprid, and it is largely used for crop production improvement in Santa, North West Region of Cameroon. This study aimed at evaluating the effects of Parastar on reproductive parameters and testicular oxidative stress in adult albino Wistar male rats. Twenty rats (154 g ± 28 g) were divided into four groups of five animals each and treated daily with either distilled water (10 mL/kg), 1.25, 2.49 or 6.23 mg/kg of Parastar, respectively, for 35 days. After treatment, animal reproductive function was evaluated through fertility tests, sperm characteristics, testosterone levels and organ weights, while oxidative stress biomarkers were determined on testicular homogenates. Parastar administration resulted into increased seminal vesicle and prostate weights, while body weight remained unaffected. Parastar dose-dependently reduced sperm density and mobility, and the highest dose decreased serum testosterone levels. Parastar also modulated stress biomarkers with increased thiobarbituric acid reactive substances levels, decreased glutathione levels and inhibition of catalase and superoxide dismutase activities. In conclusion, Parastar negatively affected male reproductive function through alteration of testosterone levels, sperm parameters and induction of oxidative stress in rats.

A consistent two-mutation model of bone cancer for two data sets of radium-injected beagles.

PubMed

Bijwaard, H; Brugmans, M J P; Leenhouts, H P

2002-09-01

A two-mutation carcinogenesis model has been applied to model osteosarcoma incidence in two data sets of beagles injected with 226Ra. Taking age-specific retention into account, the following results have been obtained: (1) a consistent and well-fitting solution for all age and dose groups, (2) mutation rates that are linearly dependent on dose rate, with an exponential decrease for the second mutation at high dose rates, (3) a linear-quadratic dose-effect relationship, which indicates that care should be taken when extrapolating linearly, (4) highest cumulative incidences for injection at young adult age, and highest risks for injection doses of a few kBq kg(-1) at these ages, and (5) when scaled appropriately, the beagle model compares fairly well with a description for radium dial painters, suggesting that a consistent model description of bone cancer induction in beagles and humans may be possible.

Evaluation of dose from kV cone-beam computed tomography during radiotherapy: a comparison of methodologies

NASA Astrophysics Data System (ADS)

Buckley, J.; Wilkinson, D.; Malaroda, A.; Metcalfe, P.

2017-01-01

Three alternative methodologies to the Computed-Tomography Dose Index for the evaluation of Cone-Beam Computed Tomography dose are compared, the Cone-Beam Dose Index, IAEA Human Health Report No. 5 recommended methodology and the AAPM Task Group 111 recommended methodology. The protocols were evaluated for Pelvis and Thorax scan modes on Varian® On-Board Imager and Truebeam kV XI imaging systems. The weighted planar average dose was highest for the AAPM methodology across all scans, with the CBDI being the second highest overall. A 17.96% and 1.14% decrease from the TG-111 protocol to the IAEA and CBDI protocols for the Pelvis mode and 18.15% and 13.10% decrease for the Thorax mode were observed for the XI system. For the OBI system, the variation was 16.46% and 7.14% for Pelvis mode and 15.93% to the CBDI protocol in Thorax mode respectively.

Effects of arbuscular mycorrhizal inoculation and fertilization on mycorrhizal Statute of Jacaranda mimosifolia D.Don cultivated in nurseries.

PubMed

Zaouchi, Yousr; Bahri, Nada Ben; Rezgui, S; Bettaieb, Taoufik

2013-10-01

The effects of fertilization and the nature of the inoculum as well as the variation of the dose intake of the latter on the level of Jacaranda mimosifolia D.Don mycorhization were tested. Young plants were treated with two inoculums presenting different origins, compositions and modes of application: one is a commercial product containing Glomus irregulare, and the other is a composite indigenous inoculum resulting from trapping five species of genus Glomus and also from multiplication on mycotrophic plants: leek (Allium porrum L.) and vetch (Vicia sativa L.). For each inoculum, two doses were tested and for each dose of inoculum, four levels of fertilization based on a complete commercial fertilizer (Osmocote) were tested: 0 g/plant, 2 g/plant, 4 g/plant, and 6g/plant. Three repetitions were performed for each combination treatment of inoculum/fertilizer. One-year-old young Jacaranda plants, being about 40 cm high, were cultured under greenhouse in 10/12 cm caliber pots. After six months, all the inoculated plants were mycorrhized. According to endomycorrhizal structures found on their roots, plants receiving doses of composite indigenous inoculum reached a more advanced stage of mycorrhization than those treated with the commercial inoculum. The existence of an interaction effect between the inoculum dose and the level of fertilization on Jacaranda mycorhization rate was excluded. These two parameters of variation were studied as simple effects. The increase in commercial inoculum dose had a significant positive influence on the level of Jacaranda plants mycorrhization (P=0.05). The rate of mycorrhization jumped from 12.69% to 21.92%. Nonetheless, for plants receiving increasing doses of composite indigenous inoculum, the level of mycorrhization has varied randomly. In both instances of inoculum treatments, increasing the dose of fertilizer significantly inhibited endomycorrhizal colonization of Jacaranda roots (P=0.01). Thus, the rate of root colonization decreased from 47.43% to 2.41% for plants receiving the composite indigenous inoculums. It decreased from 32.35% to 3.95% for those treated with the commercial inoculum. Mycorrhization had a positive effect on root dry biomass of Jacaranda, as in the case of unfertilize ave the highest rates of colonization. Copyright © 2013. Published by Elsevier SAS.

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

PubMed

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

2015-12-01

The biological effects and interactions of different radiation types in plants are still far from understood. Among different radiation types, external gamma radiation treatments have been mostly studied to assess the biological impact of radiation toxicity in organisms. Upon exposure of plants to gamma radiation, ionisation events can cause, either directly or indirectly, severe biological damage to DNA and other biomolecules. However, the biological responses and oxidative stress related mechanisms under chronic radiation conditions are poorly understood in plant systems. In the following study, it was questioned if the Lemna minor growth inhibition test is a suitable approach to also assess the radiotoxicity of this freshwater plant. Therefore, L. minor plants were continuously exposed for seven days to 12 different dose rate levels covering almost six orders of magnitude starting from 80 μGy h(-1) up to 1.5 Gy h(-1). Subsequently, growth, antioxidative defence system and genomic responses of L. minor plants were evaluated. Although L. minor plants could survive the exposure treatment at environmental relevant exposure conditions, higher dose rate levels induced dose dependent growth inhibitions starting from approximately 27 mGy h(-1). A ten-percentage growth inhibition of frond area Effective Dose Rate (EDR10) was estimated at 95 ± 7 mGy h(-1), followed by 153 ± 13 mGy h(-1) and 169 ± 12 mGy h(-1) on fresh weight and frond number, respectively. Up to a dose rate of approximately 5 mGy h(-1), antioxidative enzymes and metabolites remained unaffected in plants. A significant change in catalase enzyme activity was found at 27 mGy h(-1) which was accompanied with significant increases of other antioxidative enzyme activities and shifts in ascorbate and glutathione content at higher dose rate levels, indicating an increase in oxidative stress in plants. Recent plant research hypothesized that environmental genotoxic stress conditions can induce endoreduplication events. Here an increase in ploidy level was observed at the highest tested dose rate. In conclusion, the results revealed that in plants several mechanisms and pathways interplay to cope with radiation induced stress. Copyright © 2015 Elsevier Ltd. All rights reserved.

Measurements of carbonyls in a 13-story building.

PubMed

Báez, Armando P; Padilla, Hugo G; García, Rocío M; Belmont, Raúl D; Torres, Maria del Carmen B

2004-01-01

Formaldehyde and acetaldehyde are emitted by many mobile and stationary sources and secondary aldehydes are intermediates in the photo-oxidation of organic compounds in the atmosphere. These aldehydes are emitted indoors by many materials such as furniture, carpets, heating and cooling systems, an by smoking. Carbonyls, mainly formaldehyde and acetaldehyde, have been studied because of their adverse health effects. In addition, formaldehyde is a suspected carcinogen. Therefore, the concentrations of formaldehyde and acetaldehyde were determined to assess the inhalation exposure doses to carbonyls for people who work in a 13-story building and in order to evaluate the cancer hazard. Carbonyl compounds in indoor and outdoor air were measured at a 13-story building located in Mexico City. The mezzanine, fifth and tenth floors, and the third level-parking garage were selected for sampling. Samples were collected in two sampling periods, the first from April 20 to 29, 1998 and the second from December 1 to 20, 1998. Carbonyls were sampled by means of DNHP-coated cartridges at a flow rate of 1 l min(-1) from 9:00 to 19:00 hours, during 2-hour time intervals and analyzed by HPLC with hours, during 2-hour time intervals and analyzed by HPLC with UV/VIS detection. Mean carbonyl concentrations were highest in the 3rd level-parking garage, with the formaldehyde concentration being the highest ranging from 108 to 418 microg m(-3). In working areas, the highest carbonyl arithmetic mean concentrations (AM) were observed on the 5th floor. Acetone and formaldehyde concentrations were highest in April ranging from 161 to 348 microg m(-3) (AM = 226) and from 157 to 270 microg m(-3) (AM = 221), respectively. Propionaldehyde and butyraldehyde were present in smaller concentrations ranging from 2 to 25 and 1 to 28 microg m(-3), respectively, considering all the samples. Mean indoor/outdoor ratios of carbonyls ranged from 1.8 to 9.6. A reduction of inhalation exposure doses of 41% and 45% was observed in the fifth floor air after the air conditioning systems had been repaired. Formaldehyde and acetaldehyde concentrations were higher in smoking environments. Indoor carbonyl concentrations were significantly greater than outdoor concentrations. Tobacco smoke seems to be the main indoor source of formaldehyde. After the air conditioning system was maintained and repaired (as was recommended), an important reduction in the emission of formaldehyde and acetaldehyde was achieved on all floors, except for the 3rd level parking garage, thereby reducing the inhalation exposure doses. The results obtained in this research demonstrated that maintenance of air conditioning systems must be carried out regularly in order to avoid possible adverse effects on health. Additionally, it is mandatory that isolated smoking areas, with air extraction systems, be installed in every public building.

Comparative responses to endocrine disrupting compounds in early life stages of Atlantic salmon, Salmo salar

USGS Publications Warehouse

Duffy, Tara A.; Iwanowicz, Luke R.; McCormick, Stephen D.

2014-01-01

Atlantic salmon (Salmo salar) are endangered anadromous fish that may be exposed to feminizing endocrine disrupting compounds (EDCs) during early development, potentially altering physiological capacities, survival and fitness. To assess differential life stage sensitivity to common EDCs, we carried out short-term (four day) exposures using three doses each of 17α-ethinylestradiol (EE2), 17β-estradiol (E2), and nonylphenol (NP) on four early life stages; embryos, yolk-sac larvae, feeding fry and one year old smolts. Differential response was compared using vitellogenin (Vtg, a precursor egg protein) gene transcription. Smolts were also examined for impacts on plasma Vtg, cortisol, thyroid hormones (T4/T3) and hepatosomatic index (HSI). Compound-related mortality was not observed in any life stage, but Vtg mRNA was elevated in a dose-dependent manner in yolk-sac larvae, fry and smolts but not in embyos. The estrogens EE2 and E2 were consistently stronger inducers of Vtg than NP. Embryos responded significantly to the highest concentration of EE2 only, while older life stages responded to the highest doses of all three compounds, as well as intermediate doses of EE2 and E2. Maximal transcription was greater for fry among the three earliest life stages, suggesting fry may be the most responsive life stage in early development. Smolt plasma Vtg was also significantly increased, and this response was observed at lower doses of each compound than was detected by gene transcription suggesting this is a more sensitive indicator at this life stage. HSI was increased at the highest doses of EE2 and E2 and plasma T3 decreased at the highest dose of EE2. Our results indicate that all life stages after hatching are potentially sensitive to endocrine disruption by estrogenic compounds and that physiological responses were altered over a short window of exposure, indicating the potential for these compounds to impact fish in the wild.

Vitamin D in corticosteroid-naïve and corticosteroid-treated Duchenne muscular dystrophy: what dose achieves optimal 25(OH) vitamin D levels?

PubMed

Alshaikh, Nahla; Brunklaus, Andreas; Davis, Tracey; Robb, Stephanie A; Quinlivan, Ros; Munot, Pinki; Sarkozy, Anna; Muntoni, Francesco; Manzur, Adnan Y

2016-10-01

Assessment of the efficacy of vitamin D replenishment and maintenance doses required to attain optimal levels in boys with Duchenne muscular dystrophy (DMD). 25(OH)-vitamin D levels and concurrent vitamin D dosage were collected from retrospective case-note review of boys with DMD at the Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient at <25 nmol/L, insufficient at 25-49 nmol/L, adequate at 50-75 nmol/L and optimal at >75 nmol/L. 617 vitamin D samples were available from 197 boys (range 2-18 years)-69% from individuals on corticosteroids. Vitamin D-naïve boys (154 samples) showed deficiency in 28%, insufficiency in 42%, adequate levels in 24% and optimal levels in 6%. The vitamin D-supplemented group (463 samples) was tested while on different maintenance/replenishment doses. Three-month replenishment of daily 3000 IU (23 samples) or 6000 IU (37 samples) achieved optimal levels in 52% and 84%, respectively. 182 samples taken on 400 IU revealed deficiency in 19 (10%), insufficiency in 84 (47%), adequate levels in 67 (37%) and optimal levels in 11 (6%). 97 samples taken on 800 IU showed deficiency in 2 (2%), insufficiency in 17 (17%), adequate levels in 56 (58%) and optimal levels in 22 (23%). 81 samples were on 1000 IU and 14 samples on 1500 IU, with optimal levels in 35 (43%) and 9 (64%), respectively. No toxic level was seen (highest level 230 nmol/L). The prevalence of vitamin D deficiency and insufficiency in DMD is high. A 2-month replenishment regimen of 6000 IU and maintenance regimen of 1000-1500 IU/day was associated with optimal vitamin D levels. These data have important implications for optimising vitamin D dosing in DMD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Evaluation of an iterative model-based CT reconstruction algorithm by intra-patient comparison of standard and ultra-low-dose examinations.

PubMed

Noël, Peter B; Engels, Stephan; Köhler, Thomas; Muenzel, Daniela; Franz, Daniela; Rasper, Michael; Rummeny, Ernst J; Dobritz, Martin; Fingerle, Alexander A

2018-01-01

Background The explosive growth of computer tomography (CT) has led to a growing public health concern about patient and population radiation dose. A recently introduced technique for dose reduction, which can be combined with tube-current modulation, over-beam reduction, and organ-specific dose reduction, is iterative reconstruction (IR). Purpose To evaluate the quality, at different radiation dose levels, of three reconstruction algorithms for diagnostics of patients with proven liver metastases under tumor follow-up. Material and Methods A total of 40 thorax-abdomen-pelvis CT examinations acquired from 20 patients in a tumor follow-up were included. All patients were imaged using the standard-dose and a specific low-dose CT protocol. Reconstructed slices were generated by using three different reconstruction algorithms: a classical filtered back projection (FBP); a first-generation iterative noise-reduction algorithm (iDose4); and a next generation model-based IR algorithm (IMR). Results The overall detection of liver lesions tended to be higher with the IMR algorithm than with FBP or iDose4. The IMR dataset at standard dose yielded the highest overall detectability, while the low-dose FBP dataset showed the lowest detectability. For the low-dose protocols, a significantly improved detectability of the liver lesion can be reported compared to FBP or iDose 4 ( P = 0.01). The radiation dose decreased by an approximate factor of 5 between the standard-dose and the low-dose protocol. Conclusion The latest generation of IR algorithms significantly improved the diagnostic image quality and provided virtually noise-free images for ultra-low-dose CT imaging.

Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects.

PubMed

Gilbert, Ethel S; Curtis, Rochelle E; Hauptmann, Michael; Kleinerman, Ruth A; Lynch, Charles F; Stovall, Marilyn; Smith, Susan A; Weathers, Rita; Andersson, Michael; Dores, Graça M; Fraumeni, Joseph F; Fossa, Sophie D; Hall, Per; Hodgson, David C; Holowaty, Eric J; Joensuu, Heikki; Johannesen, Tom B; Langmark, Froydis; Kaijser, Magnus; Pukkala, Eero; Rajaraman, Preetha; Storm, Hans H; Vaalavirta, Leila; van den Belt-Dusebout, Alexandra W; Aleman, Berthe M; Travis, Lois B; Morton, Lindsay M; van Leeuwen, Flora E

2017-02-01

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.

Effects of corticosterone on contextual fear consolidation in intact and ovariectomized female rats.

PubMed

Kashefi, Adel; Rashidy-Pour, Ali

2014-10-01

Previous studies have shown that post-training administration of glucocorticoids enhances memory consolidation in male rats, but theirs effects on female rats are not known. Thus, this study was conducted to examine the effects of corticosterone (CORT) on contextual fear memory consolidation in intact and ovariectomized (OVX) female rats. In Experiment 1, post-training administration of CORT (0.3, 3, and 10 mg/kg) to OVX female rats impaired memory consolidation at a 0.3 mg dose of CORT. In Experiment 2, post-training injection of CORT (0.3 mg/kg) to female rats in proestrus stage (when the levels of estrogens are highest) enhances and in the estrus stage (when the levels of estrogens are lowest) impaired memory retention. In Experiment 3, OVX female rats injected with CORT (0.3 mg/kg) and one of the three doses of 17β-estradiol (1, 10 or 100 μg/kg) following training. 48-h memory retention test indicated that CORT enhanced memory retention in OVX female rats that received concurrent injection of 10 or 100 μg doses of 17β-estradiol. These findings indicate that cognitive effects of CORT in female rats can be modulated with the plasma levels of estrogens: when the levels of estrogens are low, corticosterone has a negative effect, while when the levels of estrogens are high; the corticosterone has a positive enhancing effect. Copyright © 2014 Elsevier Inc. All rights reserved.

Generative Adversarial Networks for Noise Reduction in Low-Dose CT.

PubMed

Wolterink, Jelmer M; Leiner, Tim; Viergever, Max A; Isgum, Ivana

2017-12-01

Noise is inherent to low-dose CT acquisition. We propose to train a convolutional neural network (CNN) jointly with an adversarial CNN to estimate routine-dose CT images from low-dose CT images and hence reduce noise. A generator CNN was trained to transform low-dose CT images into routine-dose CT images using voxelwise loss minimization. An adversarial discriminator CNN was simultaneously trained to distinguish the output of the generator from routine-dose CT images. The performance of this discriminator was used as an adversarial loss for the generator. Experiments were performed using CT images of an anthropomorphic phantom containing calcium inserts, as well as patient non-contrast-enhanced cardiac CT images. The phantom and patients were scanned at 20% and 100% routine clinical dose. Three training strategies were compared: the first used only voxelwise loss, the second combined voxelwise loss and adversarial loss, and the third used only adversarial loss. The results showed that training with only voxelwise loss resulted in the highest peak signal-to-noise ratio with respect to reference routine-dose images. However, CNNs trained with adversarial loss captured image statistics of routine-dose images better. Noise reduction improved quantification of low-density calcified inserts in phantom CT images and allowed coronary calcium scoring in low-dose patient CT images with high noise levels. Testing took less than 10 s per CT volume. CNN-based low-dose CT noise reduction in the image domain is feasible. Training with an adversarial network improves the CNNs ability to generate images with an appearance similar to that of reference routine-dose CT images.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

Carbon-Ion Radiation Therapy for Pelvic Recurrence of Rectal Cancer

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

Yamada, Shigeru, E-mail: s_yamada@nirs.go.jp; Kamada, Tadashi; Ebner, Daniel K.

Purpose: Investigation of the treatment potential of carbon-ion radiation therapy in pelvic recurrence of rectal cancer. Methods and Materials: A phase 1/2 dose escalation study was performed. One hundred eighty patients (186 lesions) with locally recurrent rectal cancer were treated with carbon-ion radiation therapy (CIRT) (phase 1/2: 37 and 143 patients, respectively). The relapse locations were 71 in the presacral region, 82 in the pelvic sidewalls, 28 in the perineum, and 5 near the colorectal anastomosis. A 16-fraction in 4 weeks dose regimen was used, with total dose ranging from 67.2 to 73.6 Gy(RBE); RBE-weighted absorbed dose: 4.2 to 4.6 Gy(RBE)/fraction. Results: Duringmore » phase 1, the highest total dose, 73.6 Gy(RBE), resulted in no grade >3 acute reactions in the 13 patients treated at that dose. Dose escalation was halted at this level, and this dose was used for phase 2, with no other grade >3 acute reactions observed. At 5 years, the local control and survival rates at 73.6 Gy(RBE) were 88% (95% confidence interval [CI], 80%-93%) and 59% (95% CI, 50%-68%), respectively. Conclusion: Carbon-ion radiation therapy may be a safe and effective treatment option for locally recurrent rectal cancer and may serve as an alternative to surgery.« less

THE EFFECT OF ENDOCRINE CHANGES, OF IRRADIATION AND OF ADDITIONAL TREATMENT OF THE SKIN ON THE INDUCTION OF TUMOURS IN THE FEMALE GENITAL TRACT OF RATS BY CHEMICAL CARCINOGENS

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

Cherry, C.P.; Glucksmann, A.

1960-09-01

Ovariectomy reduced the incidence of vaginal tumors after intravaginal application of 9,10-dimethyl-1,2benzanthracene (DMBA), and administration of oestrogen or of progesterone raised the incidence of tumors only slightly. Repeated whole-body exposures to x rays also lowered the rate of tumor incidence after painting and so to a lesser extent did repeated pelvic irradiation of virgin rats and the application of DMBA to an additional dorsal skin region. In surgical castrates adrenalectomy or repeated pelvic irradiation restored the level of tumor incidence to that of intact and pregnant rats. Three levels of vaginal tumor incidence were found, and the distribution of tumormore » types and the length of the average induction time varied with the level: at the lowest level there were only sarcomas, at the intermediate level fibromas and presarcomatous lesions were found in addition to the sarcomas; and at the highest level the incidence of sarcomas is increased and epithelial tumors appear. Tumor induction in the vulva is not affected by castration, radiation, or hormone treatment but varies at certain dose levels with the dose of the carcinogen. (auth)« less

Free radical scavenging, antidiarrheal and anthelmintic activity of Pistia stratiotes L. extracts and its phytochemical analysis.

PubMed

Bin Karim, Mohammed Faisal; Imam, Hasan; Sarker, Md Moklesur-Rahman; Uddin, Nizam; Hasan, Nahid; Paul, Nirmala; Haque, Tahmina

2015-05-01

In this phyto-pharmacological screening of Pistia stratiotes L leaf and root extracts each separately in two different solvents demonstrated its potential medicinal value. Apparent antioxidant value is demonstrated by DPPH, Nitric oxide scavenging and Ferric ion reducing method. Additionally, total flavonoid and phenolic compounds were measured. The leaf methanolic extract scavenged both nitric oxide (NO) and DPPH radical with a dose dependent manner. But the pet ether fraction of root was found to have highest efficacy in Fe(3±) reducing power assay. Flavonoid was found to contain highest in the pet ether fraction of root (411.35mg/g) in terms of quercetin equivalent, similarly highest amount (34.96mg/g) of total phenolic compounds (assayed as gallic acid equivalents) were found to contain in the same fraction. The methanolic fractions appeared less cytotoxic compared to pet ether extracts. The plant extracts caused a dose dependent decrease in faecal droppings in both castor oil and magnesium sulphate induced diarrhea, where as leaf extracts in each solvent appeared most effective. Also, the plant extracts showed anthelmintic activity in earthworm by inducing paralysis and death in a dose dependent manner. At highest doses (50 mg/ml) all fractions were almost effective as the positive control piperazine citrate (10 mg/ml). Thus, besides this cytotoxic effect it's traditional claim for therapeutic use can never be overlooked.

Meth math: modeling temperature responses to methamphetamine.

PubMed

Molkov, Yaroslav I; Zaretskaia, Maria V; Zaretsky, Dmitry V

2014-04-15

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.

Meth math: modeling temperature responses to methamphetamine

PubMed Central

Molkov, Yaroslav I.; Zaretskaia, Maria V.

2014-01-01

Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants. PMID:24500434

Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers.

PubMed

Kirkpatrick, B D; McKenzie, Robin; O'Neill, J Patrick; Larsson, Catherine J; Bourgeois, A Louis; Shimko, Janet; Bentley, Matthew; Makin, Jill; Chatfield, Steve; Hindle, Zoë; Fidler, Christine; Robinson, Brad E; Ventrone, Cassandra H; Bansal, Nivedita; Carpenter, Colleen M; Kutzko, Deborah; Hamlet, Sandra; LaPointe, Casey; Taylor, David N

2006-01-12

Salmonella enterica serovar Typhi strains with mutations in the Salmonella pathogenicity island-2 (SPI-2) may represent an effective strategy for human vaccine development, and a vectoring system for heterologous antigens. S. Typhi (Ty2 aroC-ssaV-) M01ZH09 is an attenuated, live, oral typhoid vaccine harboring defined deletion mutations in ssaV, which encodes an integral component in the SPI-2 type III secretion system (TTSS), as well as a mutation in an aromatic biosynthetic pathway needed for bacterial growth in vivo (aroC). SPI-2 mutant vaccines have yet to be evaluated in a large, randomized human trial. A simplified or single-oral dose oral typhoid vaccine using the SPI-2 strategy would offer significant advantages over the currently licensed typhoid vaccines. We performed a double-blinded, placebo-controlled, dose-escalating clinical trial in 60 healthy adult volunteers to determine the tolerability and immunogenicity of a single dose of M01ZH09. Three groups of 20 healthy adult volunteers were enrolled; 16 in each group received a single oral dose of the freeze-dried vaccine at 5 x 10(7), 5 x 10(8) or 5 x 10(9)CFU in a bicarbonate buffer. Four volunteers in each cohort received placebo in the same buffer. Adverse events were infrequent and not statistically different between vaccine and placebo recipients, although two subjects in the mid-range dose and three subjects in the highest dose had temperature measurements >37.5 degrees C. No blood or urine cultures were positive for M01ZH09, and fecal shedding was brief. The immune response was dose-related; the highest vaccine dose (5 x 10(9)CFU) was the most immunogenic. All tested subjects receiving the highest dose had a significant ASC response (mean 118 spots/10(6) cells). A >or=4-fold increase in antibody titer for S. Typhi LPS or flagellin was detected in 75% of volunteers in the highest-dose cohort by day 28. The SPI-2 mutant vaccine, M01ZH09, is a promising typhoid vaccine candidate and deserves further study as a vectoring system for heterologous vaccine antigens.

Evaluation of image quality and radiation dose by adaptive statistical iterative reconstruction technique level for chest CT examination.

PubMed

Hong, Sun Suk; Lee, Jong-Woong; Seo, Jeong Beom; Jung, Jae-Eun; Choi, Jiwon; Kweon, Dae Cheol

2013-12-01

The purpose of this research is to determine the adaptive statistical iterative reconstruction (ASIR) level that enables optimal image quality and dose reduction in the chest computed tomography (CT) protocol with ASIR. A chest phantom with 0-50 % ASIR levels was scanned and then noise power spectrum (NPS), signal and noise and the degree of distortion of peak signal-to-noise ratio (PSNR) and the root-mean-square error (RMSE) were measured. In addition, the objectivity of the experiment was measured using the American College of Radiology (ACR) phantom. Moreover, on a qualitative basis, five lesions' resolution, latitude and distortion degree of chest phantom and their compiled statistics were evaluated. The NPS value decreased as the frequency increased. The lowest noise and deviation were at the 20 % ASIR level, mean 126.15 ± 22.21. As a result of the degree of distortion, signal-to-noise ratio and PSNR at 20 % ASIR level were at the highest value as 31.0 and 41.52. However, maximum absolute error and RMSE showed the lowest deviation value as 11.2 and 16. In the ACR phantom study, all ASIR levels were within acceptable allowance of guidelines. The 20 % ASIR level performed best in qualitative evaluation at five lesions of chest phantom as resolution score 4.3, latitude 3.47 and the degree of distortion 4.25. The 20 % ASIR level was proved to be the best in all experiments, noise, distortion evaluation using ImageJ and qualitative evaluation of five lesions of a chest phantom. Therefore, optimal images as well as reduce radiation dose would be acquired when 20 % ASIR level in thoracic CT is applied.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats.

PubMed

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-12-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

PubMed Central

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-01-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

Disposition and metabolism of a novel prostanoid antiglaucoma medication, tafluprost, following ocular administration to rats.

PubMed

Fukano, Y; Kawazu, K

2009-08-01

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-prostaglandin F(2alpha) antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

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.

PCSK9 and lipoprotein (a) levels are two predictors of coronary artery calcification in asymptomatic patients with familial hypercholesterolemia.

PubMed

Alonso, Rodrigo; Mata, Pedro; Muñiz, Ovidio; Fuentes-Jimenez, Francisco; Díaz, Jose Luis; Zambón, Daniel; Tomás, Marta; Martin, Cesar; Moyon, Thomas; Croyal, Mikaël; Thedrez, Aurélie; Lambert, Gilles

2016-11-01

We aimed to assess whether elevated PCSK9 and lipoprotein (a) [Lp(a)] levels associate with coronary artery calcification (CAC), a good marker of atherosclerosis burden, in asymptomatic familial hypercholesterolemia. We selected 161 molecularly defined FH patients treated with stable doses of statins for more than a year. CAC was measured using the Agatston method and quantified as categorical variable. Fasting plasma samples were collected and analyzed for lipids and lipoproteins. PCSK9 was measured by ELISA, Lp(a) and apolipoprotein (a) concentrations by inmunoturbidimetry and LC-MS/MS, respectively. Circulating PCSK9 levels were significantly reduced in patients without CAC (n = 63), compared to those with CAC (n = 99). Patients with the highest CAC scores (above 100) had the highest levels of circulating PCSK9 and Lp(a). In multivariable regression analyses, the main predictors for a positive CAC score was age and sex followed by circulating PCSK9 and Lp(a) levels. In statin treated asymptomatic FH patients, elevated PCSK9 and Lp(a) levels are independently associated with the presence and severity of CAC, a good predictor of coronary artery disease. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Stress, Chemical Defense Agents and Cholinergic Receptors

DTIC Science & Technology

1991-07-31

suprananomolar affinities.] This was important for three reasons- i) Based on the observations of Dam et al. (1982), i.e., low-dose oxotremorine ...Upper: Localizati1ýon of the binding of 0 2 nM (3 H]-QNB. Lower: Localization of the binding of 2 0 nM (3 H- Oxotremorine -M The highest levels of... oxotremorine -M (M2) to brain sections, corrected for non-specific binding by the addition of 1 uM atropine to sections h&ndled in parallel. These results

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

PubMed Central

Midgley, John E M; Larisch, Rolf; Dietrich, Johannes W; Hoermann, Rudolf

2015-01-01

Several influences modulate biochemical responses to a weight-adjusted levothyroxine (l-T4) replacement dose. We conducted a secondary analysis of the relationship of l-T4 dose to TSH and free T3 (FT3), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state l-T4 replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T4–T3 conversion efficiency. In euthyroid subjects, the median l-T4 dose was 1.3 μg/kg per day (interquartile range (IQR) 0.94,1.60). The dose was independently associated with gender, age, aetiology and deiodinase activity (all P<0.001). Comparable FT3 levels required higher l-T4 doses in the carcinoma group (n=143), even after adjusting for different TSH levels. Euthyroid athyreotic thyroid carcinoma patients (n=50) received 1.57 μg/kg per day l-T4 (IQR 1.40, 1.69), compared to 1.19 μg/kg per day (0.85,1.47) in autoimmune thyroiditis (P<0.01, n=76) and 1.08 μg/kg per day (0.82, 1.44) in patients operated on for benign disease (P< 0.01, n=80). Stratifying patients by deiodinase activity categories of <23, 23–29 and >29 nmol/s revealed an increasing FT3–FT4 dissociation; the poorest converters showed the lowest FT3 levels in spite of the highest dose and circulating FT4 (P<0.001). An l-T4-related FT3–TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT3 above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to l-T4; FT3 measurement may be an additional treatment target; and l-T4 dose escalation may have limited success to raise FT3 appropriately in some cases. PMID:26335522

Monte Carlo simulations of the dose from imaging with GE eXplore 120 micro-CT using GATE

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

Bretin, Florian; Bahri, Mohamed Ali; Luxen, André

Purpose: Small animals are increasingly used as translational models in preclinical imaging studies involving microCT, during which the subjects can be exposed to large amounts of radiation. While the radiation levels are generally sublethal, studies have shown that low-level radiation can change physiological parameters in mice. In order to rule out any influence of radiation on the outcome of such experiments, or resulting deterministic effects in the subjects, the levels of radiation involved need to be addressed. The aim of this study was to investigate the radiation dose delivered by the GE eXplore 120 microCT non-invasively using Monte Carlo simulationsmore » in GATE and to compare results to previously obtained experimental values. Methods: Tungsten X-ray spectra were simulated at 70, 80, and 97 kVp using an analytical tool and their half-value layers were simulated for spectra validation against experimentally measured values of the physical X-ray tube. A Monte Carlo model of the microCT system was set up and four protocols that are regularly applied to live animal scanning were implemented. The computed tomography dose index (CTDI) inside a PMMA phantom was derived and multiple field of view acquisitions were simulated using the PMMA phantom, a representative mouse and rat. Results: Simulated half-value layers agreed with experimentally obtained results within a 7% error window. The CTDI ranged from 20 to 56 mGy and closely matched experimental values. Derived organ doses in mice reached 459 mGy in bones and up to 200 mGy in soft tissue organs using the highest energy protocol. Dose levels in rats were lower due to the increased mass of the animal compared to mice. The uncertainty of all dose simulations was below 14%. Conclusions: Monte Carlo simulations proved a valuable tool to investigate the 3D dose distribution in animals from microCT. Small animals, especially mice (due to their small volume), receive large amounts of radiation from the GE eXplore 120 microCT, which might alter physiological parameters in a longitudinal study setup.« less

Z-Index Parameterization for Volumetric CT Image Reconstruction via 3-D Dictionary Learning.

PubMed

Bai, Ti; Yan, Hao; Jia, Xun; Jiang, Steve; Wang, Ge; Mou, Xuanqin

2017-12-01

Despite the rapid developments of X-ray cone-beam CT (CBCT), image noise still remains a major issue for the low dose CBCT. To suppress the noise effectively while retain the structures well for low dose CBCT image, in this paper, a sparse constraint based on the 3-D dictionary is incorporated into a regularized iterative reconstruction framework, defining the 3-D dictionary learning (3-DDL) method. In addition, by analyzing the sparsity level curve associated with different regularization parameters, a new adaptive parameter selection strategy is proposed to facilitate our 3-DDL method. To justify the proposed method, we first analyze the distributions of the representation coefficients associated with the 3-D dictionary and the conventional 2-D dictionary to compare their efficiencies in representing volumetric images. Then, multiple real data experiments are conducted for performance validation. Based on these results, we found: 1) the 3-D dictionary-based sparse coefficients have three orders narrower Laplacian distribution compared with the 2-D dictionary, suggesting the higher representation efficiencies of the 3-D dictionary; 2) the sparsity level curve demonstrates a clear Z-shape, and hence referred to as Z-curve, in this paper; 3) the parameter associated with the maximum curvature point of the Z-curve suggests a nice parameter choice, which could be adaptively located with the proposed Z-index parameterization (ZIP) method; 4) the proposed 3-DDL algorithm equipped with the ZIP method could deliver reconstructions with the lowest root mean squared errors and the highest structural similarity index compared with the competing methods; 5) similar noise performance as the regular dose FDK reconstruction regarding the standard deviation metric could be achieved with the proposed method using (1/2)/(1/4)/(1/8) dose level projections. The contrast-noise ratio is improved by ~2.5/3.5 times with respect to two different cases under the (1/8) dose level compared with the low dose FDK reconstruction. The proposed method is expected to reduce the radiation dose by a factor of 8 for CBCT, considering the voted strongly discriminated low contrast tissues.

Safety assessment of nicotinamide riboside, a form of vitamin B3.

PubMed

Conze, D B; Crespo-Barreto, J; Kruger, C L

2016-01-20

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B 3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day. © The Author(s) 2016.

Histopathological evaluation of gastro protective effect of Berberis vulgaris (Zereshk) seeds against aspirin induced ulcer in albino mice.

PubMed

Majeed, Wafa; Aslam, Bilal; Javed, Ijaz; Khaliq, Tanweer; Muhammad, Faqir; Ali, Asghar; Raza, Ahmed

2015-11-01

The present study was carried out to investigate the antiulcer activity of Berberis vulgaris (Zereshk) seeds in albino mice. After acclimatization, animals were divided into six equal groups. Aspirin 150 mg/kg was used to induce gastric ulcer in all groups except normal control. Omeprazole 20mg/kg was used as synthetic anti ulcer drug in study. Three dose levels of B. vulgaris seed powder 300 mg/kg, 600 mg/kg and 900 mg/kg were used respectively orally. Histopathological analysis was carried out to evaluate the gastroprotective activity of B. vulgaris seed powder. Results of the study showed that in case of aspirin treated mice gastric luminal mucosa villi were decreased in height or were absent. In the glandular region there was connective tissue proliferation and also infiltration of cells. Similar infiltration of cells was present on muscularis mucosa. In esophageal region tumor cells were present. However three dose levels of B. vulgaris significantly reduced the tissue proliferation, infiltration of cells and sloughing induced by aspirin. Highest dose of B. vulgaris (900 mg/kg) showed similar results as synthetic antiulcer drug omeprazole.

S-Ketoprofen Inhibits Tenotomy-Induced Bone Loss and Dynamics in Weanling Rats

NASA Technical Reports Server (NTRS)

Zeng, Q. Q.; Jee, W. S. S.; Ke, H. Z.; Wechter, W. J.

1993-01-01

The objects of this study were to determine whether S-ketoprofen, a non-steroidal anti-inflammatory drug (NSAID), can prevent immobilization (tenotomy)-induced bone loss in weanling rats. Forty five 4 week-old Sprague-Dawley female rats were either sham-operated or subjected to knee tenotomy and treated simultaneously with 0, 0.02, 0.1, 0.5 or 2.5 mg of S-ketoprofen/kg per day for 21 days. We then studied double-fluorescent labeled proximal tibial longitudinal sections and tibial shaft cross sections using static and dynamic histomorphometry. Less cancellous bone mass in proximal tibial metaphyses was found in tenotomized controls than in basal (36%) and sham-operated (54%) controls. This was due to the inhibition of age-related bone gain and induced bone loss due to increased bone resorption and decreased bone formation. S-ketoprofen prevented both the inhibition of age-related bone gain and the stimulation of bone loss at the 2.5 mg/kg per day dose level, while it only prevented bone loss at the 0.5 mg/kg dose levels. In cancellous bone, dynamic histomorphometry showed that S-ketoprofen prevented the tenotomy induced decrease in bone formation and increase in bone resorption. In the tibial shaft, tenotomy inhibited the enlargement of total tissue area by depressing periosteal bone formation, and thus inhibited age-related cortical bone gain. S-ketoprofen treatment did not prevent this change at all dose levels, but reduced marrow cavity area to increase cortical bone area at the 0.1, 0.5 and 2.5 mg/kg per dose levels compared to tenotomy controls. However, the cortical bone area in the 0.1 and 0.5 mg dose-treated treated tenotomy rats was still lower than in the age-related controls. S-ketoprofen also prevented the increase in endocortical eroded perimeter induced by tenotomy. In summary, tenotomy inhibited age-related bone gain and stimulated bone loss in cancellous bone sites, and only inhibited age-related bone gain in cortical bone sites. S-ketoprofen treatment at the highest dose levels prevented the changes in cancellous bone, and reduced marrow area to increase cortical bone in the tibial shafts.

Assessing anxiety in C57BL/6J mice: a pharmacological characterization of the zero maze test.

PubMed

Heredia, Luis; Torrente, Margarita; Colomina, María T; Domingo, José L

2013-01-01

Anxiety disorders affect the quality of life and good health of millions of people over the world. Because clinical trials are expensive and frequently show high rates of placebo responses, animal models have become an important tool for drug discovery and brain research. Zero maze is a commonly used test to assess anxiety-like levels in mice, being the C57BL/6J strain one of the most widely used. However, only few studies have focused on the pharmacological characterization of this strain in the various anxiety tests. In this study, we analyzed the changes in the anxiety-like behaviors of mice exposed to chlordiazepoxide (CLZ), as an anxiolytic drug, at doses of 2.5, 5 and 10mg/kg, picrotoxine (PTX), as an anxiogenic drug, at doses of 0.5, 1 and 2mg/kg, and methylphenidate (MPH), as a psychomotor stimulant, at doses of 2.5, 5 and 10mg/kg. Data were hand recorded in situ by an observer and through a camcorder by computer software. Results showed that CLZ and MPH had an anxiogenic effect at the two highest doses. Only CLZ at 2.5mg/kg reduced the anxiety-like levels of mice. Moreover, PTX exerted an anxiogenic effect in mice only at 2mg/kg. The drugs affecting the anxiety-like levels also affected the activity levels. Thus, the differences might have been mediated by changes in activity levels. Globally, these data demonstrate that the results obtained from the zero maze test are difficult to interpret when the C57BL/6J strain is used. On the other hand, high doses of substances that interact with the GABAergic system, as CLZ, can produce sedation in these mice. In contrast, high doses of GABAA antagonists, as PTX, are necessary if anxiogenic effects should be observed. Further investigations with this strain are necessary in order to corroborate the results of the present study. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

A real-time regional adaptive exposure method for saving dose-area product in x-ray fluoroscopy

PubMed Central

Burion, Steve; Speidel, Michael A.; Funk, Tobias

2013-01-01

Purpose: Reduction of radiation dose in x-ray imaging has been recognized as a high priority in the medical community. Here the authors show that a regional adaptive exposure method can reduce dose-area product (DAP) in x-ray fluoroscopy. The authors' method is particularly geared toward providing dose savings for the pediatric population. Methods: The scanning beam digital x-ray system uses a large-area x-ray source with 8000 focal spots in combination with a small photon-counting detector. An imaging frame is obtained by acquiring and reconstructing up to 8000 detector images, each viewing only a small portion of the patient. Regional adaptive exposure was implemented by varying the exposure of the detector images depending on the local opacity of the object. A family of phantoms ranging in size from infant to obese adult was imaged in anteroposterior view with and without adaptive exposure. The DAP delivered to each phantom was measured in each case, and noise performance was compared by generating noise arrays to represent regional noise in the images. These noise arrays were generated by dividing the image into regions of about 6 mm2, calculating the relative noise in each region, and placing the relative noise value of each region in a one-dimensional array (noise array) sorted from highest to lowest. Dose-area product savings were calculated as the difference between the ratio of DAP with adaptive exposure to DAP without adaptive exposure. The authors modified this value by a correction factor that matches the noise arrays where relative noise is the highest to report a final dose-area product savings. Results: The average dose-area product saving across the phantom family was (42 ± 8)% with the highest dose-area product saving in the child-sized phantom (50%) and the lowest in the phantom mimicking an obese adult (23%). Conclusions: Phantom measurements indicate that a regional adaptive exposure method can produce large DAP savings without compromising the noise performance in the image regions with highest noise. PMID:23635281

Overexpression of the Anthocyanidin Synthase Gene in Strawberry Enhances Antioxidant Capacity and Cytotoxic Effects on Human Hepatic Cancer Cells.

PubMed

Giampieri, Francesca; Gasparrini, Massimiliano; Forbes-Hernandez, Tamara Y; Mazzoni, Luca; Capocasa, Franco; Sabbadini, Silvia; Alvarez-Suarez, Josè M; Afrin, Sadia; Rosati, Carlo; Pandolfini, Tiziana; Molesini, Barbara; Sánchez-Sevilla, José F; Amaya, Iraida; Mezzetti, Bruno; Battino, Maurizio

2018-01-24

Food fortification through the increase and/or modulation of bioactive compounds has become a major goal for preventing several diseases, including cancer. Here, strawberry lines of cv. Calypso transformed with a construct containing an anthocyanidin synthase (ANS) gene were produced to study the effects on anthocyanin biosynthesis, metabolism, and transcriptome. Three strawberry ANS transgenic lines (ANS L5, ANS L15, and ANS L18) were analyzed for phytochemical composition and total antioxidant capacity (TAC), and their fruit extracts were assessed for cytotoxic effects on hepatocellular carcinoma. ANS L18 fruits had the highest levels of total phenolics and flavonoids, while those of ANS L15 had the highest anthocyanin concentration; TAC positively correlated with total polyphenol content. Fruit transcriptome was also specifically affected in the polyphenol biosynthesis and in other related metabolic pathways. Fruit extracts of all lines exerted cytotoxic effects in a dose/time-dependent manner, increasing cellular apoptosis and free radical levels and impairing mitochondrial functionality.

Dose levels of the occupational radiation exposures in Poland based on results from the accredited dosimetry service at the IFJ PAN, Krakow.

PubMed

Budzanowski, Maciej; Kopeć, Renata; Obryk, Barbara; Olko, Paweł

2011-03-01

Individual dosimetry service based on thermoluminescence (TLD) detectors has started its activity at the Institute of Nuclear Physics (IFJ) in Krakow in 1965. In 2002, the new Laboratory of Individual and Environment Dosimetry (Polish acronym LADIS) was established and underwent the accreditation according to the EN-PN-ISO/IEC 17025 standard. Nowadays, the service is based on the worldwide known standard thermoluminescent detectors MTS-N (LiF:Mg,Ti) and MCP-N (LiF:Mg,Cu,P), developed at IFJ, processed in automatic thermoluminescent DOSACUS or RE2000 (Rados Oy, Finland) readers. Laboratory provides individual monitoring in terms of personal dose equivalent H(p)(10) and H(p)(0.07) in photon and neutron fields, over the range from 0.1 mSv to 1 Sv, and environmental dosimetry in terms of air kerma K(a) over the range from 30 μGy to 1 Gy and also ambient dose equivalent H*(10) over the range from 30 μSv to 1 Sv. Dosimetric service is currently performed for ca. 3200 institutions from Poland and abroad, monitored on quarterly and monthly basis. The goal of this paper is to identify the main activities leading to the highest radiation exposures in Poland. The paper presents the results of statistical evaluation of ∼ 100,000 quarterly H(p)(10) and K(a) measurements performed between 2002 and 2009. Sixty-five per cent up to 90 % of all individual doses in Poland are on the level of natural radiation background. The dose levels between 0.1 and 5 mSv per quarter are the most frequent in nuclear medicine, veterinary and industrial radiography sectors.

Phase 1 first-in-human studies of the reactogenicity and immunogenicity of a recombinant meningococcal NspA vaccine in healthy adults.

PubMed

Halperin, Scott A; Langley, Joanne M; Smith, Bruce; Wunderli, Peter; Kaufman, Lisa; Kimura, Alan; Martin, Denis

2007-01-05

Neisserial surface protein A (NspA) is a highly conserved, surface-exposed outer membrane protein of Neisseria meningitidis that has been shown to induce a bactericidal immune response in animals against all pathogenic Neisserial serogroups. Healthy 18-50-year-old adults were assigned to receive, in a dose escalating manner, 3 doses of 1 of 5 formulations of an experimental, unfolded, recombinant NspA (rNspA) vaccine or placebo, or 1 dose of commercially available quadravalent (A, C, Y, W-135) meningococcal polysaccharide vaccine (Menomune((R))). Adverse events were collected during the first week post-immunization, prior to the next dose and 1 month after the last dose. Serum for measurement of hematological and biochemical parameters and antibodies by enzyme immunoassay and bactericidal assay were measured before the first dose, prior to the second dose and 1 month after the last dose of vaccine. The rNspA vaccine was well tolerated by recipients. Injection-site pain was reported more frequently by recipients of the three highest doses of rNspA compared to placebo but at similar rates to the licensed meningococcal polysaccharide vaccine. Adverse events were reported less frequently after subsequent doses in the three-dose series. An antibody rise measured by enzyme immunoassay was elicited with a dose-related increase that reached a maximum with the 125mug dose. Prolongation of the dosing interval between the second and third dose appeared to be associated with increased antibody levels. No bactericidal antibodies were detected after any of the rNspA formulations. The unfolded rNspA meningococcal vaccine was well tolerated and immunogenic in healthy adult volunteers but did not elicit bactericidal antibodies.

Schistosoma mansoni: interactive effects of irradiation and cryopreservation on parasite maturation and immunization of mice

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

James, E.R.; Dobinson, A.R.

1984-06-01

Mechanically transformed schistosomula of Schistosoma mansoni were irradiated with levels of 60Co irradiation between 2.5 and 54 krad, cryopreserved by the two-step addition of ethanediol and rapid cooling technique, and were injected intramuscularly into groups of mice which were perfused 40 days later. The schistosomula were either irradiated and then cryopreserved (IC) or cryopreserved and then irradiated in the frozen state (CI). Development into adult worms was prevented with 4 krad for IC schistosomula, but for CI schistosomula a small number of worms (1.6%) was recovered using 8.8 krad. A dose of 4 krad was sufficient to prevent development ofmore » unfrozen controls (I), but for schistosomula irradiated while exposed to ethanediol (EI), a dose of 7 krad was required. Using the different protocols, the peak levels of protection against a challenge infection were achieved with 9 (IC) and 16 krad (CI), compared to 20 krad for unfrozen schistosomula (I) reported previously. The highest level of protection (65%) was achieved with CI schistosomula. Possible interactions between the radioprotective and damaging effects of cryopreservation are discussed.« less

High-dose hook effect in six automated human chorionic gonadotrophin assays.

PubMed

Al-Mahdili, Huda A; Jones, Graham R D

2010-07-01

The high-dose hook effect is a well-known phenomenon of two-site immunoassays including those for human chorionic gonadotrophin (hCG). We investigated the occurrence of a high-dose hook effect in six routinely available hCG assays using a sample with a total hCG concentration of approximately 3,600,000 IU/L. Dilutions of a sample with high hCG concentration were analysed using six common methods: Advia Centaur, Immulite 2000, Dimension RxL, Unicel DxI 800, Roche E170 and Abbott Architect. The measured concentrations and corresponding assay signals were obtained for each method. Performance was compared with manufacturer claims. Four of the tested platforms demonstrated a clear high-dose hook effect, while the other methods showed no hook effect at the highest level tested. Our results indicate that the hook effect may occur in some hCG assays, although the risk of reporting falsely low results was in most cases at higher concentrations than those indicated in manufacturers' product information. Assay design plays a major role in its occurrence. Laboratories should be aware of the assay limitations in this regard.

Prescription order risk factors for pediatric dosing alerts.

PubMed

Stultz, J S; Porter, K; Nahata, M C

2015-02-01

To determine dosing alert rates based on prescription order characteristics and identify prescription order risk factors for the occurrence of dosing alerts. A retrospective analysis of inpatient medication orders and dosing alerts occurring during October 2011 and January, April, and July 2012 at a pediatric institution. Prescription orders and alerts were categorized by: medication class, patient age, route of administration, and month of the year. There were 228,259 orders during the studied period, with 11,072 alerted orders (4.9%). The most frequently alerted medication class was the non-analgesic central nervous system agent class (14% of alerts). Age, route, medication class, and month all independently affected dosing alert rates. The alert rate was highest for immunosuppressive agents (54%), neonates (6.7%), and orders for rectal administration (9.5%). The alert rate was higher in adult patients receiving their care at a pediatric institution (5.7%) compared to children (4.7%), but after multivariate analysis, pediatric orders had higher odds for an alert (OR 1.1, 95% CI 1.05-1.16). Mercaptopurine had the highest alert rate when categorized by active ingredient (73.9%). Albuterol 2.5mg/mL continuous aerosol and heparin 1000 units in 0.9% sodium chloride injection solution were the unique medications with the highest alert rates (100.0% and 97.7%, respectively). Certain types of prescription orders have a higher risk for causing dosing alerts than others. Patient age, medication class, route of administration, and the month of year can affect dosing alert rates. Design and customization efforts should focus on these medications and prescription order characteristics that increase the risk for dosing alerts. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Response to the high-dose corticotrophin stimulation test depends on plasma adrenocotropin hormone levels in septic shock.

PubMed

Llompart-Pou, Juan Antonio; Raurich, Joan Maria; Ayestarán, Ignacio; Fernández-de-Castillo, Ana G; Pérez-Bárcena, Jon; Ibáñez, Jordi

2012-06-01

The use of the high-dose corticotrophin stimulation test (HDCST) as a guide to use low-dose steroid therapy in septic shock is controversial. The adrenocotropin hormone (ACTH) constitutes the immediate stimuli to produce cortisol. We evaluated the correlation of the response to the HDCST with plasma ACTH levels in patients with septic shock. This is a retrospective review of 102 patients with septic shock in which adrenal function was evaluated using the HDCST and plasma ACTH levels were measured. Patients with a δ cortisol of 9 μg/dL or less were considered as nonresponders or with subnormal response. The association between plasma ACTH levels and the response to the HDCST was investigated. Sixty-four patients (62.7%) had a subnormal response. Plasma ACTH levels were higher in patients with subnormal response (19.8 [11.7-31.4] vs 10.0 [7.0-21.2] pg/mL; P = .002). Patients in the highest quartile of plasma ACTH had lower δ cortisol (P = .014) and higher percentage of subnormal response (P = .005). The optimal cutoff point of plasma ACTH level with fewest false classifications was 10 pg/mL (sensitivity, 0.83 [95% confidence interval, 074-0.90] and specificity, 0.50 [95% confidence interval, 0.74-0.90]). Patients with septic shock with higher plasma ACTH values presented a subnormal response to the HDCST. The number of patients who failed to the HDCST was higher as plasma ACTH increased. Copyright © 2012 Elsevier Inc. All rights reserved.

The influence of snakehead (Channa striata) fish extract to increase hyperglycemic mice fertility based on spermatogenic cell composition

NASA Astrophysics Data System (ADS)

Hidayati, Dewi; Abdulgani, Nurlita; Ashuri, Nova Maulidina; Sa'adah, Noor Nailis; Lukitasari, Maharani

2017-06-01

Reproductive dysfunction is recognized as a consequence of diabetes mellitus. Previous study revealed that snakehead (Channa striata) fish extract can repairing the pancreas histological structure which by that decreasing the blood glucose levels. Further research was conducted to determine the influence of snakehead fish extract (SHFE) to increasing the fertility of hyperglycemic mice based on spermatogenic cell composition. Twenty five adult mice (Mus musculus) were induced intraperitoneally to be hyperglycemic using alloxan monohydrate single dose of 190 mg/kg body weight. Hyperglycemic mice treated orally for 14 days using SHFE which grouped into five treatment dosages. Testicular histology were prepared using the paraffin methods and stained with Haematoxylin and Eosin. According to ANOVA and Tukey's test, it was found that spermatogenic cells population as well as its composition in the testis of mice that treated with SHFE are significantly higher than hyperglichemic mice. The highest dose of SHFE (0.15 ml/day), showed highest spermatogenic cell. All hyperglichemic mice that treated with SHFE exhibited the ratio composition of spermatogonia: spermatocytes: spermatids as same as with control (healthy mice) i.e. 1:1:3 respectively.

Radionuclides and radiation doses in heavy mineral sands and other mining operations in Mozambique.

PubMed

Carvalho, Fernando P; Matine, Obete F; Taímo, Suzete; Oliveira, João M; Silva, Lídia; Malta, Margarida

2014-01-01

Sites at the littoral of Mozambique with heavy mineral sands exploited for ilmenite, rutile and zircon and inland mineral deposits exploited for tantalite, uranium and bauxite were surveyed for ambient radiation doses, and samples were collected for the determination of radionuclide concentrations. In heavy mineral sands, (238)U and (232)Th concentrations were 70±2 and 308±9 Bq kg(-1) dry weight (dw), respectively, whereas after separation of minerals, the concentrations in the ilmenite fraction were 2240±64 and 6125±485 Bq kg(-1) (dw), respectively. Tantalite displayed the highest concentrations with 44 738±2474 Bq kg(-1) of (238)U. Radiation exposure of workers in mining facilities is likely to occur at levels above the dose limit for members of the public (1 mSv y(-1)) and therefore radiation doses should be assessed as occupational exposures. Local populations living in these regions in general are not exposed to segregated minerals with high radionuclide concentrations. However, there is intensive artisanal mining and a large number of artisanal miners and their families may be exposed to radiation doses exceeding the dose limit. A radiation protection programme is therefore needed to ensure radiation protection of the public and workers of developing mining projects.

The biological impacts of ingested radioactive materials on the pale grass blue butterfly

NASA Astrophysics Data System (ADS)

Nohara, Chiyo; Hiyama, Atsuki; Taira, Wataru; Tanahara, Akira; Otaki, Joji M.

2014-05-01

A massive amount of radioactive materials has been released into the environment by the Fukushima Dai-ichi Nuclear Power Plant accident, but its biological impacts have rarely been examined. Here, we have quantitatively evaluated the relationship between the dose of ingested radioactive cesium and mortality and abnormality rates using the pale grass blue butterfly, Zizeeria maha. When larvae from Okinawa, which is likely the least polluted locality in Japan, were fed leaves collected from polluted localities, mortality and abnormality rates increased sharply at low doses in response to the ingested cesium dose. This dose-response relationship was best fitted by power function models, which indicated that the half lethal and abnormal doses were 1.9 and 0.76 Bq per larva, corresponding to 54,000 and 22,000 Bq per kilogram body weight, respectively. Both the retention of radioactive cesium in a pupa relative to the ingested dose throughout the larval stage and the accumulation of radioactive cesium in a pupa relative to the activity concentration in a diet were highest at the lowest level of cesium ingested. We conclude that the risk of ingesting a polluted diet is realistic, at least for this butterfly, and likely for certain other organisms living in the polluted area.

The biological impacts of ingested radioactive materials on the pale grass blue butterfly.

PubMed

Nohara, Chiyo; Hiyama, Atsuki; Taira, Wataru; Tanahara, Akira; Otaki, Joji M

2014-05-15

A massive amount of radioactive materials has been released into the environment by the Fukushima Dai-ichi Nuclear Power Plant accident, but its biological impacts have rarely been examined. Here, we have quantitatively evaluated the relationship between the dose of ingested radioactive cesium and mortality and abnormality rates using the pale grass blue butterfly, Zizeeria maha. When larvae from Okinawa, which is likely the least polluted locality in Japan, were fed leaves collected from polluted localities, mortality and abnormality rates increased sharply at low doses in response to the ingested cesium dose. This dose-response relationship was best fitted by power function models, which indicated that the half lethal and abnormal doses were 1.9 and 0.76 Bq per larva, corresponding to 54,000 and 22,000 Bq per kilogram body weight, respectively. Both the retention of radioactive cesium in a pupa relative to the ingested dose throughout the larval stage and the accumulation of radioactive cesium in a pupa relative to the activity concentration in a diet were highest at the lowest level of cesium ingested. We conclude that the risk of ingesting a polluted diet is realistic, at least for this butterfly, and likely for certain other organisms living in the polluted area.

[Risk of deterministic effects after exposure to low doses of ionizing radiation: retrospective study among health workers in view of a new publication of International Commission on Radiological Protection].

PubMed

Negrone, Mario; Di Lascio, Doriana

2016-01-01

The new recommended equivalent (publication n. 118 of International Commission on Radiological Protection) dose limit for occupational exposure of the lens of the eye is based on prevention of radiogenic cataracts, with the underlying assumption of a nominal threshold which has been adjusted from 2,5 Gy to 0.5 Gy for acute or protracted exposure. The study aim was to determine the prevalence of ocular lens opacity among healthcare workers (radiologic technologists, physicians, physician assistants) with respect to occupational exposures to ionizing radiations. Therefore, we conducted another retrospective study to explore the relationship between occupational exposure to radiation and opacity lens increase. Healthcare data (current occupational dosimetry, occupational history) are used to investigate risk of increase of opacity lens of eye. The sample of this study consisted of 148 health-workers (64 M and 84 W) aged from 28 to 66 years coming from different hospitals of the ASL of Potenza (clinic, hospital and institute with scientific feature). On the basis of the evaluation of the dosimetric history of the workers (global and effective dose) we agreed to ascribe the group of exposed subjects in cat A (equivalent dose > 2 mSV) and the group of non exposed subjects in cat B (workers with annual absorbed level of dose near 0 mSv). The analisys was conducted using SPSS 15.0 (Statistical Package for Social Science). A trend of increased ocular lens opacity was found with increasing number for workers in highest category of exposure (cat. A, Yates' chi-squared test = 13,7 p = 0,0002); variable significantly related to opacity lens results job: nurse (Χ(2)Y = 14,3 p = 0,0002) physician (Χ(2)Y = 2.2 p = 0,1360) and radiologic technologists (Χ(2)Y = 0,1 p = 0,6691). In conclusion our provides evidence that exposure to relatively low doses of ionizing radiation may be harmful to the lens of the eye and may increase a long-term risk of cataract formation; similary necessary to monitor the "equivalent dose" for the lens for the workers in highest category of exposure.

Fluoroscopy Learning Curve in Hip Arthroscopy-A Single Surgeon's Experience.

PubMed

Smith, Kevin M; Duplantier, Neil L; Crump, Kimbelyn H; Delgado, Domenica A; Sullivan, Stephanie L; McCulloch, Patrick C; Harris, Joshua D

2017-10-01

To determine if (1) absorbed radiation dose and (2) fluoroscopy time decreased with experience over the first 100 cases of a single surgeon's hip arthroscopy practice. Subjects who underwent hip arthroscopy for symptomatic femoroacetabular impingement and labral injury were eligible for analysis. Inclusion criteria included the first 100 subjects who underwent hip arthroscopy by a single surgeon (December 2013 to December 2014). Subject demographics, procedure details, fluoroscopy absorbed dose (milligray [mGy]), and time were recorded. Subjects were categorized by date of surgery to one of 4 possible groups (25 per group). One-way analysis of variance was used to determine if a significant difference in dose (mGy) or time was present between groups. Simple linear regression analysis was performed to determine the relation between case number and both radiation dose and fluoroscopy time. Subjects underwent labral repair (n = 93), cam osteoplasty (n = 90), and pincer acetabuloplasty (n = 65). There was a significant (P < .001 for both) linear regression between case number and both radiation dose and fluoroscopy time. A significant difference in mGy was observed between groups, group 1 the highest and group 4 the lowest amounts of radiation (P = .003). Comparing individual groups, group 4 was found to have a significantly lower amount of radiation than group 1 (P = .002), though it was not significantly lower than that of group 2 (P = .09) or group 3 (P = .08). A significant difference in fluoroscopy time was observed between groups, group 1 the highest and group 4 the lowest times (P = .05). Comparing individual groups, group 4 was found to have a significantly lower fluoroscopy time than group 1 (P = .039). Correction for weight, height, and body mass index all revealed the same findings: significant (P < .05) differences in both dose and time across groups. The absorbed dose of radiation and fluoroscopy time decreased significantly over the first 100 cases of a single surgeon's hip arthroscopy practice learning curve. Level IV, therapeutic, retrospective, noncomparative case series. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Nanosuspension for the delivery of a poorly soluble anti-cancer kinase inhibitor.

PubMed

Danhier, Fabienne; Ucakar, Bernard; Vanderhaegen, Marie-Lyse; Brewster, Marcus E; Arien, Tina; Préat, Véronique

2014-09-01

We hypothesized that nanosuspensions could be promising for the delivery of the poorly water soluble anti-cancer multi-targeted kinase inhibitor, MTKi-327. Hence, the aims of this work were (i) to evaluate the MTKi-327 nanosuspension for parenteral and oral administrations and (ii) to compare this nanosuspension with other nanocarriers in terms of anti-cancer efficacy and pharmacokinetics. Therefore, four formulations of MTKi-327 were studied: (i) PEGylated PLGA-based nanoparticles, (ii) self-assembling PEG₇₅₀-p-(CL-co-TMC) polymeric micelles, (iii) nanosuspensions of MTKi-327; and (iv) Captisol solution (pH=3.5). All the nano-formulations presented a size below 200 nm. Injections of the highest possible dose of the three nano-formulations did not induce any side effects in mice. In contrast, the maximum tolerated dose of the control Captisol solution was 20-fold lower than its highest possible dose. The highest regrowth delay of A-431-tumor-bearing nude mice was obtained with MTKi-327 nanosuspension, administered intravenously, at a dose of 650 mg/kg. After intravenous and oral administration, the AUC₀₋∞ of MTKi-327 nanosuspension was 2.4-fold greater than that of the Captisol solution. Nanosuspension may be considered as an effective anti-cancer MTKi-327 delivery method due to (i) the higher MTKi-327 maximum tolerated dose, (ii) the possible intravenous injection of MTKi-327, (iii) its ability to enhance the administered dose and (iv) its higher efficacy. Copyright © 2014 Elsevier B.V. All rights reserved.

Randomized, placebo-controlled trial to assess the safety and immunogenicity of an adenovirus type 35-based circumsporozoite malaria vaccine in healthy adults.

PubMed

Creech, C Buddy; Dekker, Cornelia L; Ho, Dora; Phillips, Shanda; Mackey, Sally; Murray-Krezan, Cristina; Grazia Pau, Maria; Hendriks, Jenny; Brown, Valerie; Dally, Leonard G; Versteege, Isabella; Edwards, Kathryn M

2013-12-01

Malaria results in over 650,000 deaths each year; thus, there is an urgent need for an effective vaccine. Pre-clinical studies and recently reported human trials suggest that pre-erythrocytic stage vaccines can provide protection against infection. A Phase 1, randomized, placebo-controlled, dose-escalation study was conducted with a vaccine composed of a replication-deficient adenovirus-35 backbone with P. falciparum circumsporozoite (CS) surface antigen (Ad35.CS.01). Healthy adult subjects received three doses of 10 (8), 10 (9), 10 (10), or 10 (11) vp/mL Ad35.CS.01 vaccine or saline placebo intramuscularly at 0, 1, and 6-mo intervals. Adverse events were assessed and anti-CS antibody responses were determined by ELISA. Seventy-two individuals were enrolled, with age, gender, and ethnicity similar across each study arm. While the vaccine was generally well tolerated, adverse events were more frequent in the highest dose groups (10 (10) and 10 (11) vp/mL). More robust humoral responses were also noted at the highest doses, with 73% developing a positive ELISA response after the three dose series of 10 (11) vp/mL. The Ad35.CS.01 vaccine was most immunogenic at the highest dosages (10 (10) and 10 (11) vp/mL). Reactogenicity findings were more common after the 10 (11) vp/mL dose, although most were mild or moderate in nature and resolved without therapy.

Evaluation of safety profile of black shilajit after 91 days repeated administration in rats

PubMed Central

Velmurugan, C; Vivek, B; Wilson, E; Bharathi, T; Sundaram, T

2012-01-01

Objective To evaluate the safety of shilajit by 91 days repeated administration in different dose levels in rats. Methods In this study the albino rats were divided into four groups. Group I received vehicle and group II, III and IV received 500, 2 500 and 5 000 mg/kg of shilajit, respectively. Finally animals were sacrificed and subjected to histopathology and iron was estimated by flame atomic absorption spectroscopy and graphite furnace. Results The result showed that there were no significant changes in iron level of treated groups when compared with control except liver (5 000 mg/kg) and histological slides of all organs revealed normal except negligible changes in liver and intestine with the highest dose of shilajit. The weight of all organs was normal when compared with control. Conclusions The result suggests that black shilajit, an Ayurvedic formulation, is safe for long term use as a dietary supplement for a number of disorders like iron deficiency anaemia. PMID:23569899

Evaluation of safety profile of black shilajit after 91 days repeated administration in rats.

PubMed

Velmurugan, C; Vivek, B; Wilson, E; Bharathi, T; Sundaram, T

2012-03-01

To evaluate the safety of shilajit by 91 days repeated administration in different dose levels in rats. In this study the albino rats were divided into four groups. Group I received vehicle and group II, III and IV received 500, 2 500 and 5 000 mg/kg of shilajit, respectively. Finally animals were sacrificed and subjected to histopathology and iron was estimated by flame atomic absorption spectroscopy and graphite furnace. The result showed that there were no significant changes in iron level of treated groups when compared with control except liver (5 000 mg/kg) and histological slides of all organs revealed normal except negligible changes in liver and intestine with the highest dose of shilajit. The weight of all organs was normal when compared with control. The result suggests that black shilajit, an Ayurvedic formulation, is safe for long term use as a dietary supplement for a number of disorders like iron deficiency anaemia.

Radiation dose to Malaysian infants from natural radionuclides via consumption of powdered milk

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

Uwatse, Onosohwo Bemigho; Olatunji, Michael Adekunle; Khandaker, Mayeen Uddin

Milk is the basic food stuff for the infants because they generally consume more milk on a daily basis as its minerals and proteins are essential for their growth and development, therefore, it is very important to assess the natural radioactivity levels and the associated dose in the widely consumed powered infant’s milk. As a result, 14 brands of infant’s powdered milk were collected from different supermarkets around Selangor, Malaysia and analysed for {sup 226}Ra, {sup 232}Th and {sup 40}K activities. The obtained mean activity of {sup 226}Ra, {sup 232}Th and {sup 40}K are 3.05±1.84, 2.55±2.48 and 99.1±69.5 Bqkg{sup −1},more » respectively. Among the analysed milk samples, the brand from Philippines (Lactogen) showed low level of radioactivity while Singaporean brand (S26 SMA Gold) showed the highest. The estimated mean annual effective doses due to the ingestion of natural radionuclides in the sampled milk are 635 and 111 µSv for infant ≤ 1y and infant 1-2y, respectively. The obtained dose value does not yet pose any significant radiological hazards to the population under investigation comparing with the 1.0 mSvy{sup −1} recommended by ICRP for all ages.« less

Assessing pediatrics residents' mathematical skills for prescribing medication: a need for improved training.

PubMed

Glover, Mark L; Sussmane, Jeffrey B

2002-10-01

To evaluate residents' skills in performing basic mathematical calculations used for prescribing medications to pediatric patients. In 2001, a test of ten questions on basic calculations was given to first-, second-, and third-year residents at Miami Children's Hospital in Florida. Four additional questions were included to obtain the residents' levels of training, specific pediatrics intensive care unit (PICU) experience, and whether or not they routinely double-checked doses and adjusted them for each patient's weight. The test was anonymous and calculators were permitted. The overall score and the score for each resident class were calculated. Twenty-one residents participated. The overall average test score and the mean test score of each resident class was less than 70%. Second-year residents had the highest mean test scores, although there was no significant difference between the classes of residents (p =.745) or relationship between the residents' PICU experiences and their exam scores (p =.766). There was no significant difference between residents' levels of training and whether they double-checked their calculations (p =.633) or considered each patient's weight relative to the dose prescribed (p =.869). Seven residents committed tenfold dosing errors, and one resident committed a 1,000-fold dosing error. Pediatrics residents need to receive additional education in performing the calculations needed to prescribe medications. In addition, residents should be required to demonstrate these necessary mathematical skills before they are allowed to prescribe medications.

Ultraviolet radiation in the Atacama Desert.

PubMed

Cordero, R R; Damiani, A; Jorquera, J; Sepúlveda, E; Caballero, M; Fernandez, S; Feron, S; Llanillo, P J; Carrasco, J; Laroze, D; Labbe, F

2018-03-31

The world's highest levels of surface ultraviolet (UV) irradiance have been measured in the Atacama Desert. This area is characterized by its high altitude, prevalent cloudless conditions, and a relatively low total ozone column. In this paper, we provide estimates of the surface UV (monthly UV index at noon and annual doses of UV-B and UV-A) for all sky conditions in the Atacama Desert. We found that the UV index at noon during the austral summer is expected to be greater than 11 in the whole desert. The annual UV-B (UV-A) doses were found to range from about 3.5 kWh/m 2 (130 kWh/m 2 ) in coastal areas to 5 kWh/m 2 (160 kWh/m 2 ) on the Andean plateau. Our results confirm significant interhemispherical differences. Typical annual UV-B doses in the Atacama Desert are about 40% greater than typical annual UV-B doses in northern Africa. Mostly due to seasonal changes in the ozone, the differences between the Atacama Desert and northern Africa are expected to be about 60% in the case of peak UV-B levels (i.e. the UV-B irradiances at noon close to the summer solstice in each hemisphere). Interhemispherical differences in the UV-A are significantly lower since the effect of the ozone in this part of the spectrum is minor.

A Novel ATM/TP53/p21-Mediated Checkpoint Only Activated by Chronic γ-Irradiation

PubMed Central

Sasatani, Megumi; Iizuka, Daisuke; Masuda, Yuji; Inaba, Toshiya; Suzuki, Keiji; Ootsuyama, Akira; Umata, Toshiyuki; Kamiya, Kenji; Suzuki, Fumio

2014-01-01

Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage. PMID:25093836

Comparison of Two Different Doses of Intrathecal Levobupivacaine for Transurethral Endoscopic Surgery

PubMed Central

Dizman, Secil; Turker, Gurkan; Gurbet, Alp; Mogol, Elif Basagan; Turkcan, Suat; Karakuzu, Ziyaatin

2011-01-01

Objective: To evaluate the effects of two different spinal isobaric levobupivacaine doses on spinal anesthesia characteristics and to find the minimum effective dose for surgery in patients undergoing transurethral resection (TUR) surgery. Materials and Methods: Fifty male patients undergoing TUR surgery were included in the study and were randomized into two equal groups: Group LB10 (n=25): 10 mg 0.5% isobaric levobupivacaine (2 ml) and Group LB15 (n=25): 15 mg 0.75% isobaric levobupivacaine (2 ml). Spinal anesthesia was administered via a 25G Quincke spinal needle through the L3–4 intervertebral space. Sensorial block levels were evaluated using the ‘pin-prick test’, and motor block levels were evaluated using the ‘Bromage scale’. The sensorial and motor block characteristics of patients during intraoperative and postoperative periods and recovery time from spinal anesthesia were evaluated. Results: In three cases in the Group LB10, sensorial block did not reach the T10 level. Complete motor block (Bromage=3) did not occur in eight cases in the Group LB10 and in five cases in the Group LB15. The highest sensorial dermatomal level detected was higher in Group LB15. In Group LB15, sensorial block initial time and the time of complete motor block occurrence were significantly shorter than Group LB10. Hypotension was observed in one case in Group LB15. No significant difference between groups was detected in two segments of regression times: the time to S2 regression and complete sensorial block regression time. Complete motor block regression time was significantly longer in Group LB15 than in Group LB10 (p<0.01). Conclusion: Our findings showed that the minimum effective spinal isobaric levobupivacaine dose was 10 mg for TUR surgery. PMID:25610173

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

Effective dose in the manufacturing process of rutile covered welding electrodes.

PubMed

Herranz, M; Rozas, S; Pérez, C; Idoeta, R; Núñez-Lagos, R; Legarda, F

2013-03-01

Shielded metal arc welding using covered electrodes is the most common welding process. Sometimes the covering contains naturally occurring radioactive materials (NORMs). In Spain the most used electrodes are those covered with rutile mixed with other materials. Rutile contains some detectable natural radionuclides, so it can be considered a NORM. This paper mainly focuses on the use of MCNP (Monte Carlo N-Particle Transport Code) as a predictive tool to obtain doses in a factory which produces this type of electrode and assess the radiological impact in a specific facility after estimating the internal dose.To do this, in the facility, areas of highest radiation and positions of workers were identified, radioactive content of rutile and rutile covered electrodes was measured, and, considering a worst possible scenario, external dose at working points has been calculated using MCNP. This procedure has been validated comparing the results obtained with those from a pressurised ionisation chamber and TLD dosimeters. The internal dose has been calculated using DCAL (dose and risk calculation). The doses range between 8.8 and 394 μSv yr(-1), always lower than the effective dose limit for the public, 1 mSv yr(-1). The highest dose corresponds to the mixing area.

Adaptive statistical iterative reconstruction and Veo: assessment of image quality and diagnostic performance in CT colonography at various radiation doses.

PubMed

Yoon, Min A; Kim, Se Hyung; Lee, Jeong Min; Woo, Hyoun Sik; Lee, Eun Sun; Ahn, Se Jin; Han, Joon Koo

2012-01-01

To evaluate the diagnostic performance of computed tomography (CT) colonography (CTC) reconstructed with different levels of adaptive statistical iterative reconstruction (ASiR, GE Healthcare) and Veo (model-based iterative reconstruction, GE Healthcare) at various tube currents in detection of polyps in porcine colon phantoms. Five porcine colon phantoms with 46 simulated polyps were scanned at different radiation doses (10, 30, and 50 mA s) and were reconstructed using filtered back projection (FBP), ASiR (20%, 40%, and 60%) and Veo. Eleven data sets for each phantom (10-mA s FBP, 10-mA s 20% ASiR, 10-mA s 40% ASiR, 10-mA s 60% ASiR, 10-mA s Veo, 30-mA s FBP, 30-mA s 20% ASiR, 30-mA s 40% ASiR, 30-mA s 60% ASiR, 30-mA s Veo, and 50-mA s FBP) yielded a total of 55 data sets. Polyp detection sensitivity and confidence level of 2 independent observers were evaluated with the McNemar test, the Fisher exact test, and receiver operating characteristic curve analysis. Comparative analyses of overall image quality score, measured image noise, and interpretation time were also performed. Per-polyp detection sensitivities and specificities were highest in 10-mA s Veo, 30-mA s FBP, 30-mA s 60% ASiR, and 50-mA s FBP (sensitivity, 100%; specificity, 100%). The area-under-the-curve values for the overall performance of each data set was also highest (1.000) at 50-mA s FBP, 30-mA s FBP, 30-mA s 60% ASiR, and 10-mA s Veo. Images reconstructed with ASiR showed statistically significant improvement in per-polyp detection sensitivity as the percent level of per-polyp sensitivity increased (10-mA s FBP vs 10-mA s 20% ASiR, P = 0.011; 10-mA s FBP vs 10-mA s 40% ASiR, P = 0.000; 10-mA s FBP vs 10-mA s 60% ASiR, P = 0.000; 10-mA s 20% ASiR vs 40% ASiR, P = 0.034). Overall image quality score was highest at 30-mA s Veo and 50-mA s FBP. The quantitative measurement of the image noise was lowest at 30-mA s Veo and second lowest at 10-mA s Veo. There was a trend of decrease in time required for image interpretation as the percent level of ASiR increased, and ASiR or Veo was used instead of FBP. However, differences from comparative analyses of overall image quality score, measured image noise, and interpretation time did not reach statistical significance. ASiR and Veo showed improved diagnostic performance with excellent sensitivity and specificity with less image noise and good image quality compared with FBP reconstruction of same radiation dose. Our study confirmed feasibility of low-dose CTC with iterative reconstruction as a promising screening tool with excellent diagnostic performance similar to that of the standard-dose CTC with FBP.

Irrigation dose and plant density affect the volatile composition and sensory quality of dill (Anethum graveolens L.).

PubMed

El-Zaeddi, Hussein; Martínez-Tomé, Juan; Calín-Sánchez, Ángel; Burló, Francisco; Carbonell-Barrachina, Ángel A

2017-01-01

Two independent field experiments were carried out to investigate the influence of (i) three irrigation treatments (ID0 = 1585 m 3 ha -1 , considered as a control; ID1 = 1015 m 3 ha -1 ; and ID2 = 2180 m 3 ha -1 ) and (ii) three plant density treatments (PD0 = 5.56 plants m -2 , considered as a control; PD1 = 4.44 plants m -2 ; and PD2 = 7.41 plants m -2 ) on the production, volatile composition of essential oil, and sensory quality of dill. The highest plant yield was obtained with intermediate conditions of both irrigation dose (ID0) and plant density (PD0). The main compounds of the essential oil were α-phellandrene, dill ether and β-phellandrene. The highest irrigation dose (ID2) produced the highest concentrations of most of the main compounds: α-phellandrene (49.5 mg per 100 g), β-phellandrene (6.89 mg per 100 g) and limonene (2.49 mg per 100 g). A similar pattern was found for the highest plant density (PD2): α-phellandrene (71.0 mg per 100 g), dill ether (16.7 mg per 100 g) and β-phellandrene (9.70 mg per 100 g). The use of descriptive sensory analysis helped in reaching a final decision, and the dill plants with the highest sensory quality were those of the ID2 and PD0 treatments. The final recommendation is to use the irrigation dose ID2 and the plant density PD2 if the objective is to produce dill samples with the highest aromatic and sensory quality; however, if the only objective is to produce high amounts of dill, the best options are ID0 and PD0. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Evaluation of cytotoxicity and radiation enhancement using 1.9 nm gold particles: potential application for cancer therapy

PubMed Central

Butterworth, K T; Coulter, J A; Jain, S; Forker, J; McMahon, S J; Schettino, G; Prise, K M; Currell, F J; Hirst, D G

2010-01-01

High atomic number (Z) materials such as gold preferentially absorb kilovoltage x-rays compared to soft tissue and may be used to achieve local dose enhancement in tumours during treatment with ionizing radiation. Gold nanoparticles have been demonstrated as radiation dose enhancing agents in vivo and in vitro. In the present study, we used multiple endpoints to characterize the cellular cytotoxic response of a range of cell lines to 1.9 nm gold particles and measured dose modifying effects following transient exposure at low concentrations. Gold nanoparticles caused significant levels of cell type specific cytotoxicity, apoptosis and increased oxidative stress. When used as dose modifying agents, dose enhancement factors varied between the cell lines investigated with the highest enhancement being 1.9 in AGO-1522B cells at a nanoparticle concentration of 100 μg ml−1. This study shows exposure to 1.9 nm gold particles to induce a range of cell line specific responses including decreased clonogenic survival, increased apoptosis and induction of DNA damage which may be mediated through the production of reactive oxygen species. This is the first study involving 1.9 nm nanometre sized particles to report multiple cellular responses which impact on the radiation dose modifying effect. The findings highlight the need for extensive characterization of responses to gold nanoparticles when assessing dose enhancing potential in cancer therapy. PMID:20601762

Toxicity of inhaled plutonium dioxide in beagle dogs

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

Muggenburg, M.A.; Guilmette, R.A.; Mewhinney, J.A.

This study was conducted to determine the biological effects of inhaled {sup 238}PuO{sub 2} over the life spans of 144 beagle dogs. The dogs inhaled one of two sizes of monodisperse aerosols of {sup 238}PuO{sub 2} to achieve graded levels of initial lung burden (ILB). The aerosols also contained {sup 169}Yb to provide a {gamma}-ray-emitting label for the {sup 238}Pu inhaled by each dog. Excreta were collected periodically over each dog`s life span to estimate plutonium excretion; at death, the tissues were analyzed radiochemically for plutonium activity. The tissue content and the amount of plutonium excreted were used to estimatemore » the ILB. These data for each dog were used in a dosimetry model to estimate the ILB. These data for each dog were used in a dosimetry model to estimate tissue doses. The lung, skeleton and liver received the highest {alpha}-particle doses, ranging from 0.16-68 Gy for the liver. At death, all dogs were necropsied, and all organs and lesions were sampled and examined by histopathology. Findings of non-neoplastic changes included neutropenia and lymphopenia that developed in a dose-related fashion soon after inhalation exposure. These effects persisted for up to 5 years in some animals, but no other health effects could be related to the blood changes observed. Radiation pneumonitis was observed among the dogs with the highest ILBs. Deaths from radiation pneumonitis occurred from 1.5 to 5.4 years after exposure. Tumors of the lung, skeleton and liver occurred beginning at about 3 years after exposure. These findings in dogs suggest that similar dose-related biological effects could be expected in humans accidentally exposed to {sup 238}PuO{sub 2}. 89 refs., 10 figs., 11 tab.« less

Fabrication and characterization of bolus material using polydimethyl-siloxane

NASA Astrophysics Data System (ADS)

Wiratma Jaya, Gede; Sutanto, Heri

2018-01-01

Bolus has been used in radiotherapy to reduce tissue harm and to increase the superficial dose for skin cancer treatment. Commonly, a bolus is made of melamine in several hospitals. In this research, polydimethyl-siloxane (PDMS) material was used for bolus fabrication. The aims of the study are to investigate bolus density, percentage surface dose and its structural strength for each various composition. In bolus preparation, bolus material used composition variation between PDMS volume and catalyst volume. Composition variation were 20:1, 22:1, 24:1, 26:1, 28:1, 30:1 and 32:1. PDMS and catalyst were mixed by chemical solution deposition method. Bolus was molded by using glass cast with the size of 10 × 10 × 0.5 cm3. Bolus density was analyzed by mass per volume equation, for bolus radiation was examined by the linear accelerator using two electron energy (5 and 7 MeV) and bolus strain and tensile strength were examined by Brookfield CT 3 machine. The results of bolus density were similar with soft tissue density, while the lowest and highest density each variation are 22:1 and 28:1. In general, the use of bolus has increased the surface dose. Percentage of surface dose at 5 MeV energy is higher than 7 MeV energy. The highest percentage of surface dose at 5 MeV energy with 0.5 and 1.0 cm bolus thickness was achieved at composition of 32:1. For strain and tensile strength result, the lowest and highest strain each variation are 22:1 and 28:1, then the lowest and highest tensile strength each variation are 32:1 and 28:1. These results is important to select composition material for bolus fabrication in radiotherapy treatment.

Pyrene fate affected by humic acid amendment in soil slurry systems.

PubMed

Liang, Yanna; Sorensen, Darwin L; McLean, Joan E; Sims, Ronald C

2008-09-10

Humic acid (HA) has been found to affect the solubility, mineralization, and bound residue formation of polycyclic aromatic hydrocarbons (PAHs). However, most of the studies on the interaction between HA and PAH concentrated on one or two of the three phases. Few studies have provided a simple protocol to demonstrate the overall effects of HA on PAH distribution in soil systems for all three phases. In this study, three doses of standard Elliott soil HA (ESHA), 15, 187.5, and 1,875 mug ESHA/g soil slurry, were amended to soil slurry systems. 14C-pyrene was added to the systems along with non-radiolabeled pyrene; 14C and 14CO2 were monitored for each system for a period of 120 days. The highest amendment dose significantly increased the 14C fraction in the aqueous phase within 24 h, but not after that time. Pyrene mineralization was significantly inhibited by the highest dose over the 120-day study. While organic solvent extractable 14C decreased with time in all systems, non-extractable or bound 14C was significantly enhanced with the highest dose of ESHA addition. Amendment of the highest dose of ESHA to pyrene contaminated soil was observed to have two major functions. The first was to mitigate CO2 production significantly by reducing 14CO2 from 14C pyrene mineralization. The second was to significantly increase stable bound 14C formation, which may serve as a remediation end point. Overall, this study demonstrated a practical approach for decontamination of PAH contaminated soil. This approach may be applicable to other organic contaminated environments where active bioremediation is taking place.

DNA damage in internal organs after cutaneous exposure to sulphur mustard.

PubMed

Batal, Mohamed; Boudry, Isabelle; Mouret, Stéphane; Cléry-Barraud, Cécile; Wartelle, Julien; Bérard, Izabel; Douki, Thierry

2014-07-01

Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, and liver of SKH-1 mice cutaneously exposed to 2, 6 and 60mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target. Copyright © 2014 Elsevier Inc. All rights reserved.

The levels of polycyclic aromatic hydrocarbons (PAHs) in human milk and exposure risk to breastfed infants in petrochemical industrialized Lanzhou Valley, Northwest China.

PubMed

Wang, Li; Liu, Aiping; Zhao, Yuan; Mu, Xi; Huang, Tao; Gao, Hong; Ma, Jianmin

2018-06-01

We investigated in this paper the presence of PAHs in human milk from lactating women residing in Lanzhou, a petrochemical industrialized valley city in Northwest China. The PAH concentration levels in human milk samples from 98 healthy women were determined by gas chromatography/mass spectrometry (GC/MS). The associations between the lifestyle factors and the PAHs levels of human milk were analyzed. Moreover, we applied principal component analysis (PCA) method to gain a better insight into the similarities or dissimilarities of the human milk PAH loads and different pathways of source exposure. In addition, the exposure risks of breastfed infants due to PAH ingestion via breast milk were assessed and the relative breast-feeding risk to the total intake dose of infants was addressed. The results showed that the average fat-normalized human milk ∑ 15 PAHs concentrations for the lactating women residing in four districts of Lanzhou, namely, Xigu, Anning, Qilihe, and Chengguan were 320.40, 270.36, 374.04, and 259.84 ng/g of fat, respectively. The ∑ 15 PAHs of human milk from the lactating women of Qilihe District exhibited the highest concentration level, while the concentration level for women from Xigu District is the second highest for the observed human milk ∑ 15 PAHs. And the corresponding BaPeq concentrations for women in Xigu, Anning, Qilihe, and Chengguan districts were 58.29, 47.95, 65.13, and 45.60 ng/g of fat, respectively. A significant correlation was only found between human milk and living district environment (p < 0.05). Although the Spearman correlation analysis showed that there were no significant correlation existing between other lifestyle and human milk PAHs, we confirmed that consuming barbecue food could elevate PAHs levels in human milk: the barbecue intake frequency caused 10% fluctuation of ∑ 15 PAHs concentration between high frequency and low frequency group in our study. Furthermore, the exposure to second-hand smoke can also increase the ∑ 15 PAHs levels in human milk by 4 to 11% here. Ingestion doses of PAHs by infants (19.37-77.75 ng kg -1  day -1 ) were much higher than the inhalation doses (2.83-16.48 ng kg -1  day -1 ), which indicated that the ingestion is the main exposure risk pathway for infants. Since there are limited guidelines and standards for PAHs ingestion dose in human milk by infant, we compared the ingestion dose of BaP with the upper bound estimates of BaP dietary exposure of 108 ng kg -1  day -1 for toddlers of ages between 1.5 and 2.5 years of age in the UK reported by Committee on Toxicity of Chemicals in Food (COT) and the data we obtained were lower than this upper bound. However, the estimated margin of exposure (MOE) values of BaP-MOE, PAH2-MOE, PAH4-MOE, and PAH8-MOE were smaller than 10,000 which indicated that there are potential hazard for breastfed infants consuming these human milk samples.

Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3beta.

PubMed

Whittle, Brendan J R; Varga, Csaba; Pósa, Anikó; Molnár, Andor; Collin, Marika; Thiemermann, Christoph

2006-03-01

The effects of the inhibitors of glycogen synthase kinase-3beta (GSK-3beta), TDZD-8 and SB 415286, which can substantially reduce the systemic inflammation associated with endotoxic shock in vivo, have now been investigated on the acute colitis provoked by trinitrobenzene sulphonic acid (TNBS) in the rat. Administration of the GSK-3beta inhibitor TDZD-8 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days) caused a dose-dependent reduction in the colonic inflammation induced by intracolonic TNBS assessed after 3 days, both as the area of macroscopic involvement and as a score using 0-10 scale. Likewise, following administration of the GSK-3beta inhibitor SB 415286 (0.1, 0.33 or 1.0 mg kg-1, s.c., b.i.d., for 3 days), the extent and degree of the TNBS-provoked colonic inflammation was reduced. Administration of either TDZD-8 or SB 415286 reduced the fall in body weight following challenge with TNBS at each dose level studied. The increase in myeloperoxidase activity, an index of neutrophil infiltration into the TNBS-induced inflamed colon, was significantly inhibited by both TDZD-8 and SB 415286 at each dose level. The increase in the levels of the proinflammatory cytokine, TNF-alpha, in the inflamed colon was also significantly inhibited by either compound at the highest doses evaluated. The elevated levels of the transcription factor NF-kappaB subunit p65, as determined by Western blot in the nuclear extracts from the TNBS-provoked inflamed colonic tissue, were dose-dependently reduced by TDZD-8 or SB 415286 treatment. These findings demonstrate that two chemically distinct selective inhibitors of the activity of GSK-3beta reduce the inflammation and tissue injury in a rat model of acute colitis. The mechanisms underlying this anti-inflammatory action may be related to downregulation of NF-kappaB activity, involved in the generation of proinflammatory mediators.

Background radiation and individual dosimetry in the costal area of Tamil Nadu, India.

PubMed

Matsuda, Naoki; Brahmanandhan, G M; Yoshida, Masahiro; Takamura, Noboru; Suyama, Akihiko; Koguchi, Yasuhiro; Juto, Norimichi; Raj, Y Lenin; Winsley, Godwin; Selvasekarapandian, S

2011-07-01

South coast of India is known as the high-level background radiation area (HBRA) mainly due to beach sands that contain natural radionuclides as components of the mineral monazite. The rich deposit of monazite is unevenly distributed along the coastal belt of Tamil Nadu and Kerala. An HBRA site that laid in 2×7 m along the sea was found in the beach of Chinnavillai, Tamil Nadu, where the maximum ambient dose equivalent reached as high as 162.7 mSv y(-1). From the sands collected at the HBRA spot, the high-purity germanium semi-conductor detector identified six nuclides of thorium series, four nuclides of uranium series and two nuclides belonging to actinium series. The highest radioactivity observed was 43.7 Bq g(-1) of Th-228. The individual dose of five inhabitants in Chinnavillai, as measured by the radiophotoluminescence glass dosimetry system, demonstrated the average dose of 7.17 mSv y(-1) ranging from 2.79 to 14.17 mSv y(-1).

Kinetics and toxic effects of repeated intravenous dosage of formic acid in rabbits.

PubMed Central

Liesivuori, J.; Kosma, V. M.; Naukkarinen, A.; Savolainen, H.

1987-01-01

Adult male rabbits were injected i.v. with 100 mg buffered formic acid per kg body weight daily for 5 days with 24 h between the doses. The fifth dose was labelled with 14C-formic acid. Rabbits were killed 1, 2 and 20 h after the last injection. The highest formic acid concentrations were found one hour after the fifth dose. Total formic acid concentrations were always higher than radiometrically measured. The maximum concentrations of formic acid in brain, heart, kidney and liver were roughly similar to the concentration which inhibits half of the cytochrome oxidase activity in vitro. Histological studies clearly demonstrated the histotoxic changes at cellular level. Calcium deposits were detected in all organs of the injected rabbits. They were absent in control animals. It seems that the formic acid metabolism is slow and that it may cause sufficient hypoxic acidosis to allow the calcium influx and cellular damage. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:3426949

Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits.

PubMed Central

Bonham, A C; Kott, K S; Ravi, K; Kappagoda, C T; Joad, J P

1996-01-01

1. This study tested the hypothesis that substance P stimulates rapidly adapting receptors (RARs), contributes to the increase in RAR activity produced by mild pulmonary congestion, and evokes an augmented response from RARs when combined with near-threshold levels of pulmonary congestion. 2. RAR activity, peak tracheal pressure, arterial blood pressure and left atrial pressure were measured in paralysed, anaesthetized and ventilated rabbits. Substance P was given i.v. in one-half log incremental doses to a maximum of 3 micrograms kg-1. Mild pulmonary congestion was produced by inflating a balloon in the left atrium to increase left atrial pressure by 5 mmHg. Near-threshold levels of pulmonary congestion were produced by increasing left atrial pressure by 2 mmHg. 3. Substance P produced dose-dependent increases in RAR activity. The highest dose given increased the activity from 1.3 +/- 0.5 to 11.0 +/- 3.1 impulses bin-1. Increases in left atrial pressure of 5 mmHg increased RAR activity from 3.8 +/- 1.4 to 14.7 +/- 3.9 impulses bin-1. Blockade of NK1 receptors with CP 96345 significantly attenuated RAR responses to substance P and to mild pulmonary congestion. 4. Doses of substance P, which alone had no effect, stimulated the RARs when delivered during near-threshold levels of pulmonary congestion. 5. The findings suggest that substance P augments the stimulatory effect of mild pulmonary congestion on RAR activity, most probably by enhancing hydraulically induced microvascular leak. Images Figure 6 PMID:8735708

Levels of daily light doses under changed day-night cycles regulate temporal segregation of photosynthesis and N2 Fixation in the cyanobacterium Trichodesmium erythraeum IMS101.

PubMed

Cai, Xiaoni; Gao, Kunshan

2015-01-01

While the diazotrophic cyanobacterium Trichodesmium is known to display inverse diurnal performances of photosynthesis and N2 fixation, such a phenomenon has not been well documented under different day-night (L-D) cycles and different levels of light dose exposed to the cells. Here, we show differences in growth, N2 fixation and photosynthetic carbon fixation as well as photochemical performances of Trichodesmium IMS101 grown under 12L:12D, 8L:16D and 16L:8D L-D cycles at 70 μmol photons m-2 s-1 PAR (LL) and 350 μmol photons m-2 s-1 PAR (HL). The specific growth rate was the highest under LL and the lowest under HL under 16L:8D, and it increased under LL and decreased under HL with increased levels of daytime light doses exposed under the different light regimes, respectively. N2 fixation and photosynthetic carbon fixation were affected differentially by changes in the day-night regimes, with the former increasing directly under LL with increased daytime light doses and decreased under HL over growth-saturating light levels. Temporal segregation of N2 fixation from photosynthetic carbon fixation was evidenced under all day-night regimes, showing a time lag between the peak in N2 fixation and dip in carbon fixation. Elongation of light period led to higher N2 fixation rate under LL than under HL, while shortening the light exposure to 8 h delayed the N2 fixation peaking time (at the end of light period) and extended it to night period. Photosynthetic carbon fixation rates and transfer of light photons were always higher under HL than LL, regardless of the day-night cycles. Conclusively, diel performance of N2 fixation possesses functional plasticity, which was regulated by levels of light energy supplies either via changing light levels or length of light exposure.

Evaluating the consistency of location of the most severe acute skin reaction and highest skin dose measured by thermoluminescent dosimeter during radiotherapy for breast cancer

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

Sun, Li-Min, E-mail: limin.sun@yahoo.com; Huang, Chih-Jen; Department of Faculty of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

We conducted this prospective study to evaluate whether the location of the most severe acute skin reaction matches the highest skin dose measured by thermoluminescent dosimeter (TLD) during adjuvant radiotherapy (RT) for patients with breast cancer after breast conservative surgery. To determine whether TLD measurement can reflect the location of the most severe acute skin reaction, 80 consecutive patients were enrolled in this prospective study. We divided the irradiated field into breast, axillary, inframammary fold, and areola/nipple areas. In 1 treatment session when obvious skin reaction occurred, we placed the TLD chips onto the 4 areas and measured the skinmore » dose. We determined whether the highest measured skin dose area is consistent with the location of the most severe skin reaction. The McNemar test revealed that the clinical skin reaction and TLD measurement are more consistent when the most severe skin reaction occurred at the axillary area, and the p = 0.0108. On the contrary, TLD measurement of skin dose is less likely consistent with clinical observation when the most severe skin reaction occurred at the inframammary fold, breast, and areola/nipple areas (all the p > 0.05). Considering the common site of severe skin reaction over the axillary area, TLD measurement may be an appropriate way to predict skin reaction during RT.« less

Influence of a fertilizer solution on yield and quality of bread wheat in Guadalquivir Valley (Córdoba, Spain)

NASA Astrophysics Data System (ADS)

Concepción Benítez, M.; González, José Luis; Tejada, Manuel

2014-05-01

The use of by-products of food industries in agricultural practices has become a routine over the last few decades. The addition of beet vinasse, by-products of the two sep olive mill process and by-products of defatted sunflower flour, etc., to soils is a common agricultural practice, since sensible use has been reported to improve the physical, chemical and biological aspects of the soil and to increase harvest yield, and in many cases harvest quality Previous research carried out by the authors (Ordóñez et al., 2001) examined a process whereby a protein concentrate is obtained from defatted sunflower flour. In this process, floating liquid phosphorus, potassium contents and smaller amounts of humic substances and nitrogen are obtained. The potential application of this solution as a fertiliser has been evaluated on rye grass, confirming that its effects are comparable to those produced by a nutritional solution in terms of phosphorus and potassium foliar levels. The experiment was performed on soil classified as Typic Haploxererts located in the Middle Valley of the river Guadalquivir Cajeme wheat (Triticum aestivum var) variety was used at a dose of 180 kg seeds / ha. For both crop, four fertiliser treatments were applied in triplicate to randomly distributed 7 x 8 m plots. The greatest positive effect of applying the experimental phospho-potassic solution was found for the leaf levels of K, in maturity; this influence was most significant when the highest dosage of said solution. With reference to the levels of N, P and K in wheat grain, the levels of potassium were significantly different for all the fertilising treatments, and the plot fertilised with the highest dosage of the experimental phospho-potassic solution presented the highest values. As for the data obtained for harvest yield and quality, the addition of the experimental solution was observed to have a significantly positive influence (but only in the highest dosages) on the production levels.

Diverse spectrum of tumors in male Sprague-Dawley rats following single high doses of N-ethyl-N-nitrosourea (ENU).

PubMed Central

Stoica, G.; Koestner, A.

1984-01-01

In this study, 30-day-old male Sprague-Dawley rats, were inoculated intraperitoneally with a single dose of 45, 90, and 180 mg/kg of N-ethyl-N-Nitrosourea (ENU). A wide spectrum of neoplasms occurred. The most common tumors were those of the mammary gland and of the nervous system. Although the incidence of mammary tumors was highest in the two high-dose groups (90 and 180 mg/kg ENU), the incidence of neurogenic tumors was highest in the 45 mg/kg dose group. Mammary tumor development led to early death and precluded development of tumors of the nervous system, which require a longer latency period. A variety of neoplasms of other organs have been associated particularly with high doses of ENU, including ameloblastic tumors, carcinomas of the thyroid, prostate, kidney, pancreas, intestine, and lung, hemilymphatic tumors, and sarcomas. It is concluded that large doses of ENU are capable of expanding the tumor spectrum in young male rats beyond the target organs generally affected with lower doses, as described in earlier reports. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:6465287

Comparative dose levels between CT-scanner and slot-scanning device (EOS system) in pregnant women pelvimetry.

PubMed

Ben Abdennebi, A; Aubry, S; Ounalli, L; Fayache, M S; Delabrousse, E; Petegnief, Y

2017-01-01

To estimate fetal absorbed doses for pregnant women pelvimetry, a comparative study between EOS imaging system and low-dose spiral CT-scanner was carried out. For this purpose three different studies were investigated: in vivo, in vitro and Monte Carlo calculations. In vivo dosimetry was performed, using OSL NanoDot dosimeters, to determine the dose to the skin of twenty pregnant women. In vitro studies were established by using a cubic phantom of water, in order to estimate the out of field doses. In the latter study, OSLDs were placed at depths corresponding to the lowest, average and highest position of the uterus. Monte Carlo calculations of effective doses to high radio-sensitive organs were established, using PCXMC and CTExpo software suites for EOS imaging system and CT-scanner, respectively. The EOS imaging system reduces radiation exposure 4 to 8 times compared to the CT-scanner. The entrance skin doses were 74% (p-values <0.01) higher with the CT-scanner than with the EOS system. In the out of field region, the measured doses of the EOS system were reduced by 80% (p-values <0.02). Monte Carlo calculations confirmed that effective doses to organs are less accentuated for EOS than for CT pelvimetry. The EOS system is less irradiating than the CT exam. The out-of-field dose which is significant, is lower in the EOS than in the CT-scanner and could be reduced even further by optimizing the time used for image acquisition. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Simulation of computed tomography dose based on voxel phantom

NASA Astrophysics Data System (ADS)

Liu, Chunyu; Lv, Xiangbo; Li, Zhaojun

2017-01-01

Computed Tomography (CT) is one of the preferred and the most valuable imaging tool used in diagnostic radiology, which provides a high-quality cross-sectional image of the body. It still causes higher doses of radiation to patients comparing to the other radiological procedures. The Monte-Carlo method is appropriate for estimation of the radiation dose during the CT examinations. The simulation of the Computed Tomography Dose Index (CTDI) phantom was developed in this paper. Under a similar conditions used in physical measurements, dose profiles were calculated and compared against the measured values that were reported. The results demonstrate a good agreement between the calculated and the measured doses. From different CT exam simulations using the voxel phantom, the highest absorbed dose was recorded for the lung, the brain, the bone surface. A comparison between the different scan type shows that the effective dose for a chest scan is the highest one, whereas the effective dose values during abdomen and pelvis scan are very close, respectively. The lowest effective dose resulted from the head scan. Although, the dose in CT is related to various parameters, such as the tube current, exposure time, beam energy, slice thickness and patient size, this study demonstrates that the MC simulation is a useful tool to accurately estimate the dose delivered to any specific organs for patients undergoing the CT exams and can be also a valuable technique for the design and the optimization of the CT x-ray source.

Effects of Methylphenidate on Sleep Functioning in Children with Attention-Deficit/Hyperactivity Disorder.

PubMed

Becker, Stephen P; Froehlich, Tanya E; Epstein, Jeffery N

2016-06-01

To examine the effects of stimulant medication on the sleep functioning of children with attention-deficit/hyperactivity disorder (ADHD) and identify predictors of sleep problems as a side effect of taking stimulant medication. One hundred sixty-three stimulant-naïve children (72% boys) aged 7 to 11 years diagnosed with ADHD (120 with ADHD predominantly inattentive type, 43 with ADHD combined type) participated in a 4-week, randomized, double-blind, placebo-controlled trial of once-daily (long-acting) methylphenidate (MPH). Parents completed weekly side-effect ratings including an item related to sleep problems. Ten percent of patients had parent-rated sleep problems before the initiation of medication. Rates of parent-rated sleep problems during MPH titration generally increased with increasing MPH dose (placebo: 8%; low dose: 18%; medium dose: 15%; high dose: 25%). Differences emerged between children with (n = 16) or without (n = 147) preexisting sleep problems. Although 23% of children without preexisting sleep problems went on to have sleep problems at the highest MPH dose, only 37.5% of children with preexisting sleep problems still had sleep problems at the highest MPH dose. Lower weight and lower body mass index (BMI) were associated with increased sleep problems during MPH titration. This study demonstrated a general association between increased MPH dose and increased sleep problems in children with ADHD, particularly for children of lower weight/BMI. However, a substantial proportion of children with preexisting sleep difficulties no longer had sleep problems on the highest MPH dose, which may help explain mixed findings reported to date in studies examining the impact of MPH on sleep functioning in children with ADHD and suggests that MPH dose titration should not be avoided solely on the basis of a child's premorbid sleep problems. Future research is needed to replicate and extend these findings to more specific domains of sleep functioning and to identify differences between children with persistent or improved sleep functioning as a result of MPH use.

Monte Carlo and Phantom Study of the Radiation Dose to the Body from Dedicated Computed Tomography of the Breast

PubMed Central

Sechopoulos, Ioannis; Vedantham, Srinivasan; Suryanarayanan, Sankararaman; D’Orsi, Carl J.; Karellas, Andrew

2008-01-01

Purpose To prospectively determine the radiation dose absorbed by the organs and tissues of the body during a dedicated computed tomography of the breast (DBCT) study using Monte Carlo methods and a phantom. Materials and Methods Using the Geant4 Monte Carlo toolkit, the Cristy anthropomorphic phantom and the geometry of a prototype DBCT was simulated. The simulation was used to track x-rays emitted from the source until their complete absorption or exit from the simulation limits. The interactions of the x-rays with the 65 different volumes representing organs, bones and other tissues of the anthropomorphic phantom that resulted in energy deposition were recorded. These data were used to compute the radiation dose to the organs and tissues during a complete DBCT acquisition relative to the average glandular dose to the imaged breast (ROD, relative organ dose), using the x-ray spectra proposed for DBCT imaging. The effectiveness of a lead shield for reducing the dose to the organs was investigated. Results The maximum ROD among the organs was for the ipsilateral lung with a maximum of 3.25%, followed by the heart and the thymus. Of the skeletal tissues, the sternum received the highest dose with a maximum ROD to the bone marrow of 2.24%, and to the bone surface of 7.74%. The maximum ROD to the uterus, representative of that of an early-stage fetus, was 0.026%. These maxima occurred for the highest energy x-ray spectrum (80 kVp) analyzed. A lead shield does not protect substantially the organs that receive the highest dose from DBCT. Discussion Although the dose to the organs from DBCT is substantially higher than that from planar mammography, they are comparable or considerably lower than those reached by other radiographic procedures and much lower than other CT examinations. PMID:18292479

Tracking Cumulative Radiation Exposure in Orthopaedic Surgeons and Residents: What Dose Are We Getting?

PubMed

Gausden, Elizabeth B; Christ, Alexander B; Zeldin, Roseann; Lane, Joseph M; McCarthy, Moira M

2017-08-02

The purpose of this study was to determine the amount of cumulative radiation exposure received by orthopaedic surgeons and residents in various subspecialties. We obtained dosimeter measures over 12 months on 24 residents and 16 attending surgeons. Monthly radiation exposure was measured over a 12-month period for 24 orthopaedic residents and 16 orthopaedic attending surgeons. The participants wore a Landauer Luxel dosimeter on the breast pocket of their lead apron. The dosimeters were exchanged every rotation (5 to 7 weeks) for the resident participants and every month for the attending surgeon participants. Radiation exposure was compared by orthopaedic subspecialty, level of training, and type of fluoroscopy used (regular C-arm compared with mini C-arm). Orthopaedic residents participating in this study received monthly mean radiation exposures of 0.2 to 79 mrem/month, lower than the dose limits of 5,000 mrem/year recommended by the United States Nuclear Regulatory Commission (U.S. NRC). Senior residents rotating on trauma were exposed to the highest monthly radiation (79 mrem/month [range, 15 to 243 mrem/month]) compared with all other specialty rotations (p < 0.001). Similarly, attending orthopaedic surgeons who specialize in trauma or deformity surgery received the highest radiation exposure of their peers, and the mean exposure was 53 mrem/month (range, 0 to 355 mrem/month). Residents and attending surgeons performing trauma or deformity surgical procedures are exposed to significantly higher doses of radiation compared with all other subspecialties within orthopaedic surgery, but the doses are still within the recommended limits. The use of ionizing radiation in the operating room has become an indispensable part of orthopaedic surgery. Although all surgeons in our study received lower than the yearly recommended dose limit, it is important to be aware of how much radiation we are exposed to as surgeons and to take measures to further limit that exposure.

A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster).

PubMed

Sullivan, Alana W; Beach, Elsworth C; Stetzik, Lucas A; Perry, Amy; D'Addezio, Alyssa S; Cushing, Bruce S; Patisaul, Heather B

2014-10-01

Impacts on brain and behavior have been reported in laboratory rodents after developmental exposure to bisphenol A (BPA), raising concerns about possible human effects. Epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, but potential mechanisms are unclear. Disruption of mesolimbic oxytocin (OT)/vasopressin (AVP) pathways have been proposed, but supporting evidence is minimal. To address these data gaps, we employed a novel animal model for neuroendocrine toxicology: the prairie vole (Microtus ochrogaster), which are more prosocial than lab rats or mice. Male and female prairie vole pups were orally exposed to 5-μg/kg body weight (bw)/d, 50-μg/kg bw/d, or 50-mg/kg bw/d BPA or vehicle over postnatal days 8-14. Subjects were tested as juveniles in open field and novel social tests and for partner preference as adults. Brains were then collected and assessed for immunoreactive (ir) tyrosine hydroxylase (TH) (a dopamine marker) neurons in the principal bed nucleus of the stria terminalis (pBNST) and TH-ir, OT-ir, and AVP-ir neurons in the paraventricular nucleus of the hypothalamus (PVN). Female open field activity indicated hyperactivity at the lowest dose and anxiety at the highest dose. Effects on social interactions were also observed, and partner preference formation was mildly inhibited at all dose levels. BPA masculinized principal bed nucleus of the stria terminalis TH-ir neuron numbers in females. Additionally, 50-mg/kg bw BPA-exposed females had more AVP-ir neurons in the anterior PVN and fewer OT-ir neurons in the posterior PVN. At the 2 lowest doses, BPA eliminated sex differences in PVN TH-ir neuron numbers and reversed this sex difference at the highest dose. Minimal behavioral effects were observed in BPA-exposed males. These data support the hypothesis that BPA alters affective behaviors, potentially via disruption of OT/AVP pathways.

Awareness and Knowledge Among Internal Medicine Resident Trainees for Dose Adjustment of Analgesics and Neuropsychotropic Medications in CKD.

PubMed

Saad, Chadi Y; Fogel, Joshua; Rubinstein, Sofia

2018-03-01

Errors in drug dosing lead to poor patient outcomes and are common in patients with chronic kidney disease (CKD). Because the majority of patients with CKD are being treated by physicians specializing in internal medicine, we studied the awareness and knowledge that internal medicine resident trainees (IMRTs) have regarding the correct dosage of commonly used analgesic and neuropsychotropic medications for patients with CKD. We surveyed 353 IMRTs about their awareness of whether a medication needs dose adjustment in patients with CKD and knowledge for medication adjustment by level of glomerular filtration rate. There were high percentages for lack of awareness and knowledge. For analgesics, this lack of awareness/knowledge was highest for acetaminophen (awareness 83.0%, knowledge 90.9%). For neuropsychotropics, this was highest for paroxetine (awareness 74.5%, knowledge 91.5%). Analyses for postgraduate year (PGY) -1 trainees and PGY-2 trainees for analgesics showed higher odds for lack of awareness for tramadol (PGY-1 odds ratio [OR] 2.37, 95% confidence interval [CI] 1.2-4.62, P < 0.05; PGY-2 OR 2.34, 95% CI 1.16-4.72, P < 0.05) and for lack of knowledge for meperedine (PGY-1 OR 4.01, 95% CI 1.81-8.89, P < 0.05; PGY-2 OR 3.30, 95% CI 1.44-7.59, P < 0.05). Nephrology residency rotation for the neuropsychotropic medication of gabapentin showed lower odds for both lack of awareness (OR 0.56, 95% CI 0.32-0.97, P < 0.05) and knowledge (OR 0.52, 95% CI 0.27-0.997, P < 0.05). Awareness and knowledge are poor among IMRTs for dose adjustments of analgesics and neuropsychotropic medication classes in patients with CKD. There should be a renewed focus during IMRTs' residency on additional nephrology exposure and formal didactic educational training to help them better manage complex treatment regimens to prevent medication dosing errors.

Assessment of individual organ doses in a realistic human phantom from neutron and gamma stimulated spectroscopy of the breast and liver

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

Belley, Matthew D.; Segars, William Paul; Kapadia, Anuj J., E-mail: anuj.kapadia@duke.edu

2014-06-15

Purpose: Understanding the radiation dose to a patient is essential when considering the use of an ionizing diagnostic imaging test for clinical diagnosis and screening. Using Monte Carlo simulations, the authors estimated the three-dimensional organ-dose distribution from neutron and gamma irradiation of the male liver, female liver, and female breasts for neutron- and gamma-stimulated spectroscopic imaging. Methods: Monte Carlo simulations were developed using the Geant4 GATE application and a voxelized XCAT human phantom. A male and a female whole body XCAT phantom was voxelized into 256 × 256 × 600 voxels (3.125 × 3.125 × 3.125 mm{sup 3}). A monoenergeticmore » rectangular beam of 5.0 MeV neutrons or 7.0 MeV photons was made incident on a 2 cm thick slice of the phantom. The beam was rotated at eight different angles around the phantom ranging from 0° to 180°. Absorbed dose was calculated for each individual organ in the body and dose volume histograms were computed to analyze the absolute and relative doses in each organ. Results: The neutron irradiations of the liver showed the highest organ dose absorption in the liver, with appreciably lower doses in other proximal organs. The dose distribution within the irradiated slice exhibited substantial attenuation with increasing depth along the beam path, attenuating to ∼15% of the maximum value at the beam exit side. The gamma irradiation of the liver imparted the highest organ dose to the stomach wall. The dose distribution from the gammas showed a region of dose buildup at the beam entrance, followed by a relatively uniform dose distribution to all of the deep tissue structures, attenuating to ∼75% of the maximum value at the beam exit side. For the breast scans, both the neutron and gamma irradiation registered maximum organ doses in the breasts, with all other organs receiving less than 1% of the breast dose. Effective doses ranged from 0.22 to 0.37 mSv for the neutron scans and 41 to 66 mSv for the gamma scans. Conclusions: Neutron and gamma irradiation of a primary target organ was found to impart the majority of the total dose to the primary target organ (and other large organs) within the beam plane and considerably lower dose to proximal organs outside of the beam. These results also indicate that despite the use of a highly scattering particle such as a neutron, the dose from neutron stimulated emission computed tomography scans is on par with other clinical imaging techniques such as x-ray computed tomography (x-ray CT). Given the high nonuniformity in the dose across an organ during the neutron scan, care must be taken when computing average doses from neutron irradiations. The effective doses from neutron scanning were found to be comparable to x-ray CT. Further technique modifications are needed to reduce the effective dose levels from the gamma scans.« less

Comparative responses to endocrine disrupting compounds in early life stages of Atlantic salmon, Salmo salar.

PubMed

Duffy, T A; Iwanowicz, L R; McCormick, S D

2014-07-01

Atlantic salmon (Salmo salar) are endangered anadromous fish that may be exposed to feminizing endocrine disrupting compounds (EDCs) during early development, potentially altering physiological capacities, survival and fitness. To assess differential life stage sensitivity to common EDCs, we carried out short-term (4 day) exposures using three doses each of 17 α-ethinylestradiol (EE2), 17 β-estradiol (E2), and nonylphenol (NP) on four early life stages; embryos, yolk-sac larvae, feeding fry and 1 year old smolts. Differential response was compared using vitellogenin (Vtg, a precursor egg protein) gene transcription. Smolts were also examined for impacts on plasma Vtg, cortisol, thyroid hormones (T4/T3) and hepatosomatic index (HSI). Compound-related mortality was not observed in any life stage, but Vtg mRNA was elevated in a dose-dependent manner in yolk-sac larvae, fry and smolts but not in embryos. The estrogens EE2 and E2 were consistently stronger inducers of Vtg than NP. Embryos responded significantly to the highest concentration of EE2 only, while older life stages responded to the highest doses of all three compounds, as well as intermediate doses of EE2 and E2. Maximal transcription was greater for fry among the three earliest life stages, suggesting fry may be the most responsive life stage in early development. Smolt plasma Vtg was also significantly increased, and this response was observed at lower doses of each compound than was detected by gene transcription suggesting plasma Vtg is a more sensitive indicator at this life stage. HSI was increased at the highest doses of EE2 and E2, and plasma T3 was decreased at the highest dose of EE2. Our results indicate that all life stages are potentially sensitive to endocrine disruption by estrogenic compounds and that physiological responses were altered over a short window of exposure, indicating the potential for these compounds to impact fish in the wild. Copyright © 2014 Elsevier B.V. All rights reserved.

Tuberculosis in Newborns: The Lessons of the “Lübeck Disaster” (1929–1933)

PubMed Central

Fox, Gregory J.; Orlova, Marianna; Schurr, Erwin

2016-01-01

In an accident later known as the Lübeck disaster, 251 neonates were orally given three doses of the new Bacille Calmette–Guérin (BCG) antituberculosis (TB) vaccine contaminated with Mycobacterium tuberculosis. A total of 173 infants developed clinical or radiological signs of TB but survived the infection, while 72 died from TB. While some blamed the accident on BCG itself by postulating reversion to full virulence, such a possibility was conclusively disproven. Rather, by combining clinical, microbiological, and epidemiological data, the chief public health investigator Dr. A. Moegling concluded that the BCG vaccine had been contaminated with variable amounts of fully virulent M. tuberculosis. Here, we summarize the conclusions drawn by Moegling and point out three lessons that can be learned. First, while mortality was high (approximately 29%), the majority of neonates inoculated with M. tuberculosis eventually overcame TB disease. This shows the high constitutional resistance of humans to the bacillus. Second, four semiquantitative levels of contamination were deduced by Moegling from the available data. While at low levels of M. tuberculosis there was a large spread of clinical phenotypes reflecting a good degree of innate resistance to TB, at the highest dose, the majority of neonates were highly susceptible to TB. This shows the dominating role of dose for innate resistance to TB. Third, two infants inoculated with the lowest dose nevertheless died of TB, and their median time from inoculation to death was substantially shorter than for those who died after inoculation with higher doses. This suggests that infants who developed disease after low dose inoculation are those who are most susceptible to the disease. We discuss some implications of these lessons for current study of genetic susceptibility to TB. PMID:26794678

Biological effects of α-radiation exposure by (241)Am in Arabidopsis thaliana seedlings are determined both by dose rate and (241)Am distribution.

PubMed

Biermans, Geert; Horemans, Nele; Vanhoudt, Nathalie; Vandenhove, Hildegarde; Saenen, Eline; Van Hees, May; Wannijn, Jean; Vangronsveld, Jaco; Cuypers, Ann

2015-11-01

Human activity has led to an increasing amount of radionuclides in the environment and subsequently to an increased risk of exposure of the biosphere to ionising radiation. Due to their high linear energy transfer, α-emitters form a threat to biota when absorbed or integrated in living tissue. Among these, (241)Am is of major concern due to high affinity for organic matter and high specific activity. This study examines the dose-dependent biological effects of α-radiation delivered by (241)Am at the morphological, physiological and molecular level in 14-day old seedlings of Arabidopsis thaliana after hydroponic exposure for 4 or 7 days. Our results show that (241)Am has high transfer to the roots but low translocation to the shoots. In the roots, we observed a transcriptional response of reactive oxygen species scavenging and DNA repair pathways. At the physiological and morphological level this resulted in a response which evolved from redox balance control and stable biomass at low dose rates to growth reduction, reduced transfer and redox balance decline at higher dose rates. This situation was also reflected in the shoots where, despite the absence of a transcriptional response, the control of photosynthesis performance and redox balance declined with increasing dose rate. The data further suggest that the effects in both organs were initiated in the roots, where the highest dose rates occurred, ultimately affecting photosynthesis performance and carbon assimilation. Though further detailed study of nutrient balance and (241)Am localisation is necessary, it is clear that radionuclide uptake and distribution is a major parameter in the global exposure effects on plant performance and health. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of the effects of three different Baccaurea angulata whole fruit juice doses on plasma, aorta and liver MDA levels, antioxidant enzymes and total antioxidant capacity.

PubMed

Ibrahim, Muhammad; Mikail, Maryam Abimbola; Ahmed, Idris Adewale; Hazali, Norazlanshah; Abdul Rasad, Mohammad Syaiful Bahari; Abdul Ghani, Radiah; Hashim, Ridzwan; Arief, Solachuddin Jahuari; Md Isa, Muhammad Lokman; Draman, Samsul

2017-05-17

Baccaurea angulata (common names: belimbing dayak or belimbing hutan) is a Malaysian underutilized fruit. The preliminary work on B. angulata fruit juice showed that it possesses antioxidant properties. Therefore, further work is needed to confirm the efficacy and proper dosage of B. angulata as a potential natural antioxidant. The present study was thus carried out to compare the effects of three different B. angulata whole fruit (WF) juice doses administered at nutritional doses of 0.50, 1.00 and 1.50 ml/kg/day on plasma, aorta and liver malondialdehyde (MDA) levels, antioxidant enzymes (superoxide dismutase, glutathione peroxidase and catalase) as well as total antioxidant capacity in rabbits fed high-cholesterol diet. Thirty-five male rabbits of New Zealand strain were randomly assigned to seven groups. For 12 weeks, group CH was fed 1% cholesterol diet only; group C1 was fed 1% cholesterol diet and 0.50 ml/kg/day B. angulata WF juice; group C2 was fed 1% cholesterol diet and 1.00 ml/kg/day B. angulata WF juice; group C3 was fed 1% cholesterol diet and 1.50 ml/kg/day B. angulata WF juice; group N was fed standard pellet only; group N1 was fed standard pellet and 0.50 ml/kg/day B. angulata WF juice; and group N2 was fed standard pellet and 1.00 ml/kg/day B. angulata WF juice. The three doses reduced the formation of MDA and enhanced the expression of endogenous antioxidant enzymes. The highest dose used (1.50 ml/kg/day) was, however, seen as the most potent. Higher doses of B. angulata juice exerted better antioxidant activity.

An In Vivo Study of Low-Dose Intra-Articular Tranexamic Acid Application with Prolonged Clamping Drain Method in Total Knee Replacement: Clinical Efficacy and Safety.

PubMed

Sa-ngasoongsong, Paphon; Chanplakorn, Pongsthorn; Wongsak, Siwadol; Uthadorn, Krisorn; Panpikoon, Tanapong; Jittorntam, Paisan; Aryurachai, Katcharin; Angchaisukisiri, Pantap; Kawinwonggowit, Viroj

2015-01-01

Recently, combined intra-articular tranexamic acid (IA-TXA) injection with clamping drain method showed efficacy for blood loss and transfusion reduction in total knee replacement (TKR). However, until now, none of previous studies revealed the effect of this technique on pharmacokinetics, coagulation, and fibrinolysis. An experimental study was conducted, during 2011-2012, in 30 patients undergoing unilateral TKR. Patients received IA-TXA application and then were allocated into six groups regarding clamping drain duration (2-, 4-, 6-, 8-, 10-, and 12-hours). Blood and drainage fluid were collected to measure tranexamic acid (TXA) level and related coagulation and fibrinolytic markers. Postoperative complication was followed for one year. There was no significant difference of serum TXA level at 2 hour and 24 hour among groups (p < 0.05). Serum TXA level at time of clamp release was significantly different among groups with the highest level at 2 hour (p < 0.0001). There was no significant difference of TXA level in drainage fluid, postoperative blood loss, blood transfusion, and postoperative complications (p < 0.05). Low-dose IA-TXA application in TKR with prolonged clamping drain method is a safe and effective blood conservative technique with only minimal systemic absorption and without significant increase in systemic absorption over time.

Assessment of natural radioactivity levels in rocks and their relationships with the geological structure of Johor state, Malaysia.

PubMed

Alnour, I A; Wagiran, H; Ibrahim, N; Hamzah, S; Elias, M S; Laili, Z; Omar, M

2014-01-01

The distribution of natural radionuclides ((238)U, (232)Th and (40)K) and their radiological hazard effect in rocks collected from the state of Johor, Malaysia were determined by gamma spectroscopy using a high-purity germanium detector. The highest values of (238)U, (232)Th and (40)K activity concentrations (67±6, 85±7 and 722±18 Bg kg(-1), respectively) were observed in the granite rock. The lowest concentrations of (238)U and (232)Th (2±0.1 Bq kg(-1) for (238)U and 2±0.1 Bq kg(-1) for (232)Th) were observed in gabbro rock. The lowest concentration of (40)K (45±2 Bq kg(-1)) was detected in sandstone. The radium equivalent activity concentrations for all rock samples investigated were lower than the internationally accepted value of 370 Bq kg(-1). The highest value of radium equivalent in the present study (239±17 Bq kg(-1)) was recorded in the area of granite belonging to an acid intrusive rock geological structure. The absorbed dose rate was found to range from 4 to 112 nGy h(-1). The effective dose ranged from 5 to 138 μSv h(-1). The internal and external hazard index values were given in results lower than unity. The purpose of this study is to provide information related to radioactivity background levels and the effects of radiation on residents in the study area under investigation. Moreover, the relationships between the radioactivity levels in the rocks within the geological structure of the studied area are discussed.

End-stage renal disease after occupational lead exposure: 20 years of follow-up.

PubMed

Evans, Marie; Discacciati, Andrea; Quershi, Abdul Rashid; Åkesson, Agneta; Elinder, Carl-Gustaf

2017-06-01

Whether low-level exposure to lead may give rise to chronic kidney disease or end-stage renal disease (ESRD) is debated. In this study, we aimed to specifically investigate if low-level occupational exposure to lead was associated with increased incidence of ESRD. The incidence of starting renal replacement therapy as a result of ESRD was examined in a cohort of10 303 lead-workers who had controlled blood lead concentrations due to a compulsory occupational health surveillance programme in Sweden during the time period 1977-1990. The ESRD incidence (obtained through register-linkage) among the lead-exposed workers was compared with the age, sex and calendar period-adjusted expected incidence based on data from the Swedish renal registry. Dose-response association was evaluated in external (general population) and internal (within the occupational cohort) comparisons by highest achieved blood lead level. There were 30 (0.29%) individuals in the cohort who developed ESRD during the median follow-up period of 26.3 years. The standardised incidence ratio (SIR) for ESRD incidence was 0.79 (95% CI 0.54 to 1.13). Among those who achieved the highest blood lead (>41.4 µg/dL), the SIR was 1.01 (0.44 to 1.99). There was no evidence of a dose-response relationship between the maximum achieved blood lead or the cumulative blood lead exposure and ESRD in external or internal comparisons. This study of workers with documented occupational lead exposures followed for 20 years shows no statistically significant association between lead exposure (following the current occupational recommendations for Sweden) and ESRD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Higher Caffeinated Coffee Intake Is Associated with Reduced Malignant Melanoma Risk: A Meta-Analysis Study

PubMed Central

Liu, Jibin; Shen, Biao; Shi, Minxin; Cai, Jing

2016-01-01

Background Several epidemiological studies have determined the associations between coffee intake level and skin cancer risk; however, the results were not yet conclusive. Herein, we conducted a systematic review and meta-analysis of the cohort and case-control studies for the association between coffee intake level and malignant melanoma (MM) risk. Methods Studies were identified through searching the PubMed and MEDLINE databases (to November, 2015). Study-specific risk estimates were pooled under the random-effects model. Results Two case-control studies (846 MM patients and 843 controls) and five cohort studies (including 844,246 participants and 5,737 MM cases) were identified. For caffeinated coffee, the pooled relative risk (RR) of MM was 0.81 [95% confidential interval (95% CI) = 0.68–0.97; P-value for Q-test = 0.003; I2 = 63.5%] for those with highest versus lowest quantity of intake. In the dose-response analysis, the RR of MM was 0.955 (95% CI = 0.912–0.999) for per 1 cup/day increment of caffeinated coffee consumption and linearity dose-response association was found (P-value for nonlinearity = 0.326). Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk (pooled RR = 0.92, 95% CI = 0.81–1.05; P-value for Q-test = 0.967; I2 = 0%; highest versus lowest quantity of intake). Conclusions This meta-analysis suggested that caffeinated coffee might have chemo-preventive effects against MM but not decaffeinated coffee. However, larger prospective studies and the intervention studies are warranted to confirm these findings. PMID:26816289

miR-26b enhances radiosensitivity of hepatocellular carcinoma cells by targeting EphA2

PubMed Central

Jin, Qiao; Li, Xiang Jun; Cao, Pei Guo

2016-01-01

Objective(s): Although low-dose radiotherapy (RT) that involves low collateral damage is more suitable for hepatocellular carcinoma (HCC) than traditional high-dose RT, but to achieve satisfactory therapeutic effect with low-dose RT, it is necessary to sensitize HCC cells to irradiation. This study was aimed to determine whether radiosensitivity of HCC cells can be enhanced using miR-26b by targeting erythropoietin producing human hepatocelluar A2 (EphA2). Materials and Methods: The levels of miR-26b and EphA2 expression in multiple HCC cell lines were assessed by qPCR and western blotting, respectively, and compared with those in a hepatic cell line. HCC 97H cells were transfected with miR-26b mimics, EphA2-ShRNA or EphA2 over-expression vector before exposure to low-dose irradiation. Results: Different degrees of miR-26b down-regulation and EphA2 up-regulation were observed in all HCC cell lines, among which the HCC 97H cell line expressed the lowest level of miR-26b and highest level of EphA2. EphA2 was verified as the target of miR-26b by dual luciferase reporter assay. HCC 97H cells transfected with miR-26b mimics or EphA2-ShRNA reduced the expression of EphA2 protein, with significantly lower cell proliferation rate and cell invasion ability and higher apoptosis rate in response to low-dose irradiation than those in the non-transfected cells. These results were reversed after EphA2 was overexpressed by transfection with the EphA2 overexpression vector. Co-transfection with miR-26b mimics and EphA2 overexpression vector barely altered EphA2 expression level and cell response to low-dose irradiation. Conclusion: These data suggest that miR-26b enhances radiosensitivity of HCC 97H cells by targeting EphA2 protein. PMID:27746866

α-Methylprednisolone conjugated cyclodextrin polymer-based nanoparticles for rheumatoid arthritis therapy

PubMed Central

Hwang, Jungyeon; Rodgers, Kathleen; Oliver, James C; Schluep, Thomas

2008-01-01

A glycinate derivative of α-methylprednisolone (MP) was prepared and conjugated to a linear cyclodextrin polymer (CDP) with a loading of 12.4% w/w. The polymer conjugate (CDP-MP) self-assembled into nanoparticles with a size of 27 nm. Release kinetics of MP from the polymer conjugate showed a half-life (t1/2) of 50 h in phosphate buffer solution (PBS) and 19 h in human plasma. In vitro, the proliferation of human lymphocytes was suppressed to a similar extent but with a delayed effect when CDP-MP was compared with free MP. In vivo, CDP-MP was administered intravenously to mice with collagen-induced arthritis and compared with free MP. CDP-MP was administered weekly for six weeks (0.07, 0.7, and 7 mg/kg/week) and MP was administered daily for six weeks (0.01, 0.1, and 1 mg/kg/day). Body weight changes were minimal in all animals. After 28 days, a significant decrease in arthritis score was observed in animals treated weekly with an intermediate or high dose of CDP-MP. Additionally, dorsoplantar swelling was reduced to baseline in animals treated with CDP-MP at the intermediate and high dose level. Histological evaluation showed a reduction in synovitis, pannus formation and disruption of architecture at the highest dose level of CDP-MP. MP administered daily at equivalent cumulative doses showed minimal efficacy in this model. This study demonstrates that conjugation of MP to a cyclodextrin-polymer may improve its efficacy, leading to lower doses and less frequent administration for a safer and more convenient management of rheumatoid arthritis. PMID:18990945

Influence of monte carlo variance with fluence smoothing in VMAT treatment planning with Monaco TPS.

PubMed

Sarkar, B; Manikandan, A; Nandy, M; Munshi, A; Sayan, P; Sujatha, N

2016-01-01

The study aimed to investigate the interplay between Monte Carlo Variance (MCV) and fluence smoothing factor (FSF) in volumetric modulated arc therapy treatment planning by using a sample set of complex treatment planning cases and a X-ray Voxel Monte Carlo-based treatment planning system equipped with tools to tune fluence smoothness as well as MCV. The dosimetric (dose to tumor volume, and organ at risk) and physical characteristic (treatment time, number of segments, and so on) of a set 45 treatment plans for all combinations of 1%, 3%, 5% MCV and 1, 3, 5 FSF were evaluated for five carcinoma esophagus cases under the study. Increase in FSF reduce the treatment time. Variation of MCV and FSF gives a highest planning target volume (PTV), heart and lung dose variation of 3.6%, 12.8% and 4.3%, respectively. The heart dose variation was highest among all organs at risk. Highest variation of spinal cord dose was 0.6 Gy. Variation of MCV and FSF influences the organ at risk (OAR) doses significantly but not PTV coverage and dose homogeneity. Variation in FSF causes difference in dosimetric and physical parameters for the treatment plans but variation of MCV does not. MCV 3% or less do not improve the plan quality significantly (physical and clinical) compared with MCV greater than 3%. The use of MCV between 3% and 5% gives similar results as 1% with lesser calculation time. Minimally detected differences in plan quality suggest that the optimum FSF can be set between 3 and 5.

Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects

PubMed Central

Gilbert, Ethel S.; Curtis, Rochelle E.; Hauptmann, Michael; Kleinerman, Ruth A.; Lynch, Charles F.; Stovall, Marilyn; Smith, Susan A.; Weathers, Rita; Andersson, Michael; Dores, Graça M.; Fraumeni, Joseph F.; Fossa, Sophie D.; Hall, Per; Hodgson, David C.; Holowaty, Eric J.; Joensuu, Heikki; Johannesen, Tom B.; Langmark, Froydis; Kaijser, Magnus; Pukkala, Eero; Rajaraman, Preetha; Storm, Hans H.; Vaalavirta, Leila; van den Belt-Dusebout, Alexandra W.; Aleman, Berthe M.; Travis, Lois B.; Morton, Lindsay M.; van Leeuwen, Flora E.

2017-01-01

To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036–0.20] with estimates of 0.049 (95% CI: 0.007–0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054–1.44) for testicular cancer and 0.096 (95% CI: −0.002–0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12–1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses. PMID:28118119

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

Myllymaeki, S.A.; Karjalainen, M.; Haavisto, T.E.

Phenolic compounds, such as 4-tert-octylphenol (OP), have been shown to interfere with rat ovarian steroidogenesis. However, little is known about steroidogenic effects of infantile OP exposure on immature ovary. The aim of the present study was to investigate the effects of infantile OP exposure on plasma FSH, LH, estradiol, and progesterone levels in 14-day-old female rats. The effect on ovarian steroidogenic acute regulatory protein (StAR) and FSH receptor (FSHr) expression was analyzed by Western blotting. Ex vivo analysis was carried out for follicular estradiol, progesterone, testosterone, and cAMP production. Sprague-Dawley rats were given OP (0, 10, 50, or 100 mg/kg)more » subcutaneously on postnatal days 6, 8, 10, and 12. On postnatal day 14, plasma FSH was decreased and progesterone increased significantly at a dose of 100 mg OP/kg. In addition, the highest OP dose advanced the time of vaginal opening in puberty. OP had no effect on infantile LH and estradiol levels or ovarian FSHr content. Ovarian StAR protein content and ex vivo hormone and cAMP production were decreased at all OP doses compared to controls. However, hormone levels recovered independent on FSH and even increased above the control level during a prolonged culture. On postnatal day 35, no statistically significant differences were seen between control and OP-exposed animals in plasma FSH, LH, estradiol, and progesterone levels, or in ovarian StAR protein content. The results indicate that the effect of OP on the infantile ovary is reversible, while more permanent effects in the hypothalamus and pituitary, as described earlier, are involved in the reduction of circulating FSH levels and premature vaginal opening.« less

Four Transgenerational Demographic Performance of Moina macrocopa Exposed to Chronic Levels of Cadmium.

PubMed

Gama-Flores, José Luis; Huidobro-Salas, María Elena; Sarma, S S S; Nandini, S

2017-01-01

In this study, we quantified intergenerational, demographic variability of Moina macrocopa subjected to cadmium stress. Exposure of M macrocopa to cadmium (0.2, 0.3, and 0.4 mg/L as CdCl 2 ) through 4 consecutive generations revealed changes in demographic responses not only in survivorship variables but also in reproductive parameters. Long-term demographic responses varied differently, depending on the demographic trait and the concentration of heavy metal in the medium. With the exception of generation time, all life history traits were significantly and adversely influenced due to increase in Cd concentrations. The average life span of M macrocopa varied up to 40% depending on Cd level and the generation of exposure. The highest gross reproductive rates were recorded in controls, while the lowest (∼30% less) were recorded at the highest Cd level. Survival-weighted net reproductive rates were reduced by nearly 50% due to Cd toxicity. The rate of population increase per day of M macrocopa was also significantly affected (∼25%) by Cd as compared to controls. This cladoceran showed a dose-response to Cd toxicity with a significance in both magnitude and frequency of offspring production.

Larval hemolymph of rhinoceros beetle, Allomyrina dichotoma, enhances insulin secretion through ATF3 gene expression in INS-1 pancreatic β-cells.

PubMed

Kim, Seung-Whan; Suh, Hyun-Woo; Yoo, Bo-Kyung; Kwon, Kisang; Yu, Kweon; Choi, Ji-Young; Kwon, O-Yu

2018-05-22

In this study, we show that INS-1 pancreatic β-cells treated for 2 h with hemolymph of larvae of rhinoceros beetle, Allomyrina dichotoma, secreted about twice as much insulin compared to control cells without such treatment. Activating transcription factor 3 (ATF3) was the highest upregulated gene in DNA chip analysis. The A. dichotoma hemolymph dose-dependently induced increased expression levels of genes encoding ATF3 and insulin. Conversely, treatment with ATF3 siRNA inhibited expression levels of both genes and curbed insulin secretion. These results suggest that the A. dichotoma hemolymph has potential for treating and preventing diabetes or diabetes-related complications.

Occupational radiation exposure in vascular interventional radiology: A complete evaluation of different body regions.

PubMed

Bacchim Neto, Fernando Antonio; Alves, Allan Felipe Fattori; Mascarenhas, Yvone Maria; Nicolucci, Patrícia; Pina, Diana Rodrigues de

2016-08-01

To perform a complete evaluation on radiation doses, received by primary and assistant medical staff, while performing different vascular interventional radiology procedures. We evaluated dose received in different body regions during three categories of vascular procedures: lower limb angiography (Angiography), lower limb percutaneous transluminal angioplasty (Angioplasty) and stent graft placement for abdominal aortic aneurysm treatment (A. A. A. Treatment). We positioned the dosimeters near the eye lens, thyroid, chest, abdomen, hands, and feet of the interventional physicians. Equivalent dose was compared with annual dose limits for workers in order to determine the maximum number of procedures per year that each physician could perform. We assessed 90 procedures. We found the highest equivalent doses in the A. A. A. Treatment, in which 90% of the evaluations indicated at least one region receiving more than 1mSv per procedure. Angioplasty was the only procedural modality that provided statistically different doses for different professionals, which is an important aspect on regards to radiological protection strategies. In comparison with the dose limits, the most critical region in all procedures was the eye lens. Since each body region of the interventionist is exposed to different radiation levels, dose distribution measurements are essential for radiological protection strategies. These results indicate that dosimeters placed in abdomen instead of chest may represent more accurately the whole body doses received by the medical staff. Additional dosimeters and a stationary shield for the eye lens are strongly recommended. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent.

PubMed

Allen, Joshua E; Crowder, Roslyn N; Crowder, Roslyn; El-Deiry, Wafik S

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer.

First-In-Class Small Molecule ONC201 Induces DR5 and Cell Death in Tumor but Not Normal Cells to Provide a Wide Therapeutic Index as an Anti-Cancer Agent

PubMed Central

Allen, Joshua E.; Crowder, Roslyn; El-Deiry, Wafik S.

2015-01-01

We previously identified ONC201 (TIC10) as a first-in-class orally active small molecule with robust antitumor activity that is currently in clinical trials in advanced cancers. Here, we further investigate the safety characteristics of ONC201 in preclinical models that reveal an excellent safety profile at doses that exceed efficacious doses by 10-fold. In vitro studies indicated a strikingly different dose-response relationship when comparing tumor and normal cells where maximal effects are much stronger in tumor cells than in normal cells. In further support of a wide therapeutic index, investigation of tumor and normal cell responses under identical conditions demonstrated large apoptotic effects in tumor cells and modest anti-proliferative effects in normal cells that were non-apoptotic and reversible. Probing the underlying mechanism of apoptosis indicated that ONC201 does not induce DR5 in normal cells under conditions that induce DR5 in tumor cells; DR5 is a pro-apoptotic TRAIL receptor previously linked to the anti-tumor mechanism of ONC201. GLP toxicology studies in Sprague-Dawley rats and beagle dogs at therapeutic and exaggerated doses revealed no dose-limiting toxicities. Observations in both species at the highest doses were mild and reversible at doses above 10-fold the expected therapeutic dose. The no observed adverse event level (NOAEL) was ≥42 mg/kg in dogs and ≥125 mg/kg in rats, which both correspond to a human dose of approximately 1.25 g assuming standard allometric scaling. These results provided the rationale for the 125 mg starting dose in dose escalation clinical trials that began in 2015 in patients with advanced cancer. PMID:26580220

Cosmic radiation exposure of biological test systems during the EXPOSE-E mission.

PubMed

Berger, Thomas; Hajek, Michael; Bilski, Pawel; Körner, Christine; Vanhavere, Filip; Reitz, Günther

2012-05-01

In the frame of the EXPOSE-E mission on the Columbus external payload facility EuTEF on board the International Space Station, passive thermoluminescence dosimeters were applied to measure the radiation exposure of biological samples. The detectors were located either as stacks next to biological specimens to determine the depth dose distribution or beneath the sample carriers to determine the dose levels for maximum shielding. The maximum mission dose measured in the upper layer of the depth dose part of the experiment amounted to 238±10 mGy, which relates to an average dose rate of 408±16 μGy/d. In these stacks of about 8 mm height, the dose decreased by 5-12% with depth. The maximum dose measured beneath the sample carriers was 215±16 mGy, which amounts to an average dose rate of 368±27 μGy/d. These values are close to those assessed for the interior of the Columbus module and demonstrate the high shielding of the biological experiments within the EXPOSE-E facility. Besides the shielding by the EXPOSE-E hardware itself, additional shielding was experienced by the external structures adjacent to EXPOSE-E, such as EuTEF and Columbus. This led to a dose gradient over the entire exposure area, from 215±16 mGy for the lowest to 121±6 mGy for maximum shielding. Hence, the doses perceived by the biological samples inside EXPOSE-E varied by 70% (from lowest to highest dose). As a consequence of the high shielding, the biological samples were predominantly exposed to galactic cosmic heavy ions, while electrons and a significant fraction of protons of the radiation belts and solar wind did not reach the samples.

Population pharmacokinetics of recombinant coagulation factor VIII-SingleChain in patients with severe hemophilia A.

PubMed

Zhang, Y; Roberts, J; Tortorici, M; Veldman, A; St Ledger, K; Feussner, A; Sidhu, J

2017-06-01

Essentials rVIII-SingleChain is a unique recombinant factor VIII (FVIII) molecule. A population pharmacokinetic model was based on FVIII activity of severe hemophilia A patients. The model was used to simulate factor VIII activity-time profiles for various dosing scenarios. The model supports prolonged dosing of rVIII-SingleChain with intervals of up to twice per week. Background Single-chain recombinant coagulation factor VIII (rVIII-SingleChain) is a unique recombinant coagulation factor VIII molecule. Objectives To: (i) characterize the population pharmacokinetics (PK) of rVIII-SingleChain in patients with severe hemophilia A; (ii) identify correlates of variability in rVIII-SingleChain PK; and (iii) simulate various dosing scenarios of rVIII-SingleChain. Patients/Methods A population PK model was developed, based on FVIII activity levels of 130 patients with severe hemophilia A (n = 91 for ≥ 12-65 years; n = 39 for < 12 years) who had participated in a single-dose PK investigation with rVIII-SingleChain 50 IU kg -1 . PK sampling was performed for up to 96 h. Results A two-compartment population PK model with first-order elimination adequately described FVIII activity. Body weight and predose level of von Willebrand factor were significant covariates on clearance, and body weight was a significant covariate on the central distribution volume. Simulations using the model with various dosing scenarios estimated that > 85% and > 93% of patients were predicted to maintain FVIII activity level above 1 IU dL -1 , at all times with three-times-weekly dosing (given on days 0, 2, and 4.5) at the lowest (20 IU kg -1 ) and highest (50 IU kg -1 ) doses, respectively. For twice weekly dosing (days 0 and 3.5) of 50 IU kg -1 rVIII-SingleChain, 62-80% of patients across all ages were predicted to maintain a FVIII activity level above 1 IU dL -1 at day 7. Conclusions The population PK model adequately characterized rVIII-SingleChain PK, and the model can be utilized to simulate FVIII activity-time profiles for various dosing scenarios. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Renal hemodynamic response to galanin: importance of elevated plasma glucose.

PubMed

Premen, A J

1989-12-01

Although recent data point to a possible indirect role for galanin in modulating renal blood flow (RBF) and fluid homeostasis in experimental animals, there have been no systematic studies exploring the possible direct effects of the peptide on the mammalian kidney. We ascertained the RBF, glomerular filtration rate (GFR) and plasma glucose responses to direct intrarenal infusion of three progressively increasing doses of synthetic galanin in anesthetized dogs. A 50 ng/kg per min dose (n = 6) failed to affect RBF, GFR or arterial plasma glucose (APG). Yet, a 100 ng/kg per min dose elevated RBF and GFR by 13 and 14%, respectively, while concomitantly increasing APG by 38%. At 200 ng/kg per min, galanin elevated RBF and GFR by 32 and 33%, respectively, while elevating APG by 57%. Intrarenal infusion of glucose (12.5 mg/kg per min; n = 6), reproducing the percentage rise in glucose (62%) elicited by the highest dose of galanin, elevated RBF and GFR by 20 and 23%, respectively. These data indicate that the elevated plasma glucose level, stimulated by galanin infusion, may account for about 63 and 70% of the RBF and GFR responses, respectively, elicited by galanin infusion at the 200 ng dose. The factors mediating the remaining renal hyperemia and hyperfiltration await resolution.

Pharmacokinetics, tissue distribution and metabolism of acriflavine and proflavine in the channel catfish (Ictalurus punctatus).

PubMed

Plakas, S M; el Said, K R; Bencsath, F A; Musser, S M; Hayton, W L

1998-06-01

1. The disposition of proflavine (PRO) and acriflavine (ACR) were examined in channel catfish after intravascular (i.v.) dosing (1 mg/kg) or waterborne exposure (10 mg/l for 4 h). 2. After i.v. dosing, plasma concentration-time profiles of parent PRO and ACR were best described by two- and three-compartment pharmacokinetic models respectively. Terminal elimination half-lives of PRO and ACR in plasma were 8.7 and 11.4 h respectively. 3. In animals dosed with 14C-PRO or 14C-ACR, total drug equivalent concentrations were highest in the excretory organs and lowest in muscle, fat and plasma. In PRO-dosed animals, residues in the liver and trunk kidney were composed primarily of glucuronosyl and acetyl conjugates of PRO; residues in muscle were composed mostly (> 95%) of the parent drug. In ACR-dosed animals, the parent compound comprised > 90% of the total residues in all tissues examined. 4. PRO and ACR were poorly absorbed in catfish during waterborne exposure. At the end of a 4-h exposure, parent PRO and ACR concentrations in muscle were 0.064 and 0.020 microgram/g respectively. Levels in muscle declined below the limit of determination (0.005 microgram/g) within 1-2 weeks.

Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS

PubMed Central

Madigan, Nicolas N.; Morris, Jonathan; Jentoft, Mark; Sorenson, Eric J.; Butler, Greg; Gastineau, Dennis; Dietz, Allan; Windebank, Anthony J.

2016-01-01

Objective: To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS). Methods: Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 × 107 (single dose) to 1 × 108 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis. Results: Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients. Conclusions: Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials. Classification of evidence: This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe. PMID:27784774

Evaluation of optimal parameters for using low-dose computed tomography to diagnose urolithiasis

NASA Astrophysics Data System (ADS)

Chen, Hui-Hsien; Yu, Cheng-Ching; Hsu, Fang-Yuh

2017-11-01

Urolithiasis is a common disease; patients suspected of suffering from urolithiasis will be examined by abdomen x-ray, Sono, Intraudio Videonous Urography (IVU) and Computed Tomography (CT). The detection rates for calculus in above examinations are respectively: 50-70% (x-ray), 50-60% (Sono), 70-90% (IVU) and 97% (CT). In addition, the effective doses are respectively: 0.63 mSv (x-ray), no radiation dose (Sono), 2.6 mSv (IVU) and 8-16 mSv (CT). Although CT has the highest detection rate for calculus, it also has the highest radiation dose. This research sought to lower the radiation dose by using CT scans with different dose conditions of standard dose (SD), 50% SD, 25% SD, and 15% SD to diagnose patients who suffer from urolithiasis and thus explore the feasibility of examining urolithiasis via CT with lower dose conditions. This research simulated the examination of patients with RANDO phantom, collocating PMMA slice phantom and pig's kidney. Fake calculuses made of five different materials of different sizes were put into the phantom and scanned individually. The results of the scanned images were given to two physicians who had many years of diagnostic experience to interpret the urolithiasis images. This study explored the different image qualities of CT with different dose conditions. In addition, this research used thermoluminescent dosimeters (TLD) to measure the radiation doses and compared the results with the dose values shown on the screen of the CT scanner to estimate the dose conversion factor (k). The research results showed that a low-dose CT was able to provide good image quality and thus have a lower radiation dose. Therefore, a low-dose CT is suggested the main examination method to diagnose patients with urolithiasis.

A comparison of the performance of digital mammography systems.

PubMed

Monnin, P; Gutierrez, D; Bulling, S; Guntern, D; Verdun, F R

2007-03-01

An objective analysis of image quality parameters was performed for six digital mammography systems. The presampled modulation transfer function (MTF), normalized noise power spectrum (NNPS), and detective quantum efficiency (DQE) for the systems were determined at different doses, for 28 kVp with a Mo/Mo or W/Al target/filter combination and 2 mm of additional aluminium filtration. The flat-panel units have higher MTF and DQE in the mid to high frequency range than standard CR systems. The highest DQE, over the whole dose range, is for the slit-scanning direct photon counting system. Dual-side read CR can overcome the inherent x-ray absorption and signal collection limitations of standard CR mammography, improving the low-frequency DQE by 40%, to the same level as full-field systems, but it does not improve the poor spatial resolution of phosphor.

Environmental radioactivity in the UK: the airborne geophysical view of dose rate estimates.

PubMed

Beamish, David

2014-12-01

This study considers UK airborne gamma-ray data obtained through a series of high spatial resolution, low altitude surveys over the past decade. The ground concentrations of the naturally occurring radionuclides Potassium, Thorium and Uranium are converted to air absorbed dose rates and these are used to assess terrestrial exposure levels from both natural and technologically enhanced sources. The high resolution airborne information is also assessed alongside existing knowledge from soil sampling and ground-based measurements of exposure levels. The surveys have sampled an extensive number of the UK lithological bedrock formations and the statistical information provides examples of low dose rate lithologies (the formations that characterise much of southern England) to the highest sustained values associated with granitic terrains. The maximum dose rates (e.g. >300 nGy h(-1)) encountered across the sampled granitic terrains are found to vary by a factor of 2. Excluding granitic terrains, the most spatially extensive dose rates (>50 nGy h(-1)) are found in association with the Mercia Mudstone Group (Triassic argillaceous mudstones) of eastern England. Geological associations between high dose rate and high radon values are also noted. Recent studies of the datasets have revealed the extent of source rock (i.e. bedrock) flux attenuation by soil moisture in conjunction with the density and porosity of the temperate latitude soils found in the UK. The presence or absence of soil cover (and associated presence or absence of attenuation) appears to account for a range of localised variations in the exposure levels encountered. The hypothesis is supported by a study of an extensive combined data set of dose rates obtained from soil sampling and by airborne geophysical survey. With no attenuation factors applied, except those intrinsic to the airborne estimates, a bias to high values of between 10 and 15 nGy h(-1) is observed in the soil data. A wide range of technologically enhanced, localised contributions to dose rate values are also apparent in the data sets. Two detailed examples are provided that reveal the detectability of site-scale environmental impacts due to former industrial activities and the high dose values (>500 nGy h(-1)) that are associated with former, small-scale Uranium mining operations. Copyright © 2014. Published by Elsevier Ltd.

Dose-response study of caffeine effects on cerebral functional activity with a specific focus on dependence.

PubMed

Nehlig, A; Boyet, S

2000-03-06

Caffeine is a behavioral stimulant consumed on a worldwide basis. The question of whether caffeine is addictive has been debated for over a decade. Caffeine acts as a mild positive reinforcer but is not consistently self-administered in humans or animals. With [14C]2-deoxyglucose autoradiography, we studied the effects of increasing doses of caffeine on cerebral glucose utilization in rats. At 1 mg/kg, caffeine activated the caudate nucleus mediating locomotion, and the raphe nuclei and locus coeruleus involved with mood and sleep. After 2.5 and 5 mg/kg caffeine, metabolic activation spread to other components of the nigrostriatal dopaminergic system, the thalamus, ventral tegmental area and amygdala. The functional activation of the shell of the nucleus accumbens, an area involved in addiction and reward, was only induced by the highest dose of caffeine, 10 mg/kg. At this dose, the activation of the shell of the nucleus accumbens occurred together with that of the core of the nucleus accumbens and of most other brain regions. These data correlate well with the known sensitivity of locomotion, mood and sleep to low doses of caffeine. They also show that low doses of caffeine which reflect the usual human level of consumption fail to activate reward circuits in the brain and thus provide functional evidence of the very low addictive potential of caffeine.

Bacteriophage preparation lytic for Shigella significantly reduces Shigella sonnei contamination in various foods

PubMed Central

Woolston, Joelle; Li, Manrong; Das, Chythanya; Sulakvelidze, Alexander

2017-01-01

ShigaShield™ is a phage preparation composed of five lytic bacteriophages that specifically target pathogenic Shigella species found in contaminated waters and foods. In this study, we examined the efficacy of various doses (9x105-9x107 PFU/g) of ShigaShield™ in removing experimentally added Shigella on deli meat, smoked salmon, pre-cooked chicken, lettuce, melon and yogurt. The highest dose (2x107 or 9x107 PFU/g) of ShigaShield™ applied to each food type resulted in at least 1 log (90%) reduction of Shigella in all the food types. There was significant (P<0.01) reduction in the Shigella levels in all phage treated foods compared to controls, except for the lowest phage dose (9x105 PFU/g) on melon where reduction was only ca. 45% (0.25 log). The genomes of each component phage in the cocktail were fully sequenced and analyzed, and they were found not to contain any “undesirable genes” including those listed in the US Code for Federal Regulations (40 CFR Ch1). Our data suggest that ShigaShield™ (and similar phage preparations with potent lytic activity against Shigella spp.) may offer a safe and effective approach for reducing the levels of Shigella in various foods that may be contaminated with the bacterium. PMID:28362863

Potential antimalarial activity of Methyl Jasmonate and its effect on lipid profiles in Plasmodium Berghei infected mice.

PubMed

Oyinloye, Oladapo E; Kosoko, Ayokulehin M; Emikpe, Benjamin; Falade, Catherine O; Ademowo, Olusegun G

2015-09-01

The antimalarial activity and lipid profiles of Methyl Jasmonate (MJ) were investigated against established malaria infection in vivo using BALB/c mice. Arteether (AE) and chloroquine (CQ) were used as reference drugs while ethanol was used as the vehicle for drug delivery for MJ. Mice treated with 10 and 25 mg/kg MJ showed a remarkable reduction in percentage parasitemia by 68.3% and 78.2% on day 10(post treatment) respectively while 45.4% and 87.2% reduction in percentage parasitemia were observed in the group treated with 50 mg/kg on day 3 and 10 (post treatment) respectively. The highest mean survival time was observed in CQ followed by AE and MJ in dose-dependent manner. A progressive decrease in packed cell volume (PCV) was observed in infected untreated mice which led to the death of all the mice by day 9 (post treatment). Infected mice treated with MJ showed reduced level of HDL and LDL compared with infected untreated group. As the dose of MJ increased in infected mice cholesterol levels increased while there was reduction in triglyceride. Overall there was marked decrease in parasitemia in Plasmodium berghei infected mice treated with graded doses of MJ but appears to have reduced antimalarial activity compared with CQ and AE.

Heavy construction equipment noise study using dosimetry and time-motion studies

NASA Astrophysics Data System (ADS)

Spencer, Ellsworth R.; Yantek, David S.

2005-09-01

Noise-induced hearing loss continues to afflict workers in many occupational settings despite longstanding recognition of the problems and well-known methods of prevention and regulations. Sound levels associated with heavy construction equipment range from 80 to 120 dB(A) and power tools commonly used in construction produce sound levels up to 115 dB(A). The focus of the research was to determine the noise exposures of heavy construction equipment operators while documenting the workers' tasks, (i.e., hauling, moving, and/or pushing construction material). Time-motion studies were performed at the construction sites and were used to correlate the noise dosage with the work performed by equipment operators. The cumulative dose for the operator was then plotted with references to work tasks, to identify the tasks that caused the greatest noise exposure. Three construction sites were examined and located in the western Pennsylvania and eastern Ohio areas. The types of construction equipment studied included asphalt pavers, backhoes, bulldozers, compaction equipment, excavators, haul trucks, telehandlers, and wheeled loaders. The results showed that bulldozer operators consistently had the highest noise exposures, ranging from a NIOSH REL (Recommended Exposure Limit) dose of 844% to 25836% and an OSHA PEL (Permissible Exposure Limit) dose of 139% to 1397%.

Is radon emission in caves causing deletions in satellite DNA sequences of cave-dwelling crickets?

PubMed

Allegrucci, Giuliana; Sbordoni, Valerio; Cesaroni, Donatella

2015-01-01

The most stable isotope of radon, 222Rn, represents the major source of natural radioactivity in confined environments such as mines, caves and houses. In this study, we explored the possible radon-related effects on the genome of Dolichopoda cave crickets (Orthoptera, Rhaphidophoridae) sampled in caves with different concentrations of radon. We analyzed specimens from ten populations belonging to two genetically closely related species, D. geniculata and D. laetitiae, and explored the possible association between the radioactivity dose and the level of genetic polymorphism in a specific family of satellite DNA (pDo500 satDNA). Radon concentration in the analyzed caves ranged from 221 to 26,000 Bq/m3. Specimens coming from caves with the highest radon concentration showed also the highest variability estimates in both species, and the increased sequence heterogeneity at pDo500 satDNA level can be explained as an effect of the mutation pressure induced by radon in cave. We discovered a specific category of nuclear DNA, the highly repetitive satellite DNA, where the effects of the exposure at high levels of radon-related ionizing radiation are detectable, suggesting that the satDNA sequences might be a valuable tool to disclose harmful effects also in other organisms exposed to high levels of radon concentration.

Radionuclides in Foods

PubMed Central

Bird, P. M.

1966-01-01

Levels of strontium-90 and cesium-137 in Canadian milk during the period 1960-64 were consistently higher than those in the United States or the United Kingdom, but levels in humans, while also higher, did not reflect the differences observed in milk. Annual dose rates of 27 millirads to bone and 4 millirads to the whole body correspond to the highest average concentrations of strontium-90 and cesium-137 so far observed. Levels of cesium-137 in the urine of residents of the Canadian North were found to increase with the increasing consumption of caribou or reindeer. Whole body counting of a few northern residents showed cesium-137 levels as high as 1000 nanocuries. It is concluded that protective actions are not needed but that studies in the North should be emphasized to provide a better basis for evaluating that particular situation. PMID:5948368

Probabilistic dose assessment of normal operations and accident conditions for an assured isolation facility in Texas

NASA Astrophysics Data System (ADS)

Arno, Matthew Gordon

Texas is investigating building a long-term waste storage facility, also known as an Assured Isolation Facility. This is an above-ground low-level radioactive waste storage facility that is actively maintained and from which waste may be retrieved. A preliminary, scoping-level analysis has been extended to consider more complex scenarios of radiation streaming and skyshine by using the computer code Monte Carlo N-Particle (MCNP) to model the facility in greater detail. Accidental release scenarios have been studied in more depth to better assess the potential dose to off-site individuals. Using bounding source term assumptions, the projected radiation doses and dose rates are estimated to exceed applicable limits by an order of magnitude. By altering the facility design to fill in the hollow cores of the prefabricated concrete slabs used in the roof over the "high-gamma rooms," where the waste with the highest concentration of gamma emitting radioactive material is stored, dose rates outside the facility decrease by an order of magnitude. With the modified design, the annual dose at the site fenceline is estimated at 86 mrem, below the 100 mrem annual limit for exposure of the public. Within the site perimeter, the dose rates are lowered sufficiently such that it is not necessary to categorize many workers and contractor personnel as radiation workers, saving on costs as well as being advisable under ALARA principles. A detailed analysis of bounding accidents incorporating information on the local meteorological conditions indicate that the maximum committed effective dose equivalent from the passage of a plume of material released in an accident at any of the cities near the facility is 59 :rem in the city of Eunice, NM based on the combined day and night meteorological conditions. Using the daytime meteorological conditions, the maximum dose at any city is 7 :rem, also in the city of Eunice. The maximum dose at the site boundary was determined to be 230 mrem using the combined day and night meteorological conditions and 33 mrem using the daytime conditions.

A protocol for EBT3 radiochromic film dosimetry using reflection scanning

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

Papaconstadopoulos, Pavlos, E-mail: pavpapac@gmail.com; Hegyi, Gyorgy; Seuntjens, Jan

2014-12-15

Purpose: To evaluate the performance of the EBT3 radiochromic film dosimetry system using reflection measurements and to suggest a calibration protocol for precise and accurate reflection film dosimetry. Methods: A set of 14 Gafchromic EBT3 film pieces were irradiated to various doses ranging from 0 to 8 Gy and subsequently scanned using both the reflection and transmission mode. Scanning resolution varied from 50 to 508 dpi (0.5–0.05 mm/pixel). Both the red and green color channels of scanned images were used to relate the film response to the dose. A sensitivity, uncertainty, and accuracy analysis was performed for all scanning modesmore » and color channels. The total uncertainty, along with the fitting and experimental uncertainty components, was identified and analyzed. A microscope resolution target was used to evaluate possible resolution losses under reflection scanning. The calibration range was optimized for reflection scanning in the low (<2 Gy) and high (>2 Gy) dose regions based on the reported results. Results: Reflection scanning using the red channel exhibited the highest sensitivity among all modes, being up to 150% higher than transmission mode in the red channel for the lowest dose level. Furthermore, there was no apparent loss in resolution between the two modes. However, higher uncertainties and reduced accuracy were observed for the red channel under reflection mode, especially at dose levels higher than 2 Gy. These uncertainties were mainly attributed to saturation effects which were translated in poor fitting results. By restricting the calibration to the 0–2 Gy dose range, the situation is reversed and the red reflection mode was superior to the transmission mode. For higher doses, the green channel in reflection mode presented comparable results to the red transmission. Conclusions: A two-color reflection scanning protocol can be suggested for EBT3 radiochromic film dosimetry using the red channel for doses less than 2 Gy and the green channel for higher doses. The precision and accuracy are significantly improved in the low dose region following such a protocol.« less

Effect of various methods for rectum delineation on relative and absolute dose-volume histograms for prostate IMRT treatment planning

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

Kusumoto, Chiaki; Ohira, Shingo; Department of Medical Physics and Engineering, Osaka University Graduate School of Medicine, Suita

2016-07-01

Several reports have dealt with correlations of late rectal toxicity with rectal dose-volume histograms (DVHs) for high dose levels. There are 2 techniques to assess rectal volume for reception of a specific dose: relative-DVH (R-DVH, %) that indicates relative volume for a vertical axis, and absolute-DVH (A-DVH, cc) with its vertical axis showing absolute volume of the rectum. The parameters of DVH vary depending on the rectum delineation method, but the literature does not present any standardization of such methods. The aim of the present study was to evaluate the effects of different delineation methods on rectal DVHs. The enrollmentmore » for this study comprised 28 patients with high-risk localized prostate cancer, who had undergone intensity-modulated radiation therapy (IMRT) with the prescription dose of 78 Gy. The rectum was contoured with 4 different methods using 2 lengths, short (Sh) and long (Lg), and 2 cross sections, rectum (Rec) and rectal wall (Rw). Sh means the length from 1 cm above the seminal vesicles to 1 cm below the prostate and Lg the length from the rectosigmoid junction to the anus. Rec represents the entire rectal volume including the rectal contents and Rw the rectal volume of the area with a wall thickness of 4 mm. We compared dose-volume parameters by using 4 rectal contour methods for the same plan with the R-DVHs as well as the A-DVHs. For the high dose levels, the R-DVH parameters varied widely. The mean of V{sub 70} for Sh-Rw was the highest (19.4%) and nearly twice as high as that for Lg-Rec (10.4%). On the contrary, only small variations were observed in the A-DVH parameters (4.3, 4.3, 5.5, and 5.5 cc for Sh-Rw, Lg-Rw, Sh-Rec, and Lg-Rec, respectively). As for R-DVHs, the parameters of V{sub 70} varied depending on the rectal lengths (Sh-Rec vs Lg-Rec: R = 0.76; Sh-Rw vs Lg-Rw: R = 0.85) and cross sections (Sh-Rec vs Sh-Rw: R = 0.49; Lg-Rec vs Lg-Rw: R = 0.65). For A-DVHs, however, the parameters of Sh rectal A-DVHs hardly changed regardless of differences in rectal length at all dose levels. Moreover, at high dose levels (V{sub 70}), the parameters of A-DVHs showed less dependence on rectal cross sections (Sh-Rec vs Sh-Rw: R = 0.66; Lg-Rec vs Lg-Rw: R = 0.59). This study showed that A-DVHs were less dependent on the delineation methods than R-DVHs, especially for evaluating the rectal dose at higher dose levels. It can therefore be assumed that, in addition to R-DVHs, A-DVHs can be used for evaluating rectal toxicity.« less

The combined use of oral medroxyprogesterone acetate and methyltestosterone in a male contraceptive trial programme.

PubMed

Bain, J; Rachlis, V; Robert, E; Khait, Z

1980-04-01

A male contraceptive trial was undertaken in 23 men using a combination of oral medroxyprogesterone acetate (MPA) and oral methyltestosterone (MeT). The men were divided into four groups according to varying drug dosages and were followed for 15 months (control - 3 months, treatment - 6 months, follow-up - 6 months). The parameters assessed included sperm count and motility, serum gonadotropins and sex steroids, and several biochemical and hematological tests. A questionnaire dealing with side-effects and changes in sexual function was administered intermittently. Although sperm count was suppressed (most dramatically at the highest drug doses, MPA 20mg,MeT 20mg), it was not suppressed to infertile levels. Sperm motility was unaltered; LH was modestly suppressed, FSH was not suppressed; testosterone was suppressed even at low doses; dihydrotestosterone responses were inconsistent. No significant biochemical abnormalities or side-effects occurred although some men experienced mild transient acne, gynecomastia and decreased testicular size. We conclude that in the doses used in this trial, the combination of MPA and MeT is not effective for male contraceptive, purposes and that higher doses may induce severe and undesirable side-effects.

Can high-dose fotemustine reverse MGMT resistance in glioblastoma multiforme?

PubMed

Gallo, Chiara; Buonerba, Carlo; Di Lorenzo, Giuseppe; Romeo, Valeria; De Placido, Sabino; Marinelli, Alfredo

2010-11-01

Glioblastoma multiforme (GBM), the highest grade malignant glioma, is associated with a grim prognosis-median overall survival is in the range 12-15 months, despite optimum treatment. Surgery to the maximum possible extent, external beam radiotherapy, and systemic temozolomide chemotherapy are current standard treatments for newly diagnosed GBM, with intracerebral delivery of carmustine wafers (Gliadel). Unfortunately, the effectiveness of chemotherapy can be hampered by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT), which confers resistance both to temozolomide and nitrosoureas, for example fotemustine and carmustine. MGMT activity can be measured by PCR and immunohistochemistry, with the former being the current validated technique. High-dose chemotherapy can deplete MGMT levels in GBM cells and has proved feasible in various trials on temozolomide, in both newly diagnosed and recurrent GBM. We here report the unique case of a GBM patient, with high MGMT expression by immunohistochemistry, who underwent an experimental, high-dose fotemustine schedule after surgery and radiotherapy. Although treatment caused two episodes of grade 3-4 thrombocytopenia, a complete response and survival of more than three years were achieved, with a 30% increase in dose intensity compared with the standard fotemustine schedule.

Evaluating the consistency of location of the most severe acute skin reaction and highest skin dose measured by thermoluminescent dosimeter during radiotherapy for breast cancer.

PubMed

Sun, Li-Min; Huang, Chih-Jen; Chen, Hsiao-Yun; Chang, Gia-Hsin; Tsao, Min-Jen

2016-01-01

We conducted this prospective study to evaluate whether the location of the most severe acute skin reaction matches the highest skin dose measured by thermoluminescent dosimeter (TLD) during adjuvant radiotherapy (RT) for patients with breast cancer after breast conservative surgery. To determine whether TLD measurement can reflect the location of the most severe acute skin reaction, 80 consecutive patients were enrolled in this prospective study. We divided the irradiated field into breast, axillary, inframammary fold, and areola/nipple areas. In 1 treatment session when obvious skin reaction occurred, we placed the TLD chips onto the 4 areas and measured the skin dose. We determined whether the highest measured skin dose area is consistent with the location of the most severe skin reaction. The McNemar test revealed that the clinical skin reaction and TLD measurement are more consistent when the most severe skin reaction occurred at the axillary area, and the p = 0.0108. On the contrary, TLD measurement of skin dose is less likely consistent with clinical observation when the most severe skin reaction occurred at the inframammary fold, breast, and areola/nipple areas (all the p > 0.05). Considering the common site of severe skin reaction over the axillary area, TLD measurement may be an appropriate way to predict skin reaction during RT. Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Safety of veralipride for the treatment of vasomotor symptoms of menopause.

PubMed

Valencia, Marcelino Hernández; Arias, María de Jesús Vega; González, Cuauhtémoc Celis; Marín, Imelda Hernández; González, Juan Humberto Martín; Campos, Enrique Rafael Morcate; Rodríguez, María Antonia Basavilvazo; Álvarez, Ignacio Morales; Vargas, María Antonia Valdés; Flores, José Braulio Everardo Otero; Haro, Samuel Santoyo; Bonilla, Manuel Cortes; Escudero, Roberto Bernardo; Campero, Rosalba Alonso

2014-05-01

Veralipride is a nonhormonal option for the treatment of vasomotor symptoms of menopause. Incidence of adverse events in a Mexican population and drug compliance according to correct use were evaluated. We carried out a longitudinal, prospective, and analytical study in Mexican women who received veralipride to treat symptoms of menopause from 2011 to 2012. There were 386 treatment cycles; 272 were assigned to dosing schedule 1, which included 20 days of treatment with 10 days of suspension, and 114 were assigned to dosing schedule 2, which included 5 days of treatment and 2 days of suspension. A total of 57 adverse events were registered during the 386-month treatment. For the 20 × 10 dosing schedule, the highest incidence was observed for anxiety (2.2%), drowsiness, and weakness (1.5%); for the 5 × 2 dosing schedule, the highest incidence was observed for drowsiness (5.3%) and headache (2.6%). The Hamilton Depression Rating Scale was used to assess the presence and severity of depression; improvement was noted. The Unified Parkinson's Disease Rating Scale was used to assess neurological movement disorders; no adverse neurological events were detected. Based on the assessments of both women and physicians, the highest frequency was observed for "very satisfied" (45.5% and 52.3%, respectively), followed by "satisfied" (23.9% and 27.3%, respectively). Both dosing schedules show acceptable safety profiles for up to 6 months of use when used according to the contraindications in the current prescribing information for standard use (2012) and recent medical literature.

Biomarkers of polycyclic aromatic hydrocarbon exposure in European coke oven workers.

PubMed

Talaska, Glenn; Thoroman, Jeff; Schuman, Brenda; Käfferlein, Heiko Udo

2014-12-01

Biomonitoring is an excellent method for capturing the results of all exposures, regardless of route. Coke oven workers include certain groups that have the potential for high exposure to polycyclic aromatic hydrocarbons (PAH) and other materials. Biomarkers of exposure to these agents include PAH metabolites as markers of internal dose and carcinogen-DNA adducts as measure of effective dose. The purpose of this study was to determine the levels of these biomarkers in persons with different job duties in a modern coke oven plant. We report that the mean levels of 1-hydroxypyrene (1HP) and carcinogen DNA adducts in the exfoliated urothelial cells of coke oven workers are increased the closer a group of workers is to the ovens and highest in the top oven workers with average 1HP level of 11.6 μg/l and 22 adducts per 10(9) unadducted nucleotides. Both 1HP and carcinogen DNA adduct levels increased in supervisors, area workers, side oven workers, top and side oven workers, and top oven workers, respectively. These data are the first to demonstrate an increase in target organ genotoxicity in coke oven workers and a relationship with other biomarkers. Future studies will determine the identity of the DNA adducts, their correlation with 1HP levels and the relationship between levels in individual workers. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Effect of gamma radiation on the growth, survival, hematology and histological parameters of rainbow trout (Oncorhynchus mykiss) larvae.

PubMed

Oujifard, Amin; Amiri, Roghayeh; Shahhosseini, Gholamreza; Davoodi, Reza; Moghaddam, Jamshid Amiri

2015-08-01

Effects of low (1, 2.5 and 5Gy) and high doses (10, 20 and 40Gy) of gamma radiation were examined on the growth, survival, blood parameters and morphological changes of the intestines of rainbow trout (Oncorhynchus mykiss) larvae (103±20mg) after 12 weeks of exposure. Negative effects of gamma radiation on growth and survival were observed as radiation level and time increased. Changes were well documented at 10 and 20Gy. All the fish were dead at the dose of 40Gy. In all the treatments, levels of red blood cells (RBC), hematocrit (HCT) and hemoglobin (HB) were significantly (P<0.05) declined as the irradiation levels increased, whereas the amount of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) did not change. No significant differences (P>0.05) were found in the levels of white blood cells (WBC), lymphocytes and monocytes. Destruction of the intestinal epithelium cells was indicated as the irradiation levels increased to 1Gy and above. The highest levels of growth, survival, specific growth rate (SGR), condition factor (CF) and protein efficiency rate (PER) were obtained in the control treatment. The results showed that gamma rays can be a potential means for damaging rainbow trout cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Lemna minor plants chronically exposed to ionising radiation: RNA-seq analysis indicates a dose rate dependent shift from acclimation to survival strategies.

PubMed

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

2017-04-01

Ecotoxicological research provides knowledge on ionising radiation-induced responses in different plant species. However, the sparse data currently available are mainly extracted from acute exposure treatments. To provide a better understanding of environmental exposure scenarios, the response to stress in plants must be followed in more natural relevant chronic conditions. We previously showed morphological and biochemical responses in Lemna minor plants continuously exposed for 7days in a dose-rate dependent manner. In this study responses on molecular (gene expression) and physiological (photosynthetic) level are evaluated in L. minor plants exposed to ionising radiation. To enable this, we examined the gene expression profiles of irradiated L. minor plants by using an RNA-seq approach. The gene expression data reveal indications that L. minor plants exposed at lower dose rates, can tolerate the exposure by triggering acclimation responses. In contrast, at the highest dose rate tested, a high number of genes related to antioxidative defense systems, DNA repair and cell cycle were differentially expressed suggesting that only high dose rates of ionising radiation drive L. minor plants into survival strategies. Notably, the photosynthetic process seems to be unaffected in L. minor plants among the tested dose rates. This study, supported by our earlier work, clearly indicates that plants shift from acclimation responses towards survival responses at increasing dose rates of ionising radiation. Copyright © 2017 Elsevier B.V. All rights reserved.

Fundamental research on the action mechanism of the 800 nm semiconductor laser on skin blackheads and coarse pores.

PubMed

Lin, Jie; Jing, Li; Zhu, Hao; Dong, Fu-Sheng

2017-01-01

The aim of the study was to determine the mechanism of action of the 800 nm semiconductor laser on skin blackheads and coarse pores. A total of 24 healthy purebred short-haired male guinea pigs, weighing 350-400 g, were selected and smeared with 0.5 ml coal tar suspension evenly by injector once daily. Treatment was continued for 14 days to form an experimental area of 8×3 cm on the back of the guinea pigs. The animals were divided into the following groups: Normal control group (NC), low-dose laser treatment group (L-LS), high-dose laser treatment group (H-LS), and Q-switched Nd:YAG treatment group (QC). Samples were extracted 1, 7 and 14 days after surgery and hematoxylin and eosin staining was used to identify the following: Epidermis, dermis, sebaceous gland change and hair follicle damage; the expression of proliferating cell nuclear antigen (PCNA) of sebaceous gland cells using immunohistochemistry; sebaceous gland cell apoptosis using TUNEL; and the protein expression of caspase-3, Bax and Bcl-2 using western blot analysis. With the extension of time, we observed inflammatory cell infiltration, an increase in hair follicle distortion and necrosis of the surrounding hair follicles. The expression levels of PCNA of the L-LS, H-LS and QC groups decreased with time. Regarding the respective time points, the NC group was highest, the L-LS and H-LS groups were next highest and the H-LS group was lowest. The difference was statistically significant (P<0.05). The apoptotic rate of the L-LS, H-LS and QC groups increased with time. With regard to the respective time points, the NC group was lowest, the L-LS and QC groups were next lowest and the H-LS group was highest. The difference was statistically significant (P<0.05). The protein expression of caspase-3, Bax and Bcl-2 of the L-LS, H-LS and QC groups increased with time. Regarding the respective time points, caspase-3 and Bax protein expression of the NC group was lowest, the L-LS and QC groups were next lowest and the H-LS group was highest. Bcl-2 protein expression of the NC group was highest, protein expression of the NC group was next highest and the H-LS group was lowest. The difference was statistically significant (P<0.05). In conclusion, the low-dose 800 nm semiconductor laser is an effective treatment on skin blackheads and coarse pores, and promotes hair follicle cell apoptosis without reducing the expression of PCNA.

Preliminary survey of radioactivity level in Thai medicinal herb plants

NASA Astrophysics Data System (ADS)

Kranrod, C.; Chanyotha, S.; Kritsananuwat, R.; Ploykrathok, T.; Pengvanich, P.; Tumnoi, Y.; Thumvijit, T.; Sriburee, S.

2017-06-01

In this research, the natural radioactivity concentrations and their respective annual effective dose of the naturally occurring radionuclides 226Ra, 228Ra and 40K in selected medicinal herb plants were investigated. Seven kinds of popular Thai medicinal herb plants had been studied: turmeric, ginger, safflower, moringa, gotu kola, garlic and alexandria senna. The radiological risk associated with the use of these medicinal plants was assessed. The activity concentrations of 226Ra, 228Ra and 40K were determined using the gamma-ray spectrometry technique. The radioactivity concentrations were found to range from less than 0.20 to 6.67 Bqkg-1 for 226Ra, less than 0.10 to 9.69 Bqkg-1 for 228Ra, and from 159.42 to 1216.25 Bqkg-1 for 40K. Gotu kola showed the highest activity concentrations of 226Ra and 228Ra, while ginger showed the highest activity concentration of 40K. The total annual effective dose due to ingestion of these herb plants were found to range from 0.0028 to 0.0097 mSvy-1 with an average value of 0.0060±0.0001 mSvy-1. The results conclude that the Thai medicinal herb plants samples from this research are considered safe in terms of the radiological hazard.

Relative changes in phosphatase activities as influenced by source and application rate of organic composts in field crops.

PubMed

Saha, Supradip; Mina, B L; Gopinath, K A; Kundu, S; Gupta, H S

2008-04-01

Potential impact of different levels and sources of organic composts on activities of phosphatases (acid and alkaline phosphatase, phosphodiesterase, and inorganic pyrophosphatase) was studied after three years of continuous application. Enzyme activities were compared with microbial biomass P and available P. Experimental plots were divided based on the organic source into three groups: those receiving farmyard manure (FYM), vermicompost (VC) and Lantana compost (LC). Microbial biomass P (11.7 g kg(-1) soil), available P (24.0 g kg(-1) soil) and acid phosphatase (1.3 mg g(-1) p-NP g(-1) soil h(-1)) was highest in highest dose of VC. Acid phosphatase activity was high in all plots, including those where microbial biomass P levels were low. Most of the phosphatase activities were significantly correlated with available P in FYM and VC. These relationships were negative for LC treatments. Results showed that application of earthworm casts is helpful in faster transformation of organic P by facilitating better environment to microbes and plant roots.

Genotoxicity Assessment of Volatile Organic Compounds in Landfill Gas Emission Using Comet Assay in Higher Terrestrial Plant.

PubMed

Na Roi-Et, Veerapas; Chiemchaisri, Wilai; Chiemchaisri, Chart

2017-02-01

Genotoxicity model is developed to assess the individual subacute toxicity of benzene, toluene, ethylbenzene, and xylene (BTEX) at very low levels as in a landfill gas. Golden Pothos (Epipremnum aureum), a higher plant, was tested under variation of benzene 54-5656 ng/L, toluene 10-4362 ng/L, ethylbenzene 28-4997 ng/L, xylene 53-4845 ng/L, for 96 h. DNA fragmentation in plant leaves were investigated via comet assay. The results show that DNA migration ratio increased with the BTEX concentrations, but at different rates. The 50% effective concentration (EC 50 ) of DNA fragmentation from the dose-response relationships indicated toluene has the highest EC 50 value and followed by benzene, xylene and ethylbenzene. Alternatively, ethylbenzene has the highest toxicity unit and followed by xylene, benzene and toluene as described by toxicity unit (TU). In conclusion, comet assay of Pothos can be used in differentiating DNA fragmentation against very low levels of BTEX in the atmosphere. Pothos is recommended for genotoxicity assessment of a low BTEX contaminated atmosphere.

Optimization of Submerged Cultivation Conditions for Production of Big Cup Culinary-Medicinal Mushroom Clitocybe maxima (Agaricomycetes) Biomass with Significant Antioxidative and Antihyperlipidemic Activities.

PubMed

Hu, Shu-Hui; Chen, Ker-Shew; Liu, Ming-Yi; Cheung, Peter Chi Keung; Wang, Jinn-Chyi; Chang, Sue-Joan

2017-01-01

In this study, a large Clitocybe maxima mycelium biomass was obtained by submerged cultivation under optimal conditions. Three test samples from lyophilized mycelia, including hot water extract (CW) and elutes from solvents with different polarity (CA and CB), were combined and used to explore antioxidant and antihyper-lipidemic activities in vitro and in vivo. The CA group showed the highest DPPH free radical scavenging activity and iron-reducing capability at concentrations of 6.0% and 3.0% (w/v), respectively. Further, the CA group showed the highest glutathione peroxidase and superoxide dismutase activities at a dose of 0.25 mg/kg body weight (CA-0.25 group) in all hyperlipidemic hamsters tested. Serum lipid levels (apart from high-density lipoprotein cholesterol levels) of hamsters in the CA-0.25 group were lower than those of hamsters in the negative control group in antihy-perlipidemic tests. Therefore, we believe that extracts from C. maxima mycelia are rich reservoirs of antioxidant and antihyperlipidemic activities.

Effect of cannabinoids on estrous cycle, ovulation and reproductive capacity of female A/J mice.

PubMed

Kostellow, A B; Ziegler, D; Kunar, J; Fujimoto, G I; Morrill, G A

1980-01-01

Virgin A/J female mice were intubated daily for 8 days (short term) or 70 days (long term) with 0, 1, 5, or 25 mg/kg delta 9-tetrahydrocannabinol (delta 9-THC) or 0, 3, 15, or 75 mg/kg crude marihuana extract (CME) in a sesame oil:polysorbate 80:saline vehicle. These dosages approximate light, moderate, and heavy human usage. Short-term exposure to CME has no significant effect on PMS-HCG-induced ovulation but appears to: (1) delay entry into proestrus at all dose levels; (2) depress serum progesterone during the luteal phase at the highest CME level used (75 mg/kg), and (3) inhibit female receptivity to males at least at the highest dosage. Long-term oral administration of CME or delta 9-thc had no significant effect on length of estrous cycles or mating (plug formation) but term pregnancies were reduced by 32 and 68% for medium and high dosages, respectively. After a 30-day recovery period, 80% of those females that failed to have successful pregnancies now became pregnant.

Individual dose monitoring of the nuclear medicine departments staff controlled by Central Laboratory for Radiological Protection.

PubMed

Szewczak, Kamil; Jednoróg, Sławomir; Krajewski, Paweł

2013-01-01

Presented paper describes the results of the individual doses measurements for ionizing radiation, carried out by the Laboratory of Individual and Environmental Doses Monitoring (PDIS) of the Central Laboratory for Radiological Protection in Warsaw (CLOR) for the medical staff employees in several nuclear medicine (NM) departments across Poland. In total there are48 NM departments in operation in Poland [1] (consultation in Nuclear Atomic Agency). Presented results were collected over the period from January 2011 to December 2011 at eight NM departments located in Krakow, Warszawa (two departments), Rzeszow (two departments), Opole, Przemysl and Gorzow Wielkopolski. For radiation monitoring three kinds of thermo luminescence dosimeters (TLD) were used. The first TLD h collected information about whole body (C) effective dose, the second dosimeter was mounted in the ring (P) meanwhile the third on the wrist (N) of the tested person. Reading of TLDs was performed in quarterly periods. As a good approximation of effective and equivalent dose assessment of operational quantities both the individual dose equivalent Hp(10) and the Hp(0.07) were used. The analysis of the data was performed using two methods The first method was based on quarterly estimations of Hp(10)q and Hp(0.07)q while the second measured cumulative annual doses Hp(10)a and Hp(0.07)a. The highest recorded value of the radiation dose for quarterly assessments reached 24.4 mSv and was recorded by the wrist type dosimeter worn by a worker involved in source preparation procedure. The mean values of Hp(10)q(C type dosimeter) and Hp(0.07)q (P and N type dosimeter) for all monitored departments were respectively 0.46 mSv and 3.29 mSv. There was a strong correlation between the performed job and the value of the received dose. The highest doses always were absorbed by those staff members who were involved in sources preparation. The highest annual cumulative dose for a particular worker in the considered time period was 4.22 mSv for Hp(10)a and 67.7 mSv for Hp(0.07)a. In 2011 no case of exceeding the allowed dose limits was noted.

Risk assessment of soils identified on firefighter turnout gear.

PubMed

Easter, Elizabeth; Lander, Deborah; Huston, Tabitha

2016-09-01

The purpose of this research was to identify the composition of soils on firefighter turnout gear and to determine the dermal exposure risks associated with the soils. Nine used Nomex hoods from the Philadelphia fire department were analyzed for the presence of trace metals and seven sets of used turnout gear were analyzed for semi-volatile organics. Turnout gear samples were removed from areas of the gear known to have high levels of dermal absorption including the collar, armpit, wrist, and crotch areas, from either the outer shell or thermal liner layers. The following compounds were detected: polycyclic aromatic hydrocarbons (PAHs), phthalate plasticizers, and polybrominated diphenyl ether flame retardants (PBDEs). A screening risk assessment was conducted by converting the measured concentrations to an estimated dermally absorbed dose based on estimates for the permeation coefficient (Kp) and an assumed firefighting exposure scenario. Benzo(a) pyrene had the highest dermal exposure risk based on carcinogenic effects and PBDE-99 had the highest dermal exposure risk based on non-carcinogenic effects. For the metals, arsenic had the highest dermal exposure risk for the use hoods.

Phase I Trial Using Proteasome Inhibitor Bortezomib and Concurrent Temozolomide and Radiotherapy for Central Nervous System Malignancies

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

Kubicek, Gregory J.; Werner-Wasik, Maria; Machtay, Mitchell

Purpose: To evaluate the toxicity and response rate of bortezomib with concurrent radiotherapy and temozolomide in the treatment of patients with central nervous system malignancies. Patients and Methods: This open-label, dose-escalation, Phase I clinical study evaluated the safety of three dose levels of intravenously administered bortezomib (0.7, 1.0, and 1.3 mg/m{sup 2}/dose) on Days 1, 4, 8, and 11 of a 21-day cycle, in addition to concurrent radiotherapy and temozolomide at a daily dose of 75 mg/m{sup 2} starting on Day 1. The primary endpoint was dose-limiting toxicity, defined as any Grade 4-5 toxicity or Grade 3 toxicity directly attributablemore » to protocol treatment, requiring hospitalization and/or radiotherapy interruption. The secondary endpoints included feasibility, non-dose-limiting toxicity, and treatment response. Results: A total of 27 patients were enrolled, 23 of whom had high-grade glioma (10 recurrent and 13 newly diagnosed). No dose-limiting toxicities were noted in any dose group, including the highest (1.3 mg/m{sup 2}/dose). The most frequent toxicities were Grade 1 and 2 stomatitis, erythema, and alopecia. All 27 patients were evaluable for response. At a median follow-up of 15.0 months, 9 patients were still alive, with a median survival of 17.4 months for all patients and 15.0 months for patients with high-grade glioma. Conclusion: Bortezomib administered at its typical 'systemic' dose (1.3 mg/m{sup 2}) is well tolerated and safe combined with temozolomide and radiotherapy when used in the treatment of central nervous system malignancies. A Phase II study to characterize efficacy is warranted.« less

Extract of medicinal mushroom Agaricus blazei Murill enhances the non-specific and adaptive immune activities in BALB/c mice.

PubMed

Ni, Wei-Ya; Wu, Ming-Fanf; Liao, Nien-Chieh; Yeh, Ming-Yang; Lu, Hsu-Feng; Hsueh, Shu-Ching; Liu, Jia-You; Huang, Yi-Ping; Chang, Chuan-Hsun; Chung, Jing-Gung

2013-01-01

Agaricus blazei Murill (AbM) is traditionally used against a wide range of conditions such as ulcerative colitis, Crohn's disease, foot-and-mouth disease and chronic hepatitis C infection. In this study, we evaluated the immunomodulatory effects of AbM. For the non-specific immune response experiments, a total of 40 female BALB/c mice were divided into control (group 1) and experimental (groups 2-4) groups of 10 animals each. Groups 2, 3 and 4 were orally-administered high (819 mg/kg), medium (273 mg/kg) and low (136.5 mg/kg) doses of AbM daily for six weeks and then six parameters related to non-specific immune response were detected. For the adaptive immune response experiments, 40 female mice were similarly divided into four groups. After six weeks of treatment, animals were immunized with the OVA immunogen. Two weeks later, splenocytes and sera were collected. Four parameters related to adaptive immune response were evaluated. We found that feeding mice with AbM extract increased the IgG level in serum, promoted phagocytosis of peritoneal macrophages and elevated the activity of Natural killer cells. We also found that the highest dose of AbM increased interleukin-2 (IL-2) levels in splenocytes and that a medium dose increased interferon-γ. The levels of interleukin-4 (IL-4) were reduced or unchanged. T-helper type 1 cytokine levels were increased. AbM increased the humoral immune response and also affected the cellular immune response. These results provide evidence that AbM can modulate innate and adaptive immunity.

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.

PubMed

McGuire, Brendan M; Zupanets, Igor A; Lowe, Mark E; Xiao, Xunjun; Syplyviy, Vasyliy A; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F

2010-06-01

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.

Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis

PubMed Central

MCGuire, Brendan M.; Zupanets, Igor A.; Lowe, Mark E.; Xiao, Xunjun; Syplyviy, Vasyliy A.; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F.

2013-01-01

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. Conclusion GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted. PMID:20512995

Carry-over of dioxins and PCBs from feed and soil to eggs at low contamination levels-- influence of mycotoxin binders on the carry-over from feed to eggs.

PubMed

Hoogenboom, L A P; Kan, C A; Zeilmaker, M J; Van Eijkeren, J; Traag, W A

2006-05-01

Laying hens were fed with compound feed containing six different levels of dioxins, dioxin-like PCBs and indicator PCBs for a period of 56 days. This was followed by a period of 56 days on clean feed. Dioxin levels in feed varied from background levels to three times the current EU tolerance limit of 0.75 ng TEQ/kg. At all dose levels a rapid increase was observed in the dioxin levels in eggs. There was a clear linear dose-response relationship between the dioxin levels in eggs and feed. The feed containing 0.4 ng TEQ dioxins per kg resulted in egg levels just above the EU limit of 3 pg TEQ/g fat. Dioxin-like and indicator PCB residues followed a pattern very similar to that of dioxins. Exposure to the highest indicator PCB level of 32 microg/kg resulted in egg levels around 300 ng/g fat. Exposure to dioxins through contaminated soil, mixed at 10% into the feed, resulted in a similar carry-over as from feed. Mycotoxin binders, mixed at 0.5% into the feed, had little effect on the carry-over of dioxins from the feed to the egg. It can be concluded that consumption of feed or soil with even moderate levels of dioxins and dioxin-like PCBs rapidly results in increased levels in eggs. The current EU dioxin limit for feed cannot guarantee egg dioxin levels below the EU-limit.

The biological effects of radium-224 injected into dogs

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

Muggenburg, B.A.; Hahn, F.F.; Boecker, B.B.

1996-08-01

A life-span study was conducted in 128 beagle dogs to determine the biological effects of intravenously injected {sup 224}Ra chloride. The {sup 224}Ra chloride was prepared by the same method used for intravenous injections in humans who were treated for ankylosing spondylitis and tuberculosis. Thus the results obtained from dogs can be compared directly to the population of treated humans, both for the elucidation of the effect of exposure rate and for comparison with other radionuclides for which data for humans are unavailable. Using equal numbers of males and females, the dogs were injected with one of four levels ofmore » {sup 224}Ra resulting in initial body burdens of approximately 13, 40, 120 or 350 kBq of {sup 224}Ra kg{sup -1} body mass. A control group of dogs was injected with diluent only. All dogs were divided further into three groups for which the amount of injected {sup 224}Ra (half-life of 3.62 days) or diluent was given in a single injection or divided equally into 10 or 50 weekly injections. As a result of these three injection schedules, the accumulation of dose from the injected {sup 224}Ra was distributed over approximately 1, 3 or 12 months. Each injection schedule included four different injection levels resulting in average absorbed {alpha}-particle doses to bone of 0.1, 0.3, 1 and 3 Gy, respectively. The primary early effect observed was a hematological dyscrasia in the dogs receiving either of the two highest injection levels. The effect was most severe in the dogs receiving a single injection of {sup 224}Ra and resulted in the death of three dogs injected at the highest level. The late-occurring biological effects were tumors. Bone tumors were the most common followed by tumors in the nasal mucosa. 52 refs., 8 figs., 8 tabs.« less

Protective effects of silymarin on epirubicin-induced mucosal barrier injury of the gastrointestinal tract.

PubMed

Sasu, Alciona; Herman, Hildegard; Mariasiu, Teodora; Rosu, Marcel; Balta, Cornel; Anghel, Nicoleta; Miutescu, Eftimie; Cotoraci, Coralia; Hermenean, Anca

2015-10-01

Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the protective effects of silymarin on epirubicin-induced mucosal barrier injury in CD-1 mice. Immunohistochemical activity of both pro-apoptotic Bax and anti-apoptotic Bcl-2 markers, together with p53, cyt-P450 expression and DNA damage analysis on stomach, small intestine and colon were evaluated. Our results indicated stronger expression for cyt P450 in all analyzed gastrointestinal tissues of Epi group, which demonstrate intense drug detoxification. Bax immunopositivity was intense in the absorptive enterocytes and lamina connective cells of the small intestine, surface epithelial cells of the stomach and also in the colonic epithelium and lamina concomitant with a decreased Bcl-2 expression in all analyzed tissues. Epirubicin-induced gastrointestinal damage was verified by a goblet cell count and morphology analysis on histopathological sections stained for mucins. In all analyzed tissues, Bax immunopositivity has been withdrawn by highest dose of silymarin concomitant with reversal of Bcl-2 intensity at a level comparable with control. p53 expression was found in all analyzed tissues and decreased by high dose of silymarin. Also, DNA internucleosomal fragmentation was observed in the Epi groups for all analyzed tissues was almost suppressed at 100 mg/kg Sy co-treatment. Histological aspect and goblet cell count were restored at a highest dose of Sy for both small and large intestine. In conclusion, our findings suggest that silymarin may prevent cellular damage of epirubicin-induced toxicity and was effective in reducing the severity indicators of gastrointestinal mucositis in mice.

Antihyperlipidemic Effect of Different Fractions Obtained from Teucrium polium Hydroalcoholic Extract in Rats.

PubMed

Safaeian, Leila; Ghanadian, Mustafa; Shafiee-Moghadam, Zahra

2018-01-01

This study was aimed to screen the antihyperlipidemic effect of different fractions of Teucrium polium to obtain the most efficient herbal fraction for isolation of bioactive constituents responsible for hypolipidemic activity. Chloroform, butanol, and aqueous fractions were obtained from hydroalcoholic extract of T. polium aerial parts using partitioning process. To induce hyperlipidemia, dexamethasone (Dex) was injected 10 mg/kg/day (s.c.) for 8 days. In the test groups, animals received 50, 100 and 150 mg/kg of T. polium hydroalcoholic extract and different fractions orally simultaneously with Dex. Serum lipid profile and hepatic marker enzymes were evaluated using biochemical kits. All treatments, especially chloroform and aqueous fractions, reversed serum lipid markers in hyperlipidemic rats. Maximum reduction in triglyceride (60.2%, P < 0.001) and maximum elevation in high-density lipoprotein (HDL) (35.0%, P < 0.01) was observed for chloroform fraction. Maximum cholesterol-lowering effect (29.0%, P < 0.001) and maximum reduction in low-density lipoprotein were found for hydroalcoholic extract (72.9%, P < 0.001). Aqueous fraction improved all lipid markers at the highest dose. Butanol fraction decreased triglyceride at the lowest dose (43.9%, P < 0.001) and increased HDL (33%, P < 0.05) at the highest dose. There was a significant increase in alanine aminotransferase and aspartate aminotransferase levels in all tested groups compared to normal group ( P < 0.001). This study showed strong antihyperlipidemic effect of various fractions derived from hydroalcoholic extract of T. polium . Chloroform and aqueous fractions may be worthy candidates for isolation of bioactive hypolipidemic constituents. However, possible hepatotoxicity should be considered for clinical application.

A retrospective analysis for patient-specific quality assurance of volumetric-modulated arc therapy plans.

PubMed

Li, Guangjun; Wu, Kui; Peng, Guang; Zhang, Yingjie; Bai, Sen

2014-01-01

Volumetric-modulated arc therapy (VMAT) is now widely used clinically, as it is capable of delivering a highly conformal dose distribution in a short time interval. We retrospectively analyzed patient-specific quality assurance (QA) of VMAT and examined the relationships between the planning parameters and the QA results. A total of 118 clinical VMAT cases underwent pretreatment QA. All plans had 3-dimensional diode array measurements, and 69 also had ion chamber measurements. Dose distribution and isocenter point dose were evaluated by comparing the measurements and the treatment planning system (TPS) calculations. In addition, the relationship between QA results and several planning parameters, such as dose level, control points (CPs), monitor units (MUs), average field width, and average leaf travel, were also analyzed. For delivered dose distribution, a gamma analysis passing rate greater than 90% was obtained for all plans and greater than 95% for 100 of 118 plans with the 3%/3-mm criteria. The difference (mean ± standard deviation) between the point doses measured by the ion chamber and those calculated by TPS was 0.9% ± 2.0% for all plans. For all cancer sites, nasopharyngeal carcinoma and gastric cancer have the lowest and highest average passing rates, respectively. From multivariate linear regression analysis, the dose level (p = 0.001) and the average leaf travel (p < 0.001) showed negative correlations with the passing rate, and the average field width (p = 0.003) showed a positive correlation with the passing rate, all indicating a correlation between the passing rate and the plan complexity. No statistically significant correlation was found between MU or CP and the passing rate. Analysis of the results of dosimetric pretreatment measurements as a function of VMAT plan parameters can provide important information to guide the plan parameter setting and optimization in TPS. Copyright © 2014 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

A retrospective analysis for patient-specific quality assurance of volumetric-modulated arc therapy plans

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

Li, Guangjun; Wu, Kui; Peng, Guang

2014-01-01

Volumetric-modulated arc therapy (VMAT) is now widely used clinically, as it is capable of delivering a highly conformal dose distribution in a short time interval. We retrospectively analyzed patient-specific quality assurance (QA) of VMAT and examined the relationships between the planning parameters and the QA results. A total of 118 clinical VMAT cases underwent pretreatment QA. All plans had 3-dimensional diode array measurements, and 69 also had ion chamber measurements. Dose distribution and isocenter point dose were evaluated by comparing the measurements and the treatment planning system (TPS) calculations. In addition, the relationship between QA results and several planning parameters,more » such as dose level, control points (CPs), monitor units (MUs), average field width, and average leaf travel, were also analyzed. For delivered dose distribution, a gamma analysis passing rate greater than 90% was obtained for all plans and greater than 95% for 100 of 118 plans with the 3%/3-mm criteria. The difference (mean ± standard deviation) between the point doses measured by the ion chamber and those calculated by TPS was 0.9% ± 2.0% for all plans. For all cancer sites, nasopharyngeal carcinoma and gastric cancer have the lowest and highest average passing rates, respectively. From multivariate linear regression analysis, the dose level (p = 0.001) and the average leaf travel (p < 0.001) showed negative correlations with the passing rate, and the average field width (p = 0.003) showed a positive correlation with the passing rate, all indicating a correlation between the passing rate and the plan complexity. No statistically significant correlation was found between MU or CP and the passing rate. Analysis of the results of dosimetric pretreatment measurements as a function of VMAT plan parameters can provide important information to guide the plan parameter setting and optimization in TPS.« less

Histomorphometric Evaluation of the Effects of Various Diode Lasers and Force Levels on Orthodontic Mini Screw Stability

PubMed Central

Isman, Eren; Taner, Lale; Kurkcu, Mehmet

2015-01-01

Abstract Objective The purpose of this study was to evaluate the effects of different laser dose and force levels on the stability of orthodontic mini screws used for anchorage, by histomorphometric analyses. Background data Low-level laser therapy speeds up blood flow, improves the mechanism of the revitalization processes, reduces the risk of infection, boosts metabolic activities, and accelerates the healing of the damaged tissue. Although there are many research studies about low-level laser therapy applications in a variety of areas, no investigations were found concerning mini screw stability using various laser dose levels with different force level applications. Methods Seventeen New Zealand white rabbits were used. A total of 68 cylindrical, self-drilling orthodontic mini screws were threaded at the fibula. Experimental subjects were divided into six groups; force application was not performed in the first three groups, whereas 150g of force was applied via nickel-titanium closed-coil springs placed between two mini screws in the other three groups. Measurements of the initial torque values (10 Ncm) were manipulated by a digital portable torque gauge. Various low-level laser doses were applied to the groups during the postoperative 10 days. After 4 weeks, bone-to-implant contact and cortical bone thickness were histomorphometrically analyzed. Results In the 150g force plus 20 J/cm2 dosage group, the highest bone-to-implant contact values were observed. (p<0.05) There were no statistically significant correlations between cortical bone thickness and bone-to-implant contact values; on the other hand, no significant difference was found among the same groups in terms of cortical bone thickness values (p>0.05). Conclusions Low-level laser therapy was noticed to induce the mini screw–bone contact area. Low-level laser therapy may be a supplementary treatment method to increase the stability of the orthodontic mini screw. PMID:25594769

Effects of different levels of wheat bran, rice bran and maize powder supplementation with saw dust on the production of shiitake mushroom (Lentinus edodes (Berk.) Singer).

PubMed

Moonmoon, Mahbuba; Shelly, Nasrat Jahan; Khan, Md Asaduzzaman; Uddin, Md Nazim; Hossain, Kamal; Tania, Mousumi; Ahmed, Saleh

2011-10-01

The cultivation of shiitake mushroom (Lentinus edodes) is increasing rapidly in Bangladesh due to its nutritional and medicinal importance with excellent flavor and longer shelf life. With the aim of increased production, we have cultivated L. edodes on saw dust (SD) supplemented with different levels (10%, 15%, 20%, 25%, 30%, 35% and 40%) of wheat bran (WB), rice bran (RB), maize powder (MP) and their combination (WB+RB+MP = 1:1:1) to investigate the growth, yield and quality of this mushroom. Most of the growth, yield and quality parameters varied significantly when mushrooms were cultivated with different levels of supplementation. The yield of mushroom was increased with the level of each supplementation upto a certain level, and then decreased. SD supplemented with 25% WB produced the highest number of fruiting bodies (34.8/500 g packet), highest biological yield (153.3/500 g packet), and biological efficiency (76.6%) of L. edodes. But the yield of the best quality mushroom was observed on SD with 40% WB supplementation; however, the qualities were not always supplementation dose dependent. In this study, we report that 25% WB supplementation with SD may be very effective for higher yield and 40% WB supplementation for better quality of L. edodes.

Effects of different levels of wheat bran, rice bran and maize powder supplementation with saw dust on the production of shiitake mushroom (Lentinus edodes (Berk.) Singer)

PubMed Central

Moonmoon, Mahbuba; Shelly, Nasrat Jahan; Khan, Md. Asaduzzaman; Uddin, Md. Nazim; Hossain, Kamal; Tania, Mousumi; Ahmed, Saleh

2010-01-01

The cultivation of shiitake mushroom (Lentinus edodes) is increasing rapidly in Bangladesh due to its nutritional and medicinal importance with excellent flavor and longer shelf life. With the aim of increased production, we have cultivated L. edodes on saw dust (SD) supplemented with different levels (10%, 15%, 20%, 25%, 30%, 35% and 40%) of wheat bran (WB), rice bran (RB), maize powder (MP) and their combination (WB+RB+MP = 1:1:1) to investigate the growth, yield and quality of this mushroom. Most of the growth, yield and quality parameters varied significantly when mushrooms were cultivated with different levels of supplementation. The yield of mushroom was increased with the level of each supplementation upto a certain level, and then decreased. SD supplemented with 25% WB produced the highest number of fruiting bodies (34.8/500 g packet), highest biological yield (153.3/500 g packet), and biological efficiency (76.6%) of L. edodes. But the yield of the best quality mushroom was observed on SD with 40% WB supplementation; however, the qualities were not always supplementation dose dependent. In this study, we report that 25% WB supplementation with SD may be very effective for higher yield and 40% WB supplementation for better quality of L. edodes. PMID:23961143

Identifying the most successful dose (MSD) in dose-finding studies in cancer.

PubMed

Zohar, Sarah; O'Quigley, John

2006-01-01

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not

Dual Inhibition of the Epidermal Growth Factor Receptor Pathway with Cetuximab and Erlotinib: A Phase I Study in Patients with Advanced Solid Malignancies

PubMed Central

Guarino, Michael J.; Schneider, Charles J.; Hosford, Martha A.; Brahmer, Julie R.; Rudin, Charles M.; Finckenstein, Friedrich Graf; Philip-Norton, Robyn E.; Lu, Haolan; Weber, Martin R.; Ettinger, David S.

2017-01-01

Purpose To determine the optimal dose of the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab that can be safely administered in combination with a standard daily dose of erlotinib in patients with advanced solid malignancies. Patients and Methods Patients with advanced solid malignancies who had failed standard chemotherapies received escalating doses of cetuximab without a loading dose (100, 200, 250 mg/m2 i.v. weekly) in combination with a fixed dose of erlotinib (150 mg daily orally) until disease progression or unacceptable toxicity. Results Twenty-two patients were treated, including 14 patients (64%) with non-small cell lung cancer. Twenty patients received combination treatment at the highest dose level for a median of 5.5 weeks (range, 1–31 weeks). One dose-limiting toxicity was observed: grade 3 skin rash. Overall, the most common adverse events (any grade, grade 3/4) were consistent with the safety profiles of the individual drugs: acneform rash (100%, 9%), diarrhea (77%, 5%), and hypomagnesemia (59%, 12%). Seven of 18 evaluable patients (38.9%) had stable disease lasting for a median of 16.6 weeks (range, 6.1–25.1 weeks). Conclusion Dual EGFR inhibition with cetuximab and erlotinib is feasible; the observed toxicities were manageable and consistent with the safety profiles of the individual drugs. The recommended doses for phase II studies are 250 mg/m2 i.v. weekly for cetuximab and 150 mg daily orally for erlotinib. PMID:19182243

Ocular Pharmacokinetics of Fluocinolone Acetonide Following Iluvien Implantation in the Vitreous Humor of Rabbits

PubMed Central

Kane, Frances E.

2015-01-01

Abstract Purpose: The purpose of this study was to evaluate the systemic and ocular pharmacokinetics (PK) of fluocinolone acetonide (FAc) following administration of Iluvien® intravitreal implants. Methods: The FAc intravitreal implant was administered to rabbits in 3 doses (0.2, 0.5, and 1.0 μg/day). The concentration of FAc was measured by a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method in plasma and ocular tissues at various time points through month 24. Results: Following administration of the 0.2 μg/day implant, FAc levels peaked in most tissues at day 2 or 8, reached approximate steady state levels by month 3 and very gradually decreased over the duration of the study. The FAc level in the aqueous humor was not measurable at most time points in the rabbit. FAc was still present in most ocular tissues at 2 years. The 0.5 and 1.0 μg/day dose groups followed the same pattern through month 9. The elimination half lives in the tissues for which it was measurable were greater than 83 days. Exposure to FAc was highest in the choroid/retinal pigment epithelium for all doses, followed by lens and retina. Conclusions: The results of this study demonstrate sustained delivery of FAc from the Iluvien intravitreal implant in the ocular tissue of rabbits. Retina and lens FAc levels with the Iluvien implant were approximately 1/10 those reported with the Retisert® implant. FAc levels in the aqueous were not measureable with Iluvien where they were measured for 12 months with Retisert. PMID:25562126

Microbiological quality and biogenic amines in ready-to-eat grilled chicken fillets under vacuum packing, freezing, and high-dose irradiation.

PubMed

Baptista, R F; Lemos, M; Teixeira, C E; Vital, H C; Carneiro, C S; Mársico, E T; Conte Júnior, C A; Mano, S B

2014-06-01

The combined effects of cooking, vacuum packing, freezing, and high-dose gamma irradiation in the microbiological conservation and in biogenic amine (BA) contents of ready-to-eat grilled breast chicken fillets are investigated in this work. After seasoning, cooking, and vacuum packing, one-third of the samples were stored at -25°C (T1). The remaining two-thirds were treated with 48 kGy, one-third being stored at -25°C (T2) and the other one-third kept at room temperature (T3). All samples were periodically analyzed to determine growth of heterotrophic aerobic mesophilic bacteria (HAMB) and levels of BA (tyramine, TYM; putrescine, PUT; cadaverine, CAD; spermidine, SPD; histamine, HYM; and spermine, SPM). Variance analysis was performed to determine significant changes in the measured data. Grilling caused HAMB counts in seasoned samples to drop from 5.3 log cfu/g to zero. In addition, no viable HAMB cells were detected in the samples throughout the 12-mo storage time. Regarding the BA analyses, the highest mean levels were measured for SPM and CAD with significantly higher levels (P < 0.05) being determined in nonirradiated samples (T1). Furthermore, significantly lower mean levels for the total content of BA were observed in the irradiated samples. Relative to T1 (7.5 ± 1.5 mg/kg), the figures were 47 ± 23% for T2 and 60 ± 25% for T3, mostly due to loss of CAD by radiolysis. Therefore, it can be concluded that the combination of grilling, vacuum packing, freezing, and high-dose gamma irradiation efficiently eliminated HAMB, while sustaining acceptable levels of BA in ready-to-eat chicken breast fillets throughout the 12 mo of storage at room temperature. Poultry Science Association Inc.

Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate.

PubMed

Waalkes, M P; Anver, M; Diwan, B A

1999-12-01

Cadmium is a known human carcinogen based on findings of lung cancer in exposed populations. A more controversial target site for cadmium is the human prostate gland, for which some studies indicate a link between cadmium exposure and cancer. Our work in various strains of Wistar rats has shown that cadmium can induce tumors in the ventral lobe of the prostate. The relevance of this type of lesion to human prostate cancer has been questioned because the ventral lobe of the rat prostate, unlike the dorsolateral lobe, has no embryological homolog in the human gland. In this study we investigated the chronic toxic and carcinogenic effects of cadmium in the Noble (NBL/Cr) rat, with particular attention to lesions of the prostate. Cadmium chloride (CdCl2) was given as a single sc injection (0, 1, 2, 4, 8, 16, or 32 micromol/kg) to groups (initially n = 30) of 10-week-old rats. Rats were observed for up to 72 weeks following exposure. In rats that were injected with the lower doses of cadmium (< or =4 micromol/kg), a clear dose-related increase in proliferative lesions of the dorsolateral prostate occurred (0 micromol/kg = 36% incidence, 1 micromol/kg = 62%, 2 micromol/kg = 65%; 4 micromol/kg = 79%; trend p < 0.003). Lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells, without stromal invasion. At higher doses (> or =8 micromol/kg) the proliferative-lesion response in the dorsolateral prostate gradually declined to near control levels (8 micromol/kg = 63%; 16 micromol/kg = 60%; 32 micromol/kg = 52%). The loss of prostatic response at the higher doses of cadmium was probably due to loss of testicular function secondary to cadmium treatment. This was reflected in a very high incidence (>90%) of lesions, indicative of testicular hypofunction, including tubular degeneration, mineralization, and interstitial (Leydig) cell tumors, at doses in excess of 16 micromol/kg. Malignant injection-site sarcomas occurred at the two highest doses of cadmium, while pituitary adenomas were elevated by cadmium exposure at the highest dose. These results show that cadmium induces proliferative lesions in the dorsolateral prostate of the Noble rat, a model having a presumed relevance to human prostate cancers.

Intensity-modulated radiation therapy and volumetric-modulated arc therapy for adult craniospinal irradiation—A comparison with traditional techniques

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

Studenski, Matthew T., E-mail: matthew.studenski@jeffersonhospital.org; Shen, Xinglei; Yu, Yan

2013-04-01

Craniospinal irradiation (CSI) poses a challenging planning process because of the complex target volume. Traditional 3D conformal CSI does not spare any critical organs, resulting in toxicity in patients. Here the dosimetric advantages of intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) are compared with classic conformal planning in adults for both cranial and spine fields to develop a clinically feasible technique that is both effective and efficient. Ten adult patients treated with CSI were retrospectively identified. For the cranial fields, 5-field IMRT and dual 356° VMAT arcs were compared with opposed lateral 3D conformal radiotherapy (3D-CRT) fields. Formore » the spine fields, traditional posterior-anterior (PA) PA fields were compared with isocentric 5-field IMRT plans and single 200° VMAT arcs. Two adult patients have been treated using this IMRT technique to date and extensive quality assurance, especially for the junction regions, was performed. For the cranial fields, the IMRT technique had the highest planned target volume (PTV) maximum and was the least efficient, whereas the VMAT technique provided the greatest parotid sparing with better efficiency. 3D-CRT provided the most efficient delivery but with the highest parotid dose. For the spine fields, VMAT provided the best PTV coverage but had the highest mean dose to all organs at risk (OAR). 3D-CRT had the highest PTV and OAR maximum doses but was the most efficient. IMRT provides the greatest OAR sparing but the longest delivery time. For those patients with unresectable disease that can benefit from a higher, definitive dose, 3D-CRT–opposed laterals are the most clinically feasible technique for cranial fields and for spine fields. Although inefficient, the IMRT technique is the most clinically feasible because of the increased mean OAR dose with the VMAT technique. Quality assurance of the beams, especially the junction regions, is essential.« less

Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial.

PubMed

Gheorghiade, Mihai; Greene, Stephen J; Butler, Javed; Filippatos, Gerasimos; Lam, Carolyn S P; Maggioni, Aldo P; Ponikowski, Piotr; Shah, Sanjiv J; Solomon, Scott D; Kraigher-Krainer, Elisabeth; Samano, Eliana T; Müller, Katharina; Roessig, Lothar; Pieske, Burkert

2015-12-01

Worsening chronic heart failure (HF) is a major public health problem. To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF). Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic. Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks. The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point. Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively. Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF. clinicaltrials.gov Identifier: NCT01951625.

Pathology, Organ Distribution, and Immune Response after Single and Repeated Intravenous Injection of Rats with Clinical-Grade Parvovirus H1

PubMed Central

Geletneky, Karsten; Leoni, Anne-Laure; Pohlmeyer-Esch, Gabriele; Loebhard, Stephanie; Baetz, Andrea; Leuchs, Barbara; Roscher, Mandy; Hoefer, Constance; Jochims, Karin; Dahm, Michael; Huber, Bernard; Rommelaere, Jean; Krebs, Ottheinz; Hajda, Jacek

2015-01-01

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID:25730754

Assessment of possible carcinogenicity of oxyfluorfen to humans using mode of action analysis of rodent liver effects.

PubMed

Stagg, Nicola J; LeBaron, Matthew J; Eisenbrandt, David L; Gollapudi, B Bhaskar; Klaunig, James E

2012-08-01

Oxyfluorfen is a herbicide that is not genotoxic and produces liver toxicity in rodents, following repeated administration at high dose levels. Lifetime rodent feeding studies reported in 1977 with low-purity oxyfluorfen (85%) showed no increase in any tumor type in rats (800 ppm, high dose) and only a marginally increased incidence of hepatocellular tumors in male CD-1 mice at the highest dose (200 ppm). To evaluate the potential carcinogenicity of the currently registered oxyfluorfen (> 98% purity), we conducted a series of short-term liver mode of action (MOA) toxicology studies in male CD-1 mice administered dietary doses of 0, 40, 200, 800, and 1600 ppm for durations of 3, 7, 10, or 28 days. MOA endpoints examined included liver weight, histopathology, cell proliferation, nuclear receptor-mediated gene expression, and other peroxisome proliferator-specific endpoints and their reversibility. Minimal liver effects were observed in mice administered doses at or below 200 ppm for up to 28 days. Increased liver weight, single-cell necrosis, cell proliferation, and peroxisomal acyl-CoA oxidase (ACO) were observed at 800 ppm after 28 days, but there was no increase in peroxisomes. Expression of Cyp2b10 and Cyp4a10 transcripts, markers of constitutive androstane receptor and peroxisome proliferator activated receptor α nuclear receptor activation, respectively, were increased at 800 and 1600 ppm after 3 or 10 days. Collectively, these data along with the negative genotoxicity demonstrate that oxyfluorfen (> 98% purity) has the potential to induce mouse liver tumors through a nongenotoxic, mitogenic MOA with a clear threshold and is not predicted to be carcinogenic in humans at relevant exposure levels.

The effect of nano-silica fertilizer concentration and rice hull ash doses on soybean (Glycine max (L.) Merrill) growth and yield

NASA Astrophysics Data System (ADS)

Suciaty, T.; Purnomo, D.; Sakya, A. T.; Supriyadi

2018-03-01

Agriculture is facing a number of challenges included limited water supply, low nutrient use efficiency, etc affected by climate change. Nano-silica is a product of nanotechnology, the frontier technologies to enhance crop productivity under climate change threats. The purpose of the research was to investigate the effects of nano silica concentration and rice hull ash on growth and yield of soybean. The experiment was conducted at Gagasari village, Cirebon, West Java from March until June 2017. The treatments were arranged by using factorial completely randomized block design with two factors. The first factor was a concentration of nano silica fertilizer consisted of four levels i.e., 0, 1.75, 2.5, and 3.75 ml.l‑1. The second factor was doses of rice hull ash consisted of four levels i.e., 0, 1, 2, and 3 ton.ha‑1. Each treatment combinations was repeated three times. The result showed that concentration of nano silica individually affected the number of leaves and number of branches, NAR and RGR, productive branches at 21, 30-45, and 35 daps, respectively. It also affected the seed dry weight plant‑1 and plot‑1. Meanwhile, doses of rice hull ash affected LAI, NAR, and RGR, 15-30, and 30-45 dap, respectively. Dry seed weight plot‑1 was also affected by doses of rice hull ash. There was an interaction effect between nano-silica concentration and doses of rice hull ash on number pods.plant‑1. Combinations of 2.5 ml.l‑1 nano-silica and 3 ton.ha‑1 of rice hull ash gave the highest number pods.plant‑1.

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

PubMed

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

2015-01-01

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

Factors in the intestinal absorption of oral cholecystopaques.

PubMed

Amberg, J R; Thompson, W M; Golberger, L; Williamson, S; Alexander, R; Bates, M

1980-01-01

Interest in the pharmacokinetics of cholecystopaques initially centered on transport from blood to bile. The data obtained in this effort have been valuable and have shown that the maximal iodine concentration achievable in the bile is quite similar for all of the currently available compounds. This concentration is, of course, dose dependent. the transport of contrast material from the bowel to the blood has been shown to be quite variable. Considerable progress was made in understanding this. The tremendous differences in absorption of iopanoic acid depending upon the pH of the administered solution was an initial revelation. The development of the concept that there is a water layer through which the cholecystopaque must pass before reaching the lipid membrane of the intestinal cell has added clarity to understanding the difference in absorption between water-soluble and water-insoluble cholecystopaques. A complete knowledge of what might enhance or inhibit absorption is not known. There is beginning to be an understanding of how intestinal dose relates to plasma levels. This should lead to an optimal dose-timing scheme for each cholecystopaque. The basic assumption is that the highest iodine concentration in the gallbladder leads to the most accurate cholecystography. If this is true, the gallbladder needs to be offered bile at the maximum concentrations during the period preceding filming. To accomplish this, the appropriate plasma level necessary for maximum excretion is needed. Experimental data suggest that our current clinical methods in regard to dose and dose timing need revision to optimize cholecystography. This revision needs to take place with a careful look at toxicity. Accepting the present premise that oral cholecystography can be improved, perhaps without a significant increase in morbidity, a fundamental question to be asked is: is it worth it?

Extremely high radon activity concentration in two adits of the abandoned uranium mine 'Podgórze' in Kowary (Sudety Mts., Poland).

PubMed

Fijałkowska-Lichwa, Lidia

2016-12-01

Measurements of radon activity concentration were conducted for a period of 6 months, from April to September 2011, in the air of two adits constituting part of the disused uranium mine 'Podgórze' in Kowary. Adits no. 19 and 19a in Kowary had been chosen owing to the occurrence within them of the highest documented radon concentrations in Poland, With levels higher than a million Bq m -3 . The main goal of this study was to characterize the level of 222 Rn activity concentration registered in selected workings of this underground space, investigate 222 Rn changes and their characteristics over selected periods of time (an hour, a day, a month, six months) and determine the effective doses, which provided the basis for estimating the risk of exposure to increased ionizing radiation for employees and visitors to the mine. The highest values of 222 Rn activity concentration inside the adits occurred at the time when visitors, guides and other members of the staff were present there. The recorded values of radon activity concentration, regardless of the time and the month when the measurement was performed, remained at an average level of 350-400 kBq m -3 . These values were far above the limit of 1.5 kBq·m -3 recommended by international guidelines. The maximum values ranged from 800 to more than 1000 kBq·m -3 . Radon activity concentration changes occurred only in periods determined by 7-h cycles of connecting and disconnecting the mechanical ventilation. For about 7 h after activating the ventilation system, between 7 a. m. and 2 p. m., and after closing the adit, between 7 p. m. and 2 a. m., 222 Rn activity concentrations decreased to levels even as low as 100 kBq·m-3. However, as early as 3-4 h after disconnecting the ventilation system, there was a sharp rise in the values of 222 Rn activity concentration, to the level higher than 800 kBq·m-3. The risk of receiving a radiation dose higher than the national standard of 1 mSv/year by members of the public occurred as soon as after spending 1 h inside the workings. The minimum monthly effective radiation dose received by every employee in the tourist adit no. 19 in Kowary was higher than 1/5 (4 mSv) of the annual effective dose allowed by Polish law (20 mSv/year). In the non-tourist adit no. 19, the minimum monthly radiation dose was more than 3 times as high as the allowed value of 4 mSv. Due to the highly disturbing and unfavourable, from a radiological protection point of view, conditions inside the disused uranium mine 'Podgórze' in Kowary, the mine manager decided to increase the efficiency of the designed mechanical ventilation system and launch measurements of radon activity concentration in the workplace. Copyright © 2016 Elsevier Ltd. All rights reserved.

Personal exposure to pesticide among workers engaged in pesticide container recycling operations.

PubMed

Guidotti, T L; Yoshida, K; Clough, V

1994-12-01

Pesticide container handling operations in western Canada were examined to determine the exposure of workers to residual pesticide in sorting, metal-container crushing, metal-container shredding, plastic-container shredding, metal washing, and metal melting. Environmental exposure monitoring and biological monitoring were applied, including measurement of pesticide deposition density on outer clothing (test coveralls and other protective wear), deposition on fabric and gauze patches under the outer clothing, inhalation of airborne pesticide residues, dislodgement of pesticide residues by hand washing, and pre- and postexposure urinary excretion of pesticide (2,4-D). Exposure levels were highly variable; some variability was accounted for by work practices or lapses in protection. The highest levels of exposure were observed for metal washing, metal crushing, and metal shredding; sorting and plastic shredding were intermediate, and metal melting was associated with very little exposure. Urinary 2,4-D excretion, as an indicator of internal dose, correlated most closely with exposure by the inhalation route, and both were highest for metal washing and shredding. Deposition of pesticide on garments was highest for metal crushing. Melting of washed metal does not appear to present a significant hazard of exposure. Recommendations are proposed for the protection of workers emphasizing health and safety guidelines, worker education, personal hygiene, exposure and health monitoring, and record-keeping, and specific recommendations for each process. These recommendations apply to all pesticide container recycling operations except melting of washed metal containers.

Myelin basic protein-messenger RNA (MBP-mRNA) expression during triethyltin-induced myelin edema.

PubMed

Veronesi, B; Jones, K; Gupta, S; Pringle, J; Mezei, C

1991-01-01

Triethyltin (TET) is a neurotoxicant that produces severe but transient cerebral edema, characterized ultrastructurally by vacuolation of the intraperiod line of central nervous system (CNS) myelin. TET has been reported to depress levels of myelin basic protein (MBP), a protein thought to play a critical role in myelin compaction. In the present study, the genomic expression (i.e., mRNA) of MBP was monitored throughout the pathogenesis of TET-induced myelin edema and recovery in Sprague-Dawley rats given a single injection of a neuropathic (8.0 mg/kg) or non-neuropathic (0.8 mg/kg) dose of TET-bromide. Levels of MBP-mRNA from the anterior and posterior brain were collected 1 hr, 3 hr, 2d, and 7d, postexposure. The optic nerve and caudal brainstem, representing anterior and posterior brain sites, respectively, were examined at the same time-points for ultrastructural evidence of edema and recovery. Our data indicate that neuropathic doses (8.0 mg/kg) of TET significantly stimulated MBP transcript throughout the brain at all exposure time-points. The magnitude and time-course of this stimulation differed in the anterior and posterior brain, with the latter region showing higher levels of MBP-mRNA. In the posterior brain, the highest levels of mRNA correlated with the appearance of edema in the caudal brainstem. In the anterior brain, MBP-mRNA levels were only marginally increased over controls. Ultrastructural evidence of myelin edema was confined to the brainstem in rats treated with neuropathic dose of TET. Intralamellar vacuolation appeared at 3 hr and 2d postexposure and could be correlated with peak levels of MBP transcript, whereas, recompacted myelin, which appeared by 7d postexposure, was associated with declining levels of the mRNA. Ultrastructural changes in the oligodendroglia were suggestive of metabolic stimulation and correlated with high MBP-mRNA levels. In summary, these data indicate that an initial genomic event in TET-induced myelin edema is stimulation of MBP transcript.

An In Vivo Study of Low-Dose Intra-Articular Tranexamic Acid Application with Prolonged Clamping Drain Method in Total Knee Replacement: Clinical Efficacy and Safety

PubMed Central

Sa-ngasoongsong, Paphon; Chanplakorn, Pongsthorn; Wongsak, Siwadol; Uthadorn, Krisorn; Panpikoon, Tanapong; Jittorntam, Paisan; Aryurachai, Katcharin; Angchaisukisiri, Pantap; Kawinwonggowit, Viroj

2015-01-01

Background. Recently, combined intra-articular tranexamic acid (IA-TXA) injection with clamping drain method showed efficacy for blood loss and transfusion reduction in total knee replacement (TKR). However, until now, none of previous studies revealed the effect of this technique on pharmacokinetics, coagulation, and fibrinolysis. Materials and Methods. An experimental study was conducted, during 2011-2012, in 30 patients undergoing unilateral TKR. Patients received IA-TXA application and then were allocated into six groups regarding clamping drain duration (2-, 4-, 6-, 8-, 10-, and 12-hours). Blood and drainage fluid were collected to measure tranexamic acid (TXA) level and related coagulation and fibrinolytic markers. Postoperative complication was followed for one year. Results. There was no significant difference of serum TXA level at 2 hour and 24 hour among groups (p < 0.05). Serum TXA level at time of clamp release was significantly different among groups with the highest level at 2 hour (p < 0.0001). There was no significant difference of TXA level in drainage fluid, postoperative blood loss, blood transfusion, and postoperative complications (p < 0.05).  Conclusions. Low-dose IA-TXA application in TKR with prolonged clamping drain method is a safe and effective blood conservative technique with only minimal systemic absorption and without significant increase in systemic absorption over time. PMID:26583092

Dose-dependent lipopolysaccharide-induced fetal brain injury in the guinea pig.

PubMed

Harnett, Erica L; Dickinson, Michelle A; Smith, Graeme N

2007-08-01

This study determined whether a lipopolysaccharide (LPS) dose-dependent increase in fetal brain injury occurs to further characterize the relationship between maternal inflammation and fetal brain injury. Pregnant guinea pigs (n = 59) at 70% gestation were injected intraperitoneally with 1, 5, 25, 50, 100, 200, or 300 microg LPS per kilogram of maternal body weight or an equivalent volume of vehicle. Animals were killed 7 days later. Maternal serum and amniotic fluid samples were assayed for proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 using enzyme-linked immunosorbent assay kits. Fetal brains (n = 72) were stained for evidence of cell death with NeuroTACS stain. Seven days after LPS injections, cytokine concentrations in maternal serum and amniotic fluid were not different (P > .05) from controls. Levels of cell death in all brain regions examined were highest following the maternal administration of 300 mug/kg LPS (P < .05). The dose effect was brain region-dependent (P < .05). A threshold of maternal infection/inflammation exists, beyond which demonstrable fetal brain injury may result.

The effect of glyphosate-based herbicide Roundup and its co-formulant, POEA, on the motoric activity of rat intestine - In vitro study.

PubMed

Chłopecka, Magdalena; Mendel, Marta; Dziekan, Natalia; Karlik, Wojciech

2017-01-01

The study was aimed at evaluating the effect of Roundup, polyoxyethylene tallow amine (POEA) and mixture of glyphosate and POEA in different levels on the motoric activity of jejunum strips. The incubation in the Roundup solutions caused a significant, mostly miorelaxant, reversible reaction of smooth muscle; only in the highest tested dose which is equivalent to the agricultural concentration (1% corresponding to 1.7g glyphosate/L) there was an irreversible disturbance of the spontaneous contractility and reactivity. The incubation in POEA solutions in the range of low doses (0.256; 1.28; 6.4mg/L) resulted in a biphasic muscle reaction (relaxation and contraction); whereas in the range of high doses, i.e. 32; 160 and 800mg/L (agricultural spray concentrations) induced only a miorelaxant, irreversible response. The results indicate very high toxicity of POEA which exceeds the toxicity of the commercial formulations. Besides, it is postulated that glyphosate and POEA may display antagonistic interaction towards the motoric activity of gastrointestinal tract. Copyright © 2016 Elsevier B.V. All rights reserved.

Activity concentrations and mean annual effective dose of foodstuffs on the island of Tenerife, Spain.

PubMed

Hernández, F; Hernández-Armas, J; Catalán, A; Fernández-Aldecoa, J C; Landeras, M I

2004-01-01

A total of 26 different food types and 12 elaborated diets were analysed by low-level gamma spectrometry to measure their content of 238U(234Th), 228Ra(228Ac), 226Ra(214Pb), 210Pb, 137Cs and 40K. The concentrations of these radionuclides measured in some imported foodstuffs were compared with those measured in some locally produced ones. Moreover, the concentrations found in the analysed foodstuffs and composite diets were compared with the data available in literature from other locations, such as Egypt, Brazil, Poland and Hong Kong. 40K contributed highest to the daily dose produced by the intake of comestibles. The largest 40K concentrations were measured in the chickpeas and beans with 380 +/- 30 and 380 +/- 20 Bq kg(-1) fresh weights, respectively. The artificial radionuclide 137Cs was measured only above detection limits in the potatoes and sweet potatoes. A mean annual effective dose of 362 microSv with a standard deviation of 110 microSv was calculated from the composite diets.

Diagnostic radiation exposure in pediatric trauma patients.

PubMed

Brunetti, Marissa A; Mahesh, Mahadevappa; Nabaweesi, Rosemary; Locke, Paul; Ziegfeld, Susan; Brown, Robert

2011-02-01

The amount of imaging studies performed for disease diagnosis has been rapidly increasing. We examined the amount of radiation exposure that pediatric trauma patients receive because they are an at-risk population. Our hypothesis was that pediatric trauma patients are exposed to high levels of radiation during a single hospital visit. Retrospective review of children who presented to Johns Hopkins Pediatric Trauma Center from July 1, 2004, to June 30, 2005. Radiographic studies were recorded for each patient and doses were calculated to give a total effective dose of radiation. All radiographic studies that each child received during evaluation, including any associated hospital admission, were included. A total of 945 children were evaluated during the study year. A total of 719 children were included in the analysis. Mean age was 7.8 (±4.6) years. Four thousand six hundred three radiographic studies were performed; 1,457 were computed tomography (CT) studies (31.7%). Average radiation dose was 12.8 (±12) mSv. We found that while CT accounted for only 31.7% of the radiologic studies performed, it accounted for 91% of the total radiation dose. Mean dose for admitted children was 17.9 (±13.8) mSv. Mean dose for discharged children was 8.4 (±7.8) mSv (p<0.0001). Burn injuries had the lowest radiation dose [1.2 (±2.6) mSv], whereas motor vehicle collision victims had the highest dose [18.8 (±14.7) mSv]. When the use of radiologic imaging is considered essential, cumulative radiation exposure can be high. In young children with relatively long life spans, the benefit of each imaging study and the cumulative radiation dose should be weighed against the long-term risks of increased exposure.

Treatment with low-dose atorvastatin, losartan, and their combination increases expression of vasoactive-related genes in rat aortas.

PubMed

Lunder, Mojca; Drevenšek, Gorazd; Černe, Darko; Marc, Janja; Janić, Miodrag; Šabovič, Mišo

2013-03-01

Recently it has been shown that statins and angiotensin receptor blockers (ARBs) at low doses express beneficial pleiotropic vascular effects. We aimed to explore whether these drugs at low doses induce the expression of vasoactive-related genes. Sixty adult Wistar rats were treated with low-dose atorvastatin (2 mg/kg), low-dose losartan (5 mg/kg), their combination or saline daily for 4, 6, or 8 weeks. Expression of the vasoactive-related genes endothelin receptor type A (EDNRA), endothelial nitric oxide synthase 3 (NOS3), inducible nitric oxide synthase 2 (NOS2), and angiotensin II receptor type 1 (AGTRL1a) was measured in isolated thoracic aortas. Expression of EDNRA gradually decreased, the lowest values being obtained after 8 weeks (low-dose atorvastatin, losartan [1.6- and 1-7-fold vs controls, respectively; both P < .05], and the combination [2.3-fold vs control, P < .001]). The highest values of NOS3 were obtained after 6 weeks (low-dose atorvastatin, losartan, and their combination, 3.1-fold, P < .01; 3.4-fold, P < .001; and 3.6-fold, P < .001 vs controls, respectively) and then declined after 8 weeks. The combination was more effective in inducing total NOS3 expression when compared to the separate drugs (1.4-fold; P < .05). Importantly, expression of NOS3 was associated with increased plasma NO levels and positively correlated with thoracic aorta relaxation. No changes in expression of NOS2 and AGTRL1a were observed. We showed that low-dose atorvastatin or losartan and especially their combination increases the expression of NOS3 and decreases the expression of EDNRA. These findings are valuable in explaining the effectiveness of the "low-dose pharmacological approach" for improvement in arterial function.

Radiolead (210)Pb and (210)Po/(210)Pb activity ratios in calcium supplements and the assessment of their possible dose to consumers.

PubMed

Strumińska-Parulska, Dagmara I

2016-08-23

This paper presents the results of pioneer study of the most popular calcium supplements as a potential additional source of radiolead (210)Pb in human diet. The analyzed calcium pharmaceutics contained organic or inorganic calcium compounds; some came from natural sources as mussels' shells, fish extracts, or sedimentary rocks. The idea was to investigate the naturally occurring (210)Pb activity in different calcium supplements and calculate the annual effective radiation dose from radiolead (210)Pb decay in consumed calcium supplement. The results showed (210)Pb concentrations in natural origin calcium supplements (especially sedimentary rocks) were significantly higher. The highest (210)Pb activity concentrations were determined in mineral tablets made from dolomite - 2.97 ± 0.18 mBq g(-1), while the lowest was observed in organic calcium compounds - both calcium lactate - 0.08 ± 0.01 and 0.13 ± 0.01 mBq g(-1). The highest annual radiation dose from (210)Pb taken with 1 tablet of calcium supplement per day was calculated for soluble calcium lactate sample - 1.19 ± 0.03 µSv year(-1), while the highest annual radiation dose from (210)Pb taken daily with 1 g of pure Ca for dolomite - 5.57 ± 0.34 µSv year(-1).

Low dose dynamic myocardial CT perfusion using advanced iterative reconstruction

NASA Astrophysics Data System (ADS)

Eck, Brendan L.; Fahmi, Rachid; Fuqua, Christopher; Vembar, Mani; Dhanantwari, Amar; Bezerra, Hiram G.; Wilson, David L.

2015-03-01

Dynamic myocardial CT perfusion (CTP) can provide quantitative functional information for the assessment of coronary artery disease. However, x-ray dose in dynamic CTP is high, typically from 10mSv to >20mSv. We compared the dose reduction potential of advanced iterative reconstruction, Iterative Model Reconstruction (IMR, Philips Healthcare, Cleveland, Ohio) to hybrid iterative reconstruction (iDose4) and filtered back projection (FBP). Dynamic CTP scans were obtained using a porcine model with balloon-induced ischemia in the left anterior descending coronary artery to prescribed fractional flow reserve values. High dose dynamic CTP scans were acquired at 100kVp/100mAs with effective dose of 23mSv. Low dose scans at 75mAs, 50mAs, and 25mAs were simulated by adding x-ray quantum noise and detector electronic noise to the projection space data. Images were reconstructed with FBP, iDose4, and IMR at each dose level. Image quality in static CTP images was assessed by SNR and CNR. Blood flow was obtained using a dynamic CTP analysis pipeline and blood flow image quality was assessed using flow-SNR and flow-CNR. IMR showed highest static image quality according to SNR and CNR. Blood flow in FBP was increasingly over-estimated at reduced dose. Flow was more consistent for iDose4 from 100mAs to 50mAs, but was over-estimated at 25mAs. IMR was most consistent from 100mAs to 25mAs. Static images and flow maps for 100mAs FBP, 50mAs iDose4, and 25mAs IMR showed comparable, clear ischemia, CNR, and flow-CNR values. These results suggest that IMR can enable dynamic CTP at significantly reduced dose, at 5.8mSv or 25% of the comparable 23mSv FBP protocol.

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.

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

Pokharel, S; Rana, S

Purpose: purpose of this study is to evaluate the effect of grid size in Eclipse AcurosXB dose calculation algorithm for SBRT lung. Methods: Five cases of SBRT lung previously treated have been chosen for present study. Four of the plans were 5 fields conventional IMRT and one was Rapid Arc plan. All five cases have been calculated with five grid sizes (1, 1.5, 2, 2.5 and 3mm) available for AXB algorithm with same plan normalization. Dosimetric indices relevant to SBRT along with MUs and time have been recorded for different grid sizes. The maximum difference was calculated as a percentagemore » of mean of all five values. All the plans were IMRT QAed with portal dosimetry. Results: The maximum difference of MUs was within 2%. The time increased was as high as 7 times from highest 3mm to lowest 1mm grid size. The largest difference of PTV minimum, maximum and mean dose were 7.7%, 1.5% and 1.6% respectively. The highest D2-Max difference was 6.1%. The highest difference in ipsilateral lung mean, V5Gy, V10Gy and V20Gy were 2.6%, 2.4%, 1.9% and 3.8% respectively. The maximum difference of heart, cord and esophagus dose were 6.5%, 7.8% and 4.02% respectively. The IMRT Gamma passing rate at 2%/2mm remains within 1.5% with at least 98% points passing with all grid sizes. Conclusion: This work indicates the lowest grid size of 1mm available in AXB is not necessarily required for accurate dose calculation. The IMRT passing rate was insignificant or not observed with the reduction of grid size less than 2mm. Although the maximum percentage difference of some of the dosimetric indices appear large, most of them are clinically insignificant in absolute dose values. So we conclude that 2mm grid size calculation is best compromise in light of dose calculation accuracy and time it takes to calculate dose.« less

Effects of prolonged daily low level mercuric chloride dosing in a horse

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

Roberts, M.C.; Seawright, A.A.

1978-12-01

Relatively few of the signs hitherto accepted as being consistent with chronic inorganic mercury intoxication were exhibited by a horse exposed to 31.3 g inorganic mercury (dose rate 0.4 mg/kg) given as mercuric chloride over 23.5 weeks. Clinical features included poor appetite, weight loss, debility, dullness, transient diarrhea and polydipsia, with little impairment of functional renal capacity. Limited degenerative changes were seen in the renal tubules. Edema and a mild inflammatory infiltrate of predominantly the mucosa and submucosa caused marked thickening of the lower alimentary tract. An approximate mean plasma inorganic mercury concentration of 400 ng/ml was quickly reached andmore » maintained. The kidneys had the highest tissue mercury content, almost 10 times greater than the liver and over 70 times that found in the intestinal mucosa and the dorsal root ganglia. 18 references, 6 figures.« less

Studies on the in vitro and in vivo hydrolysis and intramolecular aminolysis of L-aspartyl-l-phenylalanine methyl ester

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

Bouvette, R.E.

The disposition and metabolism of L-aspartyl-L-(/sup 14/C-phenyl) alanine methyl ester (/sup 14/C-APM) was studied in male Sprague-Dawley rats after a single intragastric injection. Plasma levels of /sup 14/C-activity increased slowly within the first four hours after a 5 ..mu..Ci dose. Within 2 hours after injection 90% of the /sup 14/C-activity observed in the plasma was incorporated into precipitated proteins. HPLC analysis of the deproteinated plasma showed the /sup 14/C-activity present to be in the form of phenylalanine Disposition studies of /sup 14/C-APM 4 hours after a single intragastric dose showed the highest organs of /sup 14/C-accumulation to be the blood,more » liver, stomach, and small intestine. The molecular form of the /sup 14/C-activity in the tissues was not determined.« less

Risk of ionising radiation to trainee orthopaedic surgeons.

PubMed

Khan, Ishrat A; Kamalasekaran, Senthil; Fazal, M Ali

2012-02-01

We undertook this study to determine the amount of scattered radiation received by the primary surgeon, assistant and patient during dynamic hip screw fixation for proximal femoral fractures. Data was collected from fifty patients. Five registrars were included as operating surgeon and four senior house officers as assistant surgeon. Radiation was monitored by thermo luminescent dosimeters placed on the surgeon and assistant. The approximate distance of surgeon and assistant from the operative site was measured. A dosimeter on the unaffected hip of patients measured the radiation to the patient. The results show that the surgeon's dominant hand receives the highest dose of radiation and radiation exposure is dependent on the experience of the operator. Our study concludes that exposure to radiation during this procedure is well below the toxic levels; however greater awareness is needed for harmful effects of exposure to long term low dose radiation.

The dose-response of time served in prison on mortality: New York State, 1989-2003.

PubMed

Patterson, Evelyn J

2013-03-01

I investigated the differential impact of the dose-response of length of stay on postprison mortality among parolees. Using 1989-2003 New York State parole administrative data from the Bureau of Justice Statistics on state correctional facilities, I employed multinomial logistic regression analyses and formal demographic techniques that used the life table of the populations to deduce changes in life expectancy. Each additional year in prison produced a 15.6% increase in the odds of death for parolees, which translated to a 2-year decline in life expectancy for each year served in prison. The risk was highest upon release from prison and declined over time. The time to recovery, or the lowest risk level, was approximately two thirds of the time served in prison. Incarceration reduces life span. Future research should investigate the pathways to this higher mortality and the possibilities of recovery.

Upper-Bound Radiation Dose Assessment for Military Personnel at McMurdo Station, Antarctica, between 1962 and 1979, Revision 1

DTIC Science & Technology

2016-07-29

using Equation 2 (DTRA, 2010, ED01): Dmonitor highest average HT TLD D = (2) where: TLDhighest = Highest TLD measurement during environmental...the processing of administrative claims or litigation. For use by Agency officials, employees, and authorized contractors . ROUTINE USES

Toxic Elements in Different Medicinal Plants and the Impact on Human Health.

PubMed

Brima, Eid I

2017-10-11

Local medicinal plants from Madina, Saudi Arabia, are used to cure various diseases. However, some can cause adverse health effects. Five different medicinal plants were collected in the city of Madina: mahareeb ( Cymbopogon ), sheeh ( Artemisia ), harjal ( Cynanchum argel delile ), nabipoot ( Equisetum ), and kafmariam ( Vitex agnus-castus ). In total, four toxic elements including Al, Pb, As, and Cd were analyzed using inductively coupled plasma mass spectrometry (ICP-MS). The range of recoveries fell between 86.1 and 90.6% for all measured elements. Al levels were the highest of any of the studied elements in all plant samples, with Cymbopogon showing the highest levels. The range of concentrations of Al was 156-1609 mg/kg. Cd appeared at the lowest levels in all plants samples, with Vitex agnus-castus containing this element at the highest levels. Cd concentrations were in the range of 0.01-0.10 mg/kg. A washing process lowered the toxic elements in all plants; average % recoveries were Al (47.32%), As (59.1%), Cd (62.03%), and Pb (32.40%). The calculated human health risk assessment in one dose for toxic elements in all plants was as follows: Al (1.33 × 10 -3 -5.57 × 10 -2 mg/kg.bw), Pb (0-8.86 × 10 -5 mg/kg.bw), As (3.43 × 10 -7 -1.33 × 10 -5 mg/kg.bw), and Cd (0-3.14 × 10 -6 mg/kg.bw). Medicinal plants are a source of exposure to toxic elements. However, none of the plants in this study exceeded the daily guideline set by the WHO for any element based on conventional use by the local population. We may cautiously conclude that these medicinal plants pose no risk to users based on conventional use.

[Vaccination against viral hepatitis A and B in adults aged over 40 years--antibody persistence and immune memory].

PubMed

Chlibek, R; Smetana, J; Bostíková, V; Splino, M

2011-09-01

Primary vaccination with combined vaccine against viral hepatitis A (VHA) and viral hepatitis B (VHB) induces higher anti-hepatitis B surface (anti-HBs) antibody responses and similar anti-hepatitis A virus (anti-HAV) antibody responses in adults aged over 40 years in comparison with concomitant monovalent vaccines against VHA and VHB. Th e objectives were to assess, in a clinical study, persistence of anti-HAV and anti-HBs antibodies in adults aged over 40 years four years after primary VHA/VHB vaccination and antibody response following a booster dose of the vaccine. Five hundred and ninety-six subjects aged > 40 years were vaccinated with three doses of the combined VHA/VHB vaccine at Months 0, 1, 6 (HAB group) or with concomitant VHA and VHB vaccines at Months 0, 6 and 0, 1, 6 (ENG+HAV and HBVX+VAQ, respectively). Blood samples were collected one month following primary vaccination (Month 7) and then at one-year intervals for four years after the booster dose with the same vaccine as used for the primary vaccination. The anti-HBs and anti-HAV antibody levels were determined prior to the booster dose and at days 14 and 30 after the booster dose. At Month 7, > 97% of study subjects were seropositive for anti-HAV antibodies in all groups analyzed. Four years after primary vaccination, anti-HAV antibody seropositivity persisted in > 93% of study subjects, increasing to > 99% after the booster dose. At Month 7, the highest proportion of study subjects with anti-HBs antibody levels > or = 10 mIU/ml was found in the HAB group (91.7% versus 79.7% in the ENG+HAV group versus 71.0% in the HBVX+VAQ group). Four years after vaccination, anti-HBs antibody levels of 10 mIU/ml persisted in 57.1% of the HAB study subjects in comparison with 40.1% and 26.6% of the study subjects in the ENG+HAV and HBVX+VAQ groups, respectively. One month after the booster dose, anti-HBs antibody levels increased and antibody levels > or = 10 mIU/ml was achived in 95.2% of study subjects in the HAB group, 90.5% in the ENG+HAV group and 85.3% in the HBVX+VAQ group. In the adults aged over 40 years, an adequate anti-HAV antibody response persisted for at least four years after vaccination and was higher and more sustained in those who received the combined HAB vaccine. A strong antibody response to the booster dose indicative ofthe presence of immune memory was seen in all study groups.

Inhalational botulism in rhesus macaques exposed to botulinum neurotoxin complex serotypes A1 and B1.

PubMed

Sanford, Daniel C; Barnewall, Roy E; Vassar, Michelle L; Niemuth, Nancy; Metcalfe, Karen; House, Robert V; Henderson, Ian; Shearer, Jeffry D

2010-09-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD(50)) and to estimate 50% lethal exposure concentrations relative to time (LCt(50)) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD(50) and LCt(50) for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication.

Inhalational Botulism in Rhesus Macaques Exposed to Botulinum Neurotoxin Complex Serotypes A1 and B1▿ †

PubMed Central

Sanford, Daniel C.; Barnewall, Roy E.; Vassar, Michelle L.; Niemuth, Nancy; Metcalfe, Karen; House, Robert V.; Henderson, Ian; Shearer, Jeffry D.

2010-01-01

A recombinant botulinum vaccine (rBV A/B) is being developed for protection against inhalational intoxication with botulinum neurotoxin (BoNT) complex serotype A, subtype A1 (BoNT/A1), and BoNT serotype B, subtype B1 (BoNT/B1). A critical component for evaluating rBV A/B efficacy will be the use of animal models in which the pathophysiology and dose-response relationships following aerosol exposure to well-characterized BoNT are thoroughly understood and documented. This study was designed to estimate inhaled 50% lethal doses (LD50) and to estimate 50% lethal exposure concentrations relative to time (LCt50) in rhesus macaques exposed to well-characterized BoNT/A1 and BoNT/B1. During the course of this study, clinical observations, body weights, clinical hematology results, clinical chemistry results, circulating neurotoxin levels, and telemetric parameters were documented to aid in the understanding of disease progression. The inhaled LD50 and LCt50 for BoNT/A1 and BoNT/B1 in rhesus macaques were determined using well-characterized challenge material. Clinical observations were consistent with the recognized pattern of botulism disease progression. A dose response was demonstrated with regard to the onset of these clinical signs for both BoNT/A1 and BoNT/B1. Dose-related changes in physiologic parameters measured by telemetry were also observed. In contrast, notable changes in body weight, hematology, and clinical chemistry parameters were not observed. Circulating levels of BoNT/B1 were detected in animals exposed to the highest levels of BoNT/B1; however, BoNT/A1 was not detected in the circulation at any aerosol exposure level. The rhesus macaque aerosol challenge model will be used for future evaluations of rBV A/B efficacy against inhalational BoNT/A1 and BoNT/B1 intoxication. PMID:20660138

Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants.

PubMed

Weissman, Alicia M; Levy, Barcey T; Hartz, Arthur J; Bentler, Suzanne; Donohue, Micca; Ellingrod, Vicki L; Wisner, Katherine L

2004-06-01

The available data on antidepressant levels in nursing infants were analyzed in order to calculate average infant drug levels and determine what factors influence plasma drug levels in breast-feeding infants of mothers treated with antidepressants. Electronic searches of MEDLINE, PreMEDLINE, Current Contents, Biological Abstracts, and PsycINFO from 1966 through July 2002 followed by bibliographic searches identified 67 relevant studies (two unpublished). By consensus the authors identified 57 studies of maternal plasma, breast milk, and/or infant plasma antidepressant levels from nursing mother-infant pairs, measured by liquid chromatography. Infants with recent prenatal exposure and symptomatic infants included in case reports were analyzed separately. Infant plasma levels were standardized against the average maternal level for each drug. The average infant-maternal plasma ratio was calculated for each drug, and correlations of infant plasma level to maternal dose, maternal plasma level, and breast milk level were calculated. Nortriptyline, paroxetine, and sertraline usually produce undetectable infant levels. Of drugs currently used, fluoxetine produces the highest proportion (22%) of infant levels that are elevated above 10% of the average maternal level. Based on smaller numbers, the data on citalopram indicate that it produces elevated levels in 17% of infants. The milk-to-plasma ratios for 11 antidepressants had a statistically significant negative association with the percentage of the drug bound to protein. Nortriptyline, paroxetine, and sertraline may be preferred choices in breast-feeding women. Minimizing the maternal dose may be helpful with citalopram. Current data do not support monitoring breast milk levels in individual patients. Future researchers should report maternal, breast milk, and infant antidepressant levels along with other appropriate variables.

Potential for amelioration of aflatoxin B1-induced immunotoxic effects in progeny of White Leghorn breeder hens co-exposed to vitamin E.

PubMed

Khan, Wajid Arshad; Khan, Muhammad Zargham; Khan, Ahrar; Ul Hassan, Zahoor; Saleemi, Muhammad Kashif

2014-01-01

This study was designed to evaluate the protective activity of Vitamin E (Vit E) on the immunotoxic effects induced by aflatoxin B1 (AFB1) in the progeny of breeder hens. For this purpose, 192 White Leghorn (WL) layer breeder hens were divided into 12 groups (A-L) and then fed test diets for either 1, 2 or 3 weeks. Group A was kept on basal feed (2900 Kcal/kg metabolizable energy) and served as control, while group B was offered a feed supplemented with Vit E at 100 mg/Kg. Groups C-G were offered feed containing 0.1, 0.5, 2.5, 5.0, and 10.0 mg/Kg AFB1, respectively, whereas groups H-L were offered the same dietary levels of AFB1 along with 100 mg/Kg Vit E supplementation. Hatching eggs were shifted to an incubator on a weekly basis to get progeny chicks. Hatched chicks in each group were maintained on basal ration and then subjected to different immunological assays. Lymphoproliferative responses (against PHA-P), antibody titers (against SRBC), oxidative damage to RBC, as well as phagocytic and nitrite production potential of the peritoneal macrophages from the chicks, were all adversely impacted by hen exposure to the higher doses of AFB1 or by increased intake (time) by the hens at a given dose of the toxin. No consistent ameliorative effects from Vit E were noted in these studies, i.e. effects seen against lower AFB1 doses were no longer apparent with the highest doses of AFB1. As such, for now it can be concluded that, with this particular single dose level of Vit E, AFB1-associated immunotoxic effects in progeny chicks can potentially be mitigated by dietary intake of Vit E by their hen dams. However, this is clearly an outcome that is driven by the level of the mycotoxin present in the feed. Future studies need to examine what impact higher Vit E doses than those employed herein might have in these ameliorative outcomes.

Environmental exposure to low-doses of ionizing radiation. Effects on early nephrotoxicity in mice.

PubMed

Bellés, Montserrat; Gonzalo, Sergio; Serra, Noemí; Esplugas, Roser; Arenas, Meritxell; Domingo, José Luis; Linares, Victoria

2017-07-01

Nuclear accidents of tremendous magnitude, such as those of Chernobyl (1986) and Fukushima (2011), mean that individuals living in the contaminated areas are potentially exposed to ionizing radiation (IR). However, the dose-response relationship for effects of low doses of radiation is not still established. The present study was aimed at investigating in mice the early effects of low-dose internal radiation exposure on the kidney. Adult male (C57BL/6J) mice were divided into three groups. Two groups received a single subcutaneous (s.c.) doses of cesium ( 137 Cs) with activities of 4000 and 8000Bq/kg bw. A third group (control group) received a single s.c. injection of 0.9% saline. To evaluate acute and subacute effects, mice (one-half of each group) were euthanized at 72h and 10 days post-exposure to 137 Cs, respectively. Urine samples were collected for biochemical analysis, including the measurement of F2-isoprostane (F2-IsoP) and kidney injury molecule-1 (KIM-1) levels. Moreover, the concentrations of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a sensitive marker of oxidative DNA damage, were measured in renal tissue. Urinary excretion of total protein significantly increased at 72h in mice exposed to Cs4000. Uric acid and lactate dehydrogenase (LDH) decreased significantly at both times post-exposure in animals exposed to Cs8000. After 72h and 10d of exposure to Cs4000, a significant increase in the γ-glutamil transferase (GGT) and N-acetyl-β-D-glucosaminidase (NAG) activities was observed. In turn, F2-IsoP levels increased -mainly in the Cs4000 group- at 72h post-exposure. Following irradiation ( 137 Cs), the highest level of KIM-1 was corresponded to the Cs4000 group at 72h. Likewise, the main DNA damage was detected in mice exposed to Cs4000, mainly at 10d after irradiation. The alterations observed in several biomarkers suggest an immediate renal damage following exposure to low doses of IR (given as 137 Cs). Further investigations are required to clarify the mechanisms involved in the internal IR-induced nephrotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

Radiation exposure to the eye lens of orthopaedic surgeons during various orthopaedic procedures.

PubMed

Romanova, K; Vassileva, J; Alyakov, M

2015-07-01

The aim of the present study was to assess the radiation dose to the eye lens of orthopaedic surgeons during various orthopaedic procedures and to make efforts to ensure that radiation protection is optimised. The study was performed for Fractura femoris and Fractura cruris procedures performed in orthopaedic operating theatres, as well as for fractures of wrist, ankle and hand/shoulder performed in the emergency trauma room. The highest mean value of the eye lens dose of 47.2 μSv and higher mean fluoroscopy time of 3 min, as well as the corresponding highest maximum values of 77.1 μSv and 5.0 min were observed for the Fractura femoris procedure performed with the Biplanar 500e fluoroscopy systems. At a normal workload, the estimated mean annual dose values do not exceed the annual occupational dose limit for the lens of eye, but at a heavy workload in the department, this dose limit could be achieved or exceeded. The use of protective lead glasses is recommended as they could reduce the radiation exposure of the lens of the eye. The phantom measurements demonstrated that the use of half-dose mode could additionally reduce dose to the operator's eye lens. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Occupational and diagnostic exposure to ionizing radiation and leukemia risk among German uranium miners.

PubMed

Möhner, Matthias; Gellissen, Johannes; Marsh, James W; Gregoratto, Demetrio

2010-09-01

Lung cancer is a well-known effect of radon exposure in uranium mines. However, little is known about the induction of leukemia by radiation exposure in mines. Moreover, miners usually have occupational medical checkup programs that include chest x-ray examinations. Therefore, the aim of the present study was to re-examine leukemia risk among miners, taking into account exposure to x rays for diagnostic purposes. The data used were from a previously analyzed individually matched case-control study of former uranium miners in East Germany with 377 cases and 980 controls. Additionally, data on x-ray examinations were taken from medical records for most of the subjects. Finally, the absorbed dose to red bone marrow was calculated considering both occupational and diagnostic exposures. Using conditional logistic regression models, a moderately but not statistically significant elevated risk was seen in the dose category above 200 mGy for the combined dose from both sources [odds ratio (OR) = 1.33, 90% confidence interval (CI): (0.82-2.14)]. Ignoring the dose accumulated in the recent 20 y, the risk in the highest dose category (>105 mGy) was higher [OR = 1.77, 90% CI: (1.06-2.95)]. Ignoring diagnostic exposure yielded similar results. For the highest dose category (absorbed dose lagged by 20 y) the risk was more than doubled [OR = 2.64, 90% CI: (1.60-4.35)].

Pediatric Phantom Dosimetry of Kodak 9000 Cone-beam Computed Tomography.

PubMed

Yepes, Juan F; Booe, Megan R; Sanders, Brian J; Jones, James E; Ehrlich, Ygal; Ludlow, John B; Johnson, Brandon

2017-05-15

The purpose of the study was to evaluate the radiation dose of the Kodak 9000 cone-beam computed tomography (CBCT) device for different anatomical areas using a pediatric phantom. Absorbed doses resulting from maxillary and mandibular region three by five cm CBCT volumes of an anthropomorphic 10-year-old child phantom were acquired using optical stimulated dosimetry. Equivalent doses were calculated for radiosensitive tissues in the head and neck area, and effective dose for maxillary and mandibular examinations were calculated following the 2007 recommendations of the International Commission on Radiological Protection (ICRP). Of the mandibular scans, the salivary glands had the highest equivalent dose (1,598 microsieverts [μSv]), followed by oral mucosa (1,263 μSv), extrathoracic airway (pharynx, larynx, and trachea; 859 μSv), and thyroid gland (578 μSv). For the maxilla, the salivary glands had the highest equivalent dose (1,847 μSv), followed closely by oral mucosa (1,673 μSv), followed by the extrathoracic airway (pharynx, larynx, and trachea; 1,011 μSv) and lens of the eye (202 μSv). Compared to previous research of the Kodak 9000, completed with the adult phantom, a child receives one to three times more radiation for mandibular scans and two to 10 times more radiation for maxillary scans.

In vitro effect of low-level laser on odontoblast-like cells

NASA Astrophysics Data System (ADS)

Oliveira, C. F.; Basso, F. G.; Lins, E. C.; Kurachi, C.; Hebling, J.; Bagnato, V. S.; de Souza Costa, C. A.

2011-02-01

The aim of this study was to evaluate the metabolism of odontoblast-like MDPC-23 cells subjected to direct LLL irradiation. The cells were seeded (20,000 cells/well) in 24-well plates and incubated for 24 hours at 37°C. After this period, the culture medium (DMEM) was replaced by fresh DMEM supplemented with 2 or 5% (stress induction by nutritional deficit) or 10% fetal bovine serum (FBS). The cells were exposed to laser doses of 2, 4, 10, 15 and 25 J/cm2 from a near infrared InGaAsP diode laser prototype (LASERTable; 780±3 nm, 40 mW). One control group (sham irradiation) was established for each experimental condition (laser dose x FBS supplementation). Three and 72 hours after the last irradiation, cells were analyzed with respect to metabolism, morphology, total protein expression and alkaline phosphatase (ALP) activity. Higher metabolism and total protein expression were observed 72 hours after the last irradiation at the doses of 15 and 25 J/cm2 (Mann-Whitney; p < 0.05). Higher ALP activity was obtained with 5% FBS when the cells were irradiated with doses of 2 and 10 J/cm2. For the dose of 25 J/cm2, the highest ALP activity was observed with 10% FBS. It was concluded that the LLLT parameters used in this study stimulated the metabolic activity of the MDPC-23 cells, especially at the doses of 15 and 25 J/cm2.

Investigation of the effect of traditional Chinese medicine on pain and inflammation in chronic nonbacterial prostatitis in rats.

PubMed

Liu, Y-J; Song, G-H; Liu, G T

2016-08-01

According to traditional Chinese medicine, the symptoms of chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CNP/CPPS) may be treated using a cocktail of herbs that stimulate blood circulation ('activating blood circulation formula'). We investigated the effect of three doses of this formula on a rat model of CNP/CPPS. Male Wistar rats were injected with a saline extract of male sex accessory glands on days 0 and 30 to induce prostatitis and then treated daily by gavage between days 32 and 60. Treatment with low, medium and high doses of activating blood circulation formula resulted in an almost total rescue of paw withdrawal threshold at day 60, and treatment with the highest dose also significantly decreased prostate inflammation (assessed histopathologically). We further observed elevated serum prostaglandin E2 levels in the CNP/CPPS model which decreased upon high-dose treatment, and increased Cox-2 expression in the prostate and spinal cord dorsal horn which was rescued in both tissues in the high-dose group and in the prostate in the medium-dose group. These results shed light on a possible mechanism by which activating blood circulation therapy may alleviate pain in a rat model of CNP/CPPS by downregulating Cox-2 expression in the spinal cord, thereby raising the pain threshold. Further research will be needed to fully characterise the mechanism by which activating blood circulation therapy produces this therapeutic effect. © 2016 Blackwell Verlag GmbH.

Mold and aflatoxin reduction by gamma radiation of packed hot peppers and their evolution during storage.

PubMed

Iqbal, Qumer; Amjad, Muhammad; Asi, Muhammad Rafique; Ariño, Agustin

2012-08-01

The effect of gamma radiation on moisture content, total mold counts, Aspergillus counts, and aflatoxins of three hot pepper hybrids (Sky Red, Maha, and Wonder King) was investigated. Whole dried peppers packed in polyethylene bags were gamma irradiated at 0 (control), 2, 4, and 6 kGy and stored at 25°C for 90 days. Gamma radiation proved to be effective in reducing total mold and Aspergillus counts in a dose-dependent relationship. Total mold counts in irradiated peppers immediately after treatments were significantly lowered compared with those in nonirradiated samples, achieving 90 and 99% reduction at 2- and 4-kGy doses, respectively. Aspergillus counts were significantly reduced, by 93 and 97%, immediately after irradiation at doses of 2 and 4 kGy, respectively. A radiation dose of 6 kGy completely eliminated the population of total molds and Aspergillus fungi. The evolution of total molds in control and irradiated samples indicated no further fungal proliferation during 3 months of storage at 25°C. Aflatoxin levels were slightly affected by radiation doses of 2 and 4 kGy and showed a nonsignificant reduction of 6% at the highest radiation dose of 6 kGy. The distinct effectiveness of gamma radiation in molds and aflatoxins can be explained by the target theory of food irradiation, which states that the likelihood of a microorganism or a molecule being inactivated by gamma rays increases as its size increases.

Adrenal hormones in rats before and after stress-experience: effects of ipsapirone.

PubMed

Korte, S M; Bouws, G A; Bohus, B

1992-06-01

The present study was designed to investigate the effects of the anxiolytic 5-HT1A receptor agonist ipsapirone on the hormonal responses in rats under nonstress and stress conditions by means of repeated blood sampling through an intracardiac catheter. Ipsapirone was given in doses of 2.5, 5, 10, and 20 mg/kg (IP) under nonstress conditions in the home cages of the rats. Plasma corticosterone levels increased in a dose-dependent way in the dose range of 5 to 20 mg/kg, whereas the plasma catecholamines were only significantly increased with the highest dose of the drug. The effect of ipsapirone in control and in stressed rats was studied with the selected dose of 5 mg/kg. Conditioned fear of inescapable electric footshock (0.6 mA, AC for 3 s) given one day earlier was used as stressor. Surprisingly, ipsapirone potentiated the magnitude of the neuroendocrine responses. Rats receiving an inescapable footshock 1 day earlier showed a further elevated corticosterone response to the 5-HT1A receptor agonist ipsapirone even before exposing them to the conditioned stress situation. The present findings suggest that if an animal has no possibilities to escape or avoid a noxious event, functional hypersensitivity will develop in the serotonergic neuronal system, which is reflected in the increased responsiveness of the HPA axis to a 5-HT1A agonist challenge.

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

PubMed

Kletzl, H; Guenther, A; Höflich, A; Höflich, C; Frystyk, J; Staack, R F; Schick, E; Wandel, C; Bleich, N; Metzger, F

2017-04-01

This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

A new biostimulation approach based on the concept of remaining P for soil bioremediation.

PubMed

Júlio, Aline Daniela Lopes; Fernandes, Rita de Cássia Rocha; Costa, Maurício Dutra; Neves, Júlio César Lima; Rodrigues, Edmo Montes; Tótola, Marcos Rogério

2018-02-01

C:N:P ratio is generally adopted to estimate the amount of nitrogen and phosphorus to be added to soils to accelerate biodegradation of organic contaminants. However, differences in P fixation among soils lead to varying amounts of available P when a specific dose of the element is applied to different soils. Thus, the application of fertilizers to achieve a previously established C:P ratio leads to biodegradation rates that can be lower than the theoretical maximum. In this study, we developed an equation to estimate the dose of P required to maximize organic contaminant biodegradation in soils as a function of remaining P (P-rem), using diesel as a model contaminant. The soils were contaminated with diesel and received six doses of P. CO 2 emission was used to estimate biodegradation of hydrocarbons. Biodegradation increased with P doses. The P level that provided the highest hydrocarbon biodegradation rate showed linear and negative correlation with P-rem. The result shows that the requirement for P decreases as the P-rem of the soil increases (or the P-fixing capacity decreases). The dose of P recommended to maximize hydrocarbon biodegradation rate in soil can be estimated by the formula P (mg/dm 3 ) = 436.5-5.39 × P-rem (mg/L). Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers.

PubMed

Piscitelli, Stephen C; Formentini, Elizabeth; Burstein, Aaron H; Alfaro, Raul; Jagannatha, Shyla; Falloon, Judith

2002-05-01

To characterize the pharmacokinetics of indinavir in the presence and absence of milk thistle and to determine the offset of any effect of milk thistle on indinavir disposition. Prospective open-label drug interaction study. Outpatient clinic. Ten healthy volunteers. Intervention. Blood samples were collected over 8 hours after the volunteers took four doses of indinavir 800 mg every 8 hours on an empty stomach for baseline pharmacokinetics. This dosing and sampling were repeated after the subjects took milk thistle 175 mg (confirmed to contain silymarin 153 mg, the active ingredient) 3 times/day for 3 weeks. After an 11-day washout, indinavir dosing and blood sampling were repeated to evaluate the offset of any potential interaction. Indinavir concentrations were measured by using a validated high-performance liquid chromatography method. The following pharmacokinetic parameters were determined: highest concentration (Cmax), hour-0 concentration, hour-8 concentration (C8), time to reach Cmax, and area under the plasma concentration-time curve over the 8-hour dosing interval (AUC8). Milk thistle did not alter significantly the overall exposure of indinavir, as evidenced by a 9% reduction in the indinavir AUC8 after 3 weeks of dosing with milk thistle, although the least squares mean trough level (C8) was significantly decreased by 25%. Milk thistle in commonly administered dosages should not interfere with indinavir therapy in patients infected with the human immunodeficiency virus.

Evaluation of safety and immunogenicity of a live attenuated tetravalent (G1-G4) Bovine-Human Reassortant Rotavirus vaccine (BRV-TV) in healthy Indian adults and infants.

PubMed

Dhingra, M S; Kundu, R; Gupta, M; Kanungo, S; Ganguly, N; Singh, M P; Bhattacharya, M K; Ghosh, R; Kumar, R; Sur, D; Chadha, S M; Saluja, T

2014-08-11

Rotavirus infections, prevalent in human populations worldwide are mostly caused by Group A viruses. Live attenuated rotavirus vaccines are highly effective in preventing severe rotavirus gastroenteritis. However, the cost of these vaccines and local availability can be a barrier for widespread adoption in public health programs in developing countries where infants suffer a heavy burden of rotavirus related morbidity and mortality. A phase I/II study was carried out with the long term aim to produce a locally licensed vaccine which is equally safe and immunogenic as compared to available licensed vaccines. This study was conducted in two cohorts. In the first cohort, 20 healthy adults were administered a single dose of the rotavirus vaccine (highest antigen concentration planned for infants) or placebo and were followed up for 10 days for safety. Following demonstration of safety in adult volunteers, 100 healthy infants were recruited (cohort 2) and randomly divided into five equal study groups. They were administered three doses of either the investigational rotavirus vaccine (BRV-TV) at one of the three antigen concentrations or Rotateq or Placebo at 6-8, 10-12 and 14-16 weeks of age. All infants were followed up for safety till 28 days after the third dose. Immune response to the vaccine, in terms of seroresponse and geometric mean concentrations, was compared across the five study groups. Increase in anti-rotavirus serum IgA antibodies from baseline, demonstrated higher immune response for all the three antigen concentrations of BRV-TV vaccine and RotaTeq in comparison with the placebo. Sero-response rates for placebo, BRV-TV dose-levels 10(5.0) FFU, 10(5.8) FFU, 10(6.4) FFU, and Rotateq at 28 days post third dose were 11.1%, 27.8%, 41.2%, 83.3%, and 63.2% respectively using the four-fold or more criteria. The BRV-TV vaccine arm corresponding to the highest antigen concentration of 10(6.4) FFU had a higher sero-response rate compared to the active comparator arm (RotaTeq), 28 days post each vaccine dose. The safety profile was comparable across the treatment groups. Overall, the results showed that all three doses of BRV-TV vaccine were safe, well tolerated and displayed good immunogenicity (dose-response) in healthy Indian infants. Copyright © 2014. Published by Elsevier Ltd.

Do we need 3D tube current modulation information for accurate organ dosimetry in chest CT? Protocols dose comparisons.

PubMed

Lopez-Rendon, Xochitl; Zhang, Guozhi; Coudyzer, Walter; Develter, Wim; Bosmans, Hilde; Zanca, Federica

2017-11-01

To compare the lung and breast dose associated with three chest protocols: standard, organ-based tube current modulation (OBTCM) and fast-speed scanning; and to estimate the error associated with organ dose when modelling the longitudinal (z-) TCM versus the 3D-TCM in Monte Carlo simulations (MC) for these three protocols. Five adult and three paediatric cadavers with different BMI were scanned. The CTDI vol of the OBTCM and the fast-speed protocols were matched to the patient-specific CTDI vol of the standard protocol. Lung and breast doses were estimated using MC with both z- and 3D-TCM simulated and compared between protocols. The fast-speed scanning protocol delivered the highest doses. A slight reduction for breast dose (up to 5.1%) was observed for two of the three female cadavers with the OBTCM in comparison to the standard. For both adult and paediatric, the implementation of the z-TCM data only for organ dose estimation resulted in 10.0% accuracy for the standard and fast-speed protocols, while relative dose differences were up to 15.3% for the OBTCM protocol. At identical CTDI vol values, the standard protocol delivered the lowest overall doses. Only for the OBTCM protocol is the 3D-TCM needed if an accurate (<10.0%) organ dosimetry is desired. • The z-TCM information is sufficient for accurate dosimetry for standard protocols. • The z-TCM information is sufficient for accurate dosimetry for fast-speed scanning protocols. • For organ-based TCM schemes, the 3D-TCM information is necessary for accurate dosimetry. • At identical CTDI vol , the fast-speed scanning protocol delivered the highest doses. • Lung dose was higher in XCare than standard protocol at identical CTDI vol .

Estimated ultraviolet radiation doses in wetlands in six national parks

USGS Publications Warehouse

Diamond, S.A.; Trenham, P.C.; Adams, Michael J.; Hossack, B.R.; Knapp, R.A.; Stark, L.; Bradford, D.; Corn, P.S.; Czarnowski, K.; Brooks, P.D.; Fagre, D.B.; Breen, B.; Dentenbeck, N.E.; Tonnessen, K.

2005-01-01

Ultraviolet-B radiation (UV-B, 280–320-nm wavelengths) doses were estimated for 1024 wetlands in six national parks: Acadia (Acadia), Glacier (Glacier), Great Smoky Mountains (Smoky), Olympic (Olympic), Rocky Mountain (Rocky), and Sequoia/Kings Canyon (Sequoia). Estimates were made using ground-based UV-B data (Brewer spectrophotometers), solar radiation models, GIS tools, field characterization of vegetative features, and quantification of DOC concentration and spectral absorbance. UV-B dose estimates were made for the summer solstice, at a depth of 1 cm in each wetland. The mean dose across all wetlands and parks was 19.3 W-h m−2 (range of 3.4–32.1 W-h m−2). The mean dose was lowest in Acadia (13.7 W-h m−2) and highest in Rocky (24.4 W-h m−2). Doses were significantly different among all parks. These wetland doses correspond to UV-B flux of 125.0 μW cm−2 (range 21.4–194.7 μW cm−2) based on a day length, averaged among all parks, of 15.5 h. Dissolved organic carbon (DOC), a key determinant of water-column UV-B flux, ranged from 0.6 (analytical detection limit) to 36.7 mg C L−1 over all wetlands and parks, and reduced potential maximal UV-B doses at 1-cm depth by 1%–87 %. DOC concentration, as well as its effect on dose, was lowest in Sequoia and highest in Acadia (DOC was equivalent in Acadia, Glacier, and Rocky). Landscape reduction of potential maximal UV-B doses ranged from zero to 77% and was lowest in Sequoia. These regional differences in UV-B wetland dose illustrate the importance of considering all aspects of exposure in evaluating the potential impact of UV-B on aquatic organisms.

Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA).

PubMed

Stover, John F; Belli, Antonio; Boret, Henry; Bulters, Diederik; Sahuquillo, Juan; Schmutzhard, Erich; Zavala, Elisabeth; Ungerstedt, Urban; Schinzel, Reinhard; Tegtmeier, Frank

2014-10-01

Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2-3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.

Frame average optimization of cine-mode EPID images used for routine clinical in vivo patient dose verification of VMAT deliveries

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

McCowan, P. M., E-mail: pmccowan@cancercare.mb.ca; McCurdy, B. M. C.; Medical Physics Department, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9

Purpose: The in vivo 3D dose delivered to a patient during volumetric modulated arc therapy (VMAT) delivery can be calculated using electronic portal imaging device (EPID) images. These images must be acquired in cine-mode (i.e., “movie” mode) in order to capture the time-dependent delivery information. The angle subtended by each cine-mode EPID image during an arc can be changed via the frame averaging number selected within the image acquisition software. A large frame average number will decrease the EPID’s angular resolution and will result in a decrease in the accuracy of the dose information contained within each image. Alternatively, lessmore » EPID images acquired per delivery will decrease the overall 3D patient dose calculation time, which is appealing for large-scale clinical implementation. Therefore, the purpose of this study was to determine the optimal frame average value per EPID image, defined as the highest frame averaging that can be used without an appreciable loss in 3D dose reconstruction accuracy for VMAT treatments. Methods: Six different VMAT plans and six different SBRT-VMAT plans were delivered to an anthropomorphic phantom. Delivery was carried out on a Varian 2300ix model linear accelerator (Linac) equipped with an aS1000 EPID running at a frame acquisition rate of 7.5 Hz. An additional PC was set up at the Linac console area, equipped with specialized frame-grabber hardware and software packages allowing continuous acquisition of all EPID frames during delivery. Frames were averaged into “frame-averaged” EPID images using MATLAB. Each frame-averaged data set was used to calculate the in vivo dose to the patient and then compared to the single EPID frame in vivo dose calculation (the single frame calculation represents the highest possible angular resolution per EPID image). A mean percentage dose difference of low dose (<20% prescription dose) and high dose regions (>80% prescription dose) was calculated for each frame averaged scenario for each plan. The authors defined their unacceptable loss of accuracy as no more than a ±1% mean dose difference in the high dose region. Optimal frame average numbers were then determined as a function of the Linac’s average gantry speed and the dose per fraction. Results: The authors found that 9 and 11 frame averages were suitable for all VMAT and SBRT-VMAT treatments, respectively. This resulted in no more than a 1% loss to any of the dose region’s mean percentage difference when compared to the single frame reconstruction. The optimized number was dependent on the treatment’s dose per fraction and was determined to be as high as 14 for 12 Gy/fraction (fx), 15 for 8 Gy/fx, 11 for 6 Gy/fx, and 9 for 2 Gy/fx. Conclusions: The authors have determined an optimal EPID frame averaging number for multiple VMAT-type treatments. These are given as a function of the dose per fraction and average gantry speed. These optimized values are now used in the authors’ clinical, 3D, in vivo patient dosimetry program. This provides a reduction in calculation time while maintaining the authors’ required level of accuracy in the dose reconstruction.« less

Pharmacokinetics and pharmacodynamics of vildagliptin in healthy Chinese volunteers.

PubMed

Hu, Pei; Yin, Qi; Deckert, Fabienne; Jiang, Ji; Liu, Dongyang; Kjems, Lise; Dole, William P; He, Yan-Ling

2009-01-01

Vildagliptin is an orally effective, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-4) that improves glycemic control in patients with type 2 diabetes. This was a randomized, double-blind, placebo-controlled, time-lagged, parallel-group study in a total of 60 healthy Chinese participants. Single- and multiple-dose pharmacokinetics and pharmacodynamics, and safety and tolerability of vildagliptin were assessed following administration of 25, 50, 100, or 200 mg qd, or 50 mg bid. Vildagliptin was rapidly absorbed (tmax 1.5-2.0 hours) across the dose range of 25 to 200 mg and was quickly eliminated with a terminal elimination half-life (t1/2) of approximately 2 hours. Consistent with the short t1/2, no accumulation of vildagliptin was observed following the administration of multiple doses (accumulation factors were 1.00-1.05 across the 25- to 200-mg dose range). Vildagliptin AUC and Cmax values increased in an approximately dose-proportional fashion (dose proportionality constant beta 1.00-1.16). Administration of vildagliptin 25 to 200 mg led to rapid and near-complete (>95%) inhibition of DPP-4 activity for at least 4 hours after dosing, which was associated with increases in plasma active glucagon-like peptide-1 of up to 2- to 3-fold compared with placebo. The duration of DPP-4 inhibition increased with dose. Glucose and insulin levels were not affected by vildagliptin in healthy participants, consistent with the fact that the glucose-lowering effects of vildagliptin occur in a glucose-dependent fashion. Vildagliptin was well tolerated at the highest tested dose of 200 mg qd. Vildagliptin 25 to 200 mg qd exhibits approximately dose-proportional pharmacokinetics with no evidence of accumulation after multiple dosing in healthy Chinese participants. Vildagliptin demonstrates potent inhibition of DPP-4 activity with excellent tolerability at doses of up to and including 200 mg qd.

Bioavailability of cyanide after consumption of a single meal of foods containing high levels of cyanogenic glycosides: a crossover study in humans.

PubMed

Abraham, Klaus; Buhrke, Thorsten; Lampen, Alfonso

2016-03-01

The acute toxicity of cyanide is determined by its peak levels reached in the body. Compared to the ingestion of free cyanide, lower peak levels may be expected after consumption of foods containing cyanogenic glycosides with the same equivalent dose of cyanide. This is due to possible delayed and/or incomplete release of cyanide from the cyanogenic glycosides depending on many factors. Data on bioavailability of cyanide after consumption of foods containing high levels of cyanogenic glycosides as presented herein were necessary to allow a meaningful risk assessment for these foods. A crossover study was carried out in 12 healthy adults who consumed persipan paste (equivalent total cyanide: 68 mg/kg), linseed (220 mg/kg), bitter apricot kernels (about 3250 mg/kg), and fresh cassava roots (76-150 mg/kg), with each "meal" containing equivalents of 6.8 mg cyanide. Cyanide levels were determined in whole blood using a GC-MS method with K(13)C(15)N as internal standard. Mean levels of cyanide at the different time points were highest after consumption of cassava (15.4 µM, after 37.5 min) and bitter apricot kernels (14.3 µM, after 20 min), followed by linseed (5.7 µM, after 40 min) and 100 g persipan (1.3 µM, after 105 min). The double dose of 13.6 mg cyanide eaten with 200 g persipan paste resulted in a mean peak level of 2.9 µM (after 150 min). An acute reference dose of 0.075 mg/kg body weight was derived being valid for a single application/meal of cyanides or hydrocyanic acid as well as of unprocessed foods with cyanogenic glycosides also containing the accompanying intact β-glucosidase. For some of these foods, this approach may be overly conservative due to delayed release of cyanide, as demonstrated for linseed. In case of missing or inactivated β-glucosidase, the hazard potential is much lower.

Disposition of styrene-acrylonitrile (SAN) trimer in female rats: single dose intravenous and gavage studies.

PubMed

Gargas, Michael L; Collins, Brad; Fennell, Timothy R; Gaudette, Norman F; Sweeney, Lisa M

2008-04-21

Styrene-acrylonitrile trimer (SAN Trimer), a mixture of six isomers (four isomers of 4-cyano-1,2,3,4-tetrahydro-alpha-methyl-1-naphthaleneacetonitrile [THAN] and two isomers of 4-cyano-1,2,3,4-tetrahydro-1-naphthaleneproprionitrile [THNP]), is a by-product of a specific production process of styrene-acrylonitrile polymer. Disposition studies in female rats were conducted to evaluate the pharmacokinetic behavior of [3H]SAN Trimer following a single intravenous administration (26 mg/kg) to nonpregnant rats; a single gavage administration (nominal doses of 25 mg/kg, 75 mg/kg, or 200 mg/kg in corn oil) to nonpregnant rats; and a single gavage administration (nominal dose of 200 mg/kg in corn oil) to pregnant and lactating rats. SAN Trimer was rapidly eliminated from blood (T1/2 approximately 1h) following a single intravenous dose and following single oral doses (T1/2 approximately 3-4h). SAN Trimer was also rapidly excreted in the urine and feces following single oral doses, while total radioactivity was cleared more slowly. In pregnant rats, the concentrations of both radioactivity and SAN Trimer 2h after dosing were highest in the blood, followed by the placenta, with the lowest levels in the fetus. In lactating rats, the concentrations of both radioactivity and SAN Trimer were higher in milk than in maternal blood. Total radioactivity and SAN Trimer blood concentrations in nonpregnant, pregnant, and lactating rats were both higher in lactating rats compared to nonpregnant and pregnant rats.

Effects of lead in nestling black-crowned night-herons (Nycticorax nycticorax) experimentally dosed in the field

USGS Publications Warehouse

Golden, N.H.; Rattner, B.A.; Cohen, J.B.; Hoffman, D.J.; Ottinger, M.A.

2000-01-01

Lead is a known environmental toxicant, and poisoning resulting from the ingestion of lead shot has been well-documented in many species of waterfowl. However, much less is known regarding exposure and effects of free environmental lead in species of birds other than waterfowl. In an attempt to evaluate toxicity of lead to herons and to determine the usefulness of feathers as a non-invasive exposure-monitoring tool, black-crowned night-heron nestlings were dosed with lead to determine its distribution among tissues, and its effects on biochemical biomarkers, growth, and survival. Five-day-old heron nestlings (one per nest) at Chincoteague Bay, Virginia were given a single intra-peritoneal injection of dosing vehicle (control; N=7) or one of three lead solutions (as lead nitrate) (10, 50, or 250 mg/kg body weight of nestling; N=7 per dose) chosen to represent levels below, at, and above those found in moderately-polluted environments. All nestlings treated with lead exhibited dose-dependent inhibition of delta-aminolevulinic acid dehydratase (ALAD) activity compared to controls, and nestlings treated with the highest concentration showed a reduced carcass weight compared to controls. Of several measures of oxidative stress that were analyzed, significant differences were found between low- and high-dosed nestlings in hepatic total thiol and protein-bound sulfhydryl concentrations. No differences in survival were detected between dosed nestlings, controls, or uninjected siblings. Lead concentrations in several matrices, including feathers, are being determined to assess distribution among tissues and will also be examined for relationships with measures of effect.

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

Xie, Tianwu; Lee, Choonsik; Bolch, Wesley E.

Purpose: Nuclear cardiology plays an important role in clinical assessment and has enormous impact on the management of a variety of cardiovascular diseases. Pediatric patients at different age groups are exposed to a spectrum of radiation dose levels and associated cancer risks different from those of adults in diagnostic nuclear medicine procedures. Therefore, comprehensive radiation dosimetry evaluations for commonly used myocardial perfusion imaging (MPI) and viability radiotracers in target population (children and adults) at different age groups are highly desired. Methods: Using Monte Carlo calculations and biological effects of ionizing radiation VII model, we calculate the S-values for a numbermore » of radionuclides (Tl-201, Tc-99m, I-123, C-11, N-13, O-15, F-18, and Rb-82) and estimate the absorbed dose and effective dose for 12 MPI radiotracers in computational models including the newborn, 1-, 5-, 10-, 15-yr-old, and adult male and female computational phantoms. Results: For most organs, {sup 201}Tl produces the highest absorbed dose whereas {sup 82}Rb and {sup 15}O-water produce the lowest absorbed dose. For the newborn baby and adult patient, the effective dose of {sup 82}Rb is 48% and 77% lower than that of {sup 99m}Tc-tetrofosmin (rest), respectively. Conclusions: {sup 82}Rb results in lower effective dose in adults compared to {sup 99m}Tc-labeled tracers. However, this advantage is less apparent in children. The produced dosimetric databases for various radiotracers used in cardiovascular imaging, using new generation of computational models, can be used for risk-benefit assessment of a spectrum of patient population in clinical nuclear cardiology practice.« less

Effects of exposure to dietary chromium on tissue mineral contents in rats fed diets with fiber.

PubMed

Prescha, Anna; Krzysik, Monika; Zabłocka-Słowińska, Katarzyna; Grajeta, Halina

2014-06-01

This study evaluated the effects of diets with fiber (cellulose and/or pectin) supplemented with chromium(III) on homeostasis of selected minerals in femurs, thigh muscles, livers, and kidneys of rats. For 6 weeks, male rats were fed experimental diets: a fiber-free diet (FF), a diet containing 5% cellulose (CEL), 5% pectin (PEC), or 2.5% cellulose and 2.5% pectin (CEL+PEC). These diets had 2.53 or 0.164 mg Cr/kg diet. The tissue levels of Ca, Mg, Zn, Fe, and Cr were determined by using atomic absorption spectrometry. Supplementing diets with Cr resulted in significantly higher Cr levels in the femurs of rats fed the CEL diet and significantly higher Cr and Fe levels in the rats fed the CEL+PEC diet compared to the rats fed FF diet. Muscle Ca content was significantly lower in the rats fed the CEL+PEC+Cr diet compared to the rats fed FF+Cr diet. The rats consuming the PEC+Cr diet had the highest liver Cr content. The highest kidney Zn content was observed in the rats fed diets containing Cr and one type of fiber. These results indicate that diets containing chromium at elevated dose and fiber have a significant effect on the mineral balance in rat tissues.

Radiation Dose and Cancer Risk Estimates in 16-Slice Computed Tomography Coronary Angiography

PubMed Central

Einstein, Andrew J.; Sanz, Javier; Dellegrottaglie, Santo; Milite, Margherita; Sirol, Marc; Henzlova, Milena; Rajagopalan, Sanjay

2008-01-01

Background Recent advances have led to a rapid increase in the number of computed tomography coronary angiography (CTCA) studies performed. While several studies have reported effective dose (E), there is no data available on cancer risk for current CTCA protocols. Methods and Results E and organ doses were estimated, using scanner-derived parameters and Monte Carlo methods, for 50 patients having 16-slice CTCA performed for clinical indications. Lifetime attributable risks (LARs) were estimated with models developed in the National Academies’ Biological Effects of Ionizing Radiation VII report. E of a complete CTCA averaged 9.5 mSv, while that of a complete study, including calcium scoring when indicated, averaged 11.7 mSv. Calcium scoring increased E by 25%, while tube current modulation reduced it by 34% and was more effective at lower heart rates. Organ doses were highest to the lungs and female breast. LAR of cancer incidence from CTCA averaged approximately 1 in 1600, but varied widely between patients, being highest in younger women. For all patients, the greatest risk was from lung cancer. Conclusions CTCA is associated with non-negligible risk of malignancy. Doses can be reduced by careful attention to scanning protocol. PMID:18371595

Cadmium and Peripheral Arterial Disease: Gender Differences in the 1999–2004 US National Health and Nutrition Examination Survey

PubMed Central

Tellez-Plaza, Maria; Navas-Acien, Ana; Crainiceanu, Ciprian M.; Sharrett, A. Richey; Guallar, Eliseo

2010-01-01

Gender differences in the association of blood and urine cadmium concentrations with peripheral arterial disease (PAD) were evaluated by using data from 6,456 US adults aged ≥40 years who participated in the 1999–2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial blood pressure index of <0.9 in at least one leg. For men, the adjusted odds ratios for PAD comparing the highest with the lowest quintiles of blood and urine cadmium concentrations were 1.82 (95% confidence interval (CI): 0.82, 4.05) and 4.90 (95% CI: 1.55, 15.54), respectively, with a progressive dose-response relation and no difference by smoking status. For women, the corresponding odds ratios were 1.19 (95% CI: 0.66, 2.16) and 0.56 (95% CI: 0.18, 1.71), but there was evidence of effect modification by smoking: among women ever smokers, there was a positive, progressive dose-response relation; among women never smokers, there was a U-shaped dose-response relation. Higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. These findings add to the concern of increased cadmium exposure as a cardiovascular risk factor in the general population. PMID:20693268

Carvacrol: from ancient flavoring to neuromodulatory agent.

PubMed

Zotti, Margherita; Colaianna, Marilena; Morgese, Maria Grazia; Tucci, Paolo; Schiavone, Stefania; Avato, Pinarosa; Trabace, Luigia

2013-05-24

Oregano and thyme essential oils are used for therapeutic, aromatic and gastronomic purposes due to their richness in active substances, like carvacrol; however, the effects of the latter on the central nervous system have been poorly investigated. The aim of our study was to define the effects of carvacrol on brain neurochemistry and behavioural outcome in rats. Biogenic amine content in the prefrontal cortex and hippocampus after chronic or acute oral carvacrol administration was measured. Animals were assessed by a forced swimming test. Carvacrol, administered for seven consecutive days (12.5 mg/kg p.o.), was able to increase dopamine and serotonin levels in the prefrontal cortex and hippocampus. When single doses were used (150 and 450 mg/kg p.o.), dopamine content was increased in the prefrontal cortex at both dose levels. On the contrary, a significant dopamine reduction in hippocampus of animals treated with 450 mg/kg of carvacrol was found. Acute carvacrol administration only significantly reduced serotonin content in either the prefrontal cortex or in the hippocampus at the highest dose. Moreover, acute carvacrol was ineffective in producing changes in the forced swimming test. Our data suggest that carvacrol is a brain-active molecule that clearly influences neuronal activity through modulation of neurotransmitters. If regularly ingested in low concentrations, it might determine feelings of well-being and could possibly have positive reinforcer effects.

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement.

PubMed

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). In vivo toxicity studies were performed in male balb 'C' mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.

Animal investigation program, 1981 annual report: Nevada Test Site and vicinity

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

Smith, D.D.; Giles, K.R.

1982-01-01

Data are presented from the radioanalysis of tissues, collected from animals that resided on or near the Nevada Test Site (NTS). Other than naturally occurring potassium-40, cesium-137 was the only gamma-emitting radionuclide frequently detected and was within a narrow range of activity. For example, 12 of 14 cattle muscle samples contained 15 to 65 pCi of cesium-137 per kilogram. Strontium-90 and plutonium-238 or -239 tissue concentrations were similar to those of recent years. Nanocurie levels of tritium were found in tissue from two deer that drank contaminated water draining from the tunnel test areas. Annual dose estimates to man weremore » calculated based on the daily consumption of 0.5 kg of tissue with peak radionuclide levels. The highest postulated dose was 45 millirems to the whole body from ingestion of deer muscle that drank from the tritium contaminated waters. This dose is about 9% of the radiation protection guide. Movement of deer on the NTS is discussed. In general, deer from Pahute Mesa winter in the Timber Mt. area with some movement off the NTS, while deer from Rainier Mesa winter in the Shoshone Mt. area. The sudden death of an offsite goat kid was investigated and death was attributed to enterotoxemia. No gross or microscopic lesions in necropsied animals were found that could be attributed to the effect of ionizing radiation.« less

Effects of intra-aortic balloon counterpulsation in a model of septic shock.

PubMed

Solomon, Steven B; Minneci, Peter C; Deans, Katherine J; Feng, Jing; Eichacker, Peter Q; Banks, Steven M; Danner, Robert L; Natanson, Charles; Solomon, Michael A

2009-01-01

Fluid refractory septic shock can develop into a hypodynamic cardiovascular state in both children and adults. Despite management of these patients with empirical inotropic therapy (with or without a vasodilator), mortality remains high. The effect of cardiovascular support using intra-aortic balloon counterpulsation was investigated in a hypodynamic, mechanically ventilated canine sepsis model in which cardiovascular and pulmonary support were titrated based on treatment protocols. Each week, three animals (n = 33, 10-12 kg) were administered intrabronchial Staphylococcus aureus challenge and then randomized to receive intra-aortic balloon counterpulsation for 68 hrs or no intra-aortic balloon counterpulsation (control). Bacterial doses were increased over the study (4-8 x 10(9) cfu/kg) to assess the effects of intra-aortic balloon counterpulsation during sepsis with increasing risk of death. Compared with lower bacterial doses (4-7 x 10(9) colony-forming units/kg), control animals challenged with the highest dose (8 x 10(9) colony-forming units/kg) had a greater risk of death (mortality rate 86% vs. 17%), with worse lung injury ([A - a]O2), and renal dysfunction (creatinine). These sicker animals required higher norepinephrine infusion rates to maintain blood pressure (and higher FIO2) and positive end-expiratory pressure levels to maintain oxygenation (p < or = 0.04 for all). In animals receiving the highest bacterial dose, intra-aortic balloon counterpulsation improved survival time (23.4 +/- 10 hrs longer; p = 0.003) and lowered norepinephrine requirements (0.43 +/- 0.17 microg/kg/min; p = 0.002) and systemic vascular resistance index (1.44 +/- 0.57 dynes/s/cm5/kg; p = 0.0001) compared with controls. Despite these beneficial effects, intra-aortic balloon counterpulsation was associated with an increase in blood urea nitrogen (p = 0.002) and creatinine (p = 0.12). In animals receiving lower doses of bacteria, intra-aortic balloon counterpulsation had no significant effects on survival or renal function. In a canine model of severe septic shock with a low cardiac index, intra-aortic balloon counterpulsation prolongs survival time and lowers vasopressor requirements.

Ocular biodistribution of bevasiranib following a single intravitreal injection to rabbit eyes

PubMed Central

Dejneka, Nadine S.; Wan, Shanhong; Bond, Ottrina S.; Kornbrust, Douglas J.

2008-01-01

Purpose The primary objective of these investigations was to determine the ocular biodistribution of bevasiranib, a small interfering RNA (siRNA) targeting vascular endothelial growth factor A (VEGF-A), following a single intravitreal injection to rabbit eyes. Methods A tissue distribution and pharmacokinetic study was conducted with 3H-bevasiranib prepared in balanced-salt solution (BSS). Single doses of either 0.5 mg/eye or 2.0 mg/eye of 3H-bevasiranib were given by intravitreal injection to Dutch-Belted rabbits (both eyes were treated). Subgroups of rabbits were serially-sacrificed at various times up to 7 days following dosing for collection of tissue samples. The right eye of each rabbit was collected whole, and the left eye was dissected to isolate five ocular tissues. All samples were analyzed by liquid scintillation counting to determine the concentrations of bevasiranib equivalents. An ocular disposition study was also performed with non-radiolabeled bevasiranib, which was administered to Dutch-Belted rabbit eyes via intravitreal injection at a dose of 2.0 mg/eye. Twenty-four hours post-dose, the eyes were enucleated and dissected into eight individual ocular structures that were analyzed for intact bevasiranib using a locked nuleic acid (LNA) noncompetitive hybridization-ligation enzyme-linked immunosorbent assay. Results Following intravitreal injection of 0.5 mg or 2.0 mg radiolabeled bevasiranib to Dutch-Belted rabbits, bevasiranib was detected in the vitreous, iris, retina, retinal pigment epithelium (RPE), and sclera (+choroid). As expected, the highest concentrations were found in the vitreous, and vitreous levels steadily decreased over time, while concentrations of radioactivity in the other ocular tissues increased to maximum values between 24 h and 72 h after dosing. Of these tissues, the highest concentration of radioactivity was detected in the retina. The LNA assay further confirmed the presence of intact bevasiranib in these tissues 24 h following intravitreal injection of non-radiolabeled bevasiranib (2 mg/eye). Conclusions These studies demonstrate distribution of bevasiranib throughout the eye following intravitreal injection, including extensive uptake into the retina. PMID:18523657

Introduction of inactivated poliovirus vaccine leading into the polio eradication endgame strategic plan; Hangzhou, China, 2010-2014.

PubMed

Liu, Yan; Wang, Jun; Liu, Shijun; Du, Jian; Wang, Liang; Gu, Wenwen; Xu, Yuyang; Zuo, Shuyan; Xu, Erping; An, Zhijie

2017-03-01

China's Expanded Program on Immunization (EPI) has provided 4 doses of oral poliovirus vaccine (OPV) since the 1970s. Inactivated poliovirus vaccine (IPV) became available in 2010 in Hangzhou as a private-sector, parent-chosen alternative to OPV. In 2015, WHO recommended that countries with all-OPV vaccination schedules introduce at least one dose of IPV, to mitigate risk associated with the withdrawal of type 2 OPV. We analyzed polio vaccine coverage and utilization in Hangzhou to determine patterns of IPV use and the occurrence of vaccine-associated paralytic polio (VAPP) in the various patterns identified. Children born between 2010 and 2014 and registered in Hangzhou's Immunization Information System (HZIIS) were included. VAPP cases were detected through the acute flaccid paralysis surveillance system. We used descriptive epidemiological methods to determine IPV and OPV usage patterns and VAPP occurrence. HZIIS data from 566,894 children were analyzed. Coverage levels of polio vaccine were greater than 92% for each birth cohort. Percentages of children using OPV-only, IPV-only, and IPV/OPV sequential schedules were 70.57%, 27.01% and 2.41%, respectively. IPV-only schedule utilization increased by birth cohort regardless of geographical area or whether the child was locally-born. The highest use of an all-IPV schedule (79.85%) was among urban, locally-born children in the 2014 birth cohort. Five VAPP cases were identified during the study years; all cases occurred following the first polio vaccine dose, which was always OPV for the cases. Type 2 vaccine virus was isolated from 2 VAPP cases, and type 2 and type 3 vaccine virus was isolated from one VAPP case. The incidence of VAPP in the 2010-2014 birth cohorts was 3.76 per 1million doses of OPV. Children in Hangzhou had high polio vaccination coverage. IPV-only schedule use increased by year, and was highest in urban areas among locally-born children. All cases of VAPP were associated with the first dose of OPV. Copyright © 2017 Elsevier Ltd. All rights reserved.

Sub-chronic toxicity study in rats orally exposed to nanostructured silica

PubMed Central

2014-01-01

Background Synthetic Amorphous Silica (SAS) is commonly used in food and drugs. Recently, a consumer intake of silica from food was estimated at 9.4 mg/kg bw/day, of which 1.8 mg/kg bw/day was estimated to be in the nano-size range. Food products containing SAS have been shown to contain silica in the nanometer size range (i.e. 5 – 200 nm) up to 43% of the total silica content. Concerns have been raised about the possible adverse effects of chronic exposure to nanostructured silica. Methods Rats were orally exposed to 100, 1000 or 2500 mg/kg bw/day of SAS, or to 100, 500 or 1000 mg/kg bw/day of NM-202 (a representative nanostructured silica for OECD testing) for 28 days, or to the highest dose of SAS or NM-202 for 84 days. Results SAS and NM-202 were extensively characterized as pristine materials, but also in the feed matrix and gut content of the animals, and after in vitro digestion. The latter indicated that the intestinal content of the mid/high-dose groups had stronger gel-like properties than the low-dose groups, implying low gelation and high bioaccessibility of silica in the human intestine at realistic consumer exposure levels. Exposure to SAS or NM-202 did not result in clearly elevated tissue silica levels after 28-days of exposure. However, after 84-days of exposure to SAS, but not to NM-202, silica accumulated in the spleen. Biochemical and immunological markers in blood and isolated cells did not indicate toxicity, but histopathological analysis, showed an increased incidence of liver fibrosis after 84-days of exposure, which only reached significance in the NM-202 treated animals. This observation was accompanied by a moderate, but significant increase in the expression of fibrosis-related genes in liver samples. Conclusions Although only few adverse effects were observed, additional studies are warranted to further evaluate the biological relevance of observed fibrosis in liver and possible accumulation of silica in the spleen in the NM-202 and SAS exposed animals respectively. In these studies, dose-effect relations should be studied at lower dosages, more representative of the current exposure of consumers, since only the highest dosages were used for the present 84-day exposure study. PMID:24507464

High-Risk Prescribing to Medicaid Enrollees Receiving Opioid Analgesics: Individual- and County-Level Factors.

PubMed

Heins, Sara E; Sorbero, Mark J; Jones, Christopher M; Dick, Andrew W; Stein, Bradley D

2018-01-05

Prescription opioid overdoses have increased dramatically in recent years, with the highest rates among Medicaid enrollees. High-risk prescribing includes practices associated with overdoses and a range of additional opioid-related problems. To identify individual- and county-level factors associated with high-risk prescribing among Medicaid enrollees receiving opioids. In a four-states, cross-sectional claims data study, Medicaid enrollees 18-64 years old with a new opioid analgesic treatment episode 2007-2009 were identified. Multivariate regression analyses were conducted to identify factors associated with high-risk prescribing, defined as high-dose opioid prescribing (morphine equivalent daily dose ≥100 mg for >6 days), opioid overlap, opioid-benzodiazepine overlap. High-risk prescribing occurred in 39.4% of episodes. Older age, rural county of residence, white race, and major depression diagnosis were associated with higher rates of all types of high-risk prescribing. Individuals with prior opioid, alcohol, and hypnotic/sedative use disorder diagnoses had lower odds of high-dose opioid prescribing but higher odds of opioid overlap and opioid-benzodiazepine overlap than individuals without such disorders. High-dose opioid prescribing in Massachusetts was less common than in California, Illinois, and New York, whereas the rate of benzodiazepine overlap in Massachusetts was more common than in other states. Conclusions/Importance: High-risk prescribing was common and associated with several important demographic, clinical, and community factors. Findings can be used to inform targeted interventions designed to reduce such prescribing, and given state variation observed, further research is needed to better understand the effects of state policies on high-risk prescribing.

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.

A strategy to optimize CT pediatric dose with a visual discrimination model

NASA Astrophysics Data System (ADS)

Gutierrez, Daniel; Gudinchet, François; Alamo-Maestre, Leonor T.; Bochud, François O.; Verdun, Francis R.

2008-03-01

Technological developments of computed tomography (CT) have led to a drastic increase of its clinical utilization, creating concerns about patient exposure. To better control dose to patients, we propose a methodology to find an objective compromise between dose and image quality by means of a visual discrimination model. A GE LightSpeed-Ultra scanner was used to perform the acquisitions. A QRM 3D low contrast resolution phantom (QRM - Germany) was scanned using CTDI vol values in the range of 1.7 to 103 mGy. Raw data obtained with the highest CTDI vol were afterwards processed to simulate dose reductions by white noise addition. Noise realism of the simulations was verified by comparing normalized noise power spectra aspect and amplitudes (NNPS) and standard deviation measurements. Patient images were acquired using the Diagnostic Reference Levels (DRL) proposed in Switzerland. Noise reduction was then simulated, as for the QRM phantom, to obtain five different CTDI vol levels, down to 3.0 mGy. Image quality of phantom images was assessed with the Sarnoff JNDmetrix visual discrimination model and compared to an assessment made by means of the ROC methodology, taken as a reference. For patient images a similar approach was taken but using as reference the Visual Grading Analysis (VGA) method. A relationship between Sarnoff JNDmetrix and ROC results was established for low contrast detection in phantom images, demonstrating that the Sarnoff JNDmetrix can be used for qualification of images with highly correlated noise. Patient image qualification showed a threshold of conspicuity loss only for children over 35 kg.

Usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions.

PubMed

Yoshimatsu, Yu; Ishizaka, Tomomichi; Chiba, Katsuyoshi; Mori, Kazuhiko

2018-05-10

Drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or hyperglycemia increase the risk for life-threatening arrhythmia. To assess the drug-induced cardiotoxic potential associated with extraordinary blood glucose (GLU) levels, the effect of gatifloxacin (GFLX) which was frequently associated with GLU abnormality and QT/QTc prolongations in the clinic on blood GLU and electrocardiogram (ECG) parameters was investigated in cynomolgus monkeys (n=4) given GFLX orally in an ascending dose regimen (10, 30, 60 and 100 mg/kg). Simultaneous and sequential GLU and ECG monitoring with a continuous GLU monitoring system and Holter ECG, respectively, were conducted for 24 h under free-moving conditions. Consequently, GFLX at 30 and 60 mg/kg dose-dependently induced a transient decrease in GLU without any ECG abnormality 2-4 h postdose. Highest dose of 100 mg/kg caused severe hypoglycemia with a mean GLU of <30 mg/dL, accompanied by remarkable QT/QTc prolongations by 20-30% in all animals. In contrast, hyperglycemia without QT/QTc prolongations was noted 24 h after dosing in one animal. A close correlation between GLU and QTc values was observed in animals treated with 100 mg/kg, suggesting that GFLX-induced hypoglycemia enhanced QT/QTc prolongations. Furthermore, the 24-h sequential GLU monitoring data clearly distinguished between GFLX-induced GLU abnormality and physiological GLU changes influenced by feeding throughout the day. In conclusion, the combined assessment of continuous GLU and ECG monitoring is valuable in predicting the drug-induced cardio-electrophysiological risk associated with both GLU and ECG abnormalities.

Comparison of the effects of letrozole and cabergoline on vascular permeability, ovarian diameter, ovarian tissue VEGF levels, and blood PEDF levels, in a rat model of ovarian hyperstimulation syndrome.

PubMed

Şahin, Nur; Apaydın, Nesin; Töz, Emrah; Sivrikoz, Oya Nermin; Genç, Mine; Turan, Gülüzar Arzu; Cengiz, Hakan; Eskicioğlu, Fatma

2016-05-01

To evaluate the effects of letrozole and cabergoline in a rat model of ovarian hyperstimulation syndrome (OHSS). In this prospective, controlled experimental study, the 28 female Wistar rats were divided into four subgroups (one non-stimulated control and three OHSS-positive groups: placebo, letrozole, and cabergoline). To induce OHSS, rats were injected with 10 IU of pregnant mare serum gonadotropin from day 29 to day 32 of life, followed by subcutaneous injection of 30 IU hCG on day 33. Letrozole rats received with a single dose of 0.1 mg/kg letrozole via oral gavage, on the hCG day. Cabergoline rats received with a single dose of 100 µg/kg cabergoline via oral gavage, on the hCG day. All animals were compared in terms of body weight, vascular permeability (VP), ovarian diameter, ovarian tissue VEGF expression (assessed via immunohistochemical staining), and blood pigment epithelium-derived growth factor (PEDF) levels. The OHSS-positive placebo group (group 2) exhibited the highest VP, ovarian diameter, extent of VEGF staining, and lowest PEDF level, as expected. No significant difference was evident between the letrozole and cabergoline groups in terms of any of body weight; VP; PEDF level; ovarian diameter; or the staining intensity of, or percentage staining for, VEGF in ovarian tissues. Letrozole and cabergoline were equally effective to prevent OHSS, reducing the ovarian diameter, VP, and PEDF and VEGF levels to similar extents.

Higher Risk Periods for Suicide Among VA Patients Receiving Depression Treatment

PubMed Central

Valenstein, Marcia; Kim, Hyungjin Myra; Ganoczy, Dara; McCarthy, John F.; Zivin, Kara; Austin, Karen L.; Hoggatt, Katherine; Eisenberg, Daniel; Piette, John D.; Blow, Frederic C.; Olfson, Mark

2010-01-01

Background Health systems with limited resources may have the greatest impact on suicide if their prevention efforts target the highest-risk treatment groups during the highest-risk periods. To date, few health systems have carefully segmented their depression treatment populations by level of risk and prioritized prevention efforts on this basis. Methods We conducted a retrospective cohort study of 887,859 VA patients receiving depression treatment between 4/1/1999 and 9/30/2004. We calculated suicide rates for five sequential 12-week periods following treatment events that health systems could readily identify: psychiatric hospitalizations, new antidepressant starts (>6 months without fills), “other” antidepressant starts, and dose changes. Using piecewise exponential models, we examined whether rates differed across time-periods. We also examined whether suicide rates differed by age-group in these periods. Results Over all time periods, the suicide rate was 114/100,000 person-years (95% CI; 108,120). In the first 12-week periods, suicide rates were: 568/100,000 p-y (95% CI; 493,651) following psychiatric hospitalizations; 210/100,000 p-y (95% CI; 187, 236) following new antidepressant starts; 193/100,000 p-y (95% CI; 167, 222) following other starts; and 154/100,000 p-y (95% CI; 133, 177) following dose changes. Suicide rates remained above the base rate for 48 weeks following hospital discharge and 12 weeks following antidepressant events. Adults aged 61–80 years were at highest risk in the first 12-weeks periods Conclusions To have the greatest impact on suicide, health systems should prioritize prevention efforts following psychiatric hospitalizations. If resources allow, closer monitoring may also be warranted in the first 12 weeks following antidepressant starts, across all age-groups. PMID:18945495

Is Pertussis Infection Neglected in China? Evidence from a Seroepidemiology Survey in Zhejiang, an Eastern Province of China.

PubMed

He, Hanqing; Yao, Pingping; Zhou, Yang; Deng, Xuan; Pan, Jinren

2016-01-01

The resurgence of pertussis has occurred in many countries. However, the epidemiological profiles of pertussis cannot be well understood by the current surveillance system in China. This study was designed to investigate the age specific serologic evidence of antibodies against pertussis, and to offer information regarding the existence of pertussis infection in Zhejiang Province, China. A cross-sectional serosurvey was carried out in 6 counties of Zhejiang Province during September and October of 2014. The immunoglobulin G-pertussis toxin (IgG-PT) levels were measured quantitatively with a commercially available enzyme-linked immunosorbent assay (ELISA). The antibody activities were expressed in the Food and Drug Administration (FDA)-U/ml and a level ≥30 FDA-U/ml was considered seropositive. An IgG-PT >80 FDA-U/ml indicated recent pertussis infection if the patient had not received immunization with the pertussis vaccine within the last year. The mean IgG-PT seropositivity rate among the 2107 subjects was 33.32% with a geometric mean concentration of 17.73 (95% confidence interval: 16.90-18.60) FDA-U/ml. The difference in the seropositivity rates reached significant means among the different age groups (waldχ2 = 198.41, P<0.0005), and children aged 3 years had the highest percentage (63.24%) of undetectable IgG-PT level. Of the 1707 subjects ≥3 years of age, 169 (9.90%) had evidence of a recent infection. The highest proportion of IgG-PT levels ≥80 FDA-U/ml was found in ≥60 years age group followed by 11-15 and 16-25 years age groups. This study indicates the rather lower IgG-PT level sustained 1 year after the acellular pertussis vaccine booster dose, and substantial proportion of population susceptibility to pertussis in Zhejiang Province, China. Moreover, pertussis infection is not uncommon; it was estimated that 10% of subjects were recently infected approximately within the last 100 days. We highly suggest that the surveillance capacity should be strengthened and consider introducing booster dose that protect against pertussis in 6 years old children.

Lung Cancer Screening May Benefit Those at Highest Risk

Cancer.gov

People at the highest risk for lung cancer, based on a risk model, may be more likely to benefit from screening with low-dose CT, a new analysis suggests. The study authors believe the findings may better define who should undergo lung cancer screening, as this Cancer Currents blog post explains.

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.

Synergistic effect of the hydroalcoholic extract from Lepidium meyenii (Brassicaceae) and Fagara tessmannii (Rutaceae) on male sexual organs and hormone level in rats.

PubMed

Lembè, Dieudonné Massoma; Gasco, Manuel; Gonzales, G F

2014-01-01

Lepidium meyenii is a plant, which has been used in folk medicine to treat infertility and to increase sexual desire. However, few reports have investigated the administration of this plant with other plants having the same properties. The present investigation was designed to evaluate whether the combination of Lepidium meyenii and Fagara tessmannii can improve spermatogenesis and testosterone level in rats. Twenty male rats were treated daily for 2 weeks with the hydroalcoholic extract of Fagara tessmannii and Lepidium meyenii (Fag + MN) as follow: (vehicle), (0.01 g + 0.5 mg), (0.1 g + 5 mg) and (1 g+ 50 mg)/kg BW. At doses Fag 0.01 g/MN 0.5 mg and Fag 0.1 g/MN 5 mg, the weight of seminal vesicle, prostate, and testis significantly decreased (P < 0.05) while at dose Fag 1 g/MN 50 mg, the weight of epididymis and testis significantly increased (P < 0.05) when compared to the control. We noticed a significant increase of the number of spermatids/test (P < 0.05), epididymis sperm count (P < 0.05), and DSP/test of the rats at dose Fag 1 g/MN 50 mg while at dose Fag 0.01 g/MN 0.5 mg and Fag 0.1 g/MN 5 mg, sperm count was reduced in male organs, particularly in vas deferens (P < 0.05) and epididymis (P < 0.001). The serum testosterone concentration significantly decreased (P < 0.05) at lowest dose Fag 0.01 g/MN 0.5 mg. However, at highest dose Fag 1 g/MN 50 mg, the serum testosterone concentration increased significantly (P < 0.05). The length of stage VII-VIII and IX-I of the seminiferous tubule significantly (P < 0.05) increased while the length of stage II-VI significantly (P < 0.05) decreased. The results indicated that the combination of Lepidium meyenii (Black Maca) with Fagara tessmannii can improve male reproductive organs activities.

Comparison of porous and nano zinc oxide for replacing high-dose dietary regular zinc oxide in weaning piglets

PubMed Central

Long, Lina; Chen, Jiashun; Zhang, Yonggang; Liang, Xiao

2017-01-01

The aim of this study was to compare the effect of dietary supplementation with low dose of porous and nano zinc oxide (ZnO) on weaning piglets, and to evaluate the possibility of using them as an alternative to high dose of regular ZnO. Piglets were randomly allocated into four treatment groups fed with four diets: (1) basal diet (NC), (2) NC+ 3000 mg/kg ZnO (PC), (3) NC + 500 mg/kg porous ZnO (HiZ) and (4) NC + 500 mg/kg nano ZnO (ZNP). The result showed that piglets in HiZ group had less diarrhea than ZNP group (P < 0.05). Besides, there was no significant difference between PC, HiZ and ZNP groups in terms of serum malondialdeyhde (MDA) concentration and glutathione peroxidase (GSH-Px) activity (P > 0.05). Analysis of trace metal elements revealed that piglets fed with high dose of regular ZnO had the highest Zn level in kidney (P < 0.05), which may induce kidney stone formation. Additionally, a decrease in ileal crypt depth was observed in PC, HiZ and ZNP group, suggesting an effective protection against intestinal injury. Results of mRNA analysis in intestine showed that ZNP supplementation had better effects on up-regulated trefoil factor 3 (TFF3) and nuclear factor erythroid 2-related factor 2 (Nrf2) levels in duodenum and jejunum than HiZ did (P < 0.05), implying that nano ZnO may possess higher anti-inflammatory capacity than porous ZnO. In conclusion, dietary supplementation with low dose of porous and nano ZnO had similar (even better) effect on improving growth performance and intestinal morphology, reducing diarrhea and intestinal inflammatory as high dose of regular ZnO in weaning piglets. Compared with nano ZnO, porous ZnO had better performance on reducing diarrhea but less effect on up-regulation of intestinal TFF3 and Nrf2. PMID:28792520

Comparison of childhood thyroid cancer prevalence among 3 areas based on external radiation dose after the Fukushima Daiichi nuclear power plant accident

PubMed Central

Ohira, Tetsuya; Takahashi, Hideto; Yasumura, Seiji; Ohtsuru, Akira; Midorikawa, Sanae; Suzuki, Satoru; Fukushima, Toshihiko; Shimura, Hiroki; Ishikawa, Tetsuo; Sakai, Akira; Yamashita, Shunichi; Tanigawa, Koichi; Ohto, Hitoshi; Abe, Masafumi; Suzuki, Shinichi

2016-01-01

Abstract The 2011 Great East Japan Earthquake led to a subsequent nuclear accident at the Fukushima Daiichi Nuclear Power Plant. In its wake, we sought to examine the association between external radiation dose and thyroid cancer in Fukushima Prefecture. We applied a cross-sectional study design with 300,476 participants aged 18 years and younger who underwent thyroid examinations between October 2011 and June 2015. Areas within Fukushima Prefecture were divided into three groups based on individual external doses (≥1% of 5 mSv, <99% of 1 mSv/y, and the other). The odds ratios (ORs) and 95% confidence intervals of thyroid cancer for all areas, with the lowest dose area as reference, were calculated using logistic regression models adjusted for age and sex. Furthermore, the ORs of thyroid cancer for individual external doses of 1 mSv or more and 2 mSv or more, with the external dose less than 1 mSv as reference, were calculated. Prevalence of thyroid cancer for the location groups were 48/100,000 for the highest dose area, 36/100,000 for the middle dose area, and 41/100,000 for the lowest dose area. Compared with the lowest dose area, age-, and sex-adjusted ORs (95% confidence intervals) for the highest-dose and middle-dose areas were 1.49 (0.36–6.23) and 1.00 (0.67–1.50), respectively. The duration between accident and thyroid examination was not associated with thyroid cancer prevalence. There were no significant associations between individual external doses and prevalence of thyroid cancer. External radiation dose was not associated with thyroid cancer prevalence among Fukushima children within the first 4 years after the nuclear accident. PMID:27583855

Comparison of childhood thyroid cancer prevalence among 3 areas based on external radiation dose after the Fukushima Daiichi nuclear power plant accident: The Fukushima health management survey.

PubMed

Ohira, Tetsuya; Takahashi, Hideto; Yasumura, Seiji; Ohtsuru, Akira; Midorikawa, Sanae; Suzuki, Satoru; Fukushima, Toshihiko; Shimura, Hiroki; Ishikawa, Tetsuo; Sakai, Akira; Yamashita, Shunichi; Tanigawa, Koichi; Ohto, Hitoshi; Abe, Masafumi; Suzuki, Shinichi

2016-08-01

The 2011 Great East Japan Earthquake led to a subsequent nuclear accident at the Fukushima Daiichi Nuclear Power Plant. In its wake, we sought to examine the association between external radiation dose and thyroid cancer in Fukushima Prefecture. We applied a cross-sectional study design with 300,476 participants aged 18 years and younger who underwent thyroid examinations between October 2011 and June 2015. Areas within Fukushima Prefecture were divided into three groups based on individual external doses (≥1% of 5 mSv, <99% of 1 mSv/y, and the other). The odds ratios (ORs) and 95% confidence intervals of thyroid cancer for all areas, with the lowest dose area as reference, were calculated using logistic regression models adjusted for age and sex. Furthermore, the ORs of thyroid cancer for individual external doses of 1 mSv or more and 2 mSv or more, with the external dose less than 1 mSv as reference, were calculated. Prevalence of thyroid cancer for the location groups were 48/100,000 for the highest dose area, 36/100,000 for the middle dose area, and 41/100,000 for the lowest dose area. Compared with the lowest dose area, age-, and sex-adjusted ORs (95% confidence intervals) for the highest-dose and middle-dose areas were 1.49 (0.36-6.23) and 1.00 (0.67-1.50), respectively. The duration between accident and thyroid examination was not associated with thyroid cancer prevalence. There were no significant associations between individual external doses and prevalence of thyroid cancer. External radiation dose was not associated with thyroid cancer prevalence among Fukushima children within the first 4 years after the nuclear accident.

Zoledronic acid at subtoxic dose extends osteoblastic stage span of primary human osteoblasts.

PubMed

Zara, Susi; De Colli, Marianna; di Giacomo, Viviana; Zizzari, Vincenzo Luca; Di Nisio, Chiara; Di Tore, Umberto; Salini, Vincenzo; Gallorini, Marialucia; Tetè, Stefano; Cataldi, Amelia

2015-04-01

This study aimed to check the effect of zoledronic acid (ZA) at subtoxic dose on human osteoblasts (HOs) in terms of cell viability, apoptosis occurrence, and differentiation induction. ZA belongs to the family of bisphosphonates (BPs), largely used in the clinical practice for the treatment of bone diseases, often associated with jaw osteonecrosis onset. Their pharmacological action consists in the direct block of the osteoclast-mediated bone resorption along with indirect action on osteoblasts. HOs were treated choosing the highest limit concentration (10(-5) M) which does not induce toxic effects. Live/dead staining, flow cytometry, mitochondrial membrane potential assay, osteocalcin western blotting, gp38 RT-PCR, collagen type I, PGE2, and IL-6 ELISA assays were performed. Similar viability level between control and ZA-treated samples is found along with no significant increase of apoptotic and necrotic cells in ZA-treated sample. To establish if an early apoptotic pathway was triggered, Bax expression and mitochondrial membrane potential were evaluated finding a higher protein expression in control sample and a good integrity of mitochondrial membrane in both experimental points. Type I collagen secretion and alkaline phosphatase (ALP) activity appear increased in ZA-treated sample, osteocalcin expression level is reduced in ZA-treated cells, whereas no modifications of gp38 mRNA level are evidenced. No statistical differences are identified in PGE2 secretion level whereas IL-6 secretion is lower in ZA-treated HOs with respect to control ones. These results highlight that ZA, delaying the osteoblastic differentiation process versus the osteocytic lineage, strengthens its pharmacological activity enhancing bone density. The knowledge of ZA effects on osteoblasts at subtoxic dose allows to improve therapeutic protocols in order to strengthen drug pharmacological activity through a combined action on both osteoclastic and osteoblastic cells.

Carvedilol induces endogenous hydrogen sulfide tissue concentration changes in various mouse organs.

PubMed

Wiliński, Bogdan; Wiliński, Jerzy; Somogyi, Eugeniusz; Piotrowska, Joanna; Góralska, Marta; Macura, Barbara

2011-01-01

Carvedilol, a third generation non-selective adrenoreceptor blocker, is widely used in cardiology. Its action has been proven to reach beyond adrenergic antagonism and involves multiple biological mechanisms. The interaction between carvedilol and endogenous 'gasotransmitter' hydrogen sulfide (H2S) is unknown. The aim of the study is to assess the influence of carvedilol on the H2S tissue level in mouse brain, liver, heart and kidney. Twenty eight SJL strain female mice were administered intraperitoneal injections of 2.5 mg/kg b.w./d (group D1, n=7), 5 mg/kg b.w./d (group D2, n=7) or 10 mg/kg b.w./d of carvedilol (group D3, n=7). The control group (n=7) received physiological saline in portions of the same volume (0.2 ml). Measurements of the free tissue H2S concentrations were performed according to the modified method of Siegel. A progressive decline in H2S tissue concentration along with an increase in carvedilol dose was observed in the brain (12.5%, 13.7% and 19.6%, respectively). Only the highest carvedilol dose induced a change in H2S tissue level in the heart - an increase by 75.5%. In the liver medium and high doses of carvedilol increased the H2S level by 48.1% and 11.8%, respectively. In the kidney, group D2 showed a significant decrease of H2S tissue level (22.5%), while in the D3 group the H2S concentration increased by 12.9%. Our study has proven that carvedilol affects H2S tissue concentration in different mouse organs.

Dose-effect of ionizing radiation-induced PIG3 gene expression alteration in human lymphoblastoid AHH-1 cells and human peripheral blood lymphocytes.

PubMed

Liu, Qing-Jie; Zhang, De-Qin; Zhang, Qing-Zhao; Feng, Jiang-Bin; Lu, Xue; Wang, Xin-Ru; Li, Kun-Peng; Chen, De-Qing; Mu, Xiao-Feng; Li, Shuang; Gao, Ling

2015-01-01

To identify new ionizing radiation (IR)-sensitive genes and observe the dose-effect of gene expression alteration (GEA) induced by IR. Microarray was used to screen the differentially expressed genes in human lymphoblastoid cells (AHH-1) using three doses of (60)Co γ-rays (0.5-8 Gy at 1 Gy/min). Given that p53-inducible gene 3 (PIG3) was consistently upregulated, the GEA of PIG3 in AHH-1 cells and human peripheral blood lymphocytes (HPBL) induced by γ-rays (1 Gy/min) was measured at messenger RNA (mRNA) and protein levels. The GEA of PIG3 in AHH-1 cells exposed to neutron radiation (californium-252, 0.073 Gy/min) was also quantified. PIG3 was one of the seven differentially expressed genes found in the microarray analysis. The PIG3 mRNA and protein levels in AHH-1 cells were significantly increased from 1-10 Gy of γ-rays 8-72 h or 8-168 h after exposure, respectively. The enhancement was also observed in AHH-1 cells from 0.4-1.6 Gy of neutrons 48 h post-irradiation. The PIG3 mRNA levels (mRNA copy numbers) in HPBL were significantly increased from 1-8 Gy of γ-rays within 4-24 h post-irradiation, but the highest increase in signal-to-noise responsiveness is approximately two-fold, which was less than that of AHH-1 (approximately 20-fold). IR can upregulate the PIG3 gene expression in AHH-1 and HPBL in the early phase after exposure; however, the IR induced expression levels of PIG3 are greater in AHH-1 than HPBL.

Nutraceutic effect of free condensed tannins of Lysiloma acapulcensis (Kunth) benth on parasite infection and performance of Pelibuey sheep.

PubMed

García-Hernández, Cesar; Arece-García, Javier; Rojo-Rubio, Rolando; Mendoza-Martínez, German David; Albarrán-Portillo, Benito; Vázquez-Armijo, José Fernando; Avendaño-Reyes, Leonel; Olmedo-Juárez, Agustín; Marie-Magdeleine, Carine; López-Leyva, Yoel

2017-01-01

Forty-five Pelibuey sheep were experimentally infested with nematodes to evaluate the effect of three free condensed tannin (FCT) levels of Lysiloma acapulcensis on fecal egg counts (FECs), packed cell volumes (PCV), ocular mucosa colors (OMC), average daily gain (ADG), and adult nematode count. Five treatments were used: 12.5, 25.0, and 37.5 mg of FCT kg -1 of body weight (BW); sterile water (control); and ivermectine (0.22 mg kg -1 of BW) as chemical group. The data were processed through repeated measurement analysis. Even though the three FCT doses decreased (P < 0.05) the FEC, the highest reduction was obtained with 37.5 mg kg -1 of BW. No differences were observed in PCV and OMC. Higher ADG (P < 0.05) was observed with 37.5 mg kg -1 of BW of FCT. The count of adult nematodes (females and males) in the higher dose of FCT was similar to chemical treatment. Dose of 37.5 mg kg -1 of BW decreased the parasite infection and improved the lamb performance. Therefore, this dose could be used as a nutraceutic product in sheep production.

Carbendazim-induced haematological, biochemical and histopathological changes to the liver and kidney of male rats.

PubMed

Selmanoglu, G; Barlas, N; Songür, S; Koçkaya, E A

2001-12-01

Carbendazim is a systemic broad-spectrum fungicide controlling a wide range of pathogens. It is also used as a preservative in paint, textile, papermaking and leather industry, as well as a preservative of fruits. In the present study, carbendazim was administered at 0, 150, 300 and 600 mg/kg per day doses orally to male rats (Rattus rattus) for 15 weeks. At the end of the experiment, blood samples, liver and kidney tissues of each animal were taken. Serum enzyme activities, and haematological and biochemical parameters were analysed. In toxicological tests, 600 mg/kg per day doses of carbendazim caused an increase of albumin, glucose, creatinine and cholesterol levels. Also, at the same doses, white blood cell and lymphocyte counts decreased. However, mean cell hemoglobin and mean cell hemoglobin concentrations increased. Histopathological examinations revealed congestion, an enlargement of the sinusoids, an increase in the number of Kupffer cells, mononuclear cell infiltration and hydropic degeneration in the liver. At the highest doses, congestion, mononuclear cell infiltration, tubular degeneration and fibrosis were observed in the kidney tissue. These results indicate that 300 and 600 mg/kg per day carbendazim affected the liver and kidney tissue and caused some changes on haematological and biochemical parameters of rats.

Paracetamol (acetaminophen) protein adduct concentrations during therapeutic dosing.

PubMed

Heard, Kennon; Green, Jody L; Anderson, Victoria; Bucher-Bartelson, Becki; Dart, Richard C

2016-03-01

Paracetamol protein adducts (PPA) are a biomarker of paracetamol exposure. PPA are quantified as paracetamol-cysteine (APAP-CYS), and concentrations above 1.1 μmol l(-1) have been suggested as a marker of paracetamol-induced hepatotoxicity. However, there is little information on the range of concentrations observed during prolonged therapeutic dosing. The aim of the present study was to describe the concentration of PPA in the serum of subjects taking therapeutic doses of paracetamol for at least 16 days. Preplanned secondary aim of a prospective randomized controlled (placebo vs. 4g day(-1) paracetamol) trial. We measured subjects' serum PPA concentrations every 3 days for a minimum of 16 days. We also measured concentrations on study days 1-3 and 16-25 in subsets of patients. PPA were quantified as APAP-CYS after gel filtration and protein digestion using liquid chromatography/mass spectrometry. Ninety per cent of subjects had detectable PPA after five doses. Median APAP-CYS concentrations in paracetamol-treated subjects increased to a plateau of 0.1 μmol l(-1) on day 7, where they remained. The highest concentration measured was 1.1 μmol l(-1) and two subjects never had detectable PPA levels. PPA were detected in the serum of 78% of subjects 9 days after their final dose. PPA are detectable in the vast majority of subjects taking therapeutic doses of paracetamol. While most have concentrations well below the threshold associated with hepatotoxicity, concentrations may approach 1.1 μmol l(-1) in rare cases. Adducts are detectable after a few doses and can persist for over a week after dosing is stopped. © 2015 The British Pharmacological Society.

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

PubMed

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

2018-01-17

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

Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain.

PubMed

Hewitt, Ellen; Pitcher, Thomas; Rizoska, Biljana; Tunblad, Karin; Henderson, Ian; Sahlberg, Britt-Louise; Grabowska, Urszula; Classon, Björn; Edenius, Charlotte; Malcangio, Marzia; Lindström, Erik

2016-09-01

Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µmol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µmol/kg) and pregabalin (63-377 µmol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µmol/kg) in combination with the minimum effective dose of pregabalin (75 µmol/kg) or gabapentin (146 µmol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µmol/kg) in combination with a subeffective dose of pregabalin (38 µmol/kg) or gabapentin (73 µmol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

TU-D-209-03: Alignment of the Patient Graphic Model Using Fluoroscopic Images for Skin Dose Mapping

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

Oines, A; Oines, A; Kilian-Meneghin, J

2016-06-15

Purpose: The Dose Tracking System (DTS) was developed to provide realtime feedback of skin dose and dose rate during interventional fluoroscopic procedures. A color map on a 3D graphic of the patient represents the cumulative dose distribution on the skin. Automated image correlation algorithms are described which use the fluoroscopic procedure images to align and scale the patient graphic for more accurate dose mapping. Methods: Currently, the DTS employs manual patient graphic selection and alignment. To improve the accuracy of dose mapping and automate the software, various methods are explored to extract information about the beam location and patient morphologymore » from the procedure images. To match patient anatomy with a reference projection image, preprocessing is first used, including edge enhancement, edge detection, and contour detection. Template matching algorithms from OpenCV are then employed to find the location of the beam. Once a match is found, the reference graphic is scaled and rotated to fit the patient, using image registration correlation functions in Matlab. The algorithm runs correlation functions for all points and maps all correlation confidences to a surface map. The highest point of correlation is used for alignment and scaling. The transformation data is saved for later model scaling. Results: Anatomic recognition is used to find matching features between model and image and image registration correlation provides for alignment and scaling at any rotation angle with less than onesecond runtime, and at noise levels in excess of 150% of those found in normal procedures. Conclusion: The algorithm provides the necessary scaling and alignment tools to improve the accuracy of dose distribution mapping on the patient graphic with the DTS. Partial support from NIH Grant R01-EB002873 and Toshiba Medical Systems Corp.« less

Predicting Grade 3 Acute Diarrhea During Radiation Therapy for Rectal Cancer Using a Cutoff-Dose Logistic Regression Normal Tissue Complication Probability Model

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

Robertson, John M., E-mail: jrobertson@beaumont.ed; Soehn, Matthias; Yan Di

Purpose: Understanding the dose-volume relationship of small bowel irradiation and severe acute diarrhea may help reduce the incidence of this side effect during adjuvant treatment for rectal cancer. Methods and Materials: Consecutive patients treated curatively for rectal cancer were reviewed, and the maximum grade of acute diarrhea was determined. The small bowel was outlined on the treatment planning CT scan, and a dose-volume histogram was calculated for the initial pelvic treatment (45 Gy). Logistic regression models were fitted for varying cutoff-dose levels from 5 to 45 Gy in 5-Gy increments. The model with the highest LogLikelihood was used to developmore » a cutoff-dose normal tissue complication probability (NTCP) model. Results: There were a total of 152 patients (48% preoperative, 47% postoperative, 5% other), predominantly treated prone (95%) with a three-field technique (94%) and a protracted venous infusion of 5-fluorouracil (78%). Acute Grade 3 diarrhea occurred in 21%. The largest LogLikelihood was found for the cutoff-dose logistic regression model with 15 Gy as the cutoff-dose, although the models for 20 Gy and 25 Gy had similar significance. According to this model, highly significant correlations (p <0.001) between small bowel volumes receiving at least 15 Gy and toxicity exist in the considered patient population. Similar findings applied to both the preoperatively (p = 0.001) and postoperatively irradiated groups (p = 0.001). Conclusion: The incidence of Grade 3 diarrhea was significantly correlated with the volume of small bowel receiving at least 15 Gy using a cutoff-dose NTCP model.« less

Carcinogenesis From Inhaled (PuO2)-Pu-239 in Beagles: Evidence for Radiation Homeostasis at Low Doses?

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

Fisher, Darrell R.; Weller, Richard E.

From the early 1970s to the late 1980s, Pacific Northwest National Laboratory conducted life-span studies in beagle dogs on the biological effects of inhaled plutonium (239PuO2, 238PuO2, and 239Pu[NO3]4) to help predict risks associated with accidental intakes in workers. Years later, the purpose of the present follow-up study is to reassess the dose-response relationship for lung cancer induction in the 239PuO2 dogs compared to controls, with particular focus on the dose-response at low lung doses. A 239PuO2 aerosol (2.3 μm AMAD, 1.9 μm GSD) was administered to six groups of 20 young (18-month old) beagle dogs (10 males and 10more » females) by inhalation at six different activity levels, as previously described in Laboratory reports. Control dogs were sham-exposed. In dose level 1, initial pulmonary lung depositions were 130 ± 48 Bq (3.5 ± 1.3 nCi), corresponding to 1 Bq g-1 lung tissue (0.029 ± 0.001 nCi g-1. Groups 2 through 6 received initial lung depositions (mean values) of 760, 2724, 10345, 37900, and 200000 Bq (22, 79, 300, 1100, and 5800 nCi) 239PuO2, respectively. For each dog, the absorbed dose to lungs was calculated from the initial lung burden and the final lung burden at time of death and lung mass, assuming a single, long-term retention function. Insoluble plutonium oxide exhibited long retention times in the lungs. Increased dose-dependent mortality due to lung cancer (bronchiolar-alveolar carcinoma, adenocarcinoma, epidermoid carcinoma) and radiation pneumonitis (highest exposures group) was observed in dogs exposed to 239PuO2. Calculated lung doses ranged from a few cGy in early-sacrificed dogs to 7764 cGy in dogs that experienced early deaths from radiation pneumonitis. Data were regrouped by lifetime lung dose and plotted as a function of lung tumor incidence. Lung tumor incidence in controls and zero-dose exposed dogs was 18% (5/28). However, no lung tumors were observed in 16 dogs with the lowest lung doses (8 to 22 cGy, mean 14.4 ± 7.6 cGy), and only one lung tumor was observed in 10 dogs with lung doses ranging from 27 to 48 cGy (mean 37.5 ± 10.9 cGy). By least-squares analysis, a quadratic function represented the overall dose-response (n = 137, r = 0.96) with no dose threshold. Reducing this function to three linear dose-response components, risk coefficients were calculated for each. The incidence of lung tumors at zero dose was significantly greater than the incidence at low dose (at the p ≤ 0.053 confidence level), suggesting a protective effect (radiation homeostasis) of alpha-particle radiation from 239PuO2. If a threshold for lung cancer incidence exists, it will be observed in the range 15 to 40 cGy.« less

Pharmacokinetics and pharmacodynamics of intrathecally administered Xen2174, a synthetic conopeptide with norepinephrine reuptake inhibitor and analgesic properties

PubMed Central

Hay, Justin L.; Sitsen, Elske; Dahan, Albert; Klaassen, Erica; Houghton, William; Groeneveld, Geert Jan

2016-01-01

Aim Xen2174 is a synthetic 13‐amino acid peptide that binds specifically to the norepinephrine transporter, which results in inhibition of norepinephrine uptake. It is being developed as a possible treatment for moderate to severe pain and is delivered intrathecally. The current study was performed to assess the pharmacodynamics (PD) and the cerebrospinal fluid (CSF) pharmacokinetics (PK) of Xen2174 in healthy subjects. Methods This was a randomized, blinded, placebo‐controlled study in healthy subjects. The study was divided into three treatment arms. Each group consisted of eight subjects on active treatment and two or three subjects on placebo. The CSF was sampled for 32 h using an intrathecal catheter. PD assessments were performed using a battery of nociceptive tasks (electrical pain, pressure pain and cold pressor tasks). Results Twenty‐five subjects were administered Xen2174. CSF PK analysis showed a higher area under the CSF concentration–time curve of Xen2174 in the highest dose group than allowed by the predefined safety margin based on nonclinical data. The most common adverse event was post‐lumbar puncture syndrome, with no difference in incidence between treatment groups. Although no statistically significant differences were observed in the PD assessments between the different dosages of Xen2174 and placebo, pain tolerability in the highest dose group was higher than in the placebo group [contrast least squares mean pressure pain tolerance threshold of Xen2174 2.5 mg–placebo (95% confidence interval), 22.2% (−5.0%, 57.1%); P = 0.1131]. Conclusions At the Xen2174 dose level of 2.5 mg, CSF concentrations exceeded the prespecified exposure limit based on the nonclinical safety margin. No statistically significant effects on evoked pain tests were observed. PMID:27987228

Management of Lignite Fly Ash for Improving Soil Fertility and Crop Productivity

NASA Astrophysics Data System (ADS)

Ram, Lal C.; Srivastava, Nishant K.; Jha, Sangeet K.; Sinha, Awadhesh K.; Masto, Reginald E.; Selvi, Vetrivel A.

2007-09-01

Lignite fly ash (LFA), being alkaline and endowed with excellent pozzolanic properties, a silt loam texture, and plant nutrients, has the potential to improve soil quality and productivity. Long-term field trials with groundnut, maize, and sun hemp were carried out to study the effect of LFA on growth and yield. Before crop I was sown, LFA was applied at various doses with and without press mud (an organic waste from the sugar industry, used as an amendment and source of nutrients). LFA with and without press mud was also applied before crops III and V were cultivated. Chemical fertilizer, along with gypsum, humic acid, and biofertilizer, was applied in all treatments, including the control. With one-time and repeat applications of LFA (with and without press mud), yield increased significantly (7.0-89.0%) in relation to the control crop. The press mud enhanced the yield (3.0-15.0%) with different LFA applications. The highest yield LFA dose was 200 t/ha for one-time and repeat applications, the maximum yield being with crop III (combination treatment). One-time and repeat application of LFA (alone and in combination with press mud) improved soil quality and the nutrient content of the produce. The highest dose of LFA (200 t/ha) with and without press mud showed the best residual effects (eco-friendly increases in the yield of succeeding crops). Some increase in trace- and heavy-metal contents and in the level of γ-emitters in soil and crop produce, but well within permissible limits, was observed. Thus, LFA can be used on a large scale to boost soil fertility and productivity with no adverse effects on the soil or crops, which may solve the problem of bulk disposal of fly ash in an eco-friendly manner.

Opioid Utilization and Opioid-Related Adverse Events in Non-Surgical Patients in U.S. Hospitals

PubMed Central

Herzig, Shoshana J.; Rothberg, Michael B.; Cheung, Michael; Ngo, Long H.; Marcantonio, Edward R.

2014-01-01

Background Recent studies in the outpatient setting have demonstrated high rates of opioid prescribing and overdose-related deaths. Prescribing practices in hospitalized patients are unexamined. Objective To investigate patterns and predictors of opioid utilization in non-surgical admissions to U.S. hospitals, variation in use, and the association between hospital-level use and rates of severe opioid-related adverse events. Design, Setting, and Patients Adult non-surgical admissions to 286 U.S. hospitals. Measurements Opioid exposure and severe opioid-related adverse events during hospitalization, defined using hospital charges and ICD-9-CM codes. Results Of 1.14 million admissions, opioids were used in 51%. The mean ± s.d. daily dose received in oral morphine equivalents (OME) was 68 ± 185 mg; 23% of exposed received a total daily dose of ≥ 100 mg OME. Opioid prescribing rates ranged from 5% in the lowest to 72% in the highest prescribing hospital (mean 51% ± 10%). After adjusting for patient characteristics, the adjusted opioid prescribing rates ranged from 33–64% (mean 50% ± s.d. 4%). Among exposed, 0.97% experienced severe opioid-related adverse events. Hospitals with higher opioid prescribing rates had higher adjusted relative risk of a severe opioid-related adverse event per patient exposed (RR 1.23 [1.14–1.33] for highest compared to lowest prescribing quartile). Conclusions The majority of hospitalized non-surgical patients were exposed to opioids, often at high doses. Hospitals that used opioids most frequently had increased adjusted risk of a severe opioid-related adverse event per patient exposed. Interventions to standardize and enhance the safety of opioid prescribing in hospitalized patients should be investigated. PMID:24227700

Oral salmon calcitonin induced suppression of urinary collagen type II degradation in postmenopausal women: a new potential treatment of osteoarthritis.

PubMed

Bagger, Yu Z; Tankó, László B; Alexandersen, Peter; Karsdal, Morten A; Olson, Melvin; Mindeholm, Linda; Azria, Moïse; Christiansen, Claus

2005-09-01

To assess the efficacy of 3 months of oral salmon calcitonin (sCT) on cartilage degradation as estimated by the changes in the urinary excretion of C-terminal telopeptide of collagen type II (CTX-II), and to investigate whether the response of oral sCT to urinary CTX-II depends on the baseline level of cartilage turnover. This was a randomized, double blind, placebo-controlled clinical setting including 152 Danish postmenopausal women aged 55-85. The subjects received treatment with the different doses of sCT (0.15, 0.4, 1.0, or 2.5 mg) combined with Eligen technology-based carrier molecule (200 mg), or placebo for 3 months. The efficacy parameter was the changes in the 24-h excretion of urinary CTX-I/II corrected for creatinine excretion at month 3. sCT induced a significant dose-dependent decrease in 24-h urinary CTX-II excretion. Similar dose-dependent responses were found in 24-h urinary CTX-I. When stratifying the study population into tertiles of baseline urinary CTX-II, the present osteoarthritic symptoms and definite cases of osteoarthritis (OA) were significantly more frequent in women in the highest tertile of CTX-II (mean 391 +/- 18 ng/mmol). Women who received 1.0 mg of sCT and had the highest cartilage turnover presented the greatest decrease in urinary CTX-II after 3 months of treatment. In addition to its pronounced effect on bone resorption, this novel oral sCT formulation may also reduce cartilage degradation and thereby provide therapeutic benefit in terms of chondroprotection. Women with high cartilage turnover are more likely to benefit from oral sCT treatment.

Testosterone inhibits the growth of prostate cancer xenografts in nude mice.

PubMed

Song, Weitao; Soni, Vikram; Soni, Samit; Khera, Mohit

2017-09-07

Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice. Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested. The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P < 0.01) and mice that underwent orchiectomy (8%, P < 0.001). Mice that had low serum T levels had the shortest tumor volume doubling time (112 h). This doubling time was significantly shorter than that in the high dose 5 mg T arm (158 h, P < 0.001) and in the orchiectomy arm (468 h, P < 0.001). These results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth.

Ultralow dose dentomaxillofacial CT imaging and iterative reconstruction techniques: variability of Hounsfield units and contrast-to-noise ratio

PubMed Central

Bischel, Alexander; Stratis, Andreas; Kakar, Apoorv; Bosmans, Hilde; Jacobs, Reinhilde; Gassner, Eva-Maria; Puelacher, Wolfgang; Pauwels, Ruben

2016-01-01

Objective: The aim of this study was to evaluate whether application of ultralow dose protocols and iterative reconstruction technology (IRT) influence quantitative Hounsfield units (HUs) and contrast-to-noise ratio (CNR) in dentomaxillofacial CT imaging. Methods: A phantom with inserts of five types of materials was scanned using protocols for (a) a clinical reference for navigated surgery (CT dose index volume 36.58 mGy), (b) low-dose sinus imaging (18.28 mGy) and (c) four ultralow dose imaging (4.14, 2.63, 0.99 and 0.53 mGy). All images were reconstructed using: (i) filtered back projection (FBP); (ii) IRT: adaptive statistical iterative reconstruction-50 (ASIR-50), ASIR-100 and model-based iterative reconstruction (MBIR); and (iii) standard (std) and bone kernel. Mean HU, CNR and average HU error after recalibration were determined. Each combination of protocols was compared using Friedman analysis of variance, followed by Dunn's multiple comparison test. Results: Pearson's sample correlation coefficients were all >0.99. Ultralow dose protocols using FBP showed errors of up to 273 HU. Std kernels had less HU variability than bone kernels. MBIR reduced the error value for the lowest dose protocol to 138 HU and retained the highest relative CNR. ASIR could not demonstrate significant advantages over FBP. Conclusions: Considering a potential dose reduction as low as 1.5% of a std protocol, ultralow dose protocols and IRT should be further tested for clinical dentomaxillofacial CT imaging. Advances in knowledge: HU as a surrogate for bone density may vary significantly in CT ultralow dose imaging. However, use of std kernels and MBIR technology reduce HU error values and may retain the highest CNR. PMID:26859336

Tissue distributions of fluoride and its toxicity in the gills of a freshwater teleost, Cyprinus carpio.

PubMed

Cao, Jinling; Chen, Jianjie; Wang, Jundong; Wu, Xiangtian; Li, Yundong; Xie, Lingtian

2013-04-15

Fish take up fluoride directly from water and are susceptible to fluoride contamination of their environment. In this study, we examined the tissue distributions of fluoride and its toxicity in the gills of the common carp (Cyprinus carpio) chronically exposed to fluoride. Carp were exposed to a range of aqueous fluoride (35-124 mg/L) and sampled at 30, 60 and 90 days. The accumulation of fluoride in the tissues increased with the level and duration of exposure. Steady state was not achieved under the experimental conditions. The gills accumulated the highest levels of fluoride followed by the liver>brain>kidney>muscle>intestine. A dose-dependent inhibition was observed for the enzyme activities of Na(+)-K(+)-ATPase and Ca(2+)-ATPase in the gills after the fish were exposed for 90 days. Also, accumulation of fluoride was associated with the inhibition of superoxide dismutase (SOD) activities and a dose-dependent stimulation of malondialdehyde (MDA) levels in the gill tissues, suggesting that fluoride promoted oxidative stress in the fish. Microscopic examinations revealed injuries to gill tissues and chloride cells, with the severity of injury increasing with exposure concentration. These results suggest that chronic exposure to elevated concentrations of fluoride may induce toxicity in the common carp. Copyright © 2012 Elsevier B.V. All rights reserved.

The effect of shade and vermicompost application on yield and flavonoid levels of Tempuyung (Sonchus arvensis)

NASA Astrophysics Data System (ADS)

Putri, D. P.; Widyastuti, Y.; Dewi, W. S.; Yunus, A.

2018-03-01

This study aims to determine the effect of shade and vermicompost on yield and level of flavonoids in Tempuyung (Sonchus arvensis). The study was conducted in May- August 2016, in Tegal Gede Village, Kab. Karanganyar. Secondary metabolite content analysis was performed in B2P2TOOT laboratory, Tawangmangu. This study used a Completely Randomized Design (CRD) arranged in a split plot. Treatment consists of shade as main plot and the dose of vermicompost as sub plot. Shade treatments are 0% (without shade), 50% and 75%. The dose of vermicompost are 0 g / polybag (control), 250 g / polybag, 500 g / polybag and 750 g / polybag. Each treatment was repeated 3 times and each in experimental unit consist of 2 sample plants. The results showed that the higher levels of shade tend to decrease vegetative growth of plants. Moreover, vermicompost give significant effect on leaf weight, l number, wet and dry weight. The combination of 0% shade and 750 gram vermicompost gave the highest value (P <0.05) to leaf weight ± 186.68 g, wet weight ± 252.08 g and dry weight ± 30,76 gTempuyung. The combination of 50% shade with 0 g vermicompost and 75% shade with 250 g vermicompost show to increasing the content of flavonoid compounds.

The effects of heavy metals and their interactions with polycyclic aromatic hydrocarbons on the oxidative stress among coke-oven workers

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

Wang, Tian; Feng, Wei; Kuang, Dan

Heavy metals and polycyclic aromatic hydrocarbons (PAHs) are predominate toxic constituents of particulate air pollution that may be related to the increased risk of cardiopulmonary events. We aim to investigate the effects of the toxic heavy metals (arsenic, As; cadmium, Cd; chromium, Cr; nickel, Ni; and lead, Pb), and their interactions with PAHs on oxidative stress among coke-oven workers. A total of 1333 male workers were recruited in this study. We determined their urinary levels of As, Cd, Cr, Ni, Pb, twelve PAH metabolites, 8-hydroxydeoxyguanosine (8-OHdG), and 8-iso-prostaglandin-F2α (8-iso-PGF2α). Multivariate linear regression models were used to analyze the effects ofmore » these metals and their interactions with PAHs on 8-OHdG and 8-iso-PGF2α levels. It was found that only urinary As and Ni showed marginal or significant positive linear dose-dependent effects on 8-OHdG in this study population, especially among smokers (β=0.103, P=0.073 and β=0.110, P=0.002, respectively). After stratifying all participants by the quartiles of ΣOH-PAH, all five metals showed linear association with 8-OHdG in the highest quartile subgroup (Q4) of ΣOH-PAHs. However, these five urinary metals showed significantly consistent linear associations with 8-iso-PGF2α in all subjects and each stratum. Urinary ΣOH-PAHs can significant modify the effects of heavy metals on oxidative stress, while co-exposure to both high levels of ΣOH-PAHs and heavy metals render the workers with highest 8-OHdG and 8-iso-PGF2α (all P{sub interaction}≤0.005). This study showed evidence on the interaction effects of heavy metals and PAHs on increasing the oxidative stress, and these results warrant further investigation in more longitudinal studies. - Highlights: • Heavy metals and PAHs are predominate toxic constituents of particulate matters. • Urinary As and Ni showed linear dose-dependent effects on 8-OHdG and 8-iso-PGF2α. • PAHs significant interact with toxic metal in increasing 8-OHdG and 8-iso-PGF2α. • Co-exposure to high PAHs and toxic metals contribute to highest oxidative stress.« less

Influence of a Commercial Lead Apron on Patient Skin Dose Delivered During Oral and Maxillofacial Examinations under Cone Beam Computed Tomography (CBCT).

PubMed

Schulze, Ralf Kurt Willy; Sazgar, Mahssa; Karle, Heiko; de Las Heras Gala, Hugo

2017-08-01

The purpose of this paper is to investigate the impact of a commercial lead apron on patient skin dose delivered during maxillofacial CBCT in five critical regions by means of solid-state-dosimetry. Five anatomical regions (thyroid gland, left and right breast, gonads, back of the phantom torso) in an adult female anthropomorphic phantom were selected for dose measurement by means of the highly sensitive solid-state dosimeter QUART didoSVM. Ten repeated single exposures were assessed for each patient body region for a total of five commercial CBCT devices with and without a lead apron present. Shielded and non-shielded exposures were compared under the paired Wilcoxon test, with absolute and relative differences computed. Reproducibility was expressed as the coefficient of variation (CV) between the 10 repeated assessments. The highest doses observed at skin level were found at the thyroid (mean shielded ± SD: 450.5 ± 346.7 μGy; non-shielded: 339.2 ± 348.8 μGy, p = 0.4922). Shielding resulted in a highly significant (p < 0.001) 93% dose reduction in skin dose in the female breast region with a mean non-shielded dose of approximately 35 μGy. Dose reduction was also significantly lower for the back-region (mean: -65%, p < 0.0001) as well as for the gonad-region (mean: -98%, p < 0.0001) in the shielded situation. Reproducibility was inversely correlated to skin dose (Rspearman = -0.748, p < 0.0001) with a mean CV of 10.45% (SD: 24.53 %). Skin dose in the thyroid region of the simulated patient was relatively high and not influenced by the lead apron, which did not shield this region. Dose reduction by means of a commercial lead apron was significant in all other regions, particularly in the region of the female breast.

Cosmic Radiation Exposure of Biological Test Systems During the EXPOSE-E Mission

PubMed Central

Hajek, Michael; Bilski, Pawel; Körner, Christine; Vanhavere, Filip; Reitz, Günther

2012-01-01

Abstract In the frame of the EXPOSE-E mission on the Columbus external payload facility EuTEF on board the International Space Station, passive thermoluminescence dosimeters were applied to measure the radiation exposure of biological samples. The detectors were located either as stacks next to biological specimens to determine the depth dose distribution or beneath the sample carriers to determine the dose levels for maximum shielding. The maximum mission dose measured in the upper layer of the depth dose part of the experiment amounted to 238±10 mGy, which relates to an average dose rate of 408±16 μGy/d. In these stacks of about 8 mm height, the dose decreased by 5–12% with depth. The maximum dose measured beneath the sample carriers was 215±16 mGy, which amounts to an average dose rate of 368±27 μGy/d. These values are close to those assessed for the interior of the Columbus module and demonstrate the high shielding of the biological experiments within the EXPOSE-E facility. Besides the shielding by the EXPOSE-E hardware itself, additional shielding was experienced by the external structures adjacent to EXPOSE-E, such as EuTEF and Columbus. This led to a dose gradient over the entire exposure area, from 215±16 mGy for the lowest to 121±6 mGy for maximum shielding. Hence, the doses perceived by the biological samples inside EXPOSE-E varied by 70% (from lowest to highest dose). As a consequence of the high shielding, the biological samples were predominantly exposed to galactic cosmic heavy ions, while electrons and a significant fraction of protons of the radiation belts and solar wind did not reach the samples. Key Words: Space radiation—Dosimetry—Passive radiation detectors—Thermoluminescence—EXPOSE-E. Astrobiology 12, 387–392. PMID:22680685

In vitro exposure of cultured porcine choroid plexus epithelial cells to immunosuppressant, anti-inflammatory, and psychoactive drugs.

PubMed

Emerich, Dwaine F; Schneider, Patricia; Bintz, Briannan; Hudak, Jebecka; Thanos, Christopher G

2007-01-01

Delivery of neurotrophic molecules to the CNS is a potential treatment for preventing the neuronal loss in neurological disorders such as Huntington's disease (HD). Choroid plexus (CP) epithelial cell transplants secrete several neurotrophic factors and are neuroprotective in rat and monkey animal models of HD. HD patients receiving CP transplants would likely receive a course of immunosuppressant/anti-inflammatory treatment postsurgery and would remain on psychoactive medications to treat their motor, psychiatric, and emotional symptoms. Therefore, we examined whether CP epithelial cells are impacted by incubation with cyclosporine A (CsA), dexmethasone, haloperidol, fluoxetine, and carbamezapine. In each case, DNA was quantified to determine cell number, a formazen dye-based assay was used to quantify cell metabolism, and vascular endothelial growth factor (VEGF) levels were measured as a marker of protein secretion. Except for the highest dose of fluoxetine, none of the drugs tested exerted any detrimental effect on cell number. Incubation with CsA or dexamethasone did not have any consistent significant effect on VEGF secretion or cell metabolism. Carbamazepine was without effect while only the highest dose of haloperidol tested modestly lowered cell metabolism. VEGF secretion and cell metabolism was not measurable from CP cells exposed to 100 microM fluoxetine. These data continue to support the potential use of CP transplants in HD.

Isolation, identification and molecular docking as cyclooxygenase (COX) inhibitors of the main constituents of Matricaria chamomilla L. extract and its synergistic interaction with diclofenac on nociception and gastric damage in rats.

PubMed

Ortiz, Mario I; Fernández-Martínez, Eduardo; Soria-Jasso, Luis Enrique; Lucas-Gómez, Isaac; Villagómez-Ibarra, Roberto; González-García, Martha P; Castañeda-Hernández, Gilberto; Salinas-Caballero, Mireya

2016-03-01

Chamomile (Matricaria chamomilla L., Asteraceae) is a medicinal plant widely used as remedy for pain and gastric disorders. The association of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase its antinociceptive activity, permit the use of lower doses and limit side effects. The aim was to isolate and identify the main chemical constituents of Matricaria chamomilla ethanolic extract (MCE) as well as to explore their activity as cyclooxygenase (COX) inhibitors in silico; besides, to examine the interaction between MCE and diclofenac on nociception in the formalin test by isobolographic analysis, and to determine the level of gastric injury in rats. Three terpenoids, α-bisabolol, bisabolol oxide A, and guaiazulene, were isolated and identified by (1)H NMR. Docking simulation predicted COX inhibitory activity for those terpenoids. Diclofenac, MCE, or their combinations produced an antinociceptive effect. The sole administration of diclofenac and the highest combined dose diclofenac-MCE produced significant a gastric damage, but that effect was not seen with MCE alone. An isobologram was constructed and the derived theoretical ED35 for the antinociceptive effect was significantly different from the experimental ED35; hence, the interaction between diclofenac and MCE that mediates the antinociceptive effect is synergist. The MCE contains three major terpenoids with plausible COX inhibitory activity in silico, but α-bisabolol showed the highest affinity. Data suggest that the diclofenac-MCE combination can interact at the systemic level in a synergic manner and may have therapeutic advantages for the clinical treatment of inflammatory pain. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

TU-F-CAMPUS-T-04: An Evaluation of Out-Of-Field Doses for Electron Beams From Modern Varian and Elekta Linear Accelerators

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

Cardenas, C; Nitsch, P; Kudchadker, R

2015-06-15

Purpose: Accurately determining out-of-field doses when using electron beam radiotherapy is of importance when treating pregnant patients or patients with implanted electronic devices. Scattered doses outside of the applicator field in electron beams have not been broadly investigated, especially since manufacturers have taken different approaches in applicator designs. Methods: In this study, doses outside of the applicator field were measured for electron beams produced by a 10×10 applicator on two Varian 21iXs operating at 6, 9, 12, 16, and 20 MeV, a Varian TrueBeam operating at 6, 9, 12, 16, and 20 MeV, and an Elekta Versa HD operating atmore » 6, 9, 12 and 15 MeV. Peripheral dose profiles and percent depth doses were measured in a Wellhofer water phantom at 100 cm SSD with a Farmer ion chamber. Doses were compared to peripheral photon doses from AAPM’s Task Group #36 report. Results: Doses were highest for the highest electron energies. Doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. Substantial dose differences were observed between different accelerators; the Elekta accelerator had much higher doses than any Varian unit examined. Surprisingly, doses were often similar to, and could be much higher than, doses from photon therapy. Doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. Conclusion: The results of this study indicate that proper shielding may be very important when utilizing electron beams, particularly on a Versa HD, while treating pregnant patients or those with implanted electronic devices. Applying a water equivalent bolus of Emax(MeV)/4 thickness (cm) on the patient would reduce fetal dose drastically for all clinical energies and is a practical solution to manage the potentially high peripheral doses seen from modern electron beams. Funding from NIH Grant number: #CA180803.« less

Toxicokinetics of fumonisin B1 in turkey poults and tissue persistence after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds.

PubMed

Tardieu, Didier; Bailly, Jean-Denis; Skiba, Fabien; Grosjean, François; Guerre, Philippe

2008-09-01

The kinetic of fumonisin B1 (FB1) after a single IV and oral dose, and FB1 persistence in tissue were investigated in turkey poults by HPLC after purification of samples on columns. After IV administration (single-dose: 10mg FB1/kg bw), serum concentration-time curves were best described by a three-compartment open model. Elimination half-life and mean residence time of FB1 were 85 and 52min, respectively. After oral administration (single-dose: 100mg FB1/kg bw) bioavailability was 3.2%; elimination half-life and mean residence time were 214 and 408min, respectively. Clearance of FB1 was 7.6 and 7.5ml/min/kg for IV and oral administration, respectively. Twenty-four hours after the administration of FB1 by the intravenous route, liver and kidney contained the highest levels of FB1 in tissues, level in muscle was low or below the limit of detection (LD, 13microg/kg). The persistence of FB1 in tissue was also studied after administration for 9 weeks of a feed that contained 5, 10 and 20mg FB1+FB2/kg diet. Eight hours after the last intake of 20mg FB1+FB2/kg feed (maximum recommended concentration of fumonisins established by the EU for avian feed), hepatic and renal FB1 concentrations were 119 and 22microg/kg, level in muscles was below the LD.

Mentha longifolia protects against acetic-acid induced colitis in rats.

PubMed

Murad, Hussam A S; Abdallah, Hossam M; Ali, Soad S

2016-08-22

Mentha longifolia L (Wild Mint or Habak) (ML) is used in traditional medicine in treatment of many gastrointestinal disorders. This study aimed to evaluate potential protecting effect of ML and its major constituent, eucalyptol, against acetic acid-induced colitis in rats, a model of human inflammatory bowel disease (IBD). Rats were divided into ten groups (n=8) given orally for three days (mg/kg/day) the following: normal control, acetic acid-induced colitis (un-treated, positive control), vehicle (DMSO), sulfasalazine (500), ML extract (100, 500, 1000), and eucalyptol (100, 200, 400). After 24h-fasting, two ML of acetic acid (3%) was administered intrarectally. On the fifth day, serum and colonic biochemical markers, and histopathological changes were evaluated. Colitis significantly increased colonic myeloperoxidase activity and malonaldehyde level, and serum tumor necrosis factor-α, interleukin-6, and malonaldehyde levels while significantly decreased colonic and serum glutathione levels. All treatments (except ML 100, ML 1000, and eucalyptol 100) significantly reversed these changes where eucalyptol (400) showed the highest activity in a dose-dependent manner. The colitis-induced histopathological changes were mild in sulfasalazine and eucalyptol 400 groups, moderate in ML 500 and eucalyptol 200 groups, and severe in ML 100, ML 1000, and eucalyptol 100 groups nearly similar to colitis-untreated rats. ML (in moderate doses) and eucalyptol (dose-dependently) exerted protective effects against acetic acid-induced colitis in rats possibly through antioxidant and antiinflammatory properties suggesting a potential benefit in treatments of IBD. To our knowledge this is the first report addressing this point. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias

PubMed Central

Zabkiewicz, Joanna; Gilmour, Marie; Hills, Robert; Vyas, Pares; Bone, Elizabeth; Davidson, Alan; Burnett, Alan; Knapper, Steven

2016-01-01

Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001) and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor γ-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs. PMID:26934551

The Role of Fructose, Sucrose and High-fructose Corn Syrup in Diabetes.

PubMed

Cozma, Adrian I; Sievenpiper, John L

2014-02-01

Concerns are growing regarding the role of dietary sugars in the development of obesity and cardiometabolic diseases, including diabetes. High-fructose corn syrup (HFCS) and sucrose are the most important dietary sweeteners. Both HFCS and sucrose have overlapping metabolic actions with adverse effects attributed to their fructose moiety. Ecological studies have linked the rise in fructose availability with the increases in obesity and diabetes worldwide. This link has been largely underpinned by animal models and select human trials of fructose overfeeding at high levels of exposure. Although prospective cohort studies have shown significant associations comparing the highest with the lowest levels of intake sugar-sweetened beverages, these associations are small, do not hold at moderate levels of intake and are subject to collinearity effects from related dietary and lifestyle factors. Most systematic reviews and meta-analyses from controlled feeding trials have shown that fructose-containing sugars in isocaloric exchange for other carbohydrates do not show evidence of harm and, in the case of fructose, may even have advantages for glycaemic control, especially at small doses. Nevertheless, trials in which fructose-containing sugars supplement diets with excess energy have shown adverse effects, effects that appear more attributable to the excess energy than the sugar. There is no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects, although there is potentially cause for concern where fructose is provided at high doses or contributes excess energy to diets. Further investigation is warranted due to the significant knowledge gaps and weaknesses in existing research.

The Role of Fructose, Sucrose and High-fructose Corn Syrup in Diabetes

PubMed Central

Cozma, Adrian I

2014-01-01

Abstract Concerns are growing regarding the role of dietary sugars in the development of obesity and cardiometabolic diseases, including diabetes. High-fructose corn syrup (HFCS) and sucrose are the most important dietary sweeteners. Both HFCS and sucrose have overlapping metabolic actions with adverse effects attributed to their fructose moiety. Ecological studies have linked the rise in fructose availability with the increases in obesity and diabetes worldwide. This link has been largely underpinned by animal models and select human trials of fructose overfeeding at high levels of exposure. Although prospective cohort studies have shown significant associations comparing the highest with the lowest levels of intake sugar-sweetened beverages, these associations are small, do not hold at moderate levels of intake and are subject to collinearity effects from related dietary and lifestyle factors. Most systematic reviews and meta-analyses from controlled feeding trials have shown that fructose-containing sugars in isocaloric exchange for other carbohydrates do not show evidence of harm and, in the case of fructose, may even have advantages for glycaemic control, especially at small doses. Nevertheless, trials in which fructose-containing sugars supplement diets with excess energy have shown adverse effects, effects that appear more attributable to the excess energy than the sugar. There is no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects, although there is potentially cause for concern where fructose is provided at high doses or contributes excess energy to diets. Further investigation is warranted due to the significant knowledge gaps and weaknesses in existing research. PMID:29872464

75 FR 40729 - Residues of Quaternary Ammonium Compounds, N-Alkyl (C12-14

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-14

.... Systemic toxicity occurs after absorption and distribution of the chemical to tissues in the body. Such... identified (the LOAEL) or a Benchmark Dose (BMD) approach is sometimes used for risk assessment. Uncertainty.... No systemic effects observed up to 20 mg/ kg/day, highest dose of technical that could be tested...

Radiation dose optimization in pediatric temporal bone computed tomography: influence of tube tension on image contrast and image quality.

PubMed

Nauer, Claude Bertrand; Zubler, Christoph; Weisstanner, Christian; Stieger, Christof; Senn, Pascal; Arnold, Andreas

2012-03-01

The purpose of this experimental study was to investigate the effect of tube tension reduction on image contrast and image quality in pediatric temporal bone computed tomography (CT). Seven lamb heads with infant-equivalent sizes were scanned repeatedly, using four tube tensions from 140 to 80 kV while the CT-Dose Index (CTDI) was held constant. Scanning was repeated with four CTDI values from 30 to 3 mGy. Image contrast was calculated for the middle ear as the Hounsfield unit (HU) difference between bone and air and for the inner ear as the HU difference between bone and fluid. The influence of tube tension on high-contrast detail delineation was evaluated using a phantom. The subjective image quality of eight middle and inner ear structures was assessed using a 4-point scale (scores 1-2 = insufficient; scores 3-4 = sufficient). Middle and inner ear contrast showed a near linear increase with tube tension reduction (r = -0.94/-0.88) and was highest at 80 kV. Tube tension had no influence on spatial resolution. Subjective image quality analysis showed significantly better scoring at lower tube tensions, with highest image quality at 80 kV. However, image quality improvement was most relevant for low-dose scans. Image contrast in the temporal bone is significantly higher at low tube tensions, leading to a better subjective image quality. Highest contrast and best quality were found at 80 kV. This image quality improvement might be utilized to further reduce the radiation dose in pediatric low-dose CT protocols.

Comparison of parameters affecting GNP-loaded choroidal melanoma dosimetry; Monte Carlo study

NASA Astrophysics Data System (ADS)

Sharabiani, Marjan; Asadi, Somayeh; Barghi, Amir Rahnamai; Vaezzadeh, Mehdi

2018-04-01

The current study reports the results of tumor dosimetry in the presence of gold nanoparticles (GNPs) with different sizes and concentrations. Due to limited number of works carried out on the brachytherapy of choroidal melanoma in combination with GNPs, this study was performed to determine the optimum size and concentration for GNPs which contributes the highest dose deposition in tumor region, using two phantom test cases namely water phantom and a full Monte Carlo model of human eye. Both water and human eye phantoms were simulated with MCNP5 code. Tumor dosimetry was performed for a typical point photon source with an energy of 0.38 MeV as a high energy source and 103Pd brachytherapy source with an average energy of 0.021 MeV as a low energy source in water phantom and eye phantom respectively. Such a dosimetry was done for different sizes and concentrations of GNPs. For all of the diameters, increase in concentration of GNPs resulted in an increase in dose deposited in the region of interest. In a certain concentration, GNPs with larger diameters contributed more dose to the tumor region, which was more pronounced using eye phantom. 100 nm was reported as the optimum size in order to achieve the highest energy deposition within the target. This work investigated the optimum parameters affecting macroscopic dose enhancement in GNP-aided brachytherapy of choroidal melanoma. The current work also had implications on using low energy photon sources in the presence of GNPs to acquire the highest dose enhancement. This study is conducted through four different sizes and concentrations of GNPs. Considering the sensitivity of human eye tissue, in order to report the precise optimum parameters affecting radiosensitivity, a comprehensive study on a wide range of sizes and concentrations are required.

Determination of (210)Po in calcium supplements and the possible related dose assessment to the consumers.

PubMed

Strumińska-Parulska, Dagmara I

2015-12-01

The aim of this pioneer study was to investigate the most popular calcium supplements as a potential additional source of polonium (210)Po in human diet. The analyzed calcium pharmaceutics contained organic or inorganic calcium compounds; some from natural sources as mussels' shells, fish extracts, or sedimentary rocks. The objectives of this research were to investigate the naturally occurring (210)Po activity concentrations in calcium supplements, find the correlations between (210)Po concentration in medicament and calcium chemical form, and calculate the effective radiation dose connected to analyzed calcium supplement consumption. As results showed, (210)Po concentrations in natural origin calcium supplements (especially sedimentary rocks) were higher than the other analyzed. Also the results of (210)Po analysis obtained for inorganic forms of calcium supplements were higher. The highest (210)Po activity concentrations were determined in mineral tablets made from sedimentary rocks: dolomite and chalk - 3.88 ± 0.22 and 3.36 ± 0.10 mBq g(-1) respectively; while the lowest in organic calcium compounds: calcium lactate and calcium gluconate - 0.07 ± 0.02 and 0.17 ± 0.01 mBq g(-1). The annual effective radiation doses from supplements intake were estimated as well. The highest annual radiation dose from (210)Po taken with 1 tablet of calcium supplement per day was connected to sample made from chalk - 2.5 ± 0.07 μSv year(-1), while the highest annual radiation dose from (210)Po taken with 1 g of pure calcium per day was connected to dolomite - 12.7 ± 0.70 μSv year(-1). Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of gamma irradiation on the microbiological quality and on the functional properties of proteins in dry red kidney beans ( Phaseolus vulgaris)

NASA Astrophysics Data System (ADS)

Dogbevi, M. K.; Vachon, C.; Lacroix, M.

2000-03-01

Gamma-irradiation was found to affect the physicochemical properties of dry red kidney beans. The highest dose used (8 kGy) significantly ( P⩽0.05) modified the extent of deamidation, the number of sulfhydryl groups, as well as the solubility and the hydrophobicity of the protein. Deamidation, protein solubility and hydrophobicity all increased with the irradiation dose while the number of sulfhydryl groups was reduced by the treatment. Furthermore, irradiation also affected the outgrowth of natural filamentous fungi contaminants present on the dry beans. A dose of 1.5 kGy reduced the number of filamentous fungi by 2 log cycles immediately after treatment. However, the highest dose used (3 kGy) did not eliminate the filamentous fungi completely. Moreover, the filamentous fungi population was a lot less diversified on the irradiated samples. Species of Aspergillus sp. and Penicillium sp. were more abundant on the unirradiated beans while the beans irradiated at 3 kGy contained were predominantly infected by species of Rhizopus sp. , Cladosporium sp. and Alternaria sp.

Early-stage central lung cancer and volumetric modulated arc therapy: a dosimetric case study with literature review.

PubMed

Valakh, Vladimir; Chan, Philip; D'Adamo, Karen; Micaily, Bizhan

2013-10-01

In the present article we review on the use of Volumetric Modulated Arc Therapy (VMAT) for a small lung nodule that was centrally located in close proximity to the mediastinal structures. An inoperable patient with central, clinical stage IA adenocarcinoma of the right lung was treated with external-beam radiation therapy of 52.5 Gy in 15 factions. A single 360° coplanar arc VMAT plan (360-VMAT) was used for treatment and compared to step-and-shoot Intensity Modulation Radiotherapy (IMRT) and a single 180° ipsilateral partial arc VMAT plan (180-VMAT). Planning Target Volume (PTV) coverage was not different, and 360-VMAT had the highest dose homogeneity. Both 360-VMAT and 180-VMAT reduced esophageal dose compared to IMRT. While IMRT had the lowest lung dose, all 3 plans achieved acceptable sparing of the lung. 180-VMAT had the highest dose conformity. Both 360-VMAT and 180-VMAT improved esophageal sparing compared to IMRT. Use of VMAT in early-stage, centrally located NSCLC is a promising treatment approach and merits additional investigation.