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Sample records for repeat dose study

  1. Acute and repeated dose toxicity studies of different β-cyclodextrin-based nanosponge formulations.

    Science.gov (United States)

    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals.

  2. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... strains of young healthy adult animals should be employed. The females should be nulliparous and...

  3. Evaluation of statistical tools used in short-term repeated dose administration toxicity studies with rodents.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Sakuratani, Yuki; Abe, Takemaru; Kamata, Eiichi; Hayashi, Makoto

    2008-02-01

    In order to know the different statistical tools used to analyze the data obtained from twenty-eight-day repeated dose oral toxicity studies with rodents and the impact of these statistical tools on interpretation of data obtained from the studies, study reports of 122 numbers of twenty-eight-day repeated dose oral toxicity studies conducted in rats were examined. It was found that both complex and easy routes of decision trees were followed for the analysis of the quantitative data. These tools include Scheffe's test, non-parametric type Dunnett's and Scheffe's tests with very low power. Few studies used the non-parametric Dunnett type test and Mann-Whitney's U test. Though Chi-square and Fisher's tests are widely used for analysis of qualitative data, their sensitivity to detect a treatment-related effect is questionable. Mann-Whitney's U test has better sensitivity to analyze qualitative data than the chi-square and Fisher's tests. We propose Dunnett's test for analysis of quantitative data obtained from twenty-eight-day repeated dose oral toxicity tests and for qualitative data, Mann-Whitney's U test. For both tests, one-sided test with p=0.05 may be applied.

  4. Statistical methodology to determine kinetically derived maximum tolerated dose in repeat dose toxicity studies.

    Science.gov (United States)

    McFadden, Lisa G; Bartels, Michael J; Rick, David L; Price, Paul S; Fontaine, Donald D; Saghir, Shakil A

    2012-07-01

    Several statistical approaches were evaluated to identify an optimum method for determining a point of nonlinearity (PONL) in toxicokinetic data. (1) A second-order least squares regression model was fit iteratively starting with data from all doses. If the second order term was significant (αmodel was fit iteratively starting with data from all doses except the highest. The mean response for the omitted dose was compared to the 95% prediction interval. If the omitted dose falls outside the confidence interval it is an estimate of the PONL. (3) Slopes of least squares linear regression lines for sections of contiguous doses were compared. Nonlinearity was suggested when slopes of compared sections differed. A total of 33 dose-response datasets were evaluated. For these toxicokinetic data, the best statistical approach was the least squares regression analysis with a second-order term. Changing the α level for the second-order term and weighting the second-order analysis by the inverse of feed consumption were also considered. This technique has been shown to give reproducible identification of nonlinearities in TK datasets.

  5. Investigation of the toxicity of some organophosphorus pesticides in a repeated dose study in rats.

    Science.gov (United States)

    Baconi, Daniela Luiza; Bârcă, Maria; Manda, Gina; Ciobanu, Anne Marie; Bălălău, C

    2013-01-01

    The study aimed to the investigation of the toxicity of organophosphorus pesticides malathion (MLT) and diazinon (DZN) in Wistar rats in a repeated dose study for 35 days. MLT and DZN in corn oil vehicle were oral administered. Body and organs weights, plasma and brain cholinesterase activities, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities, histopathological changes in liver and kidney, and some parameters of the immune function, such as leukocyte formula, spleen weight and cellularity, spleen lymphocytes proliferation in response to concanavalin A (Con A) were investigated; the potential oxidative stress (malondialdehyde in plasma and brain, and blood catalase activity) was also evaluated. No clinical toxicity signs attributed to pesticides were noted; no significant changes in the organ weights have been found. Body weight tends slightly to increase, predominantly in DZN treated rats. The results suggest that plasma cholinesterase is more susceptible than brain cholinesterase to the inhibitory effect of DZN and MLT. Other serum biochemical parameters showed no significant difference. DZN produced a marked increase of the number of spleen lymphocytes without a significant gain of the relative spleen weight. The both pesticides produced an increase of the number of mononuclear cells÷weight spleen. The splenic lymphocyte proliferation has not been influenced by MLT or DZN treatment. Histopathological observations identified some changes (vasodilatation, microvacuoles, and granular dystrophy) in the liver, with MLT, inducing macrovacuolar steatosis. The study indicates that repeated exposure, at subclinical doses, to organophosphorus MLT and DZN causes some biochemical, histopathological and immune alterations in rats.

  6. The role of exposure history on HIV acquisition: insights from repeated low-dose challenge studies.

    Directory of Open Access Journals (Sweden)

    Roland R Regoes

    Full Text Available To assess the efficacy of HIV vaccine candidates or preventive treatment, many research groups have started to challenge monkeys repeatedly with low doses of the virus. Such challenge data provide a unique opportunity to assess the importance of exposure history for the acquisition of the infection. I developed stochastic models to analyze previously published challenge data. In the mathematical models, I allowed for variation of the animals' susceptibility to infection across challenge repeats, or across animals. In none of the studies I analyzed, I found evidence for an immunizing effect of non-infecting challenges, and in most studies, there is no evidence for variation in the susceptibilities to the challenges across animals. A notable exception was a challenge experiment by Letvin et al. Sci Translat Med (2011 conducted with the strain SIVsmE660. The challenge data of this experiment showed significant susceptibility variation from animal-to-animal, which is consistent with previously established genetic differences between the involved animals. For the studies which did not show significant immunizing effects and susceptibility differences, I conducted a power analysis and could thus exclude a very strong immunization effect for some of the studies. These findings validate the assumption that non-infecting challenges do not immunize an animal - an assumption that is central in the argument that repeated low-dose challenge experiments increase the statistical power of preclinical HIV vaccine trials. They are also relevant for our understanding of the role of exposure history for HIV acquisition and forecasting the epidemiological spread of HIV.

  7. A 13-week dermal repeat-dose neurotoxicity study of hydrodesulfurized kerosene in rats.

    Science.gov (United States)

    Breglia, Rudolph; Bui, Quang; Burnett, Donald; Koschier, Francis; Lapadula, Elizabeth; Podhasky, Paula; Schreiner, Ceinwen; White, Russell

    2014-01-01

    A 13-week dermal repeat-dose toxicity study was conducted with hydrodesulfurized (HDS) kerosene, a test material that also met the commercial specifications for aviation turbine fuel (jet A). The objectives were to assess the potential for target organ toxicity and neurotoxicity. The HDS kerosene was applied to the shaved backs of Sprague-Dawley CD rats, 12/sex/group, 6 h/d, 5 d/wk in doses of 0 (vehicle control), 165 mg/kg (20% HDS kerosene), 330 mg/kg (40% HDS kerosene), or 495 mg/kg (60% HDS kerosene). Additional rats (12/sex) from the control and the high-dose groups were held without treatment for 4 weeks to assess recovery. Standard parameters of toxicity were investigated during the in-life phase. At necropsy, organs were weighed and selected tissues were processed for microscopic evaluation. Neurobehavioral evaluations included tests of motor activity and functional observations that were conducted pretest, at intervals during the exposure period and after recovery. No test substance-related effects on mortality, clinical observations (except dermal irritation), body weight, or clinical chemistry values were observed. A dose-related increase in skin irritation, confirmed histologically as minimal, was evident at the dosing site. The only statistically significant change considered potentially treatment related was an increase in the neutrophil count in females at 13 weeks. No test article-related effects were observed in the neurobehavioral assessments or gross or microscopic findings in the peripheral or central nervous system tissues in any of the dose groups. Excluding skin irritation, the no observed adverse effect level value for all effects was considered 495 mg/kg/d.

  8. Study of four week repeated dose toxic test of Sweet Bee Venom in Beagle Dogs

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    Jae-Seuk Park

    2010-12-01

    Full Text Available Objectives: This study was performed to analyse four week repeated dose toxicity of Sweet Bee Venom(Sweet BV extracted from the bee venom in Beagle dogs. Methods: All experiments were conducted under the regulations of Good Laboratory Practice (GLP at Biotoxtech Company, a non-clinical study authorized institution. Male and female Beagle dogs of 5-6 months old were chosen for the pilot study of four week repeated dose toxicity of Sweet BV which was administered at the level of 0.56㎎/㎏ body weight which is eighty times higher than the clinical application dosage as the high dosage, followed by 0.28 and 0.14㎎/㎏ as midium and low dosage, respectively. Equal amount of excipient(normal saline to the Sweet BV experiment groups was administered as the control group every day for four weeks. Results: 1. No mortality was witnessed in all of the experiment groups. 2. All experiment groups were appealed pain sense in the treating time compared to the control group, and hyperemia and movement disorder were observed around the area of administration in all experiment groups, and higher occurrence in the higher dosage treatment. 3. For weight measurement, Neither male nor female groups showed significant changes. 4. In the urine analysis, CBC and biochemistry didn't show any significant changes in the experiment groups compared with control group. 5. For weight measurement of organs, experiment groups didn't show any significant changes compared with control group. 6. To verify abnormalities of organs and tissues, thigh muscle which treated with Sweet BV, cerebrum, liver, lung, kidney, and spinal cords were removed and conducted histologocal observation with H-E staining. In the histologocal observation of thigh muscle, cell infiltration, inflammatory, degeneration, necrosis of muscle fiber, and fibrosis were found in both thigh tissue. And the changes were depend on the dose of Sweet BV. But another organs were not detected in any abnormalities. 7

  9. Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine.

    Science.gov (United States)

    Mancebo, A; Casacó, A; Sánchez, B; González, B; Gómez, D; León, A; Bada, A M; Arteaga, M E; González, Y; González, C; Pupo, M; Fuentes, Dasha

    2012-12-01

    Our goal was to assess the toxicity of two strengths (200 and 400 μg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10×), 28.6 and 57.1 μg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 μg, 57.1 μg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used.

  10. Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

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    Dent, M P

    2007-08-01

    The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert

  11. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia

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    Balaji Ramachandran

    2016-01-01

    Full Text Available EGCG (Epigallocatechin-3-gallate is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal] and limited [p.o (oral] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  12. The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse.

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    Molyneux, Gemma; Gibson, Frances M; Chen, Christabelle M; Marway, Harpal K; McKeag, Sean; Mifsud, Charles V J; Pilling, Andrew M; Whayman, Matthew J; Turton, John A

    2008-04-01

    Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

  13. Repeated-Doses Toxicity Study of the Essential Oil of Hyptis martiusii Benth. (Lamiaceae in Swiss Mice

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    Germana Freire Rocha Caldas

    2013-01-01

    Full Text Available Hyptis martiusii Benth. (Lamiaceae is found in abundance in Northeastern Brazil where it is used in traditional medicine to treat gastric disorders. Since there are no studies reporting the toxicity and safety profile of this species, we investigated repeated-doses toxicity of the essential oil of Hyptis martiusii (EOHM. Swiss mice of both sexes were orally treated with EOHM (100 and 500 mg/kg for 30 days, and biochemical, hematological, and morphological parameters were determined. No toxicity signs or deaths were recorded during the treatment with EOHM. The body weight gain was not affected, but there was an occasional variation in water and food consumption among mice of both sexes treated with both doses. The hematological and biochemical profiles did not show significant differences except for a decrease in the MCV and an increase in albumin, but these variations are within the limits described for the species. The microscopic analysis showed changes in liver, kidneys, lungs, and spleen; however, these changes do not have clinical relevance since they varied among the groups, including the control group. The results indicate that the treatment of repeated-doses with the essential oil of Hyptis martiusii showed low toxicity in mice.

  14. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study

    Science.gov (United States)

    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida

    2014-05-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.

  15. Zinc oxide nanoparticles: a 90-day repeated-dose dermal toxicity study in rats

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    Ryu HJ

    2014-12-01

    was dose-dependent irritation at the site of application, there were no abnormal findings related to ZnO NPs in other organs. Increased concentrations of ZnO in the liver, small intestine, large intestine, and feces were thought to result from oral ingestion of ZnO NPs via licking. Penetration of ZnO NPs through the skin seemed to be limited via the dermal route. This study demonstrates that there was no observed adverse effect of ZnO NPs up to 1,000 mg/kg body weight when they are applied dermally. Keywords: zinc oxide, nanoparticles, subchronic toxicity, dermal exposure

  16. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

    Science.gov (United States)

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  17. Pharmacokinetic evaluation of pamidronate after oral administration: a study on dose proportionality, absolute bioavailability, and effect of repeated administration

    DEFF Research Database (Denmark)

    Hyldstrup, Lars; Flesch, G; Hauffe, S A

    1993-01-01

    30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51-70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion...

  18. Collaborative work on evaluation of ovarian toxicity. 2) Two- or four-week repeated dose studies and fertility study of mifepristone in female rats.

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    Tamura, Toru; Yokoi, Ryohei; Okuhara, Yuji; Harada, Chiho; Terashima, Yukari; Hayashi, Morimichi; Nagasawa, Tatsuya; Onozato, Tomoya; Kobayashi, Kazuo; Kuroda, Junji; Kusama, Hiroshi

    2009-01-01

    In order to assess ovarian pathological changes and their relationship to changes in female fertility parameters, mifepristone, a progesterone receptor antagonist, was selected as the test article and was administered orally to female rats at dose levels of 0, 0.8, 4, 20 and 100 mg/kg for 2 or 4 weeks in repeated dose-toxicity studies and in a female fertility study at dose levels of 0, 0.8, 4 and 20 mg/kg from > 2 weeks before copulation to postcoital day 7. In the repeated dose toxicity studies, persistent estrus was seen in the vaginal smears, and multiple cysts in the ovaries at necropsy, increases in luteinized cysts and hypertrophy of previously formed corpora lutea were observed in the histopathological examination of ovaries in rats receiving 20 mg/kg or more for 2 or 4 weeks. In female fertility studies, persistent vaginal cornification was also observed at 20 mg/kg and the precoital interval was significantly shortened. All of the animals were completely infertile when dosed with 20 mg/kg during the post-coital period. An increase in pre-implantation losses was observed in the animals treated with 20 mg/kg during the pre-coital phase, while treatment with 4 mg/kg mifepristone during the post-coital phase induced an increase in post-implantation losses. These results suggested that a 2-week administration period would be sufficient to detect the ovarian toxicity of mifepristone in repeated dose toxicity study and the pathological findings in the ovaries would reflect the alterations in female reproductive endpoints in the female fertility study.

  19. Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.

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    Ishii, Shun-ichiro; Ube, Masayuki; Okada, Miyoko; Adachi, Tamiko; Sugimoto, Jiro; Inoue, Yoshimi; Uno, Yoshifumi; Mutai, Mamoru

    2009-01-01

    To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

  20. Influence of the adaptive iterative dose reduction 3D algorithm on the detectability of low-contrast lesions and radiation dose repeatability in abdominal computed tomography: a phantom study.

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    Yoon, Jeong Hee; Lee, Jeong Min; Hur, Bo Yun; Baek, Jeehyun; Shim, Hackjoon; Han, Joon Koo; Choi, Byung Ihn

    2015-08-01

    The purpose of the study is to evaluate the influence of the adaptive iterative dose reduction (AIDR 3D) algorithm on the detectability of low-contrast focal liver lesions (FLLs) and the radiation dose repeatability of automatic tube current modulation (ATCM) in abdominal CT scans using anthropomorphic phantoms. Three different sizes of anthropomorphic phantoms, each with 4 low-contrast FLLs, were scanned on a 320-channel CT scanner using the ATCM technique and AIDR 3D, at different radiation doses: full-dose, half-dose, and quarter-dose. Scans were repeated three times and reconstructed with filtered back projection (FBP) and AIDR 3D. Radiation dose repeatability was assessed using the intraclass correlation coefficient (ICC). Image noise, quality, and lesion conspicuity were assessed by four reviewers and the number of invisible FLLs was compared among different radiation doses and reconstruction methods. ICCs of radiation dose among the three CT scans were excellent in all phantoms (0.99). Image noise, quality, and lesion conspicuity in the half-dose group were comparable with full-dose FBP after applying AIDR 3D in all phantoms. In small phantoms, the half-dose group reconstructed with AIDR 3D showed similar sensitivity in visualizing low-contrast FLLs compared to full-dose FBP (P = 0.77-0.84). In medium and large phantoms, AIDR 3D reduced the number of missing low-contrast FLLs [3.1% (9/288), 11.5% (33/288), respectively], compared to FBP [10.4% (30/288), 21.9% (63/288), respectively] in the full-dose group. By applying AIDR 3D, half-dose CT scans may be achievable in small-sized patients without hampering diagnostic performance, while it may improve diagnostic performance in medium- and large-sized patients without increasing the radiation dose.

  1. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.

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    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi

    2015-03-01

    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals.

  2. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

    Science.gov (United States)

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

    2012-04-10

    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  3. Repeated dose pharmacokinetics of pancopride in human volunteers.

    Science.gov (United States)

    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A

    1994-11-01

    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Repeated high-dose (5 × 10(8) TCID50) toxicity study of a third generation smallpox vaccine (IMVAMUNE) in New Zealand white rabbits.

    Science.gov (United States)

    Tree, Julia A; Hall, Graham; Rees, Peter; Vipond, Julia; Funnell, Simon G P; Roberts, Allen D

    2016-07-01

    Concern over the release of variola virus as an agent of bioterrorism remains high and a rapid vaccination regimen is desirable for use in the event of a confirmed release of virus. A single, high-dose (5×10(8) TCID50) of Bavarian Nordic's IMVAMUNE was tested in a Phase-II clinical trial, in humans, as a substitute for the standard (1×10(8) TCID50), using a 2-dose, 28-days apart regimen. Prior to this clinical trial taking place a Good Laboratory Practice, repeated high-dose, toxicology study was performed using IMVAMUNE, in New Zealand white rabbits and the results are reported here. Male and female rabbits were dosed twice, subcutaneously, with 5×10(8) TCID50 of IMVAMUNE (test) or saline (control), 7-days apart. The clinical condition, body-weight, food consumption, haematology, blood chemistry, immunogenicity, organ-weight, and macroscopic and microscopic pathology were investigated. Haematological investigations indicated changes within the white blood cell profile that were attributed to treatment with IMVAMUNE; these comprised slight increases in neutrophil and monocyte numbers, on study days 1-3 and a marginal increase in lymphocyte numbers on day 10. Macroscopic pathology revealed reddening at the sites of administration and thickened skin in IMVAMUNE, treated animals. After the second dose of IMVAMUNE 9/10 rabbits seroconverted, as detected by antibody ELISA on day 10, by day 21, 10/10 rabbits seroconverted. Treatment-related changes were not detected in other parameters. In conclusion, the subcutaneous injection of 2 high-doses of IMVAMUNE, to rabbits, was well tolerated producing only minor changes at the site of administration. Vaccinia-specific antibodies were raised in IMVAMUNE-vaccinated rabbits only.

  5. Toxicity from repeated doses of acetaminophen in children: assessment of causality and dose in reported cases.

    Science.gov (United States)

    Heard, Kennon; Bui, Alison; Mlynarchek, Sara L; Green, Jody L; Bond, G Randall; Clark, Richard F; Kozer, Eran; Koff, Raymond S; Dart, Richard C

    2014-01-01

    Liver injury has been reported in children treated with repeated doses of acetaminophen. The objective of this study was to identify and validate reports of liver injury or death in children younger than 6 years who were administered repeated therapeutic doses of acetaminophen. We reviewed US Poison Center data, peer-reviewed literature, US Food and Drug Administration Adverse Event Reports, and US Manufacturer Safety Reports describing adverse effects after acetaminophen administration. Reports that described hepatic abnormalities (description of liver injury or abnormal laboratory testing) or death after acetaminophen administration to children younger than 6 years were included. The identified reports were double abstracted and then reviewed by an expert panel to determine if the hepatic injury was related to acetaminophen and whether the dose of acetaminophen was therapeutic (≤75 mg/kg) or supratherapeutic. Our search yielded 2531 reports of adverse events associated with acetaminophen use. From these cases, we identified 76 cases of hepatic injury and 26 deaths associated with repeated acetaminophen administration. There were 6 cases of hepatic abnormalities and no deaths associated with what our panel determined to be therapeutic doses. A large proportion of cases could not be fully evaluated due to incomplete case reporting. Although we identified numerous examples of liver injury and death after repeated doses of acetaminophen, all the deaths and all but 6 cases of hepatic abnormalities involved doses more than 75 mg/kg per day. This study suggests that the doses of less than 75 mg/kg per day of acetaminophen are safe for children younger than 6 years.

  6. 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs.

    Science.gov (United States)

    Yimam, Mesfin; Lee, Young Chul; Jia, Qi

    2016-07-01

    The needs for relatively safe botanical alternatives to relieve symptoms associated to arthritis have continued to grow in parallel with the ageing population. UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, has been used as over the counter joint care dietary supplements and a prescription medical food. Significant safety data have been documented in rodents and human for this composition. Here we evaluated the potential adverse effects of orally administered UP446 in beagle dogs following a 26-week repeated oral dose toxicity study. UP446 at doses of 250, 500 and 1000 mg/kg/day were administered orally to beagle dogs for 26 weeks. A 4-week recovery group from the high dose (1000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, ophthalmological examinations, electrocardiograms, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Emesis, loose feces and diarrhea were noted in both genders at the 1000 mg/kg treatment groups. These clinical signs were considered to be reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP446 was considered to be 500 mg/kg/day both in male and female beagle dogs.

  7. Repeat spinal anesthesia in cesarean section: A comparison between 10 mg and 12 mg doses of intrathecal hyperbaric (0.05%) bupivacaine repeated after failed spinal anesthesia: A prospective, parallel group study.

    Science.gov (United States)

    Bhar, Debasish; RoyBasunia, Sandip; Das, Anjan; Chhaule, Subinay; Mondal, Sudipta Kumar; Bisai, Subrata; Chattopadhyay, Surajit; Mandal, Subrata Kumar

    2016-01-01

    Spinal anesthesia for cesarean section is not a 100% successful technique. At times, despite straightforward insertion and drug administration, intrathecal anesthesia for cesarean section fails to obtain any sensory or motor block. Very few studies and literature are available regarding repeat administration of spinal anesthesia and its drug dosage, especially after first spinal failure in cesarean section lower segment cesarean section (LSCS) due to fear of the excessive spread of drug. The aim of our study is to compare the outcome between two different doses of 0.5% hyperbaric bupivacaine repeated intrathecally after failed spinal. After taking informed consent and Ethical Committee approval this prospective, randomized single-blinded study was conducted in 100 parturients of American Society of Anesthesiologists I-II who were posted for elective LSCS and had Bromage score 0 and no sensory block even at L4 dermatome after 10 min of first spinal anesthesia; were included in the study. Group A (n = 50) patients received 2.4 ml and Group B (n = 50) patients received 2 ml of 0.5% hyperbaric bupivacaine respectively for administering repeat spinal anesthesia. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), oxygen saturation, respiratory rate and electrocardiogram were monitored both intra- and post-operatively and complications were recorded. Incidence of high spinal, bradycardia, hypotension, respiratory complications, and nausea vomiting are significantly higher in Group A compared to Group B (P cesarean section with 10 mg of 0.5% hyperbaric bupivacaine provided after first spinal anesthesia, the level of sensory block is below L4 and motor power in Bromage scale is 0.

  8. Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

    Science.gov (United States)

    Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

    2014-01-01

    Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

  9. (1)H NMR-based metabolomics study on repeat dose toxicity of fine particulate matter in rats after intratracheal instillation.

    Science.gov (United States)

    Zhang, Yannan; Hu, Hejing; Shi, Yanfeng; Yang, Xiaozhe; Cao, Lige; Wu, Jing; Asweto, Collins Otieno; Feng, Lin; Duan, Junchao; Sun, Zhiwei

    2017-07-01

    Systemic metabolic effects and toxicity mechanisms of ambient fine particulate matter (PM2.5) remain uncertain. In order to investigate the mechanisms in PM2.5 toxicity, we explored the endogenous metabolic changes and possible influenced metabolic pathways in rats after intratracheal instillation of PM2.5 by using a (1)H nuclear magnetic resonance (NMR)-based metabolomics approach. Liver and kidney histopathology examinations were also performed. Chemical characterization demonstrated that PM2.5 was a complex mixture of elements. Histopathology showed cellular edema in liver and glomerulus atrophy of the PM2.5 treated rats. We systematically analyzed the metabolites changes of serum and urine in rats using (1)H NMR techniques in combination with multivariate statistical analysis. Significantly reduced levels of lactate, alanine, dimethylglycine, creatine, glycine and histidine in serum, together with increased levels of citrate, arginine, hippurate, allantoin and decreased levels of allthreonine, lactate, alanine, acetate, succinate, trimethylamine, formate in urine were observed of PM2.5 treated rats. The mainly affected metabolic pathways by PM2.5 were glycine, serine and threonine metabolism, glyoxylate and dicarboxylate metabolism, citrate cycle (TCA cycle), nitrogen metabolism and methane metabolism. Our study provided important information on assessing the toxicity of PM2.5 and demonstrated that metabolomics approach can be employed as a tool to understand the toxicity mechanism of complicated environmental pollutants. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Repeated-dose liver micronucleus test of 4,4'-methylenedianiline using young adult rats.

    Science.gov (United States)

    Sanada, Hisakazu; Koyama, Naomi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    Liver micronucleus (MN) tests using partial hepatectomized rats or juvenile rats have been shown to be useful for the detection of hepatic carcinogens. Moreover, Narumi et al. established the repeated-dose liver MN test using young adult rats for integration into general toxicity. In the present study, in order to examine the usefulness of the repeated-dose liver MN test, we investigated MN induction with a 14 or 28 day treatment protocol using young adult rats treated with 4,4′-methylenedianiline (MDA), a known hepatic carcinogen. MDA dose-dependently induced micronuclei in hepatocytes in 14- and 28-day repeated-dose tests. However, although statistically significant increases in micronuclei were observed in bone marrow cells at two dose levels in the 14-day study, there was no dose response and no increases in micronuclei in the 28-day study. These results indicate that the evaluation of genotoxic effects using hepatocytes is effective in cases where chromosomal aberrations are not clearly detectable in bone marrow cells. Moreover, the repeated-dose liver MN test allows evaluation at a dose below the maximum tolerable dose, which is required for the conventional MN test because micronucleated hepatocytes accumulate. The repeated-dose liver MN test employed in the present study can be integrated into the spectrum of general toxicity tests without further procedural modifications.

  11. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats.

    Science.gov (United States)

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

    2009-02-01

    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while testing of cosmetic ingredients.

  12. Influence of coefficient of variation in determining significant difference of quantitative values obtained from 28-day repeated-dose toxicity studies in rats.

    Science.gov (United States)

    Kobayashi, Katsumi; Sakuratani, Yuki; Abe, Takemaru; Yamazaki, Kazuko; Nishikawa, Satoshi; Yamada, Jun; Hirose, Akihiko; Kamata, Eiichi; Hayashi, Makoto

    2011-01-01

    In order to understand the influence of coefficient of variation (CV) in determining significant difference of quantitative values of 28-day repeated-dose toxicity studies, we examined 59 parameters of 153 studies conducted in accordance with Chemical Substance Control Law in 12 test facilities. Sex difference was observed in 12 parameters and 10 parameters showed large CV in females. The minimum CV was 0.74% for sodium. CV of electrolytes was comparatively small, whereas enzymes had large CV. Large differences in CV were observed for major parameters among 7-8 test facilities. The changes in CV were grossly classified into 11. Our study revealed that a statistical significant difference is usually detected if there is a difference of 7% in mean values between the groups and the groups have a CV of about 7%. A parameter with a CV as high as 30% may be significantly different, if the difference of the mean between the groups is 30%. It would be ideal to use median value to assess the treatment-related effect, rather than mean, when the CV is very high. We recommend using CV of the body weight as a standard to judge the adverse effect level.

  13. Dose estimation for repeated phosphorus-32 ingestion in human subjects

    Energy Technology Data Exchange (ETDEWEB)

    Chao, J.H.; Tseng, C.L.; Hsieh, W.A.; Hung, D.Z.; Chang, W.P. E-mail: wpc94@mailsrv.ym.edu.tw

    2001-01-15

    Dose estimation was conducted for internal phosphorus-32 exposure in one young male subject from repeated oral mis-ingestion for >1 year. Since disclosure for previous continuous contamination, a series of urine samples were collected from this individual weekly for a period of >2 months. P-32 radioactivity in urine samples were measured by the acid precipitation method. Estimation for retrospective total effective dose equivalent received by this subject was conducted for cumulative internal dose estimation. A minimum of 9.4 mSv was estimated for an assumed single ingestion. As this was a rare case in radiation protection and internal radiation dosimetry, its implications were of considerable significance.

  14. Repeated dose of ketamine effect to the rat hippocampus tissue

    Directory of Open Access Journals (Sweden)

    Mehtap Okyay Karaca

    2015-01-01

    Full Text Available Aim: We aimed to determine the neurotoxic effect of repeated ketamine administration on brain tissue and if neurotoxic effect was present, whether this effect continued 16 days later using histological stereological method, a quantitative and objective method. Materials and Methods: Female rats were divided into three groups, each containing five rats. Rats in Group I were given 0.9% saline solution 4 times a day for 5 days. The rats in Groups II and III were given ketamine as intraperitoneal injections. Rats in Groups I and II were sacrificed on 5 th day while the ones in Group III on 21 st day. Cornu ammonis (CA and gyrus dentatus (GD regions in hippocampus tissue of rats were studied using optic fractionation method. Findings: There were significantly less number of cells in hippocampal CA and GD regions of rats from Groups II and III compared to the ones from Group I. Difference in cell number was also significantly higher in Group III than in Group II, but this difference was not as pronounced as the one between Groups III and I. Conclusion: Repeated ketamine doses caused neurotoxicity in rat hippocampus.

  15. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 22). Effects of 2- and 4-week administration of theobromine on the testis.

    Science.gov (United States)

    Funabashi, H; Fujioka, M; Kohchi, M; Tateishi, Y; Matsuoka, N

    2000-10-01

    The effects of theobromine, a xanthine derivative, on the testis were compared between rats dosed for 2 and 4 weeks to determine whether a 2-week dosing period is long enough to detect toxicity. Theobromine was administered orally to male Sprague-Dawley rats at dose levels of 250 and 500 mg/kg for 2 weeks starting at the age of 6 or 8 weeks, and for 4 weeks from the age of 6 weeks. Histopathological examination of reproductive organs revealed toxic findings in the testis at 500 mg/kg after 2 weeks of dosing at both ages, and at 250 and 500 mg/kg after 4 weeks of dosing. The primary findings were degeneration/necrosis and desquamation of spermatids and spermatocytes, vacuolization of seminiferous tubules, and multinucleated giant cell formation. These findings were present mainly in stages I-VI and XII-XIV. From these results, it is concluded that the toxic effects of theobromine on the testis can be detected by repeated dosing for 2 weeks as well as for 4 weeks.

  16. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    OpenAIRE

    Collaku A; Yue Y.; Reed K

    2017-01-01

    Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly ass...

  17. Mid-Childhood Bone Mass After Exposure to Repeat Doses of Antenatal Glucocorticoids: A Randomized Trial.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2017-05-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity, but could have adverse effects on skeletal development. We assessed whether exposure to repeat antenatal betamethasone alters bone mass in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to a single dose of betamethasone or placebo, ≥7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children underwent whole-body dual-energy radiograph absorptiometry at 6 to 8 years' corrected age. Of 212 eligible childhood survivors, 185 were studied (87%; 91 repeat betamethasone group; 94 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar whole-body bone mineral content (median repeat betamethasone: 553 g, interquartile range: 442-712 g; placebo: 567 g, interquartile range: 447-750 g; geometric mean ratio: 0.99; 95% confidence interval: 0.94-1.03, P = .55) and bone area (median repeat betamethasone 832 cm(2), interquartile range: 693-963 cm(2); placebo: 822 cm(2), interquartile range: 710-1020 cm(2); geometric mean ratio: 0.99, 95% confidence interval: 0.92-1.07, P = .75). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not alter bone mass in mid-childhood. Copyright © 2017 by the American Academy of Pediatrics.

  18. A phase 1 study evaluating the pharmacokinetics, safety and tolerability of repeat dosing with a human IL-13 antibody (CAT-354 in subjects with asthma

    Directory of Open Access Journals (Sweden)

    Roskos Lorin

    2010-01-01

    Full Text Available Abstract Background IL-13 has been implicated in the development of airway inflammation and hyperresponsiveness. This study investigated the multiple-dose pharmacokinetics and safety profile of human anti-IL-13 antibody (CAT-354 in adults with asthma. Methods This was a multiple-dose, randomised, double-blind, placebo-controlled phase 1 study in asthmatics (forced expiratory volume in 1 second [FEV1] ≥ 80% predicted. Subjects were randomised to receive three intravenous infusions of CAT-354 (1 mg/kg, 5 mg/kg or 10 mg/kg or placebo at 28-day intervals. Blood samples were taken for pharmacokinetic measurements. Safety was assessed by adverse events, vital signs, ECGs, laboratory and pulmonary function parameters. Results Twenty-three subjects (aged 21-60 years, FEV1 88-95% predicted received ≥ 1 dose of study medication. The half-life of CAT-354 was 12-17 days and was dose-independent. The maximum serum concentration and area under the curve were dose-dependent. Clearance (2.2-2.6 mL/day/kg and volume of distribution (44-57 mL/kg were both low and dose-independent. The observed maximum serum concentration after each dose increased slightly from dose 1 through dose 3 at all dose levels, consistent with an accumulation ratio of 1.4 to 1.7 for area under the curve. Most adverse events were deemed mild to moderate and unrelated to study medication. One SAE was reported and deemed unrelated to study drug. There were no effects of clinical concern for vital signs, ECG, laboratory or pulmonary parameters. Conclusions CAT-354 exhibited linear pharmacokinetics and an acceptable safety profile. These findings suggest that at the doses tested, CAT-354 can be safely administered in multiple doses to patients with asthma. Trial registration NCT00974675.

  19. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster

    DEFF Research Database (Denmark)

    Langkilde, Søren; Mandimika, T.; Schrøder, Malene

    2009-01-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine...... to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity...... of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios...

  20. Pharmacology of ayahuasca administered in two repeated doses.

    Science.gov (United States)

    Dos Santos, Rafael G; Grasa, Eva; Valle, Marta; Ballester, Maria Rosa; Bouso, José Carlos; Nomdedéu, Josep F; Homs, Rosa; Barbanoj, Manel J; Riba, Jordi

    2012-02-01

    Ayahuasca is an Amazonian tea containing the natural psychedelic 5-HT(2A/2C/1A) agonist N,N-dimethyltryptamine (DMT). It is used in ceremonial contexts for its visionary properties. The human pharmacology of ayahuasca has been well characterized following its administration in single doses. To evaluate the human pharmacology of ayahuasca in repeated doses and assess the potential occurrence of acute tolerance or sensitization. In a double-blind, crossover, placebo-controlled clinical trial, nine experienced psychedelic drug users received PO the two following treatment combinations at least 1 week apart: (a) a lactose placebo and then, 4 h later, an ayahuasca dose; and (b) two ayahuasca doses 4 h apart. All ayahuasca doses were freeze-dried Amazonian-sourced tea encapsulated to a standardized 0.75 mg DMT/kg bodyweight. Subjective, neurophysiological, cardiovascular, autonomic, neuroendocrine, and cell immunity measures were obtained before and at regular time intervals until 12 h after first dose administration. DMT plasma concentrations, scores in subjective and neurophysiological variables, and serum prolactin and cortisol were significantly higher after two consecutive doses. When effects were standardized by plasma DMT concentrations, no differences were observed for subjective, neurophysiological, autonomic, or immunological effects. However, we observed a trend to reduced systolic blood pressure and heart rate, and a significant decrease for growth hormone (GH) after the second ayahuasca dose. Whereas there was no clear-cut tolerance or sensitization in the psychological sphere or most physiological variables, a trend to lower cardiovascular activation was observed, together with significant tolerance to GH secretion.

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

    Science.gov (United States)

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

    2015-03-01

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

  2. A 28-day repeat dose toxicity study of steroidal glycoalkaloids a-solanine and a-chaconine in the Syrian Golden Hamster

    NARCIS (Netherlands)

    Langkilde, S.; Mandimika, T.; Schroder, M.; Meyer, O.; Slob, W.; Peijnenburg, A.A.C.M.; Poulsen, M.

    2009-01-01

    Glycoalkaloids ¿-solanine and ¿-chaconine are naturally present toxicants in the potato plant (Solanum tuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of ¿-solanine to ¿-chaconine m

  3. A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

    Science.gov (United States)

    Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

    2014-04-01

    3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

  4. Effect of repeated doses of mercuric chloride on the kinetics of iron in rats

    Energy Technology Data Exchange (ETDEWEB)

    Grosicki, A.; Kossakowski, S. [National Veterinary Research Institute, Pulawy (Poland)

    1994-12-31

    The effect of repeated doses of 0.5 and 1.0 mg HgCl{sub 2}/kg b.w. given intragastrically for 30 days on the absorption and distribution of intragastrically trace dose of {sup 59}FeCl{sub 3} was studied in male Wistar rats. Both doses of mercury distributed the absorption of Fe-59 from the gastrointestinal track. Furthermore, the results revealed a dose-dependent influence of mercury on the content of Fe-59 in the organs and the AUC values. (author). 14 refs, 2 figs, 1 tab.

  5. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

    Science.gov (United States)

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  6. Single- and repeated-dose oral toxicity studies of citicoline free-base (choline cytidine 5'-pyrophosphate) in Sprague-Dawley rats.

    Science.gov (United States)

    Schauss, A G; Somfai-Relle, S; Financsek, I; Glavits, R; Parent, S C; Endres, J R; Varga, T; Szücs, Z; Clewell, A

    2009-01-01

    The dietary supplement Citicoline free-base (choline cytidine 5'-pyrophosphate) was toxicologically evaluated in Sprague-Dawley rats using oral gavage. In an acute 14-day study, 2000 mg/kg was well tolerated. In a 90-day study, 100, 350, and 1000 mg/kg/day doses resulted in no mortality. In males, slight significant increases in serum creatinine (350 and 1000 mg/kg/day), and decreases in urine volume (all treated groups) were observed. In females, slight significant increases in total white blood cell and absolute lymphocyte counts (1000 mg/kg/day), and blood urea nitrogen (BUN) (100 and 350, but not 1000 mg/kg/day) were noted. A dose-related increase in renal tubular mineralization, without degenerative or inflammatory reaction, was found in females (all treated groups) and two males (1000 mg/kg/day). Renal mineralization in rats (especially females) is influenced by calcium:phosphorus ratios in the diet. A high level of citicoline consumption resulted in increased phosphorus intake in the rats, and likely explains this result.

  7. Evaluation of the repeated-dose liver micronucleus assay using N-nitrosomorpholine in young adult rats: report on collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen Society (JEMS)-Mammalian Mutagenicity Study (MMS) Group.

    Science.gov (United States)

    Hayashi, Aya; Kosaka, Mizuki; Kimura, Aoi; Wako, Yumi; Kawasako, Kazufumi; Hamada, Shuichi

    2015-03-01

    The present study was conducted to evaluate the suitability of a repeated-dose liver micronucleus (LMN) assay in young adult rats as a collaborative study by the Mammalian mutagenicity study (MMS) group. All procedures were performed in accordance with the standard protocols of the MMS Group. Six-week-old male Crl:CD(SD) rats (5 animals/group) received oral doses of the hepatocarcinogen N-nitrosomorpholine (NMOR) at 0 (control), 5, 10, and 30mg/kg/day (10mL/kg) for 14 days. Control animals received vehicle (water). Hepatocytes were collected from the liver 24h after the last dose, and the number of micronucleated hepatocytes (MNHEPs) was determined by microscopy. The number of micronucleated immature erythrocytes (MNIMEs) in the femoral bone marrow was also determined. The liver was examined using histopathologic methods after formalin fixation. The results showed statistically significant and dose-dependent increases in the number of MNHEPs in the liver at doses of 10mg/kg and greater when compared with the vehicle control. However, no significant increase was noted in the number of MNIMEs in the bone marrow at doses of up to 30mg/kg. Histopathology of the liver revealed hypertrophy and single cell necrosis of hepatocytes at doses of 5mg/kg and above. These results showed that the induction of micronuclei by NMOR was detected by the repeated-dose LMN assay, but not by the repeated-dose bone marrow micronucleus assay.

  8. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT.

    Science.gov (United States)

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-02-01

    Treatment of women at risk for preterm birth with repeat doses of glucocorticoids reduces neonatal morbidity but could have adverse long-term effects on cardiometabolic health in offspring. We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial of Repeat Doses of Corticosteroids. Women were randomized to betamethasone or placebo treatment, ≥ 7 days after an initial course of glucocorticoids, repeated each week that they remained at risk for preterm birth at children were assessed at 6 to 8 years' corrected age for body composition, insulin sensitivity, ambulatory blood pressure, and renal function. Of 320 eligible childhood survivors, 258 were studied (81%; 123 repeat betamethasone group; 135 placebo [single course] group). Children exposed to repeat antenatal betamethasone and those exposed to placebo had similar total fat mass (geometric mean ratio 0.98, 95% confidence interval [CI] 0.78 to 1.23), minimal model insulin sensitivity (geometric mean ratio 0.89, 95% CI 0.74 to 1.08), 24-hour ambulatory blood pressure (mean difference systolic 0 mm Hg, 95% CI -2 to 2; diastolic 0 mm Hg, 95% CI -1 to 1), and estimated glomerular filtration rate (mean difference 1.2 mL/min/1.73 m(2), 95% CI -3.2 to 5.6). Exposure to repeat doses of antenatal betamethasone compared with a single course of glucocorticoids does not increase risk factors for cardiometabolic disease at early school age. Copyright © 2015 by the American Academy of Pediatrics.

  9. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS).

    Science.gov (United States)

    Tluczkiewicz, Inga; Batke, Monika; Kroese, Dinant; Buist, Harrie; Aldenberg, Tom; Pauné, Eduard; Grimm, Helvi; Kühne, Ralph; Schüürmann, Gerrit; Mangelsdorf, Inge; Escher, Sylvia E

    2013-11-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evaluates the conditions under which in vivo non-guideline studies are reliable. In a tiered approach three aspects of these "non-guideline" studies are assessed: the documentation of the study (reliability), the quality of the study design (adequacy) and the scope of examination (validity). The reliability is addressed by the method "Knock-out criteria", which consists of four essential criteria for repeated-dose toxicity studies. A second tool, termed QUANTOS (Quality Assessment of Non-guideline Toxicity Studies), evaluates and weights the adequacy of the study by using intra-criterion and inter-criteria weighting. Finally, the Coverage approach calculates a probability that the detected Lowest-Observed-Effect-Level (LOEL) is similar to the LOEL of a guideline study dependent on the examined targets and organs of the non-guideline study. If the validity and adequacy of the non-guideline study are insufficient for risk assessment, the ITS proposes to apply category approach or the Threshold of Toxicological Concern (TTC) concept, and only as a last resort new animal-testing.

  10. Repeated doses of melatonin protects against focal cerebral ischemia in the rat

    OpenAIRE

    Pei, Z; Pang, SF; Cheung, RTF

    2000-01-01

    We studied the time window of neuroprotection against focal ischemia by a single dose or repeated doses of melatonin (MT) at 5 mg/kg. Adult male Sprague-Dawley rats (280 to 360 g) were anesthetized with sodium pentobarbital (60 mg/kg, I.P.) to undergo reversible right-sided endovascular middle cerebral artery occlusion (MCAO) for 3 hours. Arterial blood pressure, heart rate and cerebral blood flow were monitored, and rectal temperature was kept between 36.5 and 37.5 ºC throughout anesthesia. ...

  11. Pharmacokinetics of metadoxine for injection after repeated doses in healthy volunteers

    Institute of Scientific and Technical Information of China (English)

    L(U) Yuan; KANG Zi-sheng; LIU Yan; LI Tian-yun; XIAO Yong-hong

    2007-01-01

    @@ Alcohol-induced liver disease is one of the main epidemic problems nowadays. Metadoxine is a pyridoxine-pyrrolidone carboxylate with significant scavenging property. Metadoxine is able to accelerate the elimination of alcohol from the blood and tissues, help restore the functional structure of the liver and relieve neuro-psychological disorders associated with alcohol intoxication.1-3 The purpose of the study was to assay the pharmacokinetics of domestic metadoxine after repeated doses.

  12. [Twenty-eight days repeated dose toxicity test of N-(fluorodichloromethylthio)phthalimide in rats].

    Science.gov (United States)

    Matsushima, Y; Tsuda, M; Naito, K; Saitoh, M; Isama, K; Ikarashi, Y; Kawasaki, Y; Momma, J; Kitajima, S; Kaniwa, M

    1995-01-01

    N-(Fluorodichloromethylthio)phthalimide (Fluor-folpet) has been widely used as an anti-mold and anti-bacterial agent. In this study, 28 days repeated-dose oral toxicity study of fluor-folpet was carried out in Slc:Wistar rats. An oral toxicity study for fluor-folpet, the twenty-eight days test, repeated-dose, oral administration, was performed as follows: Five week-old rats, male and female, 10 rats, each/group, were treated with intragastric administration of fluor-folpet with a dose of 0 (1% Sodium CMC, control), 20, 80 and 320 mg/kg, body weight. Recovery test, for 14 days after the last treatment, was examined for the control and the 320 mg/kg groups. The 320 mg/kg groups, both males and females, showed significantly reduced their body-weight gain compared with the control group. In the 320 mg/kg group, five out of 20 male rats and four out of 20 female rats died from dyspnea during the treatment period. In the female rats in the 320 mg/kg group, serum ChE level was decreased to 50% of control level and gamma-GT was increased in a dose-dependent manner, but these serum levels recovered after 14 days non-treatment period. No histopathological change, relating to the treatment, in liver was observed. Increased weight of the kidney and vacuolation in renal tubules were found in both sexes of 320 mg/kg group. Hyperkeratosis and hyperplasia of the stomach epithelium were observed at the dose more than 80 mg/kg in male, and more than 20 mg/kg in female. A supplemental study, repeated-dose, oral administration in rats carried out to examine the dyspnea revealed that severe acute toxic damages in epithelium of nasal cavity and meatus nasopharyngeus were induced by intragastric administration of fluor-folpet. Fluor-folpet is shown to be cytotoxic. In conclusion, the no-observed-effect level (NOEL) for fluor-folpet was not found under the experimental conditions employed in this repeated-dose toxicity study.

  13. Statistical tools for analysing the data obtained from repeated dose toxicity studies with rodents: a comparison of the statistical tools used in Japan with that of used in other countries.

    Science.gov (United States)

    Kobayashi, Katsumi; Pillai, K Sadasivan; Guhatakurta, Soma; Cherian, K M; Ohnishi, Mariko

    2011-01-01

    In the present study, an attempt was made to compare the statistical tools used for analysing the data of repeated dose toxicity studies with rodents conducted in 45 countries, with that of Japan. The study revealed that there was no congruence among the countries in the use of statistical tools for analysing the data obtained from the above studies. For example, to analyse the data obtained from repeated dose toxicity studies with rodents, Scheffé's multiple range and Dunnett type (joint type Dunnett) tests are commonly used in Japan, but in other countries use of these statistical tools is not so common. However, statistical techniques used for testing the above data for homogeneity of variance and inter-group comparisons do not differ much between Japan and other countries. In Japan, the data are generally not tested for normality and the same is true with the most of the countries investigated. In the present investigation, out of 127 studies examined, data of only 6 studies were analysed for both homogeneity of variance and normal distribution. For examining homogeneity of variance, we propose Levene's test, since the commonly used Bartlett's test may show heterogeneity in variance in all the groups, if a slight heterogeneity in variance is seen any one of the groups. We suggest the data may be examined for both homogeneity of variance and normal distribution. For the data of the groups that do not show heterogeneity of variance, to find the significant difference among the groups, we recommend Dunnett's test, and for those show heterogeneity of variance, we recommend Steel's test.

  14. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

  15. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Science.gov (United States)

    Collaku, Agron; Yue, Yong; Reed, Kenneth

    2017-01-01

    Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

  16. The 14-day repeated dose liver micronucleus test with methapyrilene hydrochloride using young adult rats.

    Science.gov (United States)

    Inoue, Kenji; Ochi, Akimu; Koda, Akira; Wako, Yumi; Kawasako, Kazufumi; Doi, Takaaki

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.

  17. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    Science.gov (United States)

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  18. Antidepressant-like effect of tetrahydroisoquinoline amines in the animal model of depressive disorder induced by repeated administration of a low dose of reserpine: behavioral and neurochemical studies in the rat.

    Science.gov (United States)

    Antkiewicz-Michaluk, Lucyna; Wąsik, Agnieszka; Możdżeń, Edyta; Romańska, Irena; Michaluk, Jerzy

    2014-07-01

    Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both

  19. The OSIRIS Weight of Evidence approach: ITS for the endpoints repeated-dose toxicity (RepDose ITS)

    NARCIS (Netherlands)

    Tluczkiewicz, I.; Batke, M.; Kroese, D.; Buist, H.; Aldenberg, T.; Pauné, E.; Grimm, H.; Kühne, R.; Schüürmann, G.; Mangelsdorf, I.; Escher, S.E.

    2013-01-01

    In the FP6 European project OSIRIS, Integrated Testing Strategies (ITSs) for relevant toxicological endpoints were developed to avoid new animal testing and thus to reduce time and costs. The present paper describes the development of an ITS for repeated-dose toxicity called RepDose ITS which evalua

  20. Tolerability and pharmacokinetics of ebrotidine in healthy subjects given single and repeated oral doses.

    Science.gov (United States)

    Farré, M; Roset, P N; Badenas, J M; Ugena, B; Márquez, M; Albet, C; Herrero, E; Ortiz, J A

    1997-04-01

    The tolerability and safety of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) and its basic pharmacokinetic parameters were determined after its oral administration to healthy volunteers. Sixteen subjects were selected to participate in two different studies: an increasing single dose study to determine the maximal tolerated dose (from 25 to 1600 mg), and a multiple dose study (stepped doses from 400 to 1600 mg daily for 12 days). The results of the studies showed that ebrotidine has a good tolerability. Vital signs and laboratory tests were not influenced by the study treatment. No clinically relevant adverse effects were reported during the investigation. Ebrotidine reached peak plasma concentrations 2-3 h after oral administration. Its elimination half-life ranged from 9 to 14 h. In conclusion, ebrotidine was well tolerated after administration of oral single doses of up to 1600 mg, and after repeated administration of up to 800 mg/12 h for 12 days.

  1. Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound

    Directory of Open Access Journals (Sweden)

    Yang FY

    2012-02-01

    Full Text Available Feng-Yi Yang1, Ming-Che Teng1, Maggie Lu2, Hsiang-Fa Liang2, Yan-Ru Lee1, Chueh-Chuan Yen3, Muh-Lii Liang4,5, Tai-Tong Wong51Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, 2Drug Delivery Laboratory, Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, 4Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, 5Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanBackground: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1-conjugated liposomes selectively to brain tumors.Methods: Firefly luciferase (Fluc-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice.Results: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug

  2. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide.

    Science.gov (United States)

    Zupancic, Dasa; Vidmar, Gaj; Jezernik, Kristijan

    2009-06-01

    Repeated cyclophosphamide (CP) chemotherapy increases the risk of developing bladder cancer, which could be due to the extremely rapid proliferation of urothelial cells observed in hyperplastic urothelium induced by CP treatment. We investigated the effect of melatonin on the development of urothelial hyperplasia induced by repeated CP treatment. Male ICR mice were injected with CP (150 mg/kg) or melatonin (10 mg/kg) with CP once a week for 3, 4 and 5 weeks. Transmission and scanning electron microscopy, immunohistochemistry and Western blot analysis were used to study the ultrastructure, apoptosis, proliferation and differentiation of urothelial cells. Repeated doses of CP caused the development of hyperplastic urothelium with up to ten cell layers and increased proliferation and apoptotic indices regarding Ki-67 and active caspase-3 immunohistochemistry, respectively. Scanning electron microscopy observations, cytokeratin and asymmetrical unit membrane immunohistochemistry and Western blot analysis showed a lower differentiation state of superficial urothelial cells. Melatonin co-treatment prevented the development of hyperplastic urothelium, statistically significantly decreased proliferation and apoptotic indices after four and five doses of CP and caused higher differentiation state of superficial urothelial cells.

  3. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

    Science.gov (United States)

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven

    2015-04-01

    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  4. Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

    Directory of Open Access Journals (Sweden)

    Collaku A

    2017-03-01

    Full Text Available Agron Collaku, Yong Yue, Kenneth Reed GlaxoSmithKline Consumer Healthcare, Parsippany, NJ, USA Background/objective: Guaifenesin, an over-the-counter (OTC expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods: This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0= not present to 10= unbearable recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results: A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion: Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of

  5. Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

    Science.gov (United States)

    Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

    2014-08-01

    Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

  6. An abbreviated repeat dose and reproductive/developmental toxicity test for high production volume chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Scala, R.A.; Bevan, C.; Beyer, B.K. (Exxon Biomedical Sciences, Inc., East Millstone, NJ (United States))

    1992-08-01

    A novel protocol is described for obtaining preliminary data on repeated dose systemic effects and reproductive/developmental toxicity. The test protocol was developed by a group of experts at the request of the U.S. Environmental Protection Agency (EPA) for use as part of a Screening Information Data Set on high production volume chemicals. Interest in this protocol is shared by several regulatory agencies, including the Organization for Economic Cooperation, the European Community, and the EPA. To validate the study protocol, ethylene glycol monomethyl ether (EGME) was used. After a dosing period of approximately 6 weeks, EGME showed both systemic and reproductive/developmental effects similar to those previously reported using standard protocols. Thus, this test protocol may be used as a screening tool for high production volume chemicals.

  7. Safety and Efficacy of Repeated-Dose Intravenous Ketamine for Treatment-Resistant Depression

    NARCIS (Netherlands)

    aan het Rot, Marije; Collins, Katherine A.; Murrough, James W.; Perez, Andrew M.; Reich, David L.; Charney, Dennis S.; Mathew, Sanjay J.

    2010-01-01

    Background: A single subanesthetic (intravenous) IV dose of ketamine might have rapid but transient antidepressant effects in patients with treatment-resistant depression (TRD). Here we tested the tolerability, safety, and efficacy of repeated-dose open-label IV ketamine (six infusions over 12 days)

  8. A GPU implementation of a track-repeating algorithm for proton radiotherapy dose calculations

    CERN Document Server

    Yepes, Pablo P; Taddei, Phillip J

    2010-01-01

    An essential component in proton radiotherapy is the algorithm to calculate the radiation dose to be delivered to the patient. The most common dose algorithms are fast but they are approximate analytical approaches. However their level of accuracy is not always satisfactory, especially for heterogeneous anatomic areas, like the thorax. Monte Carlo techniques provide superior accuracy, however, they often require large computation resources, which render them impractical for routine clinical use. Track-repeating algorithms, for example the Fast Dose Calculator, have shown promise for achieving the accuracy of Monte Carlo simulations for proton radiotherapy dose calculations in a fraction of the computation time. We report on the implementation of the Fast Dose Calculator for proton radiotherapy on a card equipped with graphics processor units (GPU) rather than a central processing unit architecture. This implementation reproduces the full Monte Carlo and CPU-based track-repeating dose calculations within 2%, w...

  9. Effect of repeated doses of sucrose during heel stick procedure in preterm neonates.

    Science.gov (United States)

    Johnston, C C; Stremler, R; Horton, L; Friedman, A

    1999-03-01

    The purpose of this randomized clinical trial was to test the efficacy of repeated versus single dose sucrose to decrease pain from routine heel stick procedures in preterm neonates. Infants (n = 48) in the first week of life with a mean gestational age of 31 weeks received 0.05 ml of 24% sucrose solution or sterile water by mouth (1) 2 min prior to actual lancing of the heel; (2) just prior to lancing, and (3) 2 min after lancing. The single-dose group received sucrose for the first dose and water for the second and third dose; the repeated-dose group received sucrose three times, and the placebo group received only water. The Premature Infant Pain Profile (PIPP) scores were obtained for five 30-second blocks from lancing. Both sucrose groups had lower PIPP scores (single sucrose pain scores, 6.8-8.2, p = 0.07; repeated sucrose pain scores, 5.3-6. 2, p < 0.01) than water (pain scores 7.9-9.1), and in the last block, the repeated dose had lower scores than the single dose (6.2 vs. 8. 2, p < 0.05).

  10. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review.

    Directory of Open Access Journals (Sweden)

    Charles H King

    2011-09-01

    Full Text Available Controversy persists about the optimal approach to drug-based control of schistosomiasis in high-risk communities. In a systematic review of published studies, we examined evidence for incremental benefits from repeated praziquantel dosing, given 2 to 8 weeks after an initial dose, in Schistosoma-endemic areas of Africa.We performed systematic searches of electronic databases PubMed and EMBASE for relevant data using search terms 'schistosomiasis', 'dosing' and 'praziquantel' and hand searches of personal collections and bibliographies of recovered articles. In 10 reports meeting study criteria, improvements in parasitological treatment outcomes after two doses of praziquantel were greater for S. mansoni infection than for S. haematobium infection. Observed cure rates (positive to negative conversion in egg detection assays were, for S. mansoni, 69-91% cure after two doses vs. 42-79% after one dose and, for S. haematobium, 46-99% cure after two doses vs. 37-93% after a single dose. Treatment benefits in terms of reduction in intensity (mean egg count were also different for the two species-for S. mansoni, the 2-dose regimen yielded an weighted average 89% reduction in standardized egg counts compared to a 83% reduction after one dose; for S. haematobium, two doses gave a 93% reduction compared to a 94% reduction with a single dose. Cost-effectiveness analysis was performed based on Markov life path modeling.Although schedules for repeated treatment with praziquantel require greater inputs in terms of direct costs and community participation, there are incremental benefits to this approach at an estimated cost of $153 (S. mansoni-$211 (S. haematobium per additional lifetime QALY gained by double treatment in school-based programs. More rapid reduction of infection-related disease may improve program adherence, and if, as an externality of the program, transmission can be reduced through more effective coverage, significant additional benefits are

  11. Assessing small-volume spinal cord dose for repeat spinal stereotactic body radiotherapy treatments

    Science.gov (United States)

    Ma, Lijun; Kirby, Neil; Korol, Renee; Larson, David A.; Sahgal, Arjun

    2012-12-01

    Spinal cord biologically effective dose (BED) limits are critical to safe spine stereotactic body radiotherapy (SBRT) delivery. In particular, when repeating SBRT to the same site, the problem of adding non-uniform BED distributions within small volumes of spinal cord has yet to be solved. We report a probability-based generalized BED (gBED) model to guide repeat spine SBRT treatment planning. The gBED was formulated by considering the sequential damaging probabilities of repeat spine SBRT treatments. Parameters from the standard linear-quadratic model, such as α/β = 2 Gy for the spinal cord, were applied. We tested the model based on SBRT specific spinal cord tolerance using a simulated and ten clinical repeat SBRT cases. The gBED provides a consistent solution for superimposing non-uniform dose distributions from different fractionation schemes, analogous to the BED for uniform dose distributions. Based on ten clinical cases, the gBED was observed to eliminate discrepancies in the cumulative BED of approximately 5% to 20% within small volumes (e.g. 0.1-2.0 cc) of spinal cord, as compared to a conventional calculation method. When assessing spinal cord tolerance for repeat spinal SBRT treatments, caution should be exercised when applying conventional BED calculations for small volumes of spinal cord irradiated, and the gBED potentially provides more conservative and consistently derived dose surrogates to guide safe treatment planning and treatment outcome modeling.

  12. Repeatability of dose painting by numbers treatment planning in prostate cancer radiotherapy based on multiparametric magnetic resonance imaging

    Science.gov (United States)

    van Schie, Marcel A.; Steenbergen, Peter; Viet Dinh, Cuong; Ghobadi, Ghazaleh; van Houdt, Petra J.; Pos, Floris J.; Heijmink, Stijn W. T. J. P.; van der Poel, Henk G.; Renisch, Steffen; Vik, Torbjørn; van der Heide, Uulke A.

    2017-07-01

    Dose painting by numbers (DPBN) refers to a voxel-wise prescription of radiation dose modelled from functional image characteristics, in contrast to dose painting by contours which requires delineations to define the target for dose escalation. The direct relation between functional imaging characteristics and DPBN implies that random variations in images may propagate into the dose distribution. The stability of MR-only prostate cancer treatment planning based on DPBN with respect to these variations is as yet unknown. We conducted a test-retest study to investigate the stability of DPBN for prostate cancer in a semi-automated MR-only treatment planning workflow. Twelve patients received a multiparametric MRI on two separate days prior to prostatectomy. The tumor probability (TP) within the prostate was derived from image features with a logistic regression model. Dose mapping functions were applied to acquire a DPBN prescription map that served to generate an intensity modulated radiation therapy (IMRT) treatment plan. Dose calculations were done on a pseudo-CT derived from the MRI. The TP and DPBN map and the IMRT dose distribution were compared between both MRI sessions, using the intraclass correlation coefficient (ICC) to quantify repeatability of the planning pipeline. The quality of each treatment plan was measured with a quality factor (QF). Median ICC values for the TP and DPBN map and the IMRT dose distribution were 0.82, 0.82 and 0.88, respectively, for linear dose mapping and 0.82, 0.84 and 0.94 for square root dose mapping. A median QF of 3.4% was found among all treatment plans. We demonstrated the stability of DPBN radiotherapy treatment planning in prostate cancer, with excellent overall repeatability and acceptable treatment plan quality. Using validated tumor probability modelling and simple dose mapping techniques it was shown that despite day-to-day variations in imaging data still consistent treatment plans were obtained.

  13. Repeat Gamma-Knife Radiosurgery for Refractory or Recurrent Trigeminal Neuralgia with Consideration About the Optimal Second Dose.

    Science.gov (United States)

    Park, Seong-Cheol; Kwon, Do Hoon; Lee, Do Hee; Lee, Jung Kyo

    2016-02-01

    To investigate adequate radiation doses for repeat Gamma Knife radiosurgery (GKS) for trigeminal neuralgia in our series and meta-analysis. Fourteen patients treated by ipsilateral repeat GKS for trigeminal neuralgia were included. Median age of patients was 65 years (range, 28-78), the median target dose, 140-180). Patients were followed a median of 10.8 months (range, 1-151) after the second gamma-knife surgery. Brainstem dose analysis and vote-counting meta-analysis of 19 studies were performed. After the second gamma-knife radiosurgeries, pain was relieved effectively in 12 patients (86%; Barrow Neurological Institute Pain Intensity Score I-III). Post-gamma-knife radiosurgery trigeminal nerve deficits were mild in 5 patients. No serious anesthesia dolorosa was occurred. The second GKS radiation dose ≤ 60 Gy was significantly associated with worse pain control outcome (P = 0.018 in our series, permutation analysis of variance, and P = 0.009 in the meta-analysis, 2-tailed Fisher's exact test). Cumulative dose ≤ 140-150 Gy was significantly associated with poor pain control outcome (P = 0.033 in our series and P = 0.013 in the meta-analysis, 2-tailed Fisher's exact test). A cumulative brainstem edge dose >12 Gy tended to be associated with trigeminal nerve deficit (P = 0.077). Our study suggests that the second GKS dose is a potentially important factor. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 4 h apart Human pharmacology of MDMA after repeated doses taken 4 h apart.

    Science.gov (United States)

    Farré, Magí; Tomillero, Angels; Pérez-Mañá, Clara; Yubero, Samanta; Papaseit, Esther; Roset, Pere-Nolasc; Pujadas, Mitona; Torrens, Marta; Camí, Jordi; de la Torre, Rafael

    2015-10-01

    3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is a popular psychostimulant, frequently associated with multiple administrations over a short period of time. Repeated administration of MDMA in experimental settings induces tolerance and metabolic inhibition. The aim is to determine the acute pharmacological effects and pharmacokinetics resulting from two consecutive 100mg doses of MDMA separated by 4h. Ten male volunteers participated in a randomized, double-blind, crossover, placebo-controlled trial. The four conditions were placebo plus placebo, placebo plus MDMA, MDMA plus placebo, and MDMA plus MDMA. Outcome variables included pharmacological effects and pharmacokinetic parameters. After a second dose of MDMA, most effects were similar to those after a single dose, despite a doubling of MDMA concentrations (except for systolic blood pressure and reaction time). After repeated MDMA administration, a 2-fold increase was observed in MDMA plasma concentrations. For a simple dose accumulation MDMA and MDA concentrations were higher (+23.1% Cmax and +17.1% AUC for MDMA and +14.2% Cmax and +10.3% AUC for MDA) and HMMA and HMA concentrations lower (-43.3% Cmax and -39.9% AUC for HMMA and -33.2% Cmax and -35.1% AUC for HMA) than expected, probably related to MDMA metabolic autoinhibition. Although MDMA concentrations doubled after the second dose, most pharmacological effects were similar or slightly higher in comparison to the single administration, except for systolic blood pressure and reaction time which were greater than predicted. The pharmacokinetic-effects relationship suggests that when MDMA is administered at a 4h interval there exists a phenomenon of acute tolerance to its effects.

  15. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    Science.gov (United States)

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully.

  16. Preclinical assessment of HIV vaccines and microbicides by repeated low-dose virus challenges.

    Directory of Open Access Journals (Sweden)

    Roland R Regoes

    2005-08-01

    Full Text Available BACKGROUND: Trials in macaque models play an essential role in the evaluation of biomedical interventions that aim to prevent HIV infection, such as vaccines, microbicides, and systemic chemoprophylaxis. These trials are usually conducted with very high virus challenge doses that result in infection with certainty. However, these high challenge doses do not realistically reflect the low probability of HIV transmission in humans, and thus may rule out preventive interventions that could protect against "real life" exposures. The belief that experiments involving realistically low challenge doses require large numbers of animals has so far prevented the development of alternatives to using high challenge doses. METHODS AND FINDINGS: Using statistical power analysis, we investigate how many animals would be needed to conduct preclinical trials using low virus challenge doses. We show that experimental designs in which animals are repeatedly challenged with low doses do not require unfeasibly large numbers of animals to assess vaccine or microbicide success. CONCLUSION: Preclinical trials using repeated low-dose challenges represent a promising alternative approach to identify potential preventive interventions.

  17. Effect of Repeat Dosing of Engineered Oncolytic Herpes Simplex Virus on Preclinical Models of Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Alicia M. Waters

    2016-10-01

    Full Text Available Rhabdomyosarcoma (RMS, a tumor of skeletal muscle origin, is the most common sarcoma of childhood. Despite multidrug chemotherapy regimens, surgical intervention, and radiation treatment, outcomes remain poor, especially in advanced disease, and novel therapies are needed for the treatment of these aggressive malignancies. Genetically engineered oncolytic viruses, such as herpes simplex virus-1 (HSV, are currently being explored as treatments for pediatric tumors. M002, an oncolytic HSV, has both copies of the γ134.5 gene deleted, enabling replication in tumor cells but thwarting infection of normal, postmitotic cells. We hypothesized that M002 would infect human RMS tumor cells and lead to decreased tumor cell survival in vitro and impede tumor growth in vivo. In the current study, we demonstrated that M002 could infect, replicate in, and decrease cell survival in both embryonal (ERMS and alveolar rhabdomyosarcoma (ARMS cells. Additionally, M002 reduced xenograft tumor growth and increased animal survival in both ARMS and ERMS. Most importantly, we showed for the first time that repeated dosing of oncolytic virus coupled with low-dose radiation provided improved tumor response in RMS. These findings provide support for the clinical investigation of oncolytic HSV in pediatric RMS.

  18. Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

    Science.gov (United States)

    Smith, C D; Lee, R B; Moran, A V; Sipos, M L

    2016-01-01

    Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

  19. Safety of Repeated-Dose Intratympanic Injections with AM-101 in Acute Inner Ear Tinnitus.

    Science.gov (United States)

    Staecker, Hinrich; Morelock, Michael; Kramer, Timothy; Chrbolka, Pavel; Ahn, Joong Ho; Meyer, Thomas

    2017-09-01

    Objective To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design Prospective, double-blind, randomized, placebo-controlled study. Setting Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups ( P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods.

  20. Anticonvulsant effects of acute treatment with cyane-carvone at repeated oral doses in epilepsy models.

    Science.gov (United States)

    Marques, Thiago Henrique Costa; Marques, Maria Leonildes Boavista Gomes Castelo Branco; Medeiros, Jand-Venes Rolim; Lima, Tamires Cardoso; de Sousa, Damião Pergentino; de Freitas, Rivelilson Mendes

    2014-09-01

    Epilepsy affects about 40 million people worldwide. Many drugs block seizures, but have little effect in preventing or curing this disease. So the search for new drugs for epilepsy treatment using animal models prior to testing in humans is important. Increasingly pharmaceutical industries invest in the Re​search & Drug Development area to seek safe and effective new therapeutic alternatives to the currently available epilepsy treatment. In this perspective, natural compounds have been investigated in epilepsy models, particularly the monoterpenes obtained from medicinal plants. In our study we investigated the effects of cyane-carvone (CC), a synthetic substance prepared from natural a monoterpene, carvone, against pilocarpine- (PILO), pentylenetetrazole- (PTZ) and picrotoxine (PTX)-induced seizures in mice after acute treatment with repeated oral doses (CC 25, 50 and 75 mg/kg) for 14 days. CC in all doses tested showed increase in latency to first seizure, decrease in percentages of seizuring animals as well as reduction percentages of dead animals (pepilepsy models. In addition, our data suggest that CC could act in an allosteric site of GABAA, which would be different from the site in which BDZ acts, since flumazenil was not able to reverse any of CC effects on the modulation of seizure parameters related with epilepsy models investigated. New studies should be conducted to investigate CC effects in other neurotransmitter systems. Nevertheless, our study reinforces the hypothesis that CC could be used, after further research, as a new pharmaceutical formulation and a promising alternative for epilepsy treatment, since it showed anticonvulsant effects. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya

    2007-11-01

    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

  2. Repeated exposure to sublethal doses of the organophosphorus compound VX activates BDNF expression in mouse brain.

    Science.gov (United States)

    Pizarro, Jose M; Chang, Wenling E; Bah, Mariama J; Wright, Linnzi K M; Saviolakis, George A; Alagappan, Arun; Robison, Christopher L; Shah, Jinesh D; Meyerhoff, James L; Cerasoli, Douglas M; Midboe, Eric G; Lumley, Lucille A

    2012-04-01

    The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

  3. [Study of personal best value of peak expiratory flow in patients with asthma--comparison of the highest value of daily PEF under good control and the highest value of daily PEF obtained after using repeated inhaled beta2-agonist during high-dose inhaled steroid treatment].

    Science.gov (United States)

    Watanabe, Naoto; Makino, Sohei; Kihara, Norio; Fukuda, Takeshi

    2008-12-01

    In the guideline for asthma management, it is important to find the personal best value of peak expiratory flow (best PEF). Recently, we have substituted the highest value of PEF in daily life under good control (daily highest PEF) for the best PEF. In the present study, we considered whether the daily highest PEF could be used as the best PEF or not. Subjects were 30 asthmatics who were well controlled but whose baseline PEF values were less than 80 percent of predicted values. We compared the daily highest PEF and the highest of PEF obtained after repeated inhaled beta2-agonist (salbutamol MDI every 20 minutes three times). All subjects then received 1600 microg/day of beclomethasone dipropionate (BDP) for 4 to 8 weeks. We studied the effect of high-dose inhaled steroid treatment on each PEF value and compared the daily highest PEF and the highest PEF obtained after using repeated salbutamol MDI during high dose inhaled steroid therapy on the examination day again. The baseline PEF, daily highest PEF and the highest PEF obtained after salbutamol MDI were significantly less than the each values obtained after high-dose BDP. The best PEF value of them was the value obtained after repeated salbutamol MDI during high dose BDP. We suggest that the daily highest PEF under good control is not a substitute for best PEF because it changes according to the degree of improvement of airway inflammation. We recommend that a course of high dose inhaled steroid is effective in finding the best value of PEF for each individual with moderate asthma.

  4. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    Science.gov (United States)

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  5. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    Science.gov (United States)

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  6. Bile Salt Homeostasis in Normal and Bsep Gene Knockout Rats with Single and Repeated Doses of Troglitazone.

    Science.gov (United States)

    Cheng, Yaofeng; Chen, Shenjue; Freeden, Chris; Chen, Weiqi; Zhang, Yueping; Abraham, Pamela; Nelson, David M; Humphreys, W Griffith; Gan, Jinping; Lai, Yurong

    2017-09-01

    The interference of bile acid secretion through bile salt export pump (BSEP) inhibition is one of the mechanisms for troglitazone (TGZ)-induced hepatotoxicity. Here, we investigated the impact of single or repeated oral doses of TGZ (200 mg/kg/day, 7 days) on bile acid homoeostasis in wild-type (WT) and Bsep knockout (KO) rats. Following oral doses, plasma exposures of TGZ were not different between WT and KO rats, and were similar on day 1 and day 7. However, plasma exposures of the major metabolite, troglitazone sulfate (TS), in KO rats were 7.6- and 9.3-fold lower than in WT on day 1 and day 7, respectively, due to increased TS biliary excretion. With Bsep KO, the mRNA levels of multidrug resistance-associated protein 2 (Mrp2), Mrp3, Mrp4, Mdr1, breast cancer resistance protein (Bcrp), sodium taurocholate cotransporting polypeptide, small heterodimer partner, and Sult2A1 were significantly altered in KO rats. Following seven daily TGZ treatments, Cyp7A1 was significantly increased in both WT and KO rats. In the vehicle groups, plasma exposures of individual bile acids demonstrated variable changes in KO rats as compared with WT. WT rats dosed with TGZ showed an increase of many bile acid species in plasma on day 1, suggesting the inhibition of Bsep. Conversely, these changes returned to base levels on day 7. In KO rats, alterations of most bile acids were observed after seven doses of TGZ. Collectively, bile acid homeostasis in rats was regulated through bile acid synthesis and transport in response to Bsep deficiency and TGZ inhibition. Additionally, our study is the first to demonstrate that repeated TGZ doses can upregulate Cyp7A1 in rats. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  7. Airway responses and inflammation in subjects with asthma after four days of repeated high-single-dose allergen challenge

    Directory of Open Access Journals (Sweden)

    Schulze Johannes

    2012-09-01

    Full Text Available Abstract Background Both standard and low-dose allergen provocations are an established tool in asthma research to improve our understanding of the pathophysiological mechanism of allergic asthma. However, clinical symptoms are less likely to be induced. Therefore, we designed a protocol for repetitive high-dose bronchial allergen challenges to generate clinical symptoms and airway inflammation. Methods A total of 27 patients aged 18 to 40 years with positive skin-prick tests and mild asthma underwent repetitive high-dose allergen challenges with household dust mites for four consecutive days. Pulmonary function and exhaled NO were measured at every visit. Induced sputum was analysed before and after the allergen challenges for cell counts, ECP, IL-5, INF-γ, IL-8, and the transcription factor Foxp3. Results We found a significant decrease in pulmonary function, an increased use of salbutamol and the development of a late asthmatic response and bronchial hyperresponsiveness, as well as a significant induction of eNO, eosinophils, and Th-2 cytokines. Repeated provocation was feasible in the majority of patients. Two subjects had severe adverse events requiring prednisolone to cope with nocturnal asthma symptoms. Conclusions Repeated high-dose bronchial allergen challenges resulted in severe asthma symptoms and marked Th-2-mediated allergic airway inflammation. The high-dose challenge model is suitable only in an attenuated form in diseased volunteers for proof-of-concept studies and in clinical settings to reduce the risk of severe asthma exacerbations. Trial registration ClinicalTrials.govNCT00677209

  8. A single whole-body low dose X-irradiation does not affect L1, B1 and IAP repeat element DNA methylation longitudinally.

    Directory of Open Access Journals (Sweden)

    Michelle R Newman

    Full Text Available The low dose radioadaptive response has been shown to be protective against high doses of radiation as well as aging-induced genomic instability. We hypothesised that a single whole-body exposure of low dose radiation would induce a radioadaptive response thereby reducing or abrogating aging-related changes in repeat element DNA methylation in mice. Following sham or 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences in Long Interspersed Nucleic Element 1 (L1, B1 and Intracisternal-A-Particle (IAP repeat element methylation between samples were assessed using high resolution melt analysis of PCR amplicons. By 420 days post-irradiation, neither radiation- or aging-related changes in the methylation of peripheral blood, spleen or liver L1, B1 and IAP elements were observed. Analysis of the spleen and liver tissues of cohorts of untreated aging mice showed that the 17-19 month age group exhibited higher repeat element methylation than younger or older mice, with no overall decline in methylation detected with age. This is the first temporal analysis of the effect of low dose radiation on repeat element methylation in mouse peripheral blood and the first to examine the long term effect of this dose on repeat element methylation in a radiosensitive tissue (spleen and a tissue fundamental to the aging process (liver. Our data indicate that the methylation of murine DNA repeat elements can fluctuate with age, but unlike human studies, do not demonstrate an overall aging-related decline. Furthermore, our results indicate that a low dose of ionising radiation does not induce detectable changes to murine repeat element DNA methylation in the tissues and at the time-points examined in this study. This radiation dose is relevant to human diagnostic radiation exposures and suggests that a dose of 10 mGy X-rays, unlike high dose radiation, does not cause significant short or long term changes to repeat element or global DNA

  9. Inhalation exposure system used for acute and repeated-dose methyl isocyanate exposures of laboratory animals.

    Science.gov (United States)

    Adkins, B; O'Connor, R W; Dement, J M

    1987-06-01

    Laboratory animals were exposed by inhalation for 2 hr/day (acute) or 6 hr/day (four consecutive days, repeated dose) to methyl isocyanate (MIC). Exposures were conducted in stainless steel and glass inhalation exposure chambers placed in stainless steel, wire mesh cages. MIC was delivered with nitrogen via stainless steel and Teflon supply lines. Chamber concentrations ranged from 0 to 60 ppm and were monitored continuously with infrared spectrophotometers to 1 ppm and at 2-hr intervals to 20 ppb with a high performance liquid chromatograph equipped with a fluorescence detector. Other operational parameters monitored on a continuous basis included chamber temperature (20-27 degrees C), relative humidity (31-64%), static (transmural) pressure (-0.3 in.), and flow (300-500 L/min). The computer-assistance system interfaced with the inhalation exposure laboratory is described in detail, including the analytical instrumentation calibration system used throughout this investigation.

  10. Radiobiological restrictions and tolerance doses of repeated single-fraction hdr-irradiation of intersecting small liver volumes for recurrent hepatic metastases

    Directory of Open Access Journals (Sweden)

    Wust Peter

    2010-05-01

    Full Text Available Abstract Background To assess radiobiological restrictions and tolerance doses as well as other toxic effects derived from repeated applications of single-fraction high dose rate irradiation of small liver volumes in clinical practice. Methods Twenty patients with liver metastases were treated repeatedly (2 - 4 times at identical or intersecting locations by CT-guided interstitial brachytherapy with varying time intervals. Magnetic resonance imaging using the hepatocyte selective contrast media Gd-BOPTA was performed before and after treatment to determine the volume of hepatocyte function loss (called pseudolesion, and the last acquired MRI data set was merged with the dose distributions of all administered brachytherapies. We calculated the BED (biologically equivalent dose for a single dose d = 2 Gy for different α/β values (2, 3, 10, 20, 100 based on the linear-quadratic model and estimated the tolerance dose for liver parenchyma D90 as the BED exposing 90% of the pseudolesion in MRI. Results The tolerance doses D90 after repeated brachytherapy sessions were found between 22 - 24 Gy and proved only slightly dependent on α/β in the clinically relevant range of α/β = 2 - 10 Gy. Variance analysis showed a significant dependency of D90 with respect to the intervals between the first irradiation and the MRI control (p 90 and the pseudolesion's volume. No symptoms of liver dysfunction or other toxic effects such as abscess formation occurred during the follow-up time, neither acute nor on the long-term. Conclusions Inactivation of liver parenchyma occurs at a BED of approx. 22 - 24 Gy corresponding to a single dose of ~10 Gy (α/β ~ 5 Gy. This tolerance dose is consistent with the large potential to treat oligotopic and/or recurrent liver metastases by CT-guided HDR brachytherapy without radiation-induced liver disease (RILD. Repeated small volume irradiation may be applied safely within the limits of this study.

  11. Repeated measures dose-finding design with time-trend detection in the presence of correlated toxicity data.

    Science.gov (United States)

    Yin, Jun; Paoletti, Xavier; Sargent, Daniel J; Mandrekar, Sumithra J

    2017-08-01

    Phase I trials are designed to determine the safety, tolerability, and recommended phase 2 dose of therapeutic agents for subsequent testing. The dose-finding paradigm has thus traditionally focused on identifying the maximum tolerable dose of an agent or combination therapy under the assumption that there is a non-decreasing relationship between dose-toxicity and dose-efficacy. The dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. A novel endpoint, the total toxicity profile, was previously developed to account for the multiple toxicity types and grades experienced in the first cycle. More recently, this was extended to a repeated measures design based on the total toxicity profile to account for longitudinal toxicities over multiple treatment cycles in the absence of within-patient correlation. In this work, we propose to extend the design in the presence of within-patient correlation. Furthermore, we provide a framework to detect a toxicity time trend (toxicity increasing, decreasing, or stable) over multiple treatment cycles. We utilize a linear mixed model in the Bayesian framework, with the addition of Bayesian risk functions for decision-making in dose assignment. The performance of this design was evaluated using simulation studies and real data from a phase I trial. We demonstrated that using available toxicity data from all cycles of treatment improves the accuracy of maximum tolerated dose identification and allows for the detection of a time trend. The performance is consistent regardless of the strength of the within-patient correlation. In addition, the use of a quasi-continuous total toxicity profile score significantly increased the power to detect time trends compared to when binary data only were used. The increased interest in molecularly targeted agents and immunotherapies in oncology necessitates innovative phase I study designs. Our proposed framework provides a tool to tackle

  12. Investigation of repeated dose (90 day oral toxicity, reproductive/developmental toxicity and mutagenic potential of ‘Calebin A’

    Directory of Open Access Journals (Sweden)

    Muhammed Majeed

    2015-01-01

    Full Text Available The present work investigated repeated dose and reproductive toxicity of Calebin A in Wistar rats. A study for assessing the mutagenic potential of Calebin A through an AMES test is also described. Calebin A was orally administered to groups of 10 male and/or 10 female Wistar rats each, assigned to three dose levels (20, 50 and 100 mg/kg/body weight once daily for 90 consecutive days. None of the animals in any of the treatment/control groups exhibited any abnormal clinical signs/behavioral changes, reproductive as well as developmental parameters, or gross and microscopic changes in both male and female rats. Calebin A was also evaluated for its ability to induce reverse mutations at selected loci of Salmonella typhimurium in the presence and absence of Aroclor 1254 induced rat liver S9 cell lines. In conclusion, 100 mg/kg/d of Calebin A is not likely to produce any significant toxic effects in male and female Wistar rats and no reproductive or developmental toxicity was observed at the same dose and hence Calebin A at 100 mg/kg was determined as “No Observed Adverse Effect Level (NOAEL” under the test conditions.

  13. Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients.

    Science.gov (United States)

    Vinken, Mathieu; Pauwels, Marleen; Ates, Gamze; Vivier, Manon; Vanhaecke, Tamara; Rogiers, Vera

    2012-03-01

    Alternative methods, replacing animal testing, are urgently needed in view of the European regulatory changes in the field of cosmetic products and their ingredients. In this context, a joint research initiative called SEURAT was recently raised by the European Commission and COLIPA, representing the European cosmetics industry, with the overall goal of developing an animal-free repeated dose toxicity testing strategy for human safety assessment purposes. Although cosmetic ingredients are usually harmless for the consumer, one of the initial tasks of this research consortium included the identification of organs that could potentially be affected by cosmetic ingredients upon systemic exposure. The strategy that was followed hereof is described in the present paper and relies on the systematic evaluation, by using a self-generated electronic databank, of published reports issued by the scientific committee of DG SANCO responsible for the safety of cosmetic ingredients. By screening of the repeated dose toxicity studies present in these reports, it was found that the liver is potentially the most frequently targeted organ by cosmetic ingredients when orally administered to experimental animals, followed by the kidney and the spleen. Combined listing of altered morphological, histopathological, and biochemical parameters subsequently indicated the possible occurrence of hepatotoxicity, including steatosis and cholestasis, triggered by a limited number of cosmetic compounds. These findings are not only of relevance for the in vitro modeling efforts and choice of compounds to be tested in the SEURAT project cluster, but also demonstrate the importance of using previously generated toxicological data through an electronic databank for addressing specific questions regarding the safety evaluation of cosmetic ingredients.

  14. Memory and mood during the night and in the morning after repeated evening doses of MDMA.

    Science.gov (United States)

    Kuypers, K P C; Wingen, M; Ramaekers, J G

    2008-11-01

    Previously it has been shown that MDMA causes memory impairment during daytime testing. However, MDMA is usually taken in the evening or during the night. In addition, it is known that sleep deprivation also causes memory impairment. The present study aimed to assess whether evening doses of MDMA added to, or interacted with the memory impairment due to sleep deprivation. Fourteen healthy subjects participated in a double-blind, placebo-controlled, two-way cross-over study. Treatments consisted of MDMA 75 and 50 mg divided over the evening or double placebo. Memory tests and subjective measures of mood were conducted at baseline and three times post dosing that is at 6.30 pm, 9.30 pm, 1.30 am and 7 am, respectively -1.5, 1.5, 5.5 and 11 h relative to drug intake (first dose). Memory performance detoriated progessively over time as a function of sleep loss, independent of treatment. MDMA added to this impairment as indicated by a significant main effect of MDMA on verbal and spatial memory performance. Mood ratings and response speed revealed an MDMA by Time interaction. After administration of MDMA response speed improved and feelings of vigor, friendliness, elation, anxiety, confusion, arousal and positive mood increased in magnitude during the night, while all these parameters returned to placebo-like levels on the final morning session. It is concluded that evening doses of MDMA selectively impair memory performance, and that this impairment is additional to the effect of sleep deprivation on memory performance.

  15. Analysis of repeated outcome measures from longitudinal studies

    Institute of Scientific and Technical Information of China (English)

    Yuanjia WANG; Naihua DUAN

    2011-01-01

    @@ In many clinical studies repeated measurements of an outcome are collected over time.For example,in an 8-week study of treatment for obsessive compulsive disorder,the severity of the disorder may be measured weekly using the Yale-Brown-Obsessive-Compulsive-Disorder-Scale (YBOCS).For each study participant who completes the study,there will be nine repeated measures of YBOCS (a baseline assessment plus eight assessments during the course of treatment).Such a study in which participants are followed and measured repeatedly over time is called a longitudinal study and the resulting data are called longitudinal data.

  16. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT

    National Research Council Canada - National Science Library

    McKinlay, Christopher J D; Cutfield, Wayne S; Battin, Malcolm R; Dalziel, Stuart R; Crowther, Caroline A; Harding, Jane E

    2015-01-01

    .... We assessed whether exposure to repeat antenatal betamethasone increased risk factors for later cardiometabolic disease in children whose mothers participated in the Australasian Collaborative Trial...

  17. Radiation-induced mutation at tandem repeat DNA Loci in the mouse germline: spectra and doubling doses.

    Science.gov (United States)

    Dubrova, Yuri E

    2005-02-01

    The spectra and dose response for mutations at expanded simple tandem repeat (ESTR) loci in the germline of male mice acutely exposed to low-LET X or gamma rays at pre-meiotic stages of spermatogenesis were compared in five strains of laboratory mice. Most mutation events involved the gain or loss of a relatively small number of repeat units, and the distributions of length changes were indistinguishable between the exposed and control males. Overall, a significant bias toward gains of repeats was detected, with approximately 60% of mutants showing gains. The values for ESTR mutation induction did not differ substantially between strains. The highest values of doubling dose were obtained for two genetically related strains, BALB/c and C.B17 (mean value 0.98 Gy). The estimates of doubling dose for three other strains (CBA/H, C57BL/6 x CBA/H F1 and 129SVJ x C57BL/6) were lower, with a mean value of 0.44 Gy. The dose response for ESTR mutation across all five strains was very close to that for the specific loci (Russell 7-locus test). The mechanisms of ESTR mutation induction and applications of this system for monitoring radiation-induced mutation in the mouse germline are discussed.

  18. Detection of the effects of repeated dose combined propoxur and heavy metal exposure by measurement of certain toxicological, haematological and immune function parameters in rats.

    Science.gov (United States)

    Institóris, L; Siroki, O; Undeger, U; Basaran, N; Banerjee, B D; Dési, I

    2001-06-21

    In the present study, an immunotoxicity test system, containing general toxicological (body weight gain, organ weights), haematological (WBC,RBC, Ht, mean cell volume of the RBCs, cell content of the femoral bone marrow), and immune function (PFC assay, DTH reaction) investigations, was used for detection the effects of a 4 weeks repeated low dose combined oral exposure of male Wistar rats with propoxur and the heavy metals arsenic or mercury. Two doses of the compounds were used: a higher one (the lowest dose which resulted in significant change of at least one parameter examined in previous dose-effect experiments), and a lower one (the highest dose which proved to be non-effective). The applied doses were: 8.51 and 0.851 mg kg(-1) of propoxur, 13.3 and 3.33 mg kg(-1) of NaAsO(2), and 3.20 and 0.40 mg kg(-1) of HgCl(2). In the combination treatment, the high dose of propoxur was combined with the low dose of arsenic or mercury, and the high doses of each heavy metals were combined with the low dose of propoxur. The main finding of this study was that some of the combinations significantly altered the relative weight of liver, adrenals and kidneys, related to both the untreated and the high dose internal control. Among the immune functions examined, only the PFC content of the spleen showed a trend of changes in certain combinations versus the corresponding high dose control. According to the present results, combined exposure with propoxur and the heavy metals examined can modify the detection limit of the single compounds and/or may alter their toxic effects.

  19. Intra-tumor distribution of PEGylated liposome upon repeated injection: No possession by prior dose.

    Science.gov (United States)

    Nakamura, Hiroyuki; Abu Lila, Amr S; Nishio, Miho; Tanaka, Masao; Ando, Hidenori; Kiwada, Hiroshi; Ishida, Tatsuhiro

    2015-12-28

    Liposomes have proven to be a viable means for the delivery of chemotherapeutic agents to solid tumors. However, significant variability has been detected in their intra-tumor accumulation and distribution, resulting in compromised therapeutic outcomes. We recently examined the intra-tumor accumulation and distribution of weekly sequentially administered oxaliplatin (l-OHP)-containing PEGylated liposomes. In that study, the first and second doses of l-OHP-containing PEGylated liposomes were distributed diversely and broadly within tumor tissues, resulting in a potent anti-tumor efficacy. However, little is known about the mechanism underlying such a diverse and broad liposome distribution. Therefore, in the present study, we investigated the influence of dosage interval on the intra-tumor accumulation and distribution of "empty" PEGylated liposomes. Intra-tumor distribution of sequentially administered "empty" PEGylated liposomes was altered in a dosing interval-dependent manner. In addition, the intra-tumor distribution pattern was closely related to the chronological alteration of tumor blood flow as well as vascular permeability in the growing tumor tissue. These results suggest that the sequential administrations of PEGylated liposomes in well-spaced intervals might allow the distribution to different areas and enhance the total bulk accumulation within tumor tissue, resulting in better therapeutic efficacy of the encapsulated payload. This study may provide useful information for a better design of therapeutic regimens involving multiple administrations of nanocarrier drug delivery systems.

  20. 注射用右旋雷贝拉唑钠大鼠13周重复给药毒性研究%Study on Repeated Dose Toxicity of Dexrabeprazole Sodium Injection in Rats for 13 Weeks

    Institute of Scientific and Technical Information of China (English)

    戴晓莉; 戴学栋; 郭峰; 胡建庭; 马玉奎

    2016-01-01

    taken the blood at ifrst and last injection for toxicokinetics. Results The rats in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 apperanced shortness of breath, unsteady gait, prone motionless and other symptoms. The levels of RBC,HGB,HCT in the dexrabeprazole sodium injection group at 80, 20 mg·kg-1 were significantly lower than those in vehicle control group at 13 weeks (P<0.05). The change of these parameters regained to normal at 4 weeks after withdrawal. The amount of small follicular in the thyroid gland increased at 13 weeks, and failed to fully recover at 4 weeks after the withdrawal.Conclusion Repeated administration of dexrabeprazole Sodium injection (80, 20 mg·kg-1) for 13 weeks could lead to abnormal indicators related erythrocyte and pathological lesions of thyroid in rats.

  1. Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: implications for treatment in Alzheimer's disease.

    Science.gov (United States)

    Ferruzzi, Mario G; Lobo, Jessica K; Janle, Elsa M; Cooper, Bruce; Simon, James E; Wu, Qing-Li; Welch, Cara; Ho, Lap; Weaver, Connie; Pasinetti, Giulio M

    2009-01-01

    The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin (C), and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. Cmax for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC0-8h) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 +/-45.9 and 576.7 +/- 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

  2. Repeated treatment with (-)-sulpiride plus a low dose of SCH 23390 displays wider neuroleptic activity without inducing dopaminergic supersensitivity.

    Science.gov (United States)

    Dall'Olio, R; Gandolfi, O; Roncada, P; Vaccheri, A; Montanaro, N

    1990-01-01

    Combined treatment with (-)-sulpiride plus a low dose of the D1 receptor antagonist SCH 23390, unlike (-)-sulpiride given alone, blocked rat striatal dopaminergic transmission. Five days after the withdrawal of 21-day repeated administration of the combined treatment, no increase in apomorphine-induced stereotyped behaviour was observed. The results suggest that the combination of a D2 blocker and a low dose of a D1 blocker produces a wider spectrum of neuroleptic activity without an overt risk of inducing dopaminergic behavioural supersensitivity.

  3. Validation of a track repeating algorithm for intensity modulated proton therapy: clinical cases study

    Science.gov (United States)

    Yepes, Pablo P.; Eley, John G.; Liu, Amy; Mirkovic, Dragan; Randeniya, Sharmalee; Titt, Uwe; Mohan, Radhe

    2016-04-01

    Monte Carlo (MC) methods are acknowledged as the most accurate technique to calculate dose distributions. However, due its lengthy calculation times, they are difficult to utilize in the clinic or for large retrospective studies. Track-repeating algorithms, based on MC-generated particle track data in water, accelerate dose calculations substantially, while essentially preserving the accuracy of MC. In this study, we present the validation of an efficient dose calculation algorithm for intensity modulated proton therapy, the fast dose calculator (FDC), based on a track-repeating technique. We validated the FDC algorithm for 23 patients, which included 7 brain, 6 head-and-neck, 5 lung, 1 spine, 1 pelvis and 3 prostate cases. For validation, we compared FDC-generated dose distributions with those from a full-fledged Monte Carlo based on GEANT4 (G4). We compared dose-volume-histograms, 3D-gamma-indices and analyzed a series of dosimetric indices. More than 99% of the voxels in the voxelized phantoms describing the patients have a gamma-index smaller than unity for the 2%/2 mm criteria. In addition the difference relative to the prescribed dose between the dosimetric indices calculated with FDC and G4 is less than 1%. FDC reduces the calculation times from 5 ms per proton to around 5 μs.

  4. Toxicological assessment of heavy straight run naphtha in a repeated dose/reproductive toxicity screening test.

    Science.gov (United States)

    McKee, Richard H; Steup, David; Schreiner, Ceinwen; Podhasky, Paula; Malley, Linda A; Roberts, Linda

    2014-01-01

    Gasoline blending stocks (naphthas) are comprised of normal, iso- and cycloparaffins and aromatic hydrocarbons with carbon numbers ranging from C4 to C12. Heavy straight run naphtha (HSRN, CAS number 64741-41-9) was selected for toxicity screening because substances of this type contain relatively high levels (28%) of cycloparaffins by comparison to other naphtha streams and the data complement toxicity information on other gasoline blending streams. Rats were exposed by inhalation to wholly vaporized material at levels of approximately 100, 500, or 3000 parts per million (ppm) daily to screen the potential for systemic toxicity, neurotoxicity, reproductive toxicity, and developmental effects to postnatal day 4. All animals survived the treatment period. Principal effects of repeated exposure included increased liver weights in males and females, increased kidney weights in males, and histological changes in the thyroid, secondary to liver enzyme induction. These changes were not considered to be toxicologically meaningful and are not relevant to humans. There were no treatment-related effects in functional observation tests or motor activity; no significant reductions in fertility or changes in other reproductive parameters; and no evidence of developmental toxicity in offspring. The overall no observed adverse effect concentration was 3000 ppm (approximately 13, 600 mg/m(3)). In conclusion the HSRN effects on liver and kidney are consistent with the results of other studies of volatile fractions or other naphthas or formulated gasoline, and there were no HSRN effects on neurological developmental or reproductive parameters.

  5. Use of a statistical model to predict the potential for repeated dose and developmental toxicity of dermally administered crude oil and relation to reproductive toxicity.

    Science.gov (United States)

    McKee, Richard H; Nicolich, Mark; Roy, Timothy; White, Russell; Daughtrey, Wayne C

    2014-01-01

    Petroleum (commonly called crude oil) is a complex substance primarily composed of hydrocarbon constituents. Based on the results of previous toxicological studies as well as occupational experience, the principal acute toxicological hazards are those associated with exposure by inhalation to volatile hydrocarbon constituents and hydrogen sulfide, and chronic hazards are associated with inhalation exposure to benzene and dermal exposure to polycyclic aromatic compounds. The current assessment was an attempt to characterize the potential for repeated dose and/or developmental effects of crude oils following dermal exposures and to generalize the conclusions across a broad range of crude oils from different sources. Statistical models were used to predict the potential for repeated dose and developmental toxicity from compositional information. The model predictions indicated that the empirical data from previously tested crude oils approximated a "worst case" situation, and that the data from previously tested crude oils could be used as a reasonable basis for characterizing the repeated dose and developmental toxicological hazards of crude oils in general.

  6. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

    Science.gov (United States)

    Wang, Bing; Feng, Weiyue; Zhu, Motao; Wang, Yun; Wang, Meng; Gu, Yiqun; Ouyang, Hong; Wang, Huajian; Li, Ming; Zhao, Yuliang; Chai, Zhifang; Wang, Haifang

    2009-01-01

    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe2O3 nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 μg) intranasal exposure of nano- and submicron-sized Fe2O3 particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe2O3 particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe2O3 particle treatment ( p < 0.05). The nano-sized Fe2O3 generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe2O3 particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe2O3 treatment. In contrast, in the submicron-sized Fe2O3 treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe2O3 nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the larger particle did. This is the first study to compare the neurotoxicity of nano- and submicron-sized Fe2O3

  7. Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang Bing; Feng Weiyue, E-mail: fengwy@mail.ihep.ac.cn; Zhu Motao; Wang Yun; Wang Meng [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Gu Yiqun [Maternity Hospital of Haidian District (China); Ouyang Hong; Wang Huajian; Li Ming; Zhao Yuliang, E-mail: zhaoyuliang@mail.ihep.ac.cn; Chai Zhifang [Chinese Academy of Sciences, Laboratory for Bio-Environmental Effects of Nanomaterials and Nanosafety and Key Laboratory of Nuclear Analytical Techniques, Institute of High Energy Physics (China); Wang Haifang [Peking University, College of Chemistry and Molecular Engineering (China)

    2009-01-15

    Olfactory tract has been demonstrated to be an important portal for inhaled solid nanoparticle transportation into the central nervous system (CNS). We have previously demonstrated that intranasally instilled Fe{sub 2}O{sub 3} nanoparticles could transport into the CNS via olfactory pathway. In this study, we investigated the neurotoxicity and size effect of repeatedly low-dose (130 {mu}g) intranasal exposure of nano- and submicron-sized Fe{sub 2}O{sub 3} particles (21 nm and 280 nm) to mice. The biomarkers of oxidative stress, activity of nitric oxide synthases and release of monoamine neurotransmitter in the brain were studied. Our results showed that significant oxidative stress was induced by the two sizes of Fe{sub 2}O{sub 3} particles. The activities of GSH-Px, Cu,Zn-SOD, and cNOS significantly elevated and the total GSH and GSH/GSSG ratio significantly decreased in the olfactory bulb and hippocampus after the nano- and submicron-sized Fe{sub 2}O{sub 3} particle treatment (p < 0.05). The nano-sized Fe{sub 2}O{sub 3} generally induced greater alteration and more significant dose-effect response than the submicron-sized particle did. Some slight perturbation of monoamine neurotransmitters were found in the hippocampus after exposure to the two sizes of Fe{sub 2}O{sub 3} particle. The TEM image showed that some ultrastructural alterations in nerve cells, including neurodendron degeneration, membranous structure disruption and lysosome increase in the olfactory bulb, slight dilation in the rough endoplasmic reticulum and lysosome increase in the hippocampus were induced by the nano-sized Fe{sub 2}O{sub 3} treatment. In contrast, in the submicron-sized Fe{sub 2}O{sub 3} treated mice, slightly swollen mitochondria and some vacuoles were observed in the olfactory bulb and hippocampus, respectively. These results indicate that intranasal exposure of Fe{sub 2}O{sub 3} nanoparticles could induce more severe oxidative stress and nerve cell damage in the brain than the

  8. Upregulation of nucleoside triphosphate diphosphohydrolase-1 and ecto-5'-nucleotidase in rat hippocampus after repeated low-dose dexamethasone administration.

    Science.gov (United States)

    Drakulić, Dunja; Stanojlović, Miloš; Nedeljković, Nadežda; Grković, Ivana; Veličković, Nataša; Guševac, Ivana; Mitrović, Nataša; Buzadžić, Ivana; Horvat, Anica

    2015-04-01

    Although dexamethasone (DEX), a synthetic glucocorticoid receptor (GR) analog with profound effects on energy metabolism, immune system, and hypothalamic-pituitary-adrenal axis, is widely used therapeutically, its impact on the brain is poorly understood. The aim of the present study was to explore the effect of repeated low-dose DEX administration on the activity and expression of the ectonucleotidase enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. Ectonucleotidases tested were ectonucleoside triphosphate diphosphohydrolase 1-3 (NTPDase1-3) and ecto-5'-nucleotidase (eN), whereas the effects were evaluated in two brain areas that show different sensitivity to glucocorticoid action, hippocampus, and cerebral cortex. In the hippocampus, but not in cerebral cortex, modest level of neurodegenerative changes as well as increase in ATP, ADP, and AMP hydrolysis and upregulation of NTPDase1 and eN mRNA expression ensued under the influence of DEX. The observed pattern of ectonucleotidase activation, which creates tissue volume with enhanced capacity for adenosine formation, is the hallmark of the response after different insults to the brain.

  9. Repeated dose oral toxicity of inorganic mercury in wistar rats: biochemical and morphological alterations

    Directory of Open Access Journals (Sweden)

    M. D. Jegoda

    2013-06-01

    Full Text Available Aim: The study was conducted to find out the possible toxic effect of mercuric chloride (HgCl2 at the histological, biochemical, and haematological levels in the wistar rats for 28 days. Materials and Methods: The biochemical and hematological alteration were estimated in four groups of rat (each group contain ten animals, which were treated with 0 (control, 2, 4, and 8 mg/kg body weight of HgCl2 through oral gavage. At the end of study all rats were sacrificed and subjected for histopathology. Result: A significantly (P < 0.05 higher level of serum alanine amino transferase (ALT, gamma Glutamyle Transferase, and creatinine were recorded in treatment groups, while the level of alkaline phosphtase (ALP was significantly decreased as compared to the control group. The toxic effect on hematoclogical parameter was characterized by significant decrease in hemoglobin, packed cell volume, total erythrocytes count, and total leukocyte count. Gross morphological changes include congestion, severe haemorrhage, necrosis, degenerative changes in kidneys, depletion of lymphocyte in spleen, decrease in concentration of mature spermatocyte, and edema in testis. It was notable that kidney was the most affected organ. Conclusion: Mercuric chloride (HgCl caused dose-dependent toxic effects on blood parameters and kidney. [Vet World 2013; 6(8.000: 563-567

  10. Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

    Science.gov (United States)

    2012-01-01

    cresyl/-4 H-1: 3: 2-benzodioxa- phosphorin-2-oxide (CBDP) on organophosphate poisoning and its therapy. Arch. Toxicol. 42, 207–216. French, S. J... organophosphates or other environmental insults, have a greater FIG. 4. Mice that received repeated exposure to low levels of VX (0.2 LD50 and 0.4 LD50...to neuro- behavioral deficits and neuropathology. Although exposure to organophosphates such as pesticides has been shown to affect the expression of

  11. Differential effects of acute and repeat dosing with the H3 antagonist GSK189254 on the sleep–wake cycle and narcoleptic episodes in Ox−/− mice

    Science.gov (United States)

    Guo, RX; Anaclet, C; Roberts, JC; Parmentier, R; Zhang, M; Guidon, G; Buda, C; Sastre, JP; Feng, JQ; Franco, P; Brown, SH; Upton, N; Medhurst, AD; Lin, JS

    2009-01-01

    Background and purpose: Histamine H3 receptor antagonists are currently being evaluated in clinical trials for a number of central nervous system disorders including narcolepsy. These agents can increase wakefulness (W) in cats and rodents following acute administration, but their effects after repeat dosing have not been reported previously. Experimental approach: EEG and EMG recordings were used to investigate the effects of acute and repeat administration of the novel H3 antagonist GSK189254 on the sleep–wake cycle in wild-type (Ox+/+) and orexin knockout (Ox−/−) mice, the latter being genetically susceptible to narcoleptic episodes. In addition, we investigated H3 and H1 receptor expression in this model using radioligand binding and autoradiography. Key results: In Ox+/+ and Ox−/− mice, acute administration of GSK189254 (3 and 10 mg·kg−1 p.o.) increased W and decreased slow wave and paradoxical sleep to a similar degree to modafinil (64 mg·kg−1), while it reduced narcoleptic episodes in Ox−/− mice. After twice daily dosing for 8 days, the effect of GSK189254 (10 mg·kg−1) on W in both Ox+/+ and Ox−/− mice was significantly reduced, while the effect on narcoleptic episodes in Ox−/− mice was significantly increased. Binding studies revealed no significant differences in H3 or H1 receptor expression between Ox+/+ and Ox−/− mice. Conclusions and implications: These studies provide further evidence to support the potential use of H3 antagonists in the treatment of narcolepsy and excessive daytime sleepiness. Moreover, the differential effects observed on W and narcoleptic episodes following repeat dosing could have important implications in clinical studies. PMID:19413575

  12. The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

    Science.gov (United States)

    Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

    2013-01-01

    The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. 啮齿类动物28天重复剂量经口毒性改良试验简介与进展%Introduction and progress on the enhancement of repeated dose 28-day oral toxicity study in rodents

    Institute of Scientific and Technical Information of China (English)

    王恒娟; 刘兆平

    2012-01-01

    Repeated dose 28-day oral toxicity study in rodents ( OECD Test Guidelines 407) is widely used to evaluate the general toxicity of chemicals. In 1998, the Organization for Economic Co-operation and Development (OECD) enhanced existing TG 407 to develop new Test Guidelines for screening and testing potential endocrine disruptors. This procedure has been verified by an extensive international validation program. To provide reference for developing endocrine disruptor evaluation system in China, the enhanced TG 407, its progress and its advantages and disadvantages were summarized in this paper.%经济合作与发展组织(Organization for Economic Co-operation and Development,OECD)推荐的啮齿类动物28天重复剂量经口毒性试验( OECD TG 407)是一种广泛用于评价化学物一般毒性的毒理学试验方案.OECD在1998年对其进行改良后,建立TG 407改良试验并经世界多国实验室验证,用于检测化学物的内分泌干扰作用.本文简要介绍了OECD TG 407改良试验指南,并对其进展情况以及优缺点进行综述,以期为我国的内分泌干扰物的评价体系提供参考.

  14. Influence of Food on the Bioavailability of an Enteric-Coated Tablet Formulation of Omeprazole 20 mg Under Repeated Dose Conditions

    Directory of Open Access Journals (Sweden)

    ABR Thomson

    1997-01-01

    Full Text Available The objective of this study was to investigate the influence of food on the bioavailability of omeprazole (20 mg given as an enteric-coated tablet under repeated dose conditions. This open randomized crossover study consisted of three seven-day treatment periods, each separated by a drug-free period. During each treatment period an enteric-coated tablet of omeprazole was taken once daily either under fasting conditions, or immediately before or after a standardized breakfast. On the last day of each treatment period, blood samples for the determination of plasma omeprazole concentrations were collected at baseline and at predetermined intervals over the 24 h period following drug administration. Fifty-seven male and female subjects, aged 18 to 52 years, completed the study according to the protocol. No statistically significant differences were found when comparing either the before breakfast or after breakfast treatment regimens with the fasting regimen for the estimated mean area under the plasma concentration-time curve (AUC. The maximum plasma concentration was not found to differ significantly among any of the treatment regimens. However, the lower limit of the CI for the comparison of fasting/before breakfast was not contained within the limits of bioequivalence. The time to reach maximum plasma concentration was significantly different when fasting and after breakfast regimens were compared. Thus, under repeated dose conditions, food has no influence on the bioavailability (expressed as AUC of omeprazole given as the enteric-coated tablet formulation.

  15. Simple benchmark for complex dose finding studies.

    Science.gov (United States)

    Cheung, Ying Kuen

    2014-06-01

    While a general goal of early phase clinical studies is to identify an acceptable dose for further investigation, modern dose finding studies and designs are highly specific to individual clinical settings. In addition, as outcome-adaptive dose finding methods often involve complex algorithms, it is crucial to have diagnostic tools to evaluate the plausibility of a method's simulated performance and the adequacy of the algorithm. In this article, we propose a simple technique that provides an upper limit, or a benchmark, of accuracy for dose finding methods for a given design objective. The proposed benchmark is nonparametric optimal in the sense of O'Quigley et al. (2002, Biostatistics 3, 51-56), and is demonstrated by examples to be a practical accuracy upper bound for model-based dose finding methods. We illustrate the implementation of the technique in the context of phase I trials that consider multiple toxicities and phase I/II trials where dosing decisions are based on both toxicity and efficacy, and apply the benchmark to several clinical examples considered in the literature. By comparing the operating characteristics of a dose finding method to that of the benchmark, we can form quick initial assessments of whether the method is adequately calibrated and evaluate its sensitivity to the dose-outcome relationships.

  16. Successive failure, repeat entrepreneurship and no learning: A case study

    Directory of Open Access Journals (Sweden)

    Marius Pretorius

    2011-02-01

    Full Text Available Orientation: Current theories of repeat entrepreneurship provide little explanation for the effect of failure as a ‘trigger’ for creating successive ventures or learning from repeated failures. Research purpose: This study attempts to establish the role of previous failures on the ventures that follow them and to determine the process of learning from successive failures.Motivation for the study: Successive failures offer potentially valuable insights into the relationship between failures on the ventures that follow and the process of learning from failure.Research design, approach and method: The researchers investigated a single case study of one entrepreneur’s successive failures over 20 years.Main findings: Although the causes varied, all the failures had fundamental similarities. This suggested that the entrepreneur had not learnt from them. The previous failures did not trigger the subsequent ventures. Instead, they played a role in causing the failures. Learning from failure does not happen immediately but requires deliberate reflection. Deliberate reflection is a prerequisite for learning from failure as the entrepreneur repeated similar mistakes time after time until he reflected on each failure.Practical/managerial implications: It confirms that failure is a part of entrepreneurial endeavours. However, learning from it requires deliberate reflection. Failure does not ‘trigger’ the next venture and educators should note this.Contribution/value-add: Knowing the effect of failure on consecutive ventures may help us to understand the development of prototypes (mental frameworks and expand the theory about entrepreneurial prototype categories.

  17. Effects of a novel organophosphorus pesticide (RPR-V) on extra hepatic detoxifying enzymes after repeated oral doses in rats.

    Science.gov (United States)

    Mahboob, Mohammed; Kaleem, Mohammed; Siddiqui, Javed

    2004-10-01

    The effects of a novel organophosphorous pesticide, 2-butenoic acid-3-(diethoxy phosphinothionyl) ethyl ester (RPR-V) on glutathione S-transferases (GST), UDP-glucuronyl transferases (UDPGT) and the level of glutathione (GSH) were evaluated in rats after repeated oral administration at 33 microg kg(-1)day(-1) (low), 66 microg kg(-1)day(-1) (mid) and 99 microg kg(-1)day(-1) (high) for 90 days and at 28 days (withdrawal) post-treatment. GSH level and GST in kidney; GSH level in brain decreased significantly at mid and high doses on 45th and 90th day (P RPR-V has the potential to modulate the extrahepatic detoxifying enzymes and thereby interact with other physiological processes in the exposed organisms.

  18. Repeating tests: different roles in research studies and clinical medicine.

    Science.gov (United States)

    Monach, Paul A

    2012-10-01

    Researchers often decide whether to average multiple results in order to produce more precise data, and clinicians often decide whether to repeat a laboratory test in order to confirm its validity or to follow a trend. Some of the major sources of variation in laboratory tests (analytical imprecision, within-subject biological variation and between-subject variation) and the effects of averaging multiple results from the same sample or from the same person over time are discussed quantitatively in this article. This analysis leads to the surprising conclusion that the strategy of averaging multiple results is only necessary and effective in a limited range of research studies. In clinical practice, it may be important to repeat a test in order to eliminate the possibility of a rare type of error that has nothing to do analytical imprecision or within-subject variation, and for this reason, paradoxically, it may be most important to repeat tests with the highest sensitivity and/or specificity (i.e., ones that are critical for clinical decision-making).

  19. PET functional volume delineation: a robustness and repeatability study

    Energy Technology Data Exchange (ETDEWEB)

    Hatt, Mathieu [CHU Morvan, INSERM, U650, LaTIM, Brest (France); CHU MORVAN, LaTIM, INSERM U650, Brest (France); Cheze-le Rest, Catherine [CHU Morvan, INSERM, U650, LaTIM, Brest (France); CHU, Academic Department of Nuclear Medicine, Brest (France); Albarghach, Nidal; Pradier, Olivier [CHU Morvan, INSERM, U650, LaTIM, Brest (France); CHU, Institute of Oncology, Brest (France); Visvikis, Dimitris [CHU Morvan, INSERM, U650, LaTIM, Brest (France)

    2011-04-15

    Current state-of-the-art algorithms for functional uptake volume segmentation in PET imaging consist of threshold-based approaches, whose parameters often require specific optimization for a given scanner and associated reconstruction algorithms. Different advanced image segmentation approaches previously proposed and extensively validated, such as among others fuzzy C-means (FCM) clustering, or fuzzy locally adaptive bayesian (FLAB) algorithm have the potential to improve the robustness of functional uptake volume measurements. The objective of this study was to investigate robustness and repeatability with respect to various scanner models, reconstruction algorithms and acquisition conditions. Robustness was evaluated using a series of IEC phantom acquisitions carried out on different PET/CT scanners (Philips Gemini and Gemini Time-of-Flight, Siemens Biograph and GE Discovery LS) with their associated reconstruction algorithms (RAMLA, TF MLEM, OSEM). A range of acquisition parameters (contrast, duration) and reconstruction parameters (voxel size) were considered for each scanner model, and the repeatability of each method was evaluated on simulated and clinical tumours and compared to manual delineation. For all the scanner models, acquisition parameters and reconstruction algorithms considered, the FLAB algorithm demonstrated higher robustness in delineation of the spheres with low mean errors (10%) and variability (5%), with respect to threshold-based methodologies and FCM. The repeatability provided by all segmentation algorithms considered was very high with a negligible variability of <5% in comparison to that associated with manual delineation (5-35%). The use of advanced image segmentation algorithms may not only allow high accuracy as previously demonstrated, but also provide a robust and repeatable tool to aid physicians as an initial guess in determining functional volumes in PET. (orig.)

  20. Receptionist input to quality and safety in repeat prescribing in UK general practice: ethnographic case study.

    Science.gov (United States)

    Swinglehurst, Deborah; Greenhalgh, Trisha; Russell, Jill; Myall, Michelle

    2011-11-03

    To describe, explore, and compare organisational routines for repeat prescribing in general practice to identify contributors and barriers to safety and quality. Ethnographic case study. Four urban UK general practices with diverse organisational characteristics using electronic patient records that supported semi-automation of repeat prescribing. 395 hours of ethnographic observation of staff (25 doctors, 16 nurses, 4 healthcare assistants, 6 managers, and 56 reception or administrative staff), and 28 documents and other artefacts relating to repeat prescribing locally and nationally. Potential threats to patient safety and characteristics of good practice. Observation of how doctors, receptionists, and other administrative staff contributed to, and collaborated on, the repeat prescribing routine. Analysis included mapping prescribing routines, building a rich description of organisational practices, and drawing these together through narrative synthesis. This was informed by a sociological model of how organisational routines shape and are shaped by information and communications technologies. Results Repeat prescribing was a complex, technology-supported social practice requiring collaboration between clinical and administrative staff, with important implications for patient safety. More than half of requests for repeat prescriptions were classed as "exceptions" by receptionists (most commonly because the drug, dose, or timing differed from what was on the electronic repeat list). They managed these exceptions by making situated judgments that enabled them (sometimes but not always) to bridge the gap between the idealised assumptions about tasks, roles, and interactions that were built into the electronic patient record and formal protocols, and the actual repeat prescribing routine as it played out in practice. This work was creative and demanded both explicit and tacit knowledge. Clinicians were often unaware of this input and it did not feature in policy

  1. Repeated Intramuscular-dose Toxicity Test of Water-soluble Carthami Flos (WCF Pharmacopuncture in Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    Yoo-min Choi

    2015-03-01

    Full Text Available Objectives: Water-soluble carthami flos (WCF is a new mixture of Carthami flos (CF pharmacopuncture. We conducted a 4-week toxicity test of repeated intramuscular injections of WCF in Sprague-Dawley rats. Methods: Forty male and 40 female rats were divided into 4 groups of 10 male and 10 female SD rats: The control group received 0.5 mL/animal/day of normal saline whereas the three experimental groups received WCF at doses of 0.125, 0.25, and 0.5 mL/animal/day, respectively. For 4 weeks, the solutions were injected into the femoral muscle of the rats alternating from side to side. Clinical signs, body weights, and food consumption were observed; opthalmological examinations and urinalyses were performed. On day 29, blood samples were taken for hematological and clinical chemistry analyses. Then, necropsy was conducted in all animals to observe weights and external and histopathological changes in the bodily organs. All data were tested using a statistical analysis system (SAS. Results: No deaths were observed. Temporary irregular respiration was observed in male rats of the experimental group for the first 10 days. Body weights, food consumptions, opthalmological examinations, urinalyses, clinical chemistry analyses, organ weights and necropsy produced no findings with toxicological meaning. In the hematological analysis, delay of prothrombin time (PT was observed in male rats of the 0.25- and the 0.5-mL/animal/day groups. In the histopathological test, a dose-dependent inflammatory cell infiltration into the fascia and panniculitis in perimuscular tissues was observed in all animals of the experimental groups. However, those symptoms were limited to local injection points. No toxicological meanings, except localized changes, were noted. Conclusion: WCF solution has no significant toxicological meaning, but does produce localized symptoms. No observed adverse effect level (NOAEL of WCF in male and female rats is expected for doses over 0.5 mL/animal/day.

  2. Prospective evaluation of potential toxicity of repeated doses of Thymus vulgaris L. extracts in rats by means of clinical chemistry, histopathology and NMR-based metabonomic approach.

    Science.gov (United States)

    Benourad, Fouzia; Kahvecioglu, Zehra; Youcef-Benkada, Mokhtar; Colet, Jean-Marie

    2014-10-01

    In the field of natural extracts, research generally focuses on the study of their biological activities for food, cosmetic, or pharmacological purposes. The evaluation of their adverse effects is often overlooked. In this study, the extracts of Thymus vulgaris L. were obtained by two different extraction methods. Intraperitoneal injections of both extracts were given daily for four days to male Wistar Han rats, at two different doses for each extract. The evaluation of the potential toxic effects included histopathological examination of liver, kidney, and lung tissues, as well as serum biochemistry of liver and kidney parameters, and (1)H-NMR-based metabonomic profiles of urine. The results showed that no histopathological changes were observed in the liver and kidney in rats treated with both extracts of thyme. Serum biochemical investigations revealed significant increases in blood urea nitrogen, creatinine, and uric acid in animals treated with polyphenolic extract at both doses. In these latter groups, metabonomic analysis revealed alterations in a number of urine metabolites involved in the energy metabolism in liver mitochondria. Indeed, the results showed alterations of glycolysis, Krebs cycle, and β-oxidative pathways as evidenced by increases in lactate and ketone bodies, and decreases in citrate, α-ketoglutarate, creatinine, hippurate, dimethylglycine, and dimethyalanine. In conclusion, this work showed that i.p. injection of repeated doses of thyme extracts causes some disturbances of intermediary metabolism in rats. The metabonomic study revealed interesting data which could be further used to determine the cellular pathways affected by such treatments.

  3. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    Science.gov (United States)

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya

    2008-01-01

    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  4. Efficacy of repeated doses of levamisole, morantel, fenbendazole, and ivermectin against gastrointestinal nematodes in ewes.

    Science.gov (United States)

    Hembry, F G; Miller, J E; Sims, D; Rodriguez, S; Stagg, L C

    1986-08-01

    Levamisole, morantel, fenbendazole, or ivermectin was administered at 2-week intervals from May 1 through Sept 14, 1985, to breeding ewes (20 ewes/drug) infected with various gastrointestinal nematodes. All ewes had fewer gastrointestinal nematode eggs per gram of feces (epg) after 2 treatments, compared with pretreatment epg counts. Ewes administered ivermectin continued to have a low mean epg (0 to 3) throughout the study. The mean epg counts of ewes treated with levamisole increased from 3 to 483 during the study. This increase was similar to that of ewes treated with morantel (7 to 485 epg). The mean epg count of fenbendazole-treated ewes increased from 4 to 192 during the study. By the end of the study, the mean epg counts when expressed as a percentage of the pretreatment epg counts were 4% (ivermectin), 249% (fenbendazole), 627% (levamisole), and 630% (morantel). With the exception of the ivermectin-treated ewes, the epg count increased almost linearly in the ewes after the 2nd anthelmintic treatment. These data indicate that the gastrointestinal nematodes (including Haemonchus contortus) may have developed more resistance to levamisole and morantel than to fenbendazole. On the basis of the epg counts, resistance to ivermectin did not develop during the 4.5-month treatment period. The percentage of ewes shedding eggs after 2, 4, and 6 anthelmintic treatments was lowest for ewes treated with ivermectin (20%) and was similar (40%) for ewes treated with 1 of the other 3 anthelmintics. At the conclusion of the study, most of the ewes (90%) were shedding at least a small number of eggs, regardless of the anthelmintic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Influence of Two Depuration Periods on the Activity and Transcription of Antioxidant Enzymes in Tilapia Exposed to Repeated Doses of Cylindrospermopsin under Laboratory Conditions

    Directory of Open Access Journals (Sweden)

    Victoria Ríos

    2014-03-01

    Full Text Available The cyanobacterial toxin Cylindrospermopsin (CYN, a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and gene expression of some glutathione related enzymes in tilapias (Oreochromis niloticus exposed to a single dose of CYN has been reported. However, little is known about the effects induced by repeated doses of this toxin in tilapias exposed by immersion and the potential reversion of these biochemical alterations after two different depuration periods (3 or 7 days. In the present study, tilapias were exposed by immersion to repeated doses of a CYN-containing culture of Aphanizomenon ovalisporum during 14 days, and then were subjected to depuration periods (3 or 7 days in clean water in order to examine the potential reversion of the effects observed. The activity and relative mRNA expression by real-time polymerase chain reaction (PCR of the antioxidant enzymes glutathione peroxidase (GPx and soluble glutathione-S-transferases (sGST, and also the sGST protein abundance by Western blot analysis were evaluated in liver and kidney of fish. Results showed significant alterations in most of the parameters evaluated and their recovery after 3 days (GPx activity, sGST relative abundance or 7 days (GPx gene expression, sGST activity. These findings not only confirm the oxidative stress effects produced in fish by cyanobacterial cells containing CYN, but also show the effectiveness of depuration processes in mitigating the CYN-containing culture toxic effects.

  6. Studies of an expanded trinucleotide repeat in transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Bingham, P.; Wang, S.; Merry, D. [Univ. of Pennsylvania, Philadelphia, PA (United States)

    1994-09-01

    Spinal and bulbar muscular atrophy (SBMA) is a progressive motor neuron disease caused by expansion of a trinucleotide repeat in the androgen receptor gene (AR{sup exp}). AR{sup exp} repeats expand further or contract in approximately 25% of transmissions. Analogous {open_quotes}dynamic mutations{close_quotes} have been reported in other expanded trinucleotide repeat disorders. We have been developing a mouse model of this disease using a transgenic approach. Expression of the SBMA AR was documented in transgenic mice with an inducible promoter. No phenotypic effects of transgene expression were observed. We have extended our previous results on stability of the expanded trinucleotide repeat in transgenic mice in two lines carrying AR{sup exp}. Tail DNA was amplified by PCR using primers spanning the repeat on 60 AR{sup exp} transgenic mice from four different transgenic lines. Migration of the PCR product through an acrylamide gel showed no change of the 45 CAG repeat length in any progeny. Similarly, PCR products from 23 normal repeat transgenics showed no change from the repeat length of the original construct. Unlike the disease allele in humans, the expanded repeat AR cDNA in transgenic mice showed no change in repeat length with transmission. The relative stability of CAG repeats seen in the transgenic mice may indicate either differences in the fidelity of replicative enzymes, or differences in error identification and repair between mice and humans. Integration site or structural properties of the transgene itself might also play a role.

  7. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats.

    Science.gov (United States)

    Sui, Hajime; Matsumoto, Hirotaka; Wako, Yumi; Kawasako, Kazufumi

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens and can be integrated into general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  8. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning

    Energy Technology Data Exchange (ETDEWEB)

    Kerkhof, E M; Put, R W van der; Raaymakers, B W; Heide, U A van der; Vulpen, M van; Lagendijk, J J W [Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht (Netherlands)], E-mail: E.Kerkhof@umcutrecht.nl

    2008-10-21

    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  9. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning

    Science.gov (United States)

    Kerkhof, E. M.; van der Put, R. W.; Raaymakers, B. W.; van der Heide, U. A.; van Vulpen, M.; Lagendijk, J. J. W.

    2008-10-01

    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  10. Variation in target and rectum dose due to prostate deformation: an assessment by repeated MR imaging and treatment planning.

    Science.gov (United States)

    Kerkhof, E M; van der Put, R W; Raaymakers, B W; van der Heide, U A; van Vulpen, M; Lagendijk, J J W

    2008-10-21

    In daily clinical practice, implanted fiducial markers are used to correct for prostate motion, but not for prostate deformation. The aim of this study is to investigate the variation in target and rectum dose due to the deformation of the prostate gland (without seminal vesicles). Therefore, we performed five to six MRI scans of eight healthy volunteers that exhibited large variation in rectal volume and thus prostate deformation. Prostate motion was corrected by a mask-based rigid registration which uses the delineation as well as the internal structures of the prostate gland. Per MRI scan, one IMRT plan with a PTV margin of 4 mm was created, resulting in 41 IMRT plans. The dose distribution of the IMRT plan based on the MRI scan with the minimum rectal volume was applied to the other rigidly registered MRI scans to evaluate the impact of prostate deformation. In conclusion, pre-treatment planning on the minimum rectal volume can cause a fraction dose increase (up to 15%) to the rectum due to prostate deformation. The impact on the total dose increase to the rectum depends on the intrapatient rectum variation during treatment, but is negligible with the currently used PTV margins in a fractionated treatment.

  11. Cytogenetic studies in couples experiencing repeated pregnancy losses.

    Science.gov (United States)

    De Braekeleer, M; Dao, T N

    1990-07-01

    A computerized database generated from the literature on cytogenetic studies in couples experiencing repeated pregnancy losses has been set up at the University of Quebec at Chicoutimi. At the present time, it contains data on 22,199 couples (44,398 individuals). The statistical analyses showed a relationship between the distribution of the chromosome abnormalities and the number of abortions. An uneven distribution of the chromosomal structural rearrangements according to the sex of the carrier was found (P less than 0.05). Overall, 4.7% of the couples ascertained for two or more spontaneous abortions included one carrier. It also appeared that only translocations (both reciprocal and Robertsonian) and inversions were associated with a higher risk of pregnancy wastage. Therefore, genetic counselling should be offered to these couples and investigations performed on their extended families.

  12. Distribution and antitumor activity of adriamycin given in a high-dose and a repeated low-dose schedule to mice.

    Science.gov (United States)

    Pacciarini, M A; Barbieri, B; Colombo, T; Broggini, M; Garattini, S; Donelli, M G

    1978-05-01

    Experimental studies on the distribution of adriamycin (AM) under different treatment conditions and possible correlations between tissue and plasma levels and chemotherapeutic activity are discussed. C57BL/6J mice bearing im Lewis lung carcinoma and (C3H x O2O)F1 mice bearing mammary carcinoma were injected iv with AM at a single dose of 15 mg/kg or with the same total amount of drug administered in spaced doses of 3.75 mg/kg for 4 consecutive days. In the two experimental systems studied, the drug reached approximately the same value in the tumor and spleen with both types of treatment, but with the 3.75-mg/kg x 4 schedule much lower AM concentrations were observed in the heart than with the single high-dose treatment. The therapeutic activity of the two treatments also differed: the antitumor and antimetastatic effect was the same in the two tumor systems, but with the 3.75-mg/kg x 4 schedule, increased survival and somewhat lower toxicity were observed. Daunorubicin, tested in the mammary carcinoma system with the two schedules of treatment, behaves very similarly to AM in terms of both distribution and chemotherapeutic effect.

  13. Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury.

    Science.gov (United States)

    Corps, Kara N; Islam, Zahidul; Pestka, James J; Harkema, Jack R

    2010-04-01

    Macrocyclic trichothecene mycotoxins encountered in water-damaged buildings have been suggested to contribute to illnesses of the upper respiratory tract. Here, the authors characterized the adverse effects of repeated exposures to roridin A (RA), a representative macrocyclic trichothecene, on the nasal airways of mice and assessed the persistence of these effects. Young, adult, female C57BL/6 mice were exposed to single daily, intranasal, instillations of RA (0.4, 2, 10, or 50 microg/kg body weight [bw]) in saline (50 microl) or saline alone (controls) over 3 weeks or 250 microg/kg RA over 2 weeks. Histopathologic, immunohistochemical, and morphometric analyses of nasal airways conducted 24 hr after the last instillation revealed that the lowest-effect level was 10 microg/kg bw. RA exposure induced a dose-dependent, neutrophilic rhinitis with mucus hypersecretion, atrophy and exfoliation of nasal transitional and respiratory epithelium, olfactory epithelial atrophy and loss of olfactory sensory neurons (OSNs). In a second study, the persistence of lesions in mice instilled with 250 microg/kg bw RA was assessed. Nasal inflammation and excess luminal mucus were resolved after 3 weeks, but OSN loss was still evident in olfactory epithelium (OE). These results suggest that nasal inflammation, mucus hypersecretion, and olfactory neurotoxicity could be important adverse health effects associated with short-term, repeated, airborne exposures to macrocyclic trichothecenes.

  14. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

    Science.gov (United States)

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott

    2015-02-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.).

  15. Study of simple sequence repeat (SSR) polymorphism for biotic ...

    African Journals Online (AJOL)

    home

    2013-10-02

    Oct 2, 2013 ... back cross breeding; SSRs, simple sequence repeats; PIC, polymorphism ..... PIC values were reported in barley wheat and rice (Gu et ... doubled-haploid rice population. Theor. ... Grover A, Aishwarya V, Sharma PC (2007).

  16. Comparison of image quality in head CT studies with different dose-reduction strategies

    DEFF Research Database (Denmark)

    Johansen, Jeppe; Nielsen, Rikke; Fink-Jensen, Vibeke;

    The number of multi-detector CT examinations is increasing rapidly. They allow high quality reformatted images providing accurate and precise diagnosis at maximum speed. Brain examinations are the most commonly requested studies, and although they come at a lower effective dose than body CT, can...... account to a considerable radiation dose as many patients undergo repeated studies. Therefore, various dose-reduction strategies are applied such as automated tube current and voltage modulation and recently different iterative reconstruction algorithms. However, the trade-off of all dose......-reduction maneuvers is reduction of image quality due to image noise or artifacts. The aim of our study was therefore to find the best diagnostic images with lowest possible dose. We present results of dose- and image quality optimizing strategies of brain CT examinations at our institution. We compare sequential...

  17. Dose fractionation and single subject studies in PET

    Science.gov (United States)

    Balakrishnan, Karthikayan

    Conventional positron emission tomography (PET) for cognitive brain studies typically relies on information collected from the distribution of decays following an injection of 15O-labeled water. The number of injections that can be administered to the subject are constrained by radiation dose to the subject and total length of the PET scan. The standard protocol involves 8--10 injections of H152O separated by approximately 5--7 half-lives of 15O. The number of activation conditions that can be realistically studied in a standard PET session is between 8 and 10. This work investigates the physiological response of a simulated subject to H152O injections that are administered in small doses (1--5 mCi) with short inter-injection intervals (40--180 seconds). A larger number of activation conditions are presented to the subject with a wider variation in the activation paradigm. Repeat conditions are studies. Signal averaging methods are feasible with this method of dose administration. Sinograms from scans with similar activation conditions are summed together before reconstruction. The signal in the primary activation region of the brain is shown to increase while suppressing the contribution of secondary activation regions in the brain. The contrast of the final image is similarly increased which leads to easier identification of the primary activation region. An automated H152O -production unit controlled by a PC running LabView software was developed to produce the dose required for the injection sequence by controlling the flow of H152O -vapor that diffuses across a semi-permeable membrane into saline. The unit is capable of producing H152O rapidly for both the standard and the proposed dose administration methods. The system also detects the bolus arrival time at the subject's lungs using a small external plastic detector. Activation sequence commences with the rise in radioactivity observed by the detector. The simulations indicate that inter-injection intervals

  18. Exposing Students to Repeat Photography: Increasing Cultural Understanding on a Short-Term Study Abroad

    Science.gov (United States)

    Lemmons, Kelly K.; Brannstrom, Christian; Hurd, Danielle

    2014-01-01

    Traditionally, repeat photography has been used to analyze land cover change. This paper describes how repeat photography may be used as a tool to enhance the short-term study abroad experience by facilitating cultural interaction and understanding. We present evidence from two cases and suggest a five-step repeat photography method for educators…

  19. Exposing Students to Repeat Photography: Increasing Cultural Understanding on a Short-Term Study Abroad

    Science.gov (United States)

    Lemmons, Kelly K.; Brannstrom, Christian; Hurd, Danielle

    2014-01-01

    Traditionally, repeat photography has been used to analyze land cover change. This paper describes how repeat photography may be used as a tool to enhance the short-term study abroad experience by facilitating cultural interaction and understanding. We present evidence from two cases and suggest a five-step repeat photography method for educators…

  20. Single and repeated elective abortions in Japan: a psychosocial study.

    Science.gov (United States)

    Kitamura, T; Toda, M A; Shima, S; Sugawara, M

    1998-09-01

    Despite its social, legal and medical importance, termination of pregnancy (TOP) (induced abortion) has rarely been the focus of psychosocial research. Of a total of 1329 women who consecutively attended the antenatal clinic of a general hospital in Japan, 635 were expecting their first baby. Of these 635 women, 103 (16.2%) had experienced TOP once previously (first aborters), while 47 (7.4%) had experienced TOP two or more times (repeated aborters). Discriminant function analysis was performed using psychosocial variables found to be significantly associated with either first abortion or repeated abortion in bivariate analyses. This revealed that both first and repeated aborters could be predicted by smoking habits and an unwanted current pregnancy while the repeated aborters appear to differ from first aborters in having a longer pre-marital dating period, non-arranged marriages, smoking habits, early maternal loss experience or a low level of maternal care during childhood. These findings suggest that both the frequency of abortion and its repetition have psychosocial origins.

  1. Dose per unit area - a study of elicitation of nickel allergy

    DEFF Research Database (Denmark)

    Fischer, Louise Arup; Menné, Torkil; Johansen, Jeanne Duus

    2007-01-01

    with a patch test and a repeated open application test (ROAT). Nickel was applied on small and large areas. The varying parameters were area, total dose and dose per unit area. RESULTS: In the patch test, at a low concentration [15 microg nickel (microg Ni)/cm(2)], there were significantly higher scores...... concentrations, even though the same dose per unit area is applied.......BACKGROUND: Experimental sensitization depends upon the amount of allergen per unit skin area and is largely independent of the area size. OBJECTIVES: This study aimed at testing if this also applies for elicitation of nickel allergy. PATIENTS/METHODS: 20 nickel allergic individuals were tested...

  2. Repeated treatment of recurrent uncomplicated Plasmodium falciparum malaria in Senegal with fixed-dose artesunate plus amodiaquine versus fixed-dose artemether plus lumefantrine: a randomized, open-label trial

    Directory of Open Access Journals (Sweden)

    Barry Aichatou

    2011-08-01

    Full Text Available Abstract Background The use of artemisinin-based combination therapy (ACT is currently recommended for treating uncomplicated malaria. The objective was to assess the efficacy and safety of repeated administrations of two fixed-dose presentations of ACT - artesunate plus amodiaquine (ASAQ and artemether-lumefantrine (AL - in subsequent episodes of Plasmodium falciparum malaria. Methods A randomized comparative study was conducted in a rural community of central Senegal from August 2007 to January 2009. Children and adults with uncomplicated P. falciparum malaria were randomized to receive open-label ASAQ once daily or AL twice daily for three days. Drug doses were given according to body weight. Treatments for first episodes were supervised. For subsequent episodes, only the first intake of study drug was supervised. ECGs and audiograms were performed in patients ≥12 years of age. Primary outcome was adequate clinical and parasitological response rate (ACPR after polymerase chain reaction (PCR correction on day 28 for the first episode. Results A total of 366 patients were enrolled in the two groups (ASAQ 184, AL 182 and followed up during two malaria transmission seasons. In the intent-to-treat population, PCR-corrected ACPRs at day 28 for the first episode were 98.4% and 96.2%, respectively, in the ASAQ and AL groups. For the per-protocol population (ASAQ 183, AL 182, PCR-corrected ACPRs at day 28 for the first episode were 98.9% and 96.7%, respectively. A 100% ACPR rate was obtained at day 28 in the 60 and four patients, respectively, who experienced second and third episodes. Treatment-related adverse events were reported in 11.7% of the patients, without significant differences between the two groups. A better improvement of haemoglobin at day 28 was noted in the ASAQ versus the AL group (12.2 versus 11.8 g/dL; p = 0.03. No sign of ototoxicity was demonstrated. A prolongation of the QTc interval was observed in both groups during

  3. Effects of repeated high-dose methamphetamine and ceftriaxone post-treatments on tissue content of dopamine and serotonin as well as glutamate and glutamine.

    Science.gov (United States)

    Althobaiti, Yusuf S; Almalki, Atiah H; Das, Sujan C; Alshehri, Fahad S; Sari, Youssef

    2016-11-10

    Repeated exposure to high doses of methamphetamine (METH) is known to alter several neurotransmitters in certain brain regions. Little is known about the effects of ceftriaxone (CEF), a β-lactam antibiotic, known to upregulate glutamate transporter subtype 1, post-treatment on METH-induced depletion of dopamine and serotonin (5-HT) tissue content in brain reward regions. Moreover, the effects of METH and CEF post-treatment on glutamate and glutamine tissue content are not well understood. In this study, Wistar rats were used to investigate the effects of METH and CEF post-treatment on tissue content of dopamine/5-HT and glutamate/glutamine in the nucleus accumbens (NAc) and prefrontal cortex (PFC). Rats received either saline or METH (10mg/kg, i.p. every 2h×4) followed by either saline or CEF (200mg/kg, i.p, every day×3) post-treatment. METH induced a significant depletion of dopamine and 5-HT in the NAc and PFC. Importantly, dopamine tissue content was completely restored in the NAc following CEF post-treatment. Additionally, METH caused a significant decrease in glutamate and glutamine tissue content in PFC, and this effect was attenuated by CEF post-treatment. These findings demonstrate for the first time the attenuating effects of CEF post-treatment on METH induced alterations in the tissue contents of dopamine, glutamate, and glutamine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Reactor pulse repeatability studies at the annular core research reactor

    Energy Technology Data Exchange (ETDEWEB)

    DePriest, K.R. [Applied Nuclear Technologies, Sandia National Laboratories, Mail Stop 1146, Post Office Box 5800, Albuquerque, NM 87185-1146 (United States); Trinh, T.Q. [Nuclear Facility Operations, Sandia National Laboratories, Mail Stop 0614, Post Office Box 5800, Albuquerque, NM 87185-1146 (United States); Luker, S. M. [Applied Nuclear Technologies, Sandia National Laboratories, Mail Stop 1146, Post Office Box 5800, Albuquerque, NM 87185-1146 (United States)

    2011-07-01

    The Annular Core Research Reactor (ACRR) at Sandia National Laboratories is a water-moderated pool-type reactor designed for testing many types of objects in the pulse and steady-state mode of operations. Personnel at Sandia began working to improve the repeatability of pulse operations for experimenters in the facility. The ACRR has a unique UO{sub 2}-BeO fuel that makes the task of producing repeatable pulses difficult with the current operating procedure. The ACRR produces a significant quantity of photoneutrons through the {sup 9}Be({gamma}, n){sup 8}Be reaction in the fuel elements. The photoneutrons are the result of the gammas produced during fission and in fission product decay, so their production is very much dependent on the reactor power history and changes throughout the day/week of experiments in the facility. Because the photoneutrons interfere with the delayed-critical measurements required for accurate pulse reactivity prediction, a new operating procedure was created. The photoneutron effects at delayed critical are minimized when using the modified procedure. In addition, the pulse element removal time is standardized for all pulse operations with the modified procedure, and this produces less variation in reactivity removal times. (authors)

  5. Responsiveness of 5-HT2C receptors in repeatedly diazepam-injected rats: a behavioral and neurochemical study.

    Science.gov (United States)

    Khan, Asma; Haleem, Darakhshan J

    2008-01-01

    The role of 5-hydroxytryptamine (serotonin; 5-HT)2C receptors in anxiety and the anxiolytic effects of drugs is well documented. In view of the withdrawal anxiety associated with repeated diazepam intake, the present study concerns the efficacy of 5-HT2C receptors in rats treated with diazepam. Results show that diazepam injections at a dose of 2 mg/kg daily for two weeks increased weekly food intake and growth rate. Anxiolytic effects of the drug monitored in a light/dark activity box were not significant after single administration. One week and two weeks of administration elicited anxiolytic effects, which were smaller after two weeks of administration as compared to one week, suggesting the development of tolerance to the anxiolytic profile of diazepam. Moreover, three days' withdrawal from repeated administration elicited anxiogenic behavior in the light/dark activity box. The behavioral and neurochemical effects of 1-(m-chlorophenyl)piperazine (m-CPP) (3 mg/kg), a 5-HT2C agonist, were monitored following withdrawal (three days) from two weeks of diazepam administration. Results showed that hypophagic as well as anxiogenic-like effects of m-CPP were not different from repeated saline or repeated diazepam-injected animals. Administration of m-CPP increased 5-HT metabolism in repeated saline as well as repeated diazepam-injected animals. However, m-CPP-induced increases in 5-HT metabolism were greater in repeated diazepam-injected animals. Results are discussed in the context of the role of 5-HT2C receptors in the precipitation of withdrawal anxiety.

  6. 氟氯氰菊酯亚急性吸入毒性实验研究%Inhalation toxicity of cyfluthrin for 28-day repeated dose in rats

    Institute of Scientific and Technical Information of China (English)

    秦珩; 乔善磊; 顾军; 钟义红; 杨洪宝; 王玉邦; 施爱民

    2012-01-01

    Objective To determine the inhalation toxicity and find the non -observed adverse effect level (NOAEL) of cyfluthrin for a 28-day repeated dose in rats. Methods Clean-grade SD rats were randomly divided into 5 groups with 5 females and 5 males in each. The animals inhaled DMSO or cyfluthrin at the concentration of 0, 7. 81 , 9. 05 and 18. 98 mg/m for 4 weeks (6 h/d, 5 d/w). At the end of inhalation , all the animals were kindly sacrificed. Their organs were collected for histopathological examination . Blood samples were collected for analysis of complete blood count , biochemistry and coagulation. Results The animals in 18. 98 mg/m3 group were found scratching repeatedly around the mouth, listless, fidgeting, trembling, discharging blood around the mouth and nose . However, symptoms in females were less serious than in males. Furthermore , the body mass , feed efficiency , weight of kidney of animals in this dose male group were found decreased compared with the control group . Biochemistry detection revealed that serum AST was elevated markedly in both genders of 18. 98 mg/m3 group and in males of 9. 05 mg/m3 group. No obvious abnormity was found in 7.81 mg/m3 group or control group. Conclusion Based on the results above, the non-observed adverse effect level (NOAEL) of cyfluthrin in SD rats is 7. 81 mg/m3 for 28 d repeated inhalation in this study.%目的 观察氟氯氰菊酯染毒大鼠亚急性吸入毒性.方法 7周龄清洁级SD大鼠随机分成5组,每组雌雄各5只,分别吸入氟氯氰菊酯0,7.81,9.05,18.98 mg/m3及溶剂二甲亚砜,每天6 h,每周5 d,共28 d.实验结束时取血液做常规生化指标、血细胞指标、血凝学指标检测.取心、肝、脾等8种主要脏器称重并做病理组织学检查.结果 18.98 mg/m3组动物在染毒中呈现反复抓挠口周、烦躁不安、鼻有血性分泌物、颤抖,染毒结束后呈现萎靡、蜂腰、四肢无力的体征.雌性动物的毒性表现较雄性低.与溶剂对照组相

  7. Feasibility Study on Applying Radiophotoluminescent Glass Dosimeters for CyberKnife SRS Dose Verification.

    Science.gov (United States)

    Hsu, Shih-Ming; Hung, Chao-Hsiung; Liao, Yi-Jen; Fu, Hsiao-Mei; Tsai, Jo-Ting; Huang, Yung-Hui; Huang, David Y C

    2017-01-01

    CyberKnife is one of multiple modalities for stereotactic radiosurgery (SRS). Due to the nature of CyberKnife and the characteristics of SRS, dose evaluation of the CyberKnife procedure is critical. A radiophotoluminescent glass dosimeter was used to verify the dose accuracy for the CyberKnife procedure and validate a viable dose verification system for CyberKnife treatment. A radiophotoluminescent glass dosimeter, thermoluminescent dosimeter, and Kodak EDR2 film were used to measure the lateral dose profile and percent depth dose of CyberKnife. A Monte Carlo simulation for dose verification was performed using BEAMnrc to verify the measured results. This study also used a radiophotoluminescent glass dosimeter coupled with an anthropomorphic phantom to evaluate the accuracy of the dose given by CyberKnife. Measurements from the radiophotoluminescent glass dosimeter were compared with the results of a thermoluminescent dosimeter and EDR2 film, and the differences found were less than 5%. The radiophotoluminescent glass dosimeter has some advantages in terms of dose measurements over CyberKnife, such as repeatability, stability, and small effective size. These advantages make radiophotoluminescent glass dosimeters a potential candidate dosimeter for the CyberKnife procedure. This study concludes that radiophotoluminescent glass dosimeters are a promising and reliable dosimeter for CyberKnife dose verification with clinically acceptable accuracy within 5%.

  8. Association between CAG repeat polymorphisms and the risk of prostate cancer: a meta-analysis by race, study design and the number of (CAG)n repeat polymorphisms.

    Science.gov (United States)

    Sun, Jun-Hyun; Lee, Sang-Ah

    2013-11-01

    Although a number of studies have been conducted on the association between prostate cancer and CAG repeat polymorphisms of the androgen receptor gene, this association remains elusive and controversial. In this meta-analysis, we aimed to evaluate the effects of (CAG)n repeat genetic polymorphisms on the incidence of prostate cancer, particularly as regards race, study design and the number of (CAG)n repeats. To collect articles published on the association between CAG repeats and prostate cancer, publications were identified from the National Center for Biotechnology Information (NCBI) database of epidemiological studies published up to October 2011; our identification of publications was not limited by a language barrier. The following search keywords were used: prostate cancer risk, CAG repeat polymorphism, androgen receptor gene and human. Stata version 10 was used for the meta-analysis and the publication bias was measured through the Begg's test and Egger's test. This meta-analysis included 47 studies with 13,346 cases and 15,172 control or non-cases and consisted of 31 reports based on Caucasians, ten on Asians, one on Hispanics and four on combined ethnic groups. The carriers of a shorter CAG repeat sequence had an increased risk of prostate cancer (OR 1.21, 95% CI 1.10-1.34 for all subjects; OR 1.21, 95% CI 1.10-1.34 for prospective studies; OR 1.32, 95% CI 1.15-1.51 for retrospective studies) regardless of the exact length of the CAG repeat, compared with carriers of a longer repeat sequence. In terms of race, the risk of carrying a shorter CAG repeat sequence was 1.10- and 1.83-fold higher than that of a longer repeat sequence in Caucasians and Asians, respectively. For the specific number of CAG repeat polymorphisms, carriers of repeats were observed to have a higher risk of prostate cancer (OR 1.16, 95% CI 1.04-1.29) compared with carriers with ≥ 22 CAG repeat polymorphisms, particularly for Asians (OR 2.06, 95% CI 1.00-4.24). This meta

  9. Needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer evaluated by repeated MRI.

    Science.gov (United States)

    Buus, Simon; Lizondo, Maria; Hokland, Steffen; Rylander, Susanne; Pedersen, Erik M; Tanderup, Kari; Bentzen, Lise

    2017-09-18

    To quantify needle migration and dosimetric impact in high-dose-rate brachytherapy for prostate cancer and propose a threshold for needle migration. Twenty-four high-risk prostate cancer patients treated with an HDR boost of 2 × 8.5 Gy were included. Patients received an MRI for planning (MRI1), before (MRI2), and after treatment (MRI3). Time from needle insertion to MRI3 was ∼3 hours. Needle migration was evaluated from coregistered images: MRI1-MRI2 and MRI1-MRI3. Dose volume histogram parameters from the treatment plan based on MRI1 were related to parameters based on needle positions in MRI2 or MRI3. Regression was used to model the average needle migration per implant and change in D90 clinical target volume, CTVprostate+3mm. The model fit was used for estimating the dosimetric impact in equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy. Needle migration was on average 2.2 ± 1.8 mm SD from MRI1-MRI2 and 5.0 ± 3.0 mm SD from MRI1-MRI3. D90 CTVprostate+3mm was robust toward average needle migration ≤3 mm, whereas for migration >3 mm D90 decreased by 4.5% per mm. A 3 mm of needle migration resulted in a decrease of 0.9, 1.7, 2.3, 4.8, and 7.6 equivalent dose in 2 Gy fractions for dose levels of 6, 8.5, 10, 15, and 19 Gy, respectively. Substantial needle migration in high-dose-rate brachytherapy occurs frequently in 1-3 hours following needle insertion. A 3-mm threshold of needle migration is proposed, but 2 mm may be considered for dose levels ≥15 Gy. Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

  10. Development of QSAR models using artificial neural network analysis for risk assessment of repeated-dose, reproductive, and developmental toxicities of cosmetic ingredients.

    Science.gov (United States)

    Hisaki, Tomoka; Aiba Née Kaneko, Maki; Yamaguchi, Masahiko; Sasa, Hitoshi; Kouzuki, Hirokazu

    2015-04-01

    Use of laboratory animals for systemic toxicity testing is subject to strong ethical and regulatory constraints, but few alternatives are yet available. One possible approach to predict systemic toxicity of chemicals in the absence of experimental data is quantitative structure-activity relationship (QSAR) analysis. Here, we present QSAR models for prediction of maximum "no observed effect level" (NOEL) for repeated-dose, developmental and reproductive toxicities. NOEL values of 421 chemicals for repeated-dose toxicity, 315 for reproductive toxicity, and 156 for developmental toxicity were collected from Japan Existing Chemical Data Base (JECDB). Descriptors to predict toxicity were selected based on molecular orbital (MO) calculations, and QSAR models employing multiple independent descriptors as the input layer of an artificial neural network (ANN) were constructed to predict NOEL values. Robustness of the models was indicated by the root-mean-square (RMS) errors after 10-fold cross-validation (0.529 for repeated-dose, 0.508 for reproductive, and 0.558 for developmental toxicity). Evaluation of the models in terms of the percentages of predicted NOELs falling within factors of 2, 5 and 10 of the in-vivo-determined NOELs suggested that the model is applicable to both general chemicals and the subset of chemicals listed in International Nomenclature of Cosmetic Ingredients (INCI). Our results indicate that ANN models using in silico parameters have useful predictive performance, and should contribute to integrated risk assessment of systemic toxicity using a weight-of-evidence approach. Availability of predicted NOELs will allow calculation of the margin of safety, as recommended by the Scientific Committee on Consumer Safety (SCCS).

  11. Efficacy and safety of fixed-dose artesunate-amodiaquine vs. artemether-lumefantrine for repeated treatment of uncomplicated malaria in Ugandan children.

    Directory of Open Access Journals (Sweden)

    Adoke Yeka

    Full Text Available The safety and efficacy of the two most widely used fixed-dose artemisinin-based combination therapies (ACT, artesunate-amodiaquine (ASAQ and artemether-lumefantrine (AL are well established for single episodes of uncomplicated Plasmodium falciparum malaria, but the effects of repeated, long-term use are not well documented. We conducted a 2-year randomized, open-label, longitudinal, phase IV clinical trial comparing the efficacy and safety of fixed-dose ASAQ and AL for repeated treatment of uncomplicated malaria in children under 5 years at Nagongera Health Centre, Uganda. Participants were randomized to ASAQ or AL and all subsequent malaria episodes were treated with the same regimen. 413 children were enrolled and experienced a total of 6027 malaria episodes (mean 15; range, 1-26. For the first malaria episode, the PCR-corrected-cure rate for ASAQ (97.5% was non-inferior to that for AL (97.0%; 95% CI [-0.028; 0.037]. PCR-corrected cure rates for subsequent malaria episodes that had over 100 cases (episodes 2-18, ranged from 88.1% to 98.9% per episode, with no clear difference between the treatment arms. Parasites were completely cleared by day 3 for all malaria episodes and gametocyte carriage was less than 1% by day 21. Fever clearance was faster in the ASAQ group for the first episode. Treatment compliance for subsequent episodes (only first dose administration observed was close to 100%. Adverse events though common were similar between treatment arms and mostly related to the disease. Serious adverse events were uncommon, comparable between treatment arms and resolved spontaneously. Anemia and neutropenia occurred in <0.5% of cases per episode, abnormal liver function tests occurred in 0.3% to 1.4% of cases. Both regimens were safe and effective for repeated treatment of malaria.Current Controlled Trials NCT00699920.

  12. Repeated exposure of male mice to low doses of lipopolysaccharide: dose and time dependent development of behavioral sensitization and tolerance in an automated light-dark anxiety test.

    Science.gov (United States)

    Banasikowski, Tomek J; Cloutier, Caylen J; Ossenkopp, Klaus-Peter; Kavaliers, Martin

    2015-06-01

    Although lipopolysaccharide (LPS) is widely used to examine immune behavior relationships there has been little consideration of the effects of low doses and the roles of sensitization and, or tolerance. Here low doses of LPS (1.0, 5.0 and 25.0 μg/kg) were peripherally administered to male mice on Days 1, 4, 28 and 32 after a baseline recording of anxiety-like behaviors in an automated light-dark apparatus (total time in the light chamber, number of light-dark transitions, nose pokes into the light chamber). LPS at 1.0 μg/kg, while having no significant effects on anxiety-like behaviors in the light-dark test on Days 1 and 4, displayed sensitization with the mice exhibiting significantly enhanced anxiety-like responses on Days 28 and 32. LPS at 5.0 μg/kg had no consistent significant effects on anxiety-like behavior on Days 1 and 4, with sensitization and enhanced anxiety-like behaviors on Day 28 followed by tolerance on Day 32. LPS at 25 μg/kg significantly enhanced anxiety-like behaviors on Day 1, followed by tolerance on Day 4, which was not evident by Day 28 and re-emerged on Day 32. There was a similar overall pattern of sensitization and tolerance for LPS-induced decreases in locomotor activity in the safe dark chamber, without, however, any significant effects on activity in the riskier light chamber. This shows that low doses of LPS induce anxiety-like behavior and these effects are subject to sensitization and tolerance in a dose, context, and time related manner.

  13. Development of immunity against viral and bacterial antigens after repeated exposures to suberythemal doses of ultraviolet light

    Directory of Open Access Journals (Sweden)

    S. A. Snopov

    2012-01-01

    Full Text Available The effects of ultraviolet (UV radiation on human infectious immunity are not well studied. On the one hand, solar and artificial UU sources have been shown to change cytokine levels in human skin, lymphocyte subpopulation counts in parepheral blood, lymphocyte DNA synthesis and prolifarative response to mitogens. On the other hand, there are just only one or two observations suggesting an influence of UV radiation on human infection course. For instance, UV irradiations have been reported to induce a reccurence of orofacial vesicular lesions caused by herpes siplex virus. Moreover, there is a lack of data concerning immune effects of suberythtemal doses of UV in spite of a long history of using them by Russian prophylactic medicine. In this work we questioned whether such suberythemal UV exposures can affect the immune responses of children to infectious conjunctivitis, to simultaneous measles and polio vaccinations and to simultaneous polio and diphtheria-tetanus vaccinations. In peripheral blood of vaccinated children we examined leukocyte counts (monocytes, neutrophils, eosinophils, lymphocytes, percentages of lymphocyte subpopulations (CD3+, CD20+, CD4+, CD8+, CD25+, HLADR+, concentrations of cytokines (IL-1 beta, TNF-alpha, IFN- amma и IL-10, DNA-synthetic activity of lymphocytes and titres of antibodies against measles and diphtheria toxin. We observed no local or systemic reactions to the vaccines in the UV-group while a moderate rise in body temperature occured in several children from unexposed group. In the blood of childeren from UV-group we found increases in CD25+ и HLADR+ cell percentages, IL- 1 beta and IL-10 concentrations, PWMinduced DNA synthesis in mononuclears, and no decreases in formation of antibodies against measles and diphreria. We concluded that suberythemal UV exposures of children modulated their further responses to imminisations perhaps through the activation of a T helper 2-like

  14. Compared efficacy of repeated annual and semi-annual doses of ivermectin and diethylcarbamazine for prevention of Wuchereria bancrofti filariasis in French Polynesia. Final evaluation.

    Science.gov (United States)

    Cartel, J L; Spiegel, A; Nguyen Ngnoc, L; Cardines, R; Plichart, R; Martin, P M; Roux, J F; Moulia-Pelat, J P

    1992-06-01

    In October 1989, 58 apparently healthy Polynesian Wuchereria bancrofti carriers, in whom microfilarial (mf) density was greater than or equal to 100 mf/ml, were randomly allocated to treatment groups receiving single doses of either ivermectin at 100 mcg/kg or diethylcarbamazine (DEC) at 3 and 6 mg/kg. Six months later, half of the carriers initially treated with ivermectin 100 mcg/kg or DEC 3 mg/kg were given a second similar dose while the rest were given a placebo. Six months later again, all of the carriers received a last treatment dose similar to the initial one. The results observed during the 12-month period which followed this last treatment have confirmed that (i) in terms of immediate clearance or complete negativation of microfilaremia, the efficacy of ivermectin is higher than that of DEC (at dosage of 3 or 6 mg/kg), (ii) DEC is more effective than ivermectin in sustaining the reduction of microfilaremia over a longer period of time and (iii) the efficacy of repeated single doses of either DEC 3 mg/kg or ivermectin 100 mcg/kg is much higher when given semi-annually than annually.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Analysing Repeat Visitation on Country Level with Passive Mobile Positioning Method: an Estonian Case Study

    Directory of Open Access Journals (Sweden)

    Andres Kuusik

    2013-01-01

    Full Text Available The purpose of this paper is to investigate the capabilities and limits of the passive mobile positioning (PMP method in studying loyalty of tourists on the macro level. The repeat visitors were identified using database of call activities of roaming phones in Estonia since 25.04.2005 till 31.01.2009. For this purpose was developed model which selected repeat visits on the basis of time interval. The findings of the study revealed that it is possible to observe the duration, density, seasonality and dynamics of repeat visitations. In addition the local destinations and events most loved by repeat visitors and the trajectory they are using could be also identified. Another important finding revealed that repeat visitors stay longer in destination than first time visitors. The results presented in this paper could be used by Estonian Ministry of Economic Affairs and Communications and by Enterprise Estonia developing the Estonian tourism policy

  16. Role of sulfite additives in wine induced asthma: single dose and cumulative dose studies

    OpenAIRE

    Vally, H; Thompson, P.

    2001-01-01

    BACKGROUND—Wine appears to be a significant trigger for asthma. Although sulfite additives have been implicated as a major cause of wine induced asthma, direct evidence is limited. Two studies were undertaken to assess sulfite reactivity in wine sensitive asthmatics. The first study assessed sensitivity to sulfites in wine using a single dose sulfited wine challenge protocol followed by a double blind, placebo controlled challenge. In the second study a cumulative dose su...

  17. Retrospective study comparing low-dose versus standard dose of bortezomib in patients with multiple myeloma

    Directory of Open Access Journals (Sweden)

    Marcela Espinoza Zelada

    2015-03-01

    Full Text Available INTRODUCTION Bortezomib is a selective inhibitor of the proteosoma that is used in multiple myeloma. In combination with other antineoplastic drugs, it has a well-documented impact in progression-free survival rates and overall survival rates with standard doses (1.3-1.5 mg/m2. However, up to 88% of patients on standard doses have unwanted side effects (neutropenia, neuropathy or anemia. Standard dose (1.3 mg/m2 is used in almost all patients and low dose (0.7-0.8 mg/m2 is reserved for patients with kidney disease and neuropathy. OBJECTIVE We aim to describe clinical, cytological, and cytometric outcomes, as well as overall survival and side effects of low dose versus standard dose of bortezomib in our institution. METHODS Retrospective, descriptive study based on data recovered from clinical charts of 48 multiple myeloma patients treated in our hospital between 2011 and 2013. We included data on age, gender, type of multiple myeloma, serum albumin, serum creatinine, beta 2 microglobulin, calcemia, imaging studies, disease stage, pre-and post-therapy bone marrow studies, adverse events and rate of progression. We also recorded events like date of death or of the last medical appointment. RESULTS Forty-eight multiple myeloma patients were treated with bortezomib-cyclophosphamide-dexamethasone. Twenty-one patients received low dose and 27 patients were treated with the standard dose. No statistical differences between the two groups were found for clinical response (p=0.6, cytological response (p=0.28, flow cytometric response (p= 0.3, rate of adverse effects and overall survival rates. CONCLUSION This retrospective analysis suggests that lower doses of bortezomib have similar effects in disease control measured by flow cytometry and cytology compared to standard doses in multiple myeloma patients.

  18. Effects of repeated low-dose exposure of the nerve agent VX on monoamine levels in different brain structures in mice.

    Science.gov (United States)

    Graziani, S; Christin, D; Daulon, S; Breton, P; Perrier, N; Taysse, L

    2014-05-01

    In a previous report, alterations of the serotonin metabolism were previously reported in mice intoxicated with repeated low doses of soman. In order to better understand the effects induced by repeated low-dose exposure to organophosphorus compounds on physiological and behavioural functions, the levels of endogenous monoamines (serotonin and dopamine) in different brain areas in mice intoxicated with sublethal dose of (O-ethyl-S-[2(di-isopropylamino) ethyl] methyl phosphonothioate) (VX) were analysed by HPLC method with electrochemical detection. Animals were injected once a day for three consecutive days with 0.10 LD50 of VX (5 μg/kg, i.p). Neither severe signs of cholinergic toxicity nor pathological changes in brain tissue of exposed animals were observed. Cholinesterase (ChE) activity was only inhibited in plasma (a maximum of 30% inhibition 24 h after the last injection of VX), but remained unchanged in the brain. Serotonin and dopamine (DA) metabolism appeared significantly modified. During the entire period of investigation, at least one of the three parameters investigated (i.e. DA and DOPAC levels and DOPAC/DA ratio) was modified. During the toxic challenge, an increase of the serotonin metabolism was noted in hippocampus (HPC), hypothalamus/thalamus, pons medulla and cerebellum (CER). This increase was maintained 4 weeks after exposure in HPC, pons medulla and CER whereas a decrease in cortex 3 weeks after the toxic challenge was observed. The lack of correlation between brain ChE activity and neurochemical outcomes points out to independent mechanisms. The involvement in possibly long-lasting behavioural disorders is discussed.

  19. Misonidazole with dexamethasone rescue: an escalating dose toxicity study

    Energy Technology Data Exchange (ETDEWEB)

    Tanasichuk, H.; Urtasun, R.C.; Fulton, D.S.; Raleigh, J.

    1984-09-01

    Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, the authors reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. The authors are presently investigating the use of DEXA, with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO given in 9 equally divided doses over 3 weeks. DEXA is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M/sub 2/. One grade I PN occurred in the first four patients receiving 15.5 gm/M/sub 2/. Six additional patients were entered at this dose level and no further incidence of PN was observed.

  20. Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

    Science.gov (United States)

    Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

    2016-02-10

    Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure.

  1. Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

    Science.gov (United States)

    Ritter, G; Cohen, L S; Williams, C; Richards, E C; Old, L J; Welt, S

    2001-09-15

    Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

  2. Chip-based human liver-intestine and liver-skin co-cultures--A first step toward systemic repeated dose substance testing in vitro.

    Science.gov (United States)

    Maschmeyer, Ilka; Hasenberg, Tobias; Jaenicke, Annika; Lindner, Marcus; Lorenz, Alexandra Katharina; Zech, Julie; Garbe, Leif-Alexander; Sonntag, Frank; Hayden, Patrick; Ayehunie, Seyoum; Lauster, Roland; Marx, Uwe; Materne, Eva-Maria

    2015-09-01

    Systemic repeated dose safety assessment and systemic efficacy evaluation of substances are currently carried out on laboratory animals and in humans due to the lack of predictive alternatives. Relevant international regulations, such as OECD and ICH guidelines, demand long-term testing and oral, dermal, inhalation, and systemic exposure routes for such evaluations. So-called "human-on-a-chip" concepts are aiming to replace respective animals and humans in substance evaluation with miniaturized functional human organisms. The major technical hurdle toward success in this field is the life-like combination of human barrier organ models, such as intestine, lung or skin, with parenchymal organ equivalents, such as liver, at the smallest biologically acceptable scale. Here, we report on a reproducible homeostatic long-term co-culture of human liver equivalents with either a reconstructed human intestinal barrier model or a human skin biopsy applying a microphysiological system. We used a multi-organ chip (MOC) platform, which provides pulsatile fluid flow within physiological ranges at low media-to-tissue ratios. The MOC supports submerse cultivation of an intact intestinal barrier model and an air-liquid interface for the skin model during their co-culture with the liver equivalents respectively at (1)/100.000 the scale of their human counterparts in vivo. To increase the degree of organismal emulation, microfluidic channels of the liver-skin co-culture could be successfully covered with human endothelial cells, thus mimicking human vasculature, for the first time. Finally, exposure routes emulating oral and systemic administration in humans have been qualified by applying a repeated dose administration of a model substance - troglitazone - to the chip-based co-cultures.

  3. Relationship between dose in vivo of ethylene oxide and exposure to ethene studied in exposed workers.

    Science.gov (United States)

    Granath, F; Rohlén, O; Göransson, C; Hansson, L; Magnusson, A L; Törnqvist, M

    1996-10-01

    1. In vivo doses of ethylene oxide, arising from ethene exposure, in plastic industry workers were estimated through hemoglobin adducts. The ethene exposure was assessed through person-worn monitors. The metabolic conversion of ethene to ethylene oxide was estimated from the exposure dose/in vivo dose ratio. 2. Two studies were done: In the first study hemoglobin adducts were determined in samples collected on one occasion in exposed groups and exposure doses were estimated by using exposure data from the hygienic surveillance program. The second study applies a newly developed study design with repeated blood sampling in a few persons combined with a complete personal exposure monitoring during the study period. This makes it possible to relate adduct formation with individual short-time exposure doses, which in theory should overcome the problems with exposure history dependence of the adduct level in a single blood sample. The results of the second study shows that it is possible, through the proposed method, to utilize occupational exposure situations for this kind of studies even if the exposure pattern is irregular and highly variable. Both studies show a metabolic conversion of ethene to ethylene oxide of only 0.5%, which is unexpectedly low. 3. The cancer risk associated with the ethene exposure in the highly exposed group (3.6 p.p.m. 40 h/week) is estimated by applying the radiation-dose-equivalence approach. The result of this evaluation leads to a risk corresponding to a radiation dose of 4 mSv/year which is about a factor 3 below the current dose limit for radiological work recommended by ICRP.

  4. Contamination study of multiple-dose vials.

    Science.gov (United States)

    Melnyk, P S; Shevchuk, Y M; Conly, J M; Richardson, C J

    1993-03-01

    To document the number of opened, dated, and expired multiple-dose vials (MDVs) in patient-care areas and to determine what proportion of MDVs were contaminated with bacteria or cellular debris. Every tenth opened MDV (69/656) identified on the wards was collected, ensuring representation from each nursing unit. Contents were examined for contamination. Medical-school-affiliated, tertiary care center. (1) Visual inspection for debris, medication type, location, lot number, manufacturer's expiration date, and date of opening; (2) culture in solid and broth media for bacterial growth; and (3) staining and microscopic examination for cellular constituents. No vials had been dated after opening and 4.6 percent were expired according to the manufacturer's expiration date. No bacterial contamination was evident; however, one vial was contaminated with red blood cells. Transmission of infection via contaminated MDVs has been well documented and contamination with red blood cells raises concerns about potential for transmission of bloodborne pathogens. Recommendations include dating MDVs after opening, emphasizing the need for proper aseptic technique, and discarding MDVs on the manufacture's date of expiration.

  5. The Study on the Ferrokinetics and Acquired Immunity in Repeated Hookworm Infections

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Mun Ho; Lee, Pyl Ung [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1967-09-15

    In order to confirm whether acquired immunity or resistance can be developed by the repeated hookworm infections, the 150 mature actively moving filariform ancylostoma duodenale larvae obtained from the severe hookworm anemia patients were orally given to 8 healthy volunteers in three divided doses, 50 in each, at 5 day interval. Also the hematological changes as well as several ferrokinetics using {sup 59}Fe were done and were compared with 10 controls. The clinical symptoms and signs were checked every day for the first 3 weeks and then twice weekly until the end of the experiment. The appearance of the ova in the stool was examined by the formalin ether method and the ova was counted by the Stoll's method. The following laboratory tests were done:1) Red blood cell count, venous blood hematocrit (micromethod), hemoglobin count (cyanomethemoglobin method) were checked every 5 to 7 day interval. 2) Plasma iron concentration (Barkan's modified method) was determined every 2 to 3 week interval. 3) Radioisotope studies:a) Ferrokinetics: Huff et al and Bothwell's method were applied. Erythropoietic Index (% of normal)= ['Subject's turnover/100 ml whole bloodX100'] over ['Average normal turnover/100 ml whole blood'] b) Quantitative measurement of the gastrointestinal absorption of iron:Radioiron ({sup 59}Fe) balance method was applied. c) Determination of the plasma erythropoietin activity: Fried's method was applied. Following were the results: 1) The serum iron level was lower. The red cell volume was decreased, but with relative increase of plasma volume. 2) The plasma iron disappearance time was accelerated and the plasma iron turnover rate was decreased. The red cell iron turnover rate was markedly increased, while all of the red cell iron concentration, circulating red cell iron, plasma iron pool were decreased. The daily iron pool turnover and red cell renewal rate were increased. 3) The erythropoietic index

  6. Dose-Escalation Study for Cardiac Radiosurgery in a Porcine Model

    Energy Technology Data Exchange (ETDEWEB)

    Blanck, Oliver, E-mail: oliver.blanck@uksh.de [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); CyberKnife Center Northern Germany, Guestrow (Germany); Bode, Frank [Medical Department II, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Gebhard, Maximilian [Institute of Pathology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Hunold, Peter [Department of Radiology and Nuclear Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Brandt, Sebastian [Department of Anaesthesiology and Intensive Care Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Bruder, Ralf [Institute for Robotics and Cognitive Systems, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Grossherr, Martin [Department of Anaesthesiology and Intensive Care Medicine, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Vonthein, Reinhard [Institute of Medical Biometry and Statistics, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Rades, Dirk [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); Dunst, Juergen [Department of Radiation Oncology, University of Luebeck and University Medical Center Schleswig-Holstein, Campus Luebeck (Germany); University Copenhagen (Denmark)

    2014-07-01

    Purpose: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. Methods and Materials: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm{sup 3}). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. Results: Transmural scarring of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. Conclusions: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.

  7. Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

    Science.gov (United States)

    Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

    2014-05-01

    In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

  8. Computational study of the human dystrophin repeats: interaction properties and molecular dynamics.

    Science.gov (United States)

    Legrand, Baptiste; Giudice, Emmanuel; Nicolas, Aurélie; Delalande, Olivier; Le Rumeur, Elisabeth

    2011-01-01

    Dystrophin is a large protein involved in the rare genetic disease Duchenne muscular dystrophy (DMD). It functions as a mechanical linker between the cytoskeleton and the sarcolemma, and is able to resist shear stresses during muscle activity. In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. In this context, we have performed a computational study of the whole dystrophin central rod domain based on the rational homology modeling of successive and overlapping tandem repeats and the analysis of their surface properties. Each tandem repeat has very specific surface properties that make it unique. However, the repeats share enough electrostatic-surface similarities to be grouped into four separate clusters. Molecular dynamics simulations of four representative tandem repeats reveal specific flexibility or bending properties depending on the repeat sequence. We thus suggest that the dystrophin central rod domain is constituted of seven biologically relevant sub-domains. Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy.

  9. Computational study of the human dystrophin repeats: interaction properties and molecular dynamics.

    Directory of Open Access Journals (Sweden)

    Baptiste Legrand

    Full Text Available Dystrophin is a large protein involved in the rare genetic disease Duchenne muscular dystrophy (DMD. It functions as a mechanical linker between the cytoskeleton and the sarcolemma, and is able to resist shear stresses during muscle activity. In all, 75% of the dystrophin molecule consists of a large central rod domain made up of 24 repeat units that share high structural homology with spectrin-like repeats. However, in the absence of any high-resolution structure of these repeats, the molecular basis of dystrophin central domain's functions has not yet been deciphered. In this context, we have performed a computational study of the whole dystrophin central rod domain based on the rational homology modeling of successive and overlapping tandem repeats and the analysis of their surface properties. Each tandem repeat has very specific surface properties that make it unique. However, the repeats share enough electrostatic-surface similarities to be grouped into four separate clusters. Molecular dynamics simulations of four representative tandem repeats reveal specific flexibility or bending properties depending on the repeat sequence. We thus suggest that the dystrophin central rod domain is constituted of seven biologically relevant sub-domains. Our results provide evidence for the role of the dystrophin central rod domain as a scaffold platform with a wide range of surface features and biophysical properties allowing it to interact with its various known partners such as proteins and membrane lipids. This new integrative view is strongly supported by the previous experimental works that investigated the isolated domains and the observed heterogeneity of the severity of dystrophin related pathologies, especially Becker muscular dystrophy.

  10. Repeat endocarditis: analysis of risk factors based on the International Collaboration on Endocarditis - Prospective Cohort Study.

    Science.gov (United States)

    Alagna, L; Park, L P; Nicholson, B P; Keiger, A J; Strahilevitz, J; Morris, A; Wray, D; Gordon, D; Delahaye, F; Edathodu, J; Miró, J M; Fernández-Hidalgo, N; Nacinovich, F M; Shahid, R; Woods, C W; Joyce, M J; Sexton, D J; Chu, V H

    2014-06-01

    Repeat episodes of infective endocarditis (IE) can occur in patients who survive an initial episode. We analysed risk factors and 1-year mortality of patients with repeat IE. We considered 1874 patients enrolled in the International Collaboration on Endocarditis - Prospective Cohort Study between January 2000 and December 2006 (ICE-PCS) who had definite native or prosthetic valve IE and 1-year follow-up. Multivariable analysis was used to determine risk factors for repeat IE and 1-year mortality. Of 1874 patients, 1783 (95.2%) had single-episode IE and 91 (4.8%) had repeat IE: 74/91 (81%) with new infection and 17/91 (19%) with presumed relapse. On bivariate analysis, repeat IE was associated with haemodialysis (p 0.002), HIV (p 0.009), injection drug use (IDU) (p < 0.001), Staphylococcus aureus IE (p 0.003), healthcare acquisition (p 0.006) and previous IE before ICE enrolment (p 0.001). On adjusted analysis, independent risk factors were haemodialysis (OR, 2.5; 95% CI, 1.2-5.3), IDU (OR, 2.9; 95% CI, 1.6-5.4), previous IE (OR, 2.8; 95% CI, 1.5-5.1) and living in the North American region (OR, 1.9; 95% CI, 1.1-3.4). Patients with repeat IE had higher 1-year mortality than those with single-episode IE (p 0.003). Repeat IE is associated with IDU, previous IE and haemodialysis. Clinicians should be aware of these risk factors in order to recognize patients who are at risk of repeat IE.

  11. Prediction of the carcinogenic potential of human pharmaceuticals using repeated dose toxicity data and their pharmacological properties

    Directory of Open Access Journals (Sweden)

    Jan Willem Van Der Laan

    2016-10-01

    Full Text Available In an exercise designed to reduce animal use, we analysed the results of rat sub-chronic toxicity studies from 289 pharmaceutical compounds with the aim to predict the tumour outcome of carcinogenicity studies in this species. The results were obtained from the assessment reports available at the Medicines Evaluation Board of the Netherlands for 289 pharmaceutical compounds that had been shown to be non-genotoxic. One hundred and forty-three of the 239 compounds not inducing putative preneoplastic lesions in the sub-chronic study did not induce tumours in the carcinogenicity study (True Negatives - TN, whereas 96 compounds were categorised as False Negatives (FN, because tumours were observed in the carcinogenicity study. For the remaining 50 compounds, 31 showed preneoplastic lesions in the subchronic study and tumours in the carcinogenicity study (True positives - TP, and 19 only showed preneoplastic lesions in subchronic studies but no tumours in the carcinogenicity study (False positives - FP. In addition, we then re-assessed the prediction of the tumour outcome by integrating the pharmacological properties of these compounds. These pharmacological properties were evaluated with respect to the presence or absence of a direct or indirect proliferative action. We found support for the absence of cellular proliferation for 204 compounds (TN. For 67 compounds the presence of cellular hyperplasia as evidence for proliferative action could be found (TP. Therefore, this approach resulted in an ability to predict non-carcinogens at a success rate of 92 % and the ability to detect carcinogens at 98 %. The combined evaluation of pharmacological and histopathological endpoints eventually led to only 18 unknown outcomes (17 categorised as FN. 1 as FP, thereby enhancing both the negative and positive predictivity of an evaluation based upon histopathological evaluation only. The data show the added value of a consideration of the pharmacological

  12. Repeat film analysis and its implications for quality assurance in dental radiology: An institutional case study

    Directory of Open Access Journals (Sweden)

    Shruthi Acharya

    2015-01-01

    Full Text Available Context: The goal of any radiologist is to produce the highest quality diagnostic radiographs, while keeping patient exposure as low as reasonably achievable (ALARA. Aims: The aim of this study was to describe the reasons for radiograph rejections through a repeat film analysis in an Indian dental school. Settings and Design: An observational study conducted in the Department of Oral Medicine and Radiology, Manipal College of Dental Sciences, Manipal. Materials and Methods: During a 6-month study period, a total of 9,495 intra-oral radiographs and 2339 extraoral radiographs taken in the Radiology Department were subjected to repeat film analysis. Statistical Analysis Used: SPSS Version 16. Descriptive analysis used. Results: The results showed that the repeat rates were 7.1% and 5.86% for intraoral and extraoral radiographs, respectively. Among the causes for errors reported, positioning error (38.7% was the most common, followed by improper angulations (26.1%, and improper film placement (11.2% for intra-oral radiographs. The study found that the maximum frequency of repeats among extraoral radiographs was for panoramic radiographs (49% followed by lateral cephalogram (33%, and paranasal sinus view (14%. It was also observed that repeat rate of intraoral radiographs was highest for internees (44.7%, and undergraduate students (28.2%. Conclusions: The study pointed to a need for more targeted interventions to achieve the goal of keeping patient exposure ALARA in a dental school setting.

  13. A study of allelic polymorphism of four short tandem repeats in the population of northwestern Russia

    Energy Technology Data Exchange (ETDEWEB)

    Aseev, M.V.; Skakun, V.N.; Baranov, V.S. [Ott Institute of Obstetrics and Gynecology, St. Petersburg (Russian Federation)

    1995-06-01

    Characteristics of the allelic polymorphisms of the trimeric AGC repeat of the androgen receptor gene (Xq11-12), exon 1 (AR); the tetrameric ATCT repeat of the von Willebrand factor gene (12p12), intron 40 (vWF); the AGAT repeat of the hypoxanthine phosphoribosyltransferase gene (Xq26) (HPRT); and the AGAT repeat of anonymous DNA sequences of the short arm of chromosome X (STRX1) were studied in 160 DNA samples from unrelated inhabitants of northwestern Russia using the method of polymerase chain reaction. Seventeen, ten, eight, and nine alleles were revealed electrophoretically for short tandem repeats of AR, vWF, HPRT, and STRX1, respectively. The heterozygosity indices for these repeats were 0.80, 0.70, 0.54, and 0.58, respectively. The values for AR and vWF correlated with those expected according to the Hardy-Weinberg equilibrium, whereas the values for HPRT and STRX1 differed significantly from those theoretically expected. The individualization potentials were 0.045, 0.135, 0.095, and 0.061 for the short tandem repeats of AR, vWF, HPRT, and STRX1, respectively. The distribution of genotypes for the set of these four loci in the population studied was determined. The possibilities of using the studied polymorphic marker systems in molecular diagnosis of the corresponding monogenic diseases - spinal and bulbar muscle atrophy (AR), Lesch-Nyhan disease (HPRT), and von Willebrand disease (vWF) - as well as in population human genetics, testing of personal identity, and molecular approaches to the estimation of mutagenic activity are discussed. 17 refs., 2 figs., 6 tabs.

  14. Construction of the Database of Rat Repeated-dose Toxicity Tests of Pesticides for the Toxicological Characterization of Hepatocyte Hypertrophy.

    Science.gov (United States)

    Masuda, Akane; Masuda, Miyabi; Kawano, Takuya; Kitsunai, Yoko; Nakayama, Haruka; Nakajima, Hiroyuki; Kojima, Hiroyuki; Kitamura, Shigeyuki; Uramaru, Naoto; Hosaka, Takuomi; Sasaki, Takamitsu; Yoshinari, Kouichi

    2017-01-01

     Liver and hepatocyte hypertrophy can be induced by exposure to chemical compounds, but the mechanisms and toxicological characteristics of these phenomena have not yet been investigated extensively. In particular, it remains unclear whether the hepatocyte hypertrophy induced by chemical compounds should be judged as an adaptive response or an adverse effect. Thus, understanding of the toxicological characteristics of hepatocyte hypertrophy is of great importance to the safety evaluation of pesticides and other chemical compounds. To this end, we have constructed a database of potentially toxic pesticides. Using risk assessment reports of pesticides that are publicly available from the Food Safety Commission of Japan, we extracted all observations/findings that were based on 90-day subacute toxicity tests and 2-year chronic toxicity and carcinogenicity tests in rats. Analysis of the database revealed that hepatocyte hypertrophy was observed for 37-47% of the pesticides investigated (varying depending on sex and testing period), and that centrilobular hepatocyte hypertrophy was the most frequent among the various types of hepatocyte hypertrophy in both the 90-day and 2-year studies. The database constructed in this study enables us to investigate the relationships between hepatocyte hypertrophy and other toxicological observations/findings, and thus will be useful for characterizing hepatocyte hypertrophy.

  15. Anterior segment biometry: a study and review of resolution and repeatability data.

    Science.gov (United States)

    Reinstein, Dan Z; Gobbe, Marine; Archer, Timothy J

    2012-07-01

    To obtain comparable resolution and repeatability data for a selection of anterior segment imaging devices. A standard letter of request was sent in May 2008 to each device manufacturer requesting resolution and repeatability data for its device to be provided according to specific definitions and protocol; if this was not already published in the peer-reviewed domain, compliant raw data were required. Where applicable, repeatability data were reported for corneal vertex corneal thickness; epithelial and flap thickness; minimum corneal thickness; corneal, epithelial and flap thickness mapping for the central 6-mm diameter; minimum residual stromal thickness; angle-to-angle diameter; sulcus-to-sulcus diameter; and anterior chamber depth. To summarize published repeatability data, a complete review of the peer-reviewed literature waas performed. Nine of the 13 manufacturers contacted agreed to take part and provided the data requested: Pentacam HD (Oculus Optikgeräte GmbH), Galilei (Ziemer), Visante OCT (Carl Zeiss Meditec), SL-OCT (Haag-Streit), RTVue (Optovue), Artemis (ArcScan), Vumax (Sonomed), HiScan (Opticon), and Eye Cubed (Ellex/Innovative). Only one (Carl Zeiss Meditec) of 9 manufacturers was able to provide the data directly upon request, without performing a prospective study. Five of the 9 manufacturers were able to provide a complete set of repeatability data for all parameters measurable with their device; the remaining 4 manufacturers admitted that repeatability of some parameters was unknown. Both literature and manufacturers' data on file were lacking and required the study to be performed. This report provides an imperfect, but most comprehensive to date, resolution and repeatability data review of biometric devices intended for surgical planning. Copyright 2012, SLACK Incorporated.

  16. Usability of tartaric acid in dose measurements: an ESR study

    Science.gov (United States)

    Korkmaz, Güney; Polat, Mustafa; Korkmaz, Mustafa

    2010-03-01

    Unirradiated tartaric acid samples do not exhibit any ESR signal. However, the ESR spectra of irradiated samples contain many resonance signals. The dose-responce curves of the resonance signals, denoted as I 1, I 2, I 3 and I 4 in the present study, were found to increase linearly with the applied radiation dose in the range of 0.04-25 kGy. Adjusting the microvawe power and modulation amplitudes of 1.0 mW and 1.0 mT, respectively, was found to increase the sensitivity of tartaric acid. From the dose-response curves and room temperature decay data, it was concluded that the I 3 resonance signal of tartaric acid can be used for dose measurements at intermediate (0.04-0.4 kGy) and high dose (0.5-25 kGy) levels.

  17. Phase I study to determine the maximal tolerated dose and dose-limiting toxicities of orally administered idarubicin in dogs with lymphoma.

    Science.gov (United States)

    Vail, D M; Husbands, B D; Kamerling, S G; Simpson, H; Kurzman, I D; McDonnell, A

    2012-01-01

    Idarubicin, a PO bioavailable anthracycline antibiotic-class chemotherapeutic, could have substantial convenience advantages over currently available similar class agents in use that require IV delivery. The primary objective of this study was to determine the maximally tolerated dose (MTD), dose-limiting toxicities (DLTs), and basic pharmacokinetic parameters of oral idarubicin exposure in dogs with lymphoma after a single oral dose. A secondary objective was to document preliminary antitumor efficacy in an expanded treatment cohort using the established MTD. Client-owned dogs with measurable lymphoma. Dogs (n = 31) were enrolled in a prospective open label phase I study of oral idarubicin. By means of a 3 + 3 cohort design, dose escalations were made with 3 dogs per dose level, and the MTD was established based on the number of patients experiencing a DLT. Plasma concentrations of idarubicin and idarubicinol were determined by postdose sampling. Assessment of antitumor efficacy focused on evaluation of accessible, measurable lymph nodes and skin lesions by modified RECIST guidelines. The MTD in dogs > 15 kg body weight was 22 mg/m(2) . Adverse hematologic events (neutropenia and thrombocytopenia) were the predominant DLT and generally correlated with higher plasma concentrations of idarubicin and idarubicinol. PO administered idarubicin was generally well-tolerated and had preliminary antitumor activity in dogs with lymphoma. Furthermore, the potential clinical advantage of a safe and efficacious oral anthracycline alternative supports further investigations of this agent in repeated-dose, randomized clinical trials. Copyright © 2012 by the American College of Veterinary Internal Medicine.

  18. Topics on study of low dose-effect relationship

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Takeshi [Toho Univ., School of Medicine, Tokyo (Japan); Ohyama, Harumi

    1999-09-01

    It is not exceptional but usually observed that a dose-effect relationship in biosystem is not linear. Sometimes, the low dose-effect relationship appears entirely contrary to the expectation from high dose-effect. This is called a 'hormesis' phenomena. A high dose irradiation inflicts certainly an injury on biosystem. No matter how low the dose may be, an irradiation might inflict some injury on biosystem according to Linear Non-Threshold hypothesis(LNT). On the contrary to the expectation, a low dose irradiation stimulates immune system, and promotes cell proliferation. This is called 'radiation hormesis'. The studies of the radiation hormesis are made on from four points of view as follows: (1) radiation adaptive response, (2) revitalization caused by a low dose stimulation, (3) a low dose response unexpected from the LNT hypothesis, (4) negation of the LNT hypothesis. The various empirical proofs of radiation hormesis are introduced in the report. (M . Suetake)

  19. Repeat-dose toxicology evaluation in cynomolgus monkeys of AVI-4658, a phosphorodiamidate morpholino oligomer (PMO) drug for the treatment of duchenne muscular dystrophy.

    Science.gov (United States)

    Sazani, Peter; Ness, Kirk P Van; Weller, Doreen L; Poage, Duane W; Palyada, Kiran; Shrewsbury, Stephen B

    2011-05-01

    AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) drug designed to restore dystrophin expression in a subset of patients with Duchenne muscular dystrophy (DMD). Previous reports demonstrated this clinical proof-of-principle in patients with DMD following intramuscular injection of AVI-4658. This preclinical study evaluated the toxicity and toxicokinetic profile of AVI-4658 when administered either intravenously (IV) or subcutaneously (SC) to cynomolgus monkeys once weekly over 12 weeks, at doses up to the maximum feasible dose of 320 mg/kg per injection. No drug-related effects were noted on survival, clinical observations, body weight, food consumption, opthalmoscopic or electrocardiographic evaluations, hematology, clinical chemistry, urinalysis, organ weights, and macroscopic evaluations. Drug-related microscopic renal effects were dose-dependent, apparently reversible, and included basophilic granules (minimal), basophilic tubules (minimal to moderate), and tubular vacuolation (minimal to mild). These data establish the tolerability of AVI-4658 at doses up to and including the maximum feasible dose of 320 mg/kg by IV bolus or SC injection.

  20. Planned Repeat Cesarean Section at Term and Adverse Childhood Health Outcomes: A Record-Linkage Study.

    Directory of Open Access Journals (Sweden)

    Mairead Black

    2016-03-01

    Full Text Available Global cesarean section (CS rates range from 1% to 52%, with a previous CS being the commonest indication. Labour following a previous CS carries risk of scar rupture, with potential for offspring hypoxic brain injury, leading to high rates of repeat elective CS. However, the effect of delivery by CS on long-term outcomes in children is unclear. Increasing evidence suggests that in avoiding exposure to maternal bowel flora during labour or vaginal birth, offspring delivered by CS may be adversely affected in terms of energy uptake from the gut and immune development, increasing obesity and asthma risks, respectively. This study aimed to address the evidence gap on long-term childhood outcomes following repeat CS by comparing adverse childhood health outcomes after (1 planned repeat CS and (2 unscheduled repeat CS with those that follow vaginal birth after CS (VBAC.A data-linkage cohort study was performed. All second-born, term, singleton offspring delivered between 1 January 1993 and 31 December 2007 in Scotland, UK, to women with a history of CS (n = 40,145 were followed up until 31 January 2015. Outcomes assessed included obesity at age 5 y, hospitalisation with asthma, learning disability, cerebral palsy, and death. Cox regression and binary logistic regression were used as appropriate to compare outcomes following planned repeat CS (n = 17,919 and unscheduled repeat CS (n = 8,847 with those following VBAC (n = 13,379. Risk of hospitalisation with asthma was greater following both unscheduled repeat CS (3.7% versus 3.3%, adjusted hazard ratio [HR] 1.18, 95% CI 1.05-1.33 and planned repeat CS (3.6% versus 3.3%, adjusted HR 1.24, 95% CI 1.09-1.42 compared with VBAC. Learning disability and death were more common following unscheduled repeat CS compared with VBAC (3.7% versus 2.3%, adjusted odds ratio 1.64, 95% CI 1.17-2.29, and 0.5% versus 0.4%, adjusted HR 1.50, 95% CI 1.00-2.25, respectively. Risk of obesity at age 5 y and risk of cerebral

  1. Evaluation of sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride. Results of a prospective, randomized, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Dulin, J; Kovács, L; Ramm, S; Horvath, F; Ebeling, L; Kohnen, R

    1998-07-01

    Sedative effects of single and repeated doses of 50 mg and 150 mg tolperisone hydrochloride (Mydocalm), a centrally active muscle-relaxing agent, were evaluated in a placebo-controlled double-blind clinical trial. A total of 72 healthy young adults balanced by sex were randomized to receive 50 mg or 150 mg tolperisone hydrochloride or placebo t.i.d. for a period of 8 days. Control examinations were performed in the mornings of days 1 and 8 before intake of the morning dose and at 1.5, 4 and 6 hours postdose. The psychomotoric test battery used in this trial revealed no sedative effects of tolperisone hydrochloride in the given doses at any control examination. Subjective mood ratings quantified by the Welzel Colored Scales were not impaired either. The lack of differences in sedative potentials of tolperisone hydrochloride and placebo was confirmed by tests on differences and by tests on equivalence using 95% CI. The present study substantiates clinical experience and previous clinical trials demonstrating that tolperisone hydrochloride, though being a centrally active muscle relaxant, does not cause any sedation and does not impair reaction times.

  2. Dose profile study in head CT scans using radiochromic films

    Energy Technology Data Exchange (ETDEWEB)

    Ladino G, A. M.; Prata M, A., E-mail: amlgphys@gmail.com [Universidade Federal de Minas Gerais, Departamento de Engenharia Nuclear, Av. Pte. Antonio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais (Brazil)

    2016-10-15

    Diagnostic images of computed tomography generate higher doses than other methods of diagnostic radiology using X-ray beam attenuation. Clinical applications of CT have been increased by technological advances, what leads to a wide variety of scanner in the Brazilian technological pool. It has been difficult to implement dose reduction strategies because of the lack of proper guidance on computed tomography examinations. However, CT scanners allow adjusting acquisition parameter according to the patients physical profile and diagnostic application for which the scan is intended. The knowledge of the dose distribution is important because changes in image acquisition parameters may provide dose reduction. In this study, it was used a cylindrical head phantom in PMMA with 5 openings, what allows dose measurement in 5 regions. In a GE CT scanner, Discovery model of 64 channels, the central slice of the head phantom was irradiated and the absorbed doses were measured using a pencil ionization chamber. Radiochromic film strips were placed in the peripheral and in the central region of the head phantom and was performed a scan of 10 cm in the phantom central region. The scan was performed using the head scanning protocol of the radiobiology service, with a voltage of 120 kV. After scanning, the radiochromic film strips were digitalized and their digital images were used to have the dose longitudinal profiles. The dose values recorded have variation in a range of 18.66 to 23.57 mGy. In the results it was compared the dose index values obtained by the pencil chamber measurement to the dose longitudinal profiles recorded by the film strips. (Author)

  3. Monte Carlo study of radiation dose enhancement by gadolinium in megavoltage and high dose rate radiotherapy.

    Directory of Open Access Journals (Sweden)

    Daniel G Zhang

    Full Text Available MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF and conventional flattened 6MV photon beams were used. High dose rate (HDR brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL would be needed.

  4. Monte Carlo study of radiation dose enhancement by gadolinium in megavoltage and high dose rate radiotherapy.

    Science.gov (United States)

    Zhang, Daniel G; Feygelman, Vladimir; Moros, Eduardo G; Latifi, Kujtim; Zhang, Geoffrey G

    2014-01-01

    MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.

  5. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif

    2014-01-01

    Full Text Available Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD concepts: (i PPARγ activation in hepatocytes and (ii PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

  6. Study of dose calculation on breast brachytherapy using prism TPS

    Energy Technology Data Exchange (ETDEWEB)

    Fendriani, Yoza; Haryanto, Freddy [Nuclear Physics and Biophysics Research Division, FMIPA Institut Teknologi Bandung, Physics Buildings, Jl. Ganesha 10, Bandung 40132 (Indonesia)

    2015-09-30

    PRISM is one of non-commercial Treatment Planning System (TPS) and is developed at the University of Washington. In Indonesia, many cancer hospitals use expensive commercial TPS. This study aims to investigate Prism TPS which been applied to the dose distribution of brachytherapy by taking into account the effect of source position and inhomogeneities. The results will be applicable for clinical Treatment Planning System. Dose calculation has been implemented for water phantom and CT scan images of breast cancer using point source and line source. This study used point source and line source and divided into two cases. On the first case, Ir-192 seed source is located at the center of treatment volume. On the second case, the source position is gradually changed. The dose calculation of every case performed on a homogeneous and inhomogeneous phantom with dimension 20 × 20 × 20 cm{sup 3}. The inhomogeneous phantom has inhomogeneities volume 2 × 2 × 2 cm{sup 3}. The results of dose calculations using PRISM TPS were compared to literature data. From the calculation of PRISM TPS, dose rates show good agreement with Plato TPS and other study as published by Ramdhani. No deviations greater than ±4% for all case. Dose calculation in inhomogeneous and homogenous cases show similar result. This results indicate that Prism TPS is good in dose calculation of brachytherapy but not sensitive for inhomogeneities. Thus, the dose calculation parameters developed in this study were found to be applicable for clinical treatment planning of brachytherapy.

  7. Longitudinal study of repeated sprint performance in youth soccer players of contrasting skeletal maturity status

    NARCIS (Netherlands)

    Valente-dos-Santos, Joao; Coelho-e-Silva, Manuel J.; Severino, Vitor; Duarte, Joao; Martins, Raul S.; Figueiredo, Antonio J.; Seabra, Andre T.; Philippaerts, Renaat M.; Cumming, Sean P.; Elferink-Gemser, Marije; Malina, Robert M.

    The purpose of the study was to evaluate the developmental changes in performance in a repeated-sprint ability (RSA) test in young soccer players of contrasting maturity status. A total of 83 regional level Portuguese youth soccer players, aged 11-13 years at baseline was assessed annually. Stature,

  8. Longitudinal study of repeated sprint performance in youth soccer players of contrasting maturity status

    NARCIS (Netherlands)

    V. Duarte; A. Seabra; A. Figueiredo; S. Cumming; R. Martins; R. Philippaerts; M. Coelho e Silva; J. Valente dos Santos; V. Severino; Marije Elferink-Gemser

    2012-01-01

    The purpose of the study was to evaluate the developmental changes in performance in a repeated-sprint ability (RSA) test in young soccer players of contrasting maturity status. A total of 83 regional level Portuguese youth soccer players, aged 11- 13 years at baseline was assessed annually.

  9. Experimentally studied dynamic dose interplay does not meaningfully affect target dose in VMAT SBRT lung treatments

    Energy Technology Data Exchange (ETDEWEB)

    Stambaugh, Cassandra [Department of Physics, University of South Florida, Tampa, Florida 33612 (United States); Nelms, Benjamin E. [Canis Lupus LLC, Merrimac, Wisconsin 53561 (United States); Dilling, Thomas; Stevens, Craig; Latifi, Kujtim; Zhang, Geoffrey; Moros, Eduardo; Feygelman, Vladimir [Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida 33612 (United States)

    2013-09-15

    Purpose: The effects of respiratory motion on the tumor dose can be divided into the gradient and interplay effects. While the interplay effect is likely to average out over a large number of fractions, it may play a role in hypofractionated [stereotactic body radiation therapy (SBRT)] treatments. This subject has been extensively studied for intensity modulated radiation therapy but less so for volumetric modulated arc therapy (VMAT), particularly in application to hypofractionated regimens. Also, no experimental study has provided full four-dimensional (4D) dose reconstruction in this scenario. The authors demonstrate how a recently described motion perturbation method, with full 4D dose reconstruction, is applied to describe the gradient and interplay effects during VMAT lung SBRT treatments.Methods: VMAT dose delivered to a moving target in a patient can be reconstructed by applying perturbations to the treatment planning system-calculated static 3D dose. Ten SBRT patients treated with 6 MV VMAT beams in five fractions were selected. The target motion (motion kernel) was approximated by 3D rigid body translation, with the tumor centroids defined on the ten phases of the 4DCT. The motion was assumed to be periodic, with the period T being an average from the empirical 4DCT respiratory trace. The real observed tumor motion (total displacement ≤8 mm) was evaluated first. Then, the motion range was artificially increased to 2 or 3 cm. Finally, T was increased to 60 s. While not realistic, making T comparable to the delivery time elucidates if the interplay effect can be observed. For a single fraction, the authors quantified the interplay effect as the maximum difference in the target dosimetric indices, most importantly the near-minimum dose (D{sub 99%}), between all possible starting phases. For the three- and five-fractions, statistical simulations were performed when substantial interplay was found.Results: For the motion amplitudes and periods obtained from

  10. Optimal selection of individuals for repeated covariate measurements in follow-up studies.

    Science.gov (United States)

    Reinikainen, Jaakko; Karvanen, Juha; Tolonen, Hanna

    2016-12-01

    Repeated covariate measurements bring important information on the time-varying risk factors in long epidemiological follow-up studies. However, due to budget limitations, it may be possible to carry out the repeated measurements only for a subset of the cohort. We study cost-efficient alternatives for the simple random sampling in the selection of the individuals to be remeasured. The proposed selection criteria are based on forms of the D-optimality. The selection methods are compared with the simulation studies and illustrated with the data from the East-West study carried out in Finland from 1959 to 1999. The results indicate that cost savings can be achieved if the selection is focused on the individuals with high expected risk of the event and, on the other hand, on those with extreme covariate values in the previous measurements. © The Author(s) 2014.

  11. Brexpiprazole Alters Monoaminergic Systems following Repeated Administration: an in Vivo Electrophysiological Study

    OpenAIRE

    Oosterhof, Chris A.; Mansari, Mostafa El; Bundgaard, Christoffer; Blier, Pierre

    2015-01-01

    Background: Brexpiprazole was recently approved as adjunctive therapy for depression and treatment of schizophrenia in adults. To complement results from a previous study in which its acute effects were characterized, the present study assessed the effect of repeated brexpiprazole administration on monoaminergic systems. Methods: Brexpiprazole (1mg/kg, subcutaneous) or vehicle was administered once daily for 2 and 14 days. Single-unit electrophysiological recordings from noradrenaline neurons...

  12. Radiation dose study in nuclear medicine using GATE

    Science.gov (United States)

    Aguwa, Kasarachi

    Dose as a result of radiation exposure is the notion generally used to disclose the imparted energy in a volume of tissue to a potential biological effect. The basic unit defined by the international system of units (SI system) is the radiation absorbed dose, which is expressed as the mean imparted energy in a mass element of the tissue known as "gray" (Gy) or J/kg. The procedure for ascertaining the absorbed dose is complicated since it involves the radiation transport of numerous types of charged particles and coupled photon interactions. The most precise method is to perform a full 3D Monte Carlo simulation of the radiation transport. There are various Monte Carlo toolkits that have tool compartments for dose calculations and measurements. The dose studies in this thesis were performed using the GEANT4 Application for Emission Tomography (GATE) software (Jan et al., 2011) GATE simulation toolkit has been used extensively in the medical imaging community, due to the fact that it uses the full capabilities of GEANT4. It also utilizes an easy to-learn GATE macro language, which is more accessible than learning the GEANT4/C++ programming language. This work combines GATE with digital phantoms generated using the NCAT (NURBS-based cardiac-torso phantom) toolkit (Segars et al., 2004) to allow efficient and effective estimation of 3D radiation dose maps. The GATE simulation tool has developed into a beneficial tool for Monte Carlo simulations involving both radiotherapy and imaging experiments. This work will present an overview of absorbed dose of common radionuclides used in nuclear medicine and serve as a guide to a user who is setting up a GATE simulation for a PET and SPECT study.

  13. Repeated vertebral augmentation for new vertebral compression fractures of postvertebral augmentation patients: a nationwide cohort study

    Directory of Open Access Journals (Sweden)

    Liang CL

    2015-03-01

    Full Text Available Cheng-Loong Liang,1 Hao-Kwan Wang,1 Fei-Kai Syu,2 Kuo-Wei Wang,1 Kang Lu,1 Po-Chou Liliang1 1Department of Neurosurgery, E-Da Hospital, I-Shou University, Kaohsiung City, Taiwan; 2Department of Pharmacy, China Medical University Hospital, Taichung City, Taiwan Purpose: Postvertebral augmentation vertebral compression fractures are common; repeated vertebral augmentation is usually performed for prompt pain relief. This study aimed to evaluate the incidence and risk factors of repeat vertebral augmentation.Methods: We performed a retrospective, nationwide, population-based longitudinal observation study, using the National Health Insurance Research Database (NHIRD of Taiwan. All patients who received vertebral augmentation for vertebral compression fractures were evaluated. The collected data included patient characteristics (demographics, comorbidities, and medication exposure and repeat vertebral augmentation. Kaplan–Meier and stratified Cox proportional hazard regressions were performed for analyses.Results: The overall incidence of repeat vertebral augmentation was 11.3% during the follow-up until 2010. Patients with the following characteristics were at greater risk for repeat vertebral augmentation: female sex (AOR=1.24; 95% confidence interval [CI]: 1.10–2.36, advanced age (AOR=1.60; 95% CI: 1.32–2.08, diabetes mellitus (AOR=4.31; 95% CI: 4.05–5.88, cerebrovascular disease (AOR=4.09; 95% CI: 3.44–5.76, dementia (AOR=1.97; 95% CI: 1.69–2.33, blindness or low vision (AOR=3.72; 95% CI: 2.32–3.95, hypertension (AOR=2.58; 95% CI: 2.35–3.47, and hyperlipidemia (AOR=2.09; 95% CI: 1.67–2.22. Patients taking calcium/ vitamin D (AOR=2.98; 95% CI: 1.83–3.93, bisphosphonates (AOR=2.11; 95% CI: 1.26–2.61, or calcitonin (AOR=4.59; 95% CI: 3.40–5.77 were less likely to undergo repeat vertebral augmentation; however, those taking steroids (AOR=7.28; 95% CI: 6.32–8.08, acetaminophen (AOR=3.54; 95% CI: 2.75–4.83, or nonsteroidal

  14. Twenty-eight-day repeated inhalation toxicity study of nano-sized lanthanum oxide in male sprague-dawley rats.

    Science.gov (United States)

    Shin, Seo-Ho; Lim, Cheol-Hong; Kim, Yong-Soon; Lee, Yong-Hoon; Kim, Sung-Hwan; Kim, Jong-Choon

    2017-04-01

    Although the use of lanthanum has increased in field of high-tech industry worldwide, potential adverse effects to human health and to the environment are largely unknown. The present study aimed to investigate the potential toxicity of nano-sized lanthanum oxide (La2 O3 ) following repeated inhalation exposure in male Sprague-Dawley rats. Male rats were exposed nose-only to nano-sized La2 O3 for 28 days (5 days/week) at doses of 0, 0.5, 2.5, and 10 mg/m(3) . In the experimental period, we evaluated treatment-related changes including clinical signs, body weight, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology findings. We also analyzed lanthanum distribution in the major organs and in the blood, bronchoalveolar lavage fluids (BALF), and oxidative stress in lung tissues. Lanthanum level was highest in lung tissues and showed a dose-dependent relation. Alveolar proteinosis was observed in all treatment groups and was accompanied by an increase in lung weight; moreover, lung inflammation was observed in the 2.5 mg/m(3) and higher dose groups and was accompanied by an increase in white blood cells. In the BALF, total cell counts including macrophages and neutrophils, lactate dehydrogenase, albumin, nitric oxide, and tumor necrosis factor-alpha increased significantly in all treatment groups. Furthermore, these changes tended to deteriorate in the 10 mg/m(3) group at the end of the recovery period. In the present experimental conditions, we found that the lowest-observed-adverse-effect level of nano-sized La2 O3 was 0.5 mg/m(3) in male rats, and the target organ was the lung. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1226-1240, 2017. © 2016 Wiley Periodicals, Inc.

  15. A comprehensive study on the relationship between image quality and imaging dose in low-dose cone beam CT

    CERN Document Server

    Yan, Hao; Jia, Xun; Jiang, Steve B

    2011-01-01

    While compressed sensing (CS) based reconstructions have been developed for low-dose CBCT, a clear understanding on the relationship between the image quality and imaging dose at low dose levels is needed. In this paper, we qualitatively investigate this subject in a comprehensive manner with extensive experimental and simulation studies. The basic idea is to plot image quality and imaging dose together as functions of number of projections and mAs per projection over the whole clinically relevant range. A clear understanding on the tradeoff between image quality and dose can be achieved and optimal low-dose CBCT scan protocols can be developed for various imaging tasks in IGRT. Main findings of this work include: 1) Under the CS framework, image quality has little degradation over a large dose range, and the degradation becomes evident when the dose < 100 total mAs. A dose < 40 total mAs leads to a dramatic image degradation. Optimal low-dose CBCT scan protocols likely fall in the dose range of 40-100 ...

  16. Prolonged repeated acupuncture stimulation induces habituation effects in pain-related brain areas: an FMRI study.

    Science.gov (United States)

    Li, Chuanfu; Yang, Jun; Park, Kyungmo; Wu, Hongli; Hu, Sheng; Zhang, Wei; Bu, Junjie; Xu, Chunsheng; Qiu, Bensheng; Zhang, Xiaochu

    2014-01-01

    Most previous studies of brain responses to acupuncture were designed to investigate the acupuncture instant effect while the cumulative effect that should be more important in clinical practice has seldom been discussed. In this study, the neural basis of the acupuncture cumulative effect was analyzed. For this experiment, forty healthy volunteers were recruited, in which more than 40 minutes of repeated acupuncture stimulation was implemented at acupoint Zhusanli (ST36). Three runs of acupuncture fMRI datasets were acquired, with each run consisting of two blocks of acupuncture stimulation. Besides general linear model (GLM) analysis, the cumulative effects of acupuncture were analyzed with analysis of covariance (ANCOVA) to find the association between the brain response and the cumulative duration of acupuncture stimulation in each stimulation block. The experimental results showed that the brain response in the initial stage was the strongest although the brain response to acupuncture was time-variant. In particular, the brain areas that were activated in the first block and the brain areas that demonstrated cumulative effects in the course of repeated acupuncture stimulation overlapped in the pain-related areas, including the bilateral middle cingulate cortex, the bilateral paracentral lobule, the SII, and the right thalamus. Furthermore, the cumulative effects demonstrated bimodal characteristics, i.e. the brain response was positive at the beginning, and became negative at the end. It was suggested that the cumulative effect of repeated acupuncture stimulation was consistent with the characteristic of habituation effects. This finding may explain the neurophysiologic mechanism underlying acupuncture analgesia.

  17. Chromosomal abnormalities in couples with repeated fetal loss: An Indian retrospective study

    Directory of Open Access Journals (Sweden)

    Frenny J Sheth

    2013-01-01

    Full Text Available Background: Recurrent pregnancy loss is a common occurrence and a matter of concern for couples planning the pregnancy. Chromosomal abnormalities, mainly balanced rearrangements, are common in couples with repeated miscarriages. Purpose: The purpose of this study is to evaluate the contribution of chromosomal anomalies causing repeated spontaneous miscarriages and provide detailed characterization of a few structurally altered chromosomes. Materials and Methods: A retrospective cytogenetic study was carried out on 4859 individuals having a history of recurrent miscarriages. The cases were analyzed using G-banding and fluorescence in situ hybridization wherever necessary. Results: Chromosomal rearrangements were found in 170 individuals (3.5%. Translocations were seen in 72 (42.35% cases. Of these, reciprocal translocations constituted 42 (24.70% cases while Robertsonian translocations were detected in 30 (17.64% cases. 7 (4.11% cases were mosaic, 8 (4.70% had small supernumerary marker chromosomes and 1 (0.6% had an interstitial microdeletion. Nearly, 78 (1.61% cases with heteromorphic variants were seen of which inversion of Y chromosome (57.70% and chromosome 9 pericentromeric variants (32.05% were predominantly involved. Conclusions: Chromosomal analysis is an important etiological investigation in couples with repeated miscarriages. Characterization of variants/marker chromosome enable calculation of a more precise recurrent risk in a subsequent pregnancy thereby facilitating genetic counseling and deciding further reproductive options.

  18. On the Applicability of Elastic Network Models for the Study of RNA CUG Trinucleotide Repeat Overexpansion.

    Directory of Open Access Journals (Sweden)

    Àlex L González

    Full Text Available Non-coding RNAs play a pivotal role in a number of diseases promoting an aberrant sequestration of nuclear RNA-binding proteins. In the particular case of myotonic dystrophy type 1 (DM1, a multisystemic autosomal dominant disease, the formation of large non-coding CUG repeats set up long-tract hairpins able to bind muscleblind-like proteins (MBNL, which trigger the deregulation of several splicing events such as cardiac troponin T (cTNT and insulin receptor's, among others. Evidence suggests that conformational changes in RNA are determinant for the recognition and binding of splicing proteins, molecular modeling simulations can attempt to shed light on the structural diversity of CUG repeats and to understand their pathogenic mechanisms. Molecular dynamics (MD are widely used to obtain accurate results at atomistic level, despite being very time consuming, and they contrast with fast but simplified coarse-grained methods such as Elastic Network Model (ENM. In this paper, we assess the application of ENM (traditionally applied on proteins for studying the conformational space of CUG repeats and compare it to conventional and accelerated MD conformational sampling. Overall, the results provided here reveal that ANM can provide useful insights into dynamic rCUG structures at a global level, and that their dynamics depend on both backbone and nucleobase fluctuations. On the other hand, ANM fail to describe local U-U dynamics of the rCUG system, which require more computationally expensive methods such as MD. Given that several limitations are inherent to both methods, we discuss here the usefulness of the current theoretical approaches for studying highly dynamic RNA systems such as CUG trinucleotide repeat overexpansions.

  19. Study of Optimal Perimetric Testing in Children (OPTIC: Feasibility, Reliability and Repeatability of Perimetry in Children.

    Directory of Open Access Journals (Sweden)

    Dipesh E Patel

    Full Text Available To investigate feasibility, reliability and repeatability of perimetry in children.A prospective, observational study recruiting 154 children aged 5-15 years, without an ophthalmic condition that affects the visual field (controls, identified consecutively between May 2012 and November 2013 from hospital eye clinics. Perimetry was undertaken in a single sitting, with standardised protocols, in a randomised order using the Humphrey static (SITA 24-2 FAST, Goldmann and Octopus kinetic perimeters. Data collected included test duration, subjective experience and test quality (incorporating examiner ratings on comprehension of instructions, fatigue, response to visual and auditory stimuli, concentration and co-operation to assess feasibility and reliability. Testing was repeated within 6 months to assess repeatability.Overall feasibility was very high (Goldmann=96.1%, Octopus=89% and Humphrey=100% completed the tests. Examiner rated reliability was 'good' in 125 (81.2% children for Goldmann, 100 (64.9% for Octopus and 98 (63.6% for Humphrey perimetry. Goldmann perimetry was the most reliable method in children under 9 years of age. Reliability improved with increasing age (multinomial logistic regression (Goldmann, Octopus and Humphrey, p<0.001. No significant differences were found for any of the three test strategies when examining initial and follow-up data outputs (Bland-Altman plots, n=43, suggesting good test repeatability, although the sample size may preclude detection of a small learning effect.Feasibility and reliability of formal perimetry in children improves with age. By the age of 9 years, all the strategies used here were highly feasible and reliable. Clinical assessment of the visual field is achievable in children as young as 5 years, and should be considered where visual field loss is suspected. Since Goldmann perimetry is the most effective strategy in children aged 5-8 years and this perimeter is no longer available, further

  20. Using Bayesian analysis in repeated preclinical in vivo studies for a more effective use of animals.

    Science.gov (United States)

    Walley, Rosalind; Sherington, John; Rastrick, Joe; Detrait, Eric; Hanon, Etienne; Watt, Gillian

    2016-05-01

    Whilst innovative Bayesian approaches are increasingly used in clinical studies, in the preclinical area Bayesian methods appear to be rarely used in the reporting of pharmacology data. This is particularly surprising in the context of regularly repeated in vivo studies where there is a considerable amount of data from historical control groups, which has potential value. This paper describes our experience with introducing Bayesian analysis for such studies using a Bayesian meta-analytic predictive approach. This leads naturally either to an informative prior for a control group as part of a full Bayesian analysis of the next study or using a predictive distribution to replace a control group entirely. We use quality control charts to illustrate study-to-study variation to the scientists and describe informative priors in terms of their approximate effective numbers of animals. We describe two case studies of animal models: the lipopolysaccharide-induced cytokine release model used in inflammation and the novel object recognition model used to screen cognitive enhancers, both of which show the advantage of a Bayesian approach over the standard frequentist analysis. We conclude that using Bayesian methods in stable repeated in vivo studies can result in a more effective use of animals, either by reducing the total number of animals used or by increasing the precision of key treatment differences. This will lead to clearer results and supports the "3Rs initiative" to Refine, Reduce and Replace animals in research. Copyright © 2016 John Wiley & Sons, Ltd.

  1. SU-D-204-06: Dose and Image Quality Evaluation of a Low-Dose Slot-Scanning X-Ray System for Pediatric Orthopedic Studies

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Z; Hoerner, M; Lamoureux, R; Rill, L; Arreola, M [Univ Florida, Jacksonville Beach, FL (United States)

    2015-06-15

    Purpose: Children in early teens with scoliosis require repeated radiographic exams over a number of years. The EOS (EOS imaging S.A., Paris, France) is a novel low-dose slot-scanning digital radiographic system designed to produce full-spine images of a free-standing patient. The radiation dose and image quality characteristics of the EOS were evaluated relative to those of a Computed Radiography (CR) system for scoliosis imaging. Methods: For dose evaluation, a full-torso anthropomorphic phantom was scanned five times using the default standard clinical protocols for both the EOS and a CR system, which include both posteroanterior and lateral full-spine views. Optically stimulated luminescent dosimeters (OSLDs), also known as nanoDots™ (Landauer, Inc., Glenwood, IL), were placed on the phantom’s surface to measure entrance skin dose. To assess image quality, MTF curves were generated from sampling the noise levels within the high-contrast regions of a line-pair phantom. Vertical and horizontal distortions were measured for the square line-pair phantom with the EOS system to evaluate the effects of geometric magnification and misalignment with the indicated imaging plane. Results: The entrance skin dose was measured to be 0.4 to 1.1 mGy for the EOS, and 0.7 to 3.6 mGy for the CR study. MTF comparison shows that CR greatly outperforms the EOS, despite both systems having a limiting resolution at 1.8 line-pairs per mm. Vertical distortion was unaffected by phantom positioning, because of the EOS slot-scanning geometry. Horizontal distortion increased linearly with miscentering distance. Conclusion: The EOS system resulted in approximately 70% lower radiation dose than CR for full-spine images. Image quality was found to be inferior to CR. Further investigation is required to see if EOS system is an acceptable modality for performing clinically diagnostic scoliosis examinations.

  2. Implementation of repeat HIV testing during pregnancy in Kenya: a qualitative study.

    Science.gov (United States)

    Rogers, Anna Joy; Weke, Elly; Kwena, Zachary; Bukusi, Elizabeth A; Oyaro, Patrick; Cohen, Craig R; Turan, Janet M

    2016-07-11

    Repeat HIV testing in late pregnancy has the potential to decrease rates of mother-to-child transmission of HIV by identifying mothers who seroconvert after having tested negative for HIV in early pregnancy. Despite being national policy in Kenya, the available data suggest that implementation rates are low. We conducted 20 in-depth semi-structured interviews with healthcare providers and managers to explore barriers and enablers to implementation of repeat HIV testing guidelines for pregnant women. Participants were from the Nyanza region of Kenya and were purposively selected to provide variation in socio-demographics and job characteristics. Interview transcripts were coded and analyzed in Dedoose software using a thematic analysis approach. Four themes were identified a priori using Ferlie and Shortell's Framework for Change and additional themes were allowed to emerge from the data. Participants identified barriers and enablers at the client, provider, facility, and health system levels. Key barriers at the client level from the perspective of providers included late initial presentation to antenatal care and low proportions of women completing the recommended four antenatal visits. Barriers to offering repeat HIV testing for providers included heavy workloads, time limitations, and failing to remember to check for retest eligibility. At the facility level, inconsistent volume of clients and lack of space required for confidential HIV retesting were cited as barriers. Finally, at the health system level, there were challenges relating to the HIV test kit supply chain and the design of nationally standardized antenatal patient registers. Enablers to improving the implementation of repeat HIV testing included client dissemination of the benefits of antenatal care through word-of-mouth, provider cooperation and task shifting, and it was suggested that use of an electronic health record system could provide automatic reminders for retest eligibility. This study

  3. The importance of carcinogen dose in chemoprevention studies: quantitative interrelationships between, dibenzo[a,l]pyrene dose, chlorophyllin dose, target organ DNA adduct biomarkers and final tumor outcome.

    Science.gov (United States)

    Pratt, M Margaret; Reddy, Ashok P; Hendricks, Jerry D; Pereira, Cliff; Kensler, Thomas W; Bailey, George S

    2007-03-01

    Chlorophyllin (CHL) is a potent antimutagen in vitro, an effective anti-carcinogen in several animal models, and significantly reduced urinary biomarkers of aflatoxin B(1) (AFB(1)) exposure in a human population. Here we report an expanded analysis of CHL chemoprevention using the potent environmental hydrocarbon dibenzo[a,l]pyrene (DBP). A dose-dose matrix design employed over 12 000 rainbow trout to evaluate the interrelationships among dietary carcinogen dose, anti-carcinogen dose, carcinogen-DNA adduct levels at exposure and eventual tumor outcome in two target organs. Included was an evaluation of the pharmaceutical CHL preparation (Derifil), used previously in a study of individuals chronically exposed to AFB(1). CHL was pre-, co- and post-fed at doses of 0-6000 p.p.m. and co-fed with DBP at doses of 0-371.5 p.p.m. for 4 weeks. This protocol generated a total of 21 dose-dose treatment groups, each evaluated with three or more replicates of 100 animals. The DBP-only treatment produced dose-responsive increases in liver and stomach DBP-DNA adducts, whereas increasing CHL co-treatment doses produced successive inhibition in liver (49-83%) and stomach (47-75%) adduct levels at each DBP dose examined. The remaining 8711 trout were necropsied, 10 months later. DBP treatment alone produced a logit incidence versus log [DBP] dose-response curve in stomach that was linear; CHL co-treatment provided dose-dependent tumor inhibition which ranged from 30 to 68% and was predictable from the adduct response. The Derifil CHL preparation was also found to effectively reduce DNA adduction and final tumor incidence in stomach (as well as liver), with a potency compatible with its total chlorin content. Liver tumor incidence in the DBP-only groups appeared to plateau near 60%. At DBP doses of doses generally reduced tumor incidence and multiplicity consistent with early DNA adducts as biomarkers. At 225 p.p.m. DBP, however, very high CHL doses were

  4. Study of teflon pads as high doses dosemeters; Estudo de pastilhas de teflon como dosimetros de doses altas

    Energy Technology Data Exchange (ETDEWEB)

    Teixeira, Maria Ines; Caldas, Linda V.E., E-mail: miteixeira@ipen.br, E-mail: lcaldas@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2013-11-01

    The aim of this work is to study the Teflon, which is used as a binder in the manufacture of dosimetric tablets, for the feasibility of this material as high dose dosemeter. In this paper we used the technique of thermally stimulated luminescence (OSL) to characterize the dosimetric properties of Teflon. Teflon samples were exposed to different doses of radiation, using a source of gamma radiation ({sup 60}Co). It was obtained dose-response curve between 100 Gy to 50 kGy and reproducibility of OSL response. The preliminary results show that Teflon is a useful material to high dose dosimetry.

  5. Factors associated with repeated outbreak of anthrax in Bangladesh: qualitative and quantitative study

    Directory of Open Access Journals (Sweden)

    Jayedul Hassan

    2015-06-01

    Full Text Available Anthrax, caused by Bacillus anthracis is an acute, febrile disease of warm blooded animals including humans. Social norms and poverty in addition to climatic factors such as soil conditions, seasons of year, ambient temperature and rainfall influence the persistence of the B. anthracis and anthrax outbreaks. The present study was designed to reveal the factors influencing the repeated outbreak of anthrax in Bangladesh. Considering the previous outbreaks of anthrax, Sirajganj, Bogra, Kushtia, Tangail and Mymensingh districts of Bangladesh were selected for this study. To elucidate the factors, qualitative data relating to the animal management, knowledge and behavior of the people; and quantitative data relating to soil conditions, ambient temperature and rainfall were acquired, and analyzed critically. Based on the outbreak histories, a year was divided into two seasons, anthrax prone season (May-November and anthrax dry season (December-April. Anthrax spores could be isolated from 11.67% (n=14/120 of the soil samples collected from the study areas. The present study revealed that poor knowledge, lack of awareness, improper carcass disposal, inadequate vaccination, high Ca content and moisture in the soil along with high ambient temperature and rainfall during the anthrax prone season were the possible influencing factors of repeated outbreaks of anthrax in the study areas. Intensive propaganda to create public awareness of anthrax together with proper vaccination may reduce anthrax outbreaks in Bangladesh.

  6. Fibrinogen Concentrate in Dilutional Coagulopathy: a Dose Study in Pigs

    Science.gov (United States)

    2014-01-01

    safety issue leading to an increased risk of thrombosis has not yet been addressed. This study was conducted to investigate the effect of fibrinogen dose... thrombosis or throm- boembolic events. Neither did the histologic examination of all tissue slides provide any signs for arterial or venous thrombosis ...massive transfusions at an army combat support hospital. J Trauma 2008;64:S79-85. 21. Jax TW, Peters AJ, Plehn G, Schoebel FC. Hemostatic risk factors

  7. Studies of the sensitivity dependence of float zone silicon diodes on gamma absorbed dose

    Energy Technology Data Exchange (ETDEWEB)

    Pascoalino, K.C.S.; Santos, T.C. dos; Barbosa, R.F.; Camargo, F. de; Goncalves, J.A.C.; Bueno, C.C. [Instituto de Pesquisas Energeticas e Nucleares (CTR/IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Tecnologia das Radiacoes

    2011-07-01

    Full text: Several advantages of silicon diodes which include small size, low cost, high sensitivity and wide availability, make them suitable for dosimetry and for radiation field mapping. However, the small radiation tolerance of ordinary silicon devices has imposed constraints on their application in intense radiation fields such as found in industrial radiation processes. This scenario has been changed with the development of radiation hard silicon devices to be used as track detectors in high-energy physics experiments. Particularly, in this work it is presented the dosimetric results obtained with a batch of nine junction silicon diodes developed, in the framework of CERN RD50 Collaboration, as good candidates for improved radiation hardness. These diodes were produced with 300 micrometer n-type silicon substrate grown by standard float zone technique and processed by the Microelectronics Center of Helsinki University of Technology. The samples irradiation was performed using a Co-60 irradiator (Gammacell 220) which delivers a dose-rate of 2 kGy/h. During the irradiation, the unbiased diodes were connected through low-noise coaxial cables to the input of a KEITHLEY 617 electrometer, in order to monitor the devices photocurrent as a function of the exposure time. To study the response uniformity of the batch of nine diodes as well the sensitivity dependence on the absorbed dose, they were irradiated with different doses from 5 kGy up to 50 kGy. The sensitivity response of each device was investigated through the on-line measurements of the current signals as a function of the exposure time. For doses up to 5 kGy, all diodes exhibited a current decay of almost six percent in comparison with the value registered at the start-time of the irradiation. However, this decrease in the current sensitivity is much smaller than those observed with ordinary diodes for the same absorbed dose. The dose-response curves of the devices were also investigated through the plot

  8. Prolonged repeated acupuncture stimulation induces habituation effects in pain-related brain areas: an FMRI study.

    Directory of Open Access Journals (Sweden)

    Chuanfu Li

    Full Text Available Most previous studies of brain responses to acupuncture were designed to investigate the acupuncture instant effect while the cumulative effect that should be more important in clinical practice has seldom been discussed. In this study, the neural basis of the acupuncture cumulative effect was analyzed. For this experiment, forty healthy volunteers were recruited, in which more than 40 minutes of repeated acupuncture stimulation was implemented at acupoint Zhusanli (ST36. Three runs of acupuncture fMRI datasets were acquired, with each run consisting of two blocks of acupuncture stimulation. Besides general linear model (GLM analysis, the cumulative effects of acupuncture were analyzed with analysis of covariance (ANCOVA to find the association between the brain response and the cumulative duration of acupuncture stimulation in each stimulation block. The experimental results showed that the brain response in the initial stage was the strongest although the brain response to acupuncture was time-variant. In particular, the brain areas that were activated in the first block and the brain areas that demonstrated cumulative effects in the course of repeated acupuncture stimulation overlapped in the pain-related areas, including the bilateral middle cingulate cortex, the bilateral paracentral lobule, the SII, and the right thalamus. Furthermore, the cumulative effects demonstrated bimodal characteristics, i.e. the brain response was positive at the beginning, and became negative at the end. It was suggested that the cumulative effect of repeated acupuncture stimulation was consistent with the characteristic of habituation effects. This finding may explain the neurophysiologic mechanism underlying acupuncture analgesia.

  9. Accuracy and repeatability of an inertial measurement unit system for field-based occupational studies.

    Science.gov (United States)

    Schall, Mark C; Fethke, Nathan B; Chen, Howard; Oyama, Sakiko; Douphrate, David I

    2016-04-01

    The accuracy and repeatability of an inertial measurement unit (IMU) system for directly measuring trunk angular displacement and upper arm elevation were evaluated over eight hours (i) in comparison to a gold standard, optical motion capture (OMC) system in a laboratory setting, and (ii) during a field-based assessment of dairy parlour work. Sample-to-sample root mean square differences between the IMU and OMC system ranged from 4.1° to 6.6° for the trunk and 7.2°-12.1° for the upper arm depending on the processing method. Estimates of mean angular displacement and angular displacement variation (difference between the 90th and 10th percentiles of angular displacement) were observed to change IMU system may serve as an acceptable instrument for directly measuring trunk and upper arm postures in field-based occupational exposure assessment studies with long sampling durations. Practitioner Summary: Few studies have evaluated inertial measurement unit (IMU) systems in the field or over long sampling durations. Results of this study indicate that the IMU system evaluated has reasonably good accuracy and repeatability for use in a field setting over a long sampling duration.

  10. Association study of the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia

    Directory of Open Access Journals (Sweden)

    Danics Zoltan

    2006-06-01

    Full Text Available Abstract Background Brahma (BRM is a key component of the multisubunit SWI/SNF complex, a complex which uses the energy of ATP hydrolysis to remodel chromatin. BRM contains an N-terminal polyglutamine domain, encoded by a polymorphic trinucleotide (CAA/CAG repeat, the only known polymorphism in the coding region of the gene (SMARCA2. We have examined the association of this polymorphism with schizophrenia in a family-based and case/control study. SMARCA2 was chosen as a candidate gene because of its specific role in developmental pathways, its high expression level in the brain and some evidence of its association with schizophrenia spectrum disorder from genome-wide linkage analysis. Results Family-based analysis with 281 complete and incomplete triads showed that there is no significant preferential transmission of any of the alleles to the affected offspring. Also, in the case/control analysis, similar allele and genotype distributions were observed between affected cases (n = 289 and unaffected controls (n = 273 in each of three Caucasian populations studied: French Canadian, Tunisian and other Caucasians of European origin. Conclusion Results from our family-based and case-control association study suggest that there is no association between the trinucleotide repeat polymorphism within SMARCA2 and schizophrenia.

  11. Bayesian multimodel inference for dose-response studies

    Science.gov (United States)

    Link, W.A.; Albers, P.H.

    2007-01-01

    Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.

  12. Potential Role of the Last Half Repeat in TAL Effectors Revealed by a Molecular Simulation Study

    Directory of Open Access Journals (Sweden)

    Hua Wan

    2016-01-01

    Full Text Available TAL effectors (TALEs contain a modular DNA-binding domain that is composed of tandem repeats. In all naturally occurring TALEs, the end of tandem repeats is invariantly a truncated half repeat. To investigate the potential role of the last half repeat in TALEs, we performed comparative molecular dynamics simulations for the crystal structure of DNA-bound TALE AvrBs3 lacking the last half repeat and its modeled structure having the last half repeat. The structural stability analysis indicates that the modeled system is more stable than the nonmodeled system. Based on the principle component analysis, it is found that the AvrBs3 increases its structural compactness in the presence of the last half repeat. The comparison of DNA groove parameters of the two systems implies that the last half repeat also causes the change of DNA major groove binding efficiency. The following calculation of hydrogen bond reveals that, by stabilizing the phosphate binding with DNA at the C-terminus, the last half repeat helps to adopt a compact conformation at the protein-DNA interface. It further mediates more contacts between TAL repeats and DNA nucleotide bases. Finally, we suggest that the last half repeat is required for the high-efficient recognition of DNA by TALE.

  13. Potential Role of the Last Half Repeat in TAL Effectors Revealed by a Molecular Simulation Study

    Science.gov (United States)

    Wan, Hua; Chang, Shan; Hu, Jian-ping; Tian, Xu-hong

    2016-01-01

    TAL effectors (TALEs) contain a modular DNA-binding domain that is composed of tandem repeats. In all naturally occurring TALEs, the end of tandem repeats is invariantly a truncated half repeat. To investigate the potential role of the last half repeat in TALEs, we performed comparative molecular dynamics simulations for the crystal structure of DNA-bound TALE AvrBs3 lacking the last half repeat and its modeled structure having the last half repeat. The structural stability analysis indicates that the modeled system is more stable than the nonmodeled system. Based on the principle component analysis, it is found that the AvrBs3 increases its structural compactness in the presence of the last half repeat. The comparison of DNA groove parameters of the two systems implies that the last half repeat also causes the change of DNA major groove binding efficiency. The following calculation of hydrogen bond reveals that, by stabilizing the phosphate binding with DNA at the C-terminus, the last half repeat helps to adopt a compact conformation at the protein-DNA interface. It further mediates more contacts between TAL repeats and DNA nucleotide bases. Finally, we suggest that the last half repeat is required for the high-efficient recognition of DNA by TALE. PMID:27803930

  14. Does repeated reading predict reading development over time? A study of children from Grade 3 to 4.

    Science.gov (United States)

    Gellert, Anna S

    2014-08-01

    The purpose of this study was to investigate whether immediate gains in reading fluency achieved during repeated reading of text can predict long-term reading development over and above traditional predictors of reading development. Eighty-one Grade 3 children read texts three times consecutively and were instructed either to read as quickly as possible (speed-focused repeated reading), or to retell the text afterwards (meaning-focused repeated reading). Measures of text reading fluency, sentence reading fluency, and text comprehension were administered to the children in Grades 3 and 4 to assess their reading development over time. The results indicate that children's immediate response to repeated reading can contribute to the prediction of their development of reading fluency over time. Even after controlling for individual differences in general cognitive ability, word reading fluency, rapid automatized naming, and vocabulary, the experimental measure with meaning-focused repeated reading remained a significant predictor.

  15. 5-Day repeated inhalation and 28-day post-exposure study of graphene.

    Science.gov (United States)

    Shin, Jae Hoon; Han, Sung Gu; Kim, Jin Kwon; Kim, Boo Wook; Hwang, Joo Hwan; Lee, Jong Seong; Lee, Ji Hyun; Baek, Jin Ee; Kim, Tae Gyu; Kim, Keun Soo; Lee, Heon Sang; Song, Nam Woong; Ahn, Kangho; Yu, Il Je

    2015-01-01

    Graphene has recently been attracting increasing attention due to its unique electronic and chemical properties and many potential applications in such fields as semiconductors, energy storage, flexible electronics, biosensors and medical imaging. However, the toxicity of graphene in the case of human exposure has not yet been clarified. Thus, a 5-day repeated inhalation toxicity study of graphene was conducted using a nose-only inhalation system for male Sprague-Dawley rats. A total of three groups (20 rats per group) were compared: (1) control (ambient air), (2) low concentration (0.68 ± 0.14 mg/m(3) graphene) and (3) high concentration (3.86 ± 0.94 mg/m(3) graphene). The rats were exposed to graphene for 6 h/day for 5 days, followed by recovery for 1, 3, 7 or 28 days. The bioaccumulation and macrophage ingestion of the graphene were evaluated in the rat lungs. The exposure to graphene did not change the body weights or organ weights of the rats after the 5-day exposure and during the recovery period. No statistically significant difference was observed in the levels of lactate dehydrogenase, protein and albumin between the exposed and control groups. However, graphene ingestion by alveolar macrophages was observed in the exposed groups. Therefore, these results suggest that the 5-day repeated exposure to graphene only had a minimal toxic effect at the concentrations and time points used in this study.

  16. Repeat Colonoscopy within 6 Months after Initial Outpatient Colonoscopy in Ontario: A Population-Based Cross-Sectional Study

    Directory of Open Access Journals (Sweden)

    Lawrence Paszat

    2017-01-01

    Full Text Available Background. The goal of this study is to examine utilization of early repeat colonoscopy ≤ 6 months after an index procedure. Methods. We identified persons having repeat colonoscopy ≤ 6 months following outpatient colonoscopy without prior colonoscopy ≤ 5 years or prior diagnosis of colorectal cancer (CRC. We modeled repeat colonoscopy using a generalized estimating equation with an exchangeable correlation structure to account for clustering of patients by endoscopist. Results. The population included 334,663 persons, 7,892 (2.36% of whom had an early repeat colonoscopy within 6 months. Overall, endoscopist prior year colonoscopy volume was inversely related to repeat ≤ 6 months. Repeat colonoscopy ≤ 6 months varied by the clinical setting of the index colonoscopy (adjusted OR = 1.41 (95% CI 1.29–1.55 at nonhospital facilities compared to teaching or community hospitals. Among those who had polypectomy or biopsy, the adjusted OR for early repeat ≤ 6 months was elevated among those whose index colonoscopy was at a nonhospital facility (OR 1.44, 95% CI 1.30–1.60, compared to those at a teaching hospital or community hospital. Conclusions. Repeat colonoscopy ≤ 6 months after an index procedure is associated with the clinical setting of the index colonoscopy.

  17. PACAP38 dose-response pilot study in migraine patients

    DEFF Research Database (Denmark)

    Vollesen, Anne Luise Haulund; Guo, Song; Ashina, Messoud

    2017-01-01

    BACKGROUND: Intravenous infusion of 10 pmol/kg/min pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces migraine-like attacks in migraine patients without aura (MO). Here, we conducted a pilot study and investigated if lower doses of PACAP38 exert similar migraine......-inducing abilities. METHODS: We randomly allocated six MO patients to receive intravenous infusion of 4, 6, and 8 pmol/kg/min of PACAP38 over 20 minutes in a double-blind, three-way cross-over study. Headache and migraine characteristics were recorded during hospital (0-2 hours) and post-hospital (2-13 hours) phases...

  18. Biological equivalent dose studies for dose escalation in the stereotactic synchrotron radiation therapy clinical trials

    Energy Technology Data Exchange (ETDEWEB)

    Prezado, Y.; Fois, G.; Edouard, M.; Nemoz, C.; Renier, M.; Requardt, H.; Esteve, F.; Adam, JF.; Elleaume, H.; Bravin, A., E-mail: prezado@esrf.fr [ID17 Biomedical Beamline, European Synchrotron Radiation Facility (ESRF), 6 rue Jules Horowitz, BP 220, 38043 Grenoble Cedex (France)

    2009-03-15

    Synchrotron radiation is an innovative tool for the treatment of brain tumors. In the stereotactic synchrotron radiation therapy (SSRT) technique a radiation dose enhancement specific to the tumor is obtained. The tumor is loaded with a high atomic number (Z) element and it is irradiated in stereotactic conditions from several entrance angles. The aim of this work was to assess dosimetric properties of the SSRT for preparing clinical trials at the European Synchrotron Radiation Facility (ESRF). To estimate the possible risks, the doses received by the tumor and healthy tissues in the future clinical conditions have been calculated by using Monte Carlo simulations (PENELOPE code). The dose enhancement factors have been determined for different iodine concentrations in the tumor, several tumor positions, tumor sizes, and different beam sizes. A scheme for the dose escalation in the various phases of the clinical trials has been proposed. The biological equivalent doses and the normalized total doses received by the skull have been calculated in order to assure that the tolerance values are not reached.

  19. Seroepidemiological studies indicate frequent and repeated exposure to Campylobacter spp. during childhood.

    Science.gov (United States)

    Ang, C W; Teunis, P F M; Herbrink, P; Keijser, J; Van Duynhoven, Y H T P; Visser, C E; Van Pelt, W

    2011-09-01

    The annual number of episodes of clinical gastroenteritis caused by Campylobacter spp. in The Netherlands is estimated to be 75 000, i.e. once per 200 person life-years. This number is based on extrapolation of culture results from population-based studies. The number of culture-confirmed cases of Campylobacter infection peaks in the first 3 years of life and again between the ages of 20 and 25 years. The seroepidemiology of Campylobacter describes the relationship between age and exposure to Campylobacter and reflects both symptomatic and asymptomatic infections. Using a validated ELISA system, antibodies to Campylobacter were measured in an age-stratified sample (n=456) of the PIENTER serum collection of the Dutch general population. The seroprevalence of Campylobacter IgG antibodies increased with age, reaching almost 100% at age 20 years. Antibody levels steadily increased with age until young adulthood, suggesting repeated exposure to Campylobacter. In conclusion, seroepidemiological data demonstrated repeated exposures to Campylobacter throughout life, most of which do not lead to clinical symptoms. From young adulthood, >95% of the population in The Netherlands had serological evidence for exposure to Campylobacter.

  20. Effects of repeated walking in a perturbing environment: a 4-day locomotor learning study.

    Science.gov (United States)

    Blanchette, Andreanne; Moffet, Helene; Roy, Jean-Sébastien; Bouyer, Laurent J

    2012-07-01

    Previous studies have shown that when subjects repeatedly walk in a perturbing environment, initial movement error becomes smaller, suggesting that retention of the adapted locomotor program occurred (learning). It has been proposed that the newly learned locomotor program may be stored separately from the baseline program. However, how locomotor performance evolves with repeated sessions of walking with the perturbation is not yet known. To address this question, 10 healthy subjects walked on a treadmill on 4 consecutive days. Each day, locomotor performance was measured using kinematics and surface electromyography (EMGs), before, during, and after exposure to a perturbation, produced by an elastic tubing that pulled the foot forward and up during swing, inducing a foot velocity error in the first strides. Initial movement error decreased significantly between days 1 and 2 and then remained stable. Associated changes in medial hamstring EMG activity stabilized only on day 3, however. Aftereffects were present after perturbation removal, suggesting that daily adaptation involved central command recalibration of the baseline program. Aftereffects gradually decreased across days but were still visible on day 4. Separation between the newly learned and baseline programs may take longer than suggested by the daily improvement in initial performance in the perturbing environment or may never be complete. These results therefore suggest that reaching optimal performance in a perturbing environment should not be used as the main indicator of a completed learning process, as central reorganization of the motor commands continues days after initial performance has stabilized.

  1. Study of Single-dose Toxicity of Guseonwangdo-go Glucose Intramuscular Injection in Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    Jo Su-jeong

    2014-03-01

    Full Text Available Objectives: This study was performed to analyze single-dose intramuscular toxicity of Guseonwangdo-go glucose pharmacopuncture. Methods: Eighty six-week-old Sprague-Dawley rats were divided into two large groups of forty rats; Guseonwangdo-go glucose 5% and Guseonwangdo-go glucose 20% groups. Each group was sub-divided into four smaller groups of five males and five females, with the following dosages of pharmacopuncture being administered by intramuscular (IM injection in each group: group 1 (G1, control group: 1.0 mL of normal saline solution, group 2 (G2, low-dose group: 0.1 mL, group 3 (G3, mid-dose group: 0.5 mL, and group 4 (G4, high-dose group: 1.0 mL. Results: No mortalities or clinical signs were observed in any group. Also, no significant changes in body weights or in hematological/biochemical analyses were observed between the control and the experimental groups during necropsy or histopathology. Conclusion: The above findings suggest that the lethal dose of Guseonwangdo-go glucose 5% and 20% pharmacopuncture administered via IM injection is more than 1.0 mL per animal in both male and female rats. Further studies on the repeated-dose toxicity of Guseonwangdo-go glucose should be conducted to yield more concrete data.

  2. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity.

    Science.gov (United States)

    Berger, A R; Schaumburg, H H; Schroeder, C; Apfel, S; Reynolds, R

    1992-07-01

    We administered either 1 or 3 g/d of pyridoxine (vitamin B6) to five healthy volunteers and repeatedly followed serum pyridoxal phosphate levels, clinical symptoms and signs, quantitative sensory thresholds (QSTs), and sural nerve electrophysiology. Pyridoxine was discontinued at the first sign of either clinical or laboratory abnormality. In all subjects, sensory symptoms and QST abnormalities occurred concurrently. Subjects receiving higher doses became symptomatic earlier than low-dose subjects. Elevation of thermal QSTs preceded or exceeded that for vibration in the three low-dose subjects; vibration and thermal QST became abnormal simultaneously in the higher-dose subjects. A reduction in the amplitude of the sural sensory potential lagged behind QST changes in two of three subjects. Symptoms continued to progress ("coasting") for 2 to 3 weeks despite stopping pyridoxine administration and the return of serum pyridoxal phosphate levels to normal. This study suggests that (1) there is a clear dose-percent relationship for pyridoxine-induced neuropathy, (2) QST is a sensitive measurement for detecting early peripheral neuropathy; QST abnormalities may precede changes in nerve conduction studies, (3) coasting appears unrelated to persistently elevated blood levels of the toxin, and (4) a dose-dependent vulnerability may exist among nerve fibers of different caliber when exposed to an axonal toxin, such as pyridoxine.

  3. Reducing impaired driving through the identification of Repeat Target Vehicles: A case study.

    Science.gov (United States)

    Stewart, James

    2012-02-01

    One of the most persistent groups of impaired drivers that are seemingly unaffected by social pressure, moral appeals, and the fear of arrest is that of the repeat impaired driver. This smaller group accounts for a disproportionate number of all impaired driving trips, often with high blood alcohol contents. New approaches are needed to identify and deal with the repeat impaired driver. We propose a method based on the discovery that almost 10% of all impaired driving calls for service involve repeat vehicles. Using the number of times a vehicle appears in our data, the average time to repeat, and the personality characteristics of the repeat impaired driver, we are able to create a comprehensive and predictive description of a Repeat Target Vehicle (RTV). Our method provides an opportunity to explore new and innovative crime reduction strategies that were never before possible. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. A study on ten short tandem repeat systems: African immigrant and Spanish population data.

    Science.gov (United States)

    Gamero, J J; Romero, J L; Gonzalez, J L; Arufe, M I; Cuesta, M I; Corte-Real, F; Carvalho, M; Anjos, M J; Vieira, D N; Vide, M C

    2000-06-05

    This work presents the results obtained from a genetic-population study for the D1S1656 system in the population of Southwest Spain (Huelva, Cádiz and Sevilla), Spaniards of Caucasian origin from North Africa (Ceuta), as well as in the black Central West African and Moroccan immigrant populations in Spain. The results of a study of the autochtonous population of the Canary Islands (n=138), and immigrant Central West African populations in Spain (n=132), obtained for nine short tandem repeat (STR) loci (D3S1358, VWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D7S820), as well as the amelogenin locus, all contained in Profiler Plus (Perkin-Elmer) PCR amplification kits, are also presented. Except for the FGA and VWA data on immigrant Central West African populations in Spain, no deviations from the Hardy-Weinberg equilibrium were detected.

  5. A Prospective Study of Psychiatric Comorbidity and Recidivism Among Repeat DUI Offenders

    OpenAIRE

    Nelson, Sarah E.; Belkin, Katerina; LaPlante, Debi A.; Bosworth, Leslie; Shaffer, Howard J.

    2015-01-01

    Psychiatric comorbidity has emerged as a key element distinguishing DUI offenders from others, and, in some cases, distinguishing repeat offenders from first-time offenders. This paper utilizes a prospective design to determine whether the comorbid disorders identified among repeat DUI offenders can predict recidivism. Seven hundred forty-three repeat DUI offenders were recruited from a two-week inpatient treatment program at which they received a standardized mental health assessment and fol...

  6. The Importance of Carotenoid Dose in Supplementation Studies with Songbirds.

    Science.gov (United States)

    Koch, Rebecca E; Wilson, Alan E; Hill, Geoffrey E

    2016-01-01

    Carotenoid coloration is the one of the most frequently studied ornamental traits in animals. Many studies of carotenoid coloration test the associations between carotenoid coloration and measures of performance, such as immunocompetence and oxidative state, proceeding from the premise that carotenoids are limited resources. Such studies commonly involve supplementing the diets of captive birds with carotenoids. In many cases, however, the amount of carotenoid administered is poorly justified, and even supposedly carotenoid-limited diets may saturate birds' systems. To quantify the relationships among the amount of carotenoids administered in experiments, levels of circulating carotenoids, and quantities of carotenoids deposited into colored ornaments, we performed a meta-analysis of 15 published studies that supplemented carotenoids to one of seven songbird species. We used allometric scaling equations to estimate the per-gram carotenoid consumption of each study's subjects, and we used meta-regression to evaluate the effects of this carotenoid dose on differences in coloration and plasma carotenoid levels between supplemented and control groups of birds. After accounting for supplementation duration and species, we observed a significant positive correlation between carotenoid intake and response of plasma carotenoid level to supplementation. The presence of supplemental carotenoids also tended to increase the expression of ornamental coloration, but the magnitude of the carotenoid dose did not significantly affect how strongly coloration changed with supplementation. Further, coloration effect sizes had no significant relationship with plasma carotenoid effect sizes. We also found significant heterogeneity in responses among studies and species, and the parameters used to measure color significantly affected response to supplementation. Our results emphasize the importance of performing dosage trials to determine what supplementation levels provide limited

  7. Bayesian latent variable models for hierarchical clustered count outcomes with repeated measures in microbiome studies.

    Science.gov (United States)

    Xu, Lizhen; Paterson, Andrew D; Xu, Wei

    2017-04-01

    Motivated by the multivariate nature of microbiome data with hierarchical taxonomic clusters, counts that are often skewed and zero inflated, and repeated measures, we propose a Bayesian latent variable methodology to jointly model multiple operational taxonomic units within a single taxonomic cluster. This novel method can incorporate both negative binomial and zero-inflated negative binomial responses, and can account for serial and familial correlations. We develop a Markov chain Monte Carlo algorithm that is built on a data augmentation scheme using Pólya-Gamma random variables. Hierarchical centering and parameter expansion techniques are also used to improve the convergence of the Markov chain. We evaluate the performance of our proposed method through extensive simulations. We also apply our method to a human microbiome study.

  8. [Repeat induced abortion: A multicenter study on medical abortions in France in 2014].

    Science.gov (United States)

    Opatowski, M; Bardy, F; David, P; Dunbavand, A; Saurel-Cubizolles, M-J

    2017-01-01

    To describe the social characteristics of women seeking a medical abortion, and the conditions of that abortion, according to whether they had one or more previous induced abortions. An observational study was carried out in 11 French units in 2013-2014, among women 18 years or older. A self-administered questionnaire on the abortion context and social situation was given to them, as well as a diary to record the pain level for each of five days following the mifepristone intake. The sample included 453 women. Among the respondents, 22% had had one previous abortion and 8% had had two or more. Women having had a previous voluntary abortion were more often isolated and in a poorer social situation than women having their first abortion. Better support for contraception after abortion could reduce the number of repeated abortions. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  9. A Review on the Study of "Repeating Earthquakes" by Cross-correlation of Seismic Waveforms~%A Review on the Study of "Repeating Earthquakes" by Cross-correlation of Seismic Waveforms~

    Institute of Scientific and Technical Information of China (English)

    Li Yutong; Jiang Changsheng

    2012-01-01

    "Repeating earthquakes", identified by cross-correlation of seismic waveforms, are found to be much more abundant in the nature than conventionally expected. In recent years, with the development of digital seismic networks, waveform cross correlation and "repeating earthquakes" have caused much attention to the measuring the variation of crustal medium properties and estimation of location accuracy and fault slip rate at depth or earthquake recurrence intervals. Moreover, as a useful tool, the "repeating earthquake" approach has also been used in the assessment of the accuracy of seismic phase picking, hypocenter location, fault structure and physics of earthquake sources, as well as the study of earthquake prediction. In this paper, we summarized the latest research and applications of "repeating earthquakes".

  10. Causal inference in longitudinal comparative effectiveness studies with repeated measures of a continuous intermediate variable.

    Science.gov (United States)

    Wang, Chen-Pin; Jo, Booil; Brown, C Hendricks

    2014-09-10

    We propose a principal stratification approach to assess causal effects in nonrandomized longitudinal comparative effectiveness studies with a binary endpoint outcome and repeated measures of a continuous intermediate variable. Our method is an extension of the principal stratification approach originally proposed for the longitudinal randomized study "Prevention of Suicide in Primary Care Elderly: Collaborative Trial" to assess the treatment effect on the continuous Hamilton depression score adjusting for the heterogeneity of repeatedly measured binary compliance status. Our motivation for this work comes from a comparison of the effect of two glucose-lowering medications on a clinical cohort of patients with type 2 diabetes. Here, we consider a causal inference problem assessing how well the two medications work relative to one another on two binary endpoint outcomes: cardiovascular disease-related hospitalization and all-cause mortality. Clinically, these glucose-lowering medications can have differential effects on the intermediate outcome, glucose level over time. Ultimately, we want to compare medication effects on the endpoint outcomes among individuals in the same glucose trajectory stratum while accounting for the heterogeneity in baseline covariates (i.e., to obtain 'principal effects' on the endpoint outcomes). The proposed method involves a three-step model estimation procedure. Step 1 identifies principal strata associated with the intermediate variable using hybrid growth mixture modeling analyses. Step 2 obtains the stratum membership using the pseudoclass technique and derives propensity scores for treatment assignment. Step 3 obtains the stratum-specific treatment effect on the endpoint outcome weighted by inverse propensity probabilities derived from Step 2.

  11. The PICTURE study: diagnostic accuracy of multiparametric MRI in men requiring a repeat prostate biopsy.

    Science.gov (United States)

    Simmons, Lucy A M; Kanthabalan, Abi; Arya, Manit; Briggs, Tim; Barratt, Dean; Charman, Susan C; Freeman, Alex; Gelister, James; Hawkes, David; Hu, Yipeng; Jameson, Charles; McCartan, Neil; Moore, Caroline M; Punwani, Shonit; Ramachandran, Navin; van der Meulen, Jan; Emberton, Mark; Ahmed, Hashim U

    2017-04-25

    Transrectal prostate biopsy has limited diagnostic accuracy. Prostate Imaging Compared to Transperineal Ultrasound-guided biopsy for significant prostate cancer Risk Evaluation (PICTURE) was a paired-cohort confirmatory study designed to assess diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) in men requiring a repeat biopsy. All underwent 3 T mpMRI and transperineal template prostate mapping biopsies (TTPM biopsies). Multiparametric MRI was reported using Likert scores and radiologists were blinded to initial biopsies. Men were blinded to mpMRI results. Clinically significant prostate cancer was defined as Gleason ⩾4+3 and/or cancer core length ⩾6 mm. Two hundred and forty-nine had both tests with mean (s.d.) age was 62 (7) years, median (IQR) PSA 6.8 ng ml (4.98-9.50), median (IQR) number of previous biopsies 1 (1-2) and mean (s.d.) gland size 37 ml (15.5). On TTPM biopsies, 103 (41%) had clinically significant prostate cancer. Two hundred and fourteen (86%) had a positive prostate mpMRI using Likert score ⩾3; sensitivity was 97.1% (95% confidence interval (CI): 92-99), specificity 21.9% (15.5-29.5), negative predictive value (NPV) 91.4% (76.9-98.1) and positive predictive value (PPV) 46.7% (35.2-47.8). One hundred and twenty-nine (51.8%) had a positive mpMRI using Likert score ⩾4; sensitivity was 80.6% (71.6-87.7), specificity 68.5% (60.3-75.9), NPV 83.3% (75.4-89.5) and PPV 64.3% (55.4-72.6). In men advised to have a repeat prostate biopsy, prostate mpMRI could be used to safely avoid a repeat biopsy with high sensitivity for clinically significant cancers. However, such a strategy can miss some significant cancers and overdiagnose insignificant cancers depending on the mpMRI score threshold used to define which men should be biopsied.

  12. SU-E-J-263: Repeatability of SUV and Texture Parameters in Serial PET Studies

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, J; Humm, J; Nehmeh, S; Schoder, H [Memorial Sloan-Kettering Cancer Center, New York, NY (United States)

    2015-06-15

    Purpose: Standardized uptake values (SUV) are standard quantitative PET measures of FDG tumor uptake used,and are used as a tool to monitor response to therapy. Textural analysis is emerging as a new tool for assessing intratumoral heterogeneity which may allow better tissue characterization and improved prediction of response and survival rate.Understanding what variations may be expected in these parameters is key in order to make decisions based on how the change throughout the course of treatment. The aim of this study was to assess repeatability in SUV measures and texture parameters,and establish criteria that differentiate changes associated with treatment rather than statistical variability. Methods: Eighty patients,167 random lesions total,were scanned in a GE Discovery STE PET/CT Scanner. One field-of-view was chosen centered on the largest lesion observed in a clinical whole-body FDG PET.Immediately following,a gated 9 min scan was acquired in list mode,without changing the patient’s position between any scans. Data was replayed into 3 time bins,3 min each,in order to insure equivalent noise characteristics in each replicate.Data was reconstructed into 128×128×47 square matrices.One VOI was drawn over each lesion for each patient and used to segment all 3 replicates. The mean.max and peak SUV were calculated for each VOI and replicate. First-order textural features were also calculated (skewness and kurtosis). Repeatability was calculated as the average standard deviation over the mean for the 3 repeated measurements for each lesion. Results: The average percent error in the SUV max,peak and mean were 3.4%(0– 12.9%),1.9% (0–7.5%),2.8% (0–12.2%),respectively.For skewness and kurtosis they were 10.9% and 17.8%. Conclusion: We have shown that there is a large variation in %error in SUV measures across patients. SUVpeak is the least variable and kurtosis and skewness parameters are less reliable thatn SUVs.Higher order textures are be.

  13. Prognostic usefulness of repeated echocardiographic evaluation after acute myocardial infarction. TRACE Study Group. TRAndolapril Cardiac Evaluation

    DEFF Research Database (Denmark)

    Korup, E; Køber, L; Torp-Pedersen, C;

    1999-01-01

    The prognostic value of repeated echocardiographic measurement of left ventricular function after acute myocardial infarction was evaluated. We found that repeated measurements of wall motion index in survivors of acute myocardial infarction, with no reinfarction, provide important prognostic inf...... information about death and worsening of heart failure....

  14. Studies of the CAG repeat in the Machado-Joseph disease gene in Taiwan.

    Science.gov (United States)

    Hsieh, M; Tsai, H F; Lu, T M; Yang, C Y; Wu, H M; Li, S Y

    1997-08-01

    Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration characterized by cerebellar ataxia and pyramidal signs associated in varying degrees with a dystonic-rigid extrapyramidal syndrome or peripheral amyotrophy. Unstable CAG trinucleotide repeat expansion in the MJD gene on the long arm of chromosome 14 has been identified as the pathological mutation for MJD. While investigating the distribution of CAG repeat lengths of the MJD gene in Taiwan's population, we have identified 18 MJD-affected patients and 12 at-risk individuals in seven families. In addition, we have analyzed the range of CAG repeat lengths in 96 control individuals. The CAG repeat number ranged from 13 to 44 in the controls and 72-85 in the affected and at-risk individuals. Our results indicated that the CAG repeat number was inversely correlated with the age of onset. The differences in CAG repeat length between parent and child and between siblings are greater with paternal transmission than maternal transmission. Our data show a tendency towards the phenomenon of anticipation in the MJD families but do not support unidirectional expansion of CAG repeats during transmission. We also demonstrated that PCR amplification of the CAG repeats in the MJD gene from villous DNA was possible and might prove useful as a diagnostic tool for affected families in the future.

  15. A study on the trinucleotide repeat associated with Huntington`s disease in the Chinese

    Energy Technology Data Exchange (ETDEWEB)

    Bing-wen Soong; Jih-tsuu Wang [Neurological Institute, Taipei (Taiwan, Province of China)

    1994-09-01

    Analysis of the polymorphic (CAG)n repeat in the hungingtin gene in the chinese confirmed the presence of an expanded repeat on all Huntington`s disease chromosomes. Measurement of the specific CAG repeat sequence in 34 HD chromosomes from 15 unrelated families and 190 control chromosomes from the Chinese population showed a range from 9 to 29 repeats in normal subjects and 40 to 58 in affected subjects. The size distributions of normal and affected alleles did not overlap. A clear correlation bewteen early onset of symptoms and very high repeat number was seen, but the spread of the age-at-onset in the major repeat range producing characteristic HD it too wide to be of diagnostic value. There was also variability in the transmitted repeat size for both sexes in the HD size range. Maternal HD alleles showed a moderate instability with a preponderance of size decrease, while paternal HD alleles had a tendency to increase in repeat size on transmission, the degree of which appeared proportional to the initial size.

  16. Repeat colonoscopy after a colonoscopy with a negative result in Ontario: a population-based cohort study.

    Science.gov (United States)

    Hol, Lieke; Sutradhar, Rinku; Gu, Sumei; Baxter, Nancy N; Rabeneck, Linda; Tinmouth, Jill M; Paszat, Lawrence F

    2015-01-01

    Data suggest the overuse of repeat colonoscopies, especially in patients at low risk for colorectal cancer. Our objective was to evaluate the time to repeat colonoscopies in low-risk patients aged 50-79 years old and the associated patient- and endoscopist-related factors. All patients aged 50-79 years of age who underwent a complete outpatient colonoscopy with a negative result between 2000 and 2007 were identified from the Ontario Health Insurance Plan database. A colonoscopy performed within 5.5 years of follow-up after the index colonoscopy was considered an early repeat colonoscopy. Patient, endoscopist and endoscopy setting characteristics were recorded and their association with an early repeat colonoscopy was determined using an extended Cox proportional hazards regression model. The cohort consisted of 546 467 patients: 55.4% of the patients were female with a mean age of 61.1 years (95% confidence interval [CI] 61.1-61.2). The cumulative percentage of early repeat colonoscopy after 5.5 years was 33.7%. The rate decreased significantly between 2000 and 2007 (hazard ratio [HR] 0.35, 95% CI 0.34-0.36). General surgeons were associated with a higher risk of early repeat colonoscopy than gastroenterologists (HR 1.27, 95% CI 1.25-1.28). Endoscopists practising in a nonhospital setting were more likely to perform an early repeat colonoscopy (HR 1.26, 95% CI 1.22-1.30) than endoscopists at a hospital. This study showed that there was overuse of early repeat colonoscopy in more than 30% of patients who were at low risk for colorectal cancer. The risk decreased significantly between 2000 and 2007 but was still greater than 20% in 2007. Our findings can be used to develop targeted educational interventions among subgroups of endoscopists with a higher rate of early repeat colonoscopy.

  17. A Prospective Study of Psychiatric Comorbidity and Recidivism Among Repeat DUI Offenders.

    Science.gov (United States)

    Nelson, Sarah E; Belkin, Katerina; LaPlante, Debi A; Bosworth, Leslie; Shaffer, Howard J

    2015-04-13

    Psychiatric comorbidity has emerged as a key element distinguishing DUI offenders from others, and, in some cases, distinguishing repeat offenders from first-time offenders. This paper utilizes a prospective design to determine whether the comorbid disorders identified among repeat DUI offenders can predict recidivism. Seven hundred forty-three repeat DUI offenders were recruited from a two-week inpatient treatment program at which they received a standardized mental health assessment and followed across five years post-treatment to track DUI offense, motor vehicle-related offenses, and general criminal offenses. Psychiatric comorbidity, though it did not predict DUI recidivism specifically, predicted criminal re-offense more generally. In addition, there was a specific relationship between lifetime attention deficit disorder and repeated motor vehicle-related offenses. These findings suggest that for many repeat offenders, DUI is one outlet in a constellation of criminal behavior, and that psychiatric comorbidity increases vulnerability for criminal re-offense.

  18. Non-target effects of repeated chlorothalonil application on soil nitrogen cycling: The key functional gene study.

    Science.gov (United States)

    Zhang, Manyun; Xu, Zhihong; Teng, Ying; Christie, Peter; Wang, Jun; Ren, Wenjie; Luo, Yongming; Li, Zhengao

    2016-02-01

    The widespread and increasing application of chlorothalonil (CTN) raises concerns about its non-target impacts, but little information is available on the effect of CTN on the key functional genes related to soil nitrogen (N) cycling, especially in the case of repeated applications. In the present study, a microcosm incubation was conducted to determine CTN residues and the impacts on the abundances of key functional genes related to N cycling after repeated CTN applications. The results demonstrated that repeated CTN applications at the recommended application rate and five times the recommended rate led to the accumulation of CTN residue in soil at concentrations of 5.59 and 78.79 mg kg(-1), respectively, by the end of incubation. Real time PCR (RT-PCR) revealed that repeated CTN applications had negative effects on the chiA and aprA gene abundances. There were significantly negative correlations between CTN residues and abundances of AOA and AOB genes. In addition, the abundances of key functional genes involved in soil denitrification were declined by repeated CTN applications with the sole exception of the nosZ gene. This study suggests that repeated CTN applications could lead to the accumulation of CTN residue and generate somewhat inconsistent and erratic effects on the abundances of key functional genes related to soil N cycling.

  19. Impact of repeated measures and sample selection on genome-wide association studies of fasting glucose

    Science.gov (United States)

    Rasmussen-Torvik, Laura J.; Alonso, Alvaro; Li, Man; Kao, Wen; Köttgen, Anna; Yan, Yuer; Couper, David; Boerwinkle, Eric; Bielinski, Suzette J.; Pankow, James S.

    2010-01-01

    Although GWAS have been performed in longitudinal studies, most used only a single trait measure. GWAS of fasting glucose have generally included only normoglycemic individuals. We examined the impact of both repeated measures and sample selection on GWAS in ARIC, a study which obtained four longitudinal measures of fasting glucose and included both individuals with and without prevalent diabetes. The sample included Caucasians and the Affymetrix 6.0 chip was used for genotyping. Sample sizes for GWAS analyses ranged from 8372 (first study visit) to 5782 (average fasting glucose). Candidate SNP analyses with SNPs identified through fasting glucose or diabetes GWAS were conducted in 9133 individuals, including 761 with prevalent diabetes. For a constant sample size, smaller p-values were obtained for the average measure of fasting glucose compared to values at any single visit, and two additional significant GWAS signals were detected. For four candidate SNPs (rs780094, rs10830963, rs7903146, and rs4607517), the strength of association between genotype and glucose was significantly (p-interaction fasting glucose candidate SNPs (rs780094, rs10830963, rs560887, rs4607517, rs13266634) the association with measured fasting glucose was more significant in the smaller sample without prevalent diabetes than in the larger combined sample of those with and without diabetes. This analysis demonstrates the potential utility of averaging trait values in GWAS studies and explores the advantage of using only individuals without prevalent diabetes in GWAS of fasting glucose. PMID:20839289

  20. Patient-optimized doses of fesoterodine improve bladder symptoms in an open-label, flexible-dose study.

    Science.gov (United States)

    Wyndaele, Jean-Jacques; Goldfischer, Evan R; Morrow, Jon D; Gong, Jason; Tseng, Li-Jung; Choo, Myung-Soo

    2011-02-01

    To assess changes in overactive bladder (OAB) symptoms and patient-reported outcomes in a post hoc analysis in which subjects from a 12-week, open-label, flexible-dose fesoterodine study were stratified according to whether they opted for dose escalation. Subjects with OAB (eight or more micturitions and three or more urgency episodes per 24 h) who reported dissatisfaction with tolterodine within 2 years of screening received fesoterodine 4 mg once daily for 4 weeks, with an optional dose increase to 8 mg after week 4 based on discussion of efficacy and tolerability between the subject and investigator. Subjects completed 5-day diaries, the Patient Perception of Bladder Condition (PPBC) and Urgency Perception Scale (UPS) at baseline and weeks 4 and 12, and the Overactive Bladder Questionnaire (OAB-q) at baseline and week 12. Subjects rated treatment satisfaction at week 12. Dose escalation to 8 mg at week 4 was chosen by 255 (50%) of 513 subjects. At baseline, subjects who opted for dose escalation at week 4 (escalators) had significantly higher means for all diary variables except urgency urinary incontinence (UUI) episodes, significantly greater OAB-q Symptom Bother scores and significantly lower OAB-q health-related quality of life (HRQL) scores (all P fesoterodine significantly improved OAB symptoms and patient-reported outcomes in subjects who chose to remain on the initial 4-mg dose, as well as in the 50% of subjects who escalated to the 8-mg dose after 4 weeks. Non-escalators had significantly fewer OAB symptoms at baseline and significantly greater improvements than escalators before dose escalation. Escalators showed increased symptom relief after dose escalation; improvements in most outcomes were similar among non-escalators and escalators by week 12. Flexible-dose fesoterodine was well tolerated, with similar adverse-event profiles observed in the escalator and non-escalator groups. These results may help clinicians to identify patients more likely to

  1. A nationwide, population-based, long-term follow-up study of repeated self-harm in Taiwan

    Directory of Open Access Journals (Sweden)

    Chung Chi-Hsiang

    2012-09-01

    Full Text Available Abstract Background Previous follow-up studies of repeated self-harm show that the cumulative risk of repeated self-harm within one year is 5.7%–15%, with females at greatest risk. However, relatively few studies have focused on the Far East. The objective of this study was to calculate the cumulative risk of repeated self-harm over different lengths of follow-up time (3 months, 6 months, and 1–8 years, to determine factors influencing repeated self-harm and to explore the interaction between gender and self-harm methods. Methods We used self-harm patient who hospitalized due to first-time self-harm between 2000 and 2007 from 1,230 hospitals in Taiwan. Hospitalization for repeated self-harm among members of this cohort was tracked after 3 months, 6 months, and 1–8 years. Tracking continued until December 31, 2008. We analyzed the cumulative risk and risk factors of repeated self-harm by using negative binomial regression. Results Of the 39,875 individual study samples, 3,388 individuals (8.50% were found to have repeatedly self-harmed. The cumulative risk of repeated self-harm within three months was 7.19% and within one year was 8%. Within 8 years, it was 8.70%. Females were more likely to repeatedly self-harm than males (RR = 1.21, 95% CI = 1.15–1.76. The main method of self-harm was solid or liquid substances (RR = 1.88, 95% CI = 1.23–2.04 or cutting or piercing (RR = 1.36, 95% CI = 1.02–1.82, and in patients with psychiatric disorders were more likely to self-harm (RR = 1.61, 95% CI = 1.48–1.75. Conclusions The key time for intervention for repeated self-harm is within three months. Appropriate prevention programs should be developed based on gender differences.

  2. Thermal stability of chicken brain {alpha}-spectrin repeat 17: a spectroscopic study

    Energy Technology Data Exchange (ETDEWEB)

    Brenner, Annette K. [University of Bergen, Department of Chemistry (Norway); Kieffer, Bruno [Ecole Superieure de Biotechnologie de Strasbourg, IGBMC Biomolecular NMR Group, CNRS UMR 7104 (France); Trave, Gilles [Ecole Superieure de Biotechnologie de Strasbourg, Equipe Oncoproteines, IREBS, UMR 7242 (France); Froystein, Nils Age [University of Bergen, Department of Chemistry (Norway); Raae, Arnt J., E-mail: arnt.raae@mbi.uib.no [University of Bergen, Department of Molecular Biology (Norway)

    2012-06-15

    Spectrin is a rod-like multi-modular protein that is mainly composed of triple-helical repeats. These repeats show very similar 3D-structures but variable conformational and thermodynamical stabilities, which may be of great importance for the flexibility and dynamic behaviour of spectrin in the cell. For instance, repeat 17 (R17) of the chicken brain spectrin {alpha}-chain is four times less stable than neighbouring repeat 16 (R16) in terms of Increment G. The structure of spectrin repeats has mainly been investigated by X-ray crystallography, but the structures of a few repeats, e.g. R16, have also been determined by NMR spectroscopy. Here, we undertook a detailed characterization of the neighbouring R17 by NMR spectroscopy. We assigned most backbone resonances and observed NOE restraints, relaxation values and coupling constants that all indicated that the fold of R17 is highly similar to that of R16, in agreement with previous X-ray analysis of a tandem repeat of the two domains. However, {sup 15}N heteronuclear NMR spectra measured at different temperatures revealed particular features of the R17 domain that might contribute to its lower stability. Conformational exchange appeared to alter the linker connecting R17 to R16 as well as the BC-loop in close proximity. In addition, heat-induced splitting was observed for backbone resonances of a few spatially related residues including V99 of helix C, which in R16 is replaced by the larger hydrophobic tryptophan residue that is relatively conserved among other spectrin repeats. These data support the view that the substitution of tryptophan by valine at this position may contribute to the lower stability of R17.

  3. Essays on diffusion and repeat sales of consumer durables : a study of the consumer electronics market

    OpenAIRE

    Kaya, Maria

    2008-01-01

    Although repeat purchases dominate overall sales of consumer durables, diffusion of innovations research has paid them far less attention than new product adoptions. A large survey of 8,077 households allowed a detailed investigation of the differences between households in terms of their repeat purchase behavior of durables. Asymmetric effects were investigated using competing hazard models and showed that consumer innovativeness has a strong impact on discretionary replacements. A modified ...

  4. CAG repeat polymorphisms in the androgen receptor and breast cancer risk in women: a meta-analysis of 17 studies.

    Science.gov (United States)

    Mao, Qixing; Qiu, Mantang; Dong, Gaochao; Xia, Wenjie; Zhang, Shuai; Xu, Youtao; Wang, Jie; Rong, Yin; Xu, Lin; Jiang, Feng

    2015-01-01

    The association between polymorphic CAG repeats in the androgen receptor gene in women and breast cancer susceptibility has been studied extensively. However, the conclusions regarding this relationship remain conflicting. The purpose of this meta-analysis was to identify whether androgen receptor CAG repeat lengths were related to breast cancer susceptibility. The MEDLINE, PubMed, and EMBASE databases were searched through to December 2014 to identify eligible studies. Data and study quality were rigorously assessed by two investigators according to the Newcastle-Ottawa Quality Assessment Scale. The publication bias was assessed by the Begg's test. Seventeen eligible studies were included in this meta-analysis. The overall analysis suggested no association between CAG polymorphisms and breast cancer risk (odds ratio [OR] 1.031, 95% confidence interval [CI] 0.855-1.245). However, in the subgroup analysis, we observed that long CAG repeats significantly increased the risk of breast cancer in the Caucasian population (OR 1.447, 95% CI 1.089-1.992). Additionally, the risk was significantly increased in Caucasian women carrying two alleles with CAG repeats ≥22 units compared with those with two shorter alleles (OR 1.315, 95% CI 1.014-1.707). These findings suggest that long CAG repeats increase the risk of breast cancer in Caucasian women. However, larger scale case-control studies are needed to validate our results.

  5. Intimate partner violence and repeat induced abortion in Italy: A cross sectional study.

    Science.gov (United States)

    Citernesi, Angela; Dubini, Valeria; Uglietti, Anna; Ricci, Elena; Cipriani, Sonia; Parazzini, Fabio

    2015-01-01

    To investigate the impact of intimate partner violence (IPV) on the risk of repeat induced abortion (RIA), we compared IPV history among women with and without previous induced abortion (IA). All consecutive women aged 18 years or more requiring IA in 12 Italian abortion clinics were eligible for inclusion in the study. They were asked to fill in an anonymous, self-developed questionnaire assessing sociodemographic data and their history of different types of violence and related risk factors. The analysis included 1030 women, 624 (60.6%) of whom reported a previous IA. Past or current IPV was reported by 19.3%: 7.0% reported sexual violence, 11.3% physical abuse and 12.1% psychological abuse. Past or current IPV was reported by 22.3% of women with RIA and 14.8% of those undergoing their first IA (adjusted odds ratio 1.57, 95% confidence interval 1.07-2.30; p = 0.02). When we considered sexual, psychological and physical abuse separately, we found that any kind of abuse was more frequent in women with RIA than in women with no previous IA. This study underlines the impact of IPV on the risk of RIA and suggests the need for screening for IPV among women requiring abortion, in order to identify women at risk of RIA and to improve their general and reproductive health.

  6. Repeated open application test with methyldibromo glutaronitrile, a multicentre study within the EECDRG.

    Science.gov (United States)

    Gruvberger, B; Andersen, K E; Brandão, F M; Bruynzeel, D P; Bruze, M; Frosch, P J; Goossens, A; Lahti, A; Maibach, H I; Menné, T; Orton, D; Seidenari, S

    2005-01-01

    Contact allergy to and allergic contact dermatitis from methyldibromo glutaronitrile (MDBGN) have frequently been reported. This study was initiated to help determine the optimal patch test preparation for MDBGN. In 51 patients with a doubtful or a positive patch test reaction to at least 1 of 4 test preparations with MDBGN in petrolatum at 1.0% w/w, 0.5%, 0.3% and 0.1%, a repeated open application test (ROAT) with moisturizers with and without MDBGN at 0.03% w/w was performed on the upper arms for 2 weeks. 18 of the 51 (35.3%) patients developed a positive ROAT. In all patients, there was a positive ROAT only to the moisturizer with MDBGN (P < 0.001). A statistically significant association was also found between the patch test reactivity (PTRL) and the outcome of the ROAT (P < 0.001). If only considering those with a PTRL above 0.3%, thus with negative or doubtful test reactions to 0.1% and 0.3%, there were still statistically significantly more patients with a positive ROAT to the moisturizer with MDBGN than to the moisturizer without MDBGN. The study demonstrates that patch testing with MDBGN at 0.3% and 0.1% will miss clinically relevant patch test reactions to MDBGN.

  7. Repeated exposure of acidic beverages on esthetic restorative materials: An in-vitro surface microhardness study.

    Science.gov (United States)

    Xavier, Arun M; Sunny, Steffy M; Rai, Kavita; Hegde, Amitha M

    2016-07-01

    A manifold increase in the consumption of aerated beverages has witnessed a twin increase in tooth wear and raised demand for esthetic restorative materials. This study aimed to evaluate the surface microhardness changes of esthetic restorative materials following treatment with aerated beverages in an in-vitro situation. The initial surface microhardness of the restorative materials GC Fuji II LC, GC Fuji IX, Nano Glass ionomer, Resin and Nano composite was recorded. These materials were studied under 3 groups that included those exposed to the acidic beverages daily, weekly once in a month and those that had no exposures at all. The final surface microhardness of the materials was recorded following experimentation and was subjected to statistical comparisons. The restorative materials were compared for their surface microhardness changes following respective treatments using the T-test and One-way ANOVA analysis. Inter-comparisons between the groups showed statistical significance (pmaterials revealed surface microhardness loss; the maximum reduction noticed with the Nano glass ionomer cement tested (pmaterials markedly reduced upon repeated exposures with acidic beverages; the product with phosphoric acid producing the maximum surface microhardness loss. Restorative materials, acidic beverages, surface microhardness, resin composites, glass ionomers.

  8. Stability Study of Iriba Brucellosis Full-dose and Reduced-dose Vaccine Produced by Razi Institute in Iran

    Directory of Open Access Journals (Sweden)

    Hasannia, E.

    2015-04-01

    Full Text Available Stability study of biological products plays an important role for determination of product changes in maintenance period and ensuring of safety and efficacy of vaccines. In this research, accelerated and long-term stability study performed for six batches of full and reduced-dose cattle Iriba strain brucellosis vaccine that manufactured by Razi vaccine and serum research institute as a new vaccine. After sampling, the vaccines were tested for accelerated stability, after four days storage at 22 0C and tested intervals in three months until 24 months for long-term stability after storage at 2-8 0C. The result indicated all batches of vaccines in accelerated stability met the specification recommended by OIE 2012 and the mean loss of activity for full-dose was 16.68, 18.87 and 17.79 % and for reduced-dose was 38.85, 36.06 and 34.98 %. In long term stability, the quality control tests including colony forming unit, purity, dissociation and physicochemical tests in all samples until 24 months, met the specification recommended by OIE 2012. The full-dose vaccines showed a mean loss of activity of 30.73, 25.53 and 32.45 % and the reduced-dose vaccines showed 63.51, 58.60 and 60.83 %. The mean increasing of moisture content was, 187.85, 214.13 and 160.77 % for full-dose and 142.35, 110.23 and 164.47 % for reduced-dose. So, the results of this research indicated in spite of moisture content increasing in second year, the brucellosis vaccines with this strain are stable at least 24months if the cold chain considered properly but the best expiry date for the vaccine is one year.

  9. Risk of solid cancer in low dose-rate radiation epidemiological studies and the dose-rate effectiveness factor.

    Science.gov (United States)

    Shore, Roy; Walsh, Linda; Azizova, Tamara; Rühm, Werner

    2017-10-01

    Estimated radiation risks used for radiation protection purposes have been based primarily on the Life Span Study (LSS) of atomic bomb survivors who received brief exposures at high dose rates, many with high doses. Information is needed regarding radiation risks from low dose-rate (LDR) exposures to low linear-energy-transfer (low-LET) radiation. We conducted a meta-analysis of LDR epidemiologic studies that provide dose-response estimates of total solid cancer risk in adulthood in comparison to corresponding LSS risks, in order to estimate a dose rate effectiveness factor (DREF). We identified 22 LDR studies with dose-response risk estimates for solid cancer after minimizing information overlap. For each study, a parallel risk estimate was derived from the LSS risk model using matching values for sex, mean ages at first exposure and attained age, targeted cancer types, and accounting for type of dosimetric assessment. For each LDR study, a ratio of the excess relative risk per Gy (ERR Gy(-1)) to the matching LSS ERR risk estimate (LDR/LSS) was calculated, and a meta-analysis of the risk ratios was conducted. The reciprocal of the resultant risk ratio provided an estimate of the DREF. The meta-analysis showed a LDR/LSS risk ratio of 0.36 (95% confidence interval [CI] 0.14, 0.57) for the 19 studies of solid cancer mortality and 0.33 (95% CI 0.13, 0.54) when three cohorts with only incidence data also were added, implying a DREF with values around 3, but statistically compatible with 2. However, the analyses were highly dominated by the Mayak worker study. When the Mayak study was excluded the LDR/LSS risk ratios increased: 1.12 (95% CI 0.40, 1.84) for mortality and 0.54 (95% CI 0.09, 0.99) for mortality + incidence, implying a lower DREF in the range of 1-2. Meta-analyses that included only cohorts in which the mean dose was radiation exposure. The LDR data provide direct evidence regarding risk from exposures at low dose rates as an important complement to the

  10. Structural Studies of a Four-MBT Repeat Protein MBTD1

    Energy Technology Data Exchange (ETDEWEB)

    Eryilmaz, Jitka; Pan, Patricia; Amaya, Maria F.; Allali-Hassani, Abdellah; Dong, Aiping; Adams-Cioaba, Melanie A.; MacKenzie, Farrell; Vedadi, Masoud; Min, Jinrong; (Toronto); (Toronto)

    2010-08-17

    The Polycomb group (PcG) of proteins is a family of important developmental regulators. The respective members function as large protein complexes involved in establishment and maintenance of transcriptional repression of developmental control genes. MBTD1, Malignant Brain Tumor domain-containing protein 1, is one such PcG protein. MBTD1 contains four MBT repeats. We have determined the crystal structure of MBTD1 (residues 130-566aa covering the 4 MBT repeats) at 2.5 {angstrom} resolution by X-ray crystallography. The crystal structure of MBTD1 reveals its similarity to another four-MBT-repeat protein L3MBTL2, which binds lower methylated lysine histones. Fluorescence polarization experiments confirmed that MBTD1 preferentially binds mono- and di-methyllysine histone peptides, like L3MBTL1 and L3MBTL2. All known MBT-peptide complex structures characterized to date do not exhibit strong histone peptide sequence selectivity, and use a 'cavity insertion recognition mode' to recognize the methylated lysine with the deeply buried methyl-lysine forming extensive interactions with the protein while the peptide residues flanking methyl-lysine forming very few contacts. Nevertheless, our mutagenesis data based on L3MBTL1 suggested that the histone peptides could not bind to MBT repeats in any orientation. The four MBT repeats in MBTD1 exhibits an asymmetric rhomboid architecture. Like other MBT repeat proteins characterized so far, MBTD1 binds mono- or dimethylated lysine histones through one of its four MBT repeats utilizing a semi-aromatic cage.

  11. Resistance repeatability study of ion-beam deposited vanadium oxide thin films

    Science.gov (United States)

    Alvarez, P.; Pearson, D. I. C.; Pochon, S.; Thomas, O.; Cooke, M.; Gunn, R.

    2016-09-01

    Ion Beam Sputter Deposition (IBSD) is a versatile technique particularly suited to applications requiring high quality, high performance layer materials as it allows independent and accurate control of the process parameters. Vanadium oxides, used for example in the fabrication of microbolometers, optical switches or optical storage, exhibit interesting properties such as a high Temperature Coefficient of Resistance (TCR), relatively low 1/f noise and a semiconductormetal phase transition close to room temperature. However, it is very challenging to control the stoichiometry of the deposited film as there are at least 25 different oxidation states of vanadium, few of which display the required electrical characteristics. In the present study, vanadium oxide thin layers were deposited by IBSD using an Oxford Ionfab300+ and analyzed with regard to their electrical properties. The impact of the system parameters on the resistance repeatability, wafer-to-wafer and batch-to-batch, was thoroughly investigated to provide the end user with a clear understanding of the factors affecting film resistivity while ensuring at the same time a steep variation of resistance with temperature, as notably required for uncooled bolometers. These parameters were balanced to also achieve a good deposition rate, throughput and uniformity over large device areas, compatible with the requirements of industrial applications.

  12. Comparative Genomic Hybridization Selection of Blastocysts for Repeated Implantation Failure Treatment: A Pilot Study

    Science.gov (United States)

    Greco, Ermanno; Bono, Sara; Ruberti, Alessandra; Lobascio, Anna Maria; Greco, Pierfrancesco; Biricik, Anil; Spizzichino, Letizia; Greco, Alessia; Tesarik, Jan; Minasi, Maria Giulia; Fiorentino, Francesco

    2014-01-01

    The aim of this study is to determine if the use of preimplantation genetic screening (PGS) by array comparative genomic hybridization (array CGH) and transfer of a single euploid blastocyst in patients with repeated implantation failure (RIF) can improve clinical results. Three patient groups are compared: 43 couples with RIF for whom embryos were selected by array CGH (group RIF-PGS), 33 couples with the same history for whom array CGH was not performed (group RIF NO PGS), and 45 good prognosis infertile couples with array CGH selected embryos (group NO RIF PGS). A single euploid blastocyst was transferred in groups RIF-PGS and NO RIF PGS. Array CGH was not performed in group RIF NO PGS in which 1-2 blastocysts were transferred. One monoembryonic sac with heartbeat was found in 28 patients of group RIF PGS and 31 patients of group NO RIF PGS showing similar clinical pregnancy and implantation rates (68.3% and 70.5%, resp.). In contrast, an embryonic sac with heartbeat was only detected in 7 (21.2%) patients of group RIF NO PGS. In conclusion, PGS by array CGH with single euploid blastocyst transfer appears to be a successful strategy for patients with multiple failed IVF attempts. PMID:24779011

  13. Study on the homocysteine metabolism of patients with unexplained repeated spontaneous abortion

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    Objective:To study the metabolism abnormality of homocysteine(Hcy) in unexplained repeated spontaneous abortion(URSA).Methods:The level of Hcy in sera was measured with hyperpressure liquid chromatography(HPLC);Folic acid and vitamin B12 were detected by radioimmune assay;anticardiolipin antibody (ACA) was detected by ELISA.Results:(1)The level of serum Hcy in URSA group was significantly higher than that in control group,showing a statistical significant difference(P<0.01).The level of Hcy was correlated with ages,but not correlated with areas,numbers of miscarriage,gestation age,primary or secondary abortions.(2)The levels of folic acid and vitamin B12 in URSA group were significantly lower than those in control group.The levels of serum folic acid and vitamin B12 were not correlated with age,area,numbers of miscarriage and abortion periods.(3)ACA positive rate in URSA was significantly higher than that in control group.The level of Hcy in ACA(+) group was significantly higher than that in ACA(-) group among URSA patients.Conclusions:Hyperhomocysteinemia,low folic acid state,and ACA were all the independent risk factors for URSA.Lacking of folic acid and vitamin B12 is one of the important causes of hyperhomocysteinemia.ACA and hyperhomocysteinemia may have synergistic action in the occurrence of URSA.

  14. Identification and characterization of simple sequence repeats (SSRs) for population studies of Puccinia novopanici.

    Science.gov (United States)

    Orquera-Tornakian, Gabriela K; Garrido, Patricia; Kronmiller, Brent; Hunger, Robert; Tyler, Brett M; Garzon, Carla D; Marek, Stephen M

    2017-08-01

    Switchgrass (Panicum virgatum L.) can be severely affected by rust disease. Recently switchgrass rust caused by P. emaculata (now confirmed to be Puccinia novopanici) has received most of the attention by the research community because this pathogen is responsible for reducing the biomass production and biofuel feedstock quality of switchgrass. Microsatellite markers found in the literature were either not informative (no allele frequency) or showed few polymorphisms in the target populations, therefore additional markers are needed for future studies of the genetic variation and population structure of P. novopanici. This study reports the development and characterization of novel simple sequence repeat (SSR) markers from a Puccinia emaculata s.l. microsatellite-enriched library and expressed sequence tags (ESTs). Microsatellites were evaluated for polymorphisms on P. emaculata s.l. urediniospores collected in Iowa (IA), Mississippi (MS), Oklahoma (OK), South Dakota (SD) and Virginia (VA). Puccinia novopanici single spore whole genome amplifications were used as templates to validate the SSR reactions protocol and to assess a preliminary population genetics statistics of the pathogen. Eighteen microsatellite markers were polymorphic (average PIC=0.72) on individual urediniospores, with an average of 8.3 alleles per locus (range 3 to 17). Of the 49 SSRs loci initially identified in P. emaculata s.l., 18 were transferable to P. striiformis f. sp. tritici, 23 to P. triticina, 20 to P. sorghi and 31 to P. andropogonis. Thus, these markers could be useful for DNA fingerprinting and population structure analysis for population genetics, epidemiology and ecological studies of P. novopanici and potentially other related Puccinia species. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Repeat sleeve gastrectomy compared with primary sleeve gastrectomy: a single-center, matched case study.

    Science.gov (United States)

    Rebibo, Lionel; Fuks, David; Verhaeghe, Pierre; Deguines, Jean-Baptiste; Dhahri, Abdennaceur; Regimbeau, Jean-Marc

    2012-12-01

    Longitudinal sleeve gastrectomy (LSG) has been validated for the treatment of morbid obesity. However, treatment failures can appear several months after SG. Additional malabsorptive surgery is generally recommended in such cases. The objective of the present study was to evaluate the outcomes of repeat SG (re-SG) relative to first-line SG. This was a retrospective study included 15 patients underwent re-SG after failure of first-line SG (i.e. University Hospital, France; Public Practice). These patients were matched (for age, gender, body mass index and comorbidities) 1:2 with 30 patients having undergone first-line SG. The efficacy criteria comprised intra-operative data and postoperative data. The overall study population comprised 45 patients. The re-SG and first-line SG groups did not differ significantly in terms of median age (p = NS). The median BMI was similar in the two groups (43 kg/m(2) vs. 42.3 kg/m(2), p = NS). The two groups were similar in terms of the prevalence of comorbidities. The mean operating time was longer in the re-SG group (116 vs. 86 min; p ≤ 0.01). The postoperative complication rate was twice as high in the re-SG group (p = 0.31). Two patients in the re-SG group developed a gastric fistula (p = 0.25) and one of the latter died. At 12 months, the Excess Weight Loss was 66% (re-SG group) and 77% (first-line SG group) (p = 0.05). Re-SG is feasible but appears to be associated with a greater risk of complications. Nevertheless, re-SG can produce results (in terms of weight loss), equivalent to those obtained after first-line SG.

  16. Quantum repeated games revisited

    CERN Document Server

    Frackiewicz, Piotr

    2011-01-01

    We present a scheme for playing quantum repeated 2x2 games based on the Marinatto and Weber's approach to quantum games. As a potential application, we study twice repeated Prisoner's Dilemma game. We show that results not available in classical game can be obtained when the game is played in the quantum way. Before we present our idea, we comment on the previous scheme of playing quantum repeated games.

  17. High-Dose Vitamin D Failed to Curb Heart Disease in Study

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_164472.html High-Dose Vitamin D Failed to Curb Heart Disease in Study ... 5, 2017 (HealthDay News) -- Taking high doses of vitamin D once a month won't lower your ...

  18. Phase I dose intensification study of 2-weekly epirubicin with GM-CSF in advanced cancer.

    Science.gov (United States)

    Michael, M; Toner, G C; Olver, I N; Fenessy, A; Bishop, J F

    1997-06-01

    This study investigated dose intensification of epirubicin administered as a 2-weekly regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) support. The aim was to define the maximally tolerated dose of epirubicin and to assess the efficacy of GM-CSF to ameliorate its toxicity. Patients with anthracycline-responsive advanced malignancies were eligible. Six dose levels, commencing at 90 mg/m2, of epirubicin administered every 2 weeks for four courses were planned with GM-CSF 10 micrograms/kg/day administered for 10 days from the second day of each course. Six patients were to be entered at each dose level, and escalation to the next level was based upon toxicity criteria. Twelve patients were entered, six at dose level 1 (90 mg/m2) and six at dose level 2 (120 mg/m2). Prospectively defined haematological dose-limiting toxicities were noted in one patient at dose level 1 and in five patients at dose level 2. Further dose escalation was not attempted. Significant nonhaematological toxicities included febrile neutropenia in two and four patients at dose levels 1 and 2, respectively. This study has demonstrated that epirubicin can be safely administered at 2 week intervals with GM-CSF at a dose of 90 mg/m2, equivalent to the previously reported maximum tolerated dose intensity of 45 mg/m2/week. Neutropenia was dose-limiting despite the use of GM-CSF.

  19. Genetic structure of the Azores Islands: a study using 15 autosomal short tandem repeat loci.

    Science.gov (United States)

    Santos, Cristina; Alvarez, Luis; Aluja, Maria Pilar; Bruges-Armas, Jacome; Lima, Manuela

    2009-12-01

    The Azores archipelago (Portugal), located in the Atlantic Ocean, 1,500 km from the European mainland, is formed by nine islands of volcanic origin. The relative position of these islands allows the definition of three geographical groups: Eastern, Central and Western. Previous studies of the Azores using Short Tandem Repeats (STRs) have highlighted differences in the frequencies of several loci, when compared to Mainland Portugal or Madleira Island. Furthermore, linkage disequilibrium (LD), described for Azorean samples has been tentatively explained as reflecting the presence of genetic sub-structuring in the archipelago. To provide information concerning the genetic profile of the Azores Islands and to evaluate the presence of substructuring we have determined the allelic frequencies of 15 autosomal STR loci, using the AmpFlSTR Identifiler Kit, in representative samples from the Azorean Islands. Either considering the Azores as a whole, or analysing by island all the loci were in conformity with Hardy-Weinberg equilibrium. Average gene diversity ranged from 0.7669 in Corvo to 0.7972 in Terceira Island. Allelic independence between loci, tested for the global sample, detected significant LD (after correction for multiple tests) for pairs D21S11/D7S820 and D3S1358/D5S818. The exact test of population differentiation, combining the information of the 15 markers analysed, revealed significant differences between the three groups of islands, and between islands. Inter-island analysis reinforces the previous data that suggested the existence of sub-structuring in the Azores archipelago. Moreover, the data generated by this study can be used in a future forensic genetic database of the Azores after the appropriate enlacement of sample size by island, preventing, in that way, misinterpretations caused by population substructuring and small sample sizes.

  20. Repeated long-term potentiation induces mossy fibre sprouting and changes the sensibility of hippocampal granule cells to subconvulsive doses of pentylenetetrazol.

    Science.gov (United States)

    Hassan, H; Pohle, W; Rüthrich, H; Brödemann, R; Krug, M

    2000-04-01

    Electrical and chemical kindling induces sprouting of the mossy fibre system and potentiation of evoked field potentials in the dentate gyrus. It has been postulated that such changes may also be induced by repeated induction of long-term potentiation (LTP) with tetanic stimulation of the perforant pathway. LTP was induced in rats chronically implanted with stimulation electrodes in the ipsilateral and contralateral angular bundles and with a recording electrode in the ipsilateral dorsal dentate gyrus. The animals were stimulated 10 times on 10 consecutive days but with different tetanization strengths. Sprouting of the mossy fibres terminating in the CA3 region was significantly induced only in the group of 'strongly' tetanized animals, but not in that of 'weakly' tetanized animals, or in low-frequency stimulated animals. Additionally, a novel form of potentiation which was previously found in pentylenetetrazol (PTZ)-kindled animals was also observed in the group of 'strongly' and 'weakly' tetanized rats. Differences in duration of this potentiation were found between the two groups of animals tetanized with different strengths. The results further demonstrate that morphological and functional changes in the hippocampus, similar to those seen after kindling, can also occur in an activation paradigm leading to long-lasting synaptic plasticity but not accompanied by seizure activity.

  1. LONGITUDINAL STUDY OF REPEATED SPRINT PERFORMANCE IN YOUTH SOCCER PLAYERS OF CONTRASTING SKELETAL MATURITY STATUS

    Directory of Open Access Journals (Sweden)

    João Valente-dos-Santos

    2012-09-01

    Full Text Available The purpose of the study was to evaluate the developmental changes in performance in a repeated-sprint ability (RSA test in young soccer players of contrasting maturity status. A total of 83 regional level Portuguese youth soccer players, aged 11- 13 years at baseline was assessed annually. Stature, body mass, 7x34.2-m sprint protocol (25-s active recovery, 20-m multi-stage continuous shuttle endurance run and counter-movement jump (CMJ without the use of the arms were measured. Fat-free mass (FFM was determined by age and gender- specific formulas. Developmental changes in total sprint time across ages were predicted using multilevel modeling. Corresponding measurements were performed on an independent cross-sectional subsample of 52 youth soccer players 11-17 years to evaluate the predictive model. CA, CA2, maturational status (SA-CA, body size (mass and stature, FFM, aerobic endurance, lower limb explosive strength and annual volume training significantly improved the statistical fit of the RSA multilevel model. In 'late' maturing athletes, the best model for predicting change in RSA was expressed by the following equation: 86.54 - 2.87 x CA + 0.05 x CA2 - 0.25 x FFM + 0.15 x body mass + 0.05 x stature - 0.05 x aerobic endurance - 0.09 x lower limb explosive strength - 0.01 x annual volume training. The best fitting models for players who were 'on time' and 'early' maturing were identical to the best model for late maturing players, less 0.64 seconds and 1.74 seconds, respectively. Multilevel modeling provided performance curves that permitted the prediction of individual RSA performance across adolescent years in regional level soccer players

  2. Population genetic study of 10 short tandem repeat loci from 600 domestic dogs in Korea

    Science.gov (United States)

    Moon, Seo Hyun; Jang, Yoon-Jeong

    2016-01-01

    Dogs have long shared close relationships with many humans. Due to the large number of dogs in human populations, they are often involved in crimes. Occasionally, canine biological evidence such as saliva, bloodstains and hairs can be found at crime scenes. Accordingly, canine DNA can be used as forensic evidence. The use of short tandem repeat (STR) loci from biological evidence is valuable for forensic investigations. In Korea, canine STR profiling-related crimes are being successfully analyzed, leading to diverse crimes such as animal cruelty, dog-attacks, murder, robbery, and missing and abandoned dogs being solved. However, the probability of random DNA profile matches cannot be analyzed because of a lack of canine STR data. Therefore, in this study, 10 STR loci were analyzed in 600 dogs in Korea (344 dogs belonging to 30 different purebreds and 256 crossbred dogs) to estimate canine forensic genetic parameters. Among purebred dogs, a separate statistical analysis was conducted for five major subgroups, 97 Maltese, 47 Poodles, 31 Shih Tzus, 32 Yorkshire Terriers, and 25 Pomeranians. Allele frequencies, expected (Hexp) and observed heterozygosity (Hobs), fixation index (F), probability of identity (P(ID)), probability of sibling identity (P(ID)sib) and probability of exclusion (PE) were then calculated. The Hexp values ranged from 0.901 (PEZ12) to 0.634 (FHC2079), while the P(ID)sib values were between 0.481 (FHC2079) and 0.304 (PEZ12) and the P(ID)sib was about 3.35 × 10−5 for the combination of all 10 loci. The results presented herein will strengthen the value of canine DNA to solving dog-related crimes. PMID:26645337

  3. Pilot study: Assessing repeatability of the EcoWalk platform resistive pressure sensors to measure plantar pressure during barefoot standing

    Science.gov (United States)

    Zequera, Martha; Perdomo, Oscar; Wilches, Carlos; Vizcaya, Pedro

    2013-06-01

    Plantar pressure provides useful information to assess the feet's condition. These systems have emerged as popular tools in clinical environment. These systems present errors and no compensation information is presented by the manufacturer, leading to uncertainty in the measurements. Ten healthy subjects, 5 females and 5 males, were recruited. Lateral load distribution, antero-posterior load distribution, average pressure, contact area, and force were recorded. The aims of this study were to assess repeatability of the EcoWalk system and identify the range of pressure values observed in the normal foot. The coefficient of repeatability was less than 4% for all parameters considered.

  4. Reduction and technical simplification of testing protocol for walking based on repeatability analyses: An Interreg IVa pilot study

    Directory of Open Access Journals (Sweden)

    Nejc Sarabon

    2010-12-01

    Full Text Available The aim of this study was to define the most appropriate gait measurement protocols to be used in our future studies in the Mobility in Ageing project. A group of young healthy volunteers took part in the study. Each subject carried out a 10-metre walking test at five different speeds (preferred, very slow, very fast, slow, and fast. Each walking speed was repeated three times, making a total of 15 trials which were carried out in a random order. Each trial was simultaneously analysed by three observers using three different technical approaches: a stop watch, photo cells and electronic kinematic dress. In analysing the repeatability of the trials, the results showed that of the five self-selected walking speeds, three of them (preferred, very fast, and very slow had a significantly higher repeatability of the average walking velocity, step length and cadence than the other two speeds. Additionally, the data showed that one of the three technical methods for gait assessment has better metric characteristics than the other two. In conclusion, based on repeatability, technical and organizational simplification, this study helped us to successfully define a simple and reliable walking test to be used in the main study of the project.

  5. Prospective study on determinants of repeat attendance and attendance patterns in breast cancer screening using the Theory of Planned Behaviour.

    NARCIS (Netherlands)

    Drossaert, Constance H.C.; Boer, Hendrik; Seydel, E.R.

    2003-01-01

    This prospective study, using the Theory of Planned Behaviour (TPB) as a theoretical framework, was carried out to identify the determinants of repeat attendance and attendance patterns in organised breast screening. A group of 2657 women filled out a baseline questionnaire, approximately 8 weeks

  6. What can be learned from epidemiologic studies of persons exposed to low doses of radiation?

    Energy Technology Data Exchange (ETDEWEB)

    Gilbert, E.S.

    1993-04-01

    The main objective of radiation risk assessment is to determine the risk of various adverse health effects associated with exposure to low doses and low dose rates. Extrapolation of risks from studies of persons exposed at high doses (generally exceeding 1 Sv) and dose rates has been the primary approach used to achieve this objective. The study of Japanese atomic bomb survivors in Hiroshima and Nagasaki has played an especially important role in risk assessment efforts. A direct assessment of the dose-response function based on studies of persons exposed at low doses and dose rates is obviously desirable. This paper focuses on the potential of both current and future nuclear workers studies for investigating the dose-response functions at low doses, and also discusses analyses making use of the low dose portion of the atomic bomb survivor data. Difficulties in using these data are the statistical imprecision of estimated dose-response parameters, and potential bias resulting from confounding factors and from uncertainties in dose estimates.

  7. Assessing the repeatability of terrestrial laser scanning for monitoring gully topography: A case study from Aratula, Queensland, Australia

    Science.gov (United States)

    Goodwin, Nicholas Robert; Armston, John; Stiller, Isaac; Muir, Jasmine

    2016-06-01

    Terrestrial laser scanning (TLS) technology is a powerful tool for quantifying gully morphology and monitoring change over time. This is due to the high sampling density, sub-centimetre positional accuracies (x, y, z), flexibility of survey configurations and ability to link multiple TLS scans together. However, to ensure correct interpretation of results, research is needed to test the repeatability of TLS derived products to quantify the accuracy and separate 'false' from 'true' geomorphic change. In this study, we use the RIEGL VZ400 scanner to test the repeatability of TLS datasets for mapping gully morphology. We then quantify change following a rainfall event of approximately 100 mm. Our study site, located in south-east Queensland, Australia was chosen to be challenging from a repeatability perspective with high topographic variability. The TLS data capture involved three sets of linked scans: one survey pre-rainfall, to be compared to two surveys post-rainfall acquired on consecutive days. Change is considered negligible in the two post-rainfall scans to test survey repeatability. To verify TLS accuracy, an independent dataset of gully extent and spot heights were acquired using traditional total station techniques. Results confirm that the TLS datasets can be registered multi-temporally at sub-centimetre levels of accuracy in three dimensions. Total station and TLS elevation samples showed strong agreement with a mean error and standard deviation (SD) of residuals equal to 0.052 and 0.047 m, respectively (n = 889). Significantly, our repeatability tests found that return type and pulse deviation influence the accuracy and repeatability of DEMs in gully environments. Analysis of consecutive day datasets showed that DEMs derived from first return data recorded 40% higher SD of residual error than DEMs using multiple return data. A significant empirical relationship between pulse deviation and the variance of residuals for repeat DEMs is also shown (r2 = 0

  8. Monitoring Levothyroxine Dose during Pregnancy: A Prospective Study

    Directory of Open Access Journals (Sweden)

    Juhi Agarwal

    2011-01-01

    Full Text Available Problem statement: Thyroid dysfunction in pregnant women can influence the outcome for mother and fetus at all stages of pregnancy. As the fetus is entirely dependent on maternal thyroid hormones for its development until about 13 weeks of gestation, it is important to ensure adequate thyroxine substitution in pregnant women during the first trimester. Objective: The aim of this prospective study was to explore whether hypothyroidic pregnant women are adequately levothyroxine (L-T4 substituted in early pregnancy. Approach: During March 2008 to July 2009, 93 pregnant females with thyroid diseases were followed at the outpatient department of INMAS. At the first visit 86 patients were on L-T4 substitution for hypothyroidism. Seven other patients had hyperthyroidism. The patients were regularly followed every 4-8 weeks during pregnancy for dose adjustment. Before each visit serum Free Thyroxine (FT4 and TSH concentrations were determined. Results: Of the 86 patients on thyroxine substitution for hypothyroidism 56 (65.12% had serum TSH values within the reference range at their first TSH test. Thirty (34.9% had TSH values outside the reference range. In 5 patients TSH was 4 increase at the first evaluation during pregnancy was 17.46±30.8µg day1. In the 50 patients who needed to increase L-T4, 26% reached a definitive therapeutic dosage within 12th week of pregnancy, 24% within the 20th week and 50% within the 31st week. Conclusion/Recommendations: In 34.9% of pregnant women on L-T4 substitution for hypothyroidism, serum TSH values were abnormal when first tested and they had increased chances of fetal loss if not treated timely. Thyroid function in pregnant women on thyroxine substitution should be monitored as soon as pregnancy has been confirmed and carefully followed during pregnancy.

  9. Dose reduction and optimization studies (ALARA) at nuclear power facilities. [PWR; BWR

    Energy Technology Data Exchange (ETDEWEB)

    Baum, J.W.; Meinhold, C.B.

    1983-01-01

    Brookhaven National Laboratory (BNL) has been commissioned by the Nuclear Regulatory Commission (NRC) to study dose-reduction techniques and effectiveness of as low as reasonably achievable (ALARA) planning at LWR plants. These studies have the following objectives: identify high-dose maintenance tasks; identify dose-reduction techniques; examine incentives for dose reduction; evaluate cost-effectiveness and optimization of dose-reduction techniques; and compile an ALARA handbook on data, engineering modifications, cost-effectiveness calculations, and other information of interest to ALARA practioners.

  10. Progress study on the mechanism of CAG repeats dynamic mutation in polyQ disease

    Directory of Open Access Journals (Sweden)

    WANG Chun-rong

    2012-06-01

    Full Text Available Polyglutamine (polyQ disease is a group of neurodegenerative disorders caused by abnormal expansion of CAG repeats within coding regions of certain causative genes, which are translated into a series of abnormally expanded polyQ tracts causing cytotoxicity. So far, nine diseases caused by expanded polyQ tracts have been demonstrated including Huntington's disease (HD, spinobulbar muscular atrophy (SBMA, dentatorubral-pallidoluysian atrophy (DRPLA and several spinocerebellar ataxias subtypes (SCA. In human, long CAG repeats tend to expand during transmissions from parent to offspring, named as dynamic mutation, leading to an earlier age of disease onset and more severe symptoms in subsequent generations. The review presents some novel mechanisms based on dynamic mutation.

  11. Patch test dose-response study of p-phenylenediamine

    DEFF Research Database (Denmark)

    Sosted, Heidi; Menné, Torkil; Johansen, Jeanne Duus

    2006-01-01

    The elicitation response in allergic contact dermatitis for the hair dye substance p-phenylenediamine (PPD) is dose dependent, but threshold concentrations have not previously been investigated. 15 PPD-sensitive patients participated in a serial dilution 48-hr patch test with PPD using 8 concentr...

  12. [Clinical study of a low-dose contraceptive--Femodene].

    Science.gov (United States)

    Rachev, E; Damianov, L; Dukovski, A; Katsarova, M

    1995-01-01

    The authors present their clinical experience with a low-dose monophasic contraceptive consisting of 30 mcg ethinylestradiol and 75 mcg a gestagen--gestodene (Femoden, Schering). 112 menstrual cycles of 22 women in fertile age were followed. The results show 100% contraception, a good control of the menstrual cycle and tolerance of the preparation.

  13. Scatter dose summation for irregular fields: speed and accuracy study.

    Science.gov (United States)

    DeWyngaert, J K; Siddon, R L; Bjarngard, B E

    1986-05-01

    Using program IRREG as a standard, we have compared speed and accuracy of several algorithms that calculate the scatter dose in an irregular field. All the algorithms, in some manner, decompose the irregular field into component triangles and obtain the scatter dose as the sum of the contributions from those triangles. Two of the algorithms replace each such component triangle with a sector of a certain "effective radius": in one case the average radius of the triangle, in the other the radius of the sector having the same area as the component triangle. A third algorithm decomposes each triangle further into two right triangles and utilizes the precalculated "equivalent radius" of each, to find the scatter contribution. For points near the center of a square field, all the methods compare favorably in accuracy to program IRREG, with less than a 1% error in total dose and with approximately a factor of 3-5 savings in computation time. Even for extreme rectangular fields (2 cm X 30 cm), the methods using the average radius and the equivalent right triangles agree to within 2% in total dose and approximately a factor of 3-4 savings in computation time.

  14. PCR bias in amplification of androgen receptor alleles, a trinucleotide repeat marker used in clonality studies.

    OpenAIRE

    Mutter, G L; Boynton, K A

    1995-01-01

    Trinucleotide CAG repeats in the X-linked human androgen receptor gene (HUMARA) have proved a useful means of determining X chromosome haplotypes, and when combined with methylation analysis of nearby cytosine residues permits identification of non-random X inactivation in tumors of women. Co-amplification of two alleles in a heterozygote generates PCR products which differ in the number of CAG units, and thus their melting and secondary structure characteristics. We have shown that under opt...

  15. Repeated low-dose 17β-estradiol treatment prevents activation of apoptotic signaling both in the synaptosomal and cellular fraction in rat prefrontal cortex following cerebral ischemia.

    Science.gov (United States)

    Stanojlović, Miloš; Zlatković, Jelena; Guševac, Ivana; Grković, Ivana; Mitrović, Nataša; Zarić, Marina; Horvat, Anica; Drakulić, Dunja

    2015-01-01

    Disturbance in blood circulation is associated with numerous pathological conditions characterized by cognitive decline and neurodegeneration. Activation of pro-apoptotic signaling previously detected in the synaptosomal fraction may underlie neurodegeneration in the prefrontal cortex of rats submitted to permanent bilateral common carotid arteries occlusion (two-vessel occlusion, 2VO). 17β-Estradiol (E) exerts potent neuroprotective effects in the brain affecting, among other, ischemia-induced pathological changes. As most significant changes in rats submitted to 2VO were observed on 7th day following the insult, of interest was to examine whether 7 day treatment with low dose of E (33.3 µg/kg/day) prevents formerly reported neurodegeneration and may represent additional therapy during the early post-ischemic period. Role of E treatment on apoptotic pathway was monitored on Bcl-2 family members, cytochrome c, caspase 3 and PARP protein level in the synaptosomal (P2) fraction of the prefrontal cortex. Furthermore, changes of these proteins were examined in the cytosolic, mitochondrial and nuclear fraction, with the emphasis on potential involvement of extracellular signal-regulated kinases (ERK) and protein kinase B (Akt) activation and their role in nuclear translocation of transcriptional nuclear factor kappa B (NF-kB) associated with alteration of Bax and Bcl-2 gene expression. The extent of cellular damage was determined using DNA fragmentation and Fluoro-Jade B staining. The absence of activation of apoptotic cascade both in the P2 and cell accompanied with decreased DNA fragmentation and number of degenerating neurons clearly indicates that E treatment ensures the efficient protection against ischemic insult. Moreover, E-mediated modulation of pro-apoptotic signaling in the cortical cellular fractions involves cooperative activation of ERK and Akt, which may be implicated in the observed prevention of neurodegenerative changes.

  16. A genetic and structural study of genome rearrangements mediated by high copy repeat Ty1 elements.

    Directory of Open Access Journals (Sweden)

    Jason E Chan

    2011-05-01

    Full Text Available Ty elements are high copy number, dispersed repeated sequences in the Saccharomyces cerevisiae genome known to mediate gross chromosomal rearrangements (GCRs. Here we found that introduction of Ty912, a previously identified Ty1 element, onto the non-essential terminal region of the left arm of chromosome V led to a 380-fold increase in the rate of accumulating GCRs in a wild-type strain. A survey of 48 different mutations identified those that either increased or decreased the rate of Ty-mediated GCRs and demonstrated that suppression of Ty-mediated GCRs differs from that of both low copy repeat sequence- and single copy sequence-mediated GCRs. The majority of the Ty912-mediated GCRs observed were monocentric nonreciprocal translocations mediated by RAD52-dependent homologous recombination (HR between Ty912 and a Ty element on another chromosome arm. The remaining Ty912-mediated GCRs appeared to involve Ty912-mediated formation of unstable dicentric translocation chromosomes that were resolved by one or more Ty-mediated breakage-fusion-bridge cycles. Overall, the results demonstrate that the Ty912-mediated GCR assay is an excellent model for understanding mechanisms and pathways that suppress genome rearrangements mediated by high copy number repeat sequences, as well as the mechanisms by which such rearrangements occur.

  17. Study of the repeatability of histone genes in the ploidy series of wheat and Aegilops

    Energy Technology Data Exchange (ETDEWEB)

    Vakhitov, V.A.; Kulikov, A.M.

    1986-10-01

    The hDNA content and number of histone genes in the genomes of different wheat and Aegilops species have been determined by molecular hybridization of DNA with /sup 125/I-histone DNA of Drosophila (L-repeat) on nitrocellulose filters. It has been demonstrated that the proportion of hDNA in the total DNA of diploid and polyploid wheat species is (1.3-7.7) x 10/sup -3/% (57-850 genes), and in the ploidy series of Aegilops species (2.0-8.0) x 10/sup -3/% (89-780 genes). The repeatability of the histone genes generally increases at each ploidy level in the species with higher DNA content. At the same time, it has been demonstrated that the DNA content is not the only factor determining repeatability of the histone genes, as some diploid and allopolyploid species have similar number of these genes. It has been concluded that genetic mechanisms are involved in the regulation of the number of histone genes.

  18. Repeatability study of mechanomyography in submaximal isometric contractions using coefficient of variation and intraclass correlation coefficient.

    Science.gov (United States)

    Akataki, K; Mita, K; Itoh, Y

    1999-01-01

    The within-day and between-day repeatability of the mechanomyogram (MMG) was assessed using the coefficient of variation (CV) and the intraclass correlation coefficient (ICC) and was compared with that of the electromyogram (EMG). The MMG and EMG were recorded simultaneously during isometric elbow flexion trials at different submaximal levels of 10% to 90% MVC. The testing session consisting of 9 submaximal trials was repeated 8 times on the same day for estimation of the within-day variation. In order to examine the between-day variation, the same testing session was also performed 8 times over 3 weeks with a 2-day rest interval between each session. The CVs within-day and between-day in both the MMG and EMG did not demonstrate any significant differences relating to the magnitude of force exerted. The CVs combined over all the force levels were approximately 10% within the same day and 25% between days for both the MMG and EMG. These corresponded to the within-day ICC of approximately 0.95 and the between-day ICC of 0.80. The repeatability of the MMG during submaximal isometric contractions of biceps brachii muscles is considered to be similar to that of the more established EMG.

  19. Calcium antagonist in the treatment of symptomatic dermographism. Low-dose and high-dose studies with nifedipine.

    Science.gov (United States)

    Lawlor, F; Ormerod, A D; Greaves, M W

    1988-01-01

    The effect of nifedipine on subjective symptoms and objective dermographometer induced whealing was assessed independently in two double-blind cross-over trials in which active drug or placebo were taken for 2 weeks. The lower dose study used nifedipine 5 mg 3 times daily and gave rise to symptomatic improvement as assessed by diary card and visual analogue scale in 5 of 11 patients. This was not statistically significant and was not accompanied by a reduction in dermographometer-induced wheal and flare responses except at highest pressures. In a separate study 7 patients were treated with nifedipine 10 mg 3 times daily. No change in whealing occurred, 3 patients' symptoms became worse and only 1 showed symptomatic improvement on nifedipine. Side effects were frequent at this dose. The reasons for the unfavourable response despite in vitro evidence for inhibition of mast cell degranulation by this drug are discussed.

  20. Digital repeat analysis; setup and operation.

    Science.gov (United States)

    Nol, J; Isouard, G; Mirecki, J

    2006-06-01

    Since the emergence of digital imaging, there have been questions about the necessity of continuing reject analysis programs in imaging departments to evaluate performance and quality. As a marketing strategy, most suppliers of digital technology focus on the supremacy of the technology and its ability to reduce the number of repeats, resulting in less radiation doses given to patients and increased productivity in the department. On the other hand, quality assurance radiographers and radiologists believe that repeats are mainly related to positioning skills, and repeat analysis is the main tool to plan training needs to up-skill radiographers. A comparative study between conventional and digital imaging was undertaken to compare outcomes and evaluate the need for reject analysis. However, digital technology still being at its early development stages, setting a credible reject analysis program became the major task of the study. It took the department, with the help of the suppliers of the computed radiography reader and the picture archiving and communication system, over 2 years of software enhancement to build a reliable digital repeat analysis system. The results were supportive of both philosophies; the number of repeats as a result of exposure factors was reduced dramatically; however, the percentage of repeats as a result of positioning skills was slightly on the increase for the simple reason that some rejects in the conventional system qualifying for both exposure and positioning errors were classified as exposure error. The ability of digitally adjusting dark or light images reclassified some of those images as positioning errors.

  1. Dosing study of massage for chronic neck pain: protocol for the dose response evaluation and analysis of massage [DREAM] trial

    Directory of Open Access Journals (Sweden)

    Sherman Karen J

    2012-09-01

    Full Text Available Abstract Background Despite the growing popularity of massage, its effectiveness for treating neck pain remains unclear, largely because of the poor quality of research. A major deficiency of previous studies has been their use of low “doses” of massage that massage therapists consider inadequate. Unfortunately, the number of minutes per massage session, sessions per week, or weeks of treatment necessary for massage to have beneficial or optimal effects are not known. This study is designed to address these gaps in our knowledge by determining, for persons with chronic neck pain: 1 the optimal combination of number of treatments per week and length of individual treatment session, and 2 the optimal number of weeks of treatment. Methods/design In this study, 228 persons with chronic non-specific neck pain will be recruited from primary health care clinics in a large health care system in the Seattle area. Participants will be randomized to a wait list control group or 4 weeks of treatment with one of 5 different dosing combinations (2 or 3 30-min treatments per week or 1, 2, or 3 60-min treatments per week. At the end of this 4-week primary treatment period, participants initially receiving each of the 5 dosing combinations will be randomized to a secondary treatment period of either no additional treatment or 6 weekly 60-min massages. The primary outcomes, neck-related dysfunction and pain, will be assessed by blinded telephone interviewers 5, 12, and 26 weeks post-randomization. To better characterize the trajectory of treatment effects, these interview data will be supplemented with outcomes data collected by internet questionnaire at 10, 16, 20 and 39 weeks. Comparisons of outcomes for the 6 groups during the primary treatment period will identify the optimal weekly dose, while comparisons of outcomes during the secondary treatment period will determine if 10 weeks of treatment is superior to 4 weeks. Discussion A broad dosing schedule

  2. Deployment Repeatability

    Science.gov (United States)

    2016-04-01

    controlled to great precision, but in a Cubesat , there may be no attitude determination at all. Such a Cubesat might treat sun angle and tumbling rates as...could be sensitive to small differences in motor controller timing. In these cases, the analyst might choose to model the entire deployment path, with...knowledge of the material damage model or motor controller timing precision. On the other hand, if many repeated and environmentally representative

  3. Study of radiation exposure dose in young dental patients

    Energy Technology Data Exchange (ETDEWEB)

    Hatakeyama, Atsushi (Fukuoka Dental College, Fukuoka (Japan))

    1983-08-01

    In order to clarify the trend in dental radiography for young patients up to 18 years old and the accompanying radiation exposures, surveys were made at Fukuoka Dental College Hospital and thirty-five dental offices in Fukuoka city and Kitakyushu city. Each kind of radiography increased in average number with age and 16-18 group was given 4.60 times of radiography of one kind or another in the clinic of college hospital. In the dental offices, the number of radiography taken was about one-fourth that of the clinic of college hospital. Although exposure dose varies with exposure factors, distance and angle of exposure, in addition to time factor, were found to affect doses subtly. In the clinic of college hospital the average of estimated doses to organs per person per year were 105.4 mrad (25.2 mrad for 5-year-old children) in the salivary gland, 55.9 mrad (18.9 mrad for 5-year-old) in the thyroid gland, 52.1 mrad (15.0 mrad for 5-year-old) in the lens of the eye and 52.2 mrad (8.7 mrad for 5-year-old) in the sella turcica. In the dental offices, the same average of estimated doses to organs were 40.5 mrad (7.4 mrad for 5-year-old) in the salivary gland, 17.4 mrad (8.0 mrad for 5-year-old) in the thyroid gland, 12.2 mrad (6.1 mrad for 5-year-old) in the lens of eye and 13.1 mrad (1.3 mrad for 5-year-old) in the sella turcica. In all kinds of radiograpy, the estimated doses in genital glands were in ..mu..rad. In the dental offices, both the percentage of young patients to all patients and the radiographing rate were lower as compared with those in the clinic of college hospital. The estimated doses were also lower at one-half to one-fifth and those by age and by organ were found to be one-tenth or lower.

  4. Variability in prefrontal hemodynamic response during exposure to repeated self-selected music excerpts, a near-infrared spectroscopy study.

    Science.gov (United States)

    Moghimi, Saba; Schudlo, Larissa; Chau, Tom; Guerguerian, Anne-Marie

    2015-01-01

    Music-induced brain activity modulations in areas involved in emotion regulation may be useful in achieving therapeutic outcomes. Clinical applications of music may involve prolonged or repeated exposures to music. However, the variability of the observed brain activity patterns in repeated exposures to music is not well understood. We hypothesized that multiple exposures to the same music would elicit more consistent activity patterns than exposure to different music. In this study, the temporal and spatial variability of cerebral prefrontal hemodynamic response was investigated across multiple exposures to self-selected musical excerpts in 10 healthy adults. The hemodynamic changes were measured using prefrontal cortex near infrared spectroscopy and represented by instantaneous phase values. Based on spatial and temporal characteristics of these observed hemodynamic changes, we defined a consistency index to represent variability across these domains. The consistency index across repeated exposures to the same piece of music was compared to the consistency index corresponding to prefrontal activity from randomly matched non-identical musical excerpts. Consistency indexes were significantly different for identical versus non-identical musical excerpts when comparing a subset of repetitions. When all four exposures were compared, no significant difference was observed between the consistency indexes of randomly matched non-identical musical excerpts and the consistency index corresponding to repetitions of the same musical excerpts. This observation suggests the existence of only partial consistency between repeated exposures to the same musical excerpt, which may stem from the role of the prefrontal cortex in regulating other cognitive and emotional processes.

  5. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products.

    Science.gov (United States)

    García-Arieta, Alfredo; Morales-Alcelay, Susana; Herranz, Marta; de la Torre-Alvarado, José María; Blázquez-Pérez, Antonio; Suárez-Gea, Ma Luisa; Alvarez, Covadonga

    2012-02-28

    In the European Union multiple dose bioequivalence studies are required for the approval of generic prolonged-release products, but they are not required by the US-FDA. In order to investigate if the multiple dose bioequivalence studies are necessary, the bioequivalence studies assessed in the Spanish Agency for Medicines and Health Care Products in the last 10 years were searched to find all reasons for rejection and identify those cases where the multiple dose study had failed to show bioequivalence and the single dose study had shown bioequivalence. In these latter cases, the plasma concentration at the end of the dosing interval (C(τ)) in the single dose study was assessed to investigate its sensitivity to predict non-bioequivalence in the steady state. The search identified six cases where the non-equivalence in the multiple dose study was not detected by the corresponding single dose study. C(τ) was not able to detect the difference in five cases and in general it was more variable than conventional metrics. In conclusion, the multiple dose bioequivalence study is necessary to ensure therapeutic equivalence and the use of C(τ) would be counterproductive, increasing the sample size of the studies without enough sensitivity to detect differences in the steady state.

  6. Dose escalation studies with caspofungin against Candida glabrata.

    Science.gov (United States)

    Domán, Marianna; Kovács, Renátó; Perlin, David S; Kardos, Gábor; Gesztelyi, Rudolf; Juhász, Béla; Bozó, Aliz; Majoros, László

    2015-09-01

    Echinocandins are recommended as first-line agents against invasive fungal infections caused by Candida glabrata, which still carry a high mortality rate. Dose escalation of echinocandins has been suggested to improve the clinical outcome against C. glabrata. To address this possibility, we performed in vitro and in vivo experiments with caspofungin against four WT C. glabrata clinical isolates, a drug-susceptible ATCC 90030 reference strain and two echinocandin-resistant strains with known FKS mutations. MIC values for the clinical isolates in RPMI 1640 were ≤ 0.03 mg l(-1 ) but increased to 0.125-0.25 mg l(-1 )in RPMI 1640+50% serum. In RPMI 1640+50% serum, the replication of C. glabrata was weaker than in RPMI 1640.Caspofungin in RPMI 1640 at 1 and 4 mg l(-1) showed a fungicidal effect within 7 h against three of the four clinical isolates but was only fungistatic at 16 and 32 mg l(-1) (paradoxically decreased killing activity). In RPMI 1640+50% serum, caspofungin at ≥ 1 mg l(-1) was rapidly fungicidal (within 3.31 h) against three of the four isolates. In a profoundly neutropenic murine model, all caspofungin doses (1, 2, 3, 5 and 20 mg kg(-1) daily) decreased the fungal tissue burdens significantly (P caspofungin dose escalation does not improve efficacy.

  7. Repeated hands-and-knees positioning during labour: a randomized pilot study.

    Science.gov (United States)

    Hodnett, Ellen D; Stremler, Robyn; Halpern, Stephen H; Weston, Julie; Windrim, Rory

    2013-01-01

    Background. Caesarean birth rates in North America continue to rise, in the absence of benefit for mothers and babies. One reason may be that hospitalized labouring women spend most of their labours in recumbent or semi-recumbent positions. Although hands-and-knees position has theoretical advantages, efforts to encourage its adoption in practice are severely hampered by the lack of compelling evidence that it is beneficial. Before a definitive, large scale trial, with spontaneous vaginal birth as the primary outcome, could be justified in terms of time, effort, and expense, several feasibility and acceptability questions had to be addressed. We aimed to enrol 60 women in a pilot study to assess feasibility and acceptability of the trial protocol, and to obtain estimates of treatment effects on method of birth and persistent back pain. Methods. We conducted a pilot study at two North American hospitals. In ten months of recruitment, 30 nulliparous women in labour at term were randomly allocated to either usual care (use of any position during labour except hands-and-knees) or to try hands-and-knees for 15 min every hour during labour. Data were collected about compliance, acceptability, persistent back pain, intrapartum interventions, and women's views of their experiences. Results. Although mean length of time from randomization to delivery was over 12 hours, only 9 of the 16 women allocated to repeated hands-and-knees used it more than twice. Two of the 14 in the usual care group used hands-and-knees once. Twenty-seven women had regional analgesia (15 in the hands-and-knees group and 12 in the usual care group). Eleven in the hands-and-knees group and 14 in the usual care group had spontaneous vaginal births. One woman (in the hands-and-knees group) had a vacuum extraction. Four women in the hands-and-knees group and none in the usual care group gave birth by caesarean section. Hourly back pain ratings were highly variable in both groups, covering the full range

  8. Repeated hands-and-knees positioning during labour: a randomized pilot study

    Directory of Open Access Journals (Sweden)

    Ellen D. Hodnett

    2013-02-01

    Full Text Available Background. Caesarean birth rates in North America continue to rise, in the absence of benefit for mothers and babies. One reason may be that hospitalized labouring women spend most of their labours in recumbent or semi-recumbent positions. Although hands-and-knees position has theoretical advantages, efforts to encourage its adoption in practice are severely hampered by the lack of compelling evidence that it is beneficial. Before a definitive, large scale trial, with spontaneous vaginal birth as the primary outcome, could be justified in terms of time, effort, and expense, several feasibility and acceptability questions had to be addressed. We aimed to enrol 60 women in a pilot study to assess feasibility and acceptability of the trial protocol, and to obtain estimates of treatment effects on method of birth and persistent back pain.Methods. We conducted a pilot study at two North American hospitals. In ten months of recruitment, 30 nulliparous women in labour at term were randomly allocated to either usual care (use of any position during labour except hands-and-knees or to try hands-and-knees for 15 min every hour during labour. Data were collected about compliance, acceptability, persistent back pain, intrapartum interventions, and women’s views of their experiences.Results. Although mean length of time from randomization to delivery was over 12 hours, only 9 of the 16 women allocated to repeated hands-and-knees used it more than twice. Two of the 14 in the usual care group used hands-and-knees once. Twenty-seven women had regional analgesia (15 in the hands-and-knees group and 12 in the usual care group. Eleven in the hands-and-knees group and 14 in the usual care group had spontaneous vaginal births. One woman (in the hands-and-knees group had a vacuum extraction. Four women in the hands-and-knees group and none in the usual care group gave birth by caesarean section. Hourly back pain ratings were highly variable in both groups

  9. Corneal epithelial toxicity of antiglaucoma formulations: in vitro study of repeated applications

    Directory of Open Access Journals (Sweden)

    Meloni M

    2012-09-01

    Full Text Available Marisa Meloni,1 Giampiero Cattaneo,2 Barbara De Servi11VitroScreen In Vitro Research Laboratories, 2Thea Farma, Milan, ItalyBackground: By using a biologically relevant and sensitive three-dimensional model of human corneal epithelium and multiple endpoint analysis, assessment of the potential for eye irritation and long-term compatibility of four registered ophthalmological preparations, ie, Timolabak®, Timoptol®, Nyogel®, and Timogel®, was performed. This approach enables classification of the potential for irritation, discriminating between mildly irritant and non-irritant ocular substances.Methods: The exposure protocol included two time periods, ie, 24 hours (acute application and 72 hours (repeated applications twice daily. This approach allows assessment of not only the acute reaction but also possible recovery, as well as mimicking the potential cumulative effects associated with long-term application. Using benzalkonium chloride (BAK 0.01% as a positive control, the following parameters were quantified: cellular viability by MTT test, histological analysis by hematoxylin and eosin staining, passive release of interleukin-1a by enzyme-linked immunosorbent assay, and OCLN gene expression by quantitative real-time polymerase chain reaction.Results: Cell viability was reduced to under the 50% cutoff value after acute exposure (24 hours to BAK 0.01%, and after repeated application (72 hours of Timoptol and Nyogel. Histological analysis after acute exposure showed signs of superficial damage with all formulations, and severe changes after repeated applications of Timoptol, BAK 0.01%, and Nyogel. Timolabak and Timogel did not significantly alter the morphology of the human corneal epithelial cells after the different exposure times. Interleukin-1α release was greater than that for the negative control (>20 pg/mL and the positive control (BAK 0.01%, Nyogel, and Timoptol treatments and not different after treatment with Timolabak and

  10. CAG repeat polymorphisms in the androgen receptor and breast cancer risk in women: a meta-analysis of 17 studies

    Directory of Open Access Journals (Sweden)

    Mao Q

    2015-08-01

    Full Text Available Qixing Mao,1–3,* Mantang Qiu,1–3,* Gaochao Dong,3 Wenjie Xia,1–3 Shuai Zhang,1,3 Youtao Xu,1,3 Jie Wang,3 Yin Rong,1,3 Lin Xu,1,3 Feng Jiang1,3 1Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Institute of Jiangsu Province, 2Fourth Clinical College of Nanjing Medical University, 3Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: The association between polymorphic CAG repeats in the androgen receptor gene in women and breast cancer susceptibility has been studied extensively. However, the conclusions regarding this relationship remain conflicting. The purpose of this meta-analysis was to identify whether androgen receptor CAG repeat lengths were related to breast cancer susceptibility. The MEDLINE, PubMed, and EMBASE databases were searched through to December 2014 to identify eligible studies. Data and study quality were rigorously assessed by two investigators according to the Newcastle-Ottawa Quality Assessment Scale. The publication bias was assessed by the Begg’s test. Seventeen eligible studies were included in this meta-analysis. The overall analysis suggested no association between CAG polymorphisms and breast cancer risk (odds ratio [OR] 1.031, 95% confidence interval [CI] 0.855–1.245. However, in the subgroup analysis, we observed that long CAG repeats significantly increased the risk of breast cancer in the Caucasian population (OR 1.447, 95% CI 1.089–1.992. Additionally, the risk was significantly increased in Caucasian women carrying two alleles with CAG repeats ≥22 units compared with those with two shorter alleles (OR 1.315, 95% CI 1.014–1.707. These findings suggest that long CAG repeats increase the risk of breast cancer in Caucasian women. However, larger scale case-control studies are needed to validate our results. Keywords: androgen, CAG repeat polymorphism, women

  11. Comparison of [11C]cocaine binding at tracer and pharmacological doses of baboon brain: A PET study

    Energy Technology Data Exchange (ETDEWEB)

    Volkow, N.D.; Fowler, J.S.; Logan, J. [Brookhaven National Lab., Upton, NY (United States)] [and others

    1994-05-01

    In vitro studies have shown that cocaine (C) binds to both high and low affinity sites on the dopamine transporter (DAT). We have previously characterized the binding of tracer doses of [{sup 11}C]cocaine (C*)to a high affinity site on the DAT. To assess if in vivo C also binds to low affinity sites we used PET to compare binding of tracer doses (17.8{plus_minus}12.2 {mu}g C) of C* to pharmacological doses (8 mg of C coadministered with C*). Sixteen paired studies were done to assess test/retest variability, specific versus non specific binding and to characterize binding profile. Dynamic scans were started immediately after injection of C* (5-8 mCi) for 50 min on the CTI-931 (6 x 6 x 6.5 mm FWHM). Time activity curves for tissue concentration and for unchanged tracer in plasma were used to calculate the transport constant between plasma and tissue (K1) and to obtain the distribution volume (DV). The ratio of the DV in striatum (ST) to that in cerebellum (CB) (which corresponds to Bmax/Kd-1) was used as model parameter. Peak brain uptake of C* was significantly higher for tracer than for pharmacological doses (0.041 versus 0.033 % dose/cc), as were the values for K1 (1.07{plus_minus}0.21 versus 0.68{plus_minus}0.26 (t=3.0 p<0.01)). Repeated measures were reproducible for tracer ({plus_minus}2%) and pharmacological doses of C* ({plus_minus}4%). Tracer dose C* showed highest binding and slowest clearance in ST which was reduced by C (0.5-2.0 mg/kg iv, -25 to -30%) and by drugs that inhibit DAT (2mg/kg nomifensine - 21%, 0.5 mg/kg methylphenidate -12%) and was increased by serotonin transporter inhibitors (5HT-Ti) (2 mg/kg citalopram +11%, 0.5 mg/kg fluoxetine +6%) and not changed by NE transporter inhibitors (0.5 mg/kg desipramine or 2 mg/kg tomoxetine). The increase with (5HT-Ti) may reflect neurotransmitter interactions or changes in bioavailability. At pharmacological doses C* showed homogeneous distribution and was not changed by C nor by any of the above drugs.

  12. Repeat prenatal corticosteroid prior to preterm birth: a systematic review and individual participant data meta-analysis for the PRECISE study group (prenatal repeat corticosteroid international IPD study group: assessing the effects using the best level of evidence - study protocol

    Directory of Open Access Journals (Sweden)

    Crowther Caroline A

    2012-02-01

    Full Text Available Abstract Background The aim of this individual participant data (IPD meta-analysis is to assess whether the effects of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies are modified in a clinically meaningful way by factors related to the women or the trial protocol. Methods/Design The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. The primary study outcomes for the infants will be serious neonatal outcome (defined by the PRECISE International IPD Study Group as one of death (foetal, neonatal or infant; severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4; chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia; use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support; and birth weight (Z-scores. For the children, the primary study outcomes will be death or any neurological disability (however defined by trialists at childhood follow up and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean, cerebral palsy (abnormality of tone with motor dysfunction, blindness (for example, corrected visual acuity worse than 6/60 in the better eye or deafness (for example, hearing loss requiring amplification or worse. For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use

  13. Evaluation of 90-day Repeated Dose Oral Toxicity, Glycometabolism, Learning and Memory Ability, and Related Enzyme of Chromium Malate Supplementation in Sprague-Dawley Rats.

    Science.gov (United States)

    Feng, Weiwei; Wu, Huiyu; Li, Qian; Zhou, Zhaoxiang; Chen, Yao; Zhao, Ting; Feng, Yun; Mao, Guanghua; Li, Fang; Yang, Liuqing; Wu, Xiangyang

    2015-11-01

    Our previous study showed that chromium malate improved the regulation of blood glucose in mice with alloxan-induced diabetes. The present study was designed to evaluate the 90-day oral toxicity of chromium malate in Sprague-Dawley rats. The present study inspected the effect of chromium malate on glycometabolism, glycometabolism-related enzymes, lipid metabolism, and learning and memory ability in metabolically healthy Sprague-Dawley rats. The results showed that all rats survived and pathological, toxic, feces, and urine changes were not observed. Chromium malate did not cause measurable damage on liver, brain, and kidney. The fasting blood glucose, serum insulin, insulin resistance index, C-peptide, hepatic glycogen, glucose-6-phosphate dehydrogenase, glucokinase, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels of normal rats in chromium malate groups had no significant change when compared with control group and chromium picolinate group under physiologically relevant conditions. The serum and organ content of Cr in chromium malate groups had no significant change compared with control group. No significant changes were found in morris water maze test and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and true choline esterase (TChE) activity. The results indicated that supplementation with chromium malate did not cause measurable toxicity and has no obvious effect on glycometabolism and related enzymes, learning and memory ability, and related enzymes and lipid metabolism of female and male rats. The results of this study suggest that chromium malate is safe for human consumption.

  14. Dose reduction potential of iterative reconstruction algorithms in neck CTA-a simulation study.

    Science.gov (United States)

    Ellmann, Stephan; Kammerer, Ferdinand; Allmendinger, Thomas; Brand, Michael; Janka, Rolf; Hammon, Matthias; Lell, Michael M; Uder, Michael; Kramer, Manuel

    2016-10-01

    This study aimed to determine the degree of radiation dose reduction in neck CT angiography (CTA) achievable with Sinogram-affirmed iterative reconstruction (SAFIRE) algorithms. 10 consecutive patients scheduled for neck CTA were included in this study. CTA images of the external carotid arteries either were reconstructed with filtered back projection (FBP) at full radiation dose level or underwent simulated dose reduction by proprietary reconstruction software. The dose-reduced images were reconstructed using either SAFIRE 3 or SAFIRE 5 and compared with full-dose FBP images in terms of vessel definition. 5 observers performed a total of 3000 pairwise comparisons. SAFIRE allowed substantial radiation dose reductions in neck CTA while maintaining vessel definition. The possible levels of radiation dose reduction ranged from approximately 34 to approximately 90% and depended on the SAFIRE algorithm strength and the size of the vessel of interest. In general, larger vessels permitted higher degrees of radiation dose reduction, especially with higher SAFIRE strength levels. With small vessels, the superiority of SAFIRE 5 over SAFIRE 3 was lost. Neck CTA can be performed with substantially less radiation dose when SAFIRE is applied. The exact degree of radiation dose reduction should be adapted to the clinical question, in particular to the smallest vessel needing excellent definition.

  15. Uncontrolled variables in frying studies: differences in repeatability between thermoxidation and frying experiments

    Directory of Open Access Journals (Sweden)

    Dobarganes, Carmen

    2007-09-01

    Full Text Available Palm oil, soybean oil and partially hydrogenated soybean oil were used to define the repeatability of oil degradation under thermoxidation in the absence of food and during the frying of potatoes. Total polar compounds and their constituent polymeric triglycerides, oxidized monomeric triglycerides and diglycerides were analyzed. The oils were thermoxidized under standard conditions in a Rancimat apparatus at 180 °C for 25 hours. Discontinuous frying experiments were carried out in triplicate in three apparently identical domestic fryers. Five batches of potatoes were fried per day in each fryer. Oils were heated at 180 °C in periods of 5 h per day during 5 consecutive days so that the total heating period was 25 h. Repeatability was high in the thermoxidation assays and rather low in the frying experiments. Significant differences between the oils were found in the thermoxidation experiments, while no significant differences were found in the frying assays due to large standard deviations. The participation of variables related to the fryer performance which are difficult to control, was deduced. Among them, differences in the heating/cooling cycles at high temperature might be important. The contribution of fryer performance to the decreased repeatability was confirmed in further frying experiments with palm oil. Results showed that repeatability for the same fryer was higher than that obtained when different fryers were considered.Se estudia la repetibilidad de los resultados obtenidos en el calentamiento de los aceites y grasas a temperatura elevada utilizando aceite de palma, aceite de soja y aceite de soja parcialmente hidrogenado. Partiendo de la repetibilidad de las determinaciones analíticas utilizadas para la evaluación de la degradación de los aceites y grasas a elevada temperatura, el análisis de compuestos polares y de su distribución en polímeros de triglicéridos, triglicéridos monómeros oxidados y diglicéridos, se

  16. Use of short tandem repeat sequences to study Mycobacterium leprae in leprosy patients in Malawi and India.

    Directory of Open Access Journals (Sweden)

    Saroj K Young

    2008-04-01

    Full Text Available Inadequate understanding of the transmission of Mycobacterium leprae makes it difficult to predict the impact of leprosy control interventions. Genotypic tests that allow tracking of individual bacterial strains would strengthen epidemiological studies and contribute to our understanding of the disease.Genotyping assays based on variation in the copy number of short tandem repeat sequences were applied to biopsies collected in population-based epidemiological studies of leprosy in northern Malawi, and from members of multi-case households in Hyderabad, India. In the Malawi series, considerable genotypic variability was observed between patients, and also within patients, when isolates were collected at different times or from different tissues. Less within-patient variability was observed when isolates were collected from similar tissues at the same time. Less genotypic variability was noted amongst the closely related Indian patients than in the Malawi series.Lineages of M. leprae undergo changes in their pattern of short tandem repeat sequences over time. Genetic divergence is particularly likely between bacilli inhabiting different (e.g., skin and nerve tissues. Such variability makes short tandem repeat sequences unsuitable as a general tool for population-based strain typing of M. leprae, or for distinguishing relapse from reinfection. Careful use of these markers may provide insights into the development of disease within individuals and for tracking of short transmission chains.

  17. Revisiting the TALE repeat.

    Science.gov (United States)

    Deng, Dong; Yan, Chuangye; Wu, Jianping; Pan, Xiaojing; Yan, Nieng

    2014-04-01

    Transcription activator-like (TAL) effectors specifically bind to double stranded (ds) DNA through a central domain of tandem repeats. Each TAL effector (TALE) repeat comprises 33-35 amino acids and recognizes one specific DNA base through a highly variable residue at a fixed position in the repeat. Structural studies have revealed the molecular basis of DNA recognition by TALE repeats. Examination of the overall structure reveals that the basic building block of TALE protein, namely a helical hairpin, is one-helix shifted from the previously defined TALE motif. Here we wish to suggest a structure-based re-demarcation of the TALE repeat which starts with the residues that bind to the DNA backbone phosphate and concludes with the base-recognition hyper-variable residue. This new numbering system is consistent with the α-solenoid superfamily to which TALE belongs, and reflects the structural integrity of TAL effectors. In addition, it confers integral number of TALE repeats that matches the number of bound DNA bases. We then present fifteen crystal structures of engineered dHax3 variants in complex with target DNA molecules, which elucidate the structural basis for the recognition of bases adenine (A) and guanine (G) by reported or uncharacterized TALE codes. Finally, we analyzed the sequence-structure correlation of the amino acid residues within a TALE repeat. The structural analyses reported here may advance the mechanistic understanding of TALE proteins and facilitate the design of TALEN with improved affinity and specificity.

  18. A method for converting dose-to-medium to dose-to-tissue in Monte Carlo studies of gold nanoparticle-enhanced radiotherapy.

    Science.gov (United States)

    Koger, B; Kirkby, C

    2016-03-07

    Gold nanoparticles (GNPs) have shown potential in recent years as a means of therapeutic dose enhancement in radiation therapy. However, a major challenge in moving towards clinical implementation is the exact characterisation of the dose enhancement they provide. Monte Carlo studies attempt to explore this property, but they often face computational limitations when examining macroscopic scenarios. In this study, a method of converting dose from macroscopic simulations, where the medium is defined as a mixture containing both gold and tissue components, to a mean dose-to-tissue on a microscopic scale was established. Monte Carlo simulations were run for both explicitly-modeled GNPs in tissue and a homogeneous mixture of tissue and gold. A dose ratio was obtained for the conversion of dose scored in a mixture medium to dose-to-tissue in each case. Dose ratios varied from 0.69 to 1.04 for photon sources and 0.97 to 1.03 for electron sources. The dose ratio is highly dependent on the source energy as well as GNP diameter and concentration, though this effect is less pronounced for electron sources. By appropriately weighting the monoenergetic dose ratios obtained, the dose ratio for any arbitrary spectrum can be determined. This allows complex scenarios to be modeled accurately without explicitly simulating each individual GNP.

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

    Science.gov (United States)

    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.

  20. Methyldibromoglutaronitrile allergy: relationship between patch test and repeated open application test thresholds

    DEFF Research Database (Denmark)

    Fischer, L.A.; Johansen, J.D.; Menne, T.

    2008-01-01

    a significant relationship between the patch test and the repeated open application test (ROAT) reactivity. Objectives To study the relationship between elicitation threshold doses at single occluded exposure and repeated open application, using MDBGN as the allergen. Methods Eighteen subjects allergic to MDBGN...

  1. Phase I Study of Continuous Weekly Dosing of Dimethylamino Benzoylphenylurea (BPU) in Patients with Solid Tumours

    OpenAIRE

    Messersmith, Wells A.; Rudek, Michelle A.; Baker, Sharyn D.; Zhao, Ming; Collins, Connie; Colevas, A. Dimitrios; Donehower, Ross C.; Carducci, Michael A.; Wolff, Antonio C.

    2006-01-01

    A phase I study of Dimethylamino Benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320mg dose level. Two subjects the...

  2. An animal model to study health effects during continuous low-dose exposure to the nerve agent VX.

    Science.gov (United States)

    Rocksén, David; Elfsmark, Daniel; Heldestad, Victoria; Wallgren, Karin; Cassel, Gudrun; Göransson Nyberg, Ann

    2008-08-19

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  3. Feasibility Study of Neutron Dose for Real Time Image Guided Proton Therapy: A Monte Carlo Study

    CERN Document Server

    Kim, Jin Sung; Kim, Daehyun; Shin, EunHyuk; Chung, Kwangzoo; Cho, Sungkoo; Ahn, Sung Hwan; Ju, Sanggyu; Chung, Yoonsun; Jung, Sang Hoon; Han, Youngyih

    2015-01-01

    Two full rotating gantry with different nozzles (Multipurpose nozzle with MLC, Scanning Dedicated nozzle) with conventional cyclotron system is installed and under commissioning for various proton treatment options at Samsung Medical Center in Korea. The purpose of this study is to investigate neutron dose equivalent per therapeutic dose, H/D, to x-ray imaging equipment under various treatment conditions with monte carlo simulation. At first, we investigated H/D with the various modifications of the beam line devices (Scattering, Scanning, Multi-leaf collimator, Aperture, Compensator) at isocenter, 20, 40, 60 cm distance from isocenter and compared with other research groups. Next, we investigated the neutron dose at x-ray equipments used for real time imaging with various treatment conditions. Our investigation showed the 0.07 ~ 0.19 mSv/Gy at x-ray imaging equipments according to various treatment options and intestingly 50% neutron dose reduction effect of flat panel detector was observed due to multi- lea...

  4. What level of accuracy is achievable for preclinical dose painting studies on a clinical irradiation platform?

    Science.gov (United States)

    Trani, Daniela; Reniers, Brigitte; Persoon, Lucas; Podesta, Mark; Nalbantov, Georgi; Leijenaar, Ralph T H; Granzier, Marlies; Yaromina, Ala; Dubois, Ludwig; Verhaegen, Frank; Lambin, Philippe

    2015-05-01

    Advancements made over the past decades in both molecular imaging and radiotherapy planning and delivery have enabled studies that explore the efficacy of heterogeneous radiation treatment ("dose painting") of solid cancers based on biological information provided by different imaging modalities. In addition to clinical trials, preclinical studies may help contribute to identifying promising dose painting strategies. The goal of this current study was twofold: to develop a reproducible positioning and set-up verification protocol for a rat tumor model to be imaged and treated on a clinical platform, and to assess the dosimetric accuracy of dose planning and delivery for both uniform and positron emission tomography-computed tomography (PET-CT) based heterogeneous dose distributions. We employed a syngeneic rat rhabdomyosarcoma model, which was irradiated by volumetric modulated arc therapy (VMAT) with uniform or heterogeneous 6 MV photon dose distributions. Mean dose to the gross tumor volume (GTV) as a whole was kept at 12 Gy for all treatment arms. For the nonuniform plans, the dose was redistributed to treat the 30% of the GTV representing the biological target volume (BTV) with a dose 40% higher than the rest of the GTV (GTV - BTV) (~15 Gy was delivered to the BTV vs. ~10.7 Gy was delivered to the GTV - BTV). Cone beam computed tomography (CBCT) images acquired for each rat prior to irradiation were used to correctly reposition the tumor and calculate the delivered 3D dose. Film quality assurance was performed using a water-equivalent rat phantom. A comparison between CT or CBCT doses and film measurements resulted in passing rates >98% with a gamma criterion of 3%/2 mm using 2D dose images. Moreover, between the CT and CBCT calculated doses for both uniform and heterogeneous plans, we observed maximum differences of <2% for mean dose to the tumor and mean dose to the biological target volumes. In conclusion, we have developed a robust method for dose painting

  5. 40 CFR 799.9365 - TSCA combined repeated dose toxicity study with the reproduction/developmental toxicity screening...

    Science.gov (United States)

    2010-07-01

    ... performance such as gonadal function, mating behavior, conception, development of the conceptus, and... not be limited to, changes in skin, fur, eyes, mucous membranes, occurrence of secretions and... recommended 1 . Investigations of plasma or serum must include sodium, potassium, glucose, total cholesterol...

  6. High-dose ifosfamide and mesna in advanced breast cancer. A phase II study.

    Science.gov (United States)

    Sanchiz, F; Milla, A

    1990-01-01

    Thirty-two patients with metastatic breast cancer had previously been treated with chemotherapy (including anthracyclines). They were included in a trial to receive 6 g/m3 ifosfamide, mixed with 6 g/m2 mesna in 1000 ml saline infusion, infused over 4 h. Therapy was repeated every 21 days; the dose was reduced by 50%. Twenty-eight patients could be evaluated. An average of 4.2 cycles (range 2-8) was applied. One patient (4%) showed complete remission. Ten patients (36%) had a partial response. Ten patients (36%) experienced SD and the remaining patients (25%) PD. We conclude that high-dose ifosfamide shows activity in this group of pretreated patients and merits further investigation.

  7. Spa Goers' Repeated Visits for Health and Wellness and the Influential Factors: An Exploratory Study of the UK Spa Goers.

    Science.gov (United States)

    Choi, Myungsuk; Poade, Donna; Sohn, Minsung; Choi, Mankyu

    2016-01-01

    Dissemination of spa services across the globe and its market saturation drive demand for differentiated communication methods. This study aims to explore the influential factors on spa goers' repeated visits and their practical applications in the health and wellness spa industry. The identified factors were used as the measurement variables to examine the relation with spa goers' repeated visits. The proposed concept was tested by a mixed method combining a self-administered questionnaire and semistructured interview with 54 survey participants and 6 interviewees. It was meaningful to use a sample of the UK spa goers from the southwest region since global spa trends stem from the EU spas, and the United Kingdom is one of the market leaders. The data were analyzed using frequency, percentage, multiple logistic regression analysis, and coding process. The survey findings demonstrated that the most significant influential factor on the repeated spa visits is a memorable experience of which showed 13.7 times higher probability than the reference up-to-date facility. The details of memorable experiences were discovered throughout the interviews that include the rediscovery of self, feeling of connectedness, recharge for positive emotions, self-reward through escapism, and experience of noncommercialized local products and attractions. Therefore, using experiential marketing methods can be effective spa service marketing.

  8. The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson disease: Clinical and imaging Studies.

    Science.gov (United States)

    Pont-Sunyer, Claustre; Tolosa, Eduardo; Caspell-Garcia, Chelsea; Coffey, Christopher; Alcalay, Roy N; Chan, Piu; Duda, John E; Facheris, Maurizio; Fernández-Santiago, Rubén; Marek, Kenneth; Lomeña, Francisco; Marras, Connie; Mondragon, Elisabet; Saunders-Pullman, Rachel; Waro, Bjorg

    2017-05-01

    Asymptomatic, nonmanifesting carriers of leucine-rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD. To investigate clinical and dopamine transporter single-photon emission computed tomography imaging characteristics of leucine-rich repeat kinase 2 asymptomatic carriers. A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine-rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine-rich repeat kinase 2/PD patients were evaluated. Motor and nonmotor symptoms were assessed using specific scales and questionnaires. Neuroimaging quantitative data were obtained in 81 carriers and compared with 41 noncarriers. G2019S carriers scored higher in motor scores and had lower radioligand uptake compared to noncarriers, but no differences in nonmotor symptoms scores were observed. R1441G carriers scored higher in motor scores, had lower radioligand uptake, and had higher scores in depression, dysautonomia, and Rapid Eye Movements Sleep Behavior Disorder Screening Questionnaire scores, but had better cognition scores than noncarriers. Among G2019S carriers, a group with "mild motor signs" was identified, and was significantly older, with worse olfaction and lower radioligand uptake. G2019S and R1441G carriers differ from their noncarriers' relatives in higher motor scores and slightly lower radioligand uptake. Nonmotor symptoms were mild, and different nonmotor profiles were observed in G2019S carriers compared to R1441G carriers. A group of G2019S carriers with known prodromal features was identified. Longitudinal studies are required to determine whether such individuals are at short-term risk of developing overt parkinsonism. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

  9. Variability in prefrontal hemodynamic response during exposure to repeated self-selected music excerpts, a near-infrared spectroscopy study.

    Directory of Open Access Journals (Sweden)

    Saba Moghimi

    Full Text Available Music-induced brain activity modulations in areas involved in emotion regulation may be useful in achieving therapeutic outcomes. Clinical applications of music may involve prolonged or repeated exposures to music. However, the variability of the observed brain activity patterns in repeated exposures to music is not well understood. We hypothesized that multiple exposures to the same music would elicit more consistent activity patterns than exposure to different music. In this study, the temporal and spatial variability of cerebral prefrontal hemodynamic response was investigated across multiple exposures to self-selected musical excerpts in 10 healthy adults. The hemodynamic changes were measured using prefrontal cortex near infrared spectroscopy and represented by instantaneous phase values. Based on spatial and temporal characteristics of these observed hemodynamic changes, we defined a consistency index to represent variability across these domains. The consistency index across repeated exposures to the same piece of music was compared to the consistency index corresponding to prefrontal activity from randomly matched non-identical musical excerpts. Consistency indexes were significantly different for identical versus non-identical musical excerpts when comparing a subset of repetitions. When all four exposures were compared, no significant difference was observed between the consistency indexes of randomly matched non-identical musical excerpts and the consistency index corresponding to repetitions of the same musical excerpts. This observation suggests the existence of only partial consistency between repeated exposures to the same musical excerpt, which may stem from the role of the prefrontal cortex in regulating other cognitive and emotional processes.

  10. Effect of repeated morphine withdrawal on spatial learning, memory and serum cortisol level in mice

    OpenAIRE

    Mahdieh Matinfar; Mahsa Masjedi Esfahani; Neda Aslany; Seyyed Hamid Reza Davoodi; Pouya Parsaei; Ghasem Zarei; Parham Reisi

    2013-01-01

    Background: One of the serious problems that opioid addicted people are facing is repeated withdrawal syndrome that is accompanying with a significant stress load for addicts. Therefore, the aim of this study was to evaluate the effects of repeated withdrawal on spatial learning, memory and serum cortisol levels in morphine-dependent mice. Materials and Methods: Male NMRI mice received morphine as daily increasing doses for 3 days. After that, the mice underwent one time or repeated spont...

  11. Retrospective study on the dose assessment in Algeria over a period 1998-2002

    Energy Technology Data Exchange (ETDEWEB)

    Boudena, B.; Chalal, M.; Bellal, A.; Imatoukene, D. [Nuclear Research Center of Algiers (Algeria)

    2006-07-01

    Full text: In Algeria, the assessment of individual doses of workers occupationally exposed to external radiations is made by the national individual monitoring service at the Nuclear Research Center of Algiers (N.R.C.A.) with photographic dosimeter. In this paper, we have undertaken a retrospective study on dose assessment of workers exposed to external radiations involved in medical and industrial activities according to the new occupational dose limits over a period of five consecutive years (1998 2002). This survey has permitted to observe the impact that would have new dose limits once adopted by our legislation. (author)

  12. Dosimetry for a study of low-dose radiation cataracts among Chernobyl clean-up workers.

    Science.gov (United States)

    Chumak, V V; Worgul, B V; Kundiyev, Y I; Sergiyenko, N M; Vitte, P M; Medvedovsky, C; Bakhanova, E V; Junk, A K; Kyrychenko, O Y; Musijachenko, N V; Sholom, S V; Shylo, S A; Vitte, O P; Xu, S; Xue, X; Shore, R E

    2007-05-01

    A cohort of 8,607 Ukrainian Chernobyl clean-up workers during 1986-1987 was formed to study cataract formation after ionizing radiation exposure. Study eligibility required the availability of sufficient exposure information to permit the reconstruction of doses to the lens of the eye. Eligible groups included civilian workers, such as those who built the "sarcophagus" over the reactor, Chernobyl Nuclear Power Plant Workers, and military reservists who were conscripted for clean-up work. Many of the official doses for workers were estimates, because only a minority wore radiation badges. For 106 military workers, electron paramagnetic resonance (EPR) measurements of extracted teeth were compared with the recorded doses as the basis to adjust the recorded gamma-ray doses and provide estimates of uncertainties. Beta-particle doses to the lens were estimated with an algorithm devised to take into account the nature and location of Chernobyl work, time since the accident, and protective measures taken. A Monte Carlo routine generated 500 random estimates for each individual from the uncertainty distributions of the gamma-ray dose and of the ratio of beta-particle to gamma-ray doses. The geometric mean of the 500 combined beta-particle and gamma-ray dose estimates for each individual was used in the data analyses. The median estimated lens dose for the cohort was 123 mGy, while 4.4% received >500 mGy.

  13. PCR bias in amplification of androgen receptor alleles, a trinucleotide repeat marker used in clonality studies.

    Science.gov (United States)

    Mutter, G L; Boynton, K A

    1995-04-25

    Trinucleotide CAG repeats in the X-linked human androgen receptor gene (HUMARA) have proved a useful means of determining X chromosome haplotypes, and when combined with methylation analysis of nearby cytosine residues permits identification of non-random X inactivation in tumors of women. Co-amplification of two alleles in a heterozygote generates PCR products which differ in the number of CAG units, and thus their melting and secondary structure characteristics. We have shown that under optimal conditions amplification efficiency of two HUMARA alleles is near-equivalent, generating PCR products in a ratio proportional to that of the genomic template. In contrast, reduction of template quantity, damage of template by ultraviolet irradiation or addition of monovalent salts (sodium chloride, sodium acetate or ammonium acetate) produces highly variable imbalances of allelic PCR products, with a strong tendency to preferentially amplify lower molecular weight alleles. Variability and biasing was diminished by substitution of 7-deaza-2'-dGTP for dGTP during amplification, an intervention which reduces stability of intramolecular and intermolecular GC base pairing. We conclude that DNA which is scanty, damaged or salt contaminated may display amplification bias of GC-rich PCR targets, potentially confounding accurate interpretation or reproducibility of assays which require co-amplification of alleles.

  14. Analyzing repeated measures semi-continuous data, with application to an alcohol dependence study.

    Science.gov (United States)

    Liu, Lei; Strawderman, Robert L; Johnson, Bankole A; O'Quigley, John M

    2016-02-01

    Two-part random effects models (Olsen and Schafer,(1) Tooze et al.(2)) have been applied to repeated measures of semi-continuous data, characterized by a mixture of a substantial proportion of zero values and a skewed distribution of positive values. In the original formulation of this model, the natural logarithm of the positive values is assumed to follow a normal distribution with a constant variance parameter. In this article, we review and consider three extensions of this model, allowing the positive values to follow (a) a generalized gamma distribution, (b) a log-skew-normal distribution, and (c) a normal distribution after the Box-Cox transformation. We allow for the possibility of heteroscedasticity. Maximum likelihood estimation is shown to be conveniently implemented in SAS Proc NLMIXED. The performance of the methods is compared through applications to daily drinking records in a secondary data analysis from a randomized controlled trial of topiramate for alcohol dependence treatment. We find that all three models provide a significantly better fit than the log-normal model, and there exists strong evidence for heteroscedasticity. We also compare the three models by the likelihood ratio tests for non-nested hypotheses (Vuong(3)). The results suggest that the generalized gamma distribution provides the best fit, though no statistically significant differences are found in pairwise model comparisons.

  15. NMR studies on domain diffusion and alignment in modular GB1 repeats.

    Science.gov (United States)

    Walsh, Joseph D; Meier, Katlyn; Ishima, Rieko; Gronenborn, Angela M

    2010-10-20

    Modular proteins contain individual domains that are often connected by flexible, unstructured linkers. Using a model system based on the GB1 domain, we constructed tandem repeat proteins and investigated the rotational diffusion and long-range angular ordering behavior of individual domains by measuring NMR relaxation parameters and residual dipolar couplings. Although they display almost identical protein-solvent interfaces, each domain exhibits distinct rotational diffusion and alignment properties. The diffusion tensor anisotropy of the N-terminal domain (NTD) is D(‖)/D(⊥) = 1.5-1.6, similar to that of single-GB1 domains (D(‖)/D(⊥) = 1.6-1.7), whereas the value for the C-terminal domain (CTD) is D(‖)/D(⊥) = 2.0-2.2. In addition, the two domains have different rotational correlation times. These effects are observed for linkers of three to 24 residues, irrespective of linker length. The NTD and CTD also differ in their degree of magnetic alignment, even with a flexible linker of 18 residues, exhibiting D(a) values of 7.7 Hz and 9.7 Hz, respectively. Our results suggest that diffusion differences and long-range influences may persist in modular protein systems, even for systems that have highly flexible linkers and exhibit no domain-domain or domain-linker interactions.

  16. Comparison in the calculation of committed effective dose using the ICRP 30 and ICRP 60 models for a repeated incorporation by inhalation of I-125; Comparacion en el calculo de la dosis efectiva comprometida usando los modelos del ICRP 30 y del ICRP 60 para una incorporacion repetida por inhalacion de I-125

    Energy Technology Data Exchange (ETDEWEB)

    Carreno P, A.L.; Cortes C, A. [CNSNS, Dr. Barragan 779, Col. Narvarte, Mexico D.F. (Mexico); Alonso V, G.; Serrano P, F. [IPN, Edificio de Fisica Avanzada Zacatenco, 07300 Mexico D.F. (Mexico)

    2005-07-01

    Presently work, a comparison in the calculation of committed effective dose using the models of the ICRP 30 and those of the ICRP 60 for the analysis of internal dose due to repeated incorporation of I-125 is shown. The estimations of incorporated activity are obtained starting from the proportionate data for an exercise of inter comparison, with which it should be determined the internal dose later on. For to estimate the initial activity incorporated by repeated dose was assumed that this it was given through of multiple individual incorporations which happened in the middle points of the monitoring periods. The results using the models of the ICRP 30 and of the ICRP 60 are compared and the causes of the differences are analyzed. (Author)

  17. Does sequential embryo transfer improve pregnancy rate in patients with repeated implantation failure? A randomized control study

    Directory of Open Access Journals (Sweden)

    Wael A. Ismail Madkour

    2015-12-01

    Full Text Available Background: Repeated failure of in vitro fertilization treatment is frustrating to the patients and their clinicians. Various treatment plans and a change of protocol have been suggested for “low responders”; however, patients who fail treatment repeatedly inspite of good quality embryos pose a special therapeutic challenge. Additional challenge would be imposed on that particular group when the local IVF regulating low does not permit surplus embryo freezing. Objective: To examine whether sequential transfer of embryos on day 3 and on day 5 after ovum pick-up improves IVF/ET success rates in patients with repeated consecutive IVF failures (⩾ 3 trials compared to day 3 alone, with the background that local regulation prohibits embryo freezing. Study design: Randomized controlled study. Women scheduled for IVF/ET with repeated consecutive IVF failures (⩾ 3 trials were randomized to either sequential transfer of embryos on day 3 and on day 5 after ovum pick-up (Group I = 74 or conventional day 3 transfer (Group II = 73 as a control. The primary outcome measures were clinical pregnancy rate and implantation rate. The secondary outcome measures were ongoing pregnancy rate and early pregnancy loss. Results: Baseline and cycle characteristics were comparable in both groups. Clinical pregnancy rate (per embryo transfer was significantly higher in sequential ET group (37. 8% compared to that in day 3 group (21.9% (P value <0.05. Also, implantation rate (per embryos transferred was significantly higher in sequential ET group (17.1% compared to that in control group (10.5% (P value <0.01. Similarly, ongoing pregnancy (per embryo transfer was significantly higher in sequential ET group (33. 8% compared to that in day 3 group (19.2% (P value <0.05. Conclusions: Patients with repeated implantation failures, treatment with the sequential embryo transfer approach had significantly improved pregnancy outcomes compared to regular day 3 transfers

  18. Dose response studies and longterm evaluation of auranofin in rheumatoid arthritis.

    Science.gov (United States)

    Champion, G D; Cairns, D R; Bieri, D; Adena, M A; Browne, C D; Cohen, M L; Day, R O; Edmonds, J P; Graham, G G; de Jager, J

    1988-01-01

    Fifty-eight patients with rheumatoid arthritis (RA) entered a double blind trial of auranofin (AF) designed to assess dose response relationships and longterm outcome. Multivariate analysis of repeated measures with trend analysis and discriminant function analysis of standard measures of RA activity were applied to a randomized double blind trial of AF at daily doses of 4, 6 and 8 mg over 6 months. Improvement occurred in each group. There was a highly significant (p less than 0.001) linear trend in the 6 mg group, 73% of whom showed linear improvement. A significant correlation (p less than 0.05) was found between response of individual patients and AF dose (mg/kg/day), but there was no significant correlation between dosage and mean steady state serum gold concentration. No significant correlation was seen between outcome and pretreatment demographic and disease variables. In a subsequent 6 month phase of dosage adjustment, aiming for optimal dosage, no advantage resulted from increasing the dose above 6 mg/day. Patients apparently benefiting from treatment continued an open long-term trial of AF. By 45 months, 33.5% had stopped treatment due to lack of efficacy and 14.5% due to toxicity, mainly rash and diarrhea.

  19. A Comparative Study of Vaginal Misoprostol and High Dose Intravenous Oxytocin for Second Trimester Pregnancy Termination

    Directory of Open Access Journals (Sweden)

    M. Rajaee

    2010-04-01

    Full Text Available Introduction & Objective: Second trimester labor induction is a major problem in obstetrics and is the cause of two-thirds of all abortion related complications and more than half of the maternal deaths associated with abortion. The goal of this study was to compare the effectiveness of vaginal misoprostol and intravenous oxytocin for termination of second trimester pregnancy.Materials & Methods: One hundred women were allocated in a randomized controlled way to one of the two induction groups: oxytocin group patients initially received an infusion of 50 units of oxytocin in 500 ml of ringer over 3 hours, 1 hour of no oxytocin followed by alternating 3 hours of oxytocin with 1 hour of rest. Oxytocin was increased by 50 units in each successive period until a final concentration of 300 units per 500 ml has been reached. Another group received 200 µg misoprostol tablets in posterior fornix vagina and was repeated after 12 hours if needed. The two groups were compared for induction to delivery intervals and their safety during induction. Results: The success rate within 24 hours of induction was 94% in the misoprostol group and 86% in oxytocin group (p= 0.182. The mean induction to delivery time was significantly longer in the oxytocin group compared with the misoprostol group.(13.5 versus 9.93 hours ; P=0.0057. Retained placenta requiring curettage was lower in the misoprostol group than the oxytocin group.Conclusion: Intravaginal misoprostol is more effective than high dose intravenous oxytocin in women with second trimester termination.

  20. Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

    Science.gov (United States)

    Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

    2012-01-01

    Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

  1. Comparison of image quality in head CT studies with different dose-reduction strategies

    DEFF Research Database (Denmark)

    Johansen, Jeppe; Nielsen, Rikke; Fink-Jensen, Vibeke

    -reduction maneuvers is reduction of image quality due to image noise or artifacts. The aim of our study was therefore to find the best diagnostic images with lowest possible dose. We present results of dose- and image quality optimizing strategies of brain CT examinations at our institution. We compare sequential...

  2. Serum 25 hydroxyvitamin D profile after single large oral doses of cholecalciferol (vitamin D3 in medical staff in North India: A pilot study

    Directory of Open Access Journals (Sweden)

    L Priyambada

    2014-01-01

    Full Text Available Background: Vitamin D deficiency is widely prevalent in India and subjects who have almost no exposure to sunlight are severely deficient. Daily oral doses of cholecalciferol (vitamin D3 are costly as compared to stoss doses and further, take a long time for the serum levels to reach a plateau. Compliance to supplementation may also be better if a regimen involves single oral doses of vitamin D at specified intervals rather than daily doses. Evidence-based guidelines regarding the dosing and the frequency of dosing for prophylactic intermittent supplementation (stoss doses in severely-deficient subjects are few. Materials and Methods: In a prospective intervention study, we serially assessed 30 asymptomatic healthy medical staff for serum 25-hydroxyvitamin D [25(OHD] and parathyroid hormone (PTH; (a at baseline; (b monthly for 3 months after single oral 60,000 units (U cholecalciferol; (c monthly for 3 months after 120,000 (or 180,000 for those with elevated alkaline phosphatase U cholecalciferol; and, (d subsequently, at 3 months after a repeat dose of 60,000 U cholecalciferol by repeated measures analysis of variance. Results: The baseline serum 25(OHD was 7.1 ± 5.4 ng/mL (< 10 ng/mL in 85% subjects which increased to 18.7 ± 8.9 ng/mL at 1 month after 60,000 U of cholecalciferol (P < 0.001 and decreased to 11.1 ± 5.3 ng/mL by the 3 rd month. The higher dose of 120,000 (or 180,000 U increased mean 25(OHD to 28.9 ± 9.9 ng/mL at the end of 1 st month, declining to 17.9 ± 4.9 ng/mL (P < 0.001 at 3 months. With the subsequent 60,000 U the serum 25(OHD was 18.4 ± 3.9 ng/mL at 3 months. PTH showed a corresponding negative trend. No hypercalcemia was observed. Conclusions: Vitamin D deficiency is highly prevalent amongst medical staff in Northern India. An initial dose of 120,000-180,000 U of cholecalciferol is required to elevate 25(OHD out of the deficiency range. Maintenance dose is needed at 2 months.

  3. Implications of Intercellular Signaling for Radiation Therapy: A Theoretical Dose-Planning Study

    Energy Technology Data Exchange (ETDEWEB)

    McMahon, Stephen J., E-mail: stephen.mcmahon@qub.ac.uk [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); McGarry, Conor K. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, Northern Ireland (United Kingdom); Butterworth, Karl T. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); O' Sullivan, Joe M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Clinical Oncology, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, Northern Ireland (United Kingdom); Hounsell, Alan R. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom); Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, Northern Ireland (United Kingdom); Prise, Kevin M. [Centre for Cancer Research and Cell Biology, Queen' s University Belfast, Belfast, Northern Ireland (United Kingdom)

    2013-12-01

    Purpose: Recent in vitro results have shown significant contributions to cell killing from signaling effects at doses that are typically used in radiation therapy. This study investigates whether these in vitro observations can be reconciled with in vivo knowledge and how signaling may have an impact on future developments in radiation therapy. Methods and Materials: Prostate cancer treatment plans were generated for a series of 10 patients using 3-dimensional conformal therapy, intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy techniques. These plans were evaluated using mathematical models of survival following modulated radiation exposures that were developed from in vitro observations and incorporate the effects of intercellular signaling. The impact on dose–volume histograms and mean doses were evaluated by converting these survival levels into “signaling-adjusted doses” for comparison. Results: Inclusion of intercellular communication leads to significant differences between the signalling-adjusted and physical doses across a large volume. Organs in low-dose regions near target volumes see the largest increases, with mean signaling-adjusted bladder doses increasing from 23 to 33 Gy in IMRT plans. By contrast, in high-dose regions, there is a small decrease in signaling-adjusted dose due to reduced contributions from neighboring cells, with planning target volume mean doses falling from 74 to 71 Gy in IMRT. Overall, however, the dose distributions remain broadly similar, and comparisons between the treatment modalities are largely unchanged whether physical or signaling-adjusted dose is compared. Conclusions: Although incorporating cellular signaling significantly affects cell killing in low-dose regions and suggests a different interpretation for many phenomena, their effect in high-dose regions for typical planning techniques is comparatively small. This indicates that the significant signaling effects observed in vitro

  4. Multiple dose study of the combined radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole)

    Energy Technology Data Exchange (ETDEWEB)

    Bleehen, N.M.; Newman, H.F.; Maughan, T.S.; Workman, P.

    1989-04-01

    The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

  5. Limiting CT radiation dose in children with craniosynostosis: phantom study using model-based iterative reconstruction

    Energy Technology Data Exchange (ETDEWEB)

    Kaasalainen, Touko; Lampinen, Anniina [University of Helsinki and Helsinki University Hospital, HUS Medical Imaging Center, Radiology, POB 340, Helsinki (Finland); University of Helsinki, Department of Physics, Helsinki (Finland); Palmu, Kirsi [University of Helsinki and Helsinki University Hospital, HUS Medical Imaging Center, Radiology, POB 340, Helsinki (Finland); School of Science, Aalto University, Department of Biomedical Engineering and Computational Science, Helsinki (Finland); Reijonen, Vappu; Kortesniemi, Mika [University of Helsinki and Helsinki University Hospital, HUS Medical Imaging Center, Radiology, POB 340, Helsinki (Finland); Leikola, Junnu [University of Helsinki and Helsinki University Hospital, Department of Plastic Surgery, Helsinki (Finland); Kivisaari, Riku [University of Helsinki and Helsinki University Hospital, Department of Neurosurgery, Helsinki (Finland)

    2015-09-15

    Medical professionals need to exercise particular caution when developing CT scanning protocols for children who require multiple CT studies, such as those with craniosynostosis. To evaluate the utility of ultra-low-dose CT protocols with model-based iterative reconstruction techniques for craniosynostosis imaging. We scanned two pediatric anthropomorphic phantoms with a 64-slice CT scanner using different low-dose protocols for craniosynostosis. We measured organ doses in the head region with metal-oxide-semiconductor field-effect transistor (MOSFET) dosimeters. Numerical simulations served to estimate organ and effective doses. We objectively and subjectively evaluated the quality of images produced by adaptive statistical iterative reconstruction (ASiR) 30%, ASiR 50% and Veo (all by GE Healthcare, Waukesha, WI). Image noise and contrast were determined for different tissues. Mean organ dose with the newborn phantom was decreased up to 83% compared to the routine protocol when using ultra-low-dose scanning settings. Similarly, for the 5-year phantom the greatest radiation dose reduction was 88%. The numerical simulations supported the findings with MOSFET measurements. The image quality remained adequate with Veo reconstruction, even at the lowest dose level. Craniosynostosis CT with model-based iterative reconstruction could be performed with a 20-μSv effective dose, corresponding to the radiation exposure of plain skull radiography, without compromising required image quality. (orig.)

  6. Evaluation of exposure dose to patients undergoing catheter ablation procedures - a phantom study

    Energy Technology Data Exchange (ETDEWEB)

    Seguchi, S. [Nagoya University, Graduate School of Medicine, Nagoya (Japan); Nagoya Daini Red Cross Hospital, Division of Radiology, Department of Medical Technology, Nagoya (Japan); Aoyama, T.; Koyama, S.; Kawaura, C. [Nagoya University, Graduate School of Medicine, Nagoya (Japan); Fujii, K. [Nagoya University, Graduate School of Medicine, Nagoya (Japan); National Institute of Radiological Sciences, Section of Radiological Protection, Chiba (Japan)

    2008-11-15

    The aim of this study was to evaluate entrance skin dose (ESD), organ dose and effective dose to patients undergoing catheter ablation for cardiac arrhythmias, based on the dosimetry in an anthropomorphic phantom. ESD values associated with mean fluoroscopy time and digital cine frames were in a range of 0.12-0.30 Gy in right anterior oblique (RAO) and 0.05-0.40 Gy in left anterior oblique (LAO) projection, the values which were less than a threshold dose of 2 Gy for the onset of skin injury. Organs that received high doses in ablation procedures were lung, followed by bone surface, esophagus, liver and red bone marrow. Doses for lung were 24.8-122.7 mGy, and effective doses were 7.9-34.8 mSv for mean fluoroscopy time of 23.4-92.3 min and digital cine frames of 263-511. Conversion coefficients of dose-area product (DAP) to ESD were 8.7 mGy/(Gy.cm{sup 2}) in RAO and 7.4 mGy/(Gy.cm{sup 2}) in LAO projection. The coefficients of DAP to the effective dose were 0.37 mSv/(Gy.cm{sup 2}) in RAO, and 0.41 mSv/(Gy.cm{sup 2}) in LAO projection. These coefficients enabled us to estimate patient exposure in real time by using monitored values of DAP. (orig.)

  7. Prescribing patterns, adherence and LDL-cholesterol response of type 2 diabetes patients initiating statin on low-dose versus standard-dose treatment : a descriptive study

    NARCIS (Netherlands)

    de Vries, F M; Voorham, J; Hak, E; Denig, P

    2016-01-01

    AIMS: The aim of this study was to describe and compare treatment modifications and discontinuation, adherence levels and response to treatment in patients with type 2 diabetes initiating on low-dose vs. standard-dose statin treatment. METHODS: A 2-year follow-up cohort study was performed using dat

  8. Repeated treatments of drooling with botulinum toxin B in neurology

    DEFF Research Database (Denmark)

    Møller, Eigild; Daugaard, Dorthe; Holm, Ole

    2015-01-01

    OBJECTIVES: To investigate efficacy, saliva flow, and composition in repeated BoNT-B treatments of drooling. MATERIALS AND METHODS: Seventeen neurological patients (median 66 years), referred for treatment of drooling participated in this observational study. Median total doses of 4000 units...

  9. Cardiac CT: are we underestimating the dose? A radiation dose study utilizing the 2007 ICRP tissue weighting factors and a cardiac specific scan volume

    Energy Technology Data Exchange (ETDEWEB)

    Gosling, O., E-mail: Oliver.gosling@pms.ac.u [Plymouth Hospitals NHS Trust, Derriford Hospital, Plymouth, Devon (United Kingdom); Loader, R.; Venables, P.; Rowles, N.; Morgan-Hughes, G. [Plymouth Hospitals NHS Trust, Derriford Hospital, Plymouth, Devon (United Kingdom); Roobottom, C. [Peninsula College of Medicine and Dentistry, University of Plymouth, Devon (United Kingdom)

    2010-12-15

    Aim: To calculate the effective dose from cardiac multidetector computed tomography (MDCT) using a computer-based model utilizing the latest International Commission on Radiation Protection (ICRP) 103 tissue-weighting factors (2007), to compare this dose with those calculated with previously published chest conversion factors and to produce a conversion factor specific for cardiac MDCT. Materials and methods: An observational study of 152 patients attending for cardiac MDCT as part of their usual clinical care in a university teaching hospital. The dose for each examination was calculated using the computer-based anthropomorphic ImPACT model (the imaging performance assessment of CT scanners) and this was compared with the dose derived from the dose-length product (DLP) and a chest conversion factor. Results: The median effective dose calculated using the ImPACT calculator (4.5 mSv) was significantly higher than the doses calculated with the chest conversion factors (2.2-3 mSv). Conclusion: The use of chest conversion factors significantly underestimates the effective dose when compared to the dose calculated using the ImPACT calculator. A conversion factor of 0.028 would give a better estimation of the effective dose from prospectively gated cardiac MDCT.

  10. Thirteen-week oral dose toxicity study of Oligonol containing oligomerized polyphenols extracted from lychee and green tea.

    Science.gov (United States)

    Kitadate, Kentaro; Homma, Kohei; Roberts, Ashley; Maeda, Takahiro

    2014-02-01

    Oligonol is a functional food containing catechin-type monomers and proanthocyanidin oligomer converted from polymer forms via a novel manufacturing process. The catechin component of green tea extract has been associated with nasal toxicity in rats following subchronic exposure. To assess the potential for Oligonol to induce nasal toxicity a 13-week repeated oral dose toxicity study was conducted in rats using doses of 100, 300, and 1000 mg/kg/d. Clinical signs and mortality were not affected by Oligonol treatment. Compound-colored stools and an increase in food consumption were observed in some treated groups; however, there were no treatment-related differences in terminal body weights or with respect to the results of the gross postmortem examinations. Histopathological evaluation of the nasal cavity tissues revealed no treatment-related lesions. The results from this toxicity study indicate that Oligonol does not induce nasal toxicity and further supports the results of previous studies demonstrating the safety of Oligonol for human consumption.

  11. Intestinal biospy in children with coeliac disease; a Swedish national study of radiation dose and risk

    Energy Technology Data Exchange (ETDEWEB)

    Persliden, J.; Pettersson, H.B.L. [Linkoeping Univ. (Sweden). Dept. of Radiation Physics; Faelth-Magnusson, K. [University of Linkoeping (Sweden). Faculty of Health Sciences

    1995-12-31

    In paediatric patients, fluoroscopy is used to monitor intestinal biopsies obtained for the diagnosis of coeliac disease. The radiation dose to the child is dependent on the equipment, the sedation of the patient and the experience of the operator. This study presents patient measurements from a national study in Sweden. The cancer excess lifetime mortality risk (CELMR) and the loss of life expectancy (LLE) are calculated for this patient group. TLD measurements were performed by dosemeters at 40 Swedish paediatric departments performing these biopsies. Information was received on sedation techniques, equipment used and fluoroscopy duration. An exponential curve fit was applied to the entrance and exit dose values and this dose distribution was integrated to get the integral dose. From this the mean absorbed dose in the irradiated volume was calculated. The mean and the median of the mean absorbed dose in the irradiated volume to the children was found to be 1.3 mGy (range 0.05-17.5 mGy) and 0.56 mGy respectively. The mean value of the entrance surface dose was 3.0 mGy (range 0.10-27.1 mGy) and the median was 1.4 mGy. The annual collective dose was calculated to 3.3 man Gy, based on 2500 biopsies per year. Variation in doses was found to depend on, e.g. the age of the equipment, focus to patient distance, sedation and operator experience. With this knowledge of doses received by the children in the diagnosis of coeliac disease, CELMR was found to be 0.5 per 25000 biopsies and LLE was 18 years. Recommendations are given on the proper choice of equipment for the reduction of fluoroscopy doses in pediatric radiology. (Author).

  12. Phase I study of continuous weekly dosing of dimethylamino benzoylphenylurea (BPU) in patients with solid tumours.

    Science.gov (United States)

    Messersmith, Wells A; Rudek, Michelle A; Baker, Sharyn D; Zhao, Ming; Collins, Connie; Colevas, A Dimitrios; Donehower, Ross C; Carducci, Michael A; Wolff, Antonio C

    2007-01-01

    A phase I study of dimethylamino benzoylphenylurea (BPU), a tubulin inhibitor, was performed using a weekly continuous schedule. Patients with refractory solid tumours received oral BPU once weekly without interruption at doses ranging from 5 to 320mg using an accelerated titration design. Nineteen subjects received 54 cycles of BPU. Early pharmacokinetic findings of decreased clearance with increasing dose and plasma accumulation led to the expansion of the 320mg dose level. Two subjects then developed late haematologic dose-limiting toxicities (DLTs) that were associated with the highest plasma exposure to BPU and metabolites. Study enrollment resumed at dose 150mg with real-time pharmacokinetic monitoring. Seven additional subjects (6 evaluable) were treated for a median of 2 cycles (range 1.5-4) without further myelotoxicity. A long half-life and accumulation of BPU and active metabolites were observed, recommending against a continuous administration. Weekly oral BPU therapy should be further tested using an interrupted schedule.

  13. GSTM1 and APE1 genotypes affect arsenic-induced oxidative stress: a repeated measures study

    Directory of Open Access Journals (Sweden)

    Quamruzzaman Quazi

    2007-12-01

    Full Text Available Abstract Background Chronic arsenic exposure is associated with an increased risk of skin, bladder and lung cancers. Generation of oxidative stress may contribute to arsenic carcinogenesis. Methods To investigate the association between arsenic exposure and oxidative stress, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG was evaluated in a cohort of 97 women recruited from an arsenic-endemic region of Bangladesh in 2003. Arsenic exposure was measured in urine, toenails, and drinking water. Drinking water and urine samples were collected on three consecutive days. Susceptibility to oxidative stress was evaluated by genotyping relevant polymorphisms in glutathione-s transferase mu (GSTM1, human 8-oxoguanine glycosylase (hOGG1 and apurinic/apyrimidinic endonuclease (APE1 genes using the Taqman method. Data were analyzed using random effects Tobit regression to account for repeated measures and 8-OHdG values below the detection limit. Results A consistent negative effect for APE1 was observed across water, toenail and urinary arsenic models. APE1 148 glu/glu + asp/glu genotype was associated with a decrease in logged 8-OHdG of 0.40 (95%CI -0.73, -0.07 compared to APE1 148 asp/asp. An association between total urinary arsenic and 8-OHdG was observed among women with the GSTM1 null genotype but not in women with GSTM1 positive. Among women with GSTM1 null, a comparison of the second, third, and fourth quartiles of total urinary arsenic to the first quartile resulted in a 0.84 increase (95% CI 0.27, 1.42, a 0.98 increase (95% CI 033, 1.66 and a 0.85 increase (95% CI 0.27, 1.44 in logged 8-OHdG, respectively. No effects between 8-OHdG and toenail arsenic or drinking water arsenic were observed. Conclusion These results suggest the APE1 variant genotype decreases repair of 8-OHdG and that arsenic exposure is associated with oxidative stress in women who lack a functional GSTM1 detoxification enzyme.

  14. Improving the reliability of aquatic toxicity testing of hydrophobic chemicals via equilibrium passive dosing - A multiple trophic level case study on bromochlorophene.

    Science.gov (United States)

    Stibany, Felix; Ewald, Franziska; Miller, Ina; Hollert, Henner; Schäffer, Andreas

    2017-01-28

    The main objective of the present study was to improve the reliability and practicability of aquatic toxicity testing of hydrophobic chemicals based upon the model substance bromochlorophene (BCP). Therefore, we adapted a passive dosing format to test the toxicity of BCP at different concentrations and in multiple test systems with aquatic organisms of various trophic levels. At the same time, the method allowed for the accurate determination of exposure concentrations (i.e., in the presence of exposed organisms; Ctest) and freely dissolved concentrations (i.e., without organisms present; Cfree) of BCP in all tested media. We report on the joint adaptation of three ecotoxicity tests - algal growth inhibition, Daphnia magna immobilization, and fish-embryo toxicity - to a silicone O-ring based equilibrium passive dosing format. Effect concentrations derived by passive dosing methods were compared with corresponding effect concentrations derived by standard co-solvent setups. The passive dosing format led to EC50-values in the lower μgL(-1) range for algae, daphnids, and fish embryos, whereas increased effect concentrations were measured in the co-solvent setups for algae and daphnids. This effect once more shows that passive dosing might offer advantages over standard methods like co-solvent setups when it comes to a reliable risk assessment of hydrophobic substances. The presented passive dosing setup offers a facilitated, practical, and repeatable way to test hydrophobic chemicals on their toxicity to aquatic organisms, and is an ideal basis for the detailed investigation of this important group of chemicals.

  15. [A case-control study of factors associated with repeat teen pregnancy based on a sample from a university maternity hospital].

    Science.gov (United States)

    Silva, Andréa de Albuquerque Arruda; Coutinho, Isabela C; Katz, Leila; Souza, Alex Sandro Rolland

    2013-03-01

    Repeat teen pregnancy is a frequent issue and is considered an aggravating factor for increased maternal and fetal morbidity and social problems. The aim of the study was to identify factors associated with repeat teen pregnancy. A case-control study was conducted in 90 postpartum adolescents with more than one pregnancy (cases) and 90 adult women with a history of only one pregnancy during adolescence (controls). Statistical analysis used hierarchical logistic regression with 5% significance. Early sexual initiation (< 15 years), early age at first pregnancy (< 16 years), not raising the children themselves, and low family income (< one minimum wage) were associated with repeat teenage pregnancy, while partner change was inversely associated. Repeat teen pregnancy was mainly associated with reproductive and socioeconomic factors. Partner change appeared as a protective factor. Measures should be adopted during the postpartum period of teenage mothers in order to avoid repeat pregnancy.

  16. NOTE: Study of Gafchromic® EBT film response over a large dose range

    Science.gov (United States)

    Martišíková, Mária; Jäkel, Oliver

    2010-05-01

    Presently Gafchromic EBT films are widely used for relative dose verification in standard radiation therapy using high-energy photons, inclusive IMRT. The use of films for dosimetry in medical ion beams is more complicated due to the strongly inhomogeneous dose deposition by ions on microscopic level. Track structure models, presently used to describe dosimeter response as a function of the ion field properties, are based on input information which can be obtained from the film response in photon beams. We therefore studied the performance of Gafchromic EBT films, ancestors of currently available EBT2 films, in 60Co photon beams. The dose-response curve was measured from 7.5 × 10-2 Gy to 3 × 104 Gy. The dynamic range, linearity and dose rate dependence of this calibration curve were studied. A high saturation dose of 3 × 103 Gy, and thus a large dynamic range, was observed. No signs of supralinearity and bleaching due to radiation were found. No dependence of the response on the dose rate at high dose rates and high doses was found. All those properties justify the use of simplified models of the film response to ions. Furthermore, fits of the calibration data by predictions of different models for signal creation mechanism of dosimetric materials were performed. The best description was found for the recently published gamma-distributed single-hit model which takes into account different sizes of the active centres.

  17. Prolonged Repeated Acupuncture Stimulation Induces Habituation Effects in Pain-Related Brain Areas: An fMRI Study

    Science.gov (United States)

    Li, Chuanfu; Yang, Jun; Park, Kyungmo; Wu, Hongli; Hu, Sheng; Zhang, Wei; Bu, Junjie; Xu, Chunsheng; Qiu, Bensheng; Zhang, Xiaochu

    2014-01-01

    Most previous studies of brain responses to acupuncture were designed to investigate the acupuncture instant effect while the cumulative effect that should be more important in clinical practice has seldom been discussed. In this study, the neural basis of the acupuncture cumulative effect was analyzed. For this experiment, forty healthy volunteers were recruited, in which more than 40 minutes of repeated acupuncture stimulation was implemented at acupoint Zhusanli (ST36). Three runs of acupuncture fMRI datasets were acquired, with each run consisting of two blocks of acupuncture stimulation. Besides general linear model (GLM) analysis, the cumulative effects of acupuncture were analyzed with analysis of covariance (ANCOVA) to find the association between the brain response and the cumulative duration of acupuncture stimulation in each stimulation block. The experimental results showed that the brain response in the initial stage was the strongest although the brain response to acupuncture was time-variant. In particular, the brain areas that were activated in the first block and the brain areas that demonstrated cumulative effects in the course of repeated acupuncture stimulation overlapped in the pain-related areas, including the bilateral middle cingulate cortex, the bilateral paracentral lobule, the SII, and the right thalamus. Furthermore, the cumulative effects demonstrated bimodal characteristics, i.e. the brain response was positive at the beginning, and became negative at the end. It was suggested that the cumulative effect of repeated acupuncture stimulation was consistent with the characteristic of habituation effects. This finding may explain the neurophysiologic mechanism underlying acupuncture analgesia. PMID:24821143

  18. Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Yan-Min Ma

    2014-06-01

    Full Text Available This study aimed to investigate the correlations among androgen receptor (AR CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and fifty-three healthy men (aged 22.8 ± 3.1 years were enrolled. The individuals were grouped as CAG short (CAG S if they harbored repeat length of ≤20 or as CAG long (CAG L if their CAG repeat length was >20. Body height/weight, penile length and other parameters were examined and recorded by the specified physicians; CAG repeat polymorphism was determined by the polymerase chain reaction (PCR method; and the serum levels of the sex hormones were detected by radioimmunoassay. Student's t-test or linear regression analysis was used to assess the associations among AR CAG repeat polymorphism, sex hormones and penile length. This investigation showed that the serum total testosterone (T level was positively associated with the AR CAG repeat length (P = 0.01; whereas, no significant correlation of T or AR CAG repeat polymorphism with the penile length was found (P = 0.593. Interestingly, an inverse association was observed between serum prolactin (PRL levels and penile length by linear regression analyses (β= −0.024, P = 0.039, 95% confidence interval (CI: −0.047, 0. Collectively, this study provides the first evidence that serum PRL, but not T or AR CAG repeat polymorphism, is correlated with penile length in the Han adult population from northwestern China.

  19. Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study.

    Science.gov (United States)

    Ma, Yan-Min; Wu, Kai-Jie; Ning, Liang; Zeng, Jin; Kou, Bo; Xie, Hong-Jun; Ma, Zhen-Kun; Wang, Xin-Yang; Gong, Yong-Guang; He, Da-Lin

    2014-01-01

    This study aimed to investigate the correlations among androgen receptor (AR) CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and fifty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAG S ) if they harbored repeat length of ≤ 20 or as CAG long (CAG L ) if their CAG repeat length was >20. Body height/weight, penile length and other parameters were examined and recorded by the specified physicians; CAG repeat polymorphism was determined by the polymerase chain reaction (PCR) method; and the serum levels of the sex hormones were detected by radioimmunoassay. Student's t-test or linear regression analysis was used to assess the associations among AR CAG repeat polymorphism, sex hormones and penile length. This investigation showed that the serum total testosterone (T) level was positively associated with the AR CAG repeat length (P = 0.01); whereas, no significant correlation of T or AR CAG repeat polymorphism with the penile length was found (P = 0.593). Interestingly, an inverse association was observed between serum prolactin (PRL) levels and penile length by linear regression analyses (β= -0.024, P = 0.039, 95% confidence interval (CI): -0.047, 0). Collectively, this study provides the first evidence that serum PRL, but not T or AR CAG repeat polymorphism, is correlated with penile length in the Han adult population from northwestern China.

  20. Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China:a cross-sectional study

    Institute of Scientific and Technical Information of China (English)

    YanMin Ma; DaLin He; KaiJie Wu; Liang Ning; Jin Zeng; Bo Kou; HongJun Xie; ZhenKun Ma; XinYang Wang; YongGuang Gong

    2014-01-01

    This study aimed to investigate the correlations among androgen receptor (AR) CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and iffty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAGS) if they harbored repeat length of≤20 or as CAG long (CAGL) if their CAG repeat length was>20. Body height/weight, penile length and other parameters were examined and recorded by the speciifed physicians;CAG repeat polymorphism was determined by the polymerase chain reaction (PCR) method;and the serum levels of the sex hormones were detected by radioimmunoassay. Student’s t-test or linear regression analysis was used to assess the associations among AR CAG repeat polymorphism, sex hormones and penile length. This investigation showed that the serum total testosterone (T) level was positively associated with the AR CAG repeat length (P= 0.01); whereas, no signiifcant correlation of T or AR CAG repeat polymorphism with the penile length was found (P= 0.593). Interestingly, an inverse association was observed between serum prolactin (PRL) levels and penile length by linear regression analyses (b=-0.024, P= 0.039, 95%conifdence interval (CI):-0.047, 0). Collectively, this study provides the ifrst evidence that serum PRL, but not T or AR CAG repeat polymorphism, is correlated with penile length in the Han adult population from northwestern China.

  1. Comparison of conventional and low dose steroid in the treatment of PFAPA syndrome: preliminary study.

    Science.gov (United States)

    Yazgan, Hamza; Gültekin, Erhan; Yazıcılar, Osman; Sagun, Ömer Faruk; Uzun, Lokman

    2012-11-01

    Steroids have been widely used to relief symptoms in the patients with PFAPA syndrome. This study was constructed to show the effectiveness of low-dose steroid therapy in patients diagnosed with PFAPA syndrome. 41 patients (86 febrile attacks) who were diagnosed using the criteria suggested by Thomas et al. were involved in the study. The cases were classified into two groups and the selection of patients in groups was made randomly. Twenty patients received prednisolone at a dose of 2 mg/kg/day (first group: 40 attacks) and 21 patients received a dose of 0.5 mg/kg/day (second group: 46 attacks). The effectiveness of the treatment was especially determined by the time needed to reduce the fever and the effect on the duration between the two attacks. The patients were re-examined 24 hours later, after a steroid treatment. The patients who were in the first group received 2mg/kg/day dose of prednisolone and their fever was dramatically decreased in 6-8 hours (7.6 ± 0.9 hours). The second group received 0.5mg/kg/day dose and 19 of these patients' fever was decreased in 8-12 hours. Two patients whose temperature did not decrease, received another dose of prednisolone 24 hours after the first dose and their fever was reduced 12 hours after the second dose (11.3 ± 6.4 hours). A comparison of the rate of fever reduction and the interval between the attacks (Group I: 5.11 ± 1.01 week and Group II: 5.2 ± 1.13 week) in the two groups did not show any statistical significance (p=0.104). Low-dose steroid treatment is as effective as normal dose in PFAPA syndrome but there is need to study with a larger group. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. A Phase I-II dose escalation study of fixed-dose rate gemcitabine, oxaliplatin and capecitabine every two weeks in advanced cholangiocarcinomas

    DEFF Research Database (Denmark)

    Lassen, Ulrik; Jensen, Lars Henrik; Sorensen, Morten;

    2011-01-01

    Gemcitabine based regimens have been widely used in patients with advanced cholangiocarcinoma (CC), but no standard therapy exists. In this study we aimed to find the maximally tolerated dose (MTD) of a two-week schedule of fixed dose rate (FDR) gemcitabine (G), oxaliplatin (O) and capecitabine (...

  3. Scattered dose to thyroid from prophylactic cranial irradiation during childhood: a Monte Carlo study.

    Science.gov (United States)

    Mazonakis, Michalis; Tzedakis, Antonis; Damilakis, John; Varveris, Haris; Kachris, Stefanos; Gourtsoyiannis, Nicholas

    2006-04-21

    The purpose of this study was to estimate the scattered dose to thyroid from prophylactic cranial irradiation during childhood. The MCNP transport code and mathematical phantoms representing the average individual at ages 3, 5, 10, 15 and 18 years old were employed to simulate cranial radiotherapy using two lateral opposed fields. The mean radiation dose received by the thyroid gland was calculated. A 10 cm thick lead block placed on the patient's couch to shield the thyroid was simulated by MCNP code. The Monte Carlo model was validated by measuring the scattered dose to the unshielded and shielded thyroid using three different humanoid phantoms and thermoluminescense dosimetry. For a cranial dose of 18 Gy, the thyroid dose obtained by Monte Carlo calculations varied from 47 to 79 cGy depending upon the age of the child. Appropriate placement of the couch block resulted in a thyroid dose reduction by 39 to 54%. Thyroid dose values at all possible positions of the radiosensitive gland with respect to the inferior field edge at five different patient ages were found. The mean difference between Monte Carlo results and thyroid dose measurements was 9.6%.

  4. NOTE: Scattered dose to thyroid from prophylactic cranial irradiation during childhood: a Monte Carlo study

    Science.gov (United States)

    Mazonakis, Michalis; Tzedakis, Antonis; Damilakis, John; Varveris, Haris; Kachris, Stefanos; Gourtsoyiannis, Nicholas

    2006-04-01

    The purpose of this study was to estimate the scattered dose to thyroid from prophylactic cranial irradiation during childhood. The MCNP transport code and mathematical phantoms representing the average individual at ages 3, 5, 10, 15 and 18 years old were employed to simulate cranial radiotherapy using two lateral opposed fields. The mean radiation dose received by the thyroid gland was calculated. A 10 cm thick lead block placed on the patient's couch to shield the thyroid was simulated by MCNP code. The Monte Carlo model was validated by measuring the scattered dose to the unshielded and shielded thyroid using three different humanoid phantoms and thermoluminescense dosimetry. For a cranial dose of 18 Gy, the thyroid dose obtained by Monte Carlo calculations varied from 47 to 79 cGy depending upon the age of the child. Appropriate placement of the couch block resulted in a thyroid dose reduction by 39 to 54%. Thyroid dose values at all possible positions of the radiosensitive gland with respect to the inferior field edge at five different patient ages were found. The mean difference between Monte Carlo results and thyroid dose measurements was 9.6%.

  5. New method for the induction of therapeutic amenorrhea: low dose endometrial afterloading irradiation. Clinical and hormonal studies

    Energy Technology Data Exchange (ETDEWEB)

    Gronroos, M.; Turunen, T.; Raekallio, J.; Ruotsalinen, P.; Salmi, T. (Turku Univ. (Finland). Dept. of Obstetrics and Gynecology)

    1982-08-01

    The authors present a new method for the induction of therapeutic amenorrhea: low dose endometrial afterloading irradiation. The problem with this method has been how to inactivate the endometrium while maintaining the physiological function of the ovaries. In 5/29 young patients regular or irregular bleedings occurred after an endometrial dose of 11+-1 Gy. These subjects were given a repeat low dose intrauterine irradiation. Thereafter no bleedings were found in four out of five patients. Two to 9 years after the repeat irradiation the plasma levels of E/sub 1/, E/sub 2/, FSH and LH corresponded closely to those of healthy women in reproductive age in three out of five patients; some high plasma P levels indicated ovulation. In two patients the E/sub 1/, E/sub 2/, and P values were more likely postmenopausal but, on the other hand, FSH and LH values reproductive ones. 19 refs.

  6. Sustained effect after lowering high-dose infliximab in patients with rheumatoid arthritis: a prospective dose titration study.

    NARCIS (Netherlands)

    Bemt, B.J. van den; Broeder, AA den; Snijders, G.F.; Hekster, Y.A.; Riel, P.L.C.M. van; Benraad, B.; Wolbink, G.J.; Hoogen, F.H.J. van den

    2008-01-01

    OBJECTIVES: In clinical trials only a small subset of patients with rheumatoid arthritis (RA) benefits from higher than standard dose of infliximab (>3 mg/kg/8 weeks). However, dose escalation of infliximab is frequently applied in clinical practice. Individual adjustment of infliximab treatment

  7. Is low dose inhaled corticosteroid therapy as effective for inflammation and remodeling in asthma? : A randomized, parallel group study

    NARCIS (Netherlands)

    Baraket, Melissa; Oliver, Brian G G; Burgess, Janette K; Lim, Sam; King, Gregory G; Black, Judith L

    2012-01-01

    BACKGROUND: While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as ef

  8. High brachytherapy doses can counteract hypoxia in cervical cancer—a modelling study

    Science.gov (United States)

    Lindblom, Emely; Dasu, Alexandru; Beskow, Catharina; Toma-Dasu, Iuliana

    2017-01-01

    Tumour hypoxia is a well-known adverse factor for the outcome of radiotherapy. For cervical tumours in particular, several studies indicate large variability in tumour oxygenation. However, clinical evidence shows that the management of cervical cancer including brachytherapy leads to high rate of success. It was the purpose of this study to investigate whether the success of brachytherapy for cervical cancer, seemingly regardless of oxygenation status, could be explained by the characteristics of the brachytherapy dose distributions. To this end, a previously used in silico model of tumour oxygenation and radiation response was further developed to simulate the treatment of cervical cancer employing a combination of external beam radiotherapy and intracavitary brachytherapy. Using a clinically-derived brachytherapy dose distribution and assuming a homogeneous dose delivered by external radiotherapy, cell survival was assessed on voxel level by taking into account the variation of sensitivity with oxygenation as well as the effects of repair, repopulation and reoxygenation during treatment. Various scenarios were considered for the conformity of the brachytherapy dose distribution to the hypoxic region in the target. By using the clinically-prescribed brachytherapy dose distribution and varying the total dose delivered with external beam radiotherapy in 25 fractions, the resulting values of the dose for 50% tumour control, D 50, were in agreement with clinically-observed values for high cure rates if fast reoxygenation was assumed. The D 50 was furthermore similar for the different degrees of conformity of the brachytherapy dose distribution to the tumour, regardless of whether the hypoxic fraction was 10%, 25%, or 40%. To achieve 50% control with external RT only, a total dose of more than 70 Gy in 25 fractions would be required for all cases considered. It can thus be concluded that the high doses delivered in brachytherapy can counteract the increased

  9. Case study on implementation of the dose constraint concept in optimization in working environment

    Energy Technology Data Exchange (ETDEWEB)

    Krajewska, Grazyna; Krajewski, Pawel [Central Laboratory for Radiological Protection, PL-03194, Warsaw (Poland)

    2014-07-01

    A case study of already fixed dose constrain values in nuclear medicine sector, indicated that, the practical implementation of ICRP principle of optimization ( Publication 103, ICRP, 2007) still hit on methodology problems due to lack of adequate numerous monitoring data of internal contamination and complicated mathematical formalism. In practice, to ensure that 'the likelihood of incurring exposure, the number of people exposed, and the magnitude of their individual doses are kept as low as reasonably achievable', the baseline of effective doses together with statistical distribution is required. Furthermore, as it has revealed in this study, doses PHP's generated with MC methods had un-regularly shapes, depending on random operations rather than routine procedures. The role of dose constraints for occupational exposures, was further elaborated in Publication 101 (ICRP, 2006) as 'the dose constraint is a value of individual dose used to limit the range of options considered in the process of optimization'. The revisions of the International Basic Safety Standards as well as the Euratom Basic Safety Standard Directive both aim to implement new ICRP recommendations and have requirements to use dose constraints, defined broadly along the lines provided by the ICRP, and suggest that values be selected from the bands recommended by the ICRP. These will be obligatory adopted in the national regulations by regulatory authorities of EU countries. However, due to accidental characteristics of monitoring data, the 95% confidence tail of the doses for the most highly exposed individuals is near the limit of 20 mSv per year. This is apparently observed in the particular endocrinology units dealing with I-131 therapy. One might concluded that dose limitation and optimization are viewed as sufficient for the management of occupational exposures and reasonably be achieved. (authors)

  10. No Improved Performance With Repeated-Sprint Training in Hypoxia Versus Normoxia: A Double-Blind and Crossover Study.

    Science.gov (United States)

    Montero, David; Lundby, Carsten

    2017-02-01

    Few recent studies indicate that short-term repeated-sprint (RS) training in hypoxia (RSH) improves RS performance compared with identical training under normoxic conditions (RSN) in endurance-trained subjects. To determine the effects of RSH against RSN on RS performance under normoxic and moderate hypoxic conditions, using a randomized, doubleblind, crossover experimental design. Fifteen endurance-trained male subjects (age 25 ± 4 y) performed 4 wk of RS training (3 sessions/wk) in normobaric hypoxia (RSH, FiO2 = 13.8%) and normoxia (RSN, FiO2 = 20.9%) in a crossover manner. Before and after completion of training, RS tests were performed on a cycle ergometer with no prior exercise (RSNE), after an incremental exercise test (RSIE), and after a time-trial test (RSTT) in normoxia and hypoxia. Peak power outputs at the incremental exercise test and time-trial performance were unaltered by RSH in normoxia and hypoxia. RS performance was generally enhanced by RSH, as well as RSN, but there were no additional effects of RSH over RSN on peak and mean sprint power output and the number of repeated sprints performed in the RSNE, RSIE, and RSTT trials under normoxic and hypoxic conditions. The present double-blind crossover study indicates that RSH does not improve RS performance compared with RSN in normoxic and hypoxic conditions in endurance-trained subjects. Therefore, caution should be exercised when proposing RSH as an advantageous method to improve exercise performance.

  11. DOSIS: a Monte Carlo simulation program for dose related studies in mammography.

    Science.gov (United States)

    Delis, H; Spyrou, G; Panayiotakis, G; Tzanakos, G

    2005-06-01

    Dosimetric studies in mammography are addressed by means of a Monte Carlo simulation program. The core of this program (DOSIS: dosimetry simulation studies) is a simulation model developed using FORTRAN 90, enriched with a graphical user interface developed in MS Visual Basic. User defined mammographic technique parameters affecting breast dose are imported to the simulation model and the produced results are provided by means of both absolute (surface dose, exposure at detector plane) and relative quantities (percentage depth dose, isodose curves). The program functionality has been demonstrated in the evaluation of various mammographic examination techniques. Specifically, the influence of tube voltage and filtration on the surface dose and the exposure at detector plane has been studied utilizing a water phantom. Increase of tube voltage from 25 to 30 kVp for a Mo/Mo system resulted in a 42% decrease of the surface dose for a thick breast (6 cm), without changing the exposure at the detector plane. Use of 1.02 mm Al filter for a W anode system operating at 30 kVp resulted in a 19.1% decrease of the surface dose delivered to a 5 cm water equivalent breast. Overall, W/Al systems appear to have improved dosimetric performance, resulting up to a 65% decrease of surface dose compared to Mo/Mo systems, for identical exposures at the detector plane and breast thicknesses.

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

    Energy Technology Data Exchange (ETDEWEB)

    Han, S; Jung, H; Kim, M; Ji, Y; Kim, K [University of Science and Technology, Daejeon (Korea, Republic of); Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Choi, S; Park, S; Yoo, H [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Yi, C [Korea Research Institute of Standards and Science, Daejeon (Korea, Republic of)

    2014-06-01

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

  13. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study.

    Science.gov (United States)

    Ouwehand, Arthur C; DongLian, Cai; Weijian, Xu; Stewart, Morgan; Ni, Jiayi; Stewart, Tad; Miller, Larry E

    2014-01-16

    Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients.

  14. Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases

    Science.gov (United States)

    Koon, Alex C.; Chan, Ho Yin Edwin

    2017-01-01

    For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development. PMID:28377694

  15. A Monte Carlo study on dose distribution evaluation of Flexisource 192Ir brachytherapy source

    Science.gov (United States)

    Alizadeh, Majid; Ghorbani, Mahdi; Haghparast, Abbas; Zare, Naser; Ahmadi Moghaddas, Toktam

    2015-01-01

    Aim The aim of this study is to evaluate the dose distribution of the Flexisource 192Ir source. Background Dosimetric evaluation of brachytherapy sources is recommended by task group number 43 (TG. 43) of American Association of Physicists in Medicine (AAPM). Materials and methods MCNPX code was used to simulate Flexisource 192Ir source. Dose rate constant and radial dose function were obtained for water and soft tissue phantoms and compared with previous data on this source. Furthermore, dose rate along the transverse axis was obtained by simulation of the Flexisource and a point source and the obtained data were compared with those from Flexiplan treatment planning system (TPS). Results The values of dose rate constant obtained for water and soft tissue phantoms were equal to 1.108 and 1.106, respectively. The values of the radial dose function are listed in the form of tabulated data. The values of dose rate (cGy/s) obtained are shown in the form of tabulated data and figures. The maximum difference between TPS and Monte Carlo (MC) dose rate values was 11% in a water phantom at 6.0 cm from the source. Conclusion Based on dosimetric parameter comparisons with values previously published, the accuracy of our simulation of Flexisource 192Ir was verified. The results of dose rate constant and radial dose function in water and soft tissue phantoms were the same for Flexisource and point sources. For Flexisource 192Ir source, the results of TPS calculations in a water phantom were in agreement with the simulations within the calculation uncertainties. Furthermore, the results from the TPS calculation for Flexisource and MC calculation for a point source were practically equal within the calculation uncertainties. PMID:25949224

  16. NMR-based metabolomics and breath studies show lipid and protein catabolism during low dose chronic T(1)AM treatment.

    Science.gov (United States)

    Haviland, J A; Reiland, H; Butz, D E; Tonelli, M; Porter, W P; Zucchi, R; Scanlan, T S; Chiellini, G; Assadi-Porter, F M

    2013-12-01

    3-Iodothyronamine (T1 AM), an analog of thyroid hormone, is a recently discovered fast-acting endogenous metabolite. Single high-dose treatments of T1 AM have produced rapid short-term effects, including a reduction of body temperature, bradycardia, and hyperglycemia in mice. The effect of daily low doses of T1 AM (10 mg/kg) for 8 days on weight loss and metabolism in spontaneously overweight mice was monitored. The experiments were repeated twice (n = 4). Nuclear magnetic resonance (NMR) spectroscopy of plasma and real-time analysis of exhaled (13) CO2 in breath by cavity ring down spectroscopy (CRDS) were used to detect T1 AM-induced lipolysis. CRDS detected increased lipolysis in breath shortly after T1 AM administration that was associated with a significant weight loss but independent of food consumption. NMR spectroscopy revealed alterations in key metabolites in serum: valine, glycine, and 3-hydroxybutyrate, suggesting that the subchronic effects of T1 AM include both lipolysis and protein breakdown. After discontinuation of T1 AM treatment, mice regained only 1.8% of the lost weight in the following 2 weeks, indicating lasting effects of T1 AM on weight maintenance. CRDS in combination with NMR and (13) C-metabolic tracing constitute a powerful method of investigation in obesity studies for identifying in vivo biochemical pathway shifts and unanticipated debilitating side effects. Copyright © 2013 The Obesity Society.

  17. A study on the indirect urea dosing method in the Selective Catalytic Reduction system

    Science.gov (United States)

    Brzeżański, M.; Sala, R.

    2016-09-01

    This article presents the results of studies on concept solution of dosing urea in a gas phase in a selective catalytic reduction system. The idea of the concept was to heat-up and evaporate the water urea solution before introducing it into the exhaust gas stream. The aim was to enhance the processes of urea converting into ammonia, what is the target reductant for nitrogen oxides treatment. The study was conducted on a medium-duty Euro 5 diesel engine with exhaust line consisting of DOC catalyst, DPF filter and an SCR system with a changeable setup allowing to dose the urea in liquid phase (regular solution) and to dose it in a gas phase (concept solution). The main criteria was to assess the effect of physical state of urea dosed on the NOx conversion ratio in the SCR catalyst. In order to compare both urea dosing methods a special test procedure was developed which consisted of six test steps covering a wide temperature range of exhaust gas generated at steady state engine operation condition. Tests were conducted for different urea dosing quantities defined by the a equivalence ratio. Based on the obtained results, a remarkable improvement in NOx reduction was found for gas urea application in comparison to the standard liquid urea dosing. Measured results indicate a high potential to increase an efficiency of the SCR catalyst by using a gas phase urea and provide the basis for further scientific research on this type of concept.

  18. Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

    Science.gov (United States)

    Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

    2015-02-01

    Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.

  19. Anti-Inflammatory Properties of Low and High Doxycycline Doses: An In Vitro Study

    Directory of Open Access Journals (Sweden)

    Roberta Di Caprio

    2015-01-01

    Full Text Available Doxycycline is used to treat infective diseases because of its broadspectrum efficacy. High dose administration (100 or 200 mg/day is often responsible for development of bacterial resistances and endogenous flora alterations, whereas low doses (20–40 mg/day do not alter bacteria susceptibility to antibiotics and exert anti-inflammatory activities. In this study, we wanted to assess the efficacy of both low and high doxycycline doses in modulating IL-8, TNF-α, and IL-6 gene expression in HaCaT cells stimulated with LPS. Three experimental settings were used, differing in the timing of doxycycline treatment in respect to the insult induced by LPS: pretreatment, concomitant, and posttreatment. Low doses were more effective than high doses in modulating gene expression of LPS-induced proinflammatory cytokines (IL-8, TNF-α, and IL-6, when added before (pretreatment or after (posttreatment LPS stimulation. This effect was not appreciated when LPS and doxycycline were simultaneously added to cell cultures: in this case high doses were more effective. In conclusion, our in vitro study suggests that low doxycycline doses could be safely used in chronic or acute skin diseases in which the inflammatory process, either constantly in progress or periodically recurring, has to be prevented or controlled.

  20. Anti-Inflammatory Properties of Low and High Doxycycline Doses: An In Vitro Study

    Science.gov (United States)

    Di Caprio, Roberta; Di Costanzo, Luisa; Monfrecola, Giuseppe

    2015-01-01

    Doxycycline is used to treat infective diseases because of its broadspectrum efficacy. High dose administration (100 or 200 mg/day) is often responsible for development of bacterial resistances and endogenous flora alterations, whereas low doses (20–40 mg/day) do not alter bacteria susceptibility to antibiotics and exert anti-inflammatory activities. In this study, we wanted to assess the efficacy of both low and high doxycycline doses in modulating IL-8, TNF-α, and IL-6 gene expression in HaCaT cells stimulated with LPS. Three experimental settings were used, differing in the timing of doxycycline treatment in respect to the insult induced by LPS: pretreatment, concomitant, and posttreatment. Low doses were more effective than high doses in modulating gene expression of LPS-induced proinflammatory cytokines (IL-8, TNF-α, and IL-6), when added before (pretreatment) or after (posttreatment) LPS stimulation. This effect was not appreciated when LPS and doxycycline were simultaneously added to cell cultures: in this case high doses were more effective. In conclusion, our in vitro study suggests that low doxycycline doses could be safely used in chronic or acute skin diseases in which the inflammatory process, either constantly in progress or periodically recurring, has to be prevented or controlled. PMID:25977597

  1. A Monte Carlo Study of dose enhancement according to the enhancement agents

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Hoon; Kim, Chang Soo [Dept. of Radiological Science, College of Health Sciences, Catholic University of Pusan, Busan (Korea, Republic of); Hwang, Chul Hwan [Dept. of Radiation Oncology, Pusan National University Hospital, Busan (Korea, Republic of)

    2017-03-15

    Dose enhancement effects at megavoltage (MV) X and γ-ray energies, and the effects of different energy levels on incident energy, dose enhancement agents, and concentrations were analyzed using Monte Carlo simulations. Gold, gadolinium, Iodine, and iron oxide (Fe2O3) were compared as dose enhancement agents. For incident energy, 4, 6, 10 and 15 MV X-ray spectra produced by a linear accelerator and a Co60 γ-ray were used. The dose enhancement factor (DEF) was calculated using an ICRU Slab phantom for concentrations of 7, 18, and 30 mg/g. The DEF was higher at higher concentrations of dose enhancement agents and at lower incident energies. The calculated DEF ranged from 1.035 to 1.079, and dose enhancement effects were highest for iron oxide, followed by iodine, gadolinium, and gold. Thus, this study contributes to improving the therapeutic ratio by delivering larger doses of radiation to tumor volume, and provides data to support further in vivo and in vitro studies.

  2. Tectonomagnetic study in the seismoactive area of Narmada–Son lineament, central India: Preliminary results on repeat field observations

    Indian Academy of Sciences (India)

    S Y Waghmare; S D Pimprikar; P B Gawali; L Carlo; A G Patil

    2009-06-01

    Repeated measurements of the total geomagnetic field on the five profiles have revealed a picture of stress-induced tectonomagnetic effect in the form of secular variation of the total geomagnetic field in the tectonically and seismically active area of Jabalpur and adjoining areas of the Narmada-Son lineament (NSL),central India.For this experiment,a reference base station was established within the study area at Jabalpur.Using proton precession magnetometers with a sensitivity of 0.1 nT, simultaneous measurements of total geomagnetic field were made annually at the base and all field stations.Five cycles of repeated observations have been performed between 2003 and 2007.For data analysis,a difference method has been applied and the residuals have been calculated as secular variations of the total geomagnetic field with values ranging from ± 0.1nT to about > ± 14.6nT/yr over the different stations.The anomalies in secular variation of the total geomagnetic field may be related to anomalous accumulation of tectonic stresses and tensions on the deep fault zones and crustal blocks due to recent geodynamic processes and active geological inhomogeneities in the NSL.

  3. Multi-laboratory validation study of multilocus variable-number tandem repeat analysis (MLVA) for Salmonella enterica serovar Enteritidis, 2015

    Science.gov (United States)

    Peters, Tansy; Bertrand, Sophie; Björkman, Jonas T; Brandal, Lin T; Brown, Derek J; Erdõsi, Tímea; Heck, Max; Ibrahem, Salha; Johansson, Karin; Kornschober, Christian; Kotila, Saara M; Le Hello, Simon; Lienemann, Taru; Mattheus, Wesley; Nielsen, Eva Møller; Ragimbeau, Catherine; Rumore, Jillian; Sabol, Ashley; Torpdahl, Mia; Trees, Eija; Tuohy, Alma; de Pinna, Elizabeth

    2017-01-01

    Multilocus variable-number tandem repeat analysis (MLVA) is a rapid and reproducible typing method that is an important tool for investigation, as well as detection, of national and multinational outbreaks of a range of food-borne pathogens. Salmonella enterica serovar Enteritidis is the most common Salmonella serovar associated with human salmonellosis in the European Union/European Economic Area and North America. Fourteen laboratories from 13 countries in Europe and North America participated in a validation study for MLVA of S. Enteritidis targeting five loci. Following normalisation of fragment sizes using a set of reference strains, a blinded set of 24 strains with known allele sizes was analysed by each participant. The S. Enteritidis 5-loci MLVA protocol was shown to produce internationally comparable results as more than 90% of the participants reported less than 5% discrepant MLVA profiles. All 14 participating laboratories performed well, even those where experience with this typing method was limited. The raw fragment length data were consistent throughout, and the inter-laboratory validation helped to standardise the conversion of raw data to repeat numbers with at least two countries updating their internal procedures. However, differences in assigned MLVA profiles remain between well-established protocols and should be taken into account when exchanging data. PMID:28277220

  4. Effect of repeated sterilization cycles on the physical properties of scaling instruments: a scanning electron microscopy study.

    Science.gov (United States)

    Porto, Alessandra Nogueira; Borges, Álvaro Henrique; Semenoff-Segundo, Alex; Raslan, Suzane A; Pedro, Fábio Luis Miranda; Jorge, Antônio Olavo Cardoso; Bandeca, Matheus Coelho

    2015-05-01

    Repeated sterilizations cycles cause undesirable alterations in the material properties of the instruments, such as corrosion, alterations in the hardness of the metal and the loss of the cutting sharpness of the instrument. This research examined the effect of repeated dry heat sterilization and autoclaves cycles on carbon steel (CS) and stainless steel (SS) curettes during the scaling and root planning. A total of 77 Gracey curettes were used in this study. Of these, 35 were SS and 42 were CS curettes submitted in different process: Dry heat, autoclave, inhibition of corrosion and autoclave, scaling, root planning and dry heat, scaling, root planning, inhibition of corrosion and autoclave. The inhibition of corrosion used on the carbon curettes (prior to sterilization in the autoclave) was sodium nitrite at 2%. The curettes received 10 consecutive cycles of sterilization and after that the cutting edges were examined in the electronic microscope, at 60 and 100 magnification times. The images were evaluated by three independent examiners, who compared the photographs of each group with the control group. The surface corrosion products and a deterioration of the edges were observed and the results showed that the SS curettes suffered little alteration with sterilization, scaling, root planning whereas the CS curettes were visibly affected by sterilization in the autoclave, but when the inhibition of corrosion was used prior to the sterilization, the oxidation was considerably reduced.

  5. Effectiveness of repeated photodynamic therapy in the elimination of intracanal Enterococcus faecalis biofilm: an in vitro study.

    Science.gov (United States)

    Prażmo, Ewa Joanna; Godlewska, Renata Alicja; Mielczarek, Agnieszka Beata

    2017-04-01

    The study aimed to investigate the effectiveness of photodynamic therapy in the elimination of intracanal Enterococcus faecalis biofilm and to analyse how a repeated light irradiation, replenishment of oxygen and photosensitiser affect the results of the photodynamic disinfecting protocol. After chemomechanical preparation, 46 single-rooted human teeth were infected with a clinical strain of E. faecalis and incubated for a week in microaerobic conditions. The experimental procedures included groups of single application of photodynamic therapy, two cycles of PDT, irrigation with 5.25% NaOCl solution and negative and positive control. The number of residing bacterial colonies in the root canals was determined based on the CFU/ml method. In the group of preparations irrigated with NaOCl, bacterial colonies were not observed. A single PDT eliminated 45% of the initial CFU/ml. Repeated PDT eradicated 95% of the intracanal bacterial biofilm. Photodynamic therapy has a high potential for the elimination of E. faecalis biofilm. There is a safe therapeutic window where photoinduced disinfection can be used as an adjuvant to conventional endodontic treatment, which remains the most effective.

  6. Broad and narrow personality traits as markers of one-time and repeated suicide attempts: A population-based study

    Directory of Open Access Journals (Sweden)

    Vitaro Frank

    2008-03-01

    Full Text Available Abstract Background Studying personality traits with the potential to differentiate between individuals engaging in suicide attempts of different degrees of severity could help us to understand the processes underlying the link of personality and nonfatal suicidal behaviours and to identify at-risk groups. One approach may be to examine whether narrow, i.e., lower-order personality traits may be more useful than their underlying, broad personality trait dimensions. Methods We investigated qualitative and quantitative differences in broad and narrow personality traits between one-time and repeated suicide attempters in a longitudinal, population-based sample of young French Canadian adults using two multivariate regression models. Results One broad (Compulsivity: OR = 2.0; 95% CI 1.2–3.5 and one narrow personality trait (anxiousness: OR = 1.1; 95% CI 1.01–1.1 differentiated between individuals with histories of repeated and one-time suicide attempts. Affective instability [(OR = 1.1; 95% CI 1.04–1.1] and anxiousness [(OR = .92; 95% CI .88–.95], on the other hand, differentiated between nonattempters and one-time suicide attempters. Conclusion Emotional and cognitive dysregulation and associated behavioural manifestations may be associated with suicide attempts of different severity. While findings associated with narrow traits may be easier to interpret and link to existing sociobiological theories, larger effect sizes associated with broad traits such as Compulsivity may be better suited to objectives with a more clinical focus.

  7. Influence of difference in cross-sectional dose profile in a CTDI phantom on X-ray CT dose estimation: a Monte Carlo study.

    Science.gov (United States)

    Haba, Tomonobu; Koyama, Shuji; Ida, Yoshihiro

    2014-01-01

    The longitudinal dose profile in a computed tomography dose index (CTDI) phantom had been studied by many researchers. The cross-sectional dose profile in the CTDI phantom, however, has not been studied. It is also important to understand the cross-sectional dose profile in the CTDI phantom for dose estimation in X-ray CT. In this study, the cross-sectional dose profile in the CTDI phantom was calculated by use of a Monte Carlo (MC) simulation method. A helical or a 320-detector-row cone-beam X-ray CT scanner was simulated. The cross-sectional dose profile in the CTDI phantom from surface to surface through the center point was calculated by MC simulation. The shape of the calculation region was a cylinder of 1-mm-diameter. The length of the cylinder was 23, 100, or 300 mm to represent various CT ionization chamber lengths. Detailed analyses of the energy depositions demonstrated that the cross-sectional dose profile was different in measurement methods and phantom sizes. In this study, we also focused on the validation of the weighting factor used in weighted CTDI (CTDI w ). As it stands now, the weighting factor used in CTDI w is (1/3, 2/3) for the (central, peripheral) axes. Our results showed that an equal weighting factor, which is (1/2, 1/2) for the (central, peripheral) axes, is more suitable to estimate the average cross-sectional dose when X-ray CT dose estimation is performed.

  8. Radiation dose reduction without degrading image quality during computed tomography examinations: Dosimetry and quality control study

    Directory of Open Access Journals (Sweden)

    George Felix Acquah

    2014-08-01

    Full Text Available Purpose: Computed tomography (CT, is an X-ray procedure that generates high quality cross-sectional images of the body, and by comparison to other radiological diagnosis, is responsible for higher doses to patients. This work studies the doses and image qualities produced from the default primary scanning factors of a Siemens CT machine and afterwards came up with scanning protocols that allow radiologists to obtain the necessary diagnostic information while reducing radiation doses to as low as reasonably achievable. Methods: Approximately 1000 CT scans from mostly common examinations; head, thorax, abdomen and pelvis routines were selected and analyzed for their image quality and radiation doses over a two year interval. Dose measurements were performed for the same routines using Computed Tomography Dose Index (CTDI phantoms, RTI barracuda system with electrometer, and CT dose Profiler detector to evaluate the doses delivered during these CT procedures. Subsequently, image quality checks were performed using the CT Catphan 600 and anthropomorphic phantoms. CTDI and Dose Length Product (DLP values were calculated for each scan. From analyzing these measurements, the appropriate machine scanning parameters were adjusted to reduce radiation does while at the same time providing good image quality.Results: Doses to patients using the default head sequence protocol had an average CTDIvol value of 65.45 mGy and a range of 7.10-16.80 mGy for thorax, abdomen and pelvis examinations whiles the new protocol had an average CTDIvol of 58.32 mGy for the head and a range of 3.83-15.24 mGy for the truck region. The DLP value for default head scans decreased from an average of 2279.85 mGy.cm to 874.53 mGy.cm with the new protocol. Tube potentials (KV and tube current-time (mAs had an effect on spatial resolution and low contrast detectability as well as doses. Conclusion: From the new protocols, lower values of KV and mAs together with other factors were

  9. A COMPARATIVE STUDY OF LOW DOSE INTRAVAGINAL MISOPR OSTOL (PGE 1 WITH INTRACERVICAL DINOPROSTONE (PGE 2 GEL FOR CERVICAL RIPENING AND LABOUR INDUCTION

    Directory of Open Access Journals (Sweden)

    Jenitha

    2013-04-01

    Full Text Available ABSTRACT: OBJECTIVES: (1 To compare the efficacy of low dose PGE 1 with PGE 2 for induction of labour at term. (2 To compare the safety of PGE 1 with PGE 2 in terms of labour and neonatal outcome. METHODOLOGY: It was an open label randomized controlled trial con ducted in the Department of Obstetrics & Gynecology, Mysore Medica l College Hospital. Total 200 patients satisfying the inclusion criteria were included in the study. One hundred of them received PGE 1 (25 μ g repeated 4 th hourly to a maximum of six doses and remaining on e hundred received PGE 2 (0.5 mg gel repeated 6 th hourly to a maximum of three doses. Analysis was done with respect to age, parity, gestational age, indication f or induction, number of doses required, oxytocin requirement, mode of delivery, indication if LSCS done, induction delivery interval, complications and neonatal outcome with respect to 5 minutes APGAR score, meconium stained liquor and NICU admission. RESULTS: Both groups were comparable to age, parity and gestational age. Oxytocin requirement was more for PGE 2 group (63% than PGE 1 group (35%. LSCS rate was 26% for PGE 1 group compared to 23% in PGE 2 group. The major indication for LSCS was fetal distress in 79.6% of PGE 1 group whereas it was failed induction or failure to progress in 60% of PGE 2 group. Incidence of traumatic PPH was 11% in PGE 1 group compared to 6% in PGE 2 group. Incidence of atonic PPH was 3% in PGE 2 group which was 2% in PGE 1 group. Other complications and induction to delivery interval were comparable in both groups. Neonatal outcome in terms of 5 minutes APGAR < 7, N ICU admission rates and meconium staining of liquor were all less with PGE 2 group. CONCLUSION: Dinoprostone appears to be a safer inducing agent in view of fewer complications with respect to labour and neonatal outcome with induction delivery interval almost equ al in both drugs. Misoprostol is efficacious and low cost agent for cervical ripening and labour

  10. Case study: videogame distraction reduces behavioral distress in a preschool-aged child undergoing repeated burn dressing changes: a single-subject design

    National Research Council Canada - National Science Library

    Sil, Soumitri; Dahlquist, Lynnda M; Burns, Andrew J

    2013-01-01

    This single-subject design study evaluated the feasibility and efficacy of passive and interactive videogame distraction on behavioral distress for a preschool-aged child receiving repeated burn dressing changes...

  11. Desensitization by progressive up-titration prevents first-dose effects on the heart: guinea pig study with ponesimod, a selective S1P1 receptor modulator.

    Directory of Open Access Journals (Sweden)

    Markus Rey

    Full Text Available Ponesimod, a selective S1P1 receptor modulator, reduces the blood lymphocyte count in all tested species by preventing egress of T and B cells from thymus and peripheral lymphoid organs. In addition, ponesimod transiently affects heart rate and atrioventricular (AV conduction in humans, effects not observed in mice, rats, and dogs with selective S1P1 receptor modulators, suggesting that the regulation of heart rate and rhythm is species dependent. In the present study, we used conscious guinea pigs implanted with a telemetry device to investigate the effects of single and multiple oral doses of ponesimod on ECG variables, heart rate, and blood pressure. Oral administration of ponesimod did not affect the sinus rate (P rate but dose-dependently induced AV block type I to III. A single oral dose of 0.1 mg/kg had no effect on ECG variables, while a dose of 3 mg/kg induced AV block type III in all treated guinea pigs. Repeated oral dosing of 1 or 3 mg/kg ponesimod resulted in rapid desensitization, so that the second dose had no or a clearly reduced effect on ECG variables as compared with the first dose. Resensitization of the S1P1 receptor in the heart was concentration dependent. After desensitization had been induced by the first dose of ponesimod, the cardiac system remained desensitized as long as the plasma concentration was ≥75 ng/ml. By using a progressive up-titration regimen, the first-dose effect of ponesimod on heart rate and AV conduction was significantly reduced due to desensitization of the S1P1 receptor. In summary, conscious guinea pigs implanted with a telemetry device represent a useful model to study first-dose effects of S1P1 receptor modulators on heart rate and rhythm. This knowledge was translated to a dosing regimen of ponesimod to be tested in humans to avoid or significantly reduce the first-dose effects.

  12. Radiation dose to children in diagnostic radiology. Measurements and methods for clinical optimisation studies

    Energy Technology Data Exchange (ETDEWEB)

    Almen, A.J.

    1995-09-01

    A method for estimating mean absorbed dose to different organs and tissues was developed for paediatric patients undergoing X-ray investigations. The absorbed dose distribution in water was measured for the specific X-ray beam used. Clinical images were studied to determine X-ray beam positions and field sizes. Size and position of organs in the patient were estimated using ORNL phantoms and complementary clinical information. Conversion factors between the mean absorbed dose to various organs and entrance surface dose for five different body sizes were calculated. Direct measurements on patients estimating entrance surface dose and energy imparted for common X-ray investigations were performed. The examination technique for a number of paediatric X-ray investigations used in 19 Swedish hospitals was studied. For a simulated pelvis investigation of a 1-year old child the entrance surface dose was measured and image quality was estimated using a contrast-detail phantom. Mean absorbed doses to organs and tissues in urography, lung, pelvis, thoracic spine, lumbar spine and scoliosis investigations was calculated. Calculations of effective dose were supplemented with risk calculations for special organs e g the female breast. The work shows that the examination technique in paediatric radiology is not yet optimised, and that the non-optimised procedures contribute to a considerable variation in radiation dose. In order to optimise paediatric radiology there is a need for more standardised methods in patient dosimetry. It is especially important to relate measured quantities to the size of the patient, using e g the patient weight and length. 91 refs, 17 figs, 8 tabs.

  13. Study of dose profile in TC scanning of cranium; Estudo do perfil de dose em varredura de TC de cranio

    Energy Technology Data Exchange (ETDEWEB)

    Goncalves Junior, R.L.; Oliveira, A.H., E-mail: heeren@nuclear.ufmg.b [Universidade Federal de Minas Gerais (DEN/UFMG), Belo Horizonte (Brazil). Dept. de Engenharia Nuclear; Mourao, A.P., E-mail: aprata@des.cefetmg.b [Centro Federal de Educacao Tecnologica de Minas Gerais (CEFET-MG), Belo Horizonte MG (Brazil). Nucleo de Engenharia Hospitalar

    2011-10-26

    In this paper it was obtained a dose distribution profile in computerized tomography, when a head simulator object, cylindrical and manufactured in PMMA, were swiped by using the clinical protocol or this device routine. The doses were determined with radiochromic films placed at the four cardinal points and the Center, taking as reference one of object faces. The films were calibrated with pencil ionization chamber in a independent experiment where the obtained doses in the chamber, when a unique central cut or the object were obtained, were confronted with the gray scales on the irradiated films in a similar manner, revealing he factors of conversion mGy.Gray tones{sup -1} which made possible the determination of doses in all the scanning

  14. The immune tolerance induction (ITI) dose debate: does the International ITI Study provide a clearer picture?

    Science.gov (United States)

    Ettingshausen, C Escuriola; Kreuz, W

    2013-01-01

    Among the proposed predictors for immune tolerance induction (ITI) outcome, the therapeutic regimen - specifically the dose and frequency of administered factor VIII (FVIII) as well as FVIII product type - is intensely debated. Are there any advantages for low-dose regimens (50 IU FVIII kg(-1) three times a week) over high-dose regimens (200 IU FVIII kg day(-1)) or vice versa? Are von Willebrand factor (VWF)-containing plasma-derived concentrates superior to recombinant FVIII concentrates for tolerance induction? A review of the available literature indicates that patients with good prognostic factors can achieve success with either low-dose or high-dose ITI regimens. Retrospective data suggest that patient characteristics such as maximum historical inhibitor titres and pre-ITI inhibitor titres are better predictors of treatment success than dose. Results of the prospective International ITI Study have recently become available. In inhibitor patients with good prognosis, success rates were similar between low-dose (50 IU FVIII kg(-1) three times a week) and high-dose (200 IU FVIII kg(-1) daily) regimens. However, patients receiving low-dose ITI took longer to achieve various ITI milestones and had a significantly higher bleed rate per month compared with the high-dose group (0.62 vs. 0.28; P = 0.00024), findings with important clinical implications. Inhibitor patients with poor prognostic features should be treated with a high-dose protocol. This conclusion is supported by a meta-analysis of the International Immune Tolerance Registry and North American Immune Tolerance Registry and by data from Germany showing good success rates with the high-dose, high-frequency Bonn protocol in poor prognosis patients. Type of concentrate also appears to have an influence on ITI success rates in this patient subgroup, with evidence suggesting an advantage for VWF-containing plasma-derived FVIII concentrates over recombinant or VWF-free concentrates. The ongoing prospective

  15. Prevention of eating disorders among minority youth: a matched-sample repeated measures study.

    Science.gov (United States)

    Cook-Cottone, Catherine; Jones, Lakaii A; Haugli, Sara

    2010-01-01

    The purpose of this study was to examine ethnic differences in primary prevention programs for eating disorders in young girls. In order to address the dearth of research in this area, this study examined the comparative response to an eating disorder prevention program on fifth-grade minority and White females. Pre- and post-test data were collected from 10 groups participating in the prevention program for a total of 50 girls. Minority participants and White participants were then matched based on Body Mass Index (BMI) and socioeconomic status in order to examine ethnic differences in group effectiveness. Findings indicated that minority and White participants were equally responsive to the prevention program.

  16. [The study of interaction between paralogous tandem repeats stellate and suppressor of stellate in the genome of Drosophila melanogaster].

    Science.gov (United States)

    Aravin, A A; Naumova, N M; Tulin, A V; Klenov, M S; Gvozdev, V A

    2000-04-01

    Testis-specific expression of tandemly repeated Stellate genes, located in eu- and heterochromatin regions of the X chromosome of Drosophila melanogaster, is suppressed by homologous Suppressor of Stellate repeats located on the Y chromosome. Using transgenic lines, we have demonstrated that three Su(Ste) copies failed to change the expression of the reporter construction carrying the bacterial beta-galactosidase gene under control of the Stellate gene regulatory sequence. Possible mechanisms of the Su(Ste) repeat suppressor activity are discussed.

  17. Discovery, Characterization, and Functional Study of a Novel MEF2D CAG Repeat in Duck (Anas platyrhynchos).

    Science.gov (United States)

    Wang, Yushi; Wang, Jiwen; Liu, Hehe; Zhang, Rongping; Zhang, Tao; Gan, Xiang; Huang, Huilan; Chen, Da; Li, Liang

    2016-08-01

    Myocyte enhancer transcription factor 2D (MEF2D) is an important transcription factor for promoting the growth and development of muscle. CAG repeats have been found in the coding sequence (CDS) of avian MEF2D; however, their functions remain unknown and require further investigation. Here, we examined the characteristics and functional role of MEF2D CAG repeat in duck. The full-length CDS of duck MEF2D was cloned for the first time, and a novel CAG repeat was identified and located in exon 9. Sequence analysis indicated that the protein domains of duck MEF2D are highly conserved relative to other vertebrates, whereas MEF2D CAG repeats with variable repeat numbers are specific to avian species. Furthermore, sequencing has revealed polymorphisms in MEF2D CAG repeat at both DNA and mRNA levels. Four MEF2D CAG repeat genotypes and 10 MEF2D cDNA variants with different CAG repeat numbers were detected in two duck populations. A t-test showed that the expanded CAG repeat generated significantly longer transcription products (p analysis demonstrated positive correlations between the expansion of the CAG repeat and five muscle-related traits. By using protein structure prediction, we suggested that the polymorphisms of the CAG repeat affect protein structures within protein domains. Taken together, these findings reveal that duck MEF2D CAG repeat is a potential functional element with polymorphisms and may cause differences in MEF2D function between duck and other vertebrate species.

  18. A phase I study of combined docetaxel and repeated high activity {sup 186}Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial)

    Energy Technology Data Exchange (ETDEWEB)

    Dodewaard-de Jong, Joyce M. van; Bloemendal, Haiko J. [Meander Medical Centre, Department of Internal Medicine, Amersfoort (Netherlands); Klerk, John M.H. de; Haas, Marie J. de [Meander Medical Centre, Department of Nuclear Medicine, Amersfoort (Netherlands); Bezooijen, Bart P.J. van [Meander Medical Centre, Department of Urology, Amersfoort (Netherlands); Wilson, Richard H.; O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast, N. Ireland (United Kingdom)

    2011-11-15

    Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and {sup 186}Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m{sup 2} 3-weekly). {sup 186}Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of {sup 186}Re-HEDP dose level 4 was not started. Combined therapy with docetaxel and {sup 186}Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m{sup 2} 3-weekly followed by {sup 188}Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m{sup 2}, followed by {sup 188}Re-HEDP 20 MBq/kg body weight. (orig.)

  19. Repeated versus wide reading: A randomized control design study examining the impact of fluency interventions on underlying reading behavior.

    Science.gov (United States)

    Ardoin, Scott P; Binder, Katherine S; Foster, Tori E; Zawoyski, Andrea M

    2016-12-01

    Repeated readings (RR) has garnered much attention as an evidence based intervention designed to improve all components of reading fluency (rate, accuracy, prosody, and comprehension). Despite this attention, there is not an abundance of research comparing its effectiveness to other potential interventions. The current study presents the findings from a randomized control trial study involving the assignment of 168second grade students to a RR, wide reading (WR), or business as usual condition. Intervention students were provided with 9-10weeks of intervention with sessions occurring four times per week. Pre- and post-testing were conducted using Woodcock-Johnson III reading achievement measures (Woodcock, McGrew, & Mather, 2001, curriculum-based measurement (CBM) probes, measures of prosody, and measures of students' eye movements when reading. Changes in fluency were also monitored using weekly CBM progress monitoring procedures. Data were collected on the amount of time students spent reading and the number of words read by students during each intervention session. Results indicate substantial gains made by students across conditions, with some measures indicating greater gains by students in the two intervention conditions. Analyses do not indicate that RR was superior to WR. In addition to expanding the RR literature, this study greatly expands research evaluating changes in reading behaviors that occur with improvements in reading fluency. Implications regarding whether schools should provide more opportunities to repeatedly practice the same text (i.e., RR) or practice a wide range of text (i.e., WR) are provided. Copyright © 2016 Society for the Study of School Psychology. Published by Elsevier Ltd. All rights reserved.

  20. Occurence and implications of radiation dose-rate effects for material aging studies

    Science.gov (United States)

    Gillen, Kenneth T.; Clough, Roger L.

    A number of commercial cable materials, including ethylene propylene rubber and crosslinked polyolefin insulations and chloroprene and chlorosulfonated polyethylene jackets have been radiation aged in air and nitrogen at radiation dose rates ranging from approximately 10 3 to 10 6{rad}/{hr}. Material degradation was followed using ultimate tensile properties (elongation and tensile strength), swelling measurements and infrared spectroscopy. The tensile results indicate that in air environments radiation dose rate effects are important for all four materials, with more mechanical damage occurring as the dose rate is lowered. These results are interpreted as coming from a competition between crosslinking and oxidative scission in which scission becomes more important as the dose rate is lowered. The swelling results offer direct evidence in support of this interpretation. In addition the infrared results show increased carbonyl content at lower dose rates, also indicative of increased oxidation. The conclusions of this study have important implications for the qualification of elastomeric materials for nuclear applications, since they clearly indicate that the mechanism of degradation is quite different (and the amount usually more severe) under low dose rate exposures compared to the mechanism occurring under the high dose rate exposures normally utilized for stimulating the natural aging.

  1. CTDI versus new AAPM metrics to assess doses in CT: a case study

    Energy Technology Data Exchange (ETDEWEB)

    Campelo, M.C.S., E-mail: maria.macalidi@gmail.com [Pontificia Universidade Catolica de Sao Paulo (PUC-SP), SP (Brazil); Silva, M.C., E-mail: marciac.silvag@gmail.com [Hospital Israelita Albert Einstein (HIAE), Sao Paulo, SP (Brazil); Terini, R.A., E-mail: ricardoaterini@gmail.com [Universidade de Sao Paulo (LABEND/USP), SP (Brazil). Laboratorio de Ensaios Nao-Destrutivos

    2016-07-01

    In modern CT, CTDI100 measurements would underestimate accumulated dose at the gantry center. AAPM TG 111 report proposed improved metrics for CT dosimetry, mainly for helical and wide beam width scanning. In this study, a methodology to assess CT dose, inspired on TG 111, was applied. Dosimeters were firstly calibrated in lab in beams like those utilized clinically. Using a reference 0.6cc Farmer chamber, two CT “pencil” chambers were calibrated in P{sub KL} by substitution method. Results showed differences ≤ 2% in the calibration coefficients, for three collimation apertures. A small 0.6cc chamber was calibrated in air kerma with this setup, without any collimator. After this, in a private Brazilian hospital, the small chamber was applied in dosimetry tests of a CT scanner, according to TG 111, determining Dose profiles and Equilibrium dose free-in-air (D{sub eq,air}) for some protocols and pitch values. Results showed that D{sub eq,air} increased when reducing pitch and Equilibrium dose-pitch product free in air (p.D{sub eq,air}) remain constant. In measurements with a 450mm CT phantom, differences between Planar Average Equilibrium Dose (D{sub eq,p}) and CTDIvol ranged between 30-37%. This occurs because CTDI{sub vol} cannot include dose profile 'tail' contribution, caused by scattering in phantom, especially for wide beam widths. (author)

  2. The Effect of Image Quality, Repeated Study, and Assessment Method on Anatomy Learning

    Science.gov (United States)

    Fenesi, Barbara; Mackinnon, Chelsea; Cheng, Lucia; Kim, Joseph A.; Wainman, Bruce C.

    2017-01-01

    The use of two-dimensional (2D) images is consistently used to prepare anatomy students for handling real specimen. This study examined whether the quality of 2D images is a critical component in anatomy learning. The visual clarity and consistency of 2D anatomical images was systematically manipulated to produce low-quality and high-quality…

  3. Repeated open application test with methyldibromo glutaronitrile, a multicentre study within the EECDRG

    DEFF Research Database (Denmark)

    Gruvberger, B; Andersen, Klaus Ejner; Brandão, F M

    2005-01-01

    Contact allergy to and allergic contact dermatitis from methyldibromo glutaronitrile (MDBGN) have frequently been reported. This study was initiated to help determine the optimal patch test preparation for MDBGN. In 51 patients with a doubtful or a positive patch test reaction to at least 1 of 4 ...

  4. Mouth opening in patients irradiated for head and neck cancer : A prospective repeated measures study

    NARCIS (Netherlands)

    Kamstra, J. I.; Dijkstra, P. U.; van Leeuwen, M.; Roodenburg, J. L. N.; Langendijk, J. A.

    2015-01-01

    Objectives: Aims of this prospective cohort study were (1) to analyze the course of mouth opening up to 48 months post-radiotherapy (RT), (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening in a large sample

  5. Mouth opening in patients irradiated for head and neck cancer : A prospective repeated measures study

    NARCIS (Netherlands)

    Kamstra, J. I.; Dijkstra, P. U.; van Leeuwen, M.; Roodenburg, J. L. N.; Langendijk, J. A.

    Objectives: Aims of this prospective cohort study were (1) to analyze the course of mouth opening up to 48 months post-radiotherapy (RT), (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening in a large sample

  6. International Mycoplasma pneumoniae typing study: interpretation of M. pneumoniae multilocus variable-number tandem-repeat analysis

    Directory of Open Access Journals (Sweden)

    V.J. Chalker

    2015-09-01

    Full Text Available Typing of Mycoplasma pneumoniae by multiple-locus variable-number tandem repeat analysis (MLVA is increasingly in use. However, no specific internationally agreed guidance is available. Thirty M. pneumoniae DNA samples including serial dilutions of a type strain were sent to six international laboratories to perform MLVA and results were compared. Good correlation was observed, indicating that this methodology can be robustly performed in multiple sites. However, differences due to interpretation of fragment size, repeat sequence identification and repeat numbering led to inconsistency in the final profiles assigned by laboratories. We propose guidelines for interpreting M. pneumoniae MLVA typing and assigning the number of repeats.

  7. Feasibility study of a simple approximation algorithm for in-vivo dose reconstruction by using the transit dose measured using an EPID

    Science.gov (United States)

    Hwang, Ui-Jung; Song, Mi Hee; Baek, Tae Seong; Chung, Eun Ji; Yoon, Myonggeun

    2015-02-01

    The purpose of this study is to verify the accuracy of the dose delivered to the patient during intensity-modulated radiation therapy (IMRT) by using in-vivo dosimetry and to avoid accidental exposure to healthy tissues and organs close to tumors. The in-vivo dose was reconstructed by back projection of the transit dose with a simple approximation that considered only the percent depth dose and inverse square law. While the average gamma index for comparisons of dose distributions between the calculated dose map and the film measurement was less than the one for 96.3% of all pixels with the homogeneous phantom, the passing rate was reduced to 92.8% with the inhomogeneous phantom, suggesting that the reduction was apparently due to the inaccuracy of the reconstruction algorithm for inhomogeneity. The proposed method of calculating the dose inside a phantom was of comparable or better accuracy than the treatment planning system, suggesting that it can be used to verify the accuracy of the dose delivered to the patient during treatment.

  8. Capecitabine based postoperative accelerated chemoradiation of pancreatic carcinoma. A dose-escalation study

    Energy Technology Data Exchange (ETDEWEB)

    Morganti, Alessio G.; Picardi, Vincenzo; Ippolito, Edy; Massaccesi, Mariangela; Macchia, Gabriella; Deodato, Francesco (Radiotherapy Unit, Dept. of Oncology, ' John Paul II' Center for High Technology Research and Education in Biomedical Sciences, Catholic Univ., Campobasso (Italy)), E-mail: gmacchia@rm.unicatt.it; Caravatta, Luciana; Tambaro, Rosa; Mignogna, Samantha (Palliative Therapies Unit, Dept. of Oncology, ' John Paul II' Center for High Technology Research and Education in Biomedical Sciences, Catholic Univ., Campobasso (Italy)); Cellini, Numa; Valentini, Vincenzo; Mattiucci, Gian Carlo (Dept. of Radiotherapy, Policlinico Universitario ' A. Gemelli' , Catholic Univ., Rome (Italy)); Di Lullo, Liberato (Dept. of Oncology, ' F. Veneziale' General Hospital, Isernia (Italy)); Giglio, Gianfranco (Dept. of Oncology, ' A. Cardarelli' General Hospital Campobasso (Italy)); Caprino, Paola; Sofo, Luigi (Surgery Unit, Dept. of Oncology, ' John Paul II' Center for High Technology Research and Education in Biomedical Sciences, Catholic Univ., Campobasso (Italy)); Ingrosso, Marcello (Endoscopy Unit, Dept. of Oncology, ' John Paul II' Center for High Technology Research and Education in Biomedical Sciences, Catholic Univ., Campobasso (Italy))

    2010-05-15

    The objective of this study was to evaluate the safety of escalating up to 55 Gy within five weeks, the dose of external beam radiotherapy to the previous tumor site concurrently with a fixed daily dose of capecitabine, in patients with resected pancreatic cancer. Material and methods. Patients with resected pancreatic carcinoma were eligible for this study. Capecitabine was administered at a daily dose of 1600 mg/m2. Regional lymph nodes received a total radiation dose of 45 Gy with 1.8 Gy per fractions. The starting radiation dose to the tumor bed was 50.0 Gy (2.0 Gy/fraction, 25 fractions). Escalation was achieved up to a total dose of 55.0 Gy by increasing the fraction size by 0.2 Gy (2.2 Gy/fraction), while keeping the duration of radiotherapy to five weeks (25 fractions). A concomitant boost technique was used. Dose limiting toxicity (DLT) was defined as any grade>3 hematologic toxicity, grade>2 liver, renal, neurologic, gastrointestinal, or skin toxicity, by RTOG criteria, or any toxicity producing prolonged (> 10 days) radiotherapy interruption. Results and discussion. Twelve patients entered the study (median age: 64 years). In the first cohort (six patients), no patient experienced DLT. Similarly in the second cohort, no DLT occurred. All 12 patients completed the planned regimen of therapy. Nine patients experienced grade 1-2 nausea and/or vomiting. Grade 2 hematological toxicity occurred in four patients. The results of our study indicate that a total radiation dose up to 55.0 Gy/5 weeks can be safely administered to the tumor bed, concurrently with capecitabine (1600 mg/m2) in patients with resected pancreatic carcinoma.

  9. Studying the potential of point detectors in time-resolved dose verification of dynamic radiotherapy

    DEFF Research Database (Denmark)

    Beierholm, Anders Ravnsborg; Behrens, C. F.; Andersen, Claus E.

    2015-01-01

    for quality assurance and dose verification. In this context, traceable in-phantom dosimetry using a well-characterized point detector is often an important supplement to 2D-based quality assurance methods based on radiochromic film or detector arrays. In this study, an in-house developed dosimetry system...... in dose delivery, although exact positioning of detectors remains critical. (C) 2015 Published by Elsevier Ltd....

  10. Repeated exposure of acidic beverages on esthetic restorative materials: an in-vitro surface microhardness study

    OpenAIRE

    Xavier, Arun M.; Sunny, Steffy M.; Rai, Kavita; Amitha M Hegde

    2016-01-01

    Background A manifold increase in the consumption of aerated beverages has witnessed a twin increase in tooth wear and raised demand for esthetic restorative materials. This study aimed to evaluate the surface microhardness changes of esthetic restorative materials following treatment with aerated beverages in an in-vitro situation. Material and Methods The initial surface microhardness of the restorative materials GC Fuji II LC, GC Fuji IX, Nano Glass ionomer, Resin and Nano composite was re...

  11. URINARY CREATINE AT REST AND AFTER REPEATED SPRINTS IN ATHLETES: A PILOT STUDY

    Directory of Open Access Journals (Sweden)

    I. Bezrati-Benayed

    2014-07-01

    Full Text Available Creatine plays a key role in muscle function and its evaluation is important in athletes. In this study, urinary creatine concentration was measured in order to highlight its possible significance in monitoring sprinters. The study included 51 sprinters and 25 age- and sex-matched untrained subjects as a control group. Body composition was measured and dietary intake estimated. Urine samples were collected before and after standardized physical exercise. Creatine was assessed by gas chromatography mass spectrometry. Basal urinary creatine (UC was significantly lower in sprinters than controls (34±30 vs. 74±3 μmol/mmol creatinine, p<0.05. UC was inversely correlated with body mass (r=-0.34, p<0.01 and lean mass (r=- 0.30, p<0.05, and positively correlated with fat mass (r=0.32, p<0.05. After acute exercise, urinary creatine significantly decreased in both athletes and controls. UC is low in sprinters at rest and further decreases after exercise, most likely due to a high uptake and use of creatine by muscles, as muscle mass and physical activity are supposed to be greater in athletes than untrained subjects. Further studies are needed to test the value of urinary creatine as a non-invasive marker of physical condition and as a parameter for managing Cr supplementation in athletes.

  12. Urinary creatine at rest and after repeated sprints in athletes: a pilot study.

    Science.gov (United States)

    Bezrati-Benayed, I; Nasrallah, F; Feki, M; Chamari, K; Omar, S; Alouane-Trabelsi, L; Ben Mansour, A; Kaabachi, N

    2014-03-01

    Creatine plays a key role in muscle function and its evaluation is important in athletes. In this study, urinary creatine concentration was measured in order to highlight its possible significance in monitoring sprinters. The study included 51 sprinters and 25 age- and sex-matched untrained subjects as a control group. Body composition was measured and dietary intake estimated. Urine samples were collected before and after standardized physical exercise. Creatine was assessed by gas chromatography mass spectrometry. Basal urinary creatine (UC) was significantly lower in sprinters than controls (34±30 vs. 74±3 µmol/mmol creatinine, p sprinters at rest and further decreases after exercise, most likely due to a high uptake and use of creatine by muscles, as muscle mass and physical activity are supposed to be greater in athletes than untrained subjects. Further studies are needed to test the value of urinary creatine as a non-invasive marker of physical condition and as a parameter for managing Cr supplementation in athletes.

  13. Relationships among androgen receptor CAG repeat polymorphism, sex hormones and penile length in Han adult men from China: a cross-sectional study

    OpenAIRE

    Yan-Min Ma; Kai-Jie Wu; Liang Ning; Jin Zeng; Bo Kou; Hong-Jun Xie; Zhen-Kun Ma; Xin-Yang Wang; Yong-Guang Gong; Da-Lin He

    2014-01-01

    This study aimed to investigate the correlations among androgen receptor (AR) CAG repeat polymorphism, sex hormones and penile length in healthy Chinese young adult men. Two hundred and fifty-three healthy men (aged 22.8 ± 3.1 years) were enrolled. The individuals were grouped as CAG short (CAG S ) if they harbored repeat length of ≤20 or as CAG long (CAG L ) if their CAG repeat length was >20. Body height/weight, penile length and other parameters were examined and recorded by the specified ...

  14. Missing doses in the life span study of Japanese atomic bomb survivors.

    Science.gov (United States)

    Richardson, David B; Wing, Steve; Cole, Stephen R

    2013-03-15

    The Life Span Study of atomic bomb survivors is an important source of risk estimates used to inform radiation protection and compensation. Interviews with survivors in the 1950s and 1960s provided information needed to estimate radiation doses for survivors proximal to ground zero. Because of a lack of interview or the complexity of shielding, doses are missing for 7,058 of the 68,119 proximal survivors. Recent analyses excluded people with missing doses, and despite the protracted collection of interview information necessary to estimate some survivors' doses, defined start of follow-up as October 1, 1950, for everyone. We describe the prevalence of missing doses and its association with mortality, distance from hypocenter, city, age, and sex. Missing doses were more common among Nagasaki residents than among Hiroshima residents (prevalence ratio = 2.05; 95% confidence interval: 1.96, 2.14), among people who were closer to ground zero than among those who were far from it, among people who were younger at enrollment than among those who were older, and among males than among females (prevalence ratio = 1.22; 95% confidence interval: 1.17, 1.28). Missing dose was associated with all-cancer and leukemia mortality, particularly during the first years of follow-up (all-cancer rate ratio = 2.16, 95% confidence interval: 1.51, 3.08; and leukemia rate ratio = 4.28, 95% confidence interval: 1.72, 10.67). Accounting for missing dose and late entry should reduce bias in estimated dose-mortality associations.

  15. Women's risk of repeat abortions is strongly associated with alcohol consumption: a longitudinal analysis of a Russian national panel study, 1994-2009.

    Directory of Open Access Journals (Sweden)

    Katherine Keenan

    Full Text Available Abortion rates in Russia, particularly repeat abortions, are among the highest in the world, and abortion complications make a substantial contribution to the country's high maternal mortality rate. Russia also has a very high rate of hazardous alcohol use. However, the association between alcohol use and abortion in Russia remains unexplored. We investigated the longitudinal predictors of first and repeat abortion, focussing on women's alcohol use as a risk factor. Follow-up data from 2,623 women of reproductive age (16-44 years was extracted from 14 waves of the Russian Longitudinal Monitoring Survey (RLMS, a nationally representative panel study covering the period 1994-2009. We used discrete time hazard models to estimate the probability of having a first and repeat abortion by social, demographic and health characteristics at the preceding study wave. Having a first abortion was associated with demographic factors such as age and parity, whereas repeat abortions were associated with low education and alcohol use. After adjustment for demographic and socioeconomic factors, the risk of having a repeat abortion increased significantly as women's drinking frequency increased (P<0.001, and binge drinking women were significantly more likely to have a repeat abortion than non-drinkers (OR 2.28, 95% CI 1.62-3.20. This association was not accounted for by contraceptive use or a higher risk of pregnancy. Therefore the determinants of first and repeat abortion in Russia between 1994-2009 were different. Women who had repeat abortions were distinguished by their heavier and more frequent alcohol use. The mechanism for the association is not well understood but could be explained by unmeasured personality factors, such as risk taking, or social non-conformity increasing the risk of unplanned pregnancy. Heavy or frequent drinkers constitute a particularly high risk group for repeat abortion, who could be targeted in prevention efforts.

  16. MO-G-BRF-09: Investigating Magnetic Field Dose Effects in Mice: A Monte Carlo Study

    Energy Technology Data Exchange (ETDEWEB)

    Rubinstein, A; Guindani, M; Followill, D; Melancon, A; Hazle, J; Court, L [UT MD Anderson Cancer Center, Houston, TX (United States)

    2014-06-15

    Purpose: In MRI-linac treatments, radiation dose distributions are affected by magnetic fields, especially at high-density/low-density interfaces. Radiobiological consequences of magnetic field dose effects are presently unknown; therefore, preclinical studies are needed to ensure the safe clinical use of MRI-linacs. This study investigates the optimal combination of beam energy and magnetic field strength needed for preclinical murine studies. Methods: The Monte Carlo code MCNP6 was used to simulate the effects of a magnetic field when irradiating a mouse-sized lung phantom with a 1.0cmx1.0cm photon beam. Magnetic field effects were examined using various beam energies (225kVp, 662keV[Cs-137], and 1.25MeV[Co-60]) and magnetic field strengths (0.75T, 1.5T, and 3T). The resulting dose distributions were compared to Monte Carlo results for humans with various field sizes and patient geometries using a 6MV/1.5T MRI-linac. Results: In human simulations, the addition of a 1.5T magnetic field caused an average dose increase of 49% (range:36%–60%) to lung at the soft tissue-to-lung interface and an average dose decrease of 30% (range:25%–36%) at the lung-to-soft tissue interface. In mouse simulations, the magnetic fields had no effect on the 225kVp dose distribution. The dose increases for the Cs-137 beam were 12%, 33%, and 49% for 0.75T, 1.5T, and 3.0T magnetic fields, respectively while the dose decreases were 7%, 23%, and 33%. For the Co-60 beam, the dose increases were 14%, 45%, and 41%, and the dose decreases were 18%, 35%, and 35%. Conclusion: The magnetic field dose effects observed in mouse phantoms using a Co-60 beam with 1.5T or 3T fields and a Cs-137 beam with a 3T field compare well with those seen in simulated human treatments with an MRI-linac. These irradiator/magnet combinations are suitable for preclinical studies investigating potential biological effects of delivering radiation therapy in the presence of a magnetic field. Partially funded by Elekta.

  17. Magnetic Resonance Spectroscopy in Patients with Insomnia: A Repeated Measurement Study.

    Science.gov (United States)

    Spiegelhalder, Kai; Regen, Wolfram; Nissen, Christoph; Feige, Bernd; Baglioni, Chiara; Riemann, Dieter; Hennig, Jürgen; Lange, Thomas

    2016-01-01

    Chronic insomnia is one of the most prevalent central nervous system disorders. It is characterized by increased arousal levels, however, the neurobiological causes and correlates of hyperarousal in insomnia remain to be further determined. In the current study, magnetic resonance spectroscopy was used in the morning and evening in a well-characterized sample of 20 primary insomnia patients (12 females; 8 males; 42.7 ± 13.4 years) and 20 healthy good sleepers (12 females; 8 males; 44.1 ± 10.6 years). The most important inhibitory and excitatory neurotransmitters of the central nervous system, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), were assessed in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). The primary hypothesis, a diurnal effect on GABA levels in patients with insomnia, could not be confirmed. Moreover, the current results did not support previous findings of altered GABA levels in individuals with insomnia. Exploratory analyses, however, suggested that GABA levels in the ACC may be positively associated with habitual sleep duration, and, thus, reduced GABA levels may be a trait marker of objective sleep disturbances. Moreover, there was a significant GROUP x MEASUREMENT TIME interaction effect on Glx in the DLPFC with increasing Glx levels across the day in the patients but not in the control group. Therefore, Glx levels may reflect hyperarousal at bedtime in those with insomnia. Future confirmatory studies should include larger sample sizes to investigate brain metabolites in different subgroups of insomnia.

  18. Global sensitivity analysis for repeated measures studies with informative drop-out: A semi-parametric approach.

    Science.gov (United States)

    Scharfstein, Daniel; McDermott, Aidan; Díaz, Iván; Carone, Marco; Lunardon, Nicola; Turkoz, Ibrahim

    2017-05-23

    In practice, both testable and untestable assumptions are generally required to draw inference about the mean outcome measured at the final scheduled visit in a repeated measures study with drop-out. Scharfstein et al. (2014) proposed a sensitivity analysis methodology to determine the robustness of conclusions within a class of untestable assumptions. In their approach, the untestable and testable assumptions were guaranteed to be compatible; their testable assumptions were based on a fully parametric model for the distribution of the observable data. While convenient, these parametric assumptions have proven especially restrictive in empirical research. Here, we relax their distributional assumptions and provide a more flexible, semi-parametric approach. We illustrate our proposal in the context of a randomized trial for evaluating a treatment of schizoaffective disorder. © 2017, The International Biometric Society.

  19. Supratherapeutic dose evaluation and effect of lesinurad on cardiac repolarization: a thorough QT/QTc study

    Directory of Open Access Journals (Sweden)

    Shen Z

    2016-10-01

    Full Text Available Zancong Shen,1 Michael Gillen,2 Kathy Tieu,1 Mai Nguyen,1 Erin Harmon,1 David M Wilson,1 Bradley Kerr,1 Caroline A Lee1 1Ardea Biosciences, Inc., San Diego, CA, 2AstraZeneca LP, Gaithersburg, MD, USA Introduction: Lesinurad is a selective uric acid reabsorption inhibitor approved in the United States and Europe for treatment of gout in combination with a xanthine oxidase inhibitor. A maximum tolerated dose study was conducted to determine the lesinurad supratherapeutic dose, followed by a thorough QTc study to characterize the effect of lesinurad on cardiac repolarization.Methods: The maximum tolerated dose study was a randomized, double-blind, placebo-controlled, single-ascending dose study that enrolled 35 healthy men and women. Lesinurad plasma exposure (maximum observed plasma concentration and area under the plasma concentration versus time curve was determined at doses of 800 mg, 1,200 mg, and 1,600 mg. The thorough QTc study was a double-blind, four-period, placebo-controlled crossover study with 54 healthy men and women who received single doses of lesinurad 1,600 mg (supratherapeutic dose, lesinurad 400 mg, moxifloxacin 400 mg, and placebo in randomized sequence. Digital 12-lead electrocardiograms were recorded at eleven time points over 24 hours in each treatment period. QT intervals were corrected for heart rate using an individual-specific correction factor (QTcI.Results: The upper bound of the one-sided 95% confidence interval for time-matched, placebo-subtracted, baseline-adjusted QTcI intervals (ΔΔQTcI was <10 ms for both the lesinurad 400 mg and 1,600 mg doses. ΔΔQTcI was independent of lesinurad concentrations. No QTcI thresholds >480 ms or QTcI increases >30 ms were observed. Moxifloxacin mean QTcI intervals were >5 ms, and the lower bounds of the 90% confidence interval were >5 ms at 2 hours, 3 hours, and 4 hours, confirming assay sensitivity.Conclusion: Lesinurad, at supratherapeutic doses, does not

  20. The effect of image quality, repeated study, and assessment method on anatomy learning.

    Science.gov (United States)

    Fenesi, Barbara; Mackinnon, Chelsea; Cheng, Lucia; Kim, Joseph A; Wainman, Bruce C

    2017-06-01

    The use of two-dimensional (2D) images is consistently used to prepare anatomy students for handling real specimen. This study examined whether the quality of 2D images is a critical component in anatomy learning. The visual clarity and consistency of 2D anatomical images was systematically manipulated to produce low-quality and high-quality images of the human hand and human eye. On day 0, participants learned about each anatomical specimen from paper booklets using either low-quality or high-quality images, and then completed a comprehension test using either 2D images or three-dimensional (3D) cadaveric specimens. On day 1, participants relearned each booklet, and on day 2 participants completed a final comprehension test using either 2D images or 3D cadaveric specimens. The effect of image quality on learning varied according to anatomical content, with high-quality images having a greater effect on improving learning of hand anatomy than eye anatomy (high-quality vs. low-quality for hand anatomy P = 0.018; high-quality vs. low-quality for eye anatomy P = 0.247). Also, the benefit of high-quality images on hand anatomy learning was restricted to performance on short-answer (SA) questions immediately after learning (high-quality vs. low-quality on SA questions P = 0.018), but did not apply to performance on multiple-choice (MC) questions (high-quality vs. low-quality on MC questions P = 0.109) or after participants had an additional learning opportunity (24 hours later) with anatomy content (high vs. low on SA questions P = 0.643). This study underscores the limited impact of image quality on anatomy learning, and questions whether investment in enhancing image quality of learning aids significantly promotes knowledge development. Anat Sci Educ 10: 249-261. © 2016 American Association of Anatomists. © 2016 American Association of Anatomists.

  1. Study of the radiological doses and hazard indices in soil samples from Karbala city, Iraq

    CERN Document Server

    Al-Kaabi, Mohammed Abdulhussain

    2015-01-01

    The radiological doses and hazard indices of natural radionuclides $^{238}$U,$^{232}$Th and $^{40} $K in soil samples from Kerbala city were evaluated using gamma-ray spectroscopy system using NaI(Tl) ${"1.5\\times 2"}$ detector in low-background with 24 hour. The average values of absorbed gamma-ray dose rate, annual effective dose equivalent and annual gonadal dose equivalent were found to be 90.83$\\pm$2.00 nGy/h, 111.89$\\pm$2.46 $\\mu$Sv/y and 640.85$\\pm$15.44 $\\mu$Sv/y respectively. The average values of gamma representative level index and external hazard index resulting from natural radionuclides for all samples in the study area were 1.43$\\pm$0.031 and 0.53$\\pm$0.011 respectively. The obtained results in current work were compared with other results for different countries.

  2. [Effectiveness of various dopamine doses in acute myocardial ischemia complicated by cardiogenic shock (an experimental study)].

    Science.gov (United States)

    Kipshidze, N N; Korotkov, A A; Marsagishvili, L A; Prigolashvili, T Sh; Bokhua, M R

    1981-06-01

    The effect of various doses of dopamine on the values of cardiac contractile and hemodynamic function under conditions of acute two-hour ischemia complicated by cardiogenic shock was studied in 27 experiments on dogs. In a dose of 5 microgram/kg/min dopamine caused an optimum increase in cardiac productive capacity, reduction of peripheral resistance, adequate increase in coronary circulation and decrease in ST segment depression on the ECG. Infusion of 10 microgram/kg/min dopamine usually caused myocardial hyperfunction with an increase in total peripheral resistance and cardiac performance. Maximum dopamine doses (10 microgram/kg/min and more) were effective in the areactive form of cardiogenic shock. In longterm dopamine infusion it is necessary to establish continuous control over the hemodynamic parameters and the ECG to prevent aggravation of ischemia and for stage-by-stage reduction of the drug concentration and determination of the minimum maintenance dose.

  3. Does Repeated Ticking Maintain Tic Behavior? An Experimental Study of Eye Blinking in Healthy Individuals

    Directory of Open Access Journals (Sweden)

    Daniel J. V. Beetsma

    2013-01-01

    Full Text Available Tics in Tourette Syndrome (TS are often preceded by 'premonitory urges': annoying feelings or bodily sensations. We hypothesized that, by reducing annoyance of premonitory urges, tic behaviour may be reinforced. In a 2X2 experimental design in healthy participants, we studied the effects of premonitory urges (operationalized as air puffs on the eye and tic behaviour (deliberate eye blinking after a puff or a sound on changes in subjective evaluation of air puffs, and EMG responses on the m. orbicularis oculi. The experimental group with air puffs+ blinking experienced a decrease in subjective annoyance of the air puff, but habituation of the EMG response was blocked and length of EMG response increased. In the control groups (air puffs without instruction to blink, no air puffs, these effects were absent. When extrapolating to the situation in TS patients, these findings suggest that performance of tics is reinforced by reducing the subjective annoyance of premonitory urges, while simultaneously preventing habituation or even inducing sensitisation of the physiological motor response.

  4. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    Directory of Open Access Journals (Sweden)

    Cui Zhi-Hua

    2012-03-01

    Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

  5. Reported food intake and distribution of body fat: a repeated cross-sectional study

    Directory of Open Access Journals (Sweden)

    Stenlund Hans

    2006-12-01

    Full Text Available Abstract Background Body mass, as well as distribution of body fat, are predictors of both diabetes and cardiovascular disease. In Northern Sweden, despite a marked increase in average body mass, prevalence of diabetes was stagnant and myocardial infarctions decreased. A more favourable distribution of body fat is a possible contributing factor. This study investigates the relative importance of individual food items for time trends in waist circumference (WC and hip circumference (HC on a population level. Methods Independent cross-sectional surveys conducted in 1986, 1990, 1994 and 1999 in the two northernmost counties of Sweden with a common population of 250000. Randomly selected age stratified samples, altogether 2982 men and 3087 women aged 25–64 years. Questionnaires were completed and anthropometric measurements taken. For each food item, associations between frequency of consumption and waist and hip circumferences were estimated. Partial regression coefficients for every level of reported intake were multiplied with differences in proportion of the population reporting the corresponding levels of intake in 1986 and 1999. The sum of these product terms for every food item was the respective estimated impact on mean circumference. Results Time trends in reported food consumption associated with the more favourable gynoid distribution of adipose tissue were increased use of vegetable oil, pasta and 1.5% fat milk. Trends associated with abdominal obesity were increased consumption of beer in men and higher intake of hamburgers and French fried potatoes in women. Conclusion Food trends as markers of time trends in body fat distribution have been identified. The method is a complement to conventional approaches to establish associations between food intake and disease risk on a population level.

  6. Breath acidification in adolescent runners exposed to atmospheric pollution: A prospective, repeated measures observational study

    Directory of Open Access Journals (Sweden)

    Van Sickle David

    2008-03-01

    Full Text Available Abstract Background Vigorous outdoors exercise during an episode of air pollution might cause airway inflammation. The purpose of this study was to examine the effects of vigorous outdoor exercise during peak smog season on breath pH, a biomarker of airway inflammation, in adolescent athletes. Methods We measured breath pH both pre- and post-exercise on ten days during peak smog season in 16 high school athletes engaged in daily long-distance running in a downwind suburb of Atlanta. The association of post-exercise breath pH with ambient ozone and particulate matter concentrations was tested with linear regression. Results We collected 144 pre-exercise and 146 post-exercise breath samples from 16 runners (mean age 14.9 years, 56% male. Median pre-exercise breath pH was 7.58 (interquartile range: 6.90 to 7.86 and did not change significantly after exercise. We observed no significant association between ambient ozone or particulate matter and post-exercise breath pH. However both pre- and post-exercise breath pH were strikingly low in these athletes when compared to a control sample of 14 relatively sedentary healthy adults and to published values of breath pH in healthy subjects. Conclusion Although we did not observe an acute effect of air pollution exposure during exercise on breath pH, breath pH was surprisingly low in this sample of otherwise healthy long-distance runners. We speculate that repetitive vigorous exercise may induce airway acidification.

  7. A Monte Carlo study of macroscopic and microscopic dose descriptors for kilovoltage cellular dosimetry

    Science.gov (United States)

    Oliver, P. A. K.; Thomson, Rowan M.

    2017-02-01

    This work investigates how doses to cellular targets depend on cell morphology, as well as relations between cellular doses and doses to bulk tissues and water. Multicellular models of five healthy and cancerous soft tissues are developed based on typical values of cell compartment sizes, elemental compositions and number densities found in the literature. Cells are modelled as two concentric spheres with nucleus and cytoplasm compartments. Monte Carlo simulations are used to calculate the absorbed dose to the nucleus and cytoplasm for incident photon energies of 20-370 keV, relevant for brachytherapy, diagnostic radiology, and out-of-field radiation in higher-energy external beam radiotherapy. Simulations involving cell clusters, single cells and single nuclear cavities are carried out for cell radii between 5 and 10~μ m, and nuclear radii between 2 and 9~μ m. Seven nucleus and cytoplasm elemental compositions representative of animal cells are considered. The presence of a cytoplasm, extracellular matrix and surrounding cells can affect the nuclear dose by up to 13 % . Differences in cell and nucleus size can affect dose to the nucleus (cytoplasm) of the central cell in a cluster of 13 cells by up to 13 % (8 % ). Furthermore, the results of this study demonstrate that neither water nor bulk tissue are reliable substitutes for subcellular targets for incident photon energies  cell model geometry, and the importance of the nucleus and cytoplasm as targets for radiation-induced cell death emphasize the importance of accurate models for cellular dosimetry studies.

  8. Applicability of dose conversion coefficients of ICRP 74 to Asian adult males: Monte Carlo simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Choonsik [Department of Nuclear and Radiological Engineering, University of Florida, Gainesville, FL 32611-8300 (United States)]. E-mail: choonsiklee@gmail.com; Lee, Choonik [Anderson Cancer Center Orlando, Orlando, FL 32806 (United States); Lee, Jai-Ki [Department of Nulcear Engineering, Hanyang University, Haengdang, Sungdong 133-791 (Korea, Republic of)

    2007-05-15

    International Commission on Radiological Protection (ICRP) reported comprehensive dose conversion coefficients for adult population, which is exposed to external photon sources in the Publication 74. However, those quantities were calculated from so-called stylized (or mathematical) phantoms composed of simplified mathematical surface equations so that the discrepancy between the phantoms and real human anatomy has been investigated by several authors using Caucasian-based voxel phantoms. To address anatomical and racial limitations of the stylized phantoms, several Asian-based voxel phantoms have been developed by Korean and Japanese investigators, independently. In the current study, photon dose conversion coefficients of ICRP 74 were compared with those from a total of five Asian-based male voxel phantoms, whose body dimensions were almost identical. Those of representative radio-sensitive organs (testes, red bone marrow, colon, lungs, and stomach), and effective dose conversion coefficients were obtained for comparison. Even though organ doses for testes, colon and lungs, and effective doses from ICRP 74 agreed well with those from Asian voxel phantoms within 10%, absorbed doses for red bone marrow and stomach showed significant discrepancies up to 30% which was mainly attributed to difference of phantom description between stylized and voxel phantoms. This study showed that the ICRP 74 dosimetry data, which have been reported to be unrealistic compared to those from Caucasian-based voxel phantoms, are also not appropriate for Asian population.

  9. Potato glycoalkaloids and adverse effects in humans: an ascending dose study.

    Science.gov (United States)

    Mensinga, Tjeert T; Sips, Adrienne J A M; Rompelberg, Cathy J M; van Twillert, Klaas; Meulenbelt, Jan; van den Top, Hester J; van Egmond, Hans P

    2005-02-01

    Glycoalkaloids in potatoes may induce gastro-intestinal and systemic effects, by cell membrane disruption and acetylcholinesterase inhibition, respectively. The present single dose study was designed to evaluate the toxicity and pharmacokinetics of orally administered potato glycoalkaloids (alpha-chaconine and alpha-solanine). It is the first published human volunteer study were pharmacokinetic data were obtained for more than 24 h post-dose. Subjects (2-3 per treatment) received one of the following six treatments: (1-3) solutions with total glycoalkaloid (TGA) doses of 0.30, 0.50 or 0.70 mg/kg body weight (BW), or (4-6) mashed potatoes with TGA doses of 0.95, 1.10 or 1.25 mg/kg BW. The mashed potatoes had a TGA concentration of nearly 200 mg/kg fresh weight (the presently recognised upper limit of safety). None of these treatments induced acute systemic effects. One subject who received the highest dose of TGA (1.25 mg/kg BW) became nauseous and started vomiting about 4 h post-dose, possibly due to local glycoalkaloid toxicity (although the dosis is lower than generally reported in the literature to cause gastro-intestinal disturbances). Most relevant, the clearance of glycoalkaloids usually takes more than 24 h, which implicates that the toxicants may accumulate in case of daily consumption.

  10. The optimal succinylcholine dose for intubating emergency patients: retrospective comparative study

    Directory of Open Access Journals (Sweden)

    M. Magdy Hussien

    2011-07-01

    Full Text Available Background : Succinylcholine remains the drug of choice for satisfactory rapid-sequence tracheal intubation. It is not clear from the literature why the 1 mg/kg dose of succinylcholine has been traditionally used. The effective dose (ED95 of succinylcholine is less than 0.3 mg/kg. The dose of 1 mg/kg represents 3.5 to 4 times the ED95. Objectives : To compare the effect of the traditionally used 1 mg/kg of succinylcholine with lower doses of 0.6 mg/kg and 0.45 mg/kg on intubation condition regarding the onset time, duration of action, duration of abdominal fasciculation, and the intubation grading. Methods : This retrospective comparative study was carried into three groups of ASA III & IV (American Society of Anesthesiologist's Physical Status III and IV non-prepared emergency patients who were intubated at emergency department of Hamad General Hospital, Doha, Qatar during January 1st 2007 to August 31, 2010. The Institutional Research Board (IRB approval was obtained. This study was limited to 88 patients who received fentanyl 1 µg/kg followed by etomidate 0.3 mg/kg intravenously as induction agents and succinylcholine as a muscle relaxant agent in doses of 0.45 mg/kg, 0.6 mg/kg, or 1 mg/kg. Results : Increasing the succinylcholine dosage shortened the onset time, prolonged the duration of action, and prolonged the duration of abdominal fasciculation significantly (P<.001. Tracheal intubation was 100% successful in the three groups of patients. Conclusion : Succinylcholine dose of 0.45 mg/kg provides an optimal intubation condition in ASA III & IV emergency non-prepared patients. Duration of action of succinylcholine is dose dependent; reducing the dose allows a more rapid return of spontaneous respiration and airway reflexes.

  11. Understanding how adherence goals promote adherence behaviours: a repeated measure observational study with HIV seropositive patients

    Directory of Open Access Journals (Sweden)

    Jones Gareth

    2012-08-01

    behaviours over and above the effects of the behaviour-specific thinking and ii the relationship between adherence to exercise and to medical treatment is stronger among those with more favourable views about the goal. Results from this study should identify the key contributing factors to inform subsequent adherence research and afford a more streamlined assessment matrix. The project also aims to inform patient care practices. UK Clinical Research Network registration number UKCRN 7842.

  12. A new technique for repeated biopsies of the mammary gland in dairy cows allotted to Latin-square design studies.

    Science.gov (United States)

    de Lima, Luciano S; Martineau, Eric; De Marchi, Francilaine E; Palin, Marie-France; Dos Santos, Geraldo T; Petit, Hélène V

    2016-07-01

    The objective of this study was to develop a technique for carrying out repeated biopsies of the mammary gland of lactating dairy cows that provides enough material to monitor enzyme activities and gene expression in mammary secretory tissue. A total of 16 Holstein cows were subjected to 4 mammary biopsies each at 3-week intervals for a total of 64 biopsies. A 0.75-cm incision was made through the skin and subcutaneous tissue of the mammary gland and a trocar and cannula were inserted using a circular motion. The trocar was withdrawn and a syringe was plugged into the base of the cannula to create a vacuum for sampling mammary tissue. To reduce bleeding, hand pressure was put on the surgery site after biopsy and skin closure and ice was applied for at least 2 h after the biopsy using a cow bra. The entire procedure took an average of 25 min. Two attempts were usually enough to obtain 800 mg of tissue. Visual examination of milk samples 10 d after the biopsy indicated no trace of blood, except in samples from 2 cows. All wounds healed without infection and subcutaneous hematomas resorbed within 7 d. There was no incidence of mastitis throughout the lactation. This technique provides a new tool for biopsy of the mammary gland repeated at short intervals with the main effect being a decrease in milk production. Although secondary complications leading to illness or death are always a risk with any procedure, this biopsy technique was carried out without complications to the health of animals and with no incidence of mastitis during the lactation.

  13. Effects of Cold Water Immersion on Muscle Oxygenation During Repeated Bouts of Fatiguing Exercise: A Randomized Controlled Study.

    Science.gov (United States)

    Yeung, Simon S; Ting, Kin Hung; Hon, Maurice; Fung, Natalie Y; Choi, Manfi M; Cheng, Juno C; Yeung, Ella W

    2016-01-01

    Postexercise cold water immersion has been advocated to athletes as a means of accelerating recovery and improving performance. Given the effects of cold water immersion on blood flow, evaluating in vivo changes in tissue oxygenation during cold water immersion may help further our understanding of this recovery modality. This study aimed to investigate the effects of cold water immersion on muscle oxygenation and performance during repeated bouts of fatiguing exercise in a group of healthy young adults. Twenty healthy subjects performed 2 fatiguing bouts of maximal dynamic knee extension and flexion contractions both concentrically on an isokinetic dynamometer with a 10-min recovery period in between. Subjects were randomly assigned to either a cold water immersion (treatment) or passive recovery (control) group. Changes in muscle oxygenation were monitored continuously using near-infrared spectroscopy. Muscle performance was measured with isokinetic dynamometry during each fatiguing bout. Skin temperature, heart rate, blood pressure, and muscle soreness ratings were also assessed. Repeated measures ANOVA analysis was used to evaluate treatment effects. The treatment group had a significantly lower mean heart rate and lower skin temperature compared to the control group (P Cold water immersion attenuated a reduction in tissue oxygenation in the second fatiguing bout by 4% when compared with control. Muscle soreness was rated lower 1 day post-testing (P cold water immersion had no significant effect on muscle performance in subsequent exercise. As the results show that cold water immersion attenuated decreased tissue oxygenation in subsequent exercise performance, the metabolic response to exercise after cold water immersion is worthy of further exploration.

  14. High-Throughput Mycobacterial Interspersed Repetitive-Unit–Variable-Number Tandem-Repeat Genotyping for Mycobacterium tuberculosis Epidemiological Studies

    Science.gov (United States)

    Bidault, Floriane; Mosnier, Amandine; Bablishvili, Nino; Tukvadze, Nestani; Somphavong, Silaphet; Paboriboune, Phimpha; Ocheretina, Oksana; Pape, Jean William; Paranhos-Baccala, Glaucia; Berland, Jean-Luc

    2014-01-01

    The emergence of drug-resistant forms of tuberculosis (TB) represents a major public health concern. Understanding the transmission routes of the disease is a key factor for its control and for the implementation of efficient interventions. Mycobacterial interspersed repetitive-unit–variable-number tandem-repeat (MIRU-VNTR) marker typing is a well-described method for lineage identification and transmission tracking. However, the conventional manual genotyping technique is cumbersome and time-consuming and entails many risks for errors, thus hindering its implementation and dissemination. We describe here a new approach using the QIAxcel system, an automated high-throughput capillary electrophoresis system that also carries out allele calling. This automated method was assessed on 1,824 amplicons from 82 TB isolates and tested with sets of markers of 15 or 24 loci. Overall allele-calling concordance between the methods from 140 to 1,317 bp was 98.9%. DNA concentrations and repeatability and reproducibility performances showed no biases in allele calling. Furthermore, turnaround time using this automated system was reduced by 81% compared to the conventional manual agarose gel method. In sum, this new automated method facilitates MIRU-VNTR genotyping and provides reliable results. Therefore, it is well suited for field genotyping. The implementation of this method will help to achieve accurate and cost-effective epidemiological studies, especially in countries with a high prevalence of TB, where the high number of strains complicates the surveillance of circulating lineages and requires efficient interventions to be carried out in an urgent manner. PMID:25428144

  15. A population-based study of dosing and persistence with anti-dementia medications.

    LENUS (Irish Health Repository)

    Brewer, Linda

    2013-02-27

    PURPOSE: Cholinesterase inhibitors and memantine are the mainstay of pharmacological intervention for the cognitive symptoms of Alzheimer\\'s disease (AD). This study assessed the adequacy of dosing and persistence with AD medications and the predictors of these variables in the \\'real world\\' (outside the clinical trial setting). METHODS: The Health Service Executive-Primary Care Reimbursement Services prescription claims database in the Republic of Ireland contains prescription information for 1.6 million people. Patients aged >70 years who received at least two prescriptions for donepezil, rivastigmine, galantamine and memantine between January 2006 and December 2010 were included in the study. Rates of dose-maximisation were recorded by examining the initiation dose of each AD drug commenced during the study period and any subsequent dose titrations. Non-persistence was defined by a gap in prescribing of more than 63 consecutive days. Predictors of dose-maximisation and non-persistence were also analysed. RESULTS: Between January 2006 and December 2010, 20,729 patients aged >70 years received a prescription for an AD medication. Despite most patients on donepezil and memantine receiving a prescription for the maximum drug dose, this dose was maintained for 2 consecutive months in only two-thirds of patients. Patients were significantly more likely to have their doses of donepezil and memantine maximised if prescribed in more recent years (2010 vs. 2007). Rates of non-persistence were 30.1 % at 6 months and 43.8 % at 12 months. Older age [75+ vs. <75 years; hazards ratio (HR) 1.16, 95 % confidence interval (CI) 1.06-1.27] and drug type (rivastigmine vs. donepezil; HR 1.15, 95 % CI 1.03-1.27) increased the risk of non-persistence. Non-persistence was lower for those commencing therapy in more recent years (2010 vs. 2007; HR 0.81, 95 % CI 0.73-0.89, p < 0.001) and for those on multiple anti-dementia medications (HR 0.59, 95 % CI 0

  16. Correction for FDG PET dose extravasations: Monte Carlo validation and quantitative evaluation of patient studies

    Energy Technology Data Exchange (ETDEWEB)

    Silva-Rodríguez, Jesús, E-mail: jesus.silva.rodriguez@sergas.es; Aguiar, Pablo, E-mail: pablo.aguiar.fernandez@sergas.es [Fundación Ramón Domínguez, Santiago de Compostela, Galicia (Spain); Servicio de Medicina Nuclear, Complexo Hospitalario Universidade de Santiago de Compostela (USC), 15782, Galicia (Spain); Grupo de Imaxe Molecular, Instituto de Investigación Sanitarias (IDIS), Santiago de Compostela, 15706, Galicia (Spain); Sánchez, Manuel; Mosquera, Javier; Luna-Vega, Víctor [Servicio de Radiofísica y Protección Radiológica, Complexo Hospitalario Universidade de Santiago de Compostela (USC), 15782, Galicia (Spain); Cortés, Julia; Garrido, Miguel [Servicio de Medicina Nuclear, Complexo Hospitalario Universitario de Santiago de Compostela, 15706, Galicia, Spain and Grupo de Imaxe Molecular, Instituto de Investigación Sanitarias (IDIS), Santiago de Compostela, 15706, Galicia (Spain); Pombar, Miguel [Servicio de Radiofísica y Protección Radiológica, Complexo Hospitalario Universitario de Santiago de Compostela, 15706, Galicia (Spain); Ruibal, Álvaro [Servicio de Medicina Nuclear, Complexo Hospitalario Universidade de Santiago de Compostela (USC), 15782, Galicia (Spain); Grupo de Imaxe Molecular, Instituto de Investigación Sanitarias (IDIS), Santiago de Compostela, 15706, Galicia (Spain); Fundación Tejerina, 28003, Madrid (Spain)

    2014-05-15

    Purpose: Current procedure guidelines for whole body [18F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) state that studies with visible dose extravasations should be rejected for quantification protocols. Our work is focused on the development and validation of methods for estimating extravasated doses in order to correct standard uptake value (SUV) values for this effect in clinical routine. Methods: One thousand three hundred sixty-seven consecutive whole body FDG-PET studies were visually inspected looking for extravasation cases. Two methods for estimating the extravasated dose were proposed and validated in different scenarios using Monte Carlo simulations. All visible extravasations were retrospectively evaluated using a manual ROI based method. In addition, the 50 patients with higher extravasated doses were also evaluated using a threshold-based method. Results: Simulation studies showed that the proposed methods for estimating extravasated doses allow us to compensate the impact of extravasations on SUV values with an error below 5%. The quantitative evaluation of patient studies revealed that paravenous injection is a relatively frequent effect (18%) with a small fraction of patients presenting considerable extravasations ranging from 1% to a maximum of 22% of the injected dose. A criterion based on the extravasated volume and maximum concentration was established in order to identify this fraction of patients that might be corrected for paravenous injection effect. Conclusions: The authors propose the use of a manual ROI based method for estimating the effectively administered FDG dose and then correct SUV quantification in those patients fulfilling the proposed criterion.

  17. The impact of dropouts on the analysis of dose-finding studies with recurrent event data.

    Science.gov (United States)

    Akacha, Mouna; Benda, Norbert

    2010-07-10

    This work is motivated by dose-finding studies, where the number of events per subject within a specified study period form the primary outcome. The aim of the considered studies is to identify the target dose for which the new drug can be shown to be as effective as a competitor medication. Given a pain-related outcome, we expect a considerable number of patients to drop out before the end of the study period. The impact of missingness on the analysis and models for the missingness process must be carefully considered.The recurrent events are modeled as over-dispersed Poisson process data, with dose as the regressor. Additional covariates may be included. Constant and time-varying rate functions are examined. Based on these models, the impact of missingness on the precision of the target dose estimation is evaluated. Diverse models for the missingness process are considered, including dependence on covariates and number of events. The performances of five different analysis methods are assessed via simulations: a complete case analysis; two analyses using different single imputation techniques; a direct-likelihood analysis and an analysis using pattern-mixture models.The target dose estimation is robust if the same missingness process holds for the target dose group and the active control group. Furthermore, we demonstrate that this robustness is lost as soon as the missingness mechanisms for the active control and the target dose differ. Of the methods explored, the direct-likelihood approach performs best, even when a missing not at random mechanism holds.

  18. Commercial production and distribution of fresh fruits and vegetables: A scoping study on the importance of produce pathways to dose. Hanford Environmental Dose Reconstruction Project

    Energy Technology Data Exchange (ETDEWEB)

    Marsh, T.L.; Anderson, D.M.; Farris, W.T.; Ikenberry, T.A.; Napier, B.A.; Wilfert, G.L.

    1992-09-01

    This letter report summarizes a scoping study that examined the potential importance of fresh fruit and vegetable pathways to dose. A simple production index was constructed with data collected from the Washington State Department of Agriculture (WSDA), the United States Bureau of the Census, and the United States Department of Agriculture (USDA). Hanford Environmental Dose Reconstruction (HEDR) Project staff from Battelle, Pacific Northwest Laboratories, in cooperation with members of the Technical Steering Panel (TSP), selected lettuce and spinach as the produce pathways most likely to impact dose. County agricultural reports published in 1956 provided historical descriptions of the predominant distribution patterns of fresh lettuce and spinach from production regions to local population centers. Pathway rankings and screening dose estimates were calculated for specific populations living in selected locations within the HEDR study area.

  19. Commercial production and distribution of fresh fruits and vegetables: A scoping study on the importance of produce pathways to dose. Hanford Environmental Dose Reconstruction Project

    Energy Technology Data Exchange (ETDEWEB)

    Marsh, T.L.; Anderson, D.M.; Farris, W.T.; Ikenberry, T.A.; Napier, B.A.; Wilfert, G.L.

    1992-09-01

    This letter report summarizes a scoping study that examined the potential importance of fresh fruit and vegetable pathways to dose. A simple production index was constructed with data collected from the Washington State Department of Agriculture (WSDA), the United States Bureau of the Census, and the United States Department of Agriculture (USDA). Hanford Environmental Dose Reconstruction (HEDR) Project staff from Battelle, Pacific Northwest Laboratories, in cooperation with members of the Technical Steering Panel (TSP), selected lettuce and spinach as the produce pathways most likely to impact dose. County agricultural reports published in 1956 provided historical descriptions of the predominant distribution patterns of fresh lettuce and spinach from production regions to local population centers. Pathway rankings and screening dose estimates were calculated for specific populations living in selected locations within the HEDR study area.

  20. Study of effective dose of various protocols in equipment cone beam CT

    Energy Technology Data Exchange (ETDEWEB)

    Soares, M. R.; Maia, A. F. [Universidade Federale de Sergipe, Departamento de Fisica, Cidade Universitaria Prof. Jose Aloisio de Campos, Marechal Rondon s/n, Jardim Rosa Elze, 49-100000 Sao Cristovao, Sergipe (Brazil); Batista, W. O. [Instituto Federal da Bahia, Rua Emidio dos Santos s/n, Barbalho, Salvador, 40301015 Bahia (Brazil); Caldas, L. V. E.; Lara, P. A., E-mail: mrs2206@gmail.com [Instituto de Pesquisas Energeticas e Nucleares / CNEN, Av. Lineu Prestes 2242, Cidade Universitaria, 05508-000 Sao Paulo (Brazil)

    2014-08-15

    Currently the cone beam computed tomography is widely used in various procedures of dental radiology. Although the doses values associated with the procedures of cone beam CT are low compared to typical values associated with dental radiology procedure in multi slices CT. However can be high compared to typical values of other techniques commonly used in dental radiology. The present scenario is a very wide range of designs of equipment and, consequently, lack of uniformity in all parameters associated with x-ray generation and geometry. In this context, this study aimed to evaluate and calculate the absorbed dose in organs and tissues relevant and estimate effective dose for different protocols with different geometries of exposure in five cone beam CT equipment. For this, a female Alderson anthropomorphic phantom, manufactured by Radiology Support Devices was used. The phantom was irradiated with 26 dosimeters LiF: Mg, Ti (TLD-100), inserted in organs and tissues along the layers forming the head and neck of the phantom. The equipment used, in this present assessment, was: i-CAT Classical, Kodak 9000 3D, Gendex GXCB 500, Sirona Orthophos X G 3D and Planmeca Pro Max 3D. The effective doses were be determined by the ICRP 103 weighting factors. The values were between 7.0 and 111.5 micro Sv, confirming the broad dose range expected due to the diversity of equipment and protocols used in each equipment. The values of effective dose per Fov size were: between 7 and 51.2 micro Sv for located Fov; between 17.6 and 52.0 micro Sv for medium Fov; and between 11.5 and 43.1 micro Sv to large Fov (maxillofacial). In obtaining the effective dose the measurements highlighted a relevance contribution of dose absorbed by the remaining organs (36%), Salivary glands (30%), thyroid (12%) and bone marrow (12%). (Author)

  1. EPR and UV spectroscopic study of table sugar as a high-dose dosimeter

    Energy Technology Data Exchange (ETDEWEB)

    Yordanov, N.D. E-mail: ndyepr@bas.bg; Gancheva, V.; Georgieva, E

    2002-10-01

    The possibilities for the estimation of the absorbed dose for high-energy radiation with a new self-calibrated dosimeter containing table sugar as a radiation-sensitive material and Mn{sup 2+}/MgO as an internal standard by the method of electron paramagnetic resonance (EPR) is reported. The dose response of this dosimeter is represented as the ratio between the EPR signal intensities of sugar and Mn{sup 2+} versus absorbed dose. Because the EPR spectra of both substances are simultaneously recorded, the influence of some related instrumental setting parameters were investigated. UV spectral studies on water solutions of irradiated solid sugar were also performed. In all solutions of irradiated sugar samples a band at 267 nm was recorded as linearly increasing intensity with the absorbed dose. The minimum detectable dose using the UV spectrum of water solutions of irradiated sugar is 100 Gy. Combination of EPR and UV spectral data is possible to use for independent internal or international calibration and control of dose estimations.

  2. Development of hibernomas in rats dosed with phentolamine mesylate during the 24-month carcinogenicity study.

    Science.gov (United States)

    Poulet, Frederique M; Berardi, Mark R; Halliwell, William; Hartman, Barbara; Auletta, Carol; Bolte, Henry

    2004-01-01

    Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora cavernosa. Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets. This study documents the previously unreported development of hibernomas in rats treated with phentolamine mesylate.

  3. Image quality vs. radiation dose for a flat-panel amorphous silicon detector: a phantom study.

    Science.gov (United States)

    Geijer, H; Beckman, K W; Andersson, T; Persliden, J

    2001-01-01

    The aim of this study was to investigate the image quality for a flat-panel amorphous silicon detector at various radiation dose settings and to compare the results with storage phosphor plates and a screen-film system. A CDRAD 2.0 contrast-detail phantom was imaged with a flat-panel detector (Philips Medical Systems, Eindhoven, The Netherlands) at three different dose levels with settings for intravenous urography. The same phantom was imaged with storage phosphor plates at a simulated system speed of 200 and a screen-film system with a system speed of 160. Entrance surface doses were recorded for all images. At each setting, three images were read by four independent observers. The flat-panel detector had equal image quality at less than half the radiation dose compared with storage phosphor plates. The difference was even larger when compared with film with the flat-panel detector having equal image quality at approximately one-fifth the dose. The flat-panel detector has a very favourable combination of image quality vs radiation dose compared with storage phosphor plates and screen film.

  4. Image quality vs radiation dose for a flat-panel amorphous silicon detector: a phantom study

    Energy Technology Data Exchange (ETDEWEB)

    Geijer, H.; Andersson, T. [Dept. of Radiology, Oerebro Medical Centre Hospital (Sweden); Beckman, K.W.; Persliden, J. [Dept. of Medical Physics, Oerebro Medical Centre Hospital (Sweden)

    2001-09-01

    The aim of this study was to investigate the image quality for a flat-panel amorphous silicon detector at various radiation dose settings and to compare the results with storage phosphor plates and a screen-film system. A CDRAD 2.0 contrast-detail phantom was imaged with a flat-panel detector (Philips Medical Systems, Eindhoven, The Netherlands) at three different dose levels with settings for intravenous urography. The same phantom was imaged with storage phosphor plates at a simulated system speed of 200 and a screen-film system with a system speed of 160. Entrance surface doses were recorded for all images. At each setting, three images were read by four independent observers. The flat-panel detector had equal image quality at less than half the radiation dose compared with storage phosphor plates. The difference was even larger when compared with film with the flat-panel detector having equal image quality at approximately one-fifth the dose. The flat-panel detector has a very favourable combination of image quality vs radiation dose compared with storage phosphor plates and screen film. (orig.)

  5. Study of the CT peripheral dose variation in a chest phantom

    Energy Technology Data Exchange (ETDEWEB)

    Alonso, T. C.; Da Silva, T. A. [Development Center of Nuclear Technology / CNEN, Av. Pte. Antonio Carlos 6627, 31270-901 Belo Horizonte, Minas Gerais (Brazil); Mourao F, A. P., E-mail: alonso@cdtn.br [Federal University of Minas Gerais, Nuclear Energy Department, Program of Nuclear Science and Techniques, 31270-901 Belo Horizonte, Minas Gerais (Brazil)

    2015-10-15

    Full text: Computed Tomography (CT) grows every year and is a diagnostic method that has revolutionized radiology with advances in procedures for obtaining image. However, the indiscriminate use of this method generates relatively high doses in patients. The diagnostic reference levels (DRL) is a practical tool to promote the evaluation of existing protocols. The optimization and the periodic review of the protocols are important to balance the risk of radiation. The purpose of this study is to investigate, in a chest scan, the variation of dose in CT. To measure the dose profile are used lithium fluoride thermoluminescent dosimeters distributed in cylinders positioned in peripheral and central regions of a phantom of polymethylmethacrylate (PMMA). The data obtained allow to observe the variation of the dose profile inside the phantom. The peripheral region shows higher dose values than the central region. The longitudinal variation can be observed and the maximum dose was recorded at the edges of the phantom (15,99 ± 2,80) mGy at the midpoint of the longitudinal axis. The results will contribute to disseminate the proper procedure and optimize the dosimetry and the tests of quality control in CT, as well as make a critical analysis of the DRL. (Author)

  6. Application of passive dosing to study the biotransformation and biodegradation of hydrophobic

    DEFF Research Database (Denmark)

    Smith, Kilian E. C.; Rein, Arno; Heringa, MB

    is significant even at low dissolved concentrations thus facilitating measurement of the relevant endpoint (e.g., metabolic products in biotransformation or growth in biodegradation). This study details two applications of passive dosing for studying bio-transformation/degradation. A format has been developed...... to study the biodegradation of phenanthrene and fluoranthene by the bacterial strain EPA 505, allowing degradation rates to be quantified at defined freely dissolved concentrations from mg/L down to ng/L levels. Passive dosing was also applied for quantifying the mutagenicity of benzo(a)pyrene metabolites...

  7. Application of passive dosing to study the biotransformation and biodegradation of hydrophobic compounds

    DEFF Research Database (Denmark)

    Smith, E. C.; Rein, Arno; Trapp, Stefan

    2011-01-01

    is significant even at low dissolved concentrations thus facilitating measurement of the relevant endpoint (e.g., metabolic products in biotransformation or growth in biodegradation). This study details two applications of passive dosing for studying bio-transformation/degradation. A format has been developed...... to study the biodegradation of phenanthrene and fluoranthene by the bacterial strain EPA 505, allowing degradation rates to be quantified at defined freely dissolved concentrations from mg/L down to ng/L levels. Passive dosing was also applied for quantifying the mutagenicity of benzo(a)pyrene metabolites...

  8. Dose-response study of spinal hyperbaric ropivacaine for cesarean section

    Institute of Scientific and Technical Information of China (English)

    CHEN Xin-zhong; CHEN Hong; LOU Ai-fei; L(U) Chang-cheng

    2006-01-01

    Background: Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind,randomized, dose-response study determined the ED50 (50% effective dose) and ED95 (95% effective dose) of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods: Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1~L2 vertebral interspace,then lumbar puncture was performed at the L3~L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels (pinprick) were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective ifan upper sensory level to pin prick ofT7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results: ED50 (95% confidence interval)of spinal hyperbaric ropivacaine was determined to be 10.37 (5.23~11.59) mg and ED95 (95% confidence interval) to be 15.39(13.81~23.59) mg. The maximum sensory block levels and the duration of motor block and the rate ofhypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion: The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery.

  9. The impact of low-Z and high-Z metal implants in IMRT: A Monte Carlo study of dose inaccuracies in commercial dose algorithms

    Energy Technology Data Exchange (ETDEWEB)

    Spadea, Maria Francesca, E-mail: mfspadea@unicz.it [Department of Experimental and Clinical Medicine, University of Magna Graecia, Catanzaro 88100, Italy and Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 (United States); Verburg, Joost Mathias; Seco, Joao [Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 (United States); Baroni, Guido [Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano University, Milano 20133, Italy and Bioengineering Unit, Fondazione CNAO, Pavia 27100 (Italy)

    2014-01-15

    Purpose: The aim of the study was to evaluate the dosimetric impact of low-Z and high-Z metallic implants on IMRT plans. Methods: Computed tomography (CT) scans of three patients were analyzed to study effects due to the presence of Titanium (low-Z), Platinum and Gold (high-Z) inserts. To eliminate artifacts in CT images, a sinogram-based metal artifact reduction algorithm was applied. IMRT dose calculations were performed on both the uncorrected and corrected images using a commercial planning system (convolution/superposition algorithm) and an in-house Monte Carlo platform. Dose differences between uncorrected and corrected datasets were computed and analyzed using gamma index (Pγ{sub <1}) and setting 2 mm and 2% as distance to agreement and dose difference criteria, respectively. Beam specific depth dose profiles across the metal were also examined. Results: Dose discrepancies between corrected and uncorrected datasets were not significant for low-Z material. High-Z materials caused under-dosage of 20%–25% in the region surrounding the metal and over dosage of 10%–15% downstream of the hardware. Gamma index test yielded Pγ{sub <1}>99% for all low-Z cases; while for high-Z cases it returned 91% < Pγ{sub <1}< 99%. Analysis of the depth dose curve of a single beam for low-Z cases revealed that, although the dose attenuation is altered inside the metal, it does not differ downstream of the insert. However, for high-Z metal implants the dose is increased up to 10%–12% around the insert. In addition, Monte Carlo method was more sensitive to the presence of metal inserts than superposition/convolution algorithm. Conclusions: The reduction in terms of dose of metal artifacts in CT images is relevant for high-Z implants. In this case, dose distribution should be calculated using Monte Carlo algorithms, given their superior accuracy in dose modeling in and around the metal. In addition, the knowledge of the composition of metal inserts improves the accuracy of

  10. Huntington CAG repeat size does not modify onset age in familial Parkinson’s disease: The GenePD Study

    Science.gov (United States)

    McNicoll, Christopher F.; Latourelle, Jeanne C.; MacDonald, Marcy E.; Lew, Mark F.; Suchowersky, Oksana; Klein, Christine; Golbe, Lawrence I.; Mark, Margery H.; Growdon, John H.; Wooten, G. Frederick; Watts, Ray L.; Guttman, Mark; Racette, Brad A.; Perlmutter, Joel S.; Ahmed, Anwar; Shill, Holly A.; Singer, Carlos; Saint-Hilaire, Marie H.; Massood, Tiffany; Huskey, Karen W.; DeStefano, Anita L.; Gillis, Tammy; Mysore, Jayalakshmi; Goldwurm, Stefano; Pezzoli, Gianni; Baker, Kenneth B.; Itin, Ilia; Litvan, Irene; Nicholson, Garth; Corbett, Alastair; Nance, Martha; Drasby, Edward; Isaacson, Stuart; Burn, David J.; Chinnery, Patrick F.; Pramstaller, Peter P.; Al-hinti, Jomana; Moller, Anette T.; Ostergaard, Karen; Sherman, Scott J.; Roxburgh, Richard; Snow, Barry; Slevin, John T.; Cambi, Franca; Gusella, James F.; Myers, Richard H.

    2009-01-01

    The ATP/ADP ratio reflects mitochondrial function and has been reported to be influenced by the size of the Huntington disease gene (HD) repeat. Impaired mitochondrial function has long been implicated in the pathogenesis of Parkinson’s disease (PD) and therefore, we evaluated the relationship of the HD CAG repeat size to PD onset age in a large sample of familial PD cases. PD affected siblings (n=495) with known onset ages from 248 families, were genotyped for the HD CAG repeat. Genotyping failed in 11 cases leaving 484 for analysis, including 35 LRRK2 carriers. All cases had HD CAG repeats (range 15 to 34) below the clinical range for HD, although 5.2 percent of the sample (n=25) had repeats in the intermediate range (the intermediate range lower limit=27; upper limit=35 repeats), suggesting that the prevalence of intermediate allele carriers in the general population is significant. No relation between the HD CAG repeat size and the age at onset for PD was found in this sample of familial PD. PMID:18649400

  11. Assessment of individual dose utilization vs. physician prescribing recommendations for recombinant activated factor VII (rFVIIa) in paediatric and adult patients with congenital haemophilia and alloantibody inhibitors (CHwI): the Dosing Observational Study in Hemophilia (DOSE).

    Science.gov (United States)

    Gruppo, R A; Kessler, C M; Neufeld, E J; Cooper, D L

    2013-07-01

    Recent data from the Dosing Observational Study in Hemophilia diary study has described home treatment with recombinant activated factor VII (rFVIIa) in congenital haemophilia with inhibitors (CHwI). The current analysis compares prescribed and patient/caregiver-reported rFVIIa administration in paediatric and adult CHwI patients in this study. Patients with ≥ 4 bleeding episodes within a 3-month period prescribed rFVIIa as first-line therapy for bleeding episodes were eligible. Patients/caregivers completed a diary for ≥ 90 days or until the patient experienced four bleeds. Initial, total and mean rFVIIa doses reported for each bleeding episode were calculated and compared with the physician-prescribed doses. Of 52 enrolled patients (25 children; 27 adults), 39 (75%) completed the study. Children and adults had similar mean durations of bleeding episodes. Both patient groups were administered higher initial rFVIIa doses for joint bleeds than prescribed: median (range) 215.2 (74.1-400.0) mcg kg(-1) vs. 200.0 (61.0-270.0) mcg kg(-1) for children, and 231.3 (59.3-379.7) mcg kg(-1) vs. 123.0 (81.0-289.0) mcg kg(-1) for adults. The median infused dose for joint bleeds was higher in adults than children (175.2 vs. 148.0 mcg kg(-1) ), but children received significantly more doses per joint bleed than adults (median 6.5 vs. 3.0). The median total dose per joint bleed was higher in children than adults (1248.7 vs. 441.6). For children and adults, both initial and additional doses administered for bleeds were higher than prescribed. Children received higher total doses per bleed due to an increased number of infusions per bleed.

  12. High-dose-rate-intracavitary brachytherapy applications and the difference in the bladder and rectum doses: A study from rural centre of Maharashatra, India

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    Jain Vandana

    2007-01-01

    Full Text Available Aim : To report the difference in the bladder and rectum doses with different applications by the radiotherapists in the same patient of the carcinoma of the uterine cervix treated by multiple fractions of high-dose-rate (HDR intracavitary brachytherapy (ICBT. Materials and Methods : Between January 2003 to December 2004, a total of 60 cases of the carcinoma uterine cervix were selected randomly for the retrospective analyses. All 60 cases were grouped in six groups according to the treating radiotherapist who did the HDR-ICBT application. Three radiotherapists were considered for this study, named A, B and C. Ten cases for each radiotherapist in whom all three applications were done by the same radiotherapist. And 10 cases for each radiotherapist with shared applications in the same patient (A+B, A+C and B+C. The bladder and rectal doses were calculated in reference to point "A" dose and were limited to 80% of prescribed point "A" dose, as per ICRU-38 recommendations. Received dose grouped in three groups- less then 80% (< 80%, 80-100% and above 100% (>100%. A total of 180 applications for 60 patients were calculated for the above analyses. Results : There is a lot of difference in the bladder and rectal doses with the application by the different radiotherapists, even in the same patient with multiple fractions of HDR-ICBT. Applications by ′A′ radiotherapist were within the limits in the self as well as in the shared groups more number of times, by ′B′ radiotherapist was more times exceeding the limit and by ′C′ radiotherapist doses were in between the A and B. Discussion and Conclusion : For the rectal and bladder doses most important factors are patient′s age, disease stage, duration between EBRT and HDR-ICRT and patient anatomy, but these differences can be minimized to some extent by careful application, proper packing and proper fixation.

  13. A new dosing schedule for gentamicin in blood pythons (Python curtus): a pharmacokinetic study.

    Science.gov (United States)

    Hilf, M; Swanson, D; Wagner, R; Yu, V L

    1991-03-01

    Gentamicin is frequently used in the treatment of aerobic Gram-negative infections in reptiles. Pharmacokinetic data to ensure proper dosing are scant, especially for large snakes. A pharmacokinetic study of gentamicin was therefore conducted in four blood pythons. Snakes were given intramus