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Sample records for linear dose response

  1. Non-Linear Dose-Response Relationships in Biology, Toxicology and Medicine

    DTIC Science & Technology

    2007-11-02

    The purpose of the conference was to attract researchers from diverse backgrounds who are working in the common area of non-linear dose - response relationships...This unique interdisciplinary conference represents an important step in furthering the understanding of the occurrence, origin, mechanisms, significance and practical applications of non-linear dose - response relationships.

  2. Linear and non-linear dose-response functions reveal a hormetic relationship between stress and learning.

    PubMed

    Zoladz, Phillip R; Diamond, David M

    2008-10-16

    Over a century of behavioral research has shown that stress can enhance or impair learning and memory. In the present review, we have explored the complex effects of stress on cognition and propose that they are characterized by linear and non-linear dose-response functions, which together reveal a hormetic relationship between stress and learning. We suggest that stress initially enhances hippocampal function, resulting from amygdala-induced excitation of hippocampal synaptic plasticity, as well as the excitatory effects of several neuromodulators, including corticosteroids, norepinephrine, corticotropin-releasing hormone, acetylcholine and dopamine. We propose that this rapid activation of the amygdala-hippocampus brain memory system results in a linear dose-response relation between emotional strength and memory formation. More prolonged stress, however, leads to an inhibition of hippocampal function, which can be attributed to compensatory cellular responses that protect hippocampal neurons from excitotoxicity. This inhibition of hippocampal functioning in response to prolonged stress is potentially relevant to the well-described curvilinear dose-response relationship between arousal and memory. Our emphasis on the temporal features of stress-brain interactions addresses how stress can activate, as well as impair, hippocampal functioning to produce a hormetic relationship between stress and learning.

  3. IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?

    EPA Science Inventory

    IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?
    Preston, RJ. Environmental Carcinogenesis Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

    For considerations of cancer risk assessment from exposure to environmenta...

  4. Linearization of dose-response curve of the radiochromic film dosimetry system

    SciTech Connect

    Devic, Slobodan; Tomic, Nada; Aldelaijan, Saad; DeBlois, Francois; Seuntjens, Jan; Chan, Maria F.; Lewis, Dave

    2012-08-15

    Purpose: Despite numerous advantages of radiochromic film dosimeter (high spatial resolution, near tissue equivalence, low energy dependence) to measure a relative dose distribution with film, one needs to first measure an absolute dose (following previously established reference dosimetry protocol) and then convert measured absolute dose values into relative doses. In this work, we present result of our efforts to obtain a functional form that would linearize the inherently nonlinear dose-response curve of the radiochromic film dosimetry system. Methods: Functional form [{zeta}= (-1){center_dot}netOD{sup (2/3)}/ln(netOD)] was derived from calibration curves of various previously established radiochromic film dosimetry systems. In order to test the invariance of the proposed functional form with respect to the film model used we tested it with three different GAFCHROMIC Trade-Mark-Sign film models (EBT, EBT2, and EBT3) irradiated to various doses and scanned on a same scanner. For one of the film models (EBT2), we tested the invariance of the functional form to the scanner model used by scanning irradiated film pieces with three different flatbed scanner models (Epson V700, 1680, and 10000XL). To test our hypothesis that the proposed functional argument linearizes the response of the radiochromic film dosimetry system, verification tests have been performed in clinical applications: percent depth dose measurements, IMRT quality assurance (QA), and brachytherapy QA. Results: Obtained R{sup 2} values indicate that the choice of the functional form of the new argument appropriately linearizes the dose response of the radiochromic film dosimetry system we used. The linear behavior was insensitive to both film model and flatbed scanner model used. Measured PDD values using the green channel response of the GAFCHROMIC Trade-Mark-Sign EBT3 film model are well within {+-}2% window of the local relative dose value when compared to the tabulated Cobalt-60 data. It was also

  5. Linearization of EBT3 film dose response and virtual film dosimetry for SBRT quality assurance

    NASA Astrophysics Data System (ADS)

    Cai, M.; Archibald-Heeren, B.; Wang, Y.; Metcalfe, P.

    2017-01-01

    EBT3 film offers high spatial resolution and low energy dependence, making it a suitable choice for quality assurance where high dose gradients are present, such as the case for SBRT. This work presents a simple method to adjust scanner settings so that dose response becomes linear. This linearity eliminates the need to obtain a calibration curve and associated uncertainties in curve fitting. Relative dosimetry can be performed after dose normalization to a reference point. Linearity is also a more robust condition than calibration curve with respect to scanner warm-up conditions, resulting in reduced uncertainty in dose measurement. An in-house developed program reads the film scan and a 2D dose map then constructs both to virtual films using grayscale values. Film intensity value was normalized to dose at reference point. Relative dosimetry was performed by comparing the two resulting images. Patient specific quality assurance was conducted for two SBRT cases. In both plans more than 95% gamma function points passed the gamma criteria of 2%/3mm.

  6. Tests of the linear, no-threshold dose-response relationship for high-LET radiation

    SciTech Connect

    Cohen, B.L.

    1987-05-01

    It is pointed out that induction of lung cancer by exposure to Rn daughters, applied at high doses to miners and at low doses to exposures in homes, provides a very stringent and sensitive test of the linear, no-threshold dose-response relationship for high-LET radiation, because this relationship predicts that a substantial fraction of lung cancer among non-smokers is due to average Rn levels. Therefore, it predicts an easily observable elevation of lung cancer rates in areas where Rn levels are many times greater than the average, especially at times before cigarette smoking began to have important effects on lung cancer statistics. While more data are needed (and will be forthcoming), some of the early indications of these studies are reviewed here. Several cases are now known where average Rn levels are very high, and in all of these cases lung cancer rates are well below average. Methods for analyzing these data are discussed, and it is concluded that, based on current evidence, they indicate at least a factor of 4 disagreement with linear, no-threshold predictions.

  7. Design and sample size for evaluating combinations of drugs of linear and loglinear dose-response curves.

    PubMed

    Fang, Hong-Bin; Tian, Guo-Liang; Li, Wei; Tan, Ming

    2009-07-01

    The study of drug combinations has become important in drug development due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. The goal is to identify which combinations are additive, synergistic, or antagonistic. Although there exists statistical framework for finding doses and sample sizes needed to detect departure from additivity, e.g., the power maximized F-test, different classes of drugs of different does-response shapes require different derivation for calculating sample size and finding doses. Motivated by two anticancer combination studies that we are involved with, this article proposes dose-finding and sample size method for detecting departures from additivity of two drugs with linear and log-linear single dose-response curves. The first study involves combination of two drugs, where one single drug dose-response curve is linear and the other is log-linear. The second study involves combinations of drugs whose single drug dose-response curves are linear. The experiment had been planned with the common fixed ratio design before we were consulted, but the resulting data missed the synergistic combinations. However, the experiment based on the proposed design was able to identify the synergistic combinations as anticipated. Thus we shall summarize the analysis of the data collected according to the proposed design and discuss why the commonly used fixed ratio method failed and the implications of the proposed method for other combination studies.

  8. Low dose radiation and cancer in A-bomb survivors: latency and non-linear dose-response in the 1950–90 mortality cohort

    PubMed Central

    Dropkin, Greg

    2007-01-01

    Background Analyses of Japanese A-bomb survivors' cancer mortality risks are used to establish recommended annual dose limits, currently set at 1 mSv (public) and 20 mSv (occupational). Do radiation doses below 20 mSv have significant impact on cancer mortality in Japanese A-bomb survivors, and is the dose-response linear? Methods I analyse stomach, liver, lung, colon, uterus, and all-solid cancer mortality in the 0 – 20 mSv colon dose subcohort of the 1950–90 (grouped) mortality cohort, by Poisson regression using a time-lagged colon dose to detect latency, while controlling for gender, attained age, and age-at-exposure. I compare linear and non-linear models, including one adapted from the cellular bystander effect for α particles. Results With a lagged linear model, Excess Relative Risk (ERR) for the liver and all-solid cancers is significantly positive and several orders of magnitude above extrapolations from the Life Span Study Report 12 analysis of the full cohort. Non-linear models are strongly superior to the linear model for the stomach (latency 11.89 years), liver (36.90), lung (13.60) and all-solid (43.86) in fitting the 0 – 20 mSv data and show significant positive ERR at 0.25 mSv and 10 mSv lagged dose. The slope of the dose-response near zero is several orders of magnitude above the slope at high doses. Conclusion The standard linear model applied to the full 1950–90 cohort greatly underestimates the risks at low doses, which are significant when the 0 – 20 mSv subcohort is modelled with latency. Non-linear models give a much better fit and are compatible with a bystander effect. PMID:17233918

  9. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.

    PubMed

    Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A

    2015-05-26

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

  10. A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.

    PubMed

    Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A

    2015-10-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.

  11. Dose-Volume Response Relationship for Brain Metastases Treated with Frameless Single-Fraction Linear Accelerator-Based Stereotactic Radiosurgery

    PubMed Central

    Pan, Jianmin; Yusuf, Mehran B; Dragun, Anthony; Dunlap, Neal; Guan, Timothy; Boling, Warren; Rai, Shesh; Woo, Shiao

    2016-01-01

    Background: Our aim was to identify a dose-volume response relationship for brain metastases treated with frameless stereotactic radiosurgery (SRS). Methods: We reviewed patients who underwent frameless single-fraction linear accelerator SRS for brain metastases between 2007 and 2013 from an institutional database. Proportional hazards modeling was used to identify predictors of outcome. A ratio of maximum lesion dose per mm-diameter (Gy/mm) was constructed to establish a dose-volume relationship. Results: There were 316 metastases evaluated in 121 patients (2 - 33 mm in the largest diameter). The median peripheral dose was 18.0 Gy (range: 10.0 – 24.0 Gy). Local control was 84.8% for all lesions and was affected by location, peripheral dose, maximum dose, and lesion size (p values < 0.050). A dose-volume response relationship was constructed using the maximum dose and lesion size. A unit increase in Gy/mm was associated with decreased local failure (p = 0.005). Local control of 80%, 85%, and 90% corresponded to maximum doses per millimeter of 1.67 Gy/mm, 2.86 Gy/mm, and 4.4 Gy/mm, respectively. Toxicity was uncommon and only 1.0% of lesions developed radionecrosis requiring surgery. Conclusions: For brain metastases less than 3 cm, a dose-volume response relationship exists between maximum radiosurgical dose and lesion size, which is predictive of local control. PMID:27284495

  12. [DNA double-strand breaks in human lymphocytes after single irradiation by low doses of pulsed X-rays: non-linear dose-response relationship].

    PubMed

    Vasil'ev, S A; Stepanova, E Iu; Kutenkov, O P; Belenko, A A; Zharkova, L P; Bol'shakov, M A; Lebedev, I N; Rostov, V V

    2012-01-01

    Effects of ionizing radiation registered in cells after low dose irradiation are still poorly understood. A pulsed mode of irradiation is even more problematic in terms of predicting the radiation-induced response in cells. Thus, the aim of this paper was to study and analyze the effects of dose and frequency of pulsed X-rays on the frequency of radiation-induced DNA double-strand breaks and their repair kinetics in human peripheral blood lymphocytes in vitro. Analysis of radiation-induced gammaH2AX and 53BP1 repair foci was used to assess the DNA damage in these cells. The dose-response curve of radiation-induced foci of both proteins has shown deviations from linearity to a higher effect in the 12-32 mGy dose range and a lower effect at 72 mGy. The dose-response curve was linear at doses higher than 100 mGy. The number of radiation-induced gammaH2AX and 53BP1 foci depended on the frequency of X-ray pulses: the highest effect was registered at 13 pulses per second. Moreover, slower repair kinetics was observed for those foci induced by very low doses with a nonlinear dose-response relationship.

  13. Ecological versus case-control studies for testing a linear-no threshold dose-response relationship.

    PubMed

    Cohen, B L

    1990-09-01

    The two basic problems with ecological studies are (A) individuals studied are not necessarily the individuals who are at risk, and (B) they are very vulnerable to confounding factors. It is shown that where the study is designed to test a linear-no threshold dose-response theory, (A) does not apply. Where the ecological study deals with the average dose and response in a large number of US counties, the available data and computer capability for reducing effects of confounders are so powerful that (B) may be no more important for the ecological than for a case-control study. The migration problem is treated and found to be relatively unimportant.

  14. Changing the Risk Paradigms Can be Good for Our Health: J-Shaped, Linear and Threshold Dose-Response Models.

    PubMed

    Ricci, P F; Straja, S R; Cox, A L

    2012-01-01

    Both the linear (at low doses)-no-threshold (LNT) and the threshold models (S-shapes) dose-response lead to no benefit from low exposure. We propose three new models that allow and include, but do not require - unlike LNT and S-shaped models - this strong assumption. We also provide the means to calculate benefits associated with bi-phasic biological behaviors, when they occur and propose:THREE HORMETIC (PHASIC) MODELS: the J-shaped, inverse J-shaped, the min-max, andMethod for calculating the direct benefits associated with the J and inverse J-shaped models.The J-shaped and min-max models for mutagens and carcinogenic agents include an experimentally justified repair stage for toxic and carcinogenic damage. We link these to stochastic transition models for cancer and show how abrupt transitions in cancer hazard rates, as functions of exposure concentrations and durations, can emerge naturally in large cell populations even when the rates of cell-level events increase smoothly (e.g., proportionally) with concentration. In this very general family of models, J-shaped dose-response curves emerge. These results are universal, i.e., independent of specific biological details represented by the stochastic transition networks. Thus, using them suggests a more complete and realistic way to assess risks at low doses or dose-rates.

  15. Origins of Total-Dose Response Variability in Linear Bipolar Microcircuits

    SciTech Connect

    BARNABY,H.J.; CIRBA,C.R.; SCHRIMPF,R.D.; FLEETWOOD,D.M.; PEASE,R.L.; SHANEYFELT,MARTY R.; TURFLINGER,T.; KRIEG,J.F.; MAHER,M.C.

    2000-11-15

    LM1ll voltage comparators exhibit a wide range of total-dose-induced degradation. Simulations show this variability may be a natural consequence of the low base doping of the substrate PNP (SPNP) input transistors. Low base doping increases the SPNP's collector to base breakdown voltage, current gain, and sensitivity to small fluctuations in the radiation-induced oxide defect densities. The build-up of oxide trapped charge (N{sub ot}) and interface traps (N{sub it}) is shown to be a function of pre-irradiation bakes. Experimental data indicate that, despite its structural similarities to the LM111, irradiated input transistors of the LM124 operational amplifier do not exhibit the same sensitivity to variations in pre-irradiation thermal cycles. Further disparities in LM111 and LM124 responses may result from a difference in the oxide defect build-up in the two part types. Variations in processing, packaging, and circuit effects are suggested as potential explanations.

  16. Non-Linear Dose-Response Relationships in Biology, Toxicology and Medicine - An International Conference

    SciTech Connect

    Calabrese, Edward J.; Kostecki, Paul T.

    2002-05-28

    Conference abstract book contains seven sections: Plenary-4 abstracts; Chemical-9 abstracts; Radiation-7 abstracts; Ultra Low Doses and Medicine-6 abstracts; Biomedical-11 abstracts; Risk Assessment-5 abstracts and Poster Sessions-25 abstracts. Each abstract was provided by the author/presenter participating in the conference.

  17. Threshold and other departures from linear-quadratic curvature in the non-cancer mortality dose-response curve in the Japanese atomic bomb survivors.

    PubMed

    Little, Mark P

    2004-07-01

    Recently released data on non-cancer mortality in Japanese atomic bomb survivors are analysed using a variety of generalised relative risk models that take account of errors in estimates of dose to assess the dose-response at low doses. If linear-threshold, quadratic-threshold or linear-quadratic-threshold relative risk models (the dose-response is assumed to be linear, quadratic or linear-quadratic above the threshold, respectively) are fitted to the non-cancer data there are no statistically significant ( p>0.10) indications of threshold departures from linearity, quadratic curvature or linear-quadratic curvature. These findings are true irrespective of the assumed magnitude of dosimetric error, between 25%-45% geometric standard deviations. In general, increasing the assumed magnitude of dosimetric error had little effect on the central estimates of the threshold, but somewhat widened the associated confidence intervals. If a power of dose model is fitted, there is little evidence ( p>0.10) that the power of dose in the dose-response is statistically significantly different from 1, again irrespective of the assumed magnitude of dosimetric errors in the range 25%-45%. Again, increasing the size of the errors resulted in wider confidence intervals on the power of dose, without marked effect on the central estimates. In general these findings remain true for various non-cancer disease subtypes.

  18. Linear Versus Non-Linear Dose-Response Relationship Between Prenatal Alcohol Exposure and Meconium Concentration of Nine Different Fatty Acid Ethyl Esters

    PubMed Central

    Yang, J.Y.; Kwak, H.S.; Choi, J.S.; Ahn, H.K.; Oh, Y.J.; Velázquez-Armenta, E.Y.; Nava-Ocampo, A.A.

    2015-01-01

    Presence of individual fatty acid ethyl esters (FAEEs) in meconium is considered to be a reliable biomarker of prenatal alcohol exposure, and their concentration has been found to be linearly associated with poor postnatal development, supporting the widely extended idea that ethanol is a non-threshold teratogen. However, a growing number of epidemiological studies have consistently found a lack of adverse short- and long-term fetal outcomes at low exposure levels. We therefore aimed to investigate the relationship between the concentration of individual FAEEs and prenatal alcohol exposure in meconium samples collected within the first 6 to 12?h after birth from 182 babies born to abstainer mothers and from 54 babies born to women who self-reported either light or moderate alcohol ingestion in the second or third trimester of pregnancy. In most cases, the individual FAEE concentrations were negligible and not significantly different (P >0.05) between exposed and control babies. The concentrations appeared to increase linearly with the dose only in the few babies born to mothers who reported >3 drinks/week. These results provide evidence that the correlation between prenatal alcohol exposure and individual FAEE concentrations in meconium is non-linear shape, with a threshold probably at 3 drinks/week. PMID:26691866

  19. An update on modeling dose-response relationships: Accounting for correlated data structure and heterogeneous error variance in linear and nonlinear mixed models.

    PubMed

    Gonçalves, M A D; Bello, N M; Dritz, S S; Tokach, M D; DeRouchey, J M; Woodworth, J C; Goodband, R D

    2016-05-01

    Advanced methods for dose-response assessments are used to estimate the minimum concentrations of a nutrient that maximizes a given outcome of interest, thereby determining nutritional requirements for optimal performance. Contrary to standard modeling assumptions, experimental data often present a design structure that includes correlations between observations (i.e., blocking, nesting, etc.) as well as heterogeneity of error variances; either can mislead inference if disregarded. Our objective is to demonstrate practical implementation of linear and nonlinear mixed models for dose-response relationships accounting for correlated data structure and heterogeneous error variances. To illustrate, we modeled data from a randomized complete block design study to evaluate the standardized ileal digestible (SID) Trp:Lys ratio dose-response on G:F of nursery pigs. A base linear mixed model was fitted to explore the functional form of G:F relative to Trp:Lys ratios and assess model assumptions. Next, we fitted 3 competing dose-response mixed models to G:F, namely a quadratic polynomial (QP) model, a broken-line linear (BLL) ascending model, and a broken-line quadratic (BLQ) ascending model, all of which included heteroskedastic specifications, as dictated by the base model. The GLIMMIX procedure of SAS (version 9.4) was used to fit the base and QP models and the NLMIXED procedure was used to fit the BLL and BLQ models. We further illustrated the use of a grid search of initial parameter values to facilitate convergence and parameter estimation in nonlinear mixed models. Fit between competing dose-response models was compared using a maximum likelihood-based Bayesian information criterion (BIC). The QP, BLL, and BLQ models fitted on G:F of nursery pigs yielded BIC values of 353.7, 343.4, and 345.2, respectively, thus indicating a better fit of the BLL model. The BLL breakpoint estimate of the SID Trp:Lys ratio was 16.5% (95% confidence interval [16.1, 17.0]). Problems with

  20. Less is more for cancer chemoprevention: evidence of a non-linear dose response for the protective effects of resveratrol in humans and mice

    PubMed Central

    Scott, Edwina; Cai, Hong; Kholghi, Abeer; Andreadi, Catherine; Rufini, Alessandro; Karmokar, Ankur; Britton, Robert G.; Horner-Glister, Emma; Greaves, Peter; Jawad, Dhafer; James, Mark; Howells, Lynne; Ognibene, Ted; Malfatti, Mike; Goldring, Christopher; Kitteringham, Neil; Walsh, Joanne; Viskaduraki, Maria; West, Kevin; Miller, Andrew; Hemingway, David; Steward, William P.; Gescher, Andreas J.

    2016-01-01

    Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials assessing efficacy. To challenge the assumption that ‘more is better’ we compared the pharmacokinetics and activity of a dietary dose with an intake 200-times higher. The dose response relationship and metabolite profile of [14C]-resveratrol in colorectal tissue of patients helped define clinically achievable concentrations. In ApcMin mice receiving a high-fat diet the low dose supressed intestinal adenoma development more potently than the higher dose. Efficacy correlated with increased AMP-activated protein kinase (AMPK) activation and the senescence marker p21. Non-linear dose responses were observed for AMPK and mTOR signalling in adenoma cells, culminating in autophagy and senescence. In human tissues low dietary exposures caused enhanced AMPK phosphorylation, autophagy and expression of the cytoprotective enzyme NQO1. These findings warrant revision of developmental strategies for diet-derived agents for cancer chemoprevention. PMID:26223300

  1. Dose Rate Effects in Linear Bipolar Transistors

    NASA Technical Reports Server (NTRS)

    Johnston, Allan; Swimm, Randall; Harris, R. D.; Thorbourn, Dennis

    2011-01-01

    Dose rate effects are examined in linear bipolar transistors at high and low dose rates. At high dose rates, approximately 50% of the damage anneals at room temperature, even though these devices exhibit enhanced damage at low dose rate. The unexpected recovery of a significant fraction of the damage after tests at high dose rate requires changes in existing test standards. Tests at low temperature with a one-second radiation pulse width show that damage continues to increase for more than 3000 seconds afterward, consistent with predictions of the CTRW model for oxides with a thickness of 700 nm.

  2. Positive linear dose-response relationships, but no J-shaped relationship, between drinking habits and estimated glomerular filtration rate in middle-aged Japanese men.

    PubMed

    Shirai, Yoshiro; Kuriki, Kiyonori; Endoh, Kaori; Miyauchi, Rie; Kasezawa, Nobuhiko; Tohyama, Kazushige; Goda, Toshinao

    2016-03-01

    The relationship between drinking frequency and amount of alcohol consumption (i.e., drinking habits) and the risk of chronic kidney disease (CKD) remains unclear. We aimed to clarify either a linear or J-shaped dose-response relationship between drinking habits and estimated glomerular filtration rate (eGFR) as a biomarker for identifying individuals at high risk of CKD. In a large-scale cross-sectional study, 403 men and 121 women with an eGFR of 30-60 mL/min per 1.73 m(2) were defined as cases, and 1209 men and 363 women with ≥60 mL/min/1.73 m(2) were randomly extracted as controls (one case subject was matched with three control subjects, matched according to age and season of data collection). We calculated multivariate-adjusted CKD risk and the corresponding mean eGFR according to drinking habits. In men, negative and positive linear relationships with drinking habits were found for CKD risk and mean eGFR (p < 0.001 for all linear terms), respectively, but there were no corresponding J-shaped relationships (not significant for all quadratic terms). In regard to the mean eGFR, however, positive linear relationships were only shown in men in the highest eGFR quartile (p < 0.05 and p < 0.01 for drinking frequency and amount of alcohol consumption, respectively). In women, no association was found. Regarding each drinking habit, we found a positive linear dose-response relationship to eGFR in middle-aged men with an eGFR ≥30 mL/min/1.73 m(2).

  3. Total dose dependency and ELDRS effects on bipolar linear devices

    NASA Technical Reports Server (NTRS)

    Yui, C. C.; McClure, S. S.; Rax, B. G.; Lehman, J. M.; Minto, T. D.; Wiedeman, M.

    2002-01-01

    The use of bipolar linear devices is prevalent in most satellite and some space applications. However, degradation as a result of low dose irradiations known as ELDERS (effects of enhanced low dose rate sensitivity) is a major concern when selecting flight hardware. Many studies and reports have been conducted on this possible phenomenon as well as their responsible physical mechanisms.

  4. Is the Linear No-Threshold Dose-Response Paradigm Still Necessary for the Assessment of Health Effects of Low Dose Radiation?

    PubMed Central

    2016-01-01

    Inevitable human exposure to ionizing radiation from man-made sources has been increased with the proceeding of human civilization and consequently public concerns focus on the possible risk to human health. Moreover, Fukushima nuclear power plant accidents after the 2011 East-Japan earthquake and tsunami has brought the great fear and anxiety for the exposure of radiation at low levels, even much lower levels similar to natural background. Health effects of low dose radiation less than 100 mSv have been debated whether they are beneficial or detrimental because sample sizes were not large enough to allow epidemiological detection of excess effects and there was lack of consistency among the available experimental data. We have reviewed an extensive literature on the low dose radiation effects in both radiation biology and epidemiology, and highlighted some of the controversies therein. This article could provide a reasonable view of utilizing radiation for human life and responding to the public questions about radiation risk. In addition, it suggests the necessity of integrated studies of radiobiology and epidemiology at the national level in order to collect more systematic and profound information about health effects of low dose radiation. PMID:26908982

  5. Evidence of a Non-Linear Dose-Response Relationship between Training Load and Stress Markers in Elite Female Futsal Players

    PubMed Central

    Milanez, Vinicius F.; Ramos, Solange P.; Okuno, Nilo M.; Boullosa, Daniel A.; Nakamura, Fabio Y.

    2014-01-01

    The aim of this study was: to describe typical training load (TL) carried out by a professional female futsal team for a period of 5 weeks; and to verify the relationship between TL, stress symptoms, salivary secretory immunoglobulin A (SIgA) levels, and symptoms of upper respiratory infections (URI). Over 45 sessions, the TL of the athletes was monitored daily by means of session-RPE method during the in-season period prior to the main national competition. Stress symptoms were measured weekly by means of the “Daily Analysis of Life Demands in Athletes Questionnaire” (DALDA), SIgA levels, and by symptoms of URI by the “Wisconsin Upper Respiratory Symptom Survey-21” (WURSS). There was a significant increase in TL, monotony, and training strain in week 3, with a concomitant and significant reduction in percentage variation (Δ%) of SIgA concentration and secretion rate (p < 0.05). Additionally, a second order regression model showed a high goodness of fit (R2 = 0.64 - 0.89) between TL and strain with SIgA concentration, secretion rate, and “worse than normal” responses of stress symptoms from the questionnaire. In conclusion, a link between TL and SIgA levels, and stress symptoms in female futsal players was evident in a non linear fashion. There appears to be an optimal range of values of daily TL between ~343 and ~419 AU and strain between ~2639 and 3060 AU, because at levels below and above these values there was an increase in stress symptoms and above ~435 and ~3160 AU to TL and strain there were a decrease in SIgA levels. In contrast, symptoms of URI failed to demonstrate relationship with the variables studied. Key Points There is a dose-response relationship between SIgA levels and stress symptoms with TL. For the athletes of the present study, values of ~436 AU and ~3161 AU to TL and strain training would be desirable because higher values would decrease responses of SIgA levels. An optimal range of values of TL between ~336 and ~412 AU to TL

  6. Isobio software: biological dose distribution and biological dose volume histogram from physical dose conversion using linear-quadratic-linear model

    PubMed Central

    Jaikuna, Tanwiwat; Khadsiri, Phatchareewan; Chawapun, Nisa; Saekho, Suwit

    2017-01-01

    Purpose To develop an in-house software program that is able to calculate and generate the biological dose distribution and biological dose volume histogram by physical dose conversion using the linear-quadratic-linear (LQL) model. Material and methods The Isobio software was developed using MATLAB version 2014b to calculate and generate the biological dose distribution and biological dose volume histograms. The physical dose from each voxel in treatment planning was extracted through Computational Environment for Radiotherapy Research (CERR), and the accuracy was verified by the differentiation between the dose volume histogram from CERR and the treatment planning system. An equivalent dose in 2 Gy fraction (EQD2) was calculated using biological effective dose (BED) based on the LQL model. The software calculation and the manual calculation were compared for EQD2 verification with pair t-test statistical analysis using IBM SPSS Statistics version 22 (64-bit). Results Two and three-dimensional biological dose distribution and biological dose volume histogram were displayed correctly by the Isobio software. Different physical doses were found between CERR and treatment planning system (TPS) in Oncentra, with 3.33% in high-risk clinical target volume (HR-CTV) determined by D90%, 0.56% in the bladder, 1.74% in the rectum when determined by D2cc, and less than 1% in Pinnacle. The difference in the EQD2 between the software calculation and the manual calculation was not significantly different with 0.00% at p-values 0.820, 0.095, and 0.593 for external beam radiation therapy (EBRT) and 0.240, 0.320, and 0.849 for brachytherapy (BT) in HR-CTV, bladder, and rectum, respectively. Conclusions The Isobio software is a feasible tool to generate the biological dose distribution and biological dose volume histogram for treatment plan evaluation in both EBRT and BT. PMID:28344603

  7. Dose Response Data for Hormonally Active Chemicals ...

    EPA Pesticide Factsheets

    The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the default assumption is that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDS), which act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses: responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and nonmonotonic dose response relationships from case studies of chemicals that disrupt reproductive development and function via the ER, AR and AhR pathways and will include in vitro and in vivo multigenerational data. The in vivo studies in this discussion include only robust, well designed, comprehensive studies that administered the chemical via a relevant route(s) of exposure over a broad dose response range, including low dose(s) in the microgram/kg/d range. The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters and 2,3,7,8 TCDD. The objective is to critically evaluate the data from well done studies in this field to address concerns that current multigenerational reproductive test gui

  8. Dose response signal detection under model uncertainty.

    PubMed

    Dette, Holger; Titoff, Stefanie; Volgushev, Stanislav; Bretz, Frank

    2015-12-01

    We investigate likelihood ratio contrast tests for dose response signal detection under model uncertainty, when several competing regression models are available to describe the dose response relationship. The proposed approach uses the complete structure of the regression models, but does not require knowledge of the parameters of the competing models. Standard likelihood ratio test theory is applicable in linear models as well as in nonlinear regression models with identifiable parameters. However, for many commonly used nonlinear dose response models the regression parameters are not identifiable under the null hypothesis of no dose response and standard arguments cannot be used to obtain critical values. We thus derive the asymptotic distribution of likelihood ratio contrast tests in regression models with a lack of identifiability and use this result to simulate the quantiles based on Gaussian processes. The new method is illustrated with a real data example and compared to existing procedures using theoretical investigations as well as simulations.

  9. The road to linearity: why linearity at low doses became the basis for carcinogen risk assessment.

    PubMed

    Calabrese, Edward J

    2009-03-01

    This article assesses the historical foundations of how linearity at low dose became accepted by the scientific/regulatory communities. While the threshold model was used in the 1920s/1930s in establishing radiation health standards, its foundations were challenged by the genetics community who argued that radiation induced mutations in reproductive cells followed a linear response, were cumulative and deleterious. Scientific foundations of linearity for gonadal mutations were based on non-conclusive evidence as well as not being conducted at low doses. Following years of debate, leaders in the genetics community participated in the U.S. National Academy of Sciences (NAS) (1956) Biological Effects of Atomic Radiation (BEAR) BEAR I Committee, getting their perspectives accepted, incorporating linearity for radiation-induced mutational effects in risk assessment. Overtime the concept of linearity was generalized to include somatic effects induced by radiation based on a protectionist philosophy. This affected the course of radiation-induced and later chemically-induced carcinogen risk assessment. Acceptance of linearity at low dose from chemical carcinogens was strongly influenced by the NAS Safe Drinking Water Committee report of 1977 which provided the critical guidance to the U.S. EPA to adopt linear at low dose modeling for risk assessment for chemical carcinogens with little supportive data, much of which has been either discredited or seriously weakened over the past 3 decades. Nonetheless, there has been little practical change of regulatory policy concerning carcinogen risk assessment. These observations suggest that while scientific disciplines are self correcting, that regulatory 'science' fails to display the same self-correcting mechanism despite contradictory data.

  10. The Dose Response Relationship for Radiation Carcinogenesis

    NASA Astrophysics Data System (ADS)

    Hall, Eric

    2008-03-01

    Recent surveys show that the collective population radiation dose from medical procedures in the U.S. has increased by 750% in the past two decades. It would be impossible to imagine the practice of medicine today without diagnostic and therapeutic radiology, but nevertheless the widespread and rapidly increasing use of a modality which is a known human carcinogen is a cause for concern. To assess the magnitude of the problem it is necessary to establish the shape of the dose response relationship for radiation carcinogenesis. Information on radiation carcinogenesis comes from the A-bomb survivors, from occupationally exposed individuals and from radiotherapy patients. The A-bomb survivor data indicates a linear relationship between dose and the risk of solid cancers up to a dose of about 2.5 Sv. The lowest dose at which there is a significant excess cancer risk is debatable, but it would appear to be between 40 and 100 mSv. Data from the occupation exposure of nuclear workers shows an excess cancer risk at an average dose of 19.4 mSv. At the other end of the dose scale, data on second cancers in radiotherapy patients indicates that cancer risk does not continue to rise as a linear function of dose, but tends towards a plateau of 40 to 60 Gy, delivered in a fractionated regime. These data can be used to estimate the impact of diagnostic radiology at the low dose end of the dose response relationship, and the impact of new radiotherapy modalities at the high end of the dose response relationship. In the case of diagnostic radiology about 90% of the collective population dose comes from procedures (principally CT scans) which involve doses at which there is credible evidence of an excess cancer incidence. While the risk to the individual is small and justified in a symptomatic patient, the same is not true of some screening procedures is asymptomatic individuals, and in any case the huge number of procedures must add up to a potential public health problem. In the

  11. Linear Response for Intermittent Maps

    NASA Astrophysics Data System (ADS)

    Baladi, Viviane; Todd, Mike

    2016-11-01

    We consider the one parameter family {α mapsto T_{α}} ({α in [0,1)}) of Pomeau-Manneville type interval maps {T_{α}(x) = x(1+2^{α} x^{α})} for {x in [0,1/2)} and {T_{α}(x)=2x-1} for {x in [1/2, 1]}, with the associated absolutely continuous invariant probability measure {μ_{α}}. For {α in (0,1)}, Sarig and Gouëzel proved that the system mixes only polynomially with rate {n^{1-1/{α}}} (in particular, there is no spectral gap). We show that for any {ψ in Lq}, the map {α to int_01 ψ d μ_{α}} is differentiable on {[0,1-1/q)}, and we give a (linear response) formula for the value of the derivative. This is the first time that a linear response formula for the SRB measure is obtained in the setting of slowly mixing dynamics. Our argument shows how cone techniques can be used in this context. For {α ≥ 1/2} we need the {n^{-1/{α}}} decorrelation obtained by Gouëzel under additional conditions.

  12. Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation.

    PubMed

    Zhao, Yuchao; Ricci, Paolo F

    2010-03-18

    For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health.

  13. The use of non-linear regression analysis and the F test for model discrimination with dose-response curves and ligand binding data.

    PubMed

    Bardsley, W G; McGinlay, P B

    1987-05-21

    Computer fitting of binding data is discussed and it is concluded that the main problem is the choice of starting estimates and internal scaling parameters, not the optimization software. Solving linear overdetermined systems of equations for starting estimates is investigated. A function, Q, is introduced to study model discrimination with binding isotherms and the behaviour of Q as a function of model parameters is calculated for the case of 2 and 3 sites. The power function of the F test is estimated for models with 2 to 5 binding sites and necessary constraints on parameters for correct model discrimination are given. The sampling distribution of F test statistics is compared to an exact F distribution using the Chi-squared and Kolmogorov-Smirnov tests. For low order modes (n less than 3) the F test statistics are approximately F distributed but for higher order models the test statistics are skewed to the left of the F distribution. The parameter covariance matrix obtained by inverting the Hessian matrix of the objective function is shown to be a good approximation to the estimate obtained by Monte Carlo sampling for low order models (n less than 3). It is concluded that analysis of up to 2 or 3 binding sites presents few problems and linear, normal statistical results are valid. To identify correctly 4 sites is much more difficult, requiring very precise data and extreme parameter values. Discrimination of 5 from 4 sites is an upper limit to the usefulness of the F test.

  14. A Bayesian Semiparametric Model for Radiation Dose-Response Estimation.

    PubMed

    Furukawa, Kyoji; Misumi, Munechika; Cologne, John B; Cullings, Harry M

    2016-06-01

    In evaluating the risk of exposure to health hazards, characterizing the dose-response relationship and estimating acceptable exposure levels are the primary goals. In analyses of health risks associated with exposure to ionizing radiation, while there is a clear agreement that moderate to high radiation doses cause harmful effects in humans, little has been known about the possible biological effects at low doses, for example, below 0.1 Gy, which is the dose range relevant to most radiation exposures of concern today. A conventional approach to radiation dose-response estimation based on simple parametric forms, such as the linear nonthreshold model, can be misleading in evaluating the risk and, in particular, its uncertainty at low doses. As an alternative approach, we consider a Bayesian semiparametric model that has a connected piece-wise-linear dose-response function with prior distributions having an autoregressive structure among the random slope coefficients defined over closely spaced dose categories. With a simulation study and application to analysis of cancer incidence data among Japanese atomic bomb survivors, we show that this approach can produce smooth and flexible dose-response estimation while reasonably handling the risk uncertainty at low doses and elsewhere. With relatively few assumptions and modeling options to be made by the analyst, the method can be particularly useful in assessing risks associated with low-dose radiation exposures.

  15. Exploring the dose response of radiochromic dosimeters

    NASA Astrophysics Data System (ADS)

    Skyt, P. S.; Wahlstedt, I.; Yates, E. S.; Muren, L. P.; Petersen, J. B. B.; Balling, P.

    2013-06-01

    The aim of this study was to explore the dose response of a newly developed radio-chromic hydrogel dosimeter based on leuco malachite green dye in a gelatine matrix. The original dosimeter composition was first investigated in terms of dose response and dose-rate dependence. In addition, the initiating compounds producing chlorine radicals were substituted with compounds producing fluorine radicals, oxygen-centered radicals, carbon-centered radicals and bromine radicals. Also the surfactant was substituted by other compounds of different molecular size and charge. The original composition gave a dose response of 3.5·10-3 Gy-1cm-1 at 6 Gy/min with a dose rate dependence giving a 27 % increase when decreasing the dose rate to 1 Gy/min. None of the substituted initiating components contributed to an increase in dose response while only one surfactant increased the dose response slightly.

  16. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation.

    PubMed

    Mueller, E A; Kovarik, J M; van Bree, J B; Tetzloff, W; Grevel, J; Kutz, K

    1994-02-01

    The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from a microemulsion formulation (Sandimmune Neoral) were compared to those of the commercial formulation (Sandimmune) over the dosage range 200 to 800 mg. Single oral administrations were given as soft gelatin capsules in an open randomized study with 48 healthy volunteers. Whole-blood cyclosporine concentrations were determined by a specific monoclonal radioimmunoassay. In comparison to Sandimmune, the absorption rate (maximum concentration) and systemic availability (area under the curve) of cyclosporine were greater for Sandimmune Neoral at all dose levels investigated. The area under the curve for Sandimmune increased in a less than proportional manner with respect to dose, whereas that for Sandimmune Neoral was consistent with linear pharmacokinetics. Because of this difference, no global assessment of relative bioavailability could be performed. The relative bioavailability of cyclosporine from Sandimmune Neoral ranged from 174 to 239% compared to Sandimmune, depending on the dose level. The improvements in oral bioavailability and dose linearity of cyclosporine exposure after administration as Sandimmune Neoral should facilitate more accurate dosage titration in the clinical setting.

  17. Total Dose Effects on Error Rates in Linear Bipolar Systems

    NASA Technical Reports Server (NTRS)

    Buchner, Stephen; McMorrow, Dale; Bernard, Muriel; Roche, Nicholas; Dusseau, Laurent

    2007-01-01

    The shapes of single event transients in linear bipolar circuits are distorted by exposure to total ionizing dose radiation. Some transients become broader and others become narrower. Such distortions may affect SET system error rates in a radiation environment. If the transients are broadened by TID, the error rate could increase during the course of a mission, a possibility that has implications for hardness assurance.

  18. Single toxin dose-response models revisited

    PubMed Central

    Glaholt, SP; Kyker-Snowman, E; Shaw, JR; Chen, CY

    2016-01-01

    The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 hours) toxicity tests with mortality as a function of NiCl or CuSO4 toxin. PMID:27847315

  19. Anthocyanin excretion increases linearly with increasing strawberry dose.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A clinical study was conducted to investigate the dose response and metabolism of strawberry anthocyanins. In a crossover study design, twelve healthy adults consumed each of three strawberry treatments. The treatments were 100 g, 200 g, and 400 g of pureed strawberries, delivering 15 micromol, 30 m...

  20. Linear low-dose extrapolation for noncancer heath effects is the exception, not the rule.

    PubMed

    Rhomberg, Lorenz R; Goodman, Julie E; Haber, Lynne T; Dourson, Michael; Andersen, Melvin E; Klaunig, James E; Meek, Bette; Price, Paul S; McClellan, Roger O; Cohen, Samuel M

    2011-01-01

    The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic endpoints should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general "additivity-to-background" argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties-properties that would not be expected for most noncancer effects. Second, the "heterogeneity in the population" argument states that variations in sensitivity among members of the target population tend to "flatten out and linearize" the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true nonthreshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.

  1. Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal?**

    EPA Science Inventory

    Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal? The shape of the dose response curve in the low dose region has been debated since the 1940s, originally focusing on linear no threshold (LNT) versus threshold responses for cancer and noncanc...

  2. Dose reduction using a dynamic, piecewise-linear attenuator

    SciTech Connect

    Hsieh, Scott S.; Fleischmann, Dominik; Pelc, Norbert J.

    2014-02-15

    Purpose: The authors recently proposed a dynamic, prepatient x-ray attenuator capable of producing a piecewise-linear attenuation profile customized to each patient and viewing angle. This attenuator was intended to reduce scatter-to-primary ratio (SPR), dynamic range, and dose by redistributing flux. In this work the authors tested the ability of the attenuator to reduce dose and SPR in simulations. Methods: The authors selected four clinical applications, including routine full field-of-view scans of the thorax and abdomen, and targeted reconstruction tasks for an abdominal aortic aneurysm and the pancreas. Raw data were estimated by forward projection of the image volume datasets. The dynamic attenuator was controlled to reduce dose while maintaining peak variance by solving a convex optimization problem, assuminga priori knowledge of the patient anatomy. In targeted reconstruction tasks, the noise in specific regions was given increased weighting. A system with a standard attenuator (or “bowtie filter”) was used as a reference, and used either convex optimized tube current modulation (TCM) or a standard TCM heuristic. The noise of the scan was determined analytically while the dose was estimated using Monte Carlo simulations. Scatter was also estimated using Monte Carlo simulations. The sensitivity of the dynamic attenuator to patient centering was also examined by shifting the abdomen in 2 cm intervals. Results: Compared to a reference system with optimized TCM, use of the dynamic attenuator reduced dose by about 30% in routine scans and 50% in targeted scans. Compared to the TCM heuristics which are typically used withouta priori knowledge, the dose reduction is about 50% for routine scans. The dynamic attenuator gives the ability to redistribute noise and variance and produces more uniform noise profiles than systems with a conventional bowtie filter. The SPR was also modestly reduced by 10% in the thorax and 24% in the abdomen. Imaging with the dynamic

  3. Linear low-dose extrapolation for noncancer health effects is the exception, not the rule

    PubMed Central

    Rhomberg, Lorenz R; Goodman, Julie E; Haber, Lynne T; Dourson, Michael; Andersen, Melvin E; Klaunig, James E; Meek, Bette; Price, Paul S; McClellan, Roger O; Cohen, Samuel M

    2011-01-01

    The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic end-points should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general “additivity-to-background” argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties—properties that would not be expected for most noncancer effects. Second, the “heterogeneity in the population” argument states that variations in sensitivity among members ofthe target population tend to “flatten out and linearize” the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true non-threshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed. PMID:21226629

  4. Minimized Doses for Linear Accelerator Radiosurgery of Brainstem Metastasis

    SciTech Connect

    Valery, Charles A.; Boskos, Christos; Boisserie, Gilbert; Lamproglou, Ioannis; Cornu, Philippe; Mazeron, Jean-Jacques; Simon, Jean-Marc

    2011-06-01

    Purpose: Treatment of cerebral metastases located inside the brainstem remains a challenge, as the brainstem is considered to be a neurological organ at risk, whatever the treatment strategy. We report a retrospective study of 30 consecutive patients treated in our institution between 2005 and 2007 with micromultileaf linear accelerator (LINAC) -radiosurgery for brainstem metastases, with reduced doses compared to those usually reported in the literature. Methods and Materials: Mean follow-up was 311 days (range, 41-1351). Median age was 57 years (range, 37-82), Mean Karnofsky Index (KI) was 80. Primary tumor site was lung (n = 13), breast (n = 4), kidney (n = 4), skin (melanoma; n = 3), and others (n = 6). Primary tumor was controlled in 17 cases; extracranial metastases were controlled in 12 cases. Mean number of metastases was 1.46 (one to three); median volume was 2.82 cc (0.06-18). Dose was delivered by a micromultileaf collimator 6-MV LINAC . Results: Dose administered at the 70% isodose was 13.4 Gy (range, 8.2-15). Median survival was 10 months. Local control rates at 3, 6, and 12 months were 100%, 100%, and 79% respectively. Median neurological control duration was 5 months. Neurological control rates at 3, 6, and 12 months were 73%, 42%, and 25%, respectively. No parameter was found to significantly correlate with survival, local, or cerebral control. No patients had severe side effects (Grade III-IV), according to the Radiation Therapy Oncology Group (RTOG) scale. Conclusion: Lower doses than previously reported can achieve the same local control and survival rates in brain metastases, with minimal side effects.

  5. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    PubMed Central

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre

    2015-01-01

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed. PMID:25799311

  6. Shared dosimetry error in epidemiological dose-response analyses

    DOE PAGES

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; ...

    2015-03-23

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takesmore » up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed.« less

  7. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    SciTech Connect

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre; Zeeb, Hajo

    2015-03-23

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. Use of these methods for several studies, including the Mayak Worker Cohort and the U.S. Atomic Veterans Study, is discussed.

  8. Shared dosimetry error in epidemiological dose-response analyses

    SciTech Connect

    Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J.; Boice, John; Beck, Harold; Till, John; Bouville, Andre; Zeeb, Hajo

    2015-03-23

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed.

  9. Shared dosimetry error in epidemiological dose-response analyses.

    PubMed

    Stram, Daniel O; Preston, Dale L; Sokolnikov, Mikhail; Napier, Bruce; Kopecky, Kenneth J; Boice, John; Beck, Harold; Till, John; Bouville, Andre

    2015-01-01

    Radiation dose reconstruction systems for large-scale epidemiological studies are sophisticated both in providing estimates of dose and in representing dosimetry uncertainty. For example, a computer program was used by the Hanford Thyroid Disease Study to provide 100 realizations of possible dose to study participants. The variation in realizations reflected the range of possible dose for each cohort member consistent with the data on dose determinates in the cohort. Another example is the Mayak Worker Dosimetry System 2013 which estimates both external and internal exposures and provides multiple realizations of "possible" dose history to workers given dose determinants. This paper takes up the problem of dealing with complex dosimetry systems that provide multiple realizations of dose in an epidemiologic analysis. In this paper we derive expected scores and the information matrix for a model used widely in radiation epidemiology, namely the linear excess relative risk (ERR) model that allows for a linear dose response (risk in relation to radiation) and distinguishes between modifiers of background rates and of the excess risk due to exposure. We show that treating the mean dose for each individual (calculated by averaging over the realizations) as if it was true dose (ignoring both shared and unshared dosimetry errors) gives asymptotically unbiased estimates (i.e. the score has expectation zero) and valid tests of the null hypothesis that the ERR slope β is zero. Although the score is unbiased the information matrix (and hence the standard errors of the estimate of β) is biased for β≠0 when ignoring errors in dose estimates, and we show how to adjust the information matrix to remove this bias, using the multiple realizations of dose. The use of these methods in the context of several studies including, the Mayak Worker Cohort, and the U.S. Atomic Veterans Study, is discussed.

  10. A broadly applicable function for describing luminescence dose response

    SciTech Connect

    Burbidge, C. I.

    2015-07-28

    The basic form of luminescence dose response is investigated, with the aim of developing a single function to account for the appearance of linear, superlinear, sublinear, and supralinear behaviors and variations in saturation signal level and rate. A function is assembled based on the assumption of first order behavior in different major factors contributing to measured luminescence-dosimetric signals. Different versions of the function are developed for standardized and non-dose-normalized responses. Data generated using a two trap two recombination center model and experimental data for natural quartz are analyzed to compare results obtained using different signals, measurement protocols, pretreatment conditions, and radiation qualities. The function well describes a range of dose dependent behavior, including sublinear, superlinear, supralinear, and non-monotonic responses and relative response to α and β radiation, based on change in relative recombination and trapping probability affecting signals sourced from a single electron trap.

  11. Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens

    EPA Science Inventory

    The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the defaul...

  12. Regulatory implications of a linear non-threshold (LNT) dose-based risks.

    PubMed

    Aleta, C R

    2009-01-01

    Current radiation protection regulatory limits are based on the linear non-threshold (LNT) theory using health data from atomic bombing survivors. Studies in recent years sparked debate on the validity of the theory, especially at low doses. The present LNT overestimates radiation risks since the dosimetry included only acute gammas and neutrons; the role of other bomb-caused factors, e.g. fallout, induced radioactivity, thermal radiation (UVR), electromagnetic pulse (EMP), and blast, were excluded. Studies are proposed to improve the dose-response relationship.

  13. Optically isolated signal coupler with linear response

    DOEpatents

    Kronberg, James W.

    1994-01-01

    An optocoupler for isolating electrical signals that translates an electrical input signal linearly to an electrical output signal. The optocoupler comprises a light emitter, a light receiver, and a light transmitting medium. The light emitter, preferably a blue, silicon carbide LED, is of the type that provides linear, electro-optical conversion of electrical signals within a narrow wavelength range. Correspondingly, the light receiver, which converts light signals to electrical signals and is preferably a cadmium sulfide photoconductor, is linearly responsive to light signals within substantially the same wavelength range as the blue LED.

  14. Dose-response-a challenge for allelopathy?

    PubMed

    Belz, Regina G; Hurle, Karl; Duke, Stephen O

    2005-04-01

    The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

  15. Linear ubiquitination signals in adaptive immune responses.

    PubMed

    Ikeda, Fumiyo

    2015-07-01

    Ubiquitin can form eight different linkage types of chains using the intrinsic Met 1 residue or one of the seven intrinsic Lys residues. Each linkage type of ubiquitin chain has a distinct three-dimensional topology, functioning as a tag to attract specific signaling molecules, which are so-called ubiquitin readers, and regulates various biological functions. Ubiquitin chains linked via Met 1 in a head-to-tail manner are called linear ubiquitin chains. Linear ubiquitination plays an important role in the regulation of cellular signaling, including the best-characterized tumor necrosis factor (TNF)-induced canonical nuclear factor-κB (NF-κB) pathway. Linear ubiquitin chains are specifically generated by an E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) and hydrolyzed by a deubiquitinase (DUB) called ovarian tumor (OTU) DUB with linear linkage specificity (OTULIN). LUBAC linearly ubiquitinates critical molecules in the TNF pathway, such as NEMO and RIPK1. The linear ubiquitin chains are then recognized by the ubiquitin readers, including NEMO, which control the TNF pathway. Accumulating evidence indicates an importance of the LUBAC complex in the regulation of apoptosis, development, and inflammation in mice. In this article, I focus on the role of linear ubiquitin chains in adaptive immune responses with an emphasis on the TNF-induced signaling pathways.

  16. Steepness of the radiation dose-response curve for dose-per-fraction escalation keeping the number of fractions fixed.

    PubMed

    Bentzen, Søren M

    2005-01-01

    Clinically, there is growing interest in strategies for intensifying radiation therapy by escalating the dose per fraction. This paper considers the steepness of the dose-response curve in this case. The steepness of a radiation dose-response curve is most conveniently quantified by the normalized dose-response gradient, gamma. Under the assumption of a linear-quadratic dose-effect model, a simple analytical relationship is derived between the gamma-value for a dose-response curve generated by varying the total dose while keeping the number of fractions constant, i.e. escalating the dose per fraction, and the gamma-value for a dose-response curve generated by varying the total dose while keeping the dose per fraction constant. This formulation is compared with clinical dose-response data from the literature and shown to be in good agreement with the observations. Some implications of this formulation for non-uniform dose distributions delivered using 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) are briefly discussed.

  17. Simplified Warfarin Dose-response Pharmacodynamic Models

    PubMed Central

    Kim, Seongho; Gaweda, Adam E.; Wu, Dongfeng; Li, Lang; Rai, Shesh N.; Brier, Michael E.

    2014-01-01

    Warfarin is a frequently used oral anticoagulant for long-term prevention and treatment of thromboembolic events. Due to its narrow therapeutic range and large inter-individual dose-response variability, it is highly desirable to personalize warfarin dosing. However, the complexity of the conventional kinetic-pharmacodynamic (K-PD) models hampers the development of the personalized dose management. To avert this challenge, we propose simplified PD models for warfarin dose-response relationship, which is motivated by ideas from control theory. The simplified models were further applied to longitudinal data of 37 patients undergoing anticoagulation treatment using the standard two-stage approach and then compared with the conventional K-PD models. Data analysis shows that all models have a similar predictive ability, but the simplified models are most parsimonious. PMID:25750489

  18. Linear Response Laws and Causality in Electrodynamics

    ERIC Educational Resources Information Center

    Yuffa, Alex J.; Scales, John A.

    2012-01-01

    Linear response laws and causality (the effect cannot precede the cause) are of fundamental importance in physics. In the context of classical electrodynamics, students often have a difficult time grasping these concepts because the physics is obscured by the intermingling of the time and frequency domains. In this paper, we analyse the linear…

  19. The debate on the use of linear no threshold for assessing the effects of low doses.

    PubMed

    Tubiana, M; Aurengo, A; Averbeck, D; Masse, R

    2006-09-01

    From December 2004 to July 2005, three reports on the effects of low doses of ionising radiation were released: ICRP (2004), the joint report of the French Academies of Science and Medicine (Tubiana et al 2005), and a report from the American Academy of Sciences (BEIR VII 2005). These reports quote the same recent articles on the biological effects of low doses, yet their conclusions diverge. The French report concludes that recent biological data show that the efficacy of defense mechanisms is modulated by dose and dose rate and that linear no threshold (LNT) is no longer plausible. The ICRP and the BEIR VII reports recognise that there are biologic arguments against LNT but feel that there are not sufficient biological proofs against it to change risk assessment methodology and subsequent regulatory policy based on LNT. They point out the remaining uncertainties and the lack of mechanistic explanations of phenomena such as low dose hyperlethality or the adaptive response. In this context, a critical analysis of the available data is necessary. The epidemiological data and the experimental data challenge the validity of the LNT hypothesis for assessing the carcinogenic effect of low doses, but do not allow its exclusion. Therefore, the main criteria for selecting the most reliable dose-effect relationship from a scientific point of view should be based on biological data. Their analysis should help one to understand the current controversy.

  20. Enhanced low dose rate sensitivity (ELDRS) of linear circuits in a space environment

    SciTech Connect

    Titus, J.L.; Emily, D.; Krieg, J.F.; Turflinger, T.; Pease, R.L.; Campbell, A.

    1999-12-01

    To investigate the ELDRS effect in a real space environment, an experiment was designed, launched, and placed in a highly elliptical orbit in November 1997. After its deployment, the electrical responses of several bipolar transistors and linear circuits have been and continue to be recorded once during every 12-hour orbit. System dosimeters are monitored to establish an average accumulated dose per orbit. With this information, the electrical parameter data are correlated with the dosimetry data to determine the total dose response of each device. This paper updates information on the ELDRS experiment through May 14, 1999. As of this date, the experiment has been in flight for a period of 18 months and has accumulated an approximate dose of 18 krd(Si). For comparison, devices, specifically linear circuits with the same date code, were irradiated using Co-60 sources, herein defined as ground-based tests. The ground-based tests are used to evaluate two hardness assurance tests, a room temperature irradiation at 10 mrd(Si)/s and an elevated temperature irradiation at 100 C and 10 rd(Si)/s and to evaluate the ELDRS response. To that end, irradiations were performed at room temperature, approximately 22 C, at fixed dose rates of 100, 1, and 0.01 rd(Si)/s and at elevated temperature, approximately 100 C, at a fixed dose rate of 10 rd(Si)/s. Currently, irradiations are being performed at room temperature at a fixed dose rate of 0.001 rd(Si)/s. Comparing the ground-based data to the flight data clearly demonstrates that enhanced parametric degradation has occurred in the flight parts. The two hardness assurance screens predicted ELDRS but the design margin for the elevated temperature test may not be adequate.

  1. Harderian Gland Tumorigenesis: Low-Dose and LET Response.

    PubMed

    Chang, Polly Y; Cucinotta, Francis A; Bjornstad, Kathleen A; Bakke, James; Rosen, Chris J; Du, Nicholas; Fairchild, David G; Cacao, Eliedonna; Blakely, Eleanor A

    2016-05-01

    Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the

  2. Dose-response model for teratological experiments involving quantal responses

    SciTech Connect

    Rai, K.; Van Ryzin, J.

    1985-03-01

    This paper introduces a dose-response model for teratological quantal response data where the probability of response for an offspring from a female at a given dose varies with the litter size. The maximum likelihood estimators for the parameters of the model are given as the solution of a nonlinear iterative algorithm. Two methods of low-dose extrapolation are presented, one based on the litter size distribution and the other a conservative method. The resulting procedures are then applied to a teratological data set from the literature.

  3. Relative Efficiency of TLD-100 to High Linear Energy Transfer Radiation: Correction to Astronaut Absorbed Dose

    NASA Technical Reports Server (NTRS)

    Badhwar, G. D.; Cash, B. L.; Semones, E. J.; Yasuda, H.; Fujitaka, K.

    1999-01-01

    Response of thermoluminescent detectors (TLD-100) to high linear energy transfer (LET) particles has been studied using helium, carbon, silicon, and iron ions from the Heavy Ion Medical Accelerator at Chiba (Japan), iron ions from the Brookhaven National Laboratory (NY) Alternate Gradient Synchrotron, and 53, 134, 185, and 232 MeV protons from the Loma Linda accelerator. Using the measured relative (to 137Cs) dose efficiency, and measured LET spectra from a tissue equivalent proportional counter (TEPC) on 20 Space Shuttle flights, and 7 Mir flights, the underestimation of absorbed dose by these detectors has been evaluated. The dose underestimation is between 15-20% depending upon the flight inclination and shielding location. This has been confirmed by direct correlation of measured dose by TEPC and TLD-100 at a low shielded location in the Shuttle mid-deck. A comparison of efficiency- LET data with a compilation of similar data from TLD-700, shows that shapes of the two curves are nearly identical, but that the TLD-100 curve is systematically lower by about 13%, and is the major cause of dose underestimation. These results strongly suggest that TLDs used for crew dose estimation be regularly calibrated using heavy ions.

  4. Relative Efficiency of TLD-100 to Linear Energy Transfer Radiation: Correction to Astronaut Absorbed Dose

    NASA Technical Reports Server (NTRS)

    Badhwar, Gautam D.; Cash, B. L.; Semones, E. J.; Yasuda, H.; Fujitaka, K.

    1999-01-01

    Response of thermoluminescent detectors (TLD-100) to high linear energy transfer (LET) particles has been studied using helium, carbon, silicon, and iron ions from the Heavy Ion Medical Accelerator at Chiba (Japan), iron ions from the Brookhaven National Laboratory (NY) Alternate Gradient Synchrotron, and 53, 134, 185, and 232 MeV protons from the Loma Linda accelerator. Using the measured relative (to (137)Cs dose efficiency, and measured LET spectra from a tissue equivalent proportional counter (TEPC) on 20 Space Shuttle flights, and 7 Mir flights, the underestimation of absorbed dose by these detectors has been evaluated. The dose underestimation is between 15-20% depending upon the flight inclination and shielding location. This has been confirmed by direct correlation of measured dose by TEPC and TLD-100 at a low shielded location in the Shuttle mid-deck. A comparison of efficiency- LET data with a compilation of similar data from TLD-700, shows that shapes of the two curves are nearly identical, but that the TLD-100 curve is systematically lower by about 13%, and is the major cause of dose underestimation. These results strongly suggest that TLDs used for crew dose estimation be regularly calibrated using heavy ions.

  5. Total dose bias dependency and ELDRS effects in bipolar linear devices

    NASA Technical Reports Server (NTRS)

    Yui, C. C.; McClure, S. S.; Rex, B. G.; Lehman, J. M.; Minto, T. D.; Wiedeman, M.

    2002-01-01

    Total dose tests of several bipolar linear devices show sensitivity to both dose rate and bias during exposure. All devices exhibited Enhanced Low Dose Rate Sensitivity (ELDRS). An accelerated ELDRS test method for three different devices demonstrate results similar to tests at low dose rate. Behavior and critical parameters from these tests are compared and discussed.

  6. Continuing evaluation of bipolar linear devices for total dose bias dependency and ELDRS effects

    NASA Technical Reports Server (NTRS)

    McClure, S. S.; Gorelick, J. J.; Yui, C. C.; Rax, B. G.; Wiedeman, M. D.

    2003-01-01

    We present results of continuing efforts to evaluate total dose bias dependency and ELDRS effects in bipolar linear microcircuits. Several devices were evaluated, each exhibiting moderate to significant bias and/or dose rate dependency.

  7. Linear Response Function of Bond-Order

    PubMed Central

    Suzuki, Nayuta; Mitsuta, Yuki; Okumura, Mitsutaka; Yamanaka, Shusuke

    2016-01-01

    We present the linear response function of bond-orders (LRF-BO) based on a real space integration scheme for molecular systems. As in the case of the LRF of density, the LRF-BO is defined as the response of the bond order of the molecule for the virtual perturbation. Our calculations show that the LRF-BO enables us not only to detect inductive and resonating effects of conjugating systems, but also to predict pKa values on substitution groups via linear relationships between the Hammett constants and the LRF-BO values for meta- and para-substituted benzoic acids. More importantly, the LRF-BO values for the O-H bonds strongly depend on the sites to which the virtual perturbation is applied, implying that the LRF-BO values include essential information about reaction mechanism of the acid-dissociation of substituted benzoic acids. PMID:27792148

  8. An update on the nonequilibrium linear response

    NASA Astrophysics Data System (ADS)

    Baiesi, M.; Maes, C.

    2013-01-01

    The unique fluctuation-dissipation theorem for equilibrium stands in contrast with the wide variety of nonequilibrium linear response formulae. Their most traditional approach is ‘analytic’, which, in the absence of detailed balance, introduces the logarithm of the stationary probability density as observable. The theory of dynamical systems offers an alternative with a formula that continues to work even when the stationary distribution is not smooth. We show that this method works equally well for stochastic dynamics, and we illustrate it with a numerical example for the perturbation of circadian cycles. A second ‘probabilistic’ approach starts from dynamical ensembles and expands the probability weights on path space. This line suggests new physical questions, as we meet the frenetic contribution to linear response, and the relevance of the change in dynamical activity in the relaxation to a (new) nonequilibrium condition.

  9. Protecting effects specifically from low doses of ionizing radiation to mammalian cells challenge the concept of linearity

    SciTech Connect

    Feinendegen, L.E.; Bond, V.P.; Sondhaus, C.A.; Altman, K.I.

    1998-12-31

    This report examines the origin of tissue effects that may follow from different cellular responses to low-dose irradiation, using published data. Two principal categories of cellular responses are considered. One response category relates to the probability of radiation-induced DNA damage. The other category consists of low-dose induced changes in intracellular signaling that induce mechanisms of DNA damage control different from those operating at high levels of exposure. Modeled in this way, tissue is treated as a complex adaptive system. The interaction of the various cellular responses results in a net tissue dose-effect relation that is likely to deviate from linearity in the low-dose region. This suggests that the LNT hypothesis should be reexamined. The aim of this paper is to demonstrate that by use of microdosimetric concepts, the energy deposited in cell mass can be related to the occurrence of cellular responses, both damaging and defensive.

  10. CALUX measurements: statistical inferences for the dose-response curve.

    PubMed

    Elskens, M; Baston, D S; Stumpf, C; Haedrich, J; Keupers, I; Croes, K; Denison, M S; Baeyens, W; Goeyens, L

    2011-09-30

    Chemical Activated LUciferase gene eXpression [CALUX] is a reporter gene mammalian cell bioassay used for detection and semi-quantitative analyses of dioxin-like compounds. CALUX dose-response curves for 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] are typically smooth and sigmoidal when the dose is portrayed on a logarithmic scale. Non-linear regression models are used to calibrate the CALUX response versus TCDD standards and to convert the sample response into Bioanalytical EQuivalents (BEQs). Several complications may arise in terms of statistical inference, specifically and most important is the uncertainty assessment of the predicted BEQ. This paper presents the use of linear calibration functions based on Box-Cox transformations to overcome the issue of uncertainty assessment. Main issues being addressed are (i) confidence and prediction intervals for the CALUX response, (ii) confidence and prediction intervals for the predicted BEQ-value, and (iii) detection/estimation capabilities for the sigmoid and linearized models. Statistical comparisons between different calculation methods involving inverse prediction, effective concentration ratios (ECR(20-50-80)) and slope ratio were achieved with example datasets in order to provide guidance for optimizing BEQ determinations and expand assay performance with the recombinant mouse hepatoma CALUX cell line H1L6.1c3.

  11. Evaluation of proposed hardness assurance method for bipolar linear circuits with enhanced low dose rate sensitivity (ELDRS)

    SciTech Connect

    Pease, R.L.; Gehlhausen, M.; Krieg, J.; Titus, J.; Turflinger, T.; Emily, D.; Cohn, L.

    1998-12-01

    Data are presented on several low dose rate sensitive bipolar linear circuits to evaluate a proposed hardness assurance method. The circuits include primarily operational amplifiers and voltage comparators with a variety of sensitive components and failure modes. The proposed method, presented in 1997, includes an option between a low dose rate test at 10 mrd(Si)/s and room temperature and a 100 C elevated temperature irradiation test at a moderate dose rate. The results of this evaluation demonstrate that a 10 mrd(Si)/s test is able (in all but one case) to bound the worst case response within a factor of 2. For the moderate dose rate, 100 C test the worst case response is within a factor of 3 for 8 of 11 circuits, and for some circuits overpredicts the low dose rate response. The irradiation bias used for these tests often represents a more degrading bias condition than would be encountered in a typical space system application.

  12. Random Response of Linear Hysteretic Damping

    SciTech Connect

    Floris, Claudio

    2008-07-08

    The probabilistic characterization of the response of a single-degree-of-freedom (SDOF) oscillator with linear hysteretic damping excited by ground motion described by zero mean stationary Gaussian processes is achieved by profiting from a steady-state solution of the motion equation, valid when the excitation is given by the superposition of harmonics. The model of linear hysteretic damping has been introduced to fit damping mechanisms in which the dissipation rate is independent of frequency, and mathematically it is described by the Hilbert transform of the response. Though this model is debated since it violates the principle of causality, its intrinsic simplicity makes it preferable to other models. The steady-state solution of the motion equation proposed in this paper allows a closed form evaluation of the respone mean square value. However, the numerical examples show that this quantity is affected by the mechanism of energy dissipation only when this is large. On the contrary, for a low capacity of dissipation the response mean square value is rather insensitive to the dissipation mechanism.

  13. A different perception of the linear, nonthreshold hypothesis for low-dose irradiation.

    PubMed Central

    Bond, V P; Benary, V; Sondhaus, C A

    1991-01-01

    Two equally useful dosimetric quantities, both of which are called dose, are used in toxicology. With radiation measurement, only one--the energy per unit mass D--is called dose. The other--the total energy in the irradiated system--is here distinguished from D by assigning it the name collective energy, epsilon. The collective energy is a more complete statement of dose because it is the product of the energy concentration D and the mass irradiated m. Especially in radioepidemiology, in which epsilon is the total energy imparted to all persons irradiated, the quantity m must be specified because it is situation specific and thus highly variable. At present, radioepidemiological dose-response curves are given only in terms of the toxicological model--i.e., the fraction (probability) of radiation-attributable cancers occurring as a function of D. Because this relation does not involve the number of persons at each value of D, it fosters the illusion that any dose, no matter how small, can result in cancer. However, we show that if the dose-response relationship is expressed in terms of the absolute number of attributable cancers as a function of epsilon, cancer occurs, on average, only if the collective energy exceeds a relatively large minimum value, the magnitude of which will be estimated. Therefore, we conclude that the nonthreshold aspect of the linear hypothesis is misleading and quite probably invalid. For example, in or around a facility in which exposure of humans to relatively low values of D occurs, attributable cancers are most unlikely to appear unless the epsilon to the irradiated population exceeds this minimum value. PMID:1924328

  14. A different perception of the linear, nonthreshold hypothesis for low-dose irradiation

    SciTech Connect

    Bond, V.P. ); Benary, V. Tel Aviv Univ. ); Sondhaus, C.A. )

    1991-10-01

    Two equally useful dosimetric quantities, both of which are called dose, are used in toxicology. With radiation measurement, only one - the energy per unit mass D - is called dose. The other - the total energy in the irradiated system - is here distinguished from D by assigning it the name collective energy, {epsilon}. The collective energy is a more complete statement of dose because it is the product of the energy concentration D and the mass irradiated m. Especially in radioepidemiology, in which {epsilon} is the total energy imparted to all persons irradiated, the quantity m must be specified because it is situation specific and thus highly variable. At present, radioepidemiological dose-response curves are given only in terms of the toxicological model - i.e., the fraction (probability) of radiation-attributable cancers occurring as a function of D. Because this relation does not involve the number of persons at each value of D, it fosters the illusion that any dose, no matter how small, can result in cancer. However, the authors show that if the dose-response relationship is expressed in terms of the absolute number of attributable cancers as a function of {epsilon}, cancer occurs, on average, only if the collective energy exceeds a relatively large minimum value, the magnitude of which will be estimated. Therefore, they conclude that the nonthreshold aspect of the linear hypothesis is misleading and quite probably invalid. For example, in or around a facility in which exposure of humans to relatively low values of D occurs, attributable cancers are most unlikely to appear unless the {epsilon} to the irradiated population exceeds this minimum value.

  15. Testing the dose-response specification in epidemiology: public health and policy consequences for lead.

    PubMed

    Rothenberg, Stephen J; Rothenberg, Jesse C

    2005-09-01

    Statistical evaluation of the dose-response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose-response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear-linear dose response) and natural-log-transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose-response relationship. We found that a log-linear lead-IQ relationship was a significantly better fit than was a linear-linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead-IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 microg/dL to 2.0 microg/dL) was 2.2 times (319 billion dollars) that calculated using a linear-linear dose-response function (149 billion dollars). The Centers for Disease Control and Prevention action limit of 10 microg/dL for children fails to protect against most damage and economic cost attributable to lead exposure.

  16. Shortcuts to adiabaticity from linear response theory

    SciTech Connect

    Acconcia, Thiago V.; Bonança, Marcus V. S.; Deffner, Sebastian

    2015-10-23

    A shortcut to adiabaticity is a finite-time process that produces the same final state as would result from infinitely slow driving. We show that such shortcuts can be found for weak perturbations from linear response theory. Moreover, with the help of phenomenological response functions, a simple expression for the excess work is found—quantifying the nonequilibrium excitations. For two specific examples, i.e., the quantum parametric oscillator and the spin 1/2 in a time-dependent magnetic field, we show that finite-time zeros of the excess work indicate the existence of shortcuts. We finally propose a degenerate family of protocols, which facilitates shortcuts to adiabaticity for specific and very short driving times.

  17. Shortcuts to adiabaticity from linear response theory

    DOE PAGES

    Acconcia, Thiago V.; Bonança, Marcus V. S.; Deffner, Sebastian

    2015-10-23

    A shortcut to adiabaticity is a finite-time process that produces the same final state as would result from infinitely slow driving. We show that such shortcuts can be found for weak perturbations from linear response theory. Moreover, with the help of phenomenological response functions, a simple expression for the excess work is found—quantifying the nonequilibrium excitations. For two specific examples, i.e., the quantum parametric oscillator and the spin 1/2 in a time-dependent magnetic field, we show that finite-time zeros of the excess work indicate the existence of shortcuts. We finally propose a degenerate family of protocols, which facilitates shortcuts tomore » adiabaticity for specific and very short driving times.« less

  18. Fewer Doses of HPV Vaccine Result in Immune Response Similar to Three-Dose Regimen

    MedlinePlus

    ... Releases NCI News Note Fewer doses of HPV vaccine result in immune response similar to three-dose ... that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody ...

  19. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

    NASA Technical Reports Server (NTRS)

    Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

  20. Mutations induced in Tradescantia by small doses of X-rays and neutrons - Analysis of dose-response curves.

    NASA Technical Reports Server (NTRS)

    Sparrow, A. H.; Underbrink, A. G.; Rossi, H. H.

    1972-01-01

    Dose-response curves for pink somatic mutations in Tradescantia stamen hairs were analyzed after neutron and X-ray irradiation with doses ranging from a fraction of a rad to the region of saturation. The dose-effect relation for neutrons indicates a linear dependence from 0.01 to 8 rads; between 0.25 and 5 rads, a linear dependence is indicated for X-rays also. As a consequence the relative biological effectiveness reaches a constant value (about 50) at low doses. The observations are in good agreement with the predictions of the theory of dual radiation action and support its interpretation of the effects of radiation on higher organisms. The doubling dose of X-rays was found to be nearly 1 rad.

  1. [Dose response curve of paclitaxel measured by histoculture drug response assay].

    PubMed

    Yoshimasu, Tatsuya; Oura, Shoji; Hirai, Issei; Kokawa, Yozo; Okamura, Yoshitaka; Furukawa, Tomoko

    2005-04-01

    Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.

  2. Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts after Exposure to Very Low Doses of High LET Radiation

    NASA Technical Reports Server (NTRS)

    Hada, M.; George, Kerry; Cucinotta, Francis A.

    2011-01-01

    The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivors with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (1-20 cGy) of 170 MeV/u Si-28- ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving greater than 2 breaks in 2 or more chromosomes). The curves for doses above 10 cGy were fitted with linear or linear-quadratic functions. For Si-28- ions no dose response was observed in the 2-10 cGy dose range, suggesting a non-target effect in this range.

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

    PubMed

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

    2016-07-08

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

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

    PubMed

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

    2016-07-01

    Out-of-field doses from radiotherapy can cause harmful side effects or eventually lead to secondary cancers. Scattered doses outside the applicator field, neutron source strength values, and neutron dose equivalents have not been broadly investigated for high-energy electron beams. To better understand the extent of these exposures, we measured out-of-field dose characteristics of electron applicators for high-energy electron beams on two Varian 21iXs, a Varian TrueBeam, and an Elekta Versa HD operating at various energy levels. Out-of-field dose profiles and percent depth-dose curves were measured in a Wellhofer water phantom using a Farmer ion chamber. Neutron dose was assessed using a combination of moderator buckets and gold activation foils placed on the treatment couch at various locations in the patient plane on both the Varian 21iX and Elekta Versa HD linear accelerators. Our findings showed that out-of-field electron doses were highest for the highest electron energies. These doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. The Elekta linear accelerator had higher electron out-of-field doses than the Varian units examined, and the Elekta dose profiles exhibited a second dose peak about 20 to 30 cm from central-axis, which was found to be higher than typical out-of-field doses from photon beams. Electron doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. With respect to neutron dosimetry, Q values and neutron dose equivalents increased with electron beam energy. Neutron contamination from electron beams was found to be much lower than that from photon beams. Even though the neutron dose equivalent for electron beams represented a small portion of neutron doses observed under photon beams, neutron doses from electron beams may need to be considered for special cases. PACS number(s): 87

  5. Population variability in biological adaptive responses to DNA damage and the shapes of carcinogen dose-response curves

    SciTech Connect

    Conolly, Rory B. . E-mail: Conolly.Rory@epa.gov; Gaylor, David W.; Lutz, Werner K.

    2005-09-01

    Carcinogen dose-response curves for both ionizing radiation and chemicals are typically assumed to be linear at environmentally relevant doses. This assumption is used to ensure protection of the public health in the absence of relevant dose-response data. A theoretical justification for the assumption has been provided by the argument that low dose linearity is expected when an exogenous agent adds to an ongoing endogenous process. Here, we use computational modeling to evaluate (1) how two biological adaptive processes, induction of DNA repair and cell cycle checkpoint control, may affect the shapes of dose-response curves for DNA-damaging carcinogens and (2) how the resulting dose-response behaviors may vary within a population. Each model incorporating an adaptive process was capable of generating not only monotonic dose-responses but also nonmonotonic (J-shaped) and threshold responses. Monte Carlo analysis suggested that all these dose-response behaviors could coexist within a population, as the spectrum of qualitative differences arose from quantitative changes in parameter values. While this analysis is largely theoretical, it suggests that (a) accurate prediction of the qualitative form of the dose-response requires a quantitative understanding of the mechanism (b) significant uncertainty is associated with human health risk prediction in the absence of such quantitative understanding and (c) a stronger experimental and regulatory focus on biological mechanisms and interindividual variability would allow flexibility in regulatory treatment of environmental carcinogens without compromising human health.

  6. Dose calculation and in-phantom measurement in BNCT using response matrix method.

    PubMed

    Rahmani, Faezeh; Shahriari, Majid

    2011-12-01

    In-phantom measurement of physical dose distribution is very important for Boron Neutron Capture Therapy (BNCT) planning validation. If any changes take place in therapeutic neutron beam due to the beam shaping assembly (BSA) change, the dose will be changed so another group of simulations should be carried out for dose calculation. To avoid this time consuming procedure and speed up the dose calculation to help patients not wait for a long time, response matrix method was used. This procedure was performed for neutron beam of the optimized BSA as a reference beam. These calculations were carried out using the MCNPX, Monte Carlo code. The calculated beam parameters were measured for a SNYDER head phantom placed 10 cm away from beam the exit of the BSA. The head phantom can be assumed as a linear system and neutron beam and dose distribution can be assumed as an input and a response of this system (head phantom), respectively. Neutron spectrum energy was digitized into 27 groups. Dose response of each group was calculated. Summation of these dose responses is equal to a total dose of the whole neutron/gamma spectrum. Response matrix is the double dimension matrix (energy/dose) in which each parameter represents a depth-dose resulted from specific energy. If the spectrum is changed, response of each energy group may be differed. By considering response matrix and energy vector, dose response can be calculated. This method was tested for some BSA, and calculations show statistical errors less than 10%.

  7. Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC

    EPA Science Inventory

    The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. Recently, claims have arisen tha...

  8. Dose response relationship in anti-stress gene regulatory networks.

    PubMed

    Zhang, Qiang; Andersen, Melvin E

    2007-03-02

    To maintain a stable intracellular environment, cells utilize complex and specialized defense systems against a variety of external perturbations, such as electrophilic stress, heat shock, and hypoxia, etc. Irrespective of the type of stress, many adaptive mechanisms contributing to cellular homeostasis appear to operate through gene regulatory networks that are organized into negative feedback loops. In general, the degree of deviation of the controlled variables, such as electrophiles, misfolded proteins, and O2, is first detected by specialized sensor molecules, then the signal is transduced to specific transcription factors. Transcription factors can regulate the expression of a suite of anti-stress genes, many of which encode enzymes functioning to counteract the perturbed variables. The objective of this study was to explore, using control theory and computational approaches, the theoretical basis that underlies the steady-state dose response relationship between cellular stressors and intracellular biochemical species (controlled variables, transcription factors, and gene products) in these gene regulatory networks. Our work indicated that the shape of dose response curves (linear, superlinear, or sublinear) depends on changes in the specific values of local response coefficients (gains) distributed in the feedback loop. Multimerization of anti-stress enzymes and transcription factors into homodimers, homotrimers, or even higher-order multimers, play a significant role in maintaining robust homeostasis. Moreover, our simulation noted that dose response curves for the controlled variables can transition sequentially through four distinct phases as stressor level increases: initial superlinear with lesser control, superlinear more highly controlled, linear uncontrolled, and sublinear catastrophic. Each phase relies on specific gain-changing events that come into play as stressor level increases. The low-dose region is intrinsically nonlinear, and depending on

  9. Compatibility of the Linear-Quadratic Formalism and Biologically Effective Dose Concept to High-Dose-Per-Fraction Irradiation in a Murine Tumor

    SciTech Connect

    Otsuka, Shinya; Shibamoto, Yuta; Iwata, Hiromitsu; Murata, Rumi; Sugie, Chikao; Ito, Masato; Ogino, Hiroyuki

    2011-12-01

    Purpose: To evaluate the compliance of linear-quadratic (LQ) model calculations in the high-dose range as used in stereotactic irradiation in a murine tumor model. Methods and Materials: Female 10-week-old Balb/c mice bearing 1-cm-diameter EMT6 tumors in the hind legs were used. Single doses of 10-25 Gy were compared with 2-5 fractions of 4-13 Gy given at 4-hour intervals. Cell survival after irradiation was determined by an in vivo-in vitro assay. Using an {alpha}/{beta} ratio determined for in vitro EMT6 cells and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with actually measured equivalent single doses for the hypofractionated doses. These fractionation schedules were also compared simultaneously to investigate the concordance/divergence of dose-survival curves plotted against actual radiation doses and biologically effective doses (BED). Results: Equivalent single doses for hypofractionated doses calculated from LQ formalism were lower than actually measured doses by 21%-31% in the 2- or 3-fraction experiments and by 27%-42% in the 4- or 5-fraction experiments. The differences were all significant. When a higher {alpha}/{beta} ratio was assumed, the discrepancy became smaller. In direct comparison of the 2- to 5-fraction schedules, respective dose-response curves almost overlapped when cell survival was plotted against actual radiation doses. However, the curves tended to shift downward by increasing the fraction number when cell survival was plotted against BED calculated using an {alpha}/{beta} ratio of 3.5 Gy for in vitro EMT6 cells. Conclusion: Conversion of hypofractionated radiation doses to single doses using the LQ formalism underestimated the in vivo effect of hypofractionated radiation by approximately 20%-40%. The discrepancy appeared to be larger than that seen in the previous in vitro study and tended to increase with the fraction number. BED appeared to be an unreliable measure

  10. Advanced Computational Approaches for Characterizing Stochastic Cellular Responses to Low Dose, Low Dose Rate Exposures

    SciTech Connect

    Scott, Bobby, R., Ph.D.

    2003-06-27

    OAK - B135 This project final report summarizes modeling research conducted in the U.S. Department of Energy (DOE), Low Dose Radiation Research Program at the Lovelace Respiratory Research Institute from October 1998 through June 2003. The modeling research described involves critically evaluating the validity of the linear nonthreshold (LNT) risk model as it relates to stochastic effects induced in cells by low doses of ionizing radiation and genotoxic chemicals. The LNT model plays a central role in low-dose risk assessment for humans. With the LNT model, any radiation (or genotoxic chemical) exposure is assumed to increase one¡¯s risk of cancer. Based on the LNT model, others have predicted tens of thousands of cancer deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Our research has focused on developing biologically based models that explain the shape of dose-response curves for low-dose radiation and genotoxic chemical-induced stochastic effects in cells. Understanding the shape of the dose-response curve for radiation and genotoxic chemical-induced stochastic effects in cells helps to better understand the shape of the dose-response curve for cancer induction in humans. We have used a modeling approach that facilitated model revisions over time, allowing for timely incorporation of new knowledge gained related to the biological basis for low-dose-induced stochastic effects in cells. Both deleterious (e.g., genomic instability, mutations, and neoplastic transformation) and protective (e.g., DNA repair and apoptosis) effects have been included in our modeling. Our most advanced model, NEOTRANS2, involves differing levels of genomic instability. Persistent genomic instability is presumed to be associated with nonspecific, nonlethal mutations and to increase both the risk for neoplastic transformation and for cancer occurrence. Our research results, based on

  11. Radiation-induced genomic instability: radiation quality and dose response

    NASA Technical Reports Server (NTRS)

    Smith, Leslie E.; Nagar, Shruti; Kim, Grace J.; Morgan, William F.

    2003-01-01

    Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

  12. Characterization of Radiation Hardened Bipolar Linear Devices for High Total Dose Missions

    NASA Technical Reports Server (NTRS)

    McClure, Steven S.; Harris, Richard D.; Rax, Bernard G.; Thorbourn, Dennis O.

    2012-01-01

    Radiation hardened linear devices are characterized for performance in combined total dose and displacement damage environments for a mission scenario with a high radiation level. Performance at low and high dose rate for both biased and unbiased conditions is compared and the impact to hardness assurance methodology is discussed.

  13. Total Dose Effects on Single Event Transients in Linear Bipolar Systems

    NASA Technical Reports Server (NTRS)

    Buchner, Stephen; McMorrow, Dale; Bernard, Muriel; Roche, Nicholas; Dusseau, Laurent

    2008-01-01

    Single Event Transients (SETs) originating in linear bipolar integrated circuits are known to undermine the reliability of electronic systems operating in the radiation environment of space. Ionizing particle radiation produces a variety of SETs in linear bipolar circuits. The extent to which these SETs threaten system reliability depends on both their shapes (amplitude and width) and their threshold energies. In general, SETs with large amplitudes and widths are the most likely to propagate from a bipolar circuit's output through a subsystem. The danger these SET pose is that, if they become latched in a follow-on circuit, they could cause an erroneous system response. Long-term exposure of linear bipolar circuits to particle radiation produces total ionizing dose (TID) and/or displacement damage dose (DDD) effects that are characterized by a gradual degradation in some of the circuit's electrical parameters. For example, an operational amplifier's gain-bandwidth product is reduced by exposure to ionizing radiation, and it is this reduction that contributes to the distortion of the SET shapes. In this paper, we compare SETs produced in a pristine LM124 operational amplifier with those produced in one exposed to ionizing radiation for three different operating configurations - voltage follower (VF), inverter with gain (IWG), and non-inverter with gain (NIWG). Each configuration produces a unique set of transient shapes that change following exposure to ionizing radiation. An important finding is that the changes depend on operating configuration; some SETs decrease in amplitude, some remain relatively unchanged, some become narrower and some become broader.

  14. Confidence bounds for nonlinear dose-response relationships.

    PubMed

    Baayen, C; Hougaard, P

    2015-11-30

    An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve. It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated using a public dataset and simulations based on the Emax and sigmoid Emax models.

  15. Adaptive dose finding based on t-statistic for dose-response trials.

    PubMed

    Ivanova, Anastasia; Bolognese, James A; Perevozskaya, Inna

    2008-05-10

    The goals of phase II dose-response studies are to prove that the treatment is effective and to choose the dose for further development. Randomized designs with equal allocation to either a high dose and placebo or to each of several doses and placebo are typically used. However, in trials where response is observed relatively quickly, adaptive designs might offer an advantage over equal allocation. We propose an adaptive design for dose-response trials that concentrates the allocation of subjects in one or more areas of interest, for example, near a minimum clinically important effect level, or near some maximal effect level, and also allows for the possibility to stop the trial early if needed. The proposed adaptive design yields higher power to detect a dose-response relationship, higher power in comparison with placebo, and selects the correct dose more frequently compared with a corresponding randomized design with equal allocation to doses.

  16. A model to calculate the induced dose rate around an 18 MV ELEKTA linear accelerator.

    PubMed

    Perrin, Bruce; Walker, Anne; Mackay, Ranald

    2003-03-07

    The dose rate due to activity induced by (gamma, n) reactions around an ELEKTA Precise accelerator running at 18 MV is reported. A model to calculate the induced dose rate for a variety of working practices has been derived and compared to the measured values. From this model, the dose received by the staff using the machine can be estimated. From measured dose rates at the face of the linear accelerator for a 10 x 10 cm2 jaw setting at 18 MV an activation coefficient per MU was derived for each of the major activation products. The relative dose rates at points around the linac head, for different energy and jaw settings, were measured. Dose rates adjacent to the patient support system and portal imager were also measured. A model to calculate the dose rate at these points was derived, and compared to those measured over a typical working week. The model was then used to estimate the maximum dose to therapists for the current working schedule on this machine. Calculated dose rates at the linac face agreed to within +/- 12% of those measured over a week, with a typical dose rate of 4.5 microSv h(-1) 2 min after the beam has stopped. The estimated maximum annual whole body dose for a treatment therapist, with the machine treating at only 18 MV, for 60000 MUs per week was 2.5 mSv. This compares well with value of 2.9 mSv published for a Clinac 21EX. A model has been derived to calculate the dose from the four dominant activation products of an ELEKTA Precise 18 MV linear accelerator. This model is a useful tool to calculate the induced dose rate around the treatment head. The model can be used to estimate the dose to the staff for typical working patterns.

  17. The increase in animal mortality risk following exposure to sparsely ionizing radiation is not linear quadratic with dose

    SciTech Connect

    Haley, Benjamin M.; Paunesku, Tatjana; Grdina, David J.; Woloschak, Gayle E.; Aravindan, Natarajan

    2015-12-09

    The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). As a result, it was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies.

  18. The increase in animal mortality risk following exposure to sparsely ionizing radiation is not linear quadratic with dose

    DOE PAGES

    Haley, Benjamin M.; Paunesku, Tatjana; Grdina, David J.; ...

    2015-12-09

    The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). As a result, it was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limitedmore » number of animal studies.« less

  19. Radiation dose response estimation with emphasis on low dose range using restricted cubic splines: application to all solid cancer mortality data, 1950-2003, in atomic bomb survivors.

    PubMed

    Nakashima, Eiji

    2015-07-01

    Using the all solid cancer mortality data set of the Life Span Study (LSS) cohort from 1950 to 2003 (LSS Report 14) data among atomic bomb survivors, excess relative risk (ERR) statistical analyses were performed using the second degree polynomial and the threshold and restricted cubic spline (RCS) dose response models. For the RCS models with 3 to 7 knots of equally spaced percentiles with margins in the dose range greater than 50 mGy, the dose response was assumed to be linear at less than 70 to 90 mGy. Due to the skewed dose distribution of atomic bomb survivors, the current knot system for the RCS analysis results in a detailed depiction of the dose response as less than approximately 0.5 Gy. The 6 knot RCS models for the all-solid cancer mortality dose response of the whole dose or less than 2 Gy were selected with the AIC model selection criterion and fit significantly better (p < 0.05) than the linear (L) model. The usual RCS includes the L-global model but not the quadratic (Q) nor linear-quadratic (LQ) global models. The authors extended the RCS to include L or LQ global models by putting L or LQ constraints on the cubic spline in the lower and upper tails, and the best RCS model selected with AIC criterion was the usual RCS with L-constraints in both the lower and upper tails. The selected RCS had a linear dose-response model in the lower dose range (i.e., < 0.2-0.3 Gy) and was compatible with the linear no-threshold (LNT) model in this dose range. The proposed method is also useful in describing the dose response of a specific cancer or non-cancer disease incidence/mortality.

  20. Differential Response and Priming Dose Effect on the Proteome of Human Fibroblast and Stem Cells Induced by Exposure to Low Doses of Ionizing Radiation.

    PubMed

    Hauptmann, Monika; Haghdoost, Siamak; Gomolka, Maria; Sarioglu, Hakan; Ueffing, Marius; Dietz, Anne; Kulka, Ulrike; Unger, Kristian; Babini, Gabriele; Harms-Ringdahl, Mats; Ottolenghi, Andrea; Hornhardt, Sabine

    2016-03-01

    It has been suggested that a mechanistic understanding of the cellular responses to low dose and dose rate may be valuable in reducing some of the uncertainties involved in current risk estimates for cancer- and non-cancer-related radiation effects that are inherited in the linear no-threshold hypothesis. In this study, the effects of low-dose radiation on the proteome in both human fibroblasts and stem cells were investigated. Particular emphasis was placed on examining: 1. the dose-response relationships for the differential expression of proteins in the low-dose range (40-140 mGy) of low-linear energy transfer (LET) radiation; and 2. the effect on differential expression of proteins of a priming dose given prior to a challenge dose (adaptive response effects). These studies were performed on cultured human fibroblasts (VH10) and human adipose-derived stem cells (ADSC). The results from the VH10 cell experiments demonstrated that low-doses of low-LET radiation induced unique patterns of differentially expressed proteins for each dose investigated. In addition, a low priming radiation dose significantly changed the protein expression induced by the subsequent challenge exposure. In the ADSC the number of differentially expressed proteins was markedly less compared to VH10 cells, indicating that ADSC differ in their intrinsic response to low doses of radiation. The proteomic results are further discussed in terms of possible pathways influenced by low-dose irradiation.

  1. Linear response theory for annealing of radiation damage in semiconductor devices

    NASA Technical Reports Server (NTRS)

    Litovchenko, Vitaly

    1988-01-01

    A theoretical study of the radiation/annealing response of MOS ICs is described. Although many experiments have been performed in this field, no comprehensive theory dealing with radiation/annealing response has been proposed. Many attempts have been made to apply linear response theory, but no theoretical foundation has been presented. The linear response theory outlined here is capable of describing a broad area of radiation/annealing response phenomena in MOS ICs, in particular, both simultaneous irradiation and annealing, as well as short- and long-term annealing, including the case when annealing is nearing completion. For the first time, a simple procedure is devised to determine the response function from experimental radiation/annealing data. In addition, this procedure enables us to study the effect of variable temperature and dose rate, effects which are of interest in spaceflight. In the past, the shift in threshold potential due to radiation/annealing has usually been assumed to depend on one variable: the time lapse between an impulse dose and the time of observation. While such a suggestion of uniformity in time is certainly true for a broad range of radiation annealing phenomena, it may not hold for some ranges of the variables of interest (temperature, dose rate, etc.). A response function is projected which is dependent on two variables: the time of observation and the time of the impulse dose. This dependence on two variables allows us to extend the theory to the treatment of a variable dose rate. Finally, the linear theory is generalized to the case in which the response is nonlinear with impulse dose, but is proportional to some impulse function of dose. A method to determine both the impulse and response functions is presented.

  2. Impact of using linear optimization models in dose planning for HDR brachytherapy

    SciTech Connect

    Holm, Aasa; Larsson, Torbjoern; Carlsson Tedgren, Aasa

    2012-02-15

    Purpose: Dose plans generated with optimization models hitherto used in high-dose-rate (HDR) brachytherapy have shown a tendency to yield longer dwell times than manually optimized plans. Concern has been raised for the corresponding undesired hot spots, and various methods to mitigate these have been developed. The hypotheses upon this work is based are (a) that one cause for the long dwell times is the use of objective functions comprising simple linear penalties and (b) that alternative penalties, as these are piecewise linear, would lead to reduced length of individual dwell times. Methods: The characteristics of the linear penalties and the piecewise linear penalties are analyzed mathematically. Experimental comparisons between the two types of penalties are carried out retrospectively for a set of prostate cancer patients. Results: When the two types of penalties are compared, significant changes can be seen in the dwell times, while most dose-volume parameters do not differ significantly. On average, total dwell times were reduced by 4.2%, with a reduction of maximum dwell times by 25%, when the alternative penalties were used. Conclusions: The use of linear penalties in optimization models for HDR brachytherapy is one cause for the undesired long dwell times that arise in mathematically optimized plans. By introducing alternative penalties, a significant reduction in dwell times can be achieved for HDR brachytherapy dose plans. Although various measures for mitigating the long dwell times are already available, the observation that linear penalties contribute to their appearance is of fundamental interest.

  3. A linear programming model for optimizing HDR brachytherapy dose distributions with respect to mean dose in the DVH-tail

    SciTech Connect

    Holm, Åsa; Larsson, Torbjörn; Tedgren, Åsa Carlsson

    2013-08-15

    Purpose: Recent research has shown that the optimization model hitherto used in high-dose-rate (HDR) brachytherapy corresponds weakly to the dosimetric indices used to evaluate the quality of a dose distribution. Although alternative models that explicitly include such dosimetric indices have been presented, the inclusion of the dosimetric indices explicitly yields intractable models. The purpose of this paper is to develop a model for optimizing dosimetric indices that is easier to solve than those proposed earlier.Methods: In this paper, the authors present an alternative approach for optimizing dose distributions for HDR brachytherapy where dosimetric indices are taken into account through surrogates based on the conditional value-at-risk concept. This yields a linear optimization model that is easy to solve, and has the advantage that the constraints are easy to interpret and modify to obtain satisfactory dose distributions.Results: The authors show by experimental comparisons, carried out retrospectively for a set of prostate cancer patients, that their proposed model corresponds well with constraining dosimetric indices. All modifications of the parameters in the authors' model yield the expected result. The dose distributions generated are also comparable to those generated by the standard model with respect to the dosimetric indices that are used for evaluating quality.Conclusions: The authors' new model is a viable surrogate to optimizing dosimetric indices and quickly and easily yields high quality dose distributions.

  4. Adaptive response to hydrogen peroxide in yeast: induction, time course, and relationship to dose-response models.

    PubMed

    Hoffmann, George R; Moczula, Andrew V; Laterza, Amanda M; Macneil, Lindsey K; Tartaglione, Jason P

    2013-07-01

    The assay for trp5 gene conversion and ilv1-92 reversion in Saccharomyces cerevisiae strain D7 was used to characterize the induction of an adaptive response by hydrogen peroxide (H(2)O(2)). Effects of a small priming dose on the genotoxic effects of a larger challenge dose were measured in exponential cultures and in early stationary phase. An adaptive response, indicated by smaller convertant and revertant frequencies after the priming dose, occurred at lower priming and challenge doses in young, well-aerated cultures. Closely spaced priming doses from 0.000975 to 2 mM, followed by a 1 mM challenge, showed that the induction of the adaptive response is biphasic. In exponential cultures it was maximal with a priming dose of 0.125-0.25 mM. Very small priming doses were insufficient to induce the adaptive response, whereas higher doses contributed to damage. A significant adaptive response was detected when the challenge dose was administered 10-20 min after the priming exposure. It was fully expressed within 45 min, and the yeast began to return to the nonadapted state after 4-6 hr. Because of the similarity of the biphasic induction to hormetic curves and the proposal that adaptive responses are a manifestation of hormesis, we evaluated whether the low doses of H(2)O(2) that induce the adaptive response show a clear hormetic response without a subsequent challenge dose. Hormesis was not evident, but there was an apparent threshold for genotoxicity at or slightly below 0.125 mM. The results are discussed with respect to linear, threshold, and hormesis dose-response models.

  5. The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery.

    PubMed

    Kirkpatrick, John P; Meyer, Jeffrey J; Marks, Lawrence B

    2008-10-01

    The linear-quadratic (LQ) model is widely used to model the effect of total dose and dose per fraction in conventionally fractionated radiotherapy. Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery. Clinically, the LQ model often underestimates tumor control observed at radiosurgical doses. The underlying mechanisms implied by the LQ model do not reflect the vascular and stromal damage produced at the high doses per fraction encountered in radiosurgery and ignore the impact of radioresistant subpopulations of cells. The appropriate modeling of both tumor control and normal tissue toxicity in radiosurgery requires the application of emerging understanding of molecular-, cellular-, and tissue-level effects of high-dose/fraction-ionizing radiation and the role of cancer stem cells.

  6. Dose-response relationships for carcinogens: a review

    SciTech Connect

    Zeise, L.; Wilson, R.; Crouch, E.A.C.

    1987-08-01

    The authors review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Their major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so they pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites.

  7. Dose-response relationships for carcinogens: a review.

    PubMed Central

    Zeise, L; Wilson, R; Crouch, E A

    1987-01-01

    We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinearities. There are few experimental examples of nonlinear dose-response relations in humans, but this may simply be due to the limitations in the data. The several examples in rodents, even though for high dose data, suggest that nonlinearity is common. In some cases such nonlinearities may be rationalized on the basis of the pharmacokinetics of the test compound or its metabolites. PMID:3311725

  8. A semiempirical method for the description of relative crossbeam dose profiles at depth from linear accelerators.

    PubMed

    Tsalafoutas, I; Xenofos, S; Stamatelatos, I E

    1997-01-01

    A semiempirical method for the calculation of the relative crossbeam dose profiles at depth is described. The parameters required to set up the formulae and their dependence with field size and depth are investigated. Using the above method, measured crossbeam dose profiles at depth from two linear accelerators, Philips (SL-18) and AEC (Therac-6) are reproduced. The results indicate that this method is applicable within a wide range of depths and field sizes.

  9. Dose response on the 110 °C thermoluminescence peak of un-heated, synthetic Merck quartz

    NASA Astrophysics Data System (ADS)

    Kaya Keleş, Şule; Meriç, Niyazi; Polymeris, George S.

    2016-07-01

    Studies on 110 °C TL peak have been carried out using natural quartz from different origins and synthetic quartz produced by different suppliers. The interest in quartz is due to its usage in dating and retrospective dosimetry as a main material; both synthetic and natural types of quartz yield the 110 °C TL peak in their glow curve. In most studies to understand the physical mechanism behind the TL system, synthetic quartz samples are used and there are many investigations about dose response, in both low and high radiation dose region. In these studies generally synthetic quartz samples produced by Sawyer Research Products are used and the studies showed that both heated and un-heated synthetic quartz samples have intense supra-linear responses. Supra-linearity was enhanced by applying a pre-irradiation while several models have been developed towards an explanation to these supra-linearity effects. In this study commercially available synthetic Merck quartz was used. Different combinations of optical filters were used to obtain dose response curves upto 266 Gy and the effect of pre-dose to these dose response curves was studied. Un-pre-dosed Merck quartz samples dose supra-linearity index is below 1 independently on the optical filters; so Merck quartz showed linear or sub-linear dose response.

  10. Cytogenetic dose-response in vitro for biological dosimetry after exposure to high doses of gamma-rays.

    PubMed

    Vinnikov, Volodymyr A; Maznyk, Nataliya A

    2013-04-01

    The dose response for dicentrics plus centric rings and total unstable chromosome-type aberrations was studied in the first mitoses of cultured human peripheral blood lymphocytes irradiated in vitro to doses of ∼2, 4, 6, 8, 10, 16 and 20 Gy of acute (60)Со gamma-rays. A dose-dependent increase of aberration yield was accompanied by a tendency to the underdispersion of dicentrics and centric rings among cells distributions compared with Poisson statistics at doses ≥6 Gy. The formal fitting of the data to a linear-quadratic model resulted in an equation with the linear and quadratic coefficients ranged 0.098-0.129×cell(-1)×Gy(-1) and 0.039-0.034×cell(-1)×Gy(-2), respectively, depending on the fitting method. The actual radiation-induced aberration yield was markedly lower than expected from a calibration curve, generated earlier within a lower dose range. Interlaboratory variations in reported dicentric yields induced by medium-to-high radiation doses in vitro are discussed.

  11. Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

    PubMed Central

    Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

    2012-01-01

    For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

  12. Dose-Response Calculator for ArcGIS

    USGS Publications Warehouse

    Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.

    2011-01-01

    The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.

  13. Linear response theory for open systems: Quantum master equation approach

    NASA Astrophysics Data System (ADS)

    Ban, Masashi; Kitajima, Sachiko; Arimitsu, Toshihico; Shibata, Fumiaki

    2017-02-01

    A linear response theory for open quantum systems is formulated by means of the time-local and time-nonlocal quantum master equations, where a relevant quantum system interacts with a thermal reservoir as well as with an external classical field. A linear response function that characterizes how a relaxation process deviates from its intrinsic process by a weak external field is obtained by extracting the linear terms with respect to the external field from the quantum master equation. It consists of four parts. One represents the linear response of a quantum system when system-reservoir correlation at an initial time and correlation between reservoir states at different times are neglected. The others are correction terms due to these effects. The linear response function is compared with the Kubo formula in the usual linear response theory. To investigate the properties of the linear response of an open quantum system, an exactly solvable model for a stochastic dephasing of a two-level system is examined. Furthermore, the method for deriving the linear response function is applied for calculating two-time correlation functions of open quantum systems. It is shown that the quantum regression theorem is not valid for open quantum systems unless their reduced time evolution is Markovian.

  14. NONMONOTONIC DOSE RESPONSE CURVES (NMDRCS) ARE COMMON AFTER ESTROGEN OR ANDROGEN SIGNALING PATHWAY DISRUPTION. FACT OR FALDERAL?

    EPA Science Inventory

    ABSTRACT BODY: The shape of the dose response curve in the low dose region has been debated since the 1940s, originally focusing on linear no threshold (LNT) versus threshold responses for cancer and noncancer effects. Recently, it has been claimed that endocrine disrupters (EDCs...

  15. Prenatal intravenous cocaine and the heart rate-orienting response: a dose-response study.

    PubMed

    Foltz, Tara L; Snow, Diane M; Strupp, Barbara J; Booze, Rosemarie M; Mactutus, Charles F

    2004-01-01

    Attentional dysfunction is a persistent behavioral abnormality that is emerging as one of the cardinal features in the investigations of the teratogenic effects of cocaine in humans and rodents. The present study sought to extend this work by using a dose-response design with an alternate strain of rat. Virgin Long-Evans female rats, implanted with an IV access port prior to breeding were administered saline, 0.5, 1.0, or 3.0 mg/kg of cocaine HCl from gestational day (GD) GD8-21 (1x per day-GD8-14, 2x per day-GD15-21). Cocaine had no significant effect on maternal or litter parameters. At 14-15 days of age, 1 male and 1 female from each litter were tested to evaluate the heart rate orienting response (HR-OR). Following 20 min for acclimation, pups were presented an olfactory stimulus for 20s per trial, across four trials, and with an intertrial interval of 2 min. The initial baseline HR was not significantly different across the treatment groups, although cocaine did alter the stability of the QRS complex duration. The magnitude of the HR-OR averaged across trials increased as a linear function of dosage of cocaine. A more complex (quadratic) interaction between cocaine dose and sex of the offspring was also noted. When examined across trials, the controls failed to display any significant within-session variation in the HR-OR; in contrast all of the prenatal cocaine treated groups displayed either sensitization (low and high dose) or habituation of the response (middle dose). Analysis of the peak HR-OR confirmed that the controls were indeed displaying the response on at least one trial of the session, albeit not consistently on any specific trial. The more vigorous HR-OR of the prenatal cocaine groups, relative to vehicle controls, most likely reflects an alteration in development of the neural basis of response; as previously shown, the most vigorous response to the olfactory stimulus is seen early (12 days of age) and progressively decreases across the

  16. The cytokinesis-blocked micronucleus assay: dose-response calibration curve, background frequency in the population and dose estimation.

    PubMed

    Rastkhah, E; Zakeri, F; Ghoranneviss, M; Rajabpour, M R; Farshidpour, M R; Mianji, F; Bayat, M

    2016-03-01

    An in vitro study of the dose responses of human peripheral blood lymphocytes was conducted with the aim of creating calibrated dose-response curves for biodosimetry measuring up to 4 Gy (0.25-4 Gy) of gamma radiation. The cytokinesis-blocked micronucleus (CBMN) assay was employed to obtain the frequencies of micronuclei (MN) per binucleated cell in blood samples from 16 healthy donors (eight males and eight females) in two age ranges of 20-34 and 35-50 years. The data were used to construct the calibration curves for men and women in two age groups, separately. An increase in micronuclei yield with the dose in a linear-quadratic way was observed in all groups. To verify the applicability of the constructed calibration curve, MN yields were measured in peripheral blood lymphocytes of two real overexposed subjects and three irradiated samples with unknown dose, and the results were compared with dose values obtained from measuring dicentric chromosomes. The comparison of the results obtained by the two techniques indicated a good agreement between dose estimates. The average baseline frequency of MN for the 130 healthy non-exposed donors (77 men and 55 women, 20-60 years old divided into four age groups) ranged from 6 to 21 micronuclei per 1000 binucleated cells. Baseline MN frequencies were higher for women and for the older age group. The results presented in this study point out that the CBMN assay is a reliable, easier and valuable alternative method for biological dosimetry.

  17. Dose-response relationship for rat liver DNA damage caused by 1,2-dimethylhydrazine.

    PubMed

    Kitchin, K T; Brown, J L

    1996-12-02

    An experimental approach was taken to the question of dose-response curves for chemical carcinogenesis, using DNA damage as a biomarker. Female rats were give 13 different doses of 1,2-dimethylhydrazine (from 1.4 to 135,000 micrograms/kg) and the subsequent hepatic DNA damage was determined by the alkaline elution technique. DMH doses below 450 micrograms/kg did not significantly damage DNA; all DMH doses of 1000 micrograms/kg or higher damaged rat hepatic DNA (P < 0.05). In this study the x values (dose) ranged over five orders of magnitude and the y values (DNA damage) ranged 30-fold. Ten different regression models (linear, quadratic, cubic, power, and six nonlinear transition models) were compared in their ability to fit the experimental data. With respect to log transformed dose, the six nonlinear transition equations fit the data considerably better than the four power type of equations. A sigmoid model fit to the log transformed dose of 1,2-dimethylhydrazine had an r2 of 0.9979, a degree of freedom adjusted r2 of 0.9969, a F-statistic of 1,457, and a fit standard error of 0.50. With respect to untransformed dose, only three equations (sigmoid, cascade and gaussian cumulative) could creditably fit the DMH data. The experimental results are interpreted with respect to hormesis, use of log transformed dose, sigmoid dose-response models, thresholds of biological response and cancer risk assessment.

  18. Filtration to reduce paediatric dose for a linear slot-scanning digital X-ray machine.

    PubMed

    Perks, T D; Dendere, R; Irving, B; Hartley, T; Scholtz, P; Lawson, A; Trauernicht, C; Steiner, S; Douglas, T S

    2015-12-01

    This paper describes modelling, application and validation of a filtration technique for a linear slot-scanning digital X-ray system to reduce radiation dose to paediatric patients while preserving diagnostic image quality. A dose prediction model was implemented, which calculates patient entrance doses using variable input parameters. Effective dose is calculated using a Monte Carlo simulation. An added filter of 1.8-mm aluminium was predicted to lower the radiation dose significantly. An objective image quality study was conducted using detective quantum efficiency (DQE). The PTW Normi 4FLU test phantom was used for quantitative assessment, showing that image contrast and spatial resolution were maintained with the proposed filter. A paediatric cadaver full-body imaging trial assessed the diagnostic quality of the images and measured the dose reduction using a 1.8-mm aluminium filter. Assessment by radiologists indicated that diagnostic quality was maintained with the added filtration, despite a reduction in DQE. A new filtration technique for full-body paediatric scanning on the Lodox Statscan has been validated, reducing entrance dose for paediatric patients by 36 % on average and effective dose by 27 % on average, while maintaining image quality.

  19. Depth dependence of absorbed dose, dose equivalent and linear energy transfer spectra of galactic and trapped particles in polyethylene and comparison with calculations of models

    NASA Technical Reports Server (NTRS)

    Badhwar, G. D.; Cucinotta, F. A.; Wilson, J. W. (Principal Investigator)

    1998-01-01

    A matched set of five tissue-equivalent proportional counters (TEPCs), embedded at the centers of 0 (bare), 3, 5, 8 and 12-inch-diameter polyethylene spheres, were flown on the Shuttle flight STS-81 (inclination 51.65 degrees, altitude approximately 400 km). The data obtained were separated into contributions from trapped protons and galactic cosmic radiation (GCR). From the measured linear energy transfer (LET) spectra, the absorbed dose and dose-equivalent rates were calculated. The results were compared to calculations made with the radiation transport model HZETRN/NUCFRG2, using the GCR free-space spectra, orbit-averaged geomagnetic transmission function and Shuttle shielding distributions. The comparison shows that the model fits the dose rates to a root mean square (rms) error of 5%, and dose-equivalent rates to an rms error of 10%. Fairly good agreement between the LET spectra was found; however, differences are seen at both low and high LET. These differences can be understood as due to the combined effects of chord-length variation and detector response function. These results rule out a number of radiation transport/nuclear fragmentation models. Similar comparisons of trapped-proton dose rates were made between calculations made with the proton transport model BRYNTRN using the AP-8 MIN trapped-proton model and Shuttle shielding distributions. The predictions of absorbed dose and dose-equivalent rates are fairly good. However, the prediction of the LET spectra below approximately 30 keV/microm shows the need to improve the AP-8 model. These results have strong implications for shielding requirements for an interplanetary manned mission.

  20. Descriptive Linear modeling of steady-state visual evoked response

    NASA Technical Reports Server (NTRS)

    Levison, W. H.; Junker, A. M.; Kenner, K.

    1986-01-01

    A study is being conducted to explore use of the steady state visual-evoke electrocortical response as an indicator of cognitive task loading. Application of linear descriptive modeling to steady state Visual Evoked Response (VER) data is summarized. Two aspects of linear modeling are reviewed: (1) unwrapping the phase-shift portion of the frequency response, and (2) parsimonious characterization of task-loading effects in terms of changes in model parameters. Model-based phase unwrapping appears to be most reliable in applications, such as manual control, where theoretical models are available. Linear descriptive modeling of the VER has not yet been shown to provide consistent and readily interpretable results.

  1. NOTE: Study of Gafchromic® EBT film response over a large dose range

    NASA Astrophysics Data System (ADS)

    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.

  2. A review of uncertainties in radiotherapy dose reconstruction and their impacts on dose-response relationships.

    PubMed

    Vũ Bezin, Jérémi; Allodji, Rodrigue S; Mège, Jean-Pierre; Beldjoudi, Guillaume; Saunier, Fleur; Chavaudra, Jean; Deutsch, Eric; de Vathaire, Florent; Bernier, Valérie; Carrie, Christian; Lefkopoulos, Dimitri; Diallo, Ibrahima

    2017-03-20

    Proper understanding of the risk of radiation-induced late effects for patients receiving external photon beam radiotherapy requires the determination of reliable dose-response relationships. Although significant efforts have been devoted to improving dose estimates for the study of late effects, the most often questioned explanatory variable is still the dose. In this work, based on a literature review, we provide an in-depth description of the radiotherapy dose reconstruction process for the study of late effects. In particular, we focus on the identification of the main sources of dose uncertainty involved in this process and summarise their impacts on the dose-response relationship for radiotherapy late effects. We provide a number of recommendations for making progress in estimating the uncertainties in current studies of radiotherapy late effects and reducing these uncertainties in future studies.

  3. Methodology for Estimating Ingestion Dose for Emergency Response at SRS

    SciTech Connect

    Simpkins, A.A.

    2003-07-21

    At the Savannah River Site (SRS), emergency response computer models are used to estimate dose following releases of radioactive materials to the environment. Downwind air and ground concentrations and their associated doses from inhalation and ground shine pathways are estimated. The emergency response model (PUFF-PLUME) uses real-time data to track either instantaneous (puff) or continuous (plume) releases. A site-specific ingestion dose model was developed for use with PUFF-PLUME that includes the following ingestion dose pathways pertinent to the surrounding SRS area: milk, beef, water, and fish. The model is simplistic and can be used with existing code output.

  4. The dose response of normoxic polymer gel dosimeters measured using X-ray CT.

    PubMed

    Hill, B; Venning, A; Baldock, C

    2005-07-01

    X-ray CT was used to determine the dose response of normoxic polymer gel dosimeters. Normoxic polymer gel dosimeters were manufactured and irradiated up to 150 Gy. Up to 50 CT images were acquired on a Toshiba Aquilion Multislice CT scanner using protocols for 80 kV and 135 kV to determine dose response. HU-dose sensitivity, the linear regression of data for the HU versus dose for the linear part of the curve up to 60 Gy was 0.38+/-0.07 HU Gy(-1) for 135 kV and 0.37+/-0.01 HU Gy(-1) for 80 kV. Dose resolution was found to be < 1.3 Gy for an absorbed dose range up to 70 Gy for 135 kV, similar to that measured previously for polyacrylamide gel (PAG). Although the HU-dose sensitivity was lower than that previously measured for PAG gel dosimeters it had a greater range of absorbed dose indicating that normoxic polymer gel dosimeters have potential in CT gel dosimetry.

  5. Stage specificity, dose response, and doubling dose for mouse minisatellite germ-line mutation induced by acute radiation.

    PubMed

    Dubrova, Y E; Plumb, M; Brown, J; Fennelly, J; Bois, P; Goodhead, D; Jeffreys, A J

    1998-05-26

    Germ-line mutation induction at mouse minisatellite loci by acute irradiation with x-rays was studied at premeiotic and postmeiotic stages of spermatogenesis. An elevated paternal mutation rate was found after irradiation of premeiotic spermatogonia and stem cells, whereas the frequency of minisatellite mutation after postmeiotic irradiation of spermatids was similar to that in control litters. In contrast, paternal irradiation did not affect the maternal mutation rate. A linear dose-response curve for paternal mutation induced at premeiotic stages was found, with a doubling dose of 0.33 Gy, a value close to those obtained in mice after acute spermatogonia irradiation using other systems for mutation detection. High frequencies of spontaneous and induced mutations at minisatellite loci allow mutation induction to be evaluated at low doses of exposure in very small population samples, which currently makes minisatellite DNA the most powerful tool for monitoring radiation-induced germ-line mutation.

  6. Dose-response relationships of FMISO between trace dose and various macro-doses in rat by ultra-performance liquid chromatography with mass spectrometry and radioactivity analysis.

    PubMed

    Du, Jinglei; Zhu, Lin; Zhou, Xue; Yin, Wei; Deng, Aifang; Qiao, Jinping

    2012-11-01

    Screening the pharmacokinetics of candidates using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) may be efficacious and safe for the research and development of new PET imaging agents. However, the PET imaging agent is administered as trace dose and the sensitivity of LC-MS/MS is often insufficient. If the dose was increased to be quantifiable, it should be necessary to prove whether the pharmacokinetics between trace and macro-doses is consistent or not. In this paper, fluoromisonidazole (FMISO), a tumor PET imaging agent, was chosen to evaluate the dose-response pharmacokinetics by administering various single intravenous doses (0.1, 0.4, 1.6 and 6.4 mg/kg) in male Sprague-Dawley rats. The plasma concentration of FMISO was determined by an ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method, and the blood radioactivity of [(18)F]FMISO was detected by a gamma counter. By calculating and comparing the pharmacokinetic parameters, the total area under the plasma concentration-time curve from time zero to infinity (AUC(0-∞)) and peak plasma concentration (C(max)) values increased with the selected FMISO doses, and showing linear dose-dependent. On the other hand, some parameters related to time, such as the elimination half-lives (t(1/2)) and elimination rate constant (K(e)) were dose-independent, and there is no significant deference between trace dose and various macro-doses. The data should be useful to evaluate the novel 2-nitroimidazole derivatives as potential PET tumor imaging agents.

  7. Oligodendroglial response to ionizing radiation: Dose and dose-rate response

    SciTech Connect

    Levy, R.P.

    1991-12-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examine the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute {gamma}-irradiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. A new compartmental cell model for radiation response in vitro of the oligodendrocyte population is proposed and examined in relation to the potential reaction to radiation injury in the brain.

  8. A comparison of depth dependence of dose and linear energy transfer spectra in aluminum and polyethylene

    NASA Technical Reports Server (NTRS)

    Badhwar, G. D.; Cucinotta, F. A.

    2000-01-01

    A set of four tissue-equivalent proportional counters (TEPCs), with their detector heads at the centers of 0 (bare), 3, 7 and 9-inch-diameter aluminum spheres, were flown on Shuttle flight STS-89. Five such detectors at the centers of polyethylene spheres were flown 1 year earlier on STS-81. The results of dose-depth dependence for the two materials convincingly show the merits of using material rich in hydrogen to decrease the radiation exposure to the crew. A comparison of the calculated galactic cosmic radiation (GCR) absorbed dose and dose-equivalent rates using the radiation transport code HZETRN with nuclear fragmentation model NUCFRG2 and the measured GCR absorbed dose rates and dose-equivalent rates shows that they agree within root mean square (rms) error of 12.5 and 8.2%, respectively. However, there are significant depth-dependent differences in the linear energy transfer (LET) spectra. A comparison for trapped protons using the proton transport code BRYNTRN and the AP-8 MIN trapped-proton model shows a systematic bias, with the model underpredicting dose and dose-equivalent rates. These results show the need for improvements in the radiation transport and/or fragmentation models.

  9. Neutron dose calculation at the maze entrance of medical linear accelerator rooms.

    PubMed

    Falcão, R C; Facure, A; Silva, A X

    2007-01-01

    Currently, teletherapy machines of cobalt and caesium are being replaced by linear accelerators. The maximum photon energy in these machines can vary from 4 to 25 MeV, and one of the great advantages of these equipments is that they do not have a radioactive source incorporated. High-energy (E > 10 MV) medical linear accelerators offer several physical advantages over lower energy ones: the skin dose is lower, the beam is more penetrating, and the scattered dose to tissues outside the target volume is smaller. Nevertheless, the contamination of undesirable neutrons in the therapeutic beam, generated by the high-energy photons, has become an additional problem as long as patient protection and occupational doses are concerned. The treatment room walls are shielded to attenuate the primary and secondary X-ray fluence, and this shielding is generally adequate to attenuate the neutrons. However, these neutrons are scattered through the treatment room maze and may result in a radiological problem at the door entrance, a high occupancy area in a radiotherapy facility. In this article, we used MCNP Monte Carlo simulation to calculate neutron doses in the maze of radiotherapy rooms and we suggest an alternative method to the Kersey semi-empirical model of neutron dose calculation at the entrance of mazes. It was found that this new method fits better measured values found in literature, as well as our Monte Carlo simulated ones.

  10. Linear and nonlinear response in sheared soft spheres

    NASA Astrophysics Data System (ADS)

    Tighe, Brian

    2013-11-01

    Packings of soft spheres provide an idealized model of foams, emulsions, and grains, while also serving as the canonical example of a system undergoing a jamming transition. Packings' mechanical response has now been studied exhaustively in the context of ``strict linear response,'' i.e. by linearizing about a stable static packing and solving the resulting equations of motion. Both because the system is close to a critical point and because the soft sphere pair potential is non-analytic at the point of contact, it is reasonable to ask under what circumstances strict linear response provides a good approximation to the actual response. We simulate sheared soft sphere packings close to jamming and identify two distinct strain scales: (i) the scale on which strict linear response fails, coinciding with a topological change in the packing's contact network; and (ii) the scale on which linear superposition of the averaged stress-strain curve breaks down. This latter scale provides a ``weak linear response'' criterion and is likely to be more experimentally relevant.

  11. Curvilinearity in the dose-response curve for cancer in Japanese atomic bomb survivors.

    PubMed Central

    Little, M P; Muirhead, C R

    1997-01-01

    Recently released data on cancer incidence in Japanese atomic bomb survivors are analyzed using a variety of relative risk models that take account of errors in estimates of dose to assess the dose response at low doses. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Among solid cancer subtypes there is strong evidence for a possible dose threshold only for nonmelanoma skin cancer. If a relative risk model with a threshold (the dose response is assumed linear above the threshold) is fitted to the leukemia data, a threshold of more than about 0.3 Sv is inconsistent with the data. In contrast to the estimates for the threshold level for solid cancer data, the best estimate for the threshold level in the leukemia data is significantly different from zero even when allowance is made for a possible quadratic term in the dose response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukemia dose response from 0.2 Sv upwards. However, possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken into account in the analysis, together with the lack of biological plausibility of a threshold, makes interpretation of this finding questionable. PMID:9467073

  12. The Dose Window for Radiation-Induced Protective Adaptive Responses

    PubMed Central

    Mitchel, Ronald E. J.

    2009-01-01

    Adaptive responses to low doses of low LET radiation occur in all organisms thus far examined, from single cell lower eukaryotes to mammals. These responses reduce the deleterious consequences of DNA damaging events, including radiation-induced or spontaneous cancer and non-cancer diseases in mice. The adaptive response in mammalian cells and mammals operates within a certain window that can be defined by upper and lower dose thresholds, typically between about 1 and 100 mGy for a single low dose rate exposure. However, these thresholds for protection are not a fixed function of total dose, but also vary with dose rate, additional radiation or non-radiation stressors, tissue type and p53 functional status. Exposures above the upper threshold are generally detrimental, while exposures below the lower threshold may or may not increase either cancer or non-cancer disease risk. PMID:20585438

  13. Linear response of an instrument entitled Sky Radiometer

    NASA Astrophysics Data System (ADS)

    Liu, Wei; Zhao, Wei; Zhou, Zhe; Wang, Dong; Xu, Wen-qing; Fan, Ren-jie

    2016-11-01

    In order to validate the good linear response of an instrument entitled Sky Radiometer(abbreviated to DTL-1) and check the great accuracy of radiance, the experiments which checked the DTL-1 using the large diameter integrating sphere system verified that the instrument had fine linearity and working stability. At the same time, the sky radiance in Hefei was measured, and the validity and correctness of DTL-1 were verified using fibre-optical spectrometer. The results indicated that the instrument had fine work ability, including good linear response, and could satisfy the scientific research and the actual application. However, the linear response of the instrument entitled Sky Radiometer in different region will be validated.

  14. Response properties of pigeon otolith afferents to linear acceleration

    NASA Technical Reports Server (NTRS)

    Si, X.; Angelaki, D. E.; Dickman, J. D.

    1997-01-01

    In the present study, the sensitivity to sinusoidal linear accelerations in the plane of the utricular macula was tested in afferents. The head orientation relative to the translation axis was varied in order to determine the head position that elicited the maximal and minimal responses for each afferent. The response gain and phase values obtained to 0.5-Hz and 2-Hz linear acceleration stimuli were then plotted as a function of head orientation and a modified cosine function was fit to the data. From the best-fit cosine function, the predicted head orientations that would produce the maximal and minimal response gains were estimated. The estimated maximum response gains to linear acceleration in the utricular plane for the afferents varied between 75 and 1420 spikes s-1 g-1. The mean maximal gains for all afferents to 0.5-Hz and 2-Hz sinusoidal linear acceleration stimuli were 282 and 367 spikes s-1 g-1, respectively. The minimal response gains were essentially zero for most units. The response phases always led linear acceleration and remained constant for each afferent, regardless of head orientation. These response characteristics indicate that otolith afferents are cosine tuned and behave as one-dimensional linear accelerometers. The directions of maximal sensitivity to linear acceleration for the afferents varied throughout the plane of the utricle; however, most vectors were directed out of the opposite ear near the interaural axis. The response dynamics of the afferents were tested using stimulus frequencies ranging between 0.25 Hz and 10 Hz (0.1 g peak acceleration). Across stimulus frequencies, most afferents had increasing gains and constant phase values. These dynamic properties for individual afferents were fit with a simple transfer function that included three parameters: a mechanical time constant, a gain constant, and a fractional order distributed adaptation operator.

  15. On relating the generalized equivalent uniform dose formalism to the linear-quadratic model.

    PubMed

    Djajaputra, David; Wu, Qiuwen

    2006-12-01

    Two main approaches are commonly used in the literature for computing the equivalent uniform dose (EUD) in radiotherapy. The first approach is based on the cell-survival curve as defined in the linear-quadratic model. The second approach assumes that EUD can be computed as the generalized mean of the dose distribution with an appropriate fitting parameter. We have analyzed the connection between these two formalisms by deriving explicit formulas for the EUD which are applicable to normal distributions. From these formulas we have established an explicit connection between the two formalisms. We found that the EUD parameter has strong dependence on the parameters that characterize the distribution, namely the mean dose and the standard deviation around the mean. By computing the corresponding parameters for clinical dose distributions, which in general do not follow the normal distribution, we have shown that our results are also applicable to actual dose distributions. Our analysis suggests that caution should be used in using generalized EUD approach for reporting and analyzing dose distributions.

  16. Photobacterial Response to Cadmium Chloride, Mercuric Chloride, and Selenium Dioxide: Dose-Response and Interaction Studies.

    DTIC Science & Technology

    1980-07-01

    activity) and producing a dose - response curve by adding different concentrations of the second compound. The EC50 values from such paired compounds...fixing the dose of the first metal at its ECIo concentra- tion and varying the concentration of the second to produce a dose - response curve . The EC5 0...concentration of one metal at approximately its EC10 and varying the concentration of the second metal to produce a dose - response curve . The six possible

  17. Bayesian Isotonic Regression Dose-response (BIRD) Model.

    PubMed

    Li, Wen; Fu, Haoda

    2016-12-21

    Understanding dose-response relationship is a crucial step in drug development. There are a few parametric methods to estimate dose-response curves, such as the Emax model and the logistic model. These parametric models are easy to interpret and, hence, widely used. However, these models often require the inclusion of patients on high-dose levels; otherwise, the model parameters cannot be reliably estimated. To have robust estimation, nonparametric models are used. However, these models are not able to estimate certain important clinical parameters, such as ED50 and Emax. Furthermore, in many therapeutic areas, dose-response curves can be assumed as non-decreasing functions. This creates an additional challenge for nonparametric methods. In this paper, we propose a new Bayesian isotonic regression dose-response model which features advantages from both parametric and nonparametric models. The ED50 and Emax can be derived from this model. Simulations are provided to evaluate the Bayesian isotonic regression dose-response model performance against two parametric models. We apply this model to a data set from a diabetes dose-finding study.

  18. Estimation of absorbed dose in clinical radiotherapy linear accelerator beams: Effect of ion chamber calibration and long-term stability.

    PubMed

    Ravichandran, Ramamoorthy; Binukumar, Johnson Pichy; Davis, Cheriyathmanjiyil Antony

    2013-10-01

    The measured dose in water at reference point in phantom is a primary parameter for planning the treatment monitor units (MU); both in conventional and intensity modulated/image guided treatments. Traceability of dose accuracy therefore still depends mainly on the calibration factor of the ion chamber/dosimeter provided by the accredited Secondary Standard Dosimetry Laboratories (SSDLs), under International Atomic Energy Agency (IAEA) network of laboratories. The data related to Nd,water calibrations, thermoluminescent dosimetry (TLD) postal dose validation, inter-comparison of different dosimeter/electrometers, and validity of Nd,water calibrations obtained from different calibration laboratories were analyzed to find out the extent of accuracy achievable. Nd,w factors in Gray/Coulomb calibrated at IBA, GmBH, Germany showed a mean variation of about 0.2% increase per year in three Farmer chambers, in three subsequent calibrations. Another ion chamber calibrated in different accredited laboratory (PTW, Germany) showed consistent Nd,w for 9 years period. The Strontium-90 beta check source response indicated long-term stability of the ion chambers within 1% for three chambers. Results of IAEA postal TL "dose intercomparison" for three photon beams, 6 MV (two) and 15 MV (one), agreed well within our reported doses, with mean deviation of 0.03% (SD 0.87%) (n = 9). All the chamber/electrometer calibrated by a single SSDL realized absorbed doses in water within 0.13% standard deviations. However, about 1-2% differences in absorbed dose estimates observed when dosimeters calibrated from different calibration laboratories are compared in solid phantoms. Our data therefore imply that the dosimetry level maintained for clinical use of linear accelerator photon beams are within recommended levels of accuracy, and uncertainties are within reported values.

  19. Updating Dosimetry for Emergency Response Dose Projections.

    PubMed

    DeCair, Sara

    2016-02-01

    In 2013, the U.S. Environmental Protection Agency (EPA) proposed an update to the 1992 Protective Action Guides (PAG) Manual. The PAG Manual provides guidance to state and local officials planning for radiological emergencies. EPA requested public comment on the proposed revisions, while making them available for interim use by officials faced with an emergency situation. Developed with interagency partners, EPA's proposal incorporates newer dosimetric methods, identifies tools and guidelines developed since the current document was issued, and extends the scope of the PAGs to all significant radiological incidents, including radiological dispersal devices or improvised nuclear devices. In order to best serve the emergency management community, scientific policy direction had to be set on how to use International Commission on Radiological Protection Publication 60 age groups in dose assessment when implementing emergency guidelines. Certain guidelines that lend themselves to different PAGs for different subpopulations are the PAGs for potassium iodide (KI), food, and water. These guidelines provide age-specific recommendations because of the radiosensitivity of the thyroid and young children with respect to ingestion and inhalation doses in particular. Taking protective actions like using KI, avoiding certain foods or using alternative sources of drinking water can be relatively simple to implement by the parents of young children. Clear public messages can convey which age groups should take which action, unlike how an evacuation or relocation order should apply to entire households or neighborhoods. New in the PAG Manual is planning guidance for the late phase of an incident, after the situation is stabilized and efforts turn toward recovery. Because the late phase can take years to complete, decision makers are faced with managing public exposures in areas not fully remediated. The proposal includes quick-reference operational guidelines to inform re-entry to

  20. VMAT linear accelerator commissioning and quality assurance: dose control and gantry speed tests.

    PubMed

    Barnes, Michael P; Rowshanfarzad, Pejman; Greer, Peter B

    2016-05-01

    In VMAT treatment delivery the ability of the linear accelerator (linac) to accurately control dose versus gantry angle is critical to delivering the plan correctly. A new VMAT test delivery was developed to specifically test the dose versus gantry angle with the full range of allowed gantry speeds and dose rates. The gantry-mounted IBA MatriXX with attached inclinometer was used in movie mode to measure the instantaneous relative dose versus gantry angle during the plan every 0.54 s. The results were compared to the expected relative dose at each gantry angle calculated from the plan. The same dataset was also used to compare the instantaneous gantry speeds throughout the delivery compared to the expected gantry speeds from the plan. Measurements performed across four linacs generally show agreement between measurement and plan to within 1.5% in the constant dose rate regions and dose rate modulation within 0.1 s of the plan. Instantaneous gantry speed was measured to be within 0.11∘/s of the plan (1 SD). An error in one linac was detected in that the nominal gantry speed was incorrectly calibrated. This test provides a practical method to quality-assure critical aspects of VMAT delivery including dose versus gantry angle and gantry speed control. The method can be performed with any detector that can acquire time-resolved dosimetric information that can be synchronized with a measurement of gantry angle. The test fulfils several of the aims of the recent Netherlands Commission on Radiation Dosimetry (NCS) Report 24, which provides recommendations for comprehensive VMAT quality assurance. PACS number(s): 87.55.Qr.

  1. VMAT linear accelerator commissioning and quality assurance: dose control and gantry speed tests.

    PubMed

    Barnes, Michael P; Rowshanfarzad, Pejman; Greer, Peter B

    2016-05-08

    In VMAT treatment delivery the ability of the linear accelerator (linac) to accurately control dose versus gantry angle is critical to delivering the plan correctly. A new VMAT test delivery was developed to specifically test the dose versus gantry angle with the full range of allowed gantry speeds and dose rates. The gantry-mounted IBA MatriXX with attached inclinometer was used in movie mode to measure the instantaneous relative dose versus gantry angle during the plan every 0.54 s. The results were compared to the expected relative dose at each gantry angle calculated from the plan. The same dataset was also used to compare the instantaneous gan-try speeds throughout the delivery compared to the expected gantry speeds from the plan. Measurements performed across four linacs generally show agreement between measurement and plan to within 1.5% in the constant dose rate regions and dose rate modulation within 0.1 s of the plan. Instantaneous gantry speed was measured to be within 0.11°/s of the plan (1 SD). An error in one linac was detected in that the nominal gantry speed was incorrectly calibrated. This test provides a practical method to quality-assure critical aspects of VMAT delivery including dose versus gantry angle and gantry speed control. The method can be performed with any detector that can acquire time-resolved dosimetric information that can be synchronized with a measurement of gantry angle. The test fulfils several of the aims of the recent Netherlands Commission on Radiation Dosimetry (NCS) Report 24, which provides recommendations for comprehensive VMAT quality assurance.

  2. Radiation Dose-Response Relationships and Risk Assessment

    SciTech Connect

    Strom, Daniel J.

    2005-07-05

    The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is also the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of individual risk is presented

  3. Linear optical response of finite systems using multishift linear system solvers

    SciTech Connect

    Hübener, Hannes; Giustino, Feliciano

    2014-07-28

    We discuss the application of multishift linear system solvers to linear-response time-dependent density functional theory. Using this technique the complete frequency-dependent electronic density response of finite systems to an external perturbation can be calculated at the cost of a single solution of a linear system via conjugate gradients. We show that multishift time-dependent density functional theory yields excitation energies and oscillator strengths in perfect agreement with the standard diagonalization of the response matrix (Casida's method), while being computationally advantageous. We present test calculations for benzene, porphin, and chlorophyll molecules. We argue that multishift solvers may find broad applicability in the context of excited-state calculations within density-functional theory and beyond.

  4. TESS-based dose-response using pediatric clonidine exposures

    SciTech Connect

    Benson, Blaine E. . E-mail: jebenson@salud.unm.edu; Spyker, Daniel A.; Troutman, William G.; Watson, William A. . E-mail: http://www.aapcc.org/

    2006-06-01

    Objective: The toxic and lethal doses of clonidine in children are unclear. This study was designed to determine whether data from the American Association of Poison Control Centers Toxic Exposure Surveillance System (TESS) could be utilized to determine a dose-response relationship for pediatric clonidine exposure. Methods: 3458 single-substance clonidine exposures in children <6 years of age reported to TESS from January 2000 through December 2003 were examined. Dose ingested, age, and medical outcome were available for 1550 cases. Respiratory arrest cases (n = 8) were classified as the most severe of the medical outcome categories (Arrest, Major, Moderate, Mild, and No effect). Exposures reported as a 'taste or lick' (n = 51) were included as a dose of 1/10 of the dosage form involved. Dose ranged from 0.4 to 1980 (median 13) {mu}g/kg. Weight was imputed based on a quadratic estimate of weight for age. Dose certainty was coded as exact (26% of cases) or not exact (74%). Medical outcome (response) was examined via logistic regression using SAS JMP (release 5.1). Results: The logistic model describing medical outcome (P < 0.0001) included Log dose/kg (P 0.0000) and Certainty (P = 0.045). Conclusion: TESS data can provide the basis for a statistically sound description of dose-response for pediatric clonidine poisoning exposures.

  5. Dose-time-response modeling using negative binomial distribution.

    PubMed

    Roy, Munmun; Choudhury, Kanak; Islam, M M; Matin, M A

    2013-01-01

    People exposed to certain diseases are required to be treated with a safe and effective dose level of a drug. In epidemiological studies to find out an effective dose level, different dose levels are applied to the exposed and a certain number of cures is observed. Negative binomial distribution is considered to fit overdispersed Poisson count data. This study investigates the time effect on the response at different time points as well as at different dose levels. The point estimation and confidence bands for ED(100p)(t) and LT(100p)(d) are formulated in closed form for the proposed dose-time-response model with the negative binomial distribution. Numerical illustrations are carried out in order to check the performance level of the proposed model.

  6. [Dose-response relation: relevance for clinical practice].

    PubMed

    Klinkhardt, U; Harder, S

    1998-12-15

    Dose-finding studies are performed routinely in patients and--if appropriate surrogate models exist--also in healthy volunteers. Such studies aim at establishing the optimal dose range for further clinical studies on the efficacy and the risk-benefit ratio of a new drug. The dose-response relationship of a drug is most often described by a sigmoidal curve. Its parameters include the mean effective dose, the maximal effect and the steepness. Interpretation of such curves should be done in the context of the intended clinical indications of the drug. The risk-benefit ratio of a drug can be assessed by overlapping the dose-response curve of wanted and unwanted clinical effects, again, any overlapping (which can be described e.g. by the therapeutic index) should be seen in the context of the indication and available therapeutic alternatives.

  7. [Dose-response relationship: relevance for medical practice].

    PubMed

    Klinkhardt, U; Harder, S

    2000-05-01

    Dose-finding studies are performed routinely in patients and--if appropriate surrogate models exist--also in healthy volunteers. Such studies aim at establishing the optimal dose range for further clinical studies on the efficacy and the risk-benefit ratio of a new drug. The dose-response relationship of a drug is most often described by a sigmoidal curve. Its parameters include the mean effective dose, the maximal effect and the steepness. Interpretation of such curves should be done in the context of the intended clinical indications of the drug. The risk-benefit ratio of a drug can be assessed by overlapping the dose-response curve of wanted and unwanted clinical effects, again, any overlapping (which can be described e.g. by the therapeutic index) should be seen in the context of the indication and available therapeutic alternatives.

  8. Interpreting 'dose-response' curves using homeodynamic data: with an improved explanation for hormesis.

    PubMed

    Stebbing, A R D

    2009-04-15

    A re-interpretation of the 'dose-response' curve is given that accommodates homeostasis. The outcome, or overall effect, of toxicity is the consequence of toxicity that is moderated by homeodynamic responses. Equilibrium is achieved by a balance of opposing forces of toxic inhibition countered by a stimulatory response. A graphical model is given consisting of two linked curves (response vs concentration and effect vs concentration), which provide the basis for a re-interpretation of the 'dose-response' curve. The model indicates that such relationships are non-linear with a threshold, which is due to homeodynamic responses. Subthreshold concentrations in 'dose-response' curves provide the sum of toxic inhibition minus the homeodynamic response; the response itself is unseen in serving its purpose of neutralizing perturbation. This interpretation suggests why the alpha- and beta-curves are non-linear. The beta-curve indicates adaptive overcorrection to toxicity that confers greater resistance to subsequent toxic exposure, with hormesis as an epiphenomenon.

  9. The Emergence of the Dose-Response Concept in Biology and Medicine.

    PubMed

    Calabrese, Edward J

    2016-12-05

    A historical assessment of the origin of the dose-response in modern toxicology and its integration as a central concept in biology and medicine is presented. This article provides an overview of how the threshold, linear and biphasic (i.e., hormetic) dose-response models emerged in the late 19th and early 20th centuries and competed for acceptance and dominance. Particular attention is directed to the hormetic model for which a general description and evaluation is provided, including its historical basis, and how it was marginalized by the medical and pharmacology communities in the early decades of the 20th century.

  10. [Mechanism of cytogenetic adaptive response induced by low dose radiation].

    PubMed

    Cai, L; Liu, S

    1990-11-01

    Cytogenetic observation on human lymphocytes indicated that pre-exposure of 10, 50 and 75 mGy X-rays could induced the adaptive response. Experimental results with different temperature treatment showed that the adaptive response induced by low dose radiation could be enhanced by 41 degrees C and 43 degrees C, but inhibited by 4 degrees C in addition the treatment by 41 degrees C for one hour could also cause the adaptive response as did low dose radiation. Results showed that adaptive response induced by low dose radiation (10 or 50 mGy X-rays) could be eliminated by the protein synthesis inhibitor, implying that the adaptive response is related with the metabolism of cells, especially with the production of certain protective proteins.

  11. Rotational IMRT delivery using a digital linear accelerator in very high dose rate 'burst mode'

    NASA Astrophysics Data System (ADS)

    Salter, Bill J.; Sarkar, Vikren; Wang, Brian; Shukla, Himanshu; Szegedi, Martin; Rassiah-Szegedi, Prema

    2011-04-01

    Recently, there has been a resurgence of interest in arc-based IMRT, through the use of 'conventional' multileaf collimator (MLC) systems that can treat large tumor volumes in a single, or very few pass(es) of the gantry. Here we present a novel 'burst mode' modulated arc delivery approach, wherein 2000 monitor units per minute (MU min-1) high dose rate bursts of dose are facilitated by a flattening-filter-free treatment beam on a Siemens Artiste (Oncology Care Systems, Siemens Medical Solutions, Concord, CA, USA) digital linear accelerator in a non-clinical configuration. Burst mode delivery differs from continuous mode delivery, used by Elekta's VMAT (Elekta Ltd, Crawley, UK) and Varian's RapidArc (Varian Medical Systems, Palo Alto, CA, USA) implementations, in that dose is not delivered while MLC leaves are moving. Instead, dose is delivered in bursts over very short arc angles and only after an MLC segment shape has been completely formed and verified by the controller. The new system was confirmed to be capable of delivering a wide array of clinically relevant treatment plans, without machine fault or other delivery anomalies. Dosimetric accuracy of the modulated arc platform, as well as the Prowess (Prowess Inc., Concord, CA, USA) prototype treatment planning version utilized here, was quantified and confirmed, and delivery times were measured as significantly brief, even with large hypofractionated doses. The burst mode modulated arc approach evaluated here appears to represent a capable, accurate and efficient delivery approach.

  12. Rotational IMRT delivery using a digital linear accelerator in very high dose rate 'burst mode'.

    PubMed

    Salter, Bill J; Sarkar, Vikren; Wang, Brian; Shukla, Himanshu; Szegedi, Martin; Rassiah-Szegedi, Prema

    2011-04-07

    Recently, there has been a resurgence of interest in arc-based IMRT, through the use of 'conventional' multileaf collimator (MLC) systems that can treat large tumor volumes in a single, or very few pass(es) of the gantry. Here we present a novel 'burst mode' modulated arc delivery approach, wherein 2000 monitor units per minute (MU min(-1)) high dose rate bursts of dose are facilitated by a flattening-filter-free treatment beam on a Siemens Artiste (Oncology Care Systems, Siemens Medical Solutions, Concord, CA, USA) digital linear accelerator in a non-clinical configuration. Burst mode delivery differs from continuous mode delivery, used by Elekta's VMAT (Elekta Ltd, Crawley, UK) and Varian's RapidArc (Varian Medical Systems, Palo Alto, CA, USA) implementations, in that dose is not delivered while MLC leaves are moving. Instead, dose is delivered in bursts over very short arc angles and only after an MLC segment shape has been completely formed and verified by the controller. The new system was confirmed to be capable of delivering a wide array of clinically relevant treatment plans, without machine fault or other delivery anomalies. Dosimetric accuracy of the modulated arc platform, as well as the Prowess (Prowess Inc., Concord, CA, USA) prototype treatment planning version utilized here, was quantified and confirmed, and delivery times were measured as significantly brief, even with large hypofractionated doses. The burst mode modulated arc approach evaluated here appears to represent a capable, accurate and efficient delivery approach.

  13. The Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD) Tool

    EPA Pesticide Factsheets

    Providing quantal response models, which are also used in the U.S. EPA benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates.

  14. Dose Response Effects of Hypertonic Saline and Dextran on Cardiovascular Responses in Sheep

    DTIC Science & Technology

    1995-02-01

    137-144, 1995 DOSE RESPONSE EFFECTS OF HYPERTONIC SALINE AND DEXTRAN ON CARDIOVASCULAR RESPONSES AND PLASMA VOLUME EXPANSION IN SHEEP Michael A...addressed the dose - response effects of HS or D-70 solutions or their possible synergistic combinations to evaluate optimal concentrations of the HS and D...205-217, 1989. 13. Halvorsen L, Günther RA, Dubick MA, Holcroft JW: Dose response characteristics of hypertonic saline dextran solution. J Trauma

  15. RESEARCH TOWARD THE DEVELOPMENT OF A BIOLOGICALLY BASED DOSE RESPONSE ASSESSMENT FOR INORGANIC ARSENIC CARCINOGENICITY: A PROGRESS REPORT

    EPA Science Inventory

    Cancer risk assessments for inorganic arsenic have been based on human epidemiological data, assuming a linear dose-response below the range of observation of tumors. Part of the reason for the continued use of the linear approach in arsenic risk assessments is the lack of an ad...

  16. Diamond detector in absorbed dose measurements in high-energy linear accelerator photon and electron beams.

    PubMed

    Ravichandran, Ramamoorthy; Binukumar, John Pichy; Al Amri, Iqbal; Davis, Cheriyathmanjiyil Antony

    2016-03-08

    Diamond detectors (DD) are preferred in small field dosimetry of radiation beams because of small dose profile penumbras, better spatial resolution, and tissue-equivalent properties. We investigated a commercially available 'microdiamond' detector in realizing absorbed dose from first principles. A microdiamond detector, type TM 60019 with tandem electrometer is used to measure absorbed doses in water, nylon, and PMMA phantoms. With sensitive volume 0.004 mm3, radius 1.1mm, thickness 1 x10(-3) mm, the nominal response is 1 nC/Gy. It is assumed that the diamond detector could collect total electric charge (nC) developed during irradiation at 0 V bias. We found that dose rate effect is less than 0.7% for changing dose rate by 500 MU/min. The reproducibility in obtaining readings with diamond detector is found to be ± 0.17% (1 SD) (n = 11). The measured absorbed doses for 6 MV and 15 MV photons arrived at using mass energy absorption coefficients and stop-ping power ratios compared well with Nd, water calibrated ion chamber measured absorbed doses within 3% in water, PMMA, and nylon media. The calibration factor obtained for diamond detector confirmed response variation is due to sensitivity due to difference in manufacturing process. For electron beams, we had to apply ratio of electron densities of water to carbon. Our results qualify diamond dosimeter as a transfer standard, based on long-term stability and reproducibility. Based on micro-dimensions, we recommend these detectors for pretreatment dose verifications in small field irradiations like stereotactic treatments with image guidance.

  17. Dose and Radioadaptive Response Analysis of Micronucleus Induction in Mouse Bone Marrow

    PubMed Central

    Bannister, Laura A.; Mantha, Rebecca R.; Devantier, Yvonne; Petoukhov, Eugenia S.; Brideau, Chantal L. A.; Serran, Mandy L.; Klokov, Dmitry Y.

    2016-01-01

    Enhanced cellular DNA repair efficiency and suppression of genomic instability have been proposed as mechanisms underlying radio-adaptive responses following low-dose radiation exposures. We previously showed that low-dose γ irradiation does not generate radio-adaptation by lowering radiation-induced cytogenetic damage in mouse spleen. Since radiation may exert tissue-specific effects, we extended these results here by examining the effects of γ radiation on cytogenetic damage and proliferative index in bone marrow erythrocytes of C57BL/6 and BALB/c mice. In C57BL/6 mice, the induction of micronuclei in polychromatic erythrocytes (MN-PCE) was observed at radiation doses of 100 mGy and greater, and suppression of erythroblast maturation occurred at doses of >500 mGy. A linear dose–response relationship for MN-PCE frequencies in C57BL/6 mice was established for radiation doses between 100 mGy and 1 Gy, with departure from linearity at doses of >1 Gy. BALB/c mice exhibited increased MN-PCE frequencies above baseline following a 20 mGy radiation exposure but did not exhibit radio-sensitivity relative to C57BL/6 mice following 2 Gy exposure. Radio-adaptation of bone marrow erythrocytes was not observed in either strain of mice exposed to low-dose priming γ irradiation (single doses of 20 mGy or 100 mGy or multiple 20 mGy doses) administered at various times prior to acute 2 Gy irradiation, confirming the lack of radio-adaptive response for induction of cytogenetic damage or suppression or erythrocyte proliferation/maturation in bone marrow of these mouse strains. PMID:27649149

  18. Analytical modelling of regional radiotherapy dose response of lung

    NASA Astrophysics Data System (ADS)

    Lee, Sangkyu; Stroian, Gabriela; Kopek, Neil; AlBahhar, Mahmood; Seuntjens, Jan; El Naqa, Issam

    2012-06-01

    Knowledge of the dose-response of radiation-induced lung disease (RILD) is necessary for optimization of radiotherapy (RT) treatment plans involving thoracic cavity irradiation. This study models the time-dependent relationship between local radiation dose and post-treatment lung tissue damage measured by computed tomography (CT) imaging. Fifty-eight follow-up diagnostic CT scans from 21 non-small-cell lung cancer patients were examined. The extent of RILD was segmented on the follow-up CT images based on the increase of physical density relative to the pre-treatment CT image. The segmented RILD was locally correlated with dose distribution calculated by analytical anisotropic algorithm and the Monte Carlo method to generate the corresponding dose-response curves. The Lyman-Kutcher-Burman (LKB) model was fit to the dose-response curves at six post-RT time periods, and temporal change in the LKB parameters was recorded. In this study, we observed significant correlation between the probability of lung tissue damage and the local dose for 96% of the follow-up studies. Dose-injury correlation at the first three months after RT was significantly different from later follow-up periods in terms of steepness and threshold dose as estimated from the LKB model. Dependence of dose response on superior-inferior tumour position was also observed. The time-dependent analytical modelling of RILD might provide better understanding of the long-term behaviour of the disease and could potentially be applied to improve inverse treatment planning optimization.

  19. Assessment of leakage doses around the treatment heads of different linear accelerators.

    PubMed

    Lonski, P; Taylor, M L; Franich, R D; Harty, P; Kron, T

    2012-12-01

    Out-of-field doses to untargeted organs may have long-term detrimental health effects for patients treated with radiotherapy. It has been observed that equivalent treatments delivered to patients with different accelerators may result in significant differences in the out-of-field dose. In this work, the points of leakage dose are identified about the gantry of several treatment units. The origin of the observed higher doses is investigated. LiF:Mg,Cu,P thermoluminescent dosimetry has been employed to quantify the dose at a several points around the linac head of various linear accelerators (linacs): a Varian 600C, Varian 21-iX, Siemens Primus and Elekta Synergy-II. Comparisons are also made between different energy modes, collimator rotations and field sizes. Significant differences in leaked photon doses were identified when comparing the various linac models. The isocentric-waveguide 600C generally exhibits the lowest leakage directed towards the patient. The Siemens and Elekta models generally produce a greater leakage than the Varian models. The leakage 'hotspots' are evident on the gantry section housing the waveguide on the 21-iX. For all machines, there are significant differences in the x and y directions. Larger field sizes result in a greater leakage at the interface plate. There is a greater leakage around the waveguide when operating in a low-energy mode, but a greater leakage for the high-energy mode at the linac face. Of the vendors investigated, the Varian 600C showed the lowest average leakage dose. The Varian 21-iX showed double the dose of the 600C. The Elekta Synergy-II had on average four times the dose leakage than the 600C, and the Siemens Primus showed an average of five times that of the 600C. All vendors show strong differences in the x and y directions. The results offer the potential for patient-positioning strategies, linac choice and shielding strategies to reduce the leakage dose to patients.

  20. Curious cases: Altered dose-response relationships in addiction genetics.

    PubMed

    Uhl, George R; Drgonova, Jana; Hall, F Scott

    2014-03-01

    Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics.

  1. Dose convolution filter: Incorporating spatial dose information into tissue response modeling

    SciTech Connect

    Huang Yimei; Joiner, Michael; Zhao Bo; Liao Yixiang; Burmeister, Jay

    2010-03-15

    Purpose: A model is introduced to integrate biological factors such as cell migration and bystander effects into physical dose distributions, and to incorporate spatial dose information in plan analysis and optimization. Methods: The model consists of a dose convolution filter (DCF) with single parameter {sigma}. Tissue response is calculated by an existing NTCP model with DCF-applied dose distribution as input. The authors determined {sigma} of rat spinal cord from published data. The authors also simulated the GRID technique, in which an open field is collimated into many pencil beams. Results: After applying the DCF, the NTCP model successfully fits the rat spinal cord data with a predicted value of {sigma}=2.6{+-}0.5 mm, consistent with 2 mm migration distances of remyelinating cells. Moreover, it enables the appropriate prediction of a high relative seriality for spinal cord. The model also predicts the sparing of normal tissues by the GRID technique when the size of each pencil beam becomes comparable to {sigma}. Conclusions: The DCF model incorporates spatial dose information and offers an improved way to estimate tissue response from complex radiotherapy dose distributions. It does not alter the prediction of tissue response in large homogenous fields, but successfully predicts increased tissue tolerance in small or highly nonuniform fields.

  2. External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

    NASA Astrophysics Data System (ADS)

    Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob

    2009-01-01

    Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

  3. Computer Simulation of Quantal Dose-Response Relationships.

    ERIC Educational Resources Information Center

    McGilliard, Kip L.

    1985-01-01

    Describes a program which simulates animal pharmacology experiments involving "all-or-none" responses. Use of the Applesoft BASIC program in the pharmacology teaching laboratory provides students with a rapid and economical way to gain experience in the design and statistical analysis of quantal dose-response experiments. Information on…

  4. Learning in higher order Boltzmann machines using linear response.

    PubMed

    Leisink, M A; Kappen, H J

    2000-04-01

    We introduce an efficient method for learning and inference in higher order Boltzmann machines. The method is based on mean field theory with the linear response correction. We compute the correlations using the exact and the approximated method for a fully connected third order network of ten neurons. In addition, we compare the results of the exact and approximate learning algorithm. Finally we use the presented method to solve the shifter problem. We conclude that the linear response approximation gives good results as long as the couplings are not too large.

  5. Arsenite Effects on Mitochondrial Bioenergetics in Human and Mouse Primary Hepatocytes Follow a Nonlinear Dose Response

    PubMed Central

    Christudoss, Pamela; Mickey, Kristen; Tessman, Robert; Ni, Hong-min; Swerdlow, Russell

    2017-01-01

    Arsenite is a known carcinogen and its exposure has been implicated in a variety of noncarcinogenic health concerns. Increased oxidative stress is thought to be the primary cause of arsenite toxicity and the toxic effect is thought to be linear with detrimental effects reported at all concentrations of arsenite. But the paradigm of linear dose response in arsenite toxicity is shifting. In the present study we demonstrate that arsenite effects on mitochondrial respiration in primary hepatocytes follow a nonlinear dose response. In vitro exposure of primary hepatocytes to an environmentally relevant, moderate level of arsenite results in increased oxidant production that appears to arise from changes in the expression and activity of respiratory Complex I of the mitochondrial proton circuit. In primary hepatocytes the excess oxidant production appears to elicit adaptive responses that promote resistance to oxidative stress and a propensity to increased proliferation. Taken together, these results suggest a nonlinear dose-response characteristic of arsenite with low-dose arsenite promoting adaptive responses in a process known as mitohormesis, with transient increase in ROS levels acting as transducers of arsenite-induced mitohormesis. PMID:28163822

  6. Dose response of commercially available optically stimulated luminescent detector, Al2O3:C for megavoltage photons and electrons.

    PubMed

    Kim, Dong Wook; Chung, Weon Kuu; Shin, Dong Oh; Yoon, Myonggeun; Hwang, Ui-Jung; Rah, Jeong-Eun; Jeong, Hojin; Lee, Sang Yeob; Shin, Dongho; Lee, Se Byeong; Park, Sung Yong

    2012-04-01

    This study examined the dose response of an optically stimulated luminescence dosemeter (OSLD) to megavoltage photon and electron beams. A nanoDot™ dosemeter was used to measure the dose response of the OSLD. Photons of 6-15 MV and electrons of 9-20 MeV were delivered by a Varian 21iX machine (Varian Medical System, Inc. Milpitas, CA, USA). The energy dependency was <1 %. For the 6-MV photons, the dose was linear until 200 cGy. The superficial dose measurements revealed photon irradiation to have an angular dependency. The nanoDot™ dosemeter has potential use as an in vivo dosimetric tool that is independent of the energy, has dose linearity and a rapid response compared with normal in vivo dosimetric tools, such as thermoluminescence detectors. However, the OSLD must be treated very carefully due to the high angular dependency of the photon beam.

  7. A Generalized QMRA Beta-Poisson Dose-Response Model.

    PubMed

    Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

    2016-10-01

    Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, Kmin , is not fixed, but a random variable following a geometric distribution with parameter 0dose-response mechanism. Since a maximum likelihood solution is not easily available, a likelihood-free approximate Bayesian computation (ABC) algorithm is employed for parameter estimation. By fitting the generalized model to four experimental data sets from the literature, this study reveals that the posterior median r* estimates produced fall short of meeting the required condition of r* = 1 for single-hit assumption. However, three out of four data sets fitted by the generalized models could not achieve an improvement in goodness of fit. These combined results imply that, at least in some cases, a single-hit assumption for characterizing the dose-response process may not be appropriate, but that the more complex models may be difficult to support especially if the sample size is small. The three-parameter generalized model provides a possibility to investigate the mechanism of a dose-response process in greater detail than is possible under a single-hit model.

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

    PubMed

    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.

  9. Effects of glycerol co-solvent on the rate and form of polymer gel dose response

    NASA Astrophysics Data System (ADS)

    Jirasek, A.; Hilts, M.; Berman, A.; McAuley, K. B.

    2009-02-01

    A factor currently limiting the clinical utility of x-ray CT polymer gel dosimetry is the overall low dose sensitivity (and hence low dose resolution) of the system. Hence, active research remains in the investigation of polymer gel formulations with increased CT dose response. An ideal polymer gel dosimeter will exhibit a sensitive CT response which is linear over a suitable dose range, making clinical implementation reasonably straightforward. This study reports on the variations in rate and form of the CT dose response of irradiated polymer gels manufactured with glycerol, which is a co-solvent that permits dissolution of additional bisacrylamide above its water solubility limit (3% by weight). This study focuses on situations where the concentration of bisacrylamide is kept at or below its water solubility limit so that the influence of the co-solvent on the dose response can be explored separately from the effects of increased cross-linker concentration. CT imaging and Raman spectroscopy are used to construct dose-response curves for irradiated gels varying in (i) initial total monomer (%T) and (ii) initial co-solvent concentration. Results indicate that: (i) for a fixed glycerol concentration, gel response increases linearly with %T. Furthermore, the functional form of the dose response remains constant, in agreement with a previous model of polymer formation. (ii) Polymer gels with constant %T and increasing co-solvent concentrations also show enhanced CT response. In addition, the functional form of the response is altered in these gels as co-solvent concentration is increased. Raman data indicate that the fraction of bis-acrylamide incorporated into polymerization, as opposed to cyclization, increases as co-solvent concentration increases. The changes in functional form indicate varying polymer yields (per unit dose), akin to relative fractional monomer/cross-linker (i.e. %C) changes in earlier studies. These results are put into context of the model of

  10. Maximum likelihood estimation for cytogenetic dose-response curves

    SciTech Connect

    Frome, E.L.; DuFrain, R.J.

    1986-03-01

    In vitro dose-response curves are used to describe the relation between chromosome aberrations and radiation dose for human lymphocytes. The lymphocytes are exposed to low-LET radiation, and the resulting dicentric chromosome aberrations follow the Poisson distribution. The expected yield depends on both the magnitude and the temporal distribution of the dose. A general dose-response model that describes this relation has been presented by Kellerer and Rossi (1972, Current Topics on Radiation Research Quarterly 8, 85-158; 1978, Radiation Research 75, 471-488) using the theory of dual radiation action. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting dose-time-response models are intrinsically nonlinear in the parameters. A general-purpose maximum likelihood estimation procedure is described, and estimation for the nonlinear models is illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

  11. Buildup region and skin-dose measurements for the Therac 6 linear accelerator for radiation therapy.

    PubMed

    Tannous, N B; Gagnon, W F; Almond, P R

    1981-01-01

    Buildup and surface-dose measurements were taken for the 6 MV photon beam from a Therac 6 linear accelerator manufactured by Atomic Energy of Canada Limited (AECL) with and without a lucite blocking tray in place. Further measurements were made with a copper filter designed to reduce secondary electrons emitted by photon interactions with the Lucite tray. The results are discussed in relation to skin-sparing for radiation therapy patients. The measurements were made with a fixed volume PTW parallel-plate ionization chamber and corrected to zero-chamber volume. The results were found to be consistent with similar measurements taken with a variable volume extrapolation chamber.

  12. Buildup region and skin-dose measurements for the Therac 6 Linear Accelerator for radiation therapy

    SciTech Connect

    Tannous, N.B.J.; Gagnon, W.F.; Almond, P.R.

    1981-05-01

    Buildup and surface-dose measurements were taken for the 6 MV photon beam from a Therac 6 linear accelerator manufactured by Atomic Energy of Canada Limited (AECL) with and without a lucite blocking tray in place. Further measurements were made with a copper filter designed to reduce secondary electrons emitted by photon interactions with the Lucite tray. The results are discussed in relation to skin-sparing for radiation therapy patients. The measurements were made with a fixed volume PTW parallel-plate ionization chamber and corrected to zero-chamber volume. The results were found to be consistent with similar measurements taken with a variable volume extrapolation chamber.

  13. Pseudomonas aeruginosa dose response and bathing water infection.

    PubMed

    Roser, D J; van den Akker, B; Boase, S; Haas, C N; Ashbolt, N J; Rice, S A

    2014-03-01

    Pseudomonas aeruginosa is the opportunistic pathogen mostly implicated in folliculitis and acute otitis externa in pools and hot tubs. Nevertheless, infection risks remain poorly quantified. This paper reviews disease aetiologies and bacterial skin colonization science to advance dose-response theory development. Three model forms are identified for predicting disease likelihood from pathogen density. Two are based on Furumoto & Mickey's exponential 'single-hit' model and predict infection likelihood and severity (lesions/m2), respectively. 'Third-generation', mechanistic, dose-response algorithm development is additionally scoped. The proposed formulation integrates dispersion, epidermal interaction, and follicle invasion. The review also details uncertainties needing consideration which pertain to water quality, outbreaks, exposure time, infection sites, biofilms, cerumen, environmental factors (e.g. skin saturation, hydrodynamics), and whether P. aeruginosa is endogenous or exogenous. The review's findings are used to propose a conceptual infection model and identify research priorities including pool dose-response modelling, epidermis ecology and infection likelihood-based hygiene management.

  14. Construction of a cytogenetic dose-response curve for low-dose range gamma-irradiation in human peripheral blood lymphocytes using three-color FISH.

    PubMed

    Suto, Yumiko; Akiyama, Miho; Noda, Takashi; Hirai, Momoki

    2015-12-01

    In order to estimate biological doses after low-dose ionizing radiation exposure, fluorescence in situ hybridization (FISH) using three differentially colored chromosome painting probes was employed to detect exchange-type chromosome aberrations. A reference dose response curve was constructed using blood samples from a female donor whose lymphocytes consistently exhibited a low frequency of cells at the second mitosis under routine culture conditions. Aberration yields were studied for a total of about 155 thousand metaphases obtained from seven dose-points of gamma irradiations (0, 50, 100, 150, 200, 250 and 300mGy). In situ hybridization was performed using commercially available painting probes for chromosomes 1, 2 and 4. With the aid of an automated image-capturing method, exchange-type aberrations involving painted chromosomes were detected with considerable accuracy and speed. The results on the exchange-type aberrations (dicentrics plus translocations) at the seven dose-points showed a good fit to the linear-quadratic model (y=0.0023+0.0015x+0.0819x(2), P=0.83). A blind test proved the reproducibility of the reference dose-response relationship. In the control experiments using blood samples from another donor, the estimated doses calculated on the basis of the present reference curve were proved to be in good agreement with the actual physical doses applied. The present dose-response curve may serve as a means to assess the individual differences in cytogenetical radio-sensitivities.

  15. Qubit Measurement with a Nonlinear Cavity Detector Beyond Linear Response

    NASA Astrophysics Data System (ADS)

    Laflamme, Catherine; Clerk, Aashish

    2012-02-01

    We consider theoretically the use of a driven, nonlinear superconducting microwave cavity to measure a coupled superconducting qubit. This is similar to setups studied in recent experiments.ootnotetextM. Hatridge et al. Phys.Rev.B, 83,134501 (2011)^,ootnotetextF.R. Ong et al. PRL 106,167002 (2011) In a previous work, we demonstrated that for weak coupling (where linear response theory holds) one misses the quantum limit on QND detection in this system by a large factor proportional to the parametric gain.ootnotetextC. Laflamme and A.A. Clerk, Phys. Rev. A 83, 033803 (2011) Here we calculate measurement backaction beyond linear response by using an approximate mapping to a detuned degenerate parametric amplifier having both linear and dispersive couplings to the qubit. We find surprisingly that the backaction dephasing rate is far more sensitive to corrections beyond linear response than the detector response. Thus, increasing the coupling strength can significantly increase the efficiency of the measurement. We interpret this behavior in terms of the non-Gaussian photon number fluctuations of the nonlinear cavity. Our results have applications to quantum information processing and quantum amplification with superconducting microwave circuits.

  16. Chaos pass filter: linear response of synchronized chaotic systems.

    PubMed

    Zeeb, Steffen; Kestler, Johannes; Kanter, Ido; Kinzel, Wolfgang

    2013-04-01

    The linear response of synchronized time-delayed chaotic systems to small external perturbations, i.e., the phenomenon of chaos pass filter, is investigated for iterated maps. The distribution of distances, i.e., the deviations between two synchronized chaotic units due to external perturbations on the transferred signal, is used as a measure of the linear response. It is calculated numerically and, for some special cases, analytically. Depending on the model parameters this distribution has power law tails in the region of synchronization leading to diverging moments of distances. This is a consequence of multiplicative and additive noise in the corresponding linear equations due to chaos and external perturbations. The linear response can also be quantified by the bit error rate of a transmitted binary message which perturbs the synchronized system. The bit error rate is given by an integral over the distribution of distances and is calculated analytically and numerically. It displays a complex nonmonotonic behavior in the region of synchronization. For special cases the distribution of distances has a fractal structure leading to a devil's staircase for the bit error rate as a function of coupling strength. The response to small harmonic perturbations shows resonances related to coupling and feedback delay times. A bidirectionally coupled chain of three units can completely filter out the perturbation. Thus the second moment and the bit error rate become zero.

  17. Induction of MRSA Biofilm by Low-Dose β-Lactam Antibiotics: Specificity, Prevalence and Dose-Response Effects.

    PubMed

    Ng, Mandy; Epstein, Samuel B; Callahan, Mary T; Piotrowski, Brian O; Simon, Gary L; Roberts, Afsoon D; Keiser, John F; Kaplan, Jeffrey B

    2014-01-01

    Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital- and community-associated infections. The formation of adherent clusters of cells known as biofilms is an important virulence factor in MRSA pathogenesis. Previous studies showed that subminimal inhibitory (sub-MIC) concentrations of methicillin induce biofilm formation in the community-associated MRSA strain LAC. In this study we measured the ability sub-MIC concentrations of eight other β-lactam antibiotics and six non-β-lactam antibiotics to induce LAC biofilm. All eight β-lactam antibiotics, but none of the non-β-lactam antibiotics, induced LAC biofilm. The dose-response effects of the eight β-lactam antibiotics on LAC biofilm varied from biphasic and bimodal to near-linear. We also found that sub-MIC methicillin induced biofilm in 33 out of 39 additional MRSA clinical isolates, which also exhibited biphasic, bimodal and linear dose-response curves. The amount of biofilm formation induced by sub-MIC methicillin was inversely proportional to the susceptibility of each strain to methicillin. Our results demonstrate that induction of biofilm by sub-MIC antibiotics is a common phenotype among MRSA clinical strains and is specific for β-lactam antibiotics. These findings may have relevance to the use of β-lactam antibiotics in clinical and agricultural settings.

  18. Surface dose for five telecobalt machines, 6MV photon beam from four linear accelerators and a Hi-Art Tomotherapy.

    PubMed

    Kinhikar, Rajesh A

    2008-10-01

    The purpose of this study was to estimate the surface dose for five telecobalt machines (four from Best Theratronics Limited, Canada, one from Panacea Medical Technologies, India), 6 MV photon beam (static) from four linear accelerators (three Varian linear accelerators and one Siemens) and Hi-Art Tomotherapy unit. The surface dose was measured with Thermoluminescent dosimeters in phantom slabs. For Tomotherapy 6 MV beam the surface dose was estimated as 32% while it was 35%, 33%, and 36% for Clinac 6EX, Clinac 2100CD, and Clinac 2100C linear accelerators, respectively. Similarly, the surface dose for 6 MV photon beam from Primus linear accelerator was estimated as 35%. Surface doses from telecobalt machines Equinox-80, Elite-80, Th-780C, Th-780, and Bhabhatron-II was found to be 30%, 29.1%, 27.8%, 29.3%, and 29.9% for 10 cm x 10 field size, respectively. Measured surface dose from all four linear accelerators were in good agreement with that of the Tomotherapy. The surface dose measurements were useful for Tomotherapy to predict the superficial dose during helical IMRT treatments.

  19. The Radiation Dose-Response of the Human Spinal Cord

    SciTech Connect

    Schultheiss, Timothy E.

    2008-08-01

    Purpose: To characterize the radiation dose-response of the human spinal cord. Methods and Materials: Because no single institution has sufficient data to establish a dose-response function for the human spinal cord, published reports were combined. Requisite data were dose and fractionation, number of patients at risk, number of myelopathy cases, and survival experience of the population. Eight data points for cervical myelopathy were obtained from five reports. Using maximum likelihood estimation correcting for the survival experience of the population, estimates were obtained for the median tolerance dose, slope parameter, and {alpha}/{beta} ratio in a logistic dose-response function. An adequate fit to thoracic data was not possible. Hyperbaric oxygen treatments involving the cervical cord were also analyzed. Results: The estimate of the median tolerance dose (cervical cord) was 69.4 Gy (95% confidence interval, 66.4-72.6). The {alpha}/{beta} = 0.87 Gy. At 45 Gy, the (extrapolated) probability of myelopathy is 0.03%; and at 50 Gy, 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Graphical analysis indicates that the sensitivity of the thoracic cord is less than that of the cervical cord. There appears to be a sensitizing effect from hyperbaric oxygen treatment. Conclusions: The estimate of {alpha}/{beta} is smaller than usually quoted, but values this small were found in some studies. Using {alpha}/{beta} = 0.87 Gy, one would expect a considerable advantage by decreasing the dose/fraction to less than 2 Gy. These results were obtained from only single fractions/day and should not be applied uncritically to hyperfractionation.

  20. Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer Dose Response: Towards Relaxing the LNT Hypothesis.

    PubMed

    Lou, In Chio; Zhao, Yuchao; Wu, Yingjie; Ricci, Paolo F

    2012-01-01

    The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency. J-shaped dose response curves have been captured with consideration of cell cycle checkpoint control mechanisms. The simulation results indicate the shape of the dose response curve relates to the behavior of the saddle-node points of the model in the bifurcation diagram. A simplified version of the model in previous work of the authors was used mathematically to analyze behaviors relating to the saddle-node points for the J-shaped dose response curve. It indicates that low-linear energy transfer (LET) is more likely to have a J-shaped dose response curve. This result emphasizes the significance of systems biology approach, which encourages collaboration of multidiscipline of biologists, toxicologists and mathematicians, to illustrate complex cancer-related events, and confirm the biphasic dose-response at low doses.

  1. Dose-time pattern of the hypercalcemic response to calcium infusion in the dog.

    PubMed

    Verine, H J; Pastor, J; Pauli, A M; Durbec, J P

    1977-04-01

    Forty-five tests were performed to study blood total [Ca] response to a 2-hours IV calcium gluconate infusion, in five conscious dogs. Calcium doses were : 2.45 ; 4.50;6.19 and 9.00 mumole kg--u min-1 ; saline was used as control. Blood samples were collected every 20 minutes and calcaemia determined by atomic absorption spectrophotometry at 422.7 nm. No plateau was reached except with lowest dose. At each Ca dose, successive calcaemia levels can be fitted by a straight line and the regression calculated. With studied doses, calculated slopes were : 3.6 ; 8.3 ; 11.8 and 19.1 mumole l--1 min--1 respectively ; these slopes were found to be significantly different from each other. A linear dose-response relationship was calculated between blood [Ca] increase rate and Ca dose : Y = --3.01 + 2.44 X (mumole l--1 min-1 increase rate per mumole kg--1 min-1 Ca dose). Correspondence analysis emphazises the influence of zero time calcaemia.

  2. Dose finding when the target dose is on a plateau of a dose-response curve: comparison of fully sequential designs.

    PubMed

    Ivanova, Anastasia; Xiao, Changfu

    2013-01-01

    Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology phase II dose-finding studies, the dose-response curve often plateaus in the range of interest, and there are several doses with the mean response equal to the target. In this case, it is usually of interest to find the lowest of these doses because higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology phase I trials is the most suitable when the dose-response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, such as the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently.

  3. Thermodynamic formalism and linear response theory for nonequilibrium steady states.

    PubMed

    Speck, Thomas

    2016-08-01

    We study the linear response in systems driven away from thermal equilibrium into a nonequilibrium steady state with nonvanishing entropy production rate. A simple derivation of a general response formula is presented under the condition that the generating function describes a transformation that (to lowest order) preserves normalization and thus describes a physical stochastic process. For Markov processes we explicitly construct the conjugate quantities and discuss their relation with known response formulas. Emphasis is put on the formal analogy with thermodynamic potentials and some consequences are discussed.

  4. The analysis of dose-response curve from bioassays with quantal response: Deterministic or statistical approaches?

    PubMed

    Mougabure-Cueto, G; Sfara, V

    2016-04-25

    Dose-response relations can be obtained from systems at any structural level of biological matter, from the molecular to the organismic level. There are two types of approaches for analyzing dose-response curves: a deterministic approach, based on the law of mass action, and a statistical approach, based on the assumed probabilities distribution of phenotypic characters. Models based on the law of mass action have been proposed to analyze dose-response relations across the entire range of biological systems. The purpose of this paper is to discuss the principles that determine the dose-response relations. Dose-response curves of simple systems are the result of chemical interactions between reacting molecules, and therefore are supported by the law of mass action. In consequence, the shape of these curves is perfectly sustained by physicochemical features. However, dose-response curves of bioassays with quantal response are not explained by the simple collision of molecules but by phenotypic variations among individuals and can be interpreted as individual tolerances. The expression of tolerance is the result of many genetic and environmental factors and thus can be considered a random variable. In consequence, the shape of its associated dose-response curve has no physicochemical bearings; instead, they are originated from random biological variations. Due to the randomness of tolerance there is no reason to use deterministic equations for its analysis; on the contrary, statistical models are the appropriate tools for analyzing these dose-response relations.

  5. Response of human fibroblasts to low dose rate gamma irradiation

    SciTech Connect

    Dritschilo, A.; Brennan, T.; Weichselbaum, R.R.; Mossman, K.L.

    1984-11-01

    Cells from 11 human strains, including fibroblasts from patients with the genetic diseases of ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and Fanconi's anemia (FA), were exposed to ..gamma.. radiation at high (1.6-2.2 Gy/min) and at low (0.03-0.07 Gy/min) dose rates. Survival curves reveal an increase inthe terminal slope (D/sub 0/) when cells are irradiated at low dose rates compared to high dose rates. This was true for all cell lines tested, although the AT, FA, and XP cells are reported or postulated to have radiation repair deficiencies. From the response of these cells, it is apparent that radiation sensitivities differ; however, at low dose rate, all tested human cells are able to repair injury.

  6. Diverse dose-response effects of yolk androgens on embryo development and nestling growth in a wild passerine.

    PubMed

    Muriel, Jaime; Pérez-Rodríguez, Lorenzo; Puerta, Marisa; Gil, Diego

    2015-07-01

    Avian egg yolks contain various amounts of maternally derived androgens that can modify offspring phenotype and adjust their development to the post-hatching environment. Seemingly adaptive variation in yolk androgen levels with respect to breeding density conditions or male attractiveness has been found in numerous studies. One important consideration that has been overlooked in previous research is the likely non-linear nature of hormone effects. To examine possible complex dose-response effects of maternal androgens on chick development, we experimentally administered three different androgen doses of the naturally occurring mixture of yolk testosterone and androstenedione to spotless starling eggs (Sturnus unicolor). We found that yolk androgens induce a non-linear dose-response pattern in several traits. Androgens had a stimulatory effect on hatchling body mass and nestling skeletal growth, but maximum values were found at intermediate doses, whereas our highest dose resulted in a decrease. However, the opposite U-shaped effect was found on nestling body mass. We also detected linear negative and positive effects on embryonic development period and nestling gape width, respectively. Our results suggest differential tissue responsiveness to yolk androgens, which may result in compromises in maternal allocation to produce adapted phenotypes. Because of the non-linear dose-response pattern, future investigations should carefully consider a wide range of concentrations, as the balance of costs and benefits may strongly differ depending on concentration.

  7. Optimization of HDR brachytherapy dose distributions using linear programming with penalty costs

    SciTech Connect

    Alterovitz, Ron; Lessard, Etienne; Pouliot, Jean; Hsu, I-Chow Joe; O'Brien, James F.; Goldberg, Ken

    2006-11-15

    Prostate cancer is increasingly treated with high-dose-rate (HDR) brachytherapy, a type of radiotherapy in which a radioactive source is guided through catheters temporarily implanted in the prostate. Clinicians must set dwell times for the source inside the catheters so the resulting dose distribution minimizes deviation from dose prescriptions that conform to patient-specific anatomy. The primary contribution of this paper is to take the well-established dwell times optimization problem defined by Inverse Planning by Simulated Annealing (IPSA) developed at UCSF and exactly formulate it as a linear programming (LP) problem. Because LP problems can be solved exactly and deterministically, this formulation provides strong performance guarantees: one can rapidly find the dwell times solution that globally minimizes IPSA's objective function for any patient case and clinical criteria parameters. For a sample of 20 prostates with volume ranging from 23 to 103 cc, the new LP method optimized dwell times in less than 15 s per case on a standard PC. The dwell times solutions currently being obtained clinically using simulated annealing (SA), a probabilistic method, were quantitatively compared to the mathematically optimal solutions obtained using the LP method. The LP method resulted in significantly improved objective function values compared to SA (P=1.54x10{sup -7}), but none of the dosimetric indices indicated a statistically significant difference (P<0.01). The results indicate that solutions generated by the current version of IPSA are clinically equivalent to the mathematically optimal solutions.

  8. A linear chromatic mechanism drives the pupillary response.

    PubMed Central

    Tsujimura, S.; Wolffsohn, J. S.; Gilmartin, B.

    2001-01-01

    Previous studies have shown that a chromatic mechanism can drive pupil responses. The aim of this research was to clarify whether a linear or nonlinear chromatic mechanism drives pupillary responses by using test stimuli of various colours that are defined in cone contrast space. The pupil and accommodation responses evoked by these test stimuli were continuously and simultaneously objectively measured by photorefraction. The results with isochromatic and isoluminant stimuli showed that the accommodative level remained approximately constant (< 0.25 D change in mean level) even when the concurrent pupillary response was large (ca. 0.30 mm). The pupillary response to an isoluminant grating was sustained, delayed (by ca. 60 ms) and larger in amplitude than that for a isochromatic uniform stimulus, which supports previous work suggesting that the chromatic mechanism contributes to the pupillary response. In a second experiment, selected chromatic test gratings were used and isoresponse contours in cone contrast space were obtained. The results showed that the isoresponse contour in cone contrast space is well described (r(2) = 0.99) by a straight line with a positive slope. The results indicate that a /L - M/ linear chromatic mechanism, whereby a signal from the long wavelength cone is subtracted from that of the middle wavelength cone and vice versa, drives pupillary responses. PMID:11674867

  9. Cell cycle alterations, apoptosis, and response to low-dose-rate radioimmunotherapy in lymphoma cells

    SciTech Connect

    Macklis, R.M.; Beresford, B.A.; Palayoor, S.; Sweeney, S.; Humm, J.L.

    1993-10-20

    In an attempt to elucidate some aspects of the radiobiological basis of radioimmunotherapy, we have evaluated the in vitro cellular response patterns for malignant lymphoma cell lines exposed to high- and low-dose-rate radiation administered within the physiological context of antibody cell-surface binding. We used two different malignant lymphoma cell lines, a Thy1.2{sup +} murine T-lymphoma line called EL-4 and a CD20{sup +} human B-lymphoma line called Raji. Irradiated cells were evaluated for viability, cell-cycle changes, patterns of post-radiation morphologic changes, and biochemical hallmarks of radiation-associated necrosis and programmed cell death. The EL-4 line was sensitive to both high-dose-rate and low-dose-rate irradiation, while the Raji showed efficient cell kill only after high-dose-rate irradiation. Studies of radiation-induced cell cycle changes demonstrated that both cell lines were efficiently blocked at the G2/M interface by high-dose-rate irradiation, with the Raji cells appearing somewhat more susceptible than the EL-4 cells to low-dose-rate radiation-induced G2/M block. Electron microscopy and DNA gel electrophoresis studies showed that a significant proportion of the EL-4 cells appeared to be dying by radiation-induced programmed cell death (apoptosis) while the Raji cells appeared to be dying primarily by classical radiation-induced cellular necrosis. We propose that the unusual clinical responsiveness of some high and low grade lymphomas to modest doses of low-dose-rate radioimmunotherapy may be explained in part by the induction of apoptosis. The unusual dose-response characteristics observed in some experimental models of radiation-induced apoptosis may require a reappraisal of standard linear quadratic and alpha/beta algorithms used to predict target tissue cytoreduction after radioimmunotheraphy. 34 refs., 4 figs.

  10. Bayesian penalized log-likelihood ratio approach for dose response clinical trial studies.

    PubMed

    Tang, Yuanyuan; Cai, Chunyan; Sun, Liangrui; He, Jianghua

    2017-02-13

    In literature, there are a few unified approaches to test proof of concept and estimate a target dose, including the multiple comparison procedure using modeling approach, and the permutation approach proposed by Klingenberg. We discuss and compare the operating characteristics of these unified approaches and further develop an alternative approach in a Bayesian framework based on the posterior distribution of a penalized log-likelihood ratio test statistic. Our Bayesian approach is much more flexible to handle linear or nonlinear dose-response relationships and is more efficient than the permutation approach. The operating characteristics of our Bayesian approach are comparable to and sometimes better than both approaches in a wide range of dose-response relationships. It yields credible intervals as well as predictive distribution for the response rate at a specific dose level for the target dose estimation. Our Bayesian approach can be easily extended to continuous, categorical, and time-to-event responses. We illustrate the performance of our proposed method with extensive simulations and Phase II clinical trial data examples.

  11. DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY

    EPA Science Inventory

    DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY. LE Gray Jr, C Wolf, J Furr, M Price, C Lambright, VS Wilson and J Ostby. USEPA, ORD, NHEERL, EB, RTD, RTP, NC, USA.
    Dose-response behavior of a...

  12. Steroid dose sparing: pharmacodynamic responses to single versus divided doses of methylprednisolone in man.

    PubMed

    Reiss, W G; Slaughter, R L; Ludwig, E A; Middleton, E; Jusko, W J

    1990-06-01

    Inhibitory drug interactions affecting the metabolism of methylprednisolone (MP) may produce either steroid sparing or adverse effects partly by increasing the exposure time to the steroid. This phenomenon can be mimicked by administering MP in divided doses. Two types of responses were compared after a single MP dose (40 mg bolus) and a divided regimen (20 mg bolus and a 5 mg bolus 8 hours later) in six healthy male volunteers. The suppression of basophils measured as whole blood histamine and plasma cortisol concentrations was assessed during 32 hours. The 37.5% reduction in dose produced a 23% overall decreased blood histamine response. A pharmacodynamic model for basophil cell distribution to and from an extravascular compartment describes the effects of MP after both regimens. A slower initial decline in blood histamine after the divided regimen may be related to incomplete suppression of basophil cell return to blood. The 50% inhibitory concentrations of MP of about 5 ng/ml were similar for both regimens. The decline and return of cortisol concentrations were similar between MP treatments with suppression continuing for 24 hours. The 50% inhibitory concentrations of MP values for adrenal suppression were about 1 ng/ml. Pharmacodynamic modeling is useful in quantitating corticosteroid responses and generally predicted the "dose-sparing" effects that were achieved by prolonging MP plasma concentrations. This study supports previous clinical observations that patients may require morning through evening exposure to MP to optimize efficacy while adrenal suppression is being minimized.

  13. A Framework for "Fit for Purpose" Dose Response Assessment

    EPA Science Inventory

    The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two ...

  14. A collimated detection system for assessing leakage dose from medical linear accelerators at the patient plane.

    PubMed

    Lonski, P; Taylor, M L; Franich, R D; Kron, T

    2014-03-01

    Leakage radiation from linear accelerators can make a significant contribution to healthy tissue dose in patients undergoing radiotherapy. In this work thermoluminescent dosimeters (LiF:Mg,Cu,P TLD chips) were used in a focused lead cone loaded with TLD chips for the purpose of evaluating leakage dose at the patient plane. By placing the TLDs at one end of a stereotactic cone, a focused measurement device is created; this was tested both in and out of the primary beam of a Varian 21-iX linac using 6 MV photons. Acrylic build up material of 1.2 cm thickness was used inside the cone and measurements made with either one or three TLD chips at a given distance from the target. Comparing the readings of three dosimeters in one plane inside the cone offered information regarding the orientation of the cone relative to a radiation source. Measurements in the patient plane with the linac gantry at various angles demonstrated that leakage dose was approximately 0.01% of the primary beam out of field when the cone was pointed directly towards the target and 0.0025% elsewhere (due to scatter within the gantry). No specific 'hot spots' (e.g., insufficient shielding or gaps at abutments) were observed. Focused cone measurements facilitate leakage dose measurements from the linac head directly at the patient plane and allow one to infer the fraction of leakage due to 'direct' photons (along the ray-path from the bremsstrahlung target) and that due to scattered photons.

  15. An analytic linear accelerator source model for GPU-based Monte Carlo dose calculations.

    PubMed

    Tian, Zhen; Li, Yongbao; Folkerts, Michael; Shi, Feng; Jiang, Steve B; Jia, Xun

    2015-10-21

    Recently, there has been a lot of research interest in developing fast Monte Carlo (MC) dose calculation methods on graphics processing unit (GPU) platforms. A good linear accelerator (linac) source model is critical for both accuracy and efficiency considerations. In principle, an analytical source model should be more preferred for GPU-based MC dose engines than a phase-space file-based model, in that data loading and CPU-GPU data transfer can be avoided. In this paper, we presented an analytical field-independent source model specifically developed for GPU-based MC dose calculations, associated with a GPU-friendly sampling scheme. A key concept called phase-space-ring (PSR) was proposed. Each PSR contained a group of particles that were of the same type, close in energy and reside in a narrow ring on the phase-space plane located just above the upper jaws. The model parameterized the probability densities of particle location, direction and energy for each primary photon PSR, scattered photon PSR and electron PSR. Models of one 2D Gaussian distribution or multiple Gaussian components were employed to represent the particle direction distributions of these PSRs. A method was developed to analyze a reference phase-space file and derive corresponding model parameters. To efficiently use our model in MC dose calculations on GPU, we proposed a GPU-friendly sampling strategy, which ensured that the particles sampled and transported simultaneously are of the same type and close in energy to alleviate GPU thread divergences. To test the accuracy of our model, dose distributions of a set of open fields in a water phantom were calculated using our source model and compared to those calculated using the reference phase-space files. For the high dose gradient regions, the average distance-to-agreement (DTA) was within 1 mm and the maximum DTA within 2 mm. For relatively low dose gradient regions, the root-mean-square (RMS) dose difference was within 1.1% and the maximum

  16. Linearity in the response of photopolymers as optical recording media.

    PubMed

    Gallego, Sergi; Marquez, Andrés; Guardiola, Francisco J; Riquelme, Marina; Fernández, Roberto; Pascual, Inmaculada; Beléndez, Augusto

    2013-05-06

    Photopolymer are appealing materials for diffractive elements recording. Two of their properties when they are illuminated are useful for this goal: the relief surface changes and the refractive index modifications. To this goal the linearity in the material response is crucial to design the optimum irradiance for each element. In this paper we measured directly some parameters to know how linear is the material response, in terms of the refractive index modulation versus exposure, then we can predict the refractive index distributions during recording. We have analyzed at different recording intensities the evolution of monomer diffusion during recording for photopolymers based on PVA/Acrylamide. This model has been successfully applied to PVA/Acrylamide photopolymers to predict the transmitted diffracted orders and the agreement with experimental values has been increased.

  17. Dose calculation for permanent prostate implants incorporating spatially anisotropic linearly time-resolving edema

    SciTech Connect

    Monajemi, T. T.; Clements, Charles M.; Sloboda, Ron S.

    2011-04-15

    Purpose: The objectives of this study were (i) to develop a dose calculation method for permanent prostate implants that incorporates a clinically motivated model for edema and (ii) to illustrate the use of the method by calculating the preimplant dosimetry error for a reference configuration of {sup 125}I, {sup 103}Pd, and {sup 137}Cs seeds subject to edema-induced motions corresponding to a variety of model parameters. Methods: A model for spatially anisotropic edema that resolves linearly with time was developed based on serial magnetic resonance imaging measurements made previously at our center to characterize the edema for a group of n=40 prostate implant patients [R. S. Sloboda et al., ''Time course of prostatic edema post permanent seed implant determined by magnetic resonance imaging,'' Brachytherapy 9, 354-361 (2010)]. Model parameters consisted of edema magnitude, {Delta}, and period, T. The TG-43 dose calculation formalism for a point source was extended to incorporate the edema model, thus enabling calculation via numerical integration of the cumulative dose around an individual seed in the presence of edema. Using an even power piecewise-continuous polynomial representation for the radial dose function, the cumulative dose was also expressed in closed analytical form. Application of the method was illustrated by calculating the preimplant dosimetry error, RE{sub preplan}, in a 5x5x5 cm{sup 3} volume for {sup 125}I (Oncura 6711), {sup 103}Pd (Theragenics 200), and {sup 131}Cs (IsoRay CS-1) seeds arranged in the Radiological Physics Center test case 2 configuration for a range of edema relative magnitudes ({Delta}=[0.1,0.2,0.4,0.6,1.0]) and periods (T=[28,56,84] d). Results were compared to preimplant dosimetry errors calculated using a variation of the isotropic edema model developed by Chen et al. [''Dosimetric effects of edema in permanent prostate seed implants: A rigorous solution,'' Int. J. Radiat. Oncol., Biol., Phys. 47, 1405-1419 (2000

  18. Absorbed dose distributions for X-ray beams and beams of electrons from the Therac 20 Saturne linear accelerator.

    PubMed

    Tronc, D; Noël, A

    1978-11-01

    After a brief description of the Therac 20 Saturne linear accelerator a complete set of absorbed-dose distribution values is given. These values define the depths on the axis as a function of the depth dose and define the penumbra (as characterized by the positions of the intersections of the isodose curves with planes parallel to the phantom surface) for beams of X-rays and for beams of electrons. Tissue-maximum ratios are given for beams of X-rays. Analytical values for the electron depth dose curve are compared with the values obtained on the Sagittaire linear accelerator.

  19. Factors limiting the linearity of response of tissue equivalent proportional counters used in micro- and nano-dosimetry

    NASA Astrophysics Data System (ADS)

    Kowalski, T. Z.

    2017-01-01

    Proportional counters filled with tissue equivalent gas mixtures are extremely useful instruments and are being used extensively as sensitive detectors for all types of radiations to measure the energy transferred to small tissue volumes. The linearity of their response is of primary importance. So the investigation and clarification of the physical phenomena taking place in the counter and of the limits within which useful results may be obtained would contribute to a more efficient use and a wider application of these counters. The linearity of response in the dose and in the gas gain has been determined. Linearity in the dose is limited by the total count rate effect, while linearity in the gas gain is limited by secondary processes occurring in the electron avalanche and by the self-induced space charge effect.

  20. Linear response of tripartite entanglement to infinitesimal noise

    SciTech Connect

    Zhang, Fu-Lin; Chen, Jing-Ling

    2014-10-15

    Recent experimental progress in prolonging the coherence time of a quantum system prompts us to explore the behavior of quantum entanglement at the beginning of the decoherence process. The response of the entanglement under an infinitesimal noise can serve as a signature of the robustness of entangled states. A crucial problem of this topic in multipartite systems is to compute the degree of entanglement in a mixed state. We find a family of global noise in three-qubit systems, which is composed of four W states. Under its influence, the linear response of the tripartite entanglement of a symmetrical three-qubit pure state is studied. A lower bound of the linear response is found to depend completely on the initial tripartite and bipartite entanglement. This result shows that the decay of tripartite entanglement is hastened by the bipartite one. - Highlights: • We study a set of W-type noise and its linear effect on symmetric pure states. • Its effect on two-qubit entanglement depends only on the initial concurrence. • A lower bound of the effect on 3-tangle is found in terms of initial entanglements. • We obtain the time of three-tangle sudden death for two families of typical states. • These reveal that the bipartite entanglement speeds up the decay of the tripartite one.

  1. Bayesian multimodel inference for dose-response studies

    USGS Publications Warehouse

    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.

  2. Non-parametric estimators of a monotonic dose-response curve and bootstrap confidence intervals.

    PubMed

    Dilleen, Maria; Heimann, Günter; Hirsch, Ian

    2003-03-30

    In this paper we consider study designs which include a placebo and an active control group as well as several dose groups of a new drug. A monotonically increasing dose-response function is assumed, and the objective is to estimate a dose with equivalent response to the active control group, including a confidence interval for this dose. We present different non-parametric methods to estimate the monotonic dose-response curve. These are derived from the isotonic regression estimator, a non-negative least squares estimator, and a bias adjusted non-negative least squares estimator using linear interpolation. The different confidence intervals are based upon an approach described by Korn, and upon two different bootstrap approaches. One of these bootstrap approaches is standard, and the second ensures that resampling is done from empiric distributions which comply with the order restrictions imposed. In our simulations we did not find any differences between the two bootstrap methods, and both clearly outperform Korn's confidence intervals. The non-negative least squares estimator yields biased results for moderate sample sizes. The bias adjustment for this estimator works well, even for small and moderate sample sizes, and surprisingly outperforms the isotonic regression method in certain situations.

  3. Dose Response in Rodents and Nonhuman Primates After Hydrodynamic Limb Vein Delivery of Naked Plasmid DNA

    PubMed Central

    Hegge, Julia O.; Zhang, Guofeng; Sebestyén, Magdolna G.; Noble, Mark; Griffin, Jacob B.; Pfannes, Loretta V.; Herweijer, Hans; Hagstrom, James E.; Braun, Serge; Huss, Thierry; Wolff, Jon A.

    2011-01-01

    Abstract The efficacy of gene therapy mediated by plasmid DNA (pDNA) depends on the selection of suitable vectors and doses. Using hydrodynamic limb vein (HLV) injection to deliver naked pDNA to skeletal muscles of the limbs, we evaluated key parameters that affect expression in muscle from genes encoded in pDNA. Short-term and long-term promoter comparisons demonstrated that kinetics of expression differed between cytomegalovirus (CMV), muscle creatine kinase, and desmin promoters, but all gave stable expression from 2 to 49 weeks after delivery to mouse muscle. Expression from the CMV promoter was highest. For mice, rats, and rhesus monkeys, the linear range for pDNA dose response could be defined by the mass of pDNA relative to the mass of target muscle. Correlation between pDNA dose and expression was linear between a threshold dose of 75 μg/g and maximal expression at approximately 400 μg/g. One HLV injection into rats of a dose of CMV-LacZ yielding maximal expression resulted in an average transfection of 28% of all hind leg muscle and 40% of the gastrocnemius and soleus. Despite an immune reaction to the reporter gene in monkeys, a single injection transfected an average of 10% of all myofibers in the targeted muscle of the arms and legs and an average of 15% of myofibers in the gastrocnemius and soleus. PMID:21338336

  4. Prediction of the mortality dose-response relationship in man

    SciTech Connect

    Morris, M.D.; Jones, T.D.

    1987-01-01

    Based upon an extensive data base including 100 separate animal studies, an estimate of the mortality dose-response relationship due to continuous photon radiation is predicted for 70 kg man. The model used in this prediction exercise includes fixed terms accounting for effects of body weight and dose rate, and random terms accounting for inter- and intra-species variation and experimental error. Point predictions and 95% prediction intervals are given for the LD/sub 05/, LD/sub 10/, LD/sub 25/, LD/sub 50/, LD/sub 75/, LD/sub 90/, and LD/sub 95/, for dose rates ranging from 1 to 50 R/min. 6 refs., 5 tabs.

  5. Biphasic dose response in low level light therapy - an update.

    PubMed

    Huang, Ying-Ying; Sharma, Sulbha K; Carroll, James; Hamblin, Michael R

    2011-01-01

    Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments.

  6. Characterization of Statin Dose-response within Electronic Medical Records

    PubMed Central

    Wei, Wei-Qi; Feng, Qiping; Jiang, Lan; Waitara, Magarya S.; Iwuchukwu, Otito F.; Roden, Dan M.; Jiang, Min; Xu, Hua; Krauss, Ronald M.; Rotter, Jerome I.; Nickerson, Deborah A.; Davis, Robert L.; Berg, Richard L.; Peissig, Peggy L.; McCarty, Catherine A.; Wilke, Russell A.; Denny, Joshua C.

    2013-01-01

    Efforts to define the genetic architecture underlying variable statin response have met with limited success possibly because previous studies were limited to effect based on one-single-dose. We leveraged electronic medical records (EMRs) to extract potency (ED50) and efficacy (Emax) of statin dose-response curves and tested them for association with 144 pre-selected variants. Two large biobanks were used to construct dose-response curves for 2,026 (simvastatin) and 2,252 subjects (atorvastatin). Atorvastatin was more efficacious, more potent, and demonstrated less inter-individual variability than simvastatin. A pharmacodynamic variant emerging from randomized trials (PRDM16) was associated with Emax for both. For atorvastatin, Emax was 51.7 mg/dl in homozygous for the minor allele versus 75.0 mg/dl for those homozygous for the major allele. We also identified several loci associated with ED50. The extraction of rigorously defined traits from EMRs for pharmacogenetic studies represents a promising approach to further understand of genetic factors contributing to drug response. PMID:24096969

  7. Changes in the Dose-Response Relationship of One Toxicant Under Simultaneous Exposure to Another Toxicant.

    PubMed

    Katsnelson, B A; Panov, V G; Varaksin, A N; Minigalieva, I A; Privalova, L I; Sutunkova, M P

    2016-01-01

    We considered, in general form for a 2(2) full factorial experiment, linear approximations of the organism's dose-response relationship for some factors operating alone and modification of this relationship by another factor operating in the background. A typological classification of such modifications is suggested. An analysis of the outcomes obtained in a number of subchronic animal experiments on rats in which this response was assessed by changes in a large number of biomedical indices revealed that all theoretically possible variants (types) of the modification under consideration are actually observed depending on a specific index and specific harmful exposure. Statistical significance estimation procedures are formulated for each of them.

  8. Role of heme Oxygenase-1 in low dose Radioadaptive response

    PubMed Central

    Bao, Lingzhi; Ma, Jie; Chen, Guodong; Hou, Jue; Hei, Tom K.; Yu, K.N.; Han, Wei

    2016-01-01

    Radioadaptive response (RAR) is an important phenomenon induced by low dose radiation. However, the molecular mechanism of RAR is obscure. In this study, we focused on the possible role of heme oxygenase 1 (HO-1) in RAR. Consistent with previous studies, priming dose of X-ray radiation (1–10 cGy) induced significant RAR in normal human skin fibroblasts (AG 1522 cells). Transcription and translation of HO-1 was up-regulated more than two fold by a priming dose of radiation (5 cGy). Zinc protoporphyrin Ⅸ, a specific competitive inhibitor of HO-1, efficiently inhibited RAR whereas hemin, an inducer of HO-1, could mimic priming dose of X-rays to induce RAR. Knocking down of HO-1 by transfection of HO-1 siRNA significantly attenuated RAR. Furthermore, the expression of HO-1 gene was modulated by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which translocated from cytoplasm to nucleus after priming dose radiation and enhance the antioxidant level of cells. PMID:26966892

  9. The dose-response curve of the gravitropic reaction: a re-analysis.

    PubMed

    Perbal, Gérald; Jeune, Bernard; Lefranc, Agnès; Carnero-Diaz, Eugénie; Driss-Ecole, Dominique

    2002-03-01

    The dose-response curve of the gravitropic reaction is often used to evaluate the gravisensing of plant organs. It has been proposed (Larsen 1957) that the response (curvature) varies linearly as a function of the logarithm of the dose of gravistimulus. As this model fitted correctly most of the data obtained in the literature, the presentation time (tp, minimal duration of stimulation in the gravitational field to induce a response) or the presentation dose (dp, minimal quantity in g.s of stimulation to induce a response) were estimated by extrapolating down to zero curvature the straight line representing the response as a function of the logarithm of the stimulus. This method was preferred to a direct measurement of dp or tp with minute stimulations, since very slight gravitropic response cannot be distinguished from the background oscillations of the extremity of the organs. In the present review, it is shown that generally the logarithmic model (L) does not fit the experimental data published in the literature as well as the hyperbolic model (H). The H model in its simplest form is related to a response in which a ligand-receptor system is the limiting phase in the cascade of events leading to the response (Weyers et al. 1987). However, it is demonstrated that the differential growth, responsible for the curvature (and the angle of curvature), would vary as a hyperbolic function of the dose of stimulation, even if several steps involving ligand-receptor systems are responsible for the gravitropic curvature. In the H model, there is theoretically no presentation time (or presentation dose) since the curve passes through the origin. The value of the derivative of the H function equals a/b and represents the slope of the cune at the origin. It could be therefore used to estimate gravisensitivity. This provides a measurement of graviresponsiveness for threshold doses of stimulation. These results imply that the presentation time (or presentation dose) derived from

  10. Linear-scaling time-dependent density-functional theory in the linear response formalism.

    PubMed

    Zuehlsdorff, T J; Hine, N D M; Spencer, J S; Harrison, N M; Riley, D J; Haynes, P D

    2013-08-14

    We present an implementation of time-dependent density-functional theory (TDDFT) in the linear response formalism enabling the calculation of low energy optical absorption spectra for large molecules and nanostructures. The method avoids any explicit reference to canonical representations of either occupied or virtual Kohn-Sham states and thus achieves linear-scaling computational effort with system size. In contrast to conventional localised orbital formulations, where a single set of localised functions is used to span the occupied and unoccupied state manifold, we make use of two sets of in situ optimised localised orbitals, one for the occupied and one for the unoccupied space. This double representation approach avoids known problems of spanning the space of unoccupied Kohn-Sham states with a minimal set of localised orbitals optimised for the occupied space, while the in situ optimisation procedure allows for efficient calculations with a minimal number of functions. The method is applied to a number of medium sized organic molecules and a good agreement with traditional TDDFT methods is observed. Furthermore, linear scaling of computational cost with system size is demonstrated on (10,0) carbon nanotubes of different lengths.

  11. Low-dose neutron dose response of zebrafish embryos obtained from the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility

    NASA Astrophysics Data System (ADS)

    Ng, C. Y. P.; Kong, E. Y.; Konishi, T.; Kobayashi, A.; Suya, N.; Cheng, S. H.; Yu, K. N.

    2015-09-01

    The dose response of embryos of the zebrafish, Danio rerio, irradiated at 5 h post fertilization (hpf) by 2-MeV neutrons with ≤100 mGy was determined. The neutron irradiations were made at the Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) facility in the National Institute of Radiological Sciences (NIRS), Chiba, Japan. A total of 10 neutron doses ranging from 0.6 to 100 mGy were employed (with a gamma-ray contribution of 14% to the total dose), and the biological effects were studied through quantification of apoptosis at 25 hpf. The responses for neutron doses of 10, 20, 25, and 50 mGy approximately fitted on a straight line, while those for neutron doses of 0.6, 1 and 2.5 mGy exhibited neutron hormetic effects. As such, hormetic responses were generically developed by different kinds of ionizing radiations with different linear energy transfer (LET) values. The responses for neutron doses of 70 and 100 mGy were significantly below the lower 95% confidence band of the best-fit line, which strongly suggested the presence of gamma-ray hormesis.

  12. Thermoelectric effects in quantum Hall systems beyond linear response

    NASA Astrophysics Data System (ADS)

    López, Rosa; Hwang, Sun-Yong; Sánchez, David

    2014-12-01

    We consider a quantum Hall system with an antidot acting as a energy dependent scatterer. In the purely charge case, we find deviations from the Wiedemann-Franz law that take place in the nonlinear regime of transport. We also discuss Peltier effects beyond linear response and describe both effects using magnetic-field asymmetric transport coefficients. For the spin case such as that arising along the helical edge states of a two-dimensional topological insulator, we investigate the generation of spin currents as a result of applied voltage and temperature differences in samples attached to ferromagnetic leads. We find that in the parallel configuration the spin current can be tuned with the leads' polarization even in the linear regime of transport. In contrast, for antiparallel magnetizations the spin currents has a strict nonlinear dependence on the the applied fields.

  13. Linearity of Climate Response to Increases in Black Carbon Aerosols

    SciTech Connect

    Mahajan, Salil; Evans, Katherine J.; Hack, James J.; Truesdale, John

    2013-04-19

    The impact of absorbing aerosols on global climate are not completely understood. Here, we present results of idealized experiments conducted with the Community Atmosphere Model (CAM4) coupled to a slab ocean model (CAM4-SOM) to simulate the climate response to increases in tropospheric black carbon aerosols (BC) by direct and semi-direct effects. CAM4-SOM was forced with 0, 1x, 2x, 5x and 10x an estimate of the present day concentration of BC while maintaining their estimated present day global spatial and vertical distribution. The top of the atmosphere (TOA) radiative forcing of BC in these experiments is positive (warming) and increases linearly as the BC burden increases. The total semi-direct effect for the 1x experiment is positive but becomes increasingly negative for higher BC concentrations. The global average surface temperature response is found to be a linear function of the TOA radiative forcing. The climate sensitivity to BC from these experiments is estimated to be 0.42 K $ W^{-1} m^{2}$ when the semi-direct effects are accounted for and 0.22 K $ W^{-1} m^{2}$ with only the direct effects considered. Global average precipitation decreases linearly as BC increases, with a precipitation sensitivity to atmospheric absorption of 0.4 $\\%$ $W^{-1}m^{2}$ . The hemispheric asymmetry of BC also causes an increase in southward cross-equatorial heat transport and a resulting northward shift of the inter-tropical convergence zone in the simulations at a rate of 4$^{\\circ}$N $ PW^{-1}$. Global average mid- and high-level clouds decrease, whereas the low-level clouds increase linearly with BC. The increase in marine stratocumulus cloud fraction over the south tropical Atlantic is caused by increased BC-induced diabatic heating of the free troposphere.

  14. Biphasic dose response in low level light therapy.

    PubMed

    Huang, Ying-Ying; Chen, Aaron C-H; Carroll, James D; Hamblin, Michael R

    2009-09-01

    The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.

  15. Myocardial adrenergic responsiveness after lethal and nonlethal doses of endotoxin

    SciTech Connect

    Shepherd, R.E.; Lang, C.H.; McDonough, K.H.

    1987-02-01

    A dose-dependent impairment of intrinsic myocardial performance has been observed following in vivo administration of endotoxin. The present study reports a dose-dependent increase in plasma catecholamines following endotoxin (ET) that may impair ..beta..-adrenergic responsiveness. Hearts were removed from pentobarbital-anesthetized rats 4 h after a bolus injection of saline or ET and were studied as isolated cell preparations following collagenase digestion. Responsiveness of isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in myocytes prepared from hearts of animals injected with 10 and 100 ..mu..g ET was decreased when compared with control rats and was significantly blunted in myocytes prepared from animals receiving 1000 ..mu..g ET. Similar sensitivities of the cAMP system existed, as judged by similar half-maximum effective concentration values. cAMP accumulation in the presence of 1 ..mu..M forskolin was depressed in myocytes from the 1000-..mu..g ET animals; ..beta..-adrenergic receptor density was decreased 25% in myocytes from high-dose ET animals when compared with control animals. This was accompanied by a nonsignificant reduction in the affinity of binding sites for (+/-)(/sup 3/H)CGP 12177. The blunted myocyte hormonal responsiveness following ET challenge appears to be related to the decreased activity of the adenylate cyclase that may be attributed to alterations in both receptor density and in the adenylate cyclase itself.

  16. Biphasic Dose Response in Low Level Light Therapy

    PubMed Central

    Huang, Ying-Ying; Chen, Aaron C.-H.; Carroll, James D.; Hamblin, Michael R.

    2009-01-01

    The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response. PMID:20011653

  17. Dose-dependent changes in the locomotor responses to methamphetamine in BALB/c mice: low doses induce hypolocomotion.

    PubMed

    Singh, Rana A K; Kosten, Therese A; Kinsey, Berma M; Shen, Xiaoyun; Lopez, Angel Y; Kosten, Thomas R; Orson, Frank M

    2012-12-01

    The overall goal of the present study was to determine the effects of different doses of (+)-methamphetamine (meth) on locomotor activity of Balb/C mice. Four experiments were designed to test a wide range of meth doses in BALB/c female mice. In Experiment 1, we examined locomotor activity induced by an acute administration of low doses of meth (0.01 and 0.03mg/kg) in a 90-min session. Experiment 2 was conducted to test higher meth doses (0.3-10mg/kg). In Experiment 3, separate sets of mice were pre-treated with various meth doses once or twice (one injection/week) prior to a locomotor challenge with a low meth dose. Finally, in Experiment 4, we tested whether locomotor activation would be affected by pretreatment with a low or moderate dose of meth one month prior to the low meth dose challenge. Results show that low doses of meth induce hypolocomotion whereas moderate to high doses induce hyperlocomotion. Prior exposure to either one moderate or high dose of meth or to two, low doses of meth attenuated the hypolocomotor effect of a low meth dose one week later. This effect was also attenuated in mice tested one month after administration of a moderate meth dose. These results show that low and high doses of meth can have opposing effects on locomotor activity. Further, prior exposure to the drug leads to tolerance, rather than sensitization, of the hypolocomotor response to low meth doses.

  18. Bayesian Dose-Response Modeling in Sparse Data

    NASA Astrophysics Data System (ADS)

    Kim, Steven B.

    This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a

  19. Accumulative dose response of CdZnTe detectors to 14.1 MeV neutrons

    NASA Astrophysics Data System (ADS)

    Chen, Xiang; Han, He-tong; Li, Gang; Lu, Yi

    2017-03-01

    The accumulative dose response of CdZnTe (CZT) detectors to 14.1 MeV neutrons is discussed experimentally in this paper. The Cockcroft-Walton Accelerator is used to obtain a steady neutron beam of 14.1 MeV neutrons. A pulsed X-ray source is used to test the response parameters of the neutron-exposed CZT detectors under the pulse mode. The irradiation time (hours) is shorter relative to the time scales (years) where annealing effects occur. Time and linearity response is analyzed to evaluate the maximum dose rate of the CZT detectors and the pulse shape. The result shows that the experimental CZT detectors maintain stable response behaviors, while the maximum dose rate and the total accumulative dose are less than 106 neutrons/(cm2·s) and 1010 neutrons/cm2, respectively.

  20. Low-Dose Gamma Radiation Does Not Induce an Adaptive Response for Micronucleus Induction in Mouse Splenocytes.

    PubMed

    Bannister, L A; Serran, M L; Mantha, R R

    2015-11-01

    Low-dose ionizing radiation is known to induce radioadaptive responses in cells in vitro as well as in mice in vivo. Low-dose radiation decreases the incidence and increases latency for spontaneous and radiation-induced tumors in mice, potentially as a result of enhanced cellular DNA repair efficiency or a reduction in genomic instability. In this study, the cytokinesis-block micronucleus (CBMN) assay was used to examine dose response and potential radioadaptive response for cytogenetic damage and cell survival in C57BL/6 and BALB/c spleen cells exposed in vitro or in vivo to low-dose 60Co gamma radiation. The effects of genetic background, radiation dose and dose rate, sampling time and cell cycle were investigated with respect to dose response and radioadaptive response. In C57BL/6 mice, a linear-quadratic dose-response relationship for the induction of micronuclei (MN) was observed for doses between 100 mGy and 2 Gy. BALB/c mice exhibited increased radiosensitivity for MN induction compared to C57BL/6 mice. A 20 mGy dose had no effect on MN frequencies in splenocytes of either mouse strain, however, increased spleen weight and a reduced number of dead cells were noted in the C57BL/6 strain only. Multiple experimental parameters were investigated in radioadaptive response studies, including dose and dose rate of the priming dose (20 mGy at 0.5 mGy/min and 100 mGy at 10 mGy/min), time interval (4 and 24 h) between priming and challenge doses, cell cycle stage (resting or proliferating) at exposure and kinetics after the challenge dose. Radioadaptive responses were not observed for MN induction for either mouse strain under any of the experimental conditions investigated. In contrast, a synergistic response for radiation-induced micronuclei in C57BL/6 spleen was detected after in vivo 20 mGy irradiation. This increase in the percentage of cells with cytogenetic damage was associated with a reduction in the number of nonviable spleen cells, suggesting that low-dose

  1. Radiation response of industrial materials: Dose-rate and morphology implications

    NASA Astrophysics Data System (ADS)

    Berejka, Anthony J.

    2007-08-01

    Industrial uses of ionizing radiation mostly rely upon high current, high dose-rate (100 kGy/s) electron beam (EB) accelerators. To a lesser extent, industry uses low dose-rate (2.8 × 10-3 kGy/s) radioactive Cobalt-60 as a gamma source, generally for some rather specific purposes, as medical device sterilization and the treatment of food and foodstuffs. There are nearly nine times as many (∼1400) high current EB units in commercial operation than gamma sources (∼160). However, gamma sources can be easily scaled-down so that much research on materials effects is conducted using gamma radiation. Likewise, laboratories are more likely to have very low beam current and consequently low dose-rate accelerators such as Van de Graaff generators and linear accelerators. With the advent of very high current EB accelerators, X-ray processing has become an industrially viable option. With X-rays from high power sources, dose-rates can be modulated based upon accelerator power and the attenuation of the X-ray by the distance of the material from the X-ray target. Dose and dose-rate dependence has been found to be of consequence in several commercial applications which can employ the use of ionizing radiation. The combination of dose and dose-rate dependence of the polymerization and crosslinking of wood impregnants and of fiber composite matrix materials can yield more economically viable results which have promising commercial potential. Monomer and oligomer structure also play an important role in attaining these desirable results. The influence of morphology is shown on the radiation response of olefin polymers, such as ethylene, propylene and isobutylene polymers and their copolymers. Both controlled morphology and controlled dose-rate have commercial consequences. These are also impacted both by the adroit selection of materials and through the possible use of X-ray processing.

  2. Estimating the strength of bone using linear response

    NASA Astrophysics Data System (ADS)

    Gunaratne, Gemunu H.

    2002-12-01

    Accurate diagnostic tools are required for effective management of osteoporosis; one method to identify additional diagnostics is to search for observable consequences of bone loss. An analysis of a model system is used to show that weakening of a bone is accompanied by a reduction of the fraction of the bone that participates in load transmission. On the basis of this observation, it is argued that the ratio Γ of linear responses of a network to dc and high-frequency ac driving can be used as a surrogate for their strength. Protocols needed to obtain Γ for bone samples are discussed.

  3. BYSTANDERS, ADAPTIVE RESPONSES AND GENOMIC INSTABILITY - POTENTIAL MODIFIERS OF LOW-DOSE CANCER RESPONSES.

    EPA Science Inventory

    Bystanders, Adaptive Responses and Genomic Instability -Potential Modifiers ofLow-Dose
    Cancer Responses
    .
    There has been a concerted effort in the field of radiation biology to better understand cellular
    responses that could have an impact on the estin1ation of cancer...

  4. Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

    NASA Technical Reports Server (NTRS)

    Chappelli, Lori J.; Cucinotta, Francis A.

    2010-01-01

    BACKGROUND: There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies. DOSE RESPONSE MODELS: The Harderian Gland data of Alpen et al.[1-3] was re-analyzed [4] using non-linear least square regression. The data set measured the induction of Harderian gland tumors in mice by high-energy protons, helium, neon, iron, niobium and lanthanum with LET s ranging from 0.4 to 950 keV/micron. We were able to strengthen the individual ion models by combining data for all ions into a model that relates both radiation dose and LET for the ion to tumor prevalence. We compared models based on Targeted Effects (TE) to one motivated by Non-targeted Effects (NTE) that included a bystander term that increased tumor induction at low doses non-linearly. When comparing fitted models to the experimental data, we considered the adjusted R2, the Akaike Information Criteria (AIC), and the Bayesian Information Criteria (BIC) to test for Goodness of fit.In the adjusted R2test, the model with the highest R2values provides a better fit to the available data. In the AIC and BIC tests, the model with the smaller values of the summary value provides the better fit. The non-linear NTE models fit the combined data better than the TE models that are linear at low doses. We evaluated the differences in the relative biological effectiveness (RBE) and found the NTE model provides a higher RBE at low dose compared to the TE model. POWER ANALYSIS: The final NTE model estimates were used to simulate example data to consider the design of new experiments to detect NTE at low dose for validation. Power and sample sizes were calculated for a variety of radiation qualities including some not considered in the Harderian Gland data

  5. Modeling Effective Dosages in Hormetic Dose-Response Studies

    PubMed Central

    Belz, Regina G.; Piepho, Hans-Peter

    2012-01-01

    Background Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. Methodology/Principal Findings The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0–1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0–26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. Conclusions/Significance The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy. PMID

  6. Effects of chewing gum on stress and health: a replication and investigation of dose-response.

    PubMed

    Smith, Andrew

    2013-04-01

    Research suggests that chewing gum may be associated with reduced stress, depression and a reduced likelihood of having high cholesterol and blood pressure. The present study aimed to replicate these findings and extend them by examining dose-response. A web-based survey was completed by a sample of 388 workers from public sector organisations (68.5% female; mean age: 42 years, range 17-64 years). The results showed that chewing gum was associated in a linear dose-response manner with lower levels of perceived stress (both at work and life in general), anxiety and depression. Occasional gum chewers also reported a reduced risk of high cholesterol and blood pressure. Intervention studies are now required to extend these findings, and the mechanisms underlying the effects reported here need further investigation.

  7. A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.

    PubMed

    Yoshimasu, Tatsuya; Ohashi, Takuya; Oura, Shoji; Kokawa, Yozo; Kawago, Mitsumasa; Hirai, Yoshimitsu; Miyasaka, Miwako; Nishiguchi, Haruka; Kawashima, Sayoko; Yata, Yumi; Honda, Mariko; Fujimoto, Takahiro; Okamura, Yoshitaka

    2015-11-01

    In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors.

  8. Exploring the dose-response relationship between resistance exercise intensity and cognitive function.

    PubMed

    Chang, Yu-Kai; Etnier, Jennifer L

    2009-10-01

    The purpose of this study was to explore the dose-response relationship between resistance exercise intensity and cognitive performance. Sixty-eight participants were randomly assigned into control, 40%, 70%, or 100% of 10-repetition maximal resistance exercise groups. Participants were tested on Day 1 (baseline) and on Day 2 (measures were taken relative to performance of the treatment). Heart rate, ratings of perceived exertion, self-reported arousal, and affect were assessed on both days. Cognitive performance was assessed on Day 1 and before and following treatment on Day 2. Results from regression analyses indicated that there is a significant linear effect of exercise intensity on information processing speed, and a significant quadratic trend for exercise intensity on executive function. Thus, there is a dose-response relationship between the intensity of resistance exercise and cognitive performance such that high-intensity exercise benefits speed of processing, but moderate intensity exercise is most beneficial for executive function.

  9. Dose response of micronuclei induced by combination radiation of α-particles and γ-rays in human lymphoblast cells.

    PubMed

    Ren, Ruiping; He, Mingyuan; Dong, Chen; Xie, Yuexia; Ye, Shuang; Yuan, Dexiao; Shao, Chunlin

    2013-01-01

    Combination radiation is a real situation of both nuclear accident exposure and space radiation environment, but its biological dosimetry is still not established. This study investigated the dose-response of micronuclei (MN) induction in lymphocyte by irradiating HMy2.CIR lymphoblast cells with α-particles, γ-rays, and their combinations. Results showed that the dose-response of MN induced by γ-rays was well-fitted with the linear-quadratic model. But for α-particle irradiation, the MN induction had a biphasic phenomenon containing a low dose hypersensitivity characteristic and its dose response could be well-stimulated with a state vector model where radiation-induced bystander effect (RIBE) was involved. For the combination exposure, the dose response of MN was similar to that of α-irradiation. However, the yield of MN was closely related to the sequence of irradiations. When the cells were irradiated with α-particles at first and then γ-rays, a synergistic effect of MN induction was observed. But when the cells were irradiated with γ-rays followed by α-particles, an antagonistic effect of MN was observed in the low dose range although this combination radiation also yielded a synergistic effect at high doses. When the interval between two irradiations was extended to 4h, a cross-adaptive response against the other irradiation was induced by a low dose of γ-rays but not α-particles.

  10. Linear control of neuronal spike timing using phase response curves.

    PubMed

    Stigen, Tyler; Danzl, Per; Moehlis, Jeff; Netoff, Theoden

    2009-01-01

    We propose a simple, robust, linear method to control the spike timing of a periodically firing neuron. The control scheme uses the neuron's phase response curve to identify an area of optimal sensitivity for the chosen stimulation parameters. The spike advance as a function of current pulse amplitude is characterized at the optimal phase and a linear least-squares regression is fit to the data. The inverted regression is used as the control function for this method. The efficacy of this method is demonstrated through numerical simulations of a Hodgkin-Huxley style neuron model as well as in real neurons from rat hippocampal slice preparations. The study shows a proof of concept for the application of a linear control scheme to control neuron spike timing in-vitro. This study was done on an individual cell level, but translation to a tissue or network level is possible. Control schemes of this type could be implemented in a closed loop implantable device to treat neuromotor disorders involving pathologically neuronal activity such as epilepsy or Parkinson's disease.

  11. Chernobyl Doses. Volume 1. Analysis of Forest Canopy Radiation Response from Multispectral Imagery and the Relationship to Doses

    DTIC Science & Technology

    1994-09-01

    AD-A284 746 Defense Nuclear Agency Alexandria, VA 22310-3398 DNA-TR-92-37-V1 Chernobyl Doses Volume 1-Analysis of Forest Canopy Radiation Response...REPORT DATE 3. REPORT TYPE AND DATES COVERED 940901 Technical 870929- 930930 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Chernobyl Doses Volume 1-Analysis of...volume of the report Chernobyl Doses presents details of a new, quantitative method for remotely sensing ionizing radiation dose to vegetation

  12. Is There a Dose-Response Relationship for Heart Disease With Low-Dose Radiation Therapy?

    SciTech Connect

    Chung, Eugene; Corbett, James R.; Moran, Jean M.; Griffith, Kent A.; Marsh, Robin B.; Feng, Mary; Jagsi, Reshma; Kessler, Marc L.; Ficaro, Edward C.; Pierce, Lori J.

    2013-03-15

    Purpose: To quantify cardiac radiation therapy (RT) exposure using sensitive measures of cardiac dysfunction; and to correlate dysfunction with heart doses, in the setting of adjuvant RT for left-sided breast cancer. Methods and Materials: On a randomized trial, 32 women with node-positive left-sided breast cancer underwent pre-RT stress single photon emission computed tomography (SPECT-CT) myocardial perfusion scans. Patients received RT to the breast/chest wall and regional lymph nodes to doses of 50 to 52.2 Gy. Repeat SPECT-CT scans were performed 1 year after RT. Perfusion defects (PD), summed stress defects scores (SSS), and ejection fractions (EF) were evaluated. Doses to the heart and coronary arteries were quantified. Results: The mean difference in pre- and post-RT PD was −0.38% ± 3.20% (P=.68), with no clinically significant defects. To assess for subclinical effects, PD were also examined using a 1.5-SD below the normal mean threshold, with a mean difference of 2.53% ± 12.57% (P=.38). The mean differences in SSS and EF before and after RT were 0.78% ± 2.50% (P=.08) and 1.75% ± 7.29% (P=.39), respectively. The average heart Dmean and D95 were 2.82 Gy (range, 1.11-6.06 Gy) and 0.90 Gy (range, 0.13-2.17 Gy), respectively. The average Dmean and D95 to the left anterior descending artery were 7.22 Gy (range, 2.58-18.05 Gy) and 3.22 Gy (range, 1.23-6.86 Gy), respectively. No correlations were found between cardiac doses and changes in PD, SSS, and EF. Conclusions: Using sensitive measures of cardiac function, no clinically significant defects were found after RT, with the average heart Dmean <5 Gy. Although a dose response may exist for measures of cardiac dysfunction at higher doses, no correlation was found in the present study for low doses delivered to cardiac structures and perfusion, SSS, or EF.

  13. Linear response theory for magnon transport in ferromagnetic insulators

    NASA Astrophysics Data System (ADS)

    Murakami, Shuichi; Matsumoto, Ryo

    2012-02-01

    We study transverse response of magnons in ferromagnetic insulators within linear response theory. In analogy with the corresponding theory for electrons [1], magnon transverse response is described, including the Hall effect, Nernst effect, and thermal Hall effect. As is also the case for electrons [1], the response functions for magnons consist of the Kubo-formula term, and the term corresponding to the orbital angular momentum. We can rewrite the response functions in terms of the Berry curvature in momentum space [2]. We apply this theory to the (quantum-mechanical) magnons and to the classical magnetostatic waves. For the magnetostatic waves, the eigenmodes are given by a generalized eigenvalue problem, giving rise to the special form of the Berry curvature [2]. We explain various properties of this Berry curvature for the generalized eigenvalue problem, and discuss its implications for the physical properties of magnetostatic modes. [1] L. Smrcka and P. Streda, J. Phys. C, 10, 2153 (1977); H. Oji, P. Streda, Phys. Rev. B 31, 7291 (1985); [2] R. Matsumoto and S. Murakami, Phys. Rev. Lett. 106, 197202 (2011); Phys. Rev. B 84, 184406 (2011).

  14. Efficient calculation of optical linear response of large silicon clusters.

    NASA Astrophysics Data System (ADS)

    Chang, Gefei; Chang, Yia-Chung

    2005-03-01

    Nanoscale silicon clusters have potential applications as light-emitting devices and bio-sensors. Ab initio calculations of the optical linear response of small-size nanoparticles have been performed via time-dependent density functional theory (TDDFT)^1 and by solving many-body Bethe-Salpeter equations (MBSE)^2,3. We show that the ab initio calculations can be made much more efficient when the nanocluster possess high point group symmetry and symmetrized basis functions are used. This allows us to extend the ab initio calculation to much larger Si clusters (up to a few hundred Si atoms) on a personal computer. The optical linear response of Si nanocluster (passivated with hydrogen) as a function of cluster size is examined. The effect of phosphorus doping of Si nanocluster on its optical properties is also studied.1. Ogũt,S., J. R. Chelikowsky, and S. G. Louie, PRL 80, 3162(1998); Marques, M., A. Castro, and A. Rubio, J. Chem. Phys. 115, 3006(2001). 2. Rohlfing, M., and S. G. Louie, PRL 80, 3320(1998);PRB 62, 4927(2000). 3. Grossman, J. C., M. Rohlfing, L. Mitas, S. G. Louie, and M. L. Cohen,PRL 86, 472(2001).

  15. Application of linear response theory to experimental data of simultaneous radiation and annealing response of a CMOS device

    NASA Technical Reports Server (NTRS)

    Litovchenko, V.

    1988-01-01

    Results from the application of linear response theory are compared to experimental data from simultaneous radiation and annealing response of a CMOS device. In particular, a method is applied which was developed earlier to determine the characteristic time, t(0), as well as the parameters A and C in the 1n(t) dependence of the linear response function R(t) = -C + A1n(1-t/t(0)). The method is based on a study of the linear response for t being much less than t(0), when R(t) can be expanded in a power series of t: R(t) = R(0) + R'(0)t + 1/2R''(0)t-squared + 1/3R'''(0)t-cubed + ..., where R'(0) and R''(0) are, respectively, the first and second derivatives of R with respect to t. To find the linear response, R(t-t') is substituted in the form of this power series equation into a general equation for the shift of the threshold potential. To test the method, irradiation experiments were conducted on RCA 10(6) rad-hard CMOS IC's. A dose rate of approximately 130 rads/min was used. An IC was irradiated with Co-60 gamma rays for several hours, taking measurements of the threshold potential for one n-channel and one p-channel transistor every ten minutes. For the p-channel transistor, t(0) was found to be approximately 110 min and for the n-channel, t(0) was approximately 70 min. For the p-channel, the theoretical curve deviates from the experimental points only after 70 min; for the n-channel, the deviation takes place after 45 min. Additional findings are discussed and the application of the method to pure annealing is described.

  16. Construction and validation of a dose-response curve using the comet assay to determine human radiosensitivity to ionizing radiation.

    PubMed

    Güerci, A; Zúñiga, L; Marcos, R

    2011-01-01

    Individual radiosensitivity is an individual characteristic associated with an increased reaction to ionizing radiation. The purpose of our work is to establish a dose-response curve useful to classify individuals as radiosensitive or radioresistant. Thus, a dose-response curve was constructed by measuring in vitro responses to increasing doses (0 to 8 Gy) of gamma radiation in the comet assay. The obtained curve fit well with a linear equation in the range of 0 to 8 Gy. The overall dose-response curve was constructed for percent DNA in tail, as a measure of the genetic damage induced by irradiation. To probe the goodness of the constructed curve, a validation study was carried out with whole blood from two donors in a blind study. Results show that, for the two applied doses (2 and 6 Gy), the obtained values fit well inside the interval of confidence of the curve. In conclusion, our results demonstrate the usefulness of the comet assay in determining individual responses to defined doses of gamma radiation. The standard dose-response curve constructed may be used to detect individuals departing from reference values.

  17. Cryptosporidium Infection Risk: Results of New Dose-Response Modeling.

    PubMed

    Messner, Michael J; Berger, Philip

    2016-10-01

    Cryptosporidium human dose-response data from seven species/isolates are used to investigate six models of varying complexity that estimate infection probability as a function of dose. Previous models attempt to explicitly account for virulence differences among C. parvum isolates, using three or six species/isolates. Four (two new) models assume species/isolate differences are insignificant and three of these (all but exponential) allow for variable human susceptibility. These three human-focused models (fractional Poisson, exponential with immunity and beta-Poisson) are relatively simple yet fit the data significantly better than the more complex isolate-focused models. Among these three, the one-parameter fractional Poisson model is the simplest but assumes that all Cryptosporidium oocysts used in the studies were capable of initiating infection. The exponential with immunity model does not require such an assumption and includes the fractional Poisson as a special case. The fractional Poisson model is an upper bound of the exponential with immunity model and applies when all oocysts are capable of initiating infection. The beta Poisson model does not allow an immune human subpopulation; thus infection probability approaches 100% as dose becomes huge. All three of these models predict significantly (>10x) greater risk at the low doses that consumers might receive if exposed through drinking water or other environmental exposure (e.g., 72% vs. 4% infection probability for a one oocyst dose) than previously predicted. This new insight into Cryptosporidium risk suggests additional inactivation and removal via treatment may be needed to meet any specified risk target, such as a suggested 10(-4) annual risk of Cryptosporidium infection.

  18. Curve fitting toxicity test data: Which comes first, the dose response or the model?

    SciTech Connect

    Gully, J.; Baird, R.; Bottomley, J.

    1995-12-31

    The probit model frequently does not fit the concentration-response curve of NPDES toxicity test data and non-parametric models must be used instead. The non-parametric models, trimmed Spearman-Karber, IC{sub p}, and linear interpolation, all require a monotonic concentration-response. Any deviation from a monotonic response is smoothed to obtain the desired concentration-response characteristics. Inaccurate point estimates may result from such procedures and can contribute to imprecision in replicate tests. The following study analyzed reference toxicant and effluent data from giant kelp (Macrocystis pyrifera), purple sea urchin (Strongylocentrotus purpuratus), red abalone (Haliotis rufescens), and fathead minnow (Pimephales promelas) bioassays using commercially available curve fitting software. The purpose was to search for alternative parametric models which would reduce the use of non-parametric models for point estimate analysis of toxicity data. Two non-linear models, power and logistic dose-response, were selected as possible alternatives to the probit model based upon their toxicological plausibility and ability to model most data sets examined. Unlike non-parametric procedures, these and all parametric models can be statistically evaluated for fit and significance. The use of the power or logistic dose response models increased the percentage of parametric model fits for each protocol and toxicant combination examined. The precision of the selected non-linear models was also compared with the EPA recommended point estimation models at several effect.levels. In general, precision of the alternative models was equal to or better than the traditional methods. Finally, use of the alternative models usually produced more plausible point estimates in data sets where the effects of smoothing and non-parametric modeling made the point estimate results suspect.

  19. Dose-Response Analysis of Chemotactic Signaling Response in Salmonella typhimurium LT2 upon Exposure to Cysteine/Cystine Redox Pair.

    PubMed

    Rosier, Bob T; Lazova, Milena D

    2016-01-01

    The chemotaxis system enables motile bacteria to search for an optimum level of environmental factors. Salmonella typhimurium senses the amino acid cysteine as an attractant and its oxidized dimeric form, cystine, as a repellent. We investigated the dose-response dependence of changes in chemotactic signaling activity upon exposure to cysteine and cystine of S. typhimurium LT2 using in vivo fluorescence resonance energy transfer (FRET) measurements. The dose-response curve of the attractant response to cysteine had a sigmoidal shape, typical for receptor-ligand interactions. However, in a knockout strain of the chemoreceptor genes tsr and tar, we detected a repellent response to cysteine solutions, scaling linearly with the logarithm of the cysteine concentration. Interestingly, the magnitude of the repellent response to cystine also showed linear dependence to the logarithm of the cystine concentration. This linear dependence was observed over more than four orders of magnitude, where detection started at nanomolar concentrations. Notably, low concentrations of another oxidized compound, benzoquinone, triggered similar responses. In contrast to S. typhimurium 14028, where no response to cystine was observed in a knockout strain of chemoreceptor genes mcpB and mcpC, here we showed that McpB/McpC-independent responses to cystine existed in the strain S. typhimurium LT2 even at nanomolar concentrations. Additionally, knocking out mcpB and mcpC did not affect the linear dose-response dependence, whereas enhanced responses were only observed to solutions that where not pH neutral (>100 μM cystine) in the case of McpC overexpression. We discuss that the linear dependence of the response on the logarithm of cystine concentrations could be a result of a McpB/C-independent redox-sensing pathway that exists in S. typhimurium LT2. We supported this hypothesis with experiments with defined cysteine/cystine mixed solutions, where a transition from repellent to attractant

  20. Dose response and factors related to interstitial pneumonitis after bone marrow transplant

    SciTech Connect

    Sampath, Sagus; Schultheiss, Timothy E. . E-mail: schultheiss@coh.org; Wong, Jeffrey

    2005-11-01

    Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The {alpha}/{beta} value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D {sub 50}, for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; in the absence of chemotherapy, the estimated D {sub 50} is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding

  1. Linear and nonlinear optical response of bismuth and antimony implanted fused silica: annealing effects

    NASA Astrophysics Data System (ADS)

    Pan, Z.; Morgan, S. H.; Henderson, D. O.; Park, S. Y.; Weeks, R. A.; Magruder, R. H.; Zuhr, R. A.

    1995-10-01

    We report the linear and nonlinear optical response of bismuth and antimony implanted fused silica with doses of 6 × 10 16 ions/cm 2. The nonlinear refractive index, n2, was measured using a Z-scan technique with a mode locked Ti:sapphire laser operating in 140 fs pulse duration at 770 nm wavelength. It is found that the nonlinear refractive index n2 of as-implanted samples is large, in the order of 10 -10 cm 2/W and the n2 value of Bi as-implanted sample is about 2.4 times lager than that of Sb as-implanted sample. The large n2 response is attributed to the presence of nanosized metal particles in the implanted layer observed by transmission electron microscopy. We also report the changes of linear and nonlinear optical response when implanted samples were subsequently annealed at temperatures from 500 to 1000 C in argon and oxygen atmospheres. The annealing effect on optical properties is found to be strongly dependent on the annealing atmospheres. Our results indicate that annealing treatment in O 2 affects the local environment of the implanted metal ions and hence the linear and nonlinear optical properties of the metal-dielectric composite. We suggest that a new phase of metal-oxygen-silicate was formed during annealing in O 2 atmosphere.

  2. Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation

    SciTech Connect

    Daila S. Gridley, PhD

    2012-03-30

    FINAL TECHNICAL REPORT Supported by the Low Dose Radiation Research Program, Office of Science U.S. Department of Energy Grant No. DE-FG02-07ER64345 Project ID: 0012965 Award Register#: ER64345 Project Manager: Noelle F. Metting, Sc.D. Phone: 301-903-8309 Division SC-23.2 noelle.metting@science.doe.gov Submitted March 2012 To: https://www.osti.gov/elink/241.3.jsp Title: Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation PI: Daila S. Gridley, Ph.D. Human low dose radiation data have been derived primarily from studies of space and airline flight personnel, nuclear plant workers and others exposed occupationally, as well as victims in the vicinity of atomic bomb explosions. The findings remain inconclusive due to population inconsistencies and complex interactions among total dose, dose rate, radiation quality and age at exposure. Thus, safe limits for low dose occupational irradiation are currently based on data obtained with doses far exceeding the levels expected for the general population and health risks have been largely extrapolated using the linear-nonthreshold dose-response model. The overall working hypothesis of the present study is that priming with low dose, low-linear energy transfer (LET) radiation can ameliorate the response to acute high-dose radiation exposure. We also propose that the efficacy of low-dose induced protection will be dependent upon the form and regimen of the high-dose exposure: photons versus protons versus simulated solar particle event protons (sSPE). The emphasis has been on gene expression and function of CD4+ T helper (Th) lymphocytes harvested from spleens of whole-body irradiated C57BL/6 mice, a strain that provides the genetic background for many genetically engineered strains. Evaluations of the responses of other selected cells, tissues such as skin, and organs such as lung, liver and brain were also initiated (partially funded by other sources). The long-term goal is to provide information

  3. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

    PubMed

    Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  4. Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework

    SciTech Connect

    Calabrese, Edward J. . E-mail: edwardc@schoolph.umass.edu; Bachmann, Kenneth A.; Bailer, A. John; Bolger, P. Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M. George; Chiueh, Chuang C.; Clarkson, Thomas W.; Cook, Ralph R.; Diamond, David M.; Doolittle, David J.; Dorato, Michael A.; Duke, Stephen O.; Feinendegen, Ludwig; Gardner, Donald E.; Hart, Ronald W.; Hastings, Kenneth L.; Hayes, A. Wallace; Hoffmann, George R.; Ives, John A.; Jaworowski, Zbigniew; Johnson, Thomas E.; Jonas, Wayne B.; Kaminski, Norbert E.

    2007-07-01

    Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

  5. Transient Genome-Wide Transcriptional Response to Low-Dose Ionizing Radiation In Vivo in Humans

    SciTech Connect

    Berglund, Susanne R.; Rocke, David M.; Dai Jian; Schwietert, Chad W.; Santana, Alison; Stern, Robin L.; Lehmann, Joerg; Hartmann Siantar, Christine L.; Goldberg, Zelanna

    2008-01-01

    Purpose: The in vivo effects of low-dose low linear energy transfer ionizing radiation on healthy human skin are largely unknown. Using a patient-based tissue acquisition protocol, we have performed a series of genomic analyses on the temporal dynamics over a 24-hour period to determine the radiation response after a single exposure of 10 cGy. Methods and Materials: RNA from each patient tissue sample was hybridized to an Affymetrix Human Genome U133 Plus 2.0 array. Data analysis was performed on selected gene groups and pathways. Results: Nineteen gene groups and seven gene pathways that had been shown to be radiation responsive were analyzed. Of these, nine gene groups showed significant transient transcriptional changes in the human tissue samples, which returned to baseline by 24 hours postexposure. Conclusions: Low doses of ionizing radiation on full-thickness human skin produce a definable temporal response out to 24 hours postexposure. Genes involved in DNA and tissue remodeling, cell cycle transition, and inflammation show statistically significant changes in expression, despite variability between patients. These data serve as a reference for the temporal dynamics of ionizing radiation response following low-dose exposure in healthy full-thickness human skin.

  6. Analysis of peripheral doses for base of tongue treatment by linear accelerator and helical TomoTherapy IMRT.

    PubMed

    Bennett, Brian Richard; Lamba, Michael A S; Elson, Howard R

    2010-06-21

    The purpose of this study was to compare the peripheral doses to various organs from a typical head and neck intensity-modulated radiation therapy (IMRT) treatment delivered by linear accelerator (linac) and helical TomoTherapy. Multiple human CT data sets were used to segment critical structures and organs at risk, fused and adjusted to an anthropomorphic phantom. Eighteen contours were designated for thermoluminescent dosimeter (TLD) placement. Following the RTOG IMRT Protocol 0522, treatment of the primary tumor and involved nodes (PTV70) and subclinical disease sites (PTV56) was planned utilizing IMRT to 70Gy and 56 Gy. Clinically acceptable treatment plans were produced for linac and TomoTherapy treatments. TLDs were placed and each treatment plan was delivered to the anthropomorphic phantom four times. Within 2.5 cm (one helical TomoTherapy field width) superior and inferior to the field edges, normal tissue doses were on average 45% lower using linear accelerator. Beyond 2.5 cm, the helical TomoTherapy normal tissue dose was an average of 52% lower. The majority of points proved to be statistically different using the Student's t-test with p > 0.05. Using one method of calculation, probability of a secondary malignancy was 5.88% for the linear accelerator and 4.08% for helical TomoTherapy. Helical TomoTherapy delivers more dose than a linac immediately above and below the treatment field, contributing to the higher peripheral doses adjacent to the field. At distances beyond one field width (where leakage is dominant), helical TomoTherapy doses are lower than linear accelerator doses.

  7. Beetroot juice and exercise: pharmacodynamic and dose-response relationships.

    PubMed

    Wylie, Lee J; Kelly, James; Bailey, Stephen J; Blackwell, Jamie R; Skiba, Philip F; Winyard, Paul G; Jeukendrup, Asker E; Vanhatalo, Anni; Jones, Andrew M

    2013-08-01

    Dietary supplementation with beetroot juice (BR), containing approximately 5-8 mmol inorganic nitrate (NO3(-)), increases plasma nitrite concentration ([NO2(-)]), reduces blood pressure, and may positively influence the physiological responses to exercise. However, the dose-response relationship between the volume of BR ingested and the physiological effects invoked has not been investigated. In a balanced crossover design, 10 healthy men ingested 70, 140, or 280 ml concentrated BR (containing 4.2, 8.4, and 16.8 mmol NO3(-), respectively) or no supplement to establish the effects of BR on resting plasma [NO3(-)] and [NO2(-)] over 24 h. Subsequently, on six separate occasions, 10 subjects completed moderate-intensity and severe-intensity cycle exercise tests, 2.5 h postingestion of 70, 140, and 280 ml BR or NO3(-)-depleted BR as placebo (PL). Following acute BR ingestion, plasma [NO2(-)] increased in a dose-dependent manner, with the peak changes occurring at approximately 2-3 h. Compared with PL, 70 ml BR did not alter the physiological responses to exercise. However, 140 and 280 ml BR reduced the steady-state oxygen (O2) uptake during moderate-intensity exercise by 1.7% (P = 0.06) and 3.0% (P < 0.05), whereas time-to-task failure was extended by 14% and 12% (both P < 0.05), respectively, compared with PL. The results indicate that whereas plasma [NO2(-)] and the O2 cost of moderate-intensity exercise are altered dose dependently with NO3(-)-rich BR, there is no additional improvement in exercise tolerance after ingesting BR containing 16.8 compared with 8.4 mmol NO3(-). These findings have important implications for the use of BR to enhance cardiovascular health and exercise performance in young adults.

  8. GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve.

    PubMed

    Brandt, A; Katschinski, M; Arnold, R; Polonsky, K S; Göke, B; Byrne, M M

    2001-08-01

    The present study was undertaken to establish in normal volunteers the alterations in beta-cell responsiveness to glucose associated with a constant infusion of glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min. A high-dose graded glucose infusion protocol was used to explore the dose-response relationship between glucose and insulin secretion. Studies were performed in 10 normal volunteers, and insulin secretion rates (ISR) were calculated by deconvolution of peripheral C-peptide levels by use of a two-compartmental model that utilized mean kinetic parameters. During the saline study, from 5 to 15 mM glucose, the relationship between glucose and ISR was linear. Constant GLP-1 infusion (0.4 pmol x kg(-1) x min(-1)) shifted the dose-response curve to the left, with an increase in the slope of this curve from 5 to 9 mM glucose from 71.0 +/- 12.4 pmol x min(-1) x mM(-1) during the saline study to 241.7 +/- 36.6 pmol x min(-1) x mM(-1) during the constant GLP-1 infusion (P < 0.0001). GLP-1 consistently stimulated a >200% increase in ISR at each 1 mM glucose interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant priming of the beta-cell response to glucose (P = 0.2). Insulin clearance rates were similar in all three studies at corresponding insulin levels. These studies demonstrate that physiological levels of GLP-1 stimulate glucose-induced insulin secretion in a linear manner, with a consistent increase in ISR at each 1 mM glucose interval, and that they have no independent effect on insulin clearance and no priming effect on subsequent insulin secretory response to glucose.

  9. The shape of the dose-response curve for radiation-induced neoplastic transformation in vitro: evidence for an adaptive response against neoplastic transformation at low doses of low-LET radiation.

    PubMed

    Redpath, J L; Liang, D; Taylor, T H; Christie, C; Elmore, E

    2001-12-01

    A dose-response curve for gamma-radiation-induced neoplastic transformation of HeLa x skin fibroblast human hybrid cells over the dose range 0.1 cGy to 1 Gy is presented. In the experimental protocol used, the spontaneous (background) frequency of neoplastic transformation of sham-irradiated cultures was compared to that of cultures which had been irradiated with (137)Cs gamma radiation and either plated immediately or held for 24 h at 37 degrees C prior to plating, for assay for neoplastic transformation. The pooled data from a minimum of three repeat large-scale experiments at each dose demonstrated a reduced transformation frequency for the irradiated compared to the sham-irradiated cells for doses of 0.1, 0.5, 1, 5 and 10 cGy for the delayed-plating arm. The probability of this happening by chance is given by 1/2(n), where n is the number of observations (5); i.e., 1/32 congruent with 0.031. This is indicative of an adaptive response against spontaneous neoplastic transformation at least up to a dose of 10 cGy of gamma radiation. The high-dose data obtained at 30 and 50 cGy and 1 Gy showed a good fit to a linear extrapolation through the sham-irradiated, zero-dose control. The delayed-plating data at 10 cGy and below showed a statistically significant divergence from this linear extrapolation.

  10. An analysis of the dose-response relationship at voltage-clamped frog neuromuscular junctions.

    PubMed Central

    Dionne, V E; Steinbach, J H; Stevens, C F

    1978-01-01

    1. Frog neuromuscular junctions were viewed with Nomarski optics and voltage clamped. Agonist was applied ionophoretically and agonist concentrations were measured using a micro-electrode sensitive to quaternary amines. 2. The dose-response relationship was studied using the agonists carbamylcholine, suberyldicholine and hydroxyphenyl-propyltrimethylammonium. 3. With all of these agonists, it appeared that the ACh receptor could be active when either one or two agonist binding sites were occupied. The receptor was much more likely to be active when both sites were occupied. Agonist dissociation constants and receptor activation probabilities were estimated by non-linear regression techniques for several possible receptor activation schemes. PMID:309004

  11. A normal tissue dose response model of dynamic repair processes

    NASA Astrophysics Data System (ADS)

    Alber, Markus; Belka, Claus

    2006-01-01

    A model is presented for serial, critical element complication mechanisms for irradiated volumes from length scales of a few millimetres up to the entire organ. The central element of the model is the description of radiation complication as the failure of a dynamic repair process. The nature of the repair process is seen as reestablishing the structural organization of the tissue, rather than mere replenishment of lost cells. The interactions between the cells, such as migration, involved in the repair process are assumed to have finite ranges, which limits the repair capacity and is the defining property of a finite-sized reconstruction unit. Since the details of the repair processes are largely unknown, the development aims to make the most general assumptions about them. The model employs analogies and methods from thermodynamics and statistical physics. An explicit analytical form of the dose response of the reconstruction unit for total, partial and inhomogeneous irradiation is derived. The use of the model is demonstrated with data from animal spinal cord experiments and clinical data about heart, lung and rectum. The three-parameter model lends a new perspective to the equivalent uniform dose formalism and the established serial and parallel complication models. Its implications for dose optimization are discussed.

  12. Motility response of rats to chronic constant-dose treatment with narcotics.

    PubMed

    Davis, W M; Hemnani, K L; Pace, H B

    1982-09-01

    The changes in effects on motor activity of rats upon repeated (48 day) dosing with four narcotic analgesics were determined. The following were administered IP once daily in a.m.: morphine sulfate (MOR), 20 mg/kg: dl-methadone HCl (MET), 5 mg/kg: meperidine HCl (MEP), 10 mg/kg; and pentazocine lactate (PEN), 20 mg/kg. Motility was measured in photocell actometers every 4 days for 6 hr after dosing. Activity was elevated after the initial dose as follows: for MOR at hours 3-5, for MET at hours 2-5, for MEP and PEN at hours 2-3. Time of peak response showed no systematic change over days. For all 4 drugs there occurred, upon repeated dosing, a considerable increase in motility over the initial acute response. For MOR the greatest increment occurred between days 12 and 16, but regression analysis showed a strong linear trend of increasing activity from day 1 through day 48. For MET and MEP, activity rose considerably between days 4 and 12 to a maximum, after which the activity trended downward for MET, but showed no continuing fall or climb for MEP. For PEN the greatest increases were from days 4 to 8 and 44 to 48, with an intervening period of relative stability. These results seem to be more readily explainable in terms of increasing sensitivity to the motor excitatory actions of these agents than merely by a development of tolerance to motor-inhibitory actions.

  13. Melatonin entrains free-running blind people according to a physiological dose-response curve.

    PubMed

    Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J; Yuhas, Krista; Jackman, Angela R

    2005-01-01

    The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 microg) of this chemical signal for the "biological night": the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase-response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 microg can entrain (synchronize) free-running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log-linear dose-response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free-running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.

  14. Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors

    EPA Science Inventory

    Dose response and time-course (DRTC) are, along with exposure, the major determinants of health risk. Adaptive changes within exposed organisms in response to environmental stress are common, and alter DRTC behaviors to minimize the effects caused by stressors. In this project, ...

  15. Long-term prediction test procedure for most ICs, based on linear response theory

    NASA Technical Reports Server (NTRS)

    Litovchenko, V.; Ivakhnenko, I.

    1991-01-01

    Experimentally, thermal annealing is known to be a factor which enables a number of different integrated circuits (IC's) to recover their operating characteristics after suffering radiation damage in the space radiation environment; thus, decreasing and limiting long term cumulative total-dose effects. This annealing is also known to be accelerated at elevated temperatures both during and after irradiation. Linear response theory (LRT) was applied, and a linear response function (LRF) to predict the radiation/annealing response of sensitive parameters of IC's for long term (several months or years) exposure to the space radiation environment were constructed. Compressing the annealing process from several years in orbit to just a few hours or days in the laboratory is achieved by subjecting the IC to elevated temperatures or by increasing the typical spaceflight dose rate by several orders of magnitude for simultaneous radiation/annealing only. The accomplishments are as follows: (1) the test procedure to make predictions of the radiation response was developed; (2) the calculation of the shift in the threshold potential due to the charge distribution in the oxide was written; (3) electron tunneling processes from the bulk Si to the oxide region in an MOS IC were estimated; (4) in order to connect the experimental annealing data to the theoretical model, constants of the model of the basic annealing process were established; (5) experimental data obtained at elevated temperatures were analyzed; (6) time compression and reliability of predictions for the long term region were shown; (7) a method to compress test time and to make predictions of response for the nonlinear region was proposed; and (8) nonlinearity of the LRF with respect to log(t) was calculated theoretically from a model.

  16. Evaluation of the Emergency Response Dose Assessment System(ERDAS)

    NASA Technical Reports Server (NTRS)

    Evans, Randolph J.; Lambert, Winifred C.; Manobianco, John T.; Taylor, Gregory E.; Wheeler, Mark M.; Yersavich, Ann M.

    1996-01-01

    The emergency response dose assessment system (ERDAS) is a protype software and hardware system configured to produce routine mesoscale meteorological forecasts and enhanced dispersion estimates on an operational basis for the Kennedy Space Center (KSC)/Cape Canaveral Air Station (CCAS) region. ERDAS provides emergency response guidance to operations at KSC/CCAS in the case of an accidental hazardous material release or an aborted vehicle launch. This report describes the evaluation of ERDAS including: evaluation of sea breeze predictions, comparison of launch plume location and concentration predictions, case study of a toxic release, evaluation of model sensitivity to varying input parameters, evaluation of the user interface, assessment of ERDA's operational capabilities, and a comparison of ERDAS models to the ocean breeze dry gultch diffusion model.

  17. Appropriate statistical methods to compare dose responses of methionine sources.

    PubMed

    Kratzer, D D; Littell, R C

    2006-05-01

    Two sources of methionine (Met) activity are frequently used in commercial feed formulation: DL-2-hydroxy-4-(methylthio) butanoic acid (HMTBA), most commonly available as an 88% solution with 12% water; and DL-methionine (DLM, 99% powder). Despite the fact that both compounds have been in commercial use for over 50 yr, controversy and confusion remain with respect to their relative bioefficacy (RBE). This paper presents a review of the use of a nonlinear common plateau asymptotic regression technique (NLCPAR) that has been used to compare the 2 Met sources with particular emphasis on the validity of the basic assumptions of that model. The thesis of this paper is that the controversy is due, at least in part, to the misapplication of this regression technique to estimate the RBE of HMTBA and DLM. The NLCPAR model is a bioassay with the key dependent assumptions that HMTBA is a dilution of DLM, and that each follows dose-response curves of the same form and approach a common plateau. Because both provide Met activity, it may be considered reasonable to accept these assumptions; however, specifically testing them demonstrated that the assumption of a common dose-response is not supported by data. The common plateau assumption was tested with an alternative approach of fitting nonlinear separate plateaus asymptotic regression (NLSPAR) to a set of 13 published broiler studies in which the NLCPAR model had been used to estimate RBE of HMTBA and DLM. The hypothesis of a common plateau was rejected (P < 0.01), meaning that the conclusion that HMTBA had lower bioefficacy than DLM based on the NLCPAR methodology was not valid. An example using published data demonstrated that the NLSPAR model was a significantly better fit than the NLCPAR model, and showed that HMTBA and DLM followed different dose responses. Consequently, there was no single value for RBE for the entire dose range; rather, the RBE of the 2 compounds varied with use level. The evidence presented here

  18. PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

    EPA Science Inventory

    PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
    Dose-response analysis requires quantitatively linking infor...

  19. Dose-response relationships and extrapolation in toxicology - Mechanistic and statistical considerations

    EPA Science Inventory

    Controversy on toxicological dose-response relationships and low-dose extrapolation of respective risks is often the consequence of misleading data presentation, lack of differentiation between types of response variables, and diverging mechanistic interpretation. In this chapter...

  20. New flux based dose-response relationships for ozone for European forest tree species.

    PubMed

    Büker, P; Feng, Z; Uddling, J; Briolat, A; Alonso, R; Braun, S; Elvira, S; Gerosa, G; Karlsson, P E; Le Thiec, D; Marzuoli, R; Mills, G; Oksanen, E; Wieser, G; Wilkinson, M; Emberson, L D

    2015-11-01

    To derive O3 dose-response relationships (DRR) for five European forest trees species and broadleaf deciduous and needleleaf tree plant functional types (PFTs), phytotoxic O3 doses (PODy) were related to biomass reductions. PODy was calculated using a stomatal flux model with a range of cut-off thresholds (y) indicative of varying detoxification capacities. Linear regression analysis showed that DRR for PFT and individual tree species differed in their robustness. A simplified parameterisation of the flux model was tested and showed that for most non-Mediterranean tree species, this simplified model led to similarly robust DRR as compared to a species- and climate region-specific parameterisation. Experimentally induced soil water stress was not found to substantially reduce PODy, mainly due to the short duration of soil water stress periods. This study validates the stomatal O3 flux concept and represents a step forward in predicting O3 damage to forests in a spatially and temporally varying climate.

  1. Methods for meta-analysis of pharmacodynamic dose-response data with application to multi-arm studies of alogliptin.

    PubMed

    Langford, Oliver; Aronson, Jeffrey K; van Valkenhoef, Gert; Stevens, Richard J

    2016-03-17

    Standard methods for meta-analysis of dose-response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used Emax model, are used to describe relationships that are bounded above and below. We propose methods for estimating the parameters of a dose-response model by meta-analysis of summary data from the results of randomized controlled trials of a drug, in which each trial uses multiple doses of the drug of interest (possibly including dose 0 or placebo). We assume that, for each randomized arm of each trial, the mean and standard error of a continuous response measure and the corresponding allocated dose are available. We consider weighted least squares fitting of the model to the mean and dose pairs from all arms of all studies, and a two-stage procedure in which scalar inverse-variance meta-analysis is performed at each dose, and the dose-response model is fitted to the results by weighted least squares. We then compare these with two further methods inspired by network meta-analysis that fit the model to the contrasts between doses. We illustrate the methods by estimating the parameters of the Emax model to a collection of multi-arm, multiple-dose, randomized controlled trials of alogliptin, a drug for the management of diabetes mellitus, and further examine the properties of the four methods with sensitivity analyses and a simulation study. We find that all four methods produce broadly comparable point estimates for the parameters of most interest, but a single-stage method based on contrasts between doses produces the most appropriate confidence intervals. Although simpler methods may have pragmatic advantages, such as the use of standard software for scalar meta-analysis, more sophisticated methods are nevertheless preferable for their advantages in estimation.

  2. Quantum optimal control theory in the linear response formalism

    SciTech Connect

    Castro, Alberto; Tokatly, I. V.

    2011-09-15

    Quantum optimal control theory (QOCT) aims at finding an external field that drives a quantum system in such a way that optimally achieves some predefined target. In practice, this normally means optimizing the value of some observable, a so-called merit function. In consequence, a key part of the theory is a set of equations, which provides the gradient of the merit function with respect to parameters that control the shape of the driving field. We show that these equations can be straightforwardly derived using the standard linear response theory, only requiring a minor generalization: the unperturbed Hamiltonian is allowed to be time dependent. As a result, the aforementioned gradients are identified with certain response functions. This identification leads to a natural reformulation of QOCT in terms of the Keldysh contour formalism of the quantum many-body theory. In particular, the gradients of the merit function can be calculated using the diagrammatic technique for nonequilibrium Green's functions, which should be helpful in the application of QOCT to computationally difficult many-electron problems.

  3. Magnetoelectric Effect in Topological Insulator Films Beyond Linear Response Regime

    NASA Astrophysics Data System (ADS)

    Tretiakov, Oleg; Baasanjav, Dashdeleg; Nomura, Kentaro

    2014-03-01

    We study the response of topological insulator films to strong magnetic and electric fields beyond the linear response theory. As a model, we use three-dimensional lattice Wilson-Dirac Hamiltonian where we simultaneously introduce both magnetic field as Aharonov Bohm phase and electric field as potential energy depending on lattice coordinate. We compute the energy spectrum by numerically diagonalizing this Hamiltonian for electrons and obtain the quantized magnetoelectric polarizability. In addition, we find that the magnetoelectric effect vanishes as width of the film decreases, due to the hybridization of surface wavefunctions. Furthermore, by applying a gate voltage between the surfaces, we observe multiple quantized plateaus of θ-term. We explain that the multiple quantization rule of θ is mainly determined by the physics of Landau level structures on the top and bottom surfaces of topological insulator, whereas the small deviations from the exact quantization are coming from the asymmetry of the surface wavefunctions in the bulk. We also show that the magnetoelectric effect persists even for strong bulk interactions with magnetic field or magnetic impurities. We acknowledge support by the Grants-in-Aid for Scientific Research (No. 24740211, No. 25800184, and No. 25247056) from the MEXT, Japan.

  4. The cytokinesis-blocked micronucleus assay: dose estimation and inter-individual differences in the response to γ-radiation.

    PubMed

    Antunes, A C; Martins, V; Cardoso, J; Santos, L; Monteiro Gil, O

    2014-01-15

    Biological dosimetry plays an important role in case of a radiation accident or incident, either when it is the only way to estimate the dose or when it is used to complement physical dosimetry. A cytogenetic study was conducted in a group of 16 Portuguese individuals by use of the cytokinesis-blocked micronucleus (CBMN) assay. A dose-response curve for micronuclei yield was established with a linear-quadratic model: Y=(0.0122±0.0010)+(0.0241±0.0023)D+(0.0193±0.0007)D(2). Also, baseline values for the micronucleus formation in the 16 donors were analyzed, with results in close agreement with those from other laboratories. A validation experiment was carried out with three individuals. The real and the estimated doses obtained with the dose-response curve were in very good agreement, allowing the use of the micronucleus dose-response calibration curve in biological dosimetry for estimation of radiation dose in case of overexposure. The results obtained for the cytogenetic endpoints, studied in the same group of 16 individuals, were also analyzed as a function of age and gender. A higher inter-variability was observed for the higher dose points and differences in response were identified between genders, above 2Gy, for all endpoints.

  5. A Novel Method of Estimating Dose Responses for Polymer Gels Using Texture Analysis of Scanning Electron Microscopy Images

    PubMed Central

    Shih, Cheng-Ting; Hsu, Jui-Ting; Han, Rou-Ping; Hsieh, Bor-Tsung; Chang, Shu-Jun; Wu, Jay

    2013-01-01

    Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM) images. The modified N-isopropyl-acrylamide (NIPAM) gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM). The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R2 value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were −7.60%, 5.80%, 2.53%, and −0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection. PMID:23843998

  6. A novel method of estimating dose responses for polymer gels using texture analysis of scanning electron microscopy images.

    PubMed

    Shih, Cheng-Ting; Hsu, Jui-Ting; Han, Rou-Ping; Hsieh, Bor-Tsung; Chang, Shu-Jun; Wu, Jay

    2013-01-01

    Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM) images. The modified N-isopropyl-acrylamide (NIPAM) gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM). The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R (2) value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were -7.60%, 5.80%, 2.53%, and -0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection.

  7. Improvements in dose accuracy delivered with static-MLC IMRT on an integrated linear accelerator control system

    SciTech Connect

    Li Ji; Wiersma, Rodney D.; Stepaniak, Christopher J.; Farrey, Karl J.; Al-Hallaq, Hania A.

    2012-05-15

    Purpose: Dose accuracy has been shown to vary with dose per segment and dose rate when delivered with static multileaf collimator (SMLC) intensity modulated radiation therapy (IMRT) by Varian C-series MLC controllers. The authors investigated the impact of monitor units (MUs) per segment and dose rate on the dose delivery accuracy of SMLC-IMRT fields on a Varian TrueBeam linear accelerator (LINAC), which delivers dose and manages motion of all components using a single integrated controller. Methods: An SMLC sequence was created consisting of ten identical 10 x 10 cm{sup 2} segments with identical MUs. Beam holding between segments was achieved by moving one out-of-field MLC leaf pair. Measurements were repeated for various combinations of MU/segment ranging from 1 to 40 and dose rates of 100-600 MU/min for a 6 MV photon beam (6X) and dose rates of 800-2400 MU/min for a 10 MV flattening-filter free photon (10XFFF) beam. All measurements were made with a Farmer (0.6 cm{sup 3}) ionization chamber placed at the isocenter in a solid-water phantom at 10 cm depth. The measurements were performed on two Varian LINACs: C-series Trilogy and TrueBeam. Each sequence was delivered three times and the dose readings for the corresponding segments were averaged. The effects of MU/segment, dose rate, and LINAC type on the relative dose variation ({Delta}{sub i}) were compared using F-tests ({alpha} = 0.05). Results: On the Trilogy, large {Delta}{sub i} was observed in small MU segments: at 1 MU/segment, the maximum {Delta}{sub i} was 10.1% and 57.9% at 100 MU/min and 600 MU/min, respectively. Also, the first segment of each sequence consistently overshot ({Delta}{sub i} > 0), while the last segment consistently undershot ({Delta}{sub i} < 0). On the TrueBeam, at 1 MU/segment, {Delta}{sub i} ranged from 3.0% to 4.5% at 100 and 600 MU/min; no obvious overshoot/undershoot trend was observed. F-tests showed statistically significant difference [(1 - {beta}) =1.0000] between the

  8. Dose-response relationship between light exposure and cycling performance.

    PubMed

    Knaier, R; Meister, S; Aeschbacher, T; Gemperle, D; Rossmeissl, A; Cajochen, C; Schmidt-Trucksäss, A

    2016-07-01

    Light has a stimulating effect on physical performance if scheduled according to the chronotype, but dose-dependent effects on performance have not yet been examined. Three groups of healthy men (25.1 ± 3.1 years) were exposed to light for different durations in a parallel group design before a 40-min time-trial. In each group, subjects were exposed to either bright light (BL, 4420 lx) or moderate light (ML, 230 lx) in a randomized order in a crossover design. The durations of light exposure were 120 min prior to and during exercise (2HEX; n = 16), 60 min prior to and during exercise (1HEX; n = 10), or only for 60 min prior to exercise (1H; n = 15). Total work performed during the time-trial in kJ in the 2HEX group was significantly higher in the BL setting (527 kJ) than in ML (512 kJ) (P = 0.002), but not in 1HEX (BL: 485 kJ; ML: 498 kJ) or 1H (BL: 519 kJ; ML: 514 kJ) (P = 0.770; P = 0.485). There was a significant (P = 0.006) positive dose-response relationship between the duration of light exposure and the work performed over the three doses of light exposure. A long duration light exposure is an effective tool to increase total work in a medium length time-trial in subjects normalized for their individual chronotype.

  9. Biological profiling and dose-response modeling tools ...

    EPA Pesticide Factsheets

    Through its ToxCast project, the U.S. EPA has developed a battery of in vitro high throughput screening (HTS) assays designed to assess the potential toxicity of environmental chemicals. At present, over 1800 chemicals have been tested in up to 600 assays, yielding a large number of concentration-response data sets. Standard processing of these data sets involves finding a best fitting mathematical model and set of model parameters that specify this model. The model parameters include quantities such as the half-maximal activity concentration (or “AC50”) that have biological significance and can be used to inform the efficacy or potency of a given chemical with respect to a given assay. All of this data is processed and stored in an online-accessible database and website: http://actor.epa.gov/dashboard2. Results from these in vitro assays are used in a multitude of ways. New pathways and targets can be identified and incorporated into new or existing adverse outcome pathways (AOPs). Pharmacokinetic models such as those implemented EPA’s HTTK R package can be used to translate an in vitro concentration into an in vivo dose; i.e., one can predict the oral equivalent dose that might be expected to activate a specific biological pathway. Such predicted values can then be compared with estimated actual human exposures prioritize chemicals for further testing.Any quantitative examination should be accompanied by estimation of uncertainty. We are developing met

  10. Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.

    PubMed

    Cornaglia, Matteo; Trouillon, Raphaël; Tekin, H Cumhur; Lehnert, Thomas; Gijs, Martin A M

    2015-09-25

    Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8μm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0μm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose-response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non-linear dose response curves.

  11. Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

    NASA Technical Reports Server (NTRS)

    Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

    1999-01-01

    To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

  12. Patients who do not respond to the "usual" dose: why Terry fell off the dose-response curve.

    PubMed

    Preskorn, Sheldon H

    2009-11-01

    Clinical trials are aimed at determining what happens in the "usual" patient; however, clinicians are interested in what happens in their patients even if they are not usual. The usual dose-response relationship is determined as part of the drug development process required for approval of a new drug. However, clinicians are likely to encounter patients who "fall off" the usual dose-response curve because they are either sensitive or resistant to the beneficial (efficacy) or adverse effects of a drug. This column is the first in a series that will examine why specific patients fall off the usual dose-response curve and how clinicians can manage such patients when they encounter them. This column discusses what a dose-response curve is, how it is determined, and why it is clinically important.

  13. Dose-response curve estimation: a semiparametric mixture approach.

    PubMed

    Yuan, Ying; Yin, Guosheng

    2011-12-01

    In the estimation of a dose-response curve, parametric models are straightforward and efficient but subject to model misspecifications; nonparametric methods are robust but less efficient. As a compromise, we propose a semiparametric approach that combines the advantages of parametric and nonparametric curve estimates. In a mixture form, our estimator takes a weighted average of the parametric and nonparametric curve estimates, in which a higher weight is assigned to the estimate with a better model fit. When the parametric model assumption holds, the semiparametric curve estimate converges to the parametric estimate and thus achieves high efficiency; when the parametric model is misspecified, the semiparametric estimate converges to the nonparametric estimate and remains consistent. We also consider an adaptive weighting scheme to allow the weight to vary according to the local fit of the models. We conduct extensive simulation studies to investigate the performance of the proposed methods and illustrate them with two real examples.

  14. Fewer doses of HPV vaccine result in immune response similar to three-dose regimen

    Cancer.gov

    NCI scientists report that two doses of a human papillomavirus (HPV) vaccine, trademarked as Cervarix, resulted in similar serum antibody levels against two of the most carcinogenic types of HPV (16 and 18), compared to a standard three dose regimen.

  15. Absorbed dose distribution for X-ray beams and beams of electrons from the Therac 10 Neptune linear accelerator.

    PubMed

    Tronc, D; Gayet, P

    1980-02-01

    After a brief presentation of the Therac 10 Neptune linear accelerator a complete set of dose distribution numerical values is given. These values define the depths on the axis as a function of the depth dose and define the penumbra (as characterized by the positions of the isodose curve intersections with parallel planes to the phantom surface) for beams of X-rays and for beams of electrons. Measurements of residual X-rays are given for a 10 MeV beam of electrons.

  16. The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

    PubMed

    Simon, Ted W; Simons, S Stoney; Preston, R Julian; Boobis, Alan R; Cohen, Samuel M; Doerrer, Nancy G; Fenner-Crisp, Penelope A; McMullin, Tami S; McQueen, Charlene A; Rowlands, J Craig

    2014-08-01

    The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.

  17. GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS

    EPA Science Inventory

    ABSTRACT In 2003, the International Union of Pure and Applied chemistry (IUPAC) issued a glossary of terms that included the defi nition of dose-effect and doseresponse relationships (Nordberg et al., 2004). Dose effect relationship is defined as an association between dose and...

  18. Process Setting through General Linear Model and Response Surface Method

    NASA Astrophysics Data System (ADS)

    Senjuntichai, Angsumalin

    2010-10-01

    The objective of this study is to improve the efficiency of the flow-wrap packaging process in soap industry through the reduction of defectives. At the 95% confidence level, with the regression analysis, the sealing temperature, temperatures of upper and lower crimper are found to be the significant factors for the flow-wrap process with respect to the number/percentage of defectives. Twenty seven experiments have been designed and performed according to three levels of each controllable factor. With the general linear model (GLM), the suggested values for the sealing temperature, temperatures of upper and lower crimpers are 185, 85 and 85° C, respectively while the response surface method (RSM) provides the optimal process conditions at 186, 89 and 88° C. Due to different assumptions between percentage of defective and all three temperature parameters, the suggested conditions from the two methods are then slightly different. Fortunately, the estimated percentage of defectives at 5.51% under GLM process condition and the predicted percentage of defectives at 4.62% under RSM process condition are not significant different. But at 95% confidence level, the percentage of defectives under RSM condition can be much lower approximately 2.16% than those under GLM condition in accordance with wider variation. Lastly, the percentages of defectives under the conditions suggested by GLM and RSM are reduced by 55.81% and 62.95%, respectively.

  19. Linear response formula for piecewise expanding unimodal maps

    NASA Astrophysics Data System (ADS)

    Baladi, Viviane; Smania, Daniel

    2008-04-01

    The average R(t)=\\int \\varphi\\,\\rmd \\mu_t of a smooth function phiv with respect to the SRB measure μt of a smooth one-parameter family ft of piecewise expanding interval maps is not always Lipschitz (Baladi 2007 Commun. Math. Phys. 275 839-59, Mazzolena 2007 Master's Thesis Rome 2, Tor Vergata). We prove that if ft is tangent to the topological class of f, and if ∂t ft|t = 0 = X circle f, then R(t) is differentiable at zero, and R'(0) coincides with the resummation proposed (Baladi 2007) of the (a priori divergent) series \\sum_{n=0}^\\infty \\int X(y) \\partial_y (\\varphi \\circ f^n)(y)\\,\\rmd \\mu_0(y) given by Ruelle's conjecture. In fact, we show that t map μt is differentiable within Radon measures. Linear response is violated if and only if ft is transversal to the topological class of f.

  20. A noble refractive optical scanner with linear response

    NASA Astrophysics Data System (ADS)

    Mega, Yair J.; Lai, Zhenhua; DiMarzio, Charles A.

    2013-03-01

    Many applications in various fields of science and engineering use steered optical beam systems. Currently, many methods utilize mirrors in order to steer the beam. However, this approach is an off-axis solution, which normally increases the total size of the system as well as its error and complexity. Other methods use a "Risely Prisms" based solution, which is on-axis solution, however it poses some difficulties from an engineering standpoint, and therefore isn't widely used. We present here a novel technique for steering a beam on its optical axis with a linear deflection response. We derived the formulation for the profile required of the refractive optical component necessary for preforming the beam steering. The functionality of the device was simulated analytically using Matlab, as well as using a ray-tracing software, Zemax, and showed agreement with the analytical model. An optical element was manufactured based on the proposed design and the device was tested. The results show agreement with our hypothesis. We also present some proposed geometries of the several other devices, all based on the same concept, which can be used for higher performance applications such as two-dimensional scanner, video rate scanner etc.

  1. Biologically Based Dose-Response Modeling. What is the potential for accurate description of the biological linkages in the applied dose - tissue dose-health effect continuum?

    EPA Science Inventory

    Given knowledge of exposure, the shape of the dose response curve is the key to predicting health risk, which in turn determines allowable levels of exposure and the associated economic costs of compliance.

  2. Coffee and tea consumption and risk of lung cancer: a dose-response analysis of observational studies.

    PubMed

    Wang, Yaopeng; Yu, Xuyi; Wu, Yili; Zhang, Dongfeng

    2012-11-01

    Results from the recent meta-analysis suggested a favorable effect of green tea consumption and risk of lung cancer, while no significant association was found between black tea consumption and risk of lung cancer. Besides, a significantly positive association was found between coffee consumption and risk of lung cancer. However, the relationship of green tea and coffee consumption is unclear. Thus the dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. Results suggested that a linear dose-response relationship exists between coffee consumption and risk of lung cancer, while the dose-response relationship is nonlinear between green tea consumption and risk of lung cancer.

  3. The effect of field modifier blocks on the fast photoneutron dose equivalent from two high-energy medical linear accelerators.

    PubMed

    Hashemi, Seyed Mehdi; Hashemi-Malayeri, Bijan; Raisali, Gholamreza; Shokrani, Parvaneh; Sharafi, Ali Akbar; Jafarizadeh, Mansour

    2008-01-01

    High-energy linear accelerators (linacs) have several advantages, including low skin doses and high dose rates at deep-seated tumours. But, at energies more than 8 MeV, photonuclear reactions produce neutron contamination around the therapeutic beam, which may induce secondary malignancies. In spite of improvements achieved in medical linac designs, many countries still use conventional (non-intensity-modulated radiotherapy) linacs. Hence, in these conventional machines, fitting the beam over the treatment volume may require using blocks. Therefore, the effect of these devices on neutron production of linacs needs to be studied. The aim of this study was to investigate the effect of field shaping blocks on photoneutron dose in the treatment plane for two high-energy medical linacs. Two medical linacs, a Saturn 43 (25 MeV) and an Elekta SL 75/25 (18 MeV), were studied. Polycarbonate (PC) films were used to measure the fluence of photoneutrons produced by these linacs. After electrochemical etching of the PC films, the neutron dose equivalent was calculated at the isocentre and 50 cm away from the isocentre. It was noted that by increasing the distance from the centre of the X-ray beam towards the periphery, the photoneutron dose equivalent decreases rapidly for both the open and blocked fields. Increasing the energy of the photons causes an increase in the amount of photoneutron dose equivalent. At 25 MeV photon energy, the lead blocks cause a meaningful increase in the dose equivalent of photoneutrons. In this research, a 30% increase was seen in neutron dose contribution to central axis dose at the isocentre of a 25 MeV irregular field shaped by lead blocks. It is concluded that lead blocks must be considered as a source of photoneutron production when treating irregular fields with high-energy photons.

  4. Biologically Effective Dose-Response Relationship for Breast Cancer Treated by Conservative Surgery and Postoperative Radiotherapy

    SciTech Connect

    Plataniotis, George A. Dale, Roger G.

    2009-10-01

    Purpose: To find a biologically effective dose (BED) response for adjuvant breast radiotherapy (RT) for initial-stage breast cancer. Methods and Materials: Results of randomized trials of RT vs. non-RT were reviewed and the tumor control probability (TCP) after RT was calculated for each of them. Using the linear-quadratic formula and Poisson statistics of cell-kill, the average initial number of clonogens per tumor before RT and the average tumor cell radiosensitivity (alpha-value) were calculated. An {alpha}/{beta} ratio of 4 Gy was assumed for these calculations. Results: A linear regression equation linking BED to TCP was derived: -ln[-ln(TCP)] = -ln(No) + {alpha}{sup *} BED = -4.08 + 0.07 * BED, suggesting a rather low radiosensitivity of breast cancer cells (alpha = 0.07 Gy{sup -1}), which probably reflects population heterogeneity. From the linear relationship a sigmoid BED-response curve was constructed. Conclusion: For BED values higher than about 90 Gy{sub 4} the radiation-induced TCP is essentially maximizing at 90-100%. The relationship presented here could be an approximate guide in the design and reporting of clinical trials of adjuvant breast RT.

  5. Dose-responses from multi-model inference for the non-cancer disease mortality of atomic bomb survivors.

    PubMed

    Schöllnberger, H; Kaiser, J C; Jacob, P; Walsh, L

    2012-05-01

    The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates.

  6. Ozone as U-Shaped Dose Responses Molecules (Hormetins)

    PubMed Central

    Martínez- Sánchez, G.; Pérez-Davison, G.; Re, L.; Giuliani, A.

    2010-01-01

    Redox environment involves a broad network of pro-oxidant and antioxidant components. Health benefit or damage can be induced as a consequence of an adaptive cellular stress response. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of an increased defense capacity and a reduced load of damaged macromolecules. Ozone, when used at appropriate doses, promotes the formation of reactive oxygen species and lipid peroxides allows them to become late and long-lasting messengers. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The paradoxical concept that ozone eventually induces an antioxidant response capable of reversing a chronic oxidative stress is common in the animal and vegetal kingdom; it is already supported by findings of an increased level of antioxidant enzymes during ozone therapy. Those facts can include ozone as a hormetin. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in redox-related disease research and intervention; ozone therapy can be a good candidate. PMID:21431076

  7. Ozone as u-shaped dose responses molecules (hormetins).

    PubMed

    Martínez-Sánchez, G; Pérez-Davison, G; Re, L; Giuliani, A

    2010-05-10

    Redox environment involves a broad network of pro-oxidant and antioxidant components. Health benefit or damage can be induced as a consequence of an adaptive cellular stress response. A consequence of hormetic amplification is an increase in the homeodynamic space of a living system in terms of an increased defense capacity and a reduced load of damaged macromolecules. Ozone, when used at appropriate doses, promotes the formation of reactive oxygen species and lipid peroxides allows them to become late and long-lasting messengers. Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The paradoxical concept that ozone eventually induces an antioxidant response capable of reversing a chronic oxidative stress is common in the animal and vegetal kingdom; it is already supported by findings of an increased level of antioxidant enzymes during ozone therapy. Those facts can include ozone as a hormetin. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in redox-related disease research and intervention; ozone therapy can be a good candidate.

  8. Continuous Toxicological Dose-Response Relationships Are Pretty Homogeneous (Society for Risk Analysis Annual Meeting)

    EPA Science Inventory

    Dose-response relationships for a wide range of in vivo and in vitro continuous datasets are well-described by a four-parameter exponential or Hill model, based on a recent analysis of multiple historical dose-response datasets, mostly with more than five dose groups (Slob and Se...

  9. Do non-targeted effects increase or decrease low dose risk in relation to the linear-non-threshold (LNT) model?

    PubMed

    Little, M P

    2010-05-01

    In this paper we review the evidence for departure from linearity for malignant and non-malignant disease and in the light of this assess likely mechanisms, and in particular the potential role for non-targeted effects. Excess cancer risks observed in the Japanese atomic bomb survivors and in many medically and occupationally exposed groups exposed at low or moderate doses are generally statistically compatible. For most cancer sites the dose-response in these groups is compatible with linearity over the range observed. The available data on biological mechanisms do not provide general support for the idea of a low dose threshold or hormesis. This large body of evidence does not suggest, indeed is not statistically compatible with, any very large threshold in dose for cancer, or with possible hormetic effects, and there is little evidence of the sorts of non-linearity in response implied by non-DNA-targeted effects. There are also excess risks of various types of non-malignant disease in the Japanese atomic bomb survivors and in other groups. In particular, elevated risks of cardiovascular disease, respiratory disease and digestive disease are observed in the A-bomb data. In contrast with cancer, there is much less consistency in the patterns of risk between the various exposed groups; for example, radiation-associated respiratory and digestive diseases have not been seen in these other (non-A-bomb) groups. Cardiovascular risks have been seen in many exposed populations, particularly in medically exposed groups, but in contrast with cancer there is much less consistency in risk between studies: risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, a cause-and-effect interpretation of the reported

  10. Evaluation of linear array MOSFET detectors for in vivo dosimetry to measure rectal dose in HDR brachytherapy.

    PubMed

    Haughey, Aisling; Coalter, George; Mugabe, Koki

    2011-09-01

    The study aimed to assess the suitability of linear array metal oxide semiconductor field effect transistor detectors (MOSFETs) as in vivo dosimeters to measure rectal dose in high dose rate brachytherapy treatments. The MOSFET arrays were calibrated with an Ir192 source and phantom measurements were performed to check agreement with the treatment planning system. The angular dependence, linearity and constancy of the detectors were evaluated. For in vivo measurements two sites were investigated, transperineal needle implants for prostate cancer and Fletcher suites for cervical cancer. The MOSFETs were inserted into the patients' rectum in theatre inside a modified flatus tube. The patients were then CT scanned for treatment planning. Measured rectal doses during treatment were compared with point dose measurements predicted by the TPS. The MOSFETs were found to require individual calibration factors. The calibration was found to drift by approximately 1% ±0.8 per 500 mV accumulated and varies with distance from source due to energy dependence. In vivo results for prostate patients found only 33% of measured doses agreed with the TPS within ±10%. For cervix cases 42% of measured doses agreed with the TPS within ±10%, however of those not agreeing variations of up to 70% were observed. One of the most limiting factors in this study was found to be the inability to prevent the MOSFET moving internally between the time of CT and treatment. Due to the many uncertainties associated with MOSFETs including calibration drift, angular dependence and the inability to know their exact position at the time of treatment, we consider them to be unsuitable for in vivo dosimetry in rectum for HDR brachytherapy.

  11. Household physical activity and cancer risk: a systematic review and dose-response meta-analysis of epidemiological studies.

    PubMed

    Shi, Yun; Li, Tingting; Wang, Ying; Zhou, Lingling; Qin, Qin; Yin, Jieyun; Wei, Sheng; Liu, Li; Nie, Shaofa

    2015-10-07

    Controversial results of the association between household physical activity and cancer risk were reported among previous epidemiological studies. We conducted a meta-analysis to investigate the relationship of household physical activity and cancer risk quantitatively, especially in dose-response manner. PubMed, Embase, Web of science and the Cochrane Library were searched for cohort or case-control studies that examined the association between household physical activity and cancer risks. Random-effect models were conducted to estimate the summary relative risks (RRs), nonlinear or linear dose-response meta-analyses were performed to estimate the trend from the correlated log RR estimates across levels of household physical activity quantitatively. Totally, 30 studies including 41 comparisons met the inclusion criteria. Total cancer risks were reduced 16% among the people with highest household physical activity compared to those with lowest household physical activity (RR = 0.84, 95% CI = 0.76-0.93). The dose-response analyses indicated an inverse linear association between household physical activity and cancer risk. The relative risk was 0.98 (95% CI = 0.97-1.00) for per additional 10 MET-hours/week and it was 0.99 (95% CI = 0.98-0.99) for per 1 hour/week increase. These findings provide quantitative data supporting household physical activity is associated with decreased cancer risk in dose-response effect.

  12. X-ray dose response of calcite-A comprehensive analysis for optimal application in TL dosimetry

    NASA Astrophysics Data System (ADS)

    Kalita, J. M.; Wary, G.

    2016-09-01

    The effect of various annealing treatments on dosimetric characteristics of orange calcite (CaCO3) mineral has been studied in detail. Quantitative analysis on the dose response shows that the 573 K annealed sample showed sublinear dose response from 10 mGy to 1 Gy. The fading and reproducibility of this sample are also good enough for dosimetric application. However, a specific annealing treatment after irradiation shows some significant improvements in the dosimetric characteristics of the sample. The 773 K pre-annealed sample, after X-ray irradiation post-annealing at 340 K for 6 min provides linear dose response from 10 mGy to 3.60 Gy, very less fading and good reproducibility. Moreover, this sample after post-annealing at 380 K for 6 min shows linear dose response from 10 mGy to 5.40 Gy when analyzed from the ∼408 K thermoluminescence (TL) glow peak. Analysis of TL glow curves confirmed that the 1.30 eV trap center in calcite crystal is the most effective trapping site for dosimetric application.

  13. Modeling dose-dependent neural processing responses using mixed effects spline models: with application to a PET study of ethanol.

    PubMed

    Guo, Ying; Bowman, F DuBois

    2008-04-01

    For functional neuroimaging studies that involve experimental stimuli measuring dose levels, e.g. of an anesthetic agent, typical statistical techniques include correlation analysis, analysis of variance or polynomial regression models. These standard approaches have limitations: correlation analysis only provides a crude estimate of the linear relationship between dose levels and brain activity; ANOVA is designed to accommodate a few specified dose levels; polynomial regression models have limited capacity to model varying patterns of association between dose levels and measured activity across the brain. These shortcomings prompt the need to develop methods that more effectively capture dose-dependent neural processing responses. We propose a class of mixed effects spline models that analyze the dose-dependent effect using either regression or smoothing splines. Our method offers flexible accommodation of different response patterns across various brain regions, controls for potential confounding factors, and accounts for subject variability in brain function. The estimates from the mixed effects spline model can be readily incorporated into secondary analyses, for instance, targeting spatial classifications of brain regions according to their modeled response profiles. The proposed spline models are also extended to incorporate interaction effects between the dose-dependent response function and other factors. We illustrate our proposed statistical methodology using data from a PET study of the effect of ethanol on brain function. A simulation study is conducted to compare the performance of the proposed mixed effects spline models and a polynomial regression model. Results show that the proposed spline models more accurately capture varying response patterns across voxels, especially at voxels with complex response shapes. Finally, the proposed spline models can be used in more general settings as a flexible modeling tool for investigating the effects of any

  14. Bayesian designs of phase II oncology trials to select maximum effective dose assuming monotonic dose-response relationship

    PubMed Central

    2014-01-01

    Background For many molecularly targeted agents, the probability of response may be assumed to either increase or increase and then plateau in the tested dose range. Therefore, identifying the maximum effective dose, defined as the lowest dose that achieves a pre-specified target response and beyond which improvement in the response is unlikely, becomes increasingly important. Recently, a class of Bayesian designs for single-arm phase II clinical trials based on hypothesis tests and nonlocal alternative prior densities has been proposed and shown to outperform common Bayesian designs based on posterior credible intervals and common frequentist designs. We extend this and related approaches to the design of phase II oncology trials, with the goal of identifying the maximum effective dose among a small number of pre-specified doses. Methods We propose two new Bayesian designs with continuous monitoring of response rates across doses to identify the maximum effective dose, assuming monotonicity of the response rate across doses. The first design is based on Bayesian hypothesis tests. To determine whether each dose level achieves a pre-specified target response rate and whether the response rates between doses are equal, multiple statistical hypotheses are defined using nonlocal alternative prior densities. The second design is based on Bayesian model averaging and also uses nonlocal alternative priors. We conduct simulation studies to evaluate the operating characteristics of the proposed designs, and compare them with three alternative designs. Results In terms of the likelihood of drawing a correct conclusion using similar between-design average sample sizes, the performance of our proposed design based on Bayesian hypothesis tests and nonlocal alternative priors is more robust than that of the other designs. Specifically, the proposed Bayesian hypothesis test-based design has the largest probability of being the best design among all designs under comparison and

  15. A new linear array detector for high resolution and low dose digital radiography

    NASA Astrophysics Data System (ADS)

    Bettuzzi, Matteo; Cornacchia, Samantha; Rossi, Massimo; Paltrinieri, Enrica; Morigi, Maria Pia; Brancaccio, Rosa; Romani, Davide; Casali, Franco

    2004-01-01

    At the Department of Physics of the University of Bologna a new intensified linear array detector is under development. The core of the system is a digital intensified CCD camera, the electron bombarded charge coupled device (EBCCD). The main innovation is a coherent rectangular-to-linear fiber optics adapter coupling the 1 in. diameter photocathode of the camera with a linear 129 mm × 1.45 mm strip of Gd 2O 2S:Tb. In this way a high spatial resolution over an extended length is obtained. The detector works as an X-ray scanner by means of a high-precision translation mechanical device to inspect a 13 cm × 18 cm area. A complete characterisation of the system has been made in terms of linearity, dynamic range, modulation transfer function (MTF), noise power spectrum (NPS) and detective quantum efficiency (DQE). At last, radiographic tests on a set of samples have been made and will be presented.

  16. Severity of killer whale behavioral responses to ship noise: a dose-response study.

    PubMed

    Williams, Rob; Erbe, Christine; Ashe, Erin; Beerman, Amber; Smith, Jodi

    2014-02-15

    Critical habitats of at-risk populations of northeast Pacific "resident" killer whales can be heavily trafficked by large ships, with transits occurring on average once every hour in busy shipping lanes. We modeled behavioral responses of killer whales to ship transits during 35 "natural experiments" as a dose-response function of estimated received noise levels in both broadband and audiogram-weighted terms. Interpreting effects is contingent on a subjective and seemingly arbitrary decision about severity threshold indicating a response. Subtle responses were observed around broadband received levels of 130 dB re 1 μPa (rms); more severe responses are hypothesized to occur at received levels beyond 150 dB re 1 μPa, where our study lacked data. Avoidance responses are expected to carry minor energetic costs in terms of increased energy expenditure, but future research must assess the potential for reduced prey acquisition, and potential population consequences, under these noise levels.

  17. Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis

    PubMed Central

    Senthivel, Vivek Raj; Sturrock, Marc; Piedrafita, Gabriel; Isalan, Mark

    2016-01-01

    Nonlinear responses to signals are widespread natural phenomena that affect various cellular processes. Nonlinearity can be a desirable characteristic for engineering living organisms because it can lead to more switch-like responses, similar to those underlying the wiring in electronics. Steeper functions are described as ultrasensitive, and can be applied in synthetic biology by using various techniques including receptor decoys, multiple co-operative binding sites, and sequential positive feedbacks. Here, we explore the inherent non-linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering. For this, we performed genome-wide transcription profiling to identify genes with ultrasensitive response functions to Hepatocyte Growth Factor (HGF). We identified 3,527 genes that react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells, grown as cysts in 3D collagen cell culture. By fitting a generic Hill function to the dose-responses of these genes we obtained a measure of the ultrasensitivity of HGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1, SNORD75, SNORD86 and ERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling. PMID:27982133

  18. Plasma adrenocorticotropin responses to opioid blockade with naloxone: generating a dose-response curve in a single session.

    PubMed

    Mangold, D; McCaul, M E; Ali, M; Wand, G S

    2000-08-15

    We examined two methods of generating a dose-response curve to the opioid receptor antagonist naloxone. In 15 healthy male subjects (18-25 years) plasma adrenocorticotropin (ACTH) responses to five doses of naloxone studied over 5 separate days were compared to plasma ACTH responses to five incremental doses of naloxone studied within a single session. There was a statistically significant positive correlation in ACTH responses (area under the curve and peak) between dosing methods. Furthermore, the doses of naloxone that produced half-maximal and maximal ACTH response were similar. The comparability of ACTH responses between the two naloxone dosing techniques, combined with the safety and ease associated with the single-session methodology, underscores the usefulness of the single-session technique for future investigations.

  19. High-Dose Atomoxetine Treatment of ADHD in Youths with Limited Response to Standard Doses

    ERIC Educational Resources Information Center

    Kratochvil, Christopher J.; Michelson, David; Newcorn, Jeffrey H.; Weiss, Margaret D.; Busner, Joan; Moore, Rodney J.; Ruff, Dustin D.; Ramsey, Janet; Dickson, Ruth; Turgay, Atilla; Saylor, Keith E.; Luber, Stephen; Vaughan, Brigette; Allen, Albert J.

    2007-01-01

    Objective: To assess the utility and tolerability of higher than standard atomoxetine doses to treat attention-deficit/hyperactivity disorder (ADHD). Method: Two randomized, double-blind trials of atomoxetine nonresponders ages 6 to 16 years were conducted comparing continued treatment with same-dose atomoxetine to treatment using greater than…

  20. Comparison of linear and nonlinear programming approaches for "worst case dose" and "minmax" robust optimization of intensity-modulated proton therapy dose distributions.

    PubMed

    Zaghian, Maryam; Cao, Wenhua; Liu, Wei; Kardar, Laleh; Randeniya, Sharmalee; Mohan, Radhe; Lim, Gino

    2017-03-01

    Robust optimization of intensity-modulated proton therapy (IMPT) takes uncertainties into account during spot weight optimization and leads to dose distributions that are resilient to uncertainties. Previous studies demonstrated benefits of linear programming (LP) for IMPT in terms of delivery efficiency by considerably reducing the number of spots required for the same quality of plans. However, a reduction in the number of spots may lead to loss of robustness. The purpose of this study was to evaluate and compare the performance in terms of plan quality and robustness of two robust optimization approaches using LP and nonlinear programming (NLP) models. The so-called "worst case dose" and "minmax" robust optimization approaches and conventional planning target volume (PTV)-based optimization approach were applied to designing IMPT plans for five patients: two with prostate cancer, one with skull-based cancer, and two with head and neck cancer. For each approach, both LP and NLP models were used. Thus, for each case, six sets of IMPT plans were generated and assessed: LP-PTV-based, NLP-PTV-based, LP-worst case dose, NLP-worst case dose, LP-minmax, and NLP-minmax. The four robust optimization methods behaved differently from patient to patient, and no method emerged as superior to the others in terms of nominal plan quality and robustness against uncertainties. The plans generated using LP-based robust optimization were more robust regarding patient setup and range uncertainties than were those generated using NLP-based robust optimization for the prostate cancer patients. However, the robustness of plans generated using NLP-based methods was superior for the skull-based and head and neck cancer patients. Overall, LP-based methods were suitable for the less challenging cancer cases in which all uncertainty scenarios were able to satisfy tight dose constraints, while NLP performed better in more difficult cases in which most uncertainty scenarios were hard to meet

  1. The peripheral vascular effects of diltiazem--dose-response characteristics.

    PubMed Central

    Finch, M B; Johnston, G D

    1985-01-01

    The acute effects of increasing doses of diltiazem on peripheral blood flow were observed in six subjects. Each subject received, in random order, a single oral dose of placebo or diltiazem 60, 120 or 180 mg. Supine heart rate, blood pressure, skin temperature, digital systolic pressure, forearm and digital blood flow were recorded before and at 1, 2, 3, 4 and 6 h post-dosing. Plasma diltiazem concentrations were measured at each time interval and at 12 and 24 h after the 120 mg dose. At doses of 120 and 180 mg, diltiazem significantly increased digital blood flow at 1, 2, 3, 4 and 6 h post-dosing and forearm blood flow at 2 and 3 h following 180 mg and 3 h following 120 mg. No correlation was observed between plasma diltiazem concentration and changes in peripheral blood flow. PMID:4074614

  2. Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids

    PubMed Central

    Laine, Kari; Anttila, Markku; Helminen, Antti; Karnani, Hari; Huupponen, Risto

    1999-01-01

    Aims The purpose of this study was to characterize the dose relationship of selegiline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg. Methods Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four-period randomized study. Concentrations of selegiline and desmethylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication. Results The total AUC and Cmax of selegiline were 10-to 20-fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5-fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several-fold lower in the group receiving oral steroids compared with the no-concomitant-medication group (P<0.005 at all the four dose levels). Conclusions Concomitant use of oral contraceptives caused a drastic (20-fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced N-demethylation of selegiline. The present results suggest

  3. TH-E-BRE-02: A Forward Scattering Approximation to Dose Calculation Using the Linear Boltzmann Transport Equation

    SciTech Connect

    Catt, B; Snyder, M

    2014-06-15

    Purpose: To investigate the use of the linear Boltzmann transport equation as a dose calculation tool which can account for interface effects, while still having faster computation times than Monte Carlo methods. In particular, we introduce a forward scattering approximation, in hopes of improving calculation time without a significant hindrance to accuracy. Methods: Two coupled Boltzmann transport equations were constructed, one representing the fluence of photons within the medium, and the other, the fluence of electrons. We neglect the scattering term within the electron transport equation, resulting in an extreme forward scattering approximation to reduce computational complexity. These equations were then solved using a numerical technique for solving partial differential equations, known as a finite difference scheme, where the fluence at each discrete point in space is calculated based on the fluence at the previous point in the particle's path. Using this scheme, it is possible to develop a solution to the Boltzmann transport equations by beginning with boundary conditions and iterating across the entire medium. The fluence of electrons can then be used to find the dose at any point within the medium. Results: Comparisons with Monte Carlo simulations indicate that even simplistic techniques for solving the linear Boltzmann transport equation yield expected interface effects, which many popular dose calculation algorithms are not capable of predicting. Implementation of a forward scattering approximation does not appear to drastically reduce the accuracy of this algorithm. Conclusion: Optimized implementations of this algorithm have been shown to be very accurate when compared with Monte Carlo simulations, even in build up regions where many models fail. Use of a forward scattering approximation could potentially give a reasonably accurate dose distribution in a shorter amount of time for situations where a completely accurate dose distribution is not

  4. Statistical methods for clinical verification of dose response parameters related to esophageal stricture and AVM obliteration from radiotherapy

    NASA Astrophysics Data System (ADS)

    Mavroidis, Panayiotis; Lind, Bengt K.; Theodorou, Kyriaki; Laurell, Göran; Fernberg, Jan-Olof; Lefkopoulos, Dimitrios; Kappas, Constantin; Brahme, Anders

    2004-08-01

    The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and khgr2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.

  5. Dose response characteristics of special opti-chromic waveguides

    NASA Astrophysics Data System (ADS)

    Humprerys, K. C.; Kantz, A. D.

    In 1981 Kronenberg, McLaughlin, and Siebentritt proposed measurement of radiation dosage using optical waveguides with leuco dye solutions. Based on this work, an opti-chromic system was proposed at the Fourth International Meeting on Radiation Processing. This opti-chromic system has been evaluated by McLaughlin and Radak. The opti-chromic waveguide system may be even more valuable for other applications which involve measurements with special requirements and configurations. The linearity of the radiation response can be enhanced by proper selection of leuco dye concentration, waveguide materials, organic activator solvents, and trace chemical additives. This paper presents experimental data resulting from an examination of the organic solvents TEP, DMSO, and n-propyl alcohol in relationship to stability, temperature characteristics, and radiation chemistry. The experimental data indicates that by varying the types and combinations of organic solvents, special opti-chromic waveguides can be fabricated to measure various radiation ranges under a variety of temperature ranges which have stability over time.

  6. Predicting nonlinear properties of metamaterials from the linear response.

    PubMed

    O'Brien, Kevin; Suchowski, Haim; Rho, Junsuk; Salandrino, Alessandro; Kante, Boubacar; Yin, Xiaobo; Zhang, Xiang

    2015-04-01

    The discovery of optical second harmonic generation in 1961 started modern nonlinear optics. Soon after, R. C. Miller found empirically that the nonlinear susceptibility could be predicted from the linear susceptibilities. This important relation, known as Miller's Rule, allows a rapid determination of nonlinear susceptibilities from linear properties. In recent years, metamaterials, artificial materials that exhibit intriguing linear optical properties not found in natural materials, have shown novel nonlinear properties such as phase-mismatch-free nonlinear generation, new quasi-phase matching capabilities and large nonlinear susceptibilities. However, the understanding of nonlinear metamaterials is still in its infancy, with no general conclusion on the relationship between linear and nonlinear properties. The key question is then whether one can determine the nonlinear behaviour of these artificial materials from their exotic linear behaviour. Here, we show that the nonlinear oscillator model does not apply in general to nonlinear metamaterials. We show, instead, that it is possible to predict the relative nonlinear susceptibility of large classes of metamaterials using a more comprehensive nonlinear scattering theory, which allows efficient design of metamaterials with strong nonlinearity for important applications such as coherent Raman sensing, entangled photon generation and frequency conversion.

  7. Shape and Steepness of Toxicological Dose-Response Relationships of Continuous Endpoints

    EPA Science Inventory

    A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters both adequately describe toxicological dose-responses. The four parameters relate to the background response, the potency o...

  8. Emesis in Ferrets Following Exposure to Different Types of Radiation: A Dose-Response Study

    DTIC Science & Technology

    1992-08-01

    SR92-34 Emesis in Ferrets Following Exposure to Different Types of Radiation: N A Dose -Response Study L51 BERNARD M. RABIN, Ph.D., WALTER A. HUNT...fission neutrons (1500-2000 following exposure to different types o" radiation: a dose -response cGy), Young (13) reported that increasing the propor...order to establish the dose -response relationships monkey, but did not produce an increase in the total for emesis following exposure to different types

  9. Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses.

    PubMed

    Tomita, Masanori; Maeda, Munetoshi

    2015-03-01

    Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect.

  10. Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses

    PubMed Central

    Tomita, Masanori; Maeda, Munetoshi

    2015-01-01

    Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

  11. 3'-deoxy-3'-[{sup 18}F]fluorothymidine PET Quantification of Bone Marrow Response to Radiation Dose

    SciTech Connect

    McGuire, Sarah M.; Menda, Yusuf; Boles Ponto, Laura L.; Gross, Brandie; Buatti, John; Bayouth, John E.

    2011-11-01

    Purpose: The purpose of this study was to quantify the relationship of bone marrow response to radiation dose, using 3'-deoxy-3'-[{sup 18}F]fluorothymidine ([{sup 18}F]FLT)-labeled uptake quantified in positron-emission tomography (PET) scans. Methods and Materials: Pre- and post-Week 1 treatment [{sup 18}F]FLT PET images were registered to the CT images used to create the radiation treatment plan. Changes in [{sup 18}F]FLT uptake values were measured using profile data of standardized uptake values (SUVs) and doses along the vertebral bodies located at a field border where a range of radiation doses were present for 10 patients. Data from the profile measurements were grouped into 1 Gy dose bins from 1 to 9 Gy to compare SUV changes for all patients. Additionally, the maximum pretreatment, the post-Week 1 treatment, and the dose values located within the C6-T7 vertebrae that straddled the field edge were measured for all patients. Results: Both the profile and the individual vertebral data showed a strong correlation between SUV change and radiation dose. Relative differences in SUVs between bins >1 Gy and <7 Gy were statistically significant (p < 0.01, two-sample t test). The reduction in SUV was approximately linear until it reached a reduction threshold of 75%-80% in SUV for doses greater than 6 Gy/week for both the dose-binned data and the vertebral maximum SUVs. Conclusions: The change in SUV observed in head and neck cancer patients treated with chemoradiation shows the potential for using [{sup 18}F]FLT PET images for identifying active bone marrow and monitoring changes due to radiation dose. Additionally, the change in [{sup 18}F]FLT uptake observed in bone marrow for different weekly doses suggests potential dose thresholds for reducing bone marrow toxicity.

  12. Dose-response Relationships between Mouse Allergen Exposure and Asthma Morbidity Among Urban Children and Adolescents

    PubMed Central

    Torjusen, Erika N.; Diette, Gregory B.; Breysse, Patrick N.; Curtin-Brosnan, Jean; Aloe, Charles; Matsui, Elizabeth C.

    2012-01-01

    Home mouse allergen exposure is associated with asthma morbidity, but little is known about the shape of the dose-response relationship or the relevance of location of exposure within the home. Asthma outcome and allergen exposure data were collected every three months for 1 year in 150 urban children with asthma. Participants were stratified by mouse sensitization and relationships between continuous measures of mouse allergen exposure and outcomes of interest were analyzed. Every ten-fold increase in the bed mouse allergen level was associated with an 87% increase in the odds of any asthma-related health care use among mouse sensitized (OR (95% CI): 1.87 (1.21–2.88)), but not non-mouse sensitized participants. Similar relationships were observed for emergency department visit and unscheduled doctor visit among mouse sensitized participants. Kitchen floor and bedroom air mouse allergen concentrations were also associated with greater odds of asthma-related healthcare utilization; however, the magnitude of the association was less than that observed for bed mouse allergen concentrations. In this population of urban children with asthma, there is a linear dose-response relationship between mouse allergen concentrations and asthma morbidity among mouse-sensitized asthmatics. Bed and bedroom air mouse allergen exposure compartments may have a greater impact on asthma morbidity than other compartments. PMID:23067271

  13. Dose-response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: Results of a workshop.

    PubMed

    Andersen, Melvin E; Preston, R Julian; Maier, Andrew; Willis, Alison M; Patterson, Jacqueline

    2014-01-01

    A public workshop, organized by a Steering Committee of scientists from government, industry, universities and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose-response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of sub-threshold doses for a number of receptor-mediated MOAs. The workshop explored the development of dose-response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance Framework (HRF). Case studies addressed activation of the AHR, the CAR and the PPARα. This article describes the workshop process, key issues discussed and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose-response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the MOA, and similar data gaps in early steps. Three additional papers in this series describe the results and conclusions for each case-study receptor regarding its MOA, relevance of the MOA to humans and the resulting dose-response implications.

  14. Mass shootings: a meta-analysis of the dose-response relationship.

    PubMed

    Wilson, Laura C

    2014-12-01

    A meta-analysis was conducted to examine the dose-response theory as it relates to posttraumatic stress symptoms (PTSSs) following mass shootings. It was hypothesized that greater exposure to a mass shooting would be associated with greater PTSSs. Trauma exposure in the current study was broadly defined as the extent to which a person experienced or learned about a mass shooting. The meta-analysis identified 11 qualifying studies that included 13 independent effect sizes from a total of 8,047 participants. The overall weighted mean effect size, based on a random effects model, was r = .19, p < .001, 95% CI [.13, .25]. Maximum likelihood meta-regressions revealed no significant linear effects of participant gender, participant age, or time elapsed since the shooting on the relationship between exposure and PTSSs. Because so few studies satisfied the inclusion criteria, the present study also documents that this area of the literature is underresearched.

  15. Coffee consumption and risk of colorectal cancer: a dose-response analysis of observational studies.

    PubMed

    Tian, Changwei; Wang, Wenming; Hong, Zhiqiang; Zhang, Xingliang

    2013-06-01

    Coffee consumption has been linked to risk of colorectal cancer theoretically, but the findings were conflicting from observational studies. Results from the recent meta-analysis suggested a moderate favorable effect of coffee consumption on colorectal cancer risk, especially for colon cancer. However, the relationship, if exists, between coffee consumption and colorectal cancer risk is unclear. Thus, the dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. The results suggested that a significant association was found between coffee consumption and decreased risk of colorectal and colon cancer among subjects consuming ≥4 cups of coffee per day. A potential nonlinear relationship should be assessed before assuming a linear relationship.

  16. A latent pharmacokinetic time profile to model dose-response survival data.

    PubMed

    Jacobs, Tom; Straetemans, Roel; Molenberghs, Geert; Adriaan Bouwknecht, J; Bijnens, Luc

    2010-07-01

    The accelerating rotarod test is a preclinical pharmacodynamic test to assess the effect of a treatment on an animal's motor coordination. Two models are proposed to analyze the dose-response time-to-event data that typically result from such experiments: (1) a linear regression model and (2) an E(max) model with latent drug concentration at the site of action. Both cope with the survival character of the data. The latter model allows a direct comparison of compounds, but raises the question of whether the study design would benefit from the inclusion of additional mice for plasma concentration sampling on the one hand or whether additional time-to-event data without plasma concentration sampling should be ascertained from these additional mice on the other hand. A simulation study explores the impact on operational characteristics of this change of study design.

  17. Development and characterization of an interferometer for calorimeter-based absorbed dose to water measurements in a medical linear accelerator

    NASA Astrophysics Data System (ADS)

    Flores-Martinez, Everardo; Malin, Martha J.; DeWerd, Larry A.

    2016-11-01

    The quantity of relevance for external beam radiotherapy is absorbed dose to water (ADW). An interferometer was built, characterized, and tested to measure ADW within the dose range of interest for external beam radiotherapy using the temperature dependence of the refractive index of water. The interferometer was used to measure radiation-induced phase shifts of a laser beam passing through a (10 × 10 × 10) cm3 water-filled glass phantom, irradiated with a 6 MV photon beam from a medical linear accelerator. The field size was (7 × 7) cm2 and the dose was measured at a depth of 5 cm in the water phantom. The intensity of the interference pattern was measured with a photodiode and was used to calculate the time-dependent phase shift curve. The system was thermally insulated to achieve temperature drifts of less than 1.5 mK/min. Data were acquired 60 s before and after the irradiation. The radiation-induced phase shifts were calculated by taking the difference in the pre- and post-irradiation drifts extrapolated to the midpoint of the irradiation. For 200, 300, and 400 monitor units, the measured doses were 1.6 ± 0.3, 2.6 ± 0.3, and 3.1 ± 0.3 Gy, respectively. Measurements agreed within the uncertainty with dose calculations performed with a treatment planning system. The estimated type-A, k = 1 uncertainty in the measured doses was 0.3 Gy which is an order of magnitude lower than previously published interferometer-based ADW measurements.

  18. Development and characterization of an interferometer for calorimeter-based absorbed dose to water measurements in a medical linear accelerator.

    PubMed

    Flores-Martinez, Everardo; Malin, Martha J; DeWerd, Larry A

    2016-11-01

    The quantity of relevance for external beam radiotherapy is absorbed dose to water (ADW). An interferometer was built, characterized, and tested to measure ADW within the dose range of interest for external beam radiotherapy using the temperature dependence of the refractive index of water. The interferometer was used to measure radiation-induced phase shifts of a laser beam passing through a (10 × 10 × 10) cm(3) water-filled glass phantom, irradiated with a 6 MV photon beam from a medical linear accelerator. The field size was (7 × 7) cm(2) and the dose was measured at a depth of 5 cm in the water phantom. The intensity of the interference pattern was measured with a photodiode and was used to calculate the time-dependent phase shift curve. The system was thermally insulated to achieve temperature drifts of less than 1.5 mK/min. Data were acquired 60 s before and after the irradiation. The radiation-induced phase shifts were calculated by taking the difference in the pre- and post-irradiation drifts extrapolated to the midpoint of the irradiation. For 200, 300, and 400 monitor units, the measured doses were 1.6 ± 0.3, 2.6 ± 0.3, and 3.1 ± 0.3 Gy, respectively. Measurements agreed within the uncertainty with dose calculations performed with a treatment planning system. The estimated type-A, k = 1 uncertainty in the measured doses was 0.3 Gy which is an order of magnitude lower than previously published interferometer-based ADW measurements.

  19. Sublinear response in lacZ mutant frequency of Muta™ Mouse spermatogonial stem cells after low dose subchronic exposure to N-ethyl-N-nitrosourea.

    PubMed

    O'Brien, Jason M; Walker, Mike; Sivathayalan, Ahalya; Douglas, George R; Yauk, Carole L; Marchetti, Francesco

    2015-05-01

    The transgenic rodent mutation assay was used to compare the dose-response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N-ethyl-N-nitrosourea (ENU). Muta(™) Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28-day subchronic exposures. LacZ MF was measured in sperm collected 70 days post-exposure to target spermatogonial stem cells. Dose-response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose-dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose-response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28-day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose-response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens.

  20. Chronic periodontitis and smoking Prevalence and dose-response relationship

    PubMed Central

    Khan, Shahrukh; Khalid, Taimur; Awan, Kamran H.

    2016-01-01

    Objectives: To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan. Methods: This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (±6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (>5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables. Results: Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p<0.007), male gender (p<0.001), and lower education level (p<0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p<0.001) and severity (p<0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p<0.001). Conclusion: Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis. PMID:27464867

  1. Linear Energy Transfer Painting With Proton Therapy: A Means of Reducing Radiation Doses With Equivalent Clinical Effectiveness

    SciTech Connect

    Fager, Marcus; Toma-Dasu, Iuliana; Kirk, Maura; Dolney, Derek; Diffenderfer, Eric S.; Vapiwala, Neha; Carabe, Alejandro

    2015-04-01

    Purpose: The purpose of this study was to propose a proton treatment planning method that trades physical dose (D) for dose-averaged linear energy transfer (LET{sub d}) while keeping the radiobiologically weighted dose (D{sub RBE}) to the target the same. Methods and Materials: The target is painted with LET{sub d} by using 2, 4, and 7 fields aimed at the proximal segment of the target (split target planning [STP]). As the LET{sub d} within the target increases with increasing number of fields, D decreases to maintain the D{sub RBE} the same as the conventional treatment planning method by using beams treating the full target (full target planning [FTP]). Results: The LET{sub d} increased 61% for 2-field STP (2STP) compared to FTP, 72% for 4STP, and 82% for 7STP inside the target. This increase in LET{sub d} led to a decrease of D with 5.3 ± 0.6 Gy for 2STP, 4.4 ± 0.7 Gy for 4STP, and 5.3 ± 1.1 Gy for 7STP, keeping the DRBE at 90% of the volume (DRBE, 90) constant to FTP. Conclusions: LET{sub d} painting offers a method to reduce prescribed dose at no cost to the biological effectiveness of the treatment.

  2. KINETIC SIMULATIONS OF THERMOLUMINESCENCE DOSE RESPONSE: LONG OVERDUE CONFRONTATION WITH THE EFFECTS OF IONISATION DENSITY.

    PubMed

    Horowitz, Y S; Eliyahu, I; Oster, L

    2016-12-01

    The reader will time-travel through almost seven decades of kinetic models and mathematical simulations of thermoluminescence (TL) characteristics based on the band-gap theory of the solid state. From post-World-War II, ideas concerning electron trapping mechanisms to the highly idealised one trap-one recombination (OTOR) model first elaborated in 1956 but still in 'high gear' today. The review caresses but purposely avoids in-depth discussion of the endless stream of papers discussing the intricacies of glow peak shapes arising from first-order, second-order, mixed-order and general-order kinetics predominantly based on non-interacting systems, and then on to the more physically realistic scenarios that have attempted to analyse complex systems involving ever greater numbers of interacting trapping centres, luminescent centres and non-luminescent centres. The review emphasises the difficulty the band-gap models have in the simulation of dose response linear/supralinear behaviour and especially the dependence of the supralinearity on ionisation density. The significance of the non-observation of filling-rate supralinearity in the absorption stage is emphasised since it removes from consideration the possibility of TL supralinearity arising from irradiation stage supralinearity. The importance of the simultaneous action of both localised and delocalised transitions has gradually penetrated the mindset of the community of kinetic researchers, but most simulations have concentrated on the shape of glow peaks and the extraction of the glow peak parameters, E (the thermal activation energy) and s (the attempt-to-escape frequency). The simulation of linear/supralinear dose response and its dependence on ionisation density have been largely avoided until recently due to the fundamental schism between the effects of ionisation density and some basic assumptions of the band-gap model. The review finishes with an in-depth presentation and discussion of the most recent

  3. Idiorrhythmic dose-rate variability in dietary zinc intake generates a different response pattern of zinc metabolism than conventional dose-response feeding.

    PubMed

    Momcilović, B; Reeves, P G; Blake, M J

    1997-07-01

    We compared the effects of idiorrhythmic dose-rate feeding and conventional dose-response on the induction of intestinal metallothionein (iMT), expression of aortal heat-shock protein mRNA (HSP70mRNA) induced by restraint stress, and accumulation of Zn in the femur and incisor of young growing male rats. An idiorrhythmic approach requires that the average dietary Zn concentration (modulo, M) over the whole experiment (epoch, E) is kept constant across different groups. This is done by adjusting the Zn concentration of the supplemented diet supplied to compensate for the reduction in the number of days on which Zn-supplemented diet is fed, the latter being spread evenly over the experiment. Idiorrhythms involve offering the diet with n times the overall Zn concentration (M) only every nth day with Zn-deficient diet offered on other days. Idiorrythmic Zn dose-rate feeding changed Zn accumulation in the femur and incisor in a complex bi-modal fashion, indicating that metabolic efficiency of dietary Zn is not constant but depends on Zn dose-rate. In contrast to feeding Zn in the conventional dose-response scheme, iMT and HSP70mRNA were not affected by idiorrhythmic dose-rate feeding. Idiorrhythmic cycling in dietary Zn load posed no risk of a biochemical overload nor caused the animals to be stressed. Idiorrhythmic dose-rate feeding brings the dimension of time to the conventional dose-response model.

  4. Effect of Photon Hormesis on Dose Responses to Alpha Particles in Zebrafish Embryos

    PubMed Central

    Ng, Candy Yuen Ping; Cheng, Shuk Han; Yu, Kwan Ngok

    2017-01-01

    Photon hormesis refers to the phenomenon where the biological effect of ionizing radiation with a high linear energy transfer (LET) value is diminished by photons with a low LET value. The present paper studied the effect of photon hormesis from X-rays on dose responses to alpha particles using embryos of the zebrafish (Danio rerio) as the in vivo vertebrate model. The toxicity of these ionizing radiations in the zebrafish embryos was assessed using the apoptotic counts at 20, 24, or 30 h post fertilization (hpf) revealed through acridine orange (AO) staining. For alpha-particle doses ≥ 4.4 mGy, the additional X-ray dose of 10 mGy significantly reduced the number of apoptotic cells at 24 hpf, which proved the presence of photon hormesis. Smaller alpha-particle doses might not have inflicted sufficient aggregate damages to trigger photon hormesis. The time gap T between the X-ray (10 mGy) and alpha-particle (4.4 mGy) exposures was also studied. Photon hormesis was present when T ≤ 30 min, but was absent when T = 60 min, at which time repair of damage induced by alpha particles would have completed to prevent their interactions with those induced by X-rays. Finally, the drop in the apoptotic counts at 24 hpf due to photon hormesis was explained by bringing the apoptotic events earlier to 20 hpf, which strongly supported the removal of aberrant cells through apoptosis as an underlying mechanism for photon hormesis. PMID:28208665

  5. CFORM- LINEAR CONTROL SYSTEM DESIGN AND ANALYSIS: CLOSED FORM SOLUTION AND TRANSIENT RESPONSE OF THE LINEAR DIFFERENTIAL EQUATION

    NASA Technical Reports Server (NTRS)

    Jamison, J. W.

    1994-01-01

    CFORM was developed by the Kennedy Space Center Robotics Lab to assist in linear control system design and analysis using closed form and transient response mechanisms. The program computes the closed form solution and transient response of a linear (constant coefficient) differential equation. CFORM allows a choice of three input functions: the Unit Step (a unit change in displacement); the Ramp function (step velocity); and the Parabolic function (step acceleration). It is only accurate in cases where the differential equation has distinct roots, and does not handle the case for roots at the origin (s=0). Initial conditions must be zero. Differential equations may be input to CFORM in two forms - polynomial and product of factors. In some linear control analyses, it may be more appropriate to use a related program, Linear Control System Design and Analysis (KSC-11376), which uses root locus and frequency response methods. CFORM was written in VAX FORTRAN for a VAX 11/780 under VAX VMS 4.7. It has a central memory requirement of 30K. CFORM was developed in 1987.

  6. The linear and non-linear magnetic response of a tri-uranium single molecule magnet

    NASA Astrophysics Data System (ADS)

    Shivaram, B. S.; Colineau, E.; Griveau, J.; Kumar, P.; Celli, V.

    2017-03-01

    We report here low temperature magnetization isotherms for the single molecule magnet, (UO2-L)3. By analyzing the low temperature magnetization in terms of M  =  χ 1 B  +  χ 3 B 3 we extract the linear susceptibility χ 1 and the leading order nonlinear susceptibility χ 3. We find that χ 1 exhibits a peak at a temperature of T 1  =  10.4 K with χ 3 also exhibiting a peak but at a reduced temperature T 3  =  5 K. At the lowest temperatures the isotherms exhibit a critical field B c  =  11.5 T marked by a clear point of inflection. A minimal Hamiltonian employing S  =  1 (pseudo) spins with only a single energy scale (successfully used to model the behavior of bulk f-electron metamagnets) is shown to provide a good description of the observed linear scaling between T 1, T 3 and B c. We further show that a Heisenberg Hamiltonian previously employed by Carretta et al (2013 J. Phys.: Condens. Matter 25 486001) to model this single molecule magnet gives formulas for the angle averaged susceptibilities (in the Ising limit) very similar to those of the minimal model.

  7. Effect of aspirin dose, preparation, and withdrawal on platelet response in normal volunteers.

    PubMed

    Coleman, Jacqueline L; Alberts, Mark J

    2006-09-15

    A significant difference in individual response to aspirin therapy has been described, and studies have shown that a minimal response to aspirin may be associated with increased risk for some cardiovascular events. However, it remains unclear if aspirin dose, coating, or termination alters the antiplatelet effects of aspirin. Normal volunteers were randomly assigned to enteric-coated or uncoated aspirin 81 or 325 mg and monitored over 12 days with a point-of-care aspirin assay that incorporates the platelet agonist arachidonic acid. The antiplatelet response was greater with a 325-mg dose than with an 81-mg dose. A coating slowed the antiplatelet response to the 81-mg dose only. There were no differences among the groups after maximum response was achieved between days 4 and 7. There was significant recovery of platelet aggregation <48 hours after the cessation of aspirin, with a return to baseline values by the fifth day. A significant interpatient variation in response to the 4 dosing regimes was observed. In conclusion, the antiplatelet response was more rapid to a 325-mg/day dose of aspirin compared with an 81-mg/day dose. An enteric-coated preparation delayed the time of response to an 81-mg/day dose. These results suggest that aspirin dose and preparation may be important mediators of the antiplatelet effects of aspirin in some patients.

  8. EPA’s Nonmonotonic Dose Response Curve Workplan

    EPA Pesticide Factsheets

    EPA’s standard guidelines for reproductive and developmental toxicity testing and risk assessment are needed in order to detect and characterize low-dose adverse effects of endocrine disrupting chemicals (EDCs).

  9. Response of silicon-Based Linear Energy Transfer Spectrometers

    NASA Technical Reports Server (NTRS)

    Aman, A.; Bman, B.; Badhwar, G. D.; ONeill, P. M. O.

    2000-01-01

    Silicon-based linear energy transfer (LET) telescope,(e. g., DOSTEL and RRMD) have recently been flown in space. LET spectra measured using tissue equivalent proportional counters show differences that need to be fully understood. A Monte Carlo technique based on: 1. radiation transport cluster intra-cascade model. 2. Landau-Vavilov distribution, 3. telescope geometry and detector coincidence & discriminator settings, 4. spacecraft shielding geometry, and 5. the external free space radiation environment, including recent albedo measurements, was developed.

  10. The Simplest Complete Model of Choice Response Time: Linear Ballistic Accumulation

    ERIC Educational Resources Information Center

    Brown, Scott D.; Heathcote, Andrew

    2008-01-01

    We propose a linear ballistic accumulator (LBA) model of decision making and reaction time. The LBA is simpler than other models of choice response time, with independent accumulators that race towards a common response threshold. Activity in the accumulators increases in a linear and deterministic manner. The simplicity of the model allows…

  11. Using crosscorrelation techniques to determine the impulse response of linear systems

    NASA Technical Reports Server (NTRS)

    Dallabetta, Michael J.; Li, Harry W.; Demuth, Howard B.

    1993-01-01

    A crosscorrelation method of measuring the impulse response of linear systems is presented. The technique, implementation, and limitations of this method are discussed. A simple system is designed and built using discrete components and the impulse response of a linear circuit is measured. Theoretical and software simulation results are presented.

  12. Surface and buildup dose characteristics for 6, 10, and 18 MV photons from an Elekta Precise linear accelerator.

    PubMed

    Klein, Eric E; Esthappan, Jacqueline; Li, Zuofeng

    2003-01-01

    Understanding head scatter characteristics of photon beams is vital to properly commission treatment planning (TP) algorithms. Simultaneously, having definitive surface and buildup region dosimetry is important to optimize bolus. The Elekta Precise linacs have unique beam flattening filter configurations for each photon beam (6, 10, and 18 MV) in terms of material and location. We performed a comprehensive set of surface and buildup dose measurements with a thin window parallel-plate (PP) chamber to examine effects of field size (FS), source-to-skin distance (SSD), and attenuating media. Relative ionization data were converted to fractional depth dose (FDD) after correcting for bias effects and using the Gerbi method to account for chamber characteristics. Data were compared with a similar vintage Varian linac. At short SSDs the surface and buildup dose characteristics were similar to published data for Varian and Elekta accelerators. The FDD at surface (FDD(0)) for 6, 10, and 18 MV photons was 0.171, 0.159, and 0.199, respectively, for a 15x15 cm2, 100 cm SSD field. A blocking tray increased FDD(0) to 0.200, 0.200, and 0.256, while the universal wedge decreased FDD(0) to 0.107, 0.124, and 0.176. FDD(0) increased linearly with FS (approximately 1.16%/cm). FDD(0) decreased exponentially for 10 and 18 MV with increasing SSD. However, the 6 MV FDD(0) actually increased slightly with increasing SSD. This is likely due to the unique distal flattening filter for 6 MV. The measured buildup curves have been used to optimize TP calculations and guide bolus decisions. Overall the FDD(0) and buildup doses were very similar to published data. Of interest were the relatively low 10 MV surface doses, and the 6 MV FDD(0)'s dependence on SSD.

  13. Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X-rays with different levels of hardness

    PubMed Central

    Kong, Eva Yi; Cheng, Shuk Han; Yu, Kwan Ngok

    2016-01-01

    The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead. PMID:26951078

  14. Total Dose Effects on Single Event Transients in Digital CMOS and Linear Bipolar Circuits

    NASA Technical Reports Server (NTRS)

    Buchner, S.; McMorrow, D.; Sibley, M.; Eaton, P.; Mavis, D.; Dusseau, L.; Roche, N. J-H.; Bernard, M.

    2009-01-01

    This presentation discusses the effects of ionizing radiation on single event transients (SETs) in circuits. The exposure of integrated circuits to ionizing radiation changes electrical parameters. The total ionizing dose effect is observed in both complementary metal-oxide-semiconductor (CMOS) and bipolar circuits. In bipolar circuits, transistors exhibit grain degradation, while in CMOS circuits, transistors exhibit threshold voltage shifts. Changes in electrical parameters can cause changes in single event upset(SEU)/SET rates. Depending on the effect, the rates may increase or decrease. Therefore, measures taken for SEU/SET mitigation might work at the beginning of a mission but not at the end following TID exposure. The effect of TID on SET rates should be considered if SETs cannot be tolerated.

  15. Body Mass Index and Risk of Breast Cancer: A Nonlinear Dose-Response Meta-Analysis of Prospective Studies

    PubMed Central

    Xia, Xiaoping; Chen, Wei; Li, Jiaoyuan; Chen, Xueqin; Rui, Rui; Liu, Cheng; Sun, Yu; Liu, Li; Gong, Jing; Yuan, Peng

    2014-01-01

    The role of Body Mass Index (BMI) for Breast Cancer (BC) remains to be great interest for a long time. However, the precise effect of nonlinear dose-response for BMI and BC risk is still unclear. We conducted a dose-response meta-analysis to quantitatively assess the effect of BMI on BC risk. Twelve prospective studies with 4,699 cases identified among 426,199 participants and 25 studies of 22,809 cases identified among 1,155,110 participants in premenopausal and postmenopausal groups, respectively, were included in this meta-analysis. Significant non-linear dose-response (P < 0.001) association was identified between BMI and BC risk in postmenopausal women. Individuals with BMI of 25, 30, and 35 kg/m2 yielded relative risks (RRs) of 1.02 [95% confidence interval (CI): 0.98–1.06], 1.12 (95% CI: 1.01–1.24), and 1.26 (95% CI: 1.07–1.50), respectively, when compared to the mean level of the normal BMI range. However, inverse result though not significant was observed in premenopausal women. In conclusion, the results of this meta-analysis highlighted that obesity contributed to increased BC risk in a nonlinear dose-response manner in postmenopausal women, and it is important to realize that body weight control may be a crucial process to reduce BC susceptibility. PMID:25504309

  16. Effect of intravenous fructose on the P-31 MR spectrum of the liver: dose response in healthy volunteers.

    PubMed

    Terrier, F; Vock, P; Cotting, J; Ladebeck, R; Reichen, J; Hentschel, D

    1989-05-01

    Dynamic phosphorus-31 magnetic resonance (MR) spectroscopy of the liver after intravenous administration of fructose has been suggested as a test of liver function. To establish dose-response curves of the phosphorus metabolites in the normal human liver, each of four healthy volunteers was given two to four different fructose doses on separate days: 62.5, 125, 250, 375, or 500 mg per kilogram of body weight. P-31 MR spectra of the liver were acquired with a 2-T whole-body magnetic, both before and after fructose administration, at 2.5-minute intervals over at least 30 minutes. The fructose load caused a significant, linearly dose-dependent accumulation of phosphomonoesters (r = .72, P less than .01) and a decrease in inorganic phosphate (r = .78, P less than .005) and adenosine triphosphate (r = .73, P less than .01). On the basis of these experiments, dynamic P-31 MR spectroscopy seems promising in the assessment of liver function.

  17. Linear β-1,3 Glucans Are Elicitors of Defense Responses in Tobacco

    PubMed Central

    Klarzynski, Olivier; Plesse, Bertrand; Joubert, Jean-Marie; Yvin, Jean-Claude; Kopp, Marguerite; Kloareg, Bernard; Fritig, Bernard

    2000-01-01

    Laminarin, a linear β-1,3 glucan (mean degree of polymerization of 33) was extracted and purified from the brown alga Laminaria digitata. Its elicitor activity on tobacco (Nicotiana tabacum) was compared to that of oligogalacturonides with a mean degree of polymerization of 10. The two oligosaccharides were perceived by suspension-cultured cells as distinct chemical stimuli but triggered a similar and broad spectrum of defense responses. A dose of 200 μg mL−1 laminarin or oligogalacturonides induced within a few minutes a 1.9-pH-units alkalinization of the extracellular medium and a transient release of H2O2. After a few hours, a strong stimulation of Phe ammonia-lyase, caffeic acid O-methyltransferase, and lipoxygenase activities occurred, as well as accumulation of salicylic acid. Neither of the two oligosaccharides induced tissue damage or cell death nor did they induce accumulation of the typical tobacco phytoalexin capsidiol, in contrast with the effects of the proteinaceous elicitor β-megaspermin. Structure activity studies with laminarin, laminarin oligomers, high molecular weight β-1,3–1,6 glucans from fungal cell walls, and the β-1,6–1,3 heptaglucan showed that the elicitor effects observed in tobacco with β-glucans are specific to linear β-1,3 linkages, with laminaripentaose being the smallest elicitor-active structure. In accordance with its strong stimulating effect on defense responses in tobacco cells, infiltration of 200 μg mL−1 laminarin in tobacco leaves triggered accumulation within 48 h of the four families of antimicrobial pathogenesis-related proteins investigated. Challenge of the laminarin-infiltrated leaves 5 d after treatment with the soft rot pathogen Erwinia carotovora subsp. carotovora resulted in a strong reduction of the infection when compared with water-treated leaves. PMID:11080280

  18. ENDOCRINE ACTIVE SUBSTANCES AND DOSE-RESPONSE FOR INDIVIDUALS AND POPULATIONS

    EPA Science Inventory

    Endocrine Active Substances and Dose-Response for Individuals and Populations
    Hugh A. Barton

    Abstract for IUPAC-SCOPE article

    Dose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ec...

  19. EVALUATING QUANTITATIVE FORMULAS FOR DOSE-RESPONSE ASSESSMENT OF CHEMICAL MIXTURES

    EPA Science Inventory

    Risk assessment formulas are often distinguished from dose-response models by being rough but necessary. The evaluation of these rough formulas is described here, using the example of mixture risk assessment. Two conditions make the dose-response part of mixture risk assessment d...

  20. Molecular dissection of the roles of the SOD genes in mammalian response to low dose irradiation

    SciTech Connect

    Li, Chuan-Yaun

    2009-01-27

    “Molecular dissection of the roles of the SOD genes in mammalian response to low dose irradiation " was started on 09/01/03 and ended on 08/31/07. The primary objective of the project was to carry out mechanistic studies of the roles of the anti-oxidant SOD genes in mammalian cellular response to low dose ionizing radiation.

  1. BY HOW MUCH DO SHAPES OF TOXICOLOGICAL DOSE-RESPONSE RELATIONSHIPS VARY? (SOT)

    EPA Science Inventory

    A re-analysis of a large number of historical dose-response data for continuous endpoints showed that the shapes of the dose-response relationships were surprisingly homogenous. The datasets were selected on the sole criterion that they were expected to provide relatively good in...

  2. Kalman Filter Models for Extrapolations in Dose-Response Experiments and Accelerated Life-Tests.

    DTIC Science & Technology

    1988-09-09

    Kalman-Filter models with Gaussian innovations provide a useful and easy to implement tool for inference from dose - response experiments and...proposed dose - response relationship. This is in contrast to the currently used approaches wherein there is an implicit commitment to the validity of

  3. NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

    EPA Science Inventory

    Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
    S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

    Dose-response estimation is a critical feature of risk assessment. It can be...

  4. USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

    EPA Science Inventory

    Use of Mechanistic Data to Help Define Dose-Response Curves

    The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default l...

  5. Estimation of dose-response models for discrete and continuous data in weed science

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dose-response analysis is widely used in biological sciences and has application to a variety of risk assessment, bioassay, and calibration problems. In weed science, dose-response methodologies have typically relied on least squares estimation under an assumption of normality. Advances in computati...

  6. Testing the Capacity of the National Biological Dose Response Plan (NBDRP) EX40801

    DTIC Science & Technology

    2009-11-01

    Testing the capacity of the National Biological Dose Response Plan (NBDRP) EX40801 Ruth Wilkins, James McNamee, Hillary...2. REPORT TYPE 3. DATES COVERED 4. TITLE AND SUBTITLE Testing the capacity of the National Biological Dose Response Plan (NBDRP) EX40801 5a...Report July 2009 Page 2 of 11 Testing the capacity of the NBDRP

  7. LARGE SCALE CARCINOGEN DOSE RESPONSE STUDIES WITH JAPANESE MEDAKA (ORYZIAS LATIPES)

    EPA Science Inventory

    To investigate the responses to low carcinogen doses in animal models, large sample sizes are needed and it is an advantage if the model has a low spontaneous tumor rate. Three large scale dose response studies were conducted using Japanese medaka and the carcinogen diethylnitros...

  8. Statistical strategies for averaging EC50 from multiple dose-response experiments.

    PubMed

    Jiang, Xiaoqi; Kopp-Schneider, Annette

    2015-11-01

    In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

  9. Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms.

    PubMed

    Urbain, Paul; Jakobsen, Jette

    2015-09-23

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P < 0.0001), which is equivalent to 17.6 μg (704 IU) vitamin D2 per 100 g of fresh mushrooms and comparable to levels found in fatty fish like the Atlantic salmon.

  10. [Dose-response curve in the study of the effects of exposure to crystalline silica].

    PubMed

    Di Lorenzo, L; Cassano, F

    2003-01-01

    The cumulative exposure to crystalline silica (SiO2) implies a linear relation between duration of exposure and SiO2 concentration, not always suitable to working situations of the last decades. A more correct definition of dose-response curve has currently to consider also different characteristics of SiO2, specifically: possible short-term increases in environmental SiO2 concentration, different mineralogical and surface properties of natural silica polymorphs, age of SiO2 particles, presence of contaminants on the surface of silica particles or even in the respirable fraction of total dust, respirable dust concentration in which SiO2 is diluted and other conditions, also affecting the host, able to slow alveolar clearance and lengthen permanence time of particles in the lung. Many models of definition of cumulative exposure so conceived have been proposed. However, to define the occupational risk threshold to contract silicosis and other silica-related diseases a number of models of cumulative exposure, i.e. biologically effective dose of SiO2, are likely to be delineated that take into account only factors specifically present in different occupational situations.

  11. Mechanisms of action for an anti-radiation vaccine in reducing the biological impact of high dose and dose-rate, low-linear energy transfer radiation exposure.

    PubMed

    Maliev, V; Popov, D; Casey, R C; Jones, J A

    2007-01-01

    were irradiated with doses known to induce the development of cerebral (SRD-1), non-specific toxic effects (SRD-2), gastrointestinal (SRD-3) and hematological (bone marrow) (SRD-4) syndromes. Our results suggest that an anti-radiation vaccine can be developed for prophylactic use against radiation damage induced by acute exposure to significant doses of low Linear Energy Transfer (LET) radiation for humans, including nuclear power workers, commercial and military pilots, cosmonauts/astronauts, nuclear-powered engine vessel operators and possibly even the civilian population in the case of a nuclear terrorism event.

  12. A strategy to model nonmonotonic dose-response curve and estimate IC50.

    PubMed

    Zhang, Hui; Holden-Wiltse, Jeanne; Wang, Jiong; Liang, Hua

    2013-01-01

    The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and ignore observations that may be of biologic significance. Therefore, we propose a nonparametric model to describe the dose response relationship and fit the curve using local polynomial regression. The nonparametric approach is shown to be promising especially for estimating the IC[Formula: see text] of some HIV inhibitory drugs, in which there is a dose-dependent stimulation of response for mutant strains. This model strategy may be applicable to general pharmacologic, toxicologic, or other biomedical data that exhibits a nonmonotonic dose response relationship for which traditional parametric models fail.

  13. Lead-induced anemia: Dose-response relationships and evidence for a threshold

    SciTech Connect

    Schwartz, J.; Landrigan, P.J.; Baker, E.L. Jr.; Orenstein, W.A.; von Lindern, I.H. )

    1990-02-01

    We conducted a cross-sectional epidemiologic study to assess the association between blood lead level and hematocrit in 579 one to five year-old children living near a primary lead smelter in 1974. Blood lead levels ranged from 0.53 to 7.91 mumol/L (11 to 164 micrograms/dl). To predict hematocrit as a function of blood lead level and age, we derived non-linear regression models and fit percentile curves. We used logistic regression to predict the probability of hematocrit values less than 35 per cent. We found a strong non-linear, dose-response relationship between blood lead level and hematocrit. This relationship was influenced by age, but (in this age group) not by sex; the effect was strongest in youngest children. In one year-olds, the age group most severely affected, the risk of an hematocrit value below 35 percent was 2 percent above background at blood lead levels between 0.97 and 1.88 mumol/L (20 and 39 micrograms/dl), 18 percent above background at lead levels of 1.93 to 2.85 mumol/L (40 to 59 micrograms/dl), and 40 percent above background at lead levels of 2.9 mumol/L (60 micrograms/dl) and greater; background was defined as a blood lead level below 1.88 mumol/L (20 micrograms/dl). This effect appeared independent of iron deficiency. These findings suggest that blood lead levels close to the currently recommended limit value of 1.21 mumol/L (25 micrograms/dl) are associated with dose-related depression of hematocrit in young children.

  14. Linear ubiquitination by LUBEL has a role in Drosophila heat stress response.

    PubMed

    Asaoka, Tomoko; Almagro, Jorge; Ehrhardt, Christine; Tsai, Isabella; Schleiffer, Alexander; Deszcz, Luiza; Junttila, Sini; Ringrose, Leonie; Mechtler, Karl; Kavirayani, Anoop; Gyenesei, Attila; Hofmann, Kay; Duchek, Peter; Rittinger, Katrin; Ikeda, Fumiyo

    2016-11-01

    The HOIP ubiquitin E3 ligase generates linear ubiquitin chains by forming a complex with HOIL-1L and SHARPIN in mammals. Here, we provide the first evidence of linear ubiquitination induced by a HOIP orthologue in Drosophila We identify Drosophila CG11321, which we named Linear Ubiquitin E3 ligase (LUBEL), and find that it catalyzes linear ubiquitination in vitro We detect endogenous linear ubiquitin chain-derived peptides by mass spectrometry in Drosophila Schneider 2 cells and adult flies. Furthermore, using CRISPR/Cas9 technology, we establish linear ubiquitination-defective flies by mutating residues essential for the catalytic activity of LUBEL Linear ubiquitination signals accumulate upon heat shock in flies. Interestingly, flies with LUBEL mutations display reduced survival and climbing defects upon heat shock, which is also observed upon specific LUBEL depletion in muscle. Thus, LUBEL is involved in the heat response by controlling linear ubiquitination in flies.

  15. An automated fitting procedure and software for dose-response curves with multiphasic features

    PubMed Central

    Veroli, Giovanni Y. Di; Fornari, Chiara; Goldlust, Ian; Mills, Graham; Koh, Siang Boon; Bramhall, Jo L; Richards, Frances M.; Jodrell, Duncan I.

    2015-01-01

    In cancer pharmacology (and many other areas), most dose-response curves are satisfactorily described by a classical Hill equation (i.e. 4 parameters logistical). Nevertheless, there are instances where the marked presence of more than one point of inflection, or the presence of combined agonist and antagonist effects, prevents straight-forward modelling of the data via a standard Hill equation. Here we propose a modified model and automated fitting procedure to describe dose-response curves with multiphasic features. The resulting general model enables interpreting each phase of the dose-response as an independent dose-dependent process. We developed an algorithm which automatically generates and ranks dose-response models with varying degrees of multiphasic features. The algorithm was implemented in new freely available Dr Fit software (sourceforge.net/projects/drfit/). We show how our approach is successful in describing dose-response curves with multiphasic features. Additionally, we analysed a large cancer cell viability screen involving 11650 dose-response curves. Based on our algorithm, we found that 28% of cases were better described by a multiphasic model than by the Hill model. We thus provide a robust approach to fit dose-response curves with various degrees of complexity, which, together with the provided software implementation, should enable a wide audience to easily process their own data. PMID:26424192

  16. Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

    SciTech Connect

    Howells, Christopher C.; Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.; Miften, Moyed

    2012-11-01

    Purpose: To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change ({Delta}HU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue. Results: Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, -0.65 {Delta}HU/5 Gy). The threshold for significant change (-7 {Delta}HU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated. Conclusions: SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

  17. A dose homogeneity and conformity evaluation between ViewRay and pinnacle-based linear accelerator IMRT treatment plans.

    PubMed

    Saenz, Daniel L; Paliwal, Bhudatt R; Bayouth, John E

    2014-04-01

    ViewRay, a novel technology providing soft-tissue imaging during radiotherapy is investigated for treatment planning capabilities assessing treatment plan dose homogeneity and conformity compared with linear accelerator plans. ViewRay offers both adaptive radiotherapy and image guidance. The combination of cobalt-60 (Co-60) with 0.35 Tesla magnetic resonance imaging (MRI) allows for magnetic resonance (MR)-guided intensity-modulated radiation therapy (IMRT) delivery with multiple beams. This study investigated head and neck, lung, and prostate treatment plans to understand what is possible on ViewRay to narrow focus toward sites with optimal dosimetry. The goal is not to provide a rigorous assessment of planning capabilities, but rather a first order demonstration of ViewRay planning abilities. Images, structure sets, points, and dose from treatment plans created in Pinnacle for patients in our clinic were imported into ViewRay. The same objectives were used to assess plan quality and all critical structures were treated as similarly as possible. Homogeneity index (HI), conformity index (CI), and volume receiving <20% of prescription dose (DRx) were calculated to assess the plans. The 95% confidence intervals were recorded for all measurements and presented with the associated bars in graphs. The homogeneity index (D5/D95) had a 1-5% inhomogeneity increase for head and neck, 3-8% for lung, and 4-16% for prostate. CI revealed a modest conformity increase for lung. The volume receiving 20% of the prescription dose increased 2-8% for head and neck and up to 4% for lung and prostate. Overall, for head and neck Co-60 ViewRay treatments planned with its Monte Carlo treatment planning software were comparable with 6 MV plans computed with convolution superposition algorithm on Pinnacle treatment planning system.

  18. Item Response Theory Using Hierarchical Generalized Linear Models

    ERIC Educational Resources Information Center

    Ravand, Hamdollah

    2015-01-01

    Multilevel models (MLMs) are flexible in that they can be employed to obtain item and person parameters, test for differential item functioning (DIF) and capture both local item and person dependence. Papers on the MLM analysis of item response data have focused mostly on theoretical issues where applications have been add-ons to simulation…

  19. Dose-dependent hepatic transcriptional responses in Atlantic salmon (Salmo salar) exposed to sublethal doses of gamma radiation.

    PubMed

    Song, You; Salbu, Brit; Teien, Hans-Christian; Heier, Lene Sørlie; Rosseland, Bjørn Olav; Tollefsen, Knut Erik

    2014-11-01

    Due to the production of free radicals, gamma radiation may pose a hazard to living organisms. The high-dose radiation effects have been extensively studied, whereas the ecotoxicity data on low-dose gamma radiation is still limited. The present study was therefore performed using Atlantic salmon (Salmo salar) to characterize effects of low-dose (15, 70 and 280 mGy) gamma radiation after short-term (48h) exposure. Global transcriptional changes were studied using a combination of high-density oligonucleotide microarrays and quantitative real-time reverse transcription polymerase chain reaction (qPCR). Differentially expressed genes (DEGs; in this article the phrase gene expression is taken as a synonym of gene transcription, although it is acknowledged that gene expression can also be regulated, e.g., at protein stability and translational level) were determined and linked to their biological meanings predicted using both Gene Ontology (GO) and mammalian ortholog-based functional analyses. The plasma glucose level was also measured as a general stress biomarker at the organism level. Results from the microarray analysis revealed a dose-dependent pattern of global transcriptional responses, with 222, 495 and 909 DEGs regulated by 15, 70 and 280 mGy gamma radiation, respectively. Among these DEGs, only 34 were commonly regulated by all radiation doses, whereas the majority of differences were dose-specific. No GO functions were identified at low or medium doses, but repression of DEGs associated with GO functions such as DNA replication, cell cycle regulation and response to reactive oxygen species (ROS) were observed after 280mGy gamma exposure. Ortholog-based toxicity pathway analysis further showed that 15mGy radiation affected DEGs associated with cellular signaling and immune response; 70mGy radiation affected cell cycle regulation and DNA damage repair, cellular energy production; and 280mGy radiation affected pathways related to cell cycle regulation and DNA

  20. Efficient Algorithms for Estimating the Absorption Spectrum within Linear Response TDDFT

    SciTech Connect

    Brabec, Jiri; Lin, Lin; Shao, Meiyue; Govind, Niranjan; Yang, Chao; Saad, Yousef; Ng, Esmond

    2015-10-06

    We present two iterative algorithms for approximating the absorption spectrum of molecules within linear response of time-dependent density functional theory (TDDFT) framework. These methods do not attempt to compute eigenvalues or eigenvectors of the linear response matrix. They are designed to approximate the absorption spectrum as a function directly. They take advantage of the special structure of the linear response matrix. Neither method requires the linear response matrix to be constructed explicitly. They only require a procedure that performs the multiplication of the linear response matrix with a vector. These methods can also be easily modified to efficiently estimate the density of states (DOS) of the linear response matrix without computing the eigenvalues of this matrix. We show by computational experiments that the methods proposed in this paper can be much more efficient than methods that are based on the exact diagonalization of the linear response matrix. We show that they can also be more efficient than real-time TDDFT simulations. We compare the pros and cons of these methods in terms of their accuracy as well as their computational and storage cost.

  1. Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners.

    PubMed

    Manzi, Vincenzo; Castagna, Carlo; Padua, Elvira; Lombardo, Mauro; D'Ottavio, Stefano; Massaro, Michele; Volterrani, Maurizio; Iellamo, Ferdinando

    2009-06-01

    In athletes, exercise training induces autonomic nervous system (ANS) adaptations that could be used to monitor training status. However, the relationship between training and ANS in athletes has been investigated without regard for individual training loads. We tested the hypothesis that in long-distance athletes, changes in ANS parameters are dose-response related to individual volume/intensity training load and could predict athletic performance. A spectral analysis of heart rate (HR), systolic arterial pressure variability, and baroreflex sensitivity by the sequences technique was investigated in eight recreational athletes during a 6-mo training period culminating with a marathon. Individualized training load responses were monitored by a modified training impulse (TRIMP(i)) method, which was determined in each athlete using the individual HR and lactate profiling determined during a treadmill test. Monthly TRIMP(i) steadily increased during the training period. All the ANS parameters were significantly and very highly correlated to the dose of exercise with a second-order regression model (r(2) ranged from 0.90 to 0.99; P < 0.001). Variance, high-frequency oscillations of HR variability (HRV), and baroreflex sensitivity resembled a bell-shaped curve with a minimum at the highest TRIMP(i), whereas low-frequency oscillations of HR and systolic arterial pressure variability and the low frequency (LF)-to-high frequency ratio resembled an U-shaped curve with a maximum at the highest TRIMP(i). The LF component of HRV assessed at the last recording session was significantly and inversely correlated to the time needed to complete the nearing marathon. These results suggest that in recreational athletes, ANS adaptations to exercise training are dose related on an individual basis, showing a progressive shift toward a sympathetic predominance, and that LF oscillations in HRV at peak training load could predict athletic achievement in this athlete population.

  2. Oxidative Stress and Skeletal Health with Low-Dose, Low-LET (Linear Energy Transfer) Ionizing Radiation

    SciTech Connect

    Globus, Ruth K.

    2014-11-03

    month after irradiation (IR). At four months post-IR, these animals were comparable to sham-treated controls with regards to the abovementioned structural parameters. Irradation at 1 or 10 cGy did not result in any significant changes in bone structural parameters. (3) Irradiation of 16-wk old male mice with high doses of 56Fe or proton (50 or 200cGy), but not at low doses (5 or 10cGy), showed a similar loss of cancellous BV/TV and trabecular number at five weeks post-IR. (4) Age-related bone loss overtook acute radiation-induced decrements in bone structure within four months post-IR with 100 cGy gamma and 12 months post-IR with 200 cGy iron. Transgenic mice globally overexpressing human catalase gene in mitochondria did not exhibit cancellous bone loss as assessed at four month post-IR with 10 cGy proton, 50 cGy iron, or in combination. (5) The cellular and molecular mechanisms responsible for loss of bone with radiation are mediated primarily through increased osteoclastogenesis. Our data provide evidence that there are increases in gene expression of TNF alpha and MCP1 in the bone marrow cells 24 hours post-IR and of osteoclastogenic differentiation factor RANKL by day 3. These cytokines in the marrow may stimulate mature osteoclasts or drive osteoclastogenesis from precursors. (6) Osteoblastogenesis from marrow progenitors evaluated ex vivo decreased following whole body 56Fe irradiation at a dose threshold between 20 and 50 cGy whereas osteoclastogenesis ex vivo increased with doses as low as 10cGy two days post-IR of mice. However, the latter finding was not observed in more than a single experiment. (7) Gamma irradiation of cells in vitro requires relatively high doses (200cGy) to disturb normal osteoblastogenesis and osteoclastogenesis as evidenced by decrements in mineralized nodule formation, osteoclast counts, and expression of osteoblast related genes such as runx2, col1a1. (8) We also investigated the effect of antioxidants on osteoblastogenesis following

  3. Linear response of homogeneous nuclear matter with energy density functionals

    NASA Astrophysics Data System (ADS)

    Pastore, A.; Davesne, D.; Navarro, J.

    2015-03-01

    Response functions of infinite nuclear matter with arbitrary isospin asymmetry are studied in the framework of the random phase approximation. The residual interaction is derived from a general nuclear Skyrme energy density functional. Besides the usual central, spin-orbit and tensor terms it could also include other components as new density-dependent terms or three-body terms. Algebraic expressions for the response functions are obtained from the Bethe-Salpeter equation for the particle-hole propagator. Applications to symmetric nuclear matter, pure neutron matter and asymmetric nuclear matter are presented and discussed. Spin-isospin strength functions are analyzed for varying conditions of density, momentum transfer, isospin asymmetry, and temperature for some representative Skyrme functionals. Particular attention is paid to the discussion of instabilities, either real or unphysical, which could manifest in finite nuclei.

  4. Human Lymphocytes Response to Low Gamma-ray Doses

    NASA Astrophysics Data System (ADS)

    Vega-Carrillo, Héctor René; Manzanares-Acuña, Eduardo; Bañuelos-Valenzuela, Rómulo

    2002-08-01

    Radiation and non-radiation workers lymphocytes were exposed to a low strength gamma-ray field to determine heat shock protein expression in function of radiation dose. Protein identification was carried out using mAb raised against Hsp25, Hsp60, Hsp70 and Hsp90; from these, only Hsp70 protein was detected before and after lymphocyte irradiation. In all cases, an increasing trend of relative amounts of Hsp70 in function to irradiation time was observed. After 70.5 uGy gamma-ray dose, radiation worker's lymphocytes expressed more Hsp70 protein, than non radiation workers' lymphocytes, indicating a larger tolerance to gamma rays (gammatolerance), due to an adaptation process developed by his labor condition.

  5. The Response of Rats to Cutaneous Dosing with Trichothecene Mycotoxins,

    DTIC Science & Technology

    1983-10-01

    without epidermis . Those which received DAS showed a similar result, but the crust which had formed by the fourth day broke up as scaly flakes and fell...off (7 to 11 days) revealing an apparently intact epidermis . The rats dosed with the mixture showed an intermediate condition, with some scaliness of...rats exhibited exactly the same lesions with destruction of the epidermis , as described in Table 1. There was no indication that the mixture of toxins

  6. Responses of astrocytes in culture after low dose laser irradiation

    SciTech Connect

    Yew, D.T.; Zheng, D.R.; Au, C.; Li, W.W. )

    1990-03-01

    The effect of Helium-Neon low dose laser on astrocytes was investigated in cultures of isolated astrocytes from albino neonatal rats. The laser appeared to inhibit the growth of astrocytes as exemplified by the smaller sizes of the cells and the decreased leucine uptake in each cell after treatment. Temporary decrease in the number of mitoses was also observed, but this trend was reversed soon after. Electron microscopic studies revealed an increase in buddings from cell bodies and processes (branches) after irradiation.

  7. ACB-PCR MEASUREMENT OF K-RAS CODON 12 MUTATION IN A/J MOUSE LUNG EXPOSED TO BENZO[A]PYRENE: A DOSE-RESPONSE ASSESSMENT

    EPA Science Inventory

    Benzo[a]pyrene (B[a]P) is a known human carcinogen and environmental contaminant. The direct measurement of K-Ras mutant fraction (MF) was developed as a metric with which to examine the default assumption of low dose linearity in the mutational response to B...

  8. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies.

    PubMed

    Yang, Wan-Shui; Deng, Qin; Fan, Wen-Yan; Wang, Wei-Ye; Wang, Xin

    2014-07-01

    Evidence from observational studies on light at night (LAN) exposure, sleep duration, endogenous melatonin levels, and risk for breast cancer in women is conflicting. This led us to conduct a dose-response analysis of published observational data. Pertinent studies were identified by searching Medline, Web of Science, and EMBASE through April 2013. The dose-response relationship between sleep duration, urinary 6-sulphatoxymelatonin levels, and breast cancer was assessed using the restricted cubic spline model and by multivariate random-effects metaregression. A separate meta-analysis was also carried out to calculate the relative risks (RRs) with 95% confidence intervals (CIs) for breast cancer for the comparable categories or highest levels of exposure versus the lowest levels. Twelve case-control and four cohort studies were included in the analysis. High artificial LAN exposure is associated with an increased risk for breast cancer (RR=1.17, 95% CI: 1.11-1.23), but not ambient LAN exposure (RR=0.91, 95% CI: 0.78-1.07). The summary RR for breast cancer is 1.00 (95% CI: 0.995-1.01) for an increment of 1 h of sleep per night. No significant dose-response relationship between sleep duration and breast cancer was found either for the linearity test (Ptrend=0.725) or for the nonlinearity (Ptrend=0.091) test. An increasein of 15 ng/mg creatinine in urinary 6-sulphatoxymelatonin is associated with a 14% reduced risk for breast cancer (RR=0.86, 95% CI: 0.78-0.95), with a linear dose-response trend (Ptrend=0.003). There was no evidence of substantial heterogeneity or publication bias in the analysis. Our study adds to the evidence of LAN breast cancer theory. Further research in this area is warranted.

  9. Early Dose Response to Yttrium-90 Microsphere Treatment of Metastatic Liver Cancer by a Patient-Specific Method Using Single Photon Emission Computed Tomography and Positron Emission Tomography

    SciTech Connect

    Campbell, Janice M. Wong, C. Oliver; Muzik, Otto; Marples, Brian; Joiner, Michael; Burmeister, Jay

    2009-05-01

    Purpose: To evaluate a patient-specific single photon emission computed tomography (SPECT)-based method of dose calculation for treatment planning of yttrium-90 ({sup 90}Y) microsphere selective internal radiotherapy (SIRT). Methods and Materials: Fourteen consecutive {sup 90}Y SIRTs for colorectal liver metastasis were retrospectively analyzed. Absorbed dose to tumor and normal liver tissue was calculated by partition methods with two different tumor/normal liver vascularity ratios: an average 3:1 and a patient-specific ratio derived from pretreatment technetium-99m macroaggregated albumin SPECT. Tumor response was quantitatively evaluated from fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography scans. Results: Positron emission tomography showed a significant decrease in total tumor standardized uptake value (average, 52%). There was a significant difference in the tumor absorbed dose between the average and specific methods (p = 0.009). Response vs. dose curves fit by linear and linear-quadratic modeling showed similar results. Linear fit r values increased for all tumor response parameters with the specific method (+0.20 for mean standardized uptake value). Conclusion: Tumor dose calculated with the patient-specific method was more predictive of response in liver-directed {sup 90}Y SIRT.

  10. The linearity and selectivity of neuronal responses in awake visual cortex

    PubMed Central

    Chen, Yao; Anand, Sanjiv; Martinez-Conde, Susana; Macknik, Stephen L.; Bereshpolova, Yulia; Swadlow, Harvey A.; Alonso, Jose-Manuel

    2011-01-01

    Neurons in primary visual cortex (V1) are frequently classified based on their response linearity: the extent in which their visual responses to drifting gratings resemble a linear replica of the stimulus. This classification is supported by the finding that response linearity is bimodally distributed across neurons in area V1 of anesthetized animals. However, recent studies suggest that such bimodal distribution may not reflect two neuronal types but a nonlinear relationship between the membrane potential and the spike output. A main limitation of these previous studies is that they measured response linearity in anesthetized animals, where the distance between the neuronal membrane potential and spike threshold is artificially increased by anesthesia. Here, we measured V1 response linearity in the awake brain and its correlation with the neuronal spontaneous firing rate, which is related to the distance between membrane potential and threshold. Our results demonstrate that response linearity is bimodally distributed in awake V1 but that it is poorly correlated with spontaneous firing rate. In contrast, the spontaneous firing rate is best correlated to the response selectivity and response latency to stimuli. PMID:19761345

  11. The Inhibitory Effects of Low-Dose Ionizing Radiation in IgE-Mediated Allergic Responses

    PubMed Central

    Nam, Seon Young; Yang, Kwang Hee; Kim, Cha Soon; Lee, In Kyung; Kim, Ji Young

    2015-01-01

    Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration ([Ca2+]i). The phosphorylation of signaling molecules and [Ca2+]i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro. PMID:26317642

  12. Estimation of Errors Associated With Use of Linear-Quadratic Formalism for Evaluation of Biologic Equivalence Between Single and Hypofractionated Radiation Doses: An In Vitro Study

    SciTech Connect

    Iwata, Hiromitsu Shibamoto, Yuta; Murata, Rumi; Tomita, Natsuo; Ayakawa, Shiho; Ogino, Hiroyuki; Ito, Masato

    2009-10-01

    Purpose: To investigate the reliability of the linear-quadratic (LQ) formalism and the magnitude of errors associated with its use in assessing biologic equivalence between single, high radiation doses and hypofractionated radiation doses. Methods and Materials: V79 and EMT6 single cells received single doses of 2-12 Gy or two or three fractions of 4 or 5 Gy, each at 4-h intervals. Single and fractionated doses to actually reduce the cell survival to the same level were determined by a colony assay. The {alpha}/{beta} ratio was obtained from the cell survival curves. Using the {alpha}/{beta} ratio and the LQ formalism, equivalent single doses for the hypofractionated doses were calculated. They were then compared with the actually determined equivalent single doses for the hypofractionated doses. The V79 spheroids received single doses of 5-26 Gy or two to five fractions of 5-12 Gy at 2 or 4-h interval, and then were assayed for cell survival. Next, equivalent single doses for the hypofractionated doses were determined, as were done for the single cells. Results: The {alpha}/{beta} ratio was 5.1 Gy for the V79 single cells and 0.36 Gy for EMT6. In V79, the equivalent single doses for the hypofractionated doses calculated using the LQ formalism were 12-19% lower than the actually measured biologically equivalent single doses. In the EMT6 cells, this trend was also seen, but the differences were not significant. In the V79 spheroids, the calculated doses were 18-30% lower than the measured doses. Conclusion: Conversion of hypofractionated radiation doses to single doses using the LQ formalism could underestimate the effect of hypofractionated radiation by {<=}30%.

  13. Thermal shifts and intermittent linear response of aging systems.

    PubMed

    Sibani, Paolo; Christiansen, Simon

    2008-04-01

    At time t after an initial quench, an aging system responds to a perturbation turned on at time twresponse on the ratio t/tw . Further insight is obtained imposing small temperature steps, so-called T shifts. The average response as a function of t/tw,eff , where tw,eff is the effective age, is similar to the response of a system aged isothermally at the final temperature. Using an Ising model with plaquette interactions, the applicability of analytic formulas for the average isothermal magnetization is confirmed. The T -shifted aging behavior of the model is approximately described using effective ages. Large positive shifts nearly reset the effective age. Negative T shifts offer a more detailed probe of the dynamics. Assuming the marginal stability of the "current" attractor against thermal noise fluctuations, the scaling form tw,eff=tw x and the dependence of the exponent x on the aging temperatures before and after the shift are theoretically available. The predicted form of x has no adjustable parameters. Both the algebraic scaling of the effective age and the form of the exponent reasonably agree with the data. The present simulations thus confirm the crucial role of marginal stability in glassy relaxation.

  14. Interpretation of the margin of exposure for genotoxic carcinogens - elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.

    PubMed

    Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi

    2013-07-01

    The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship.

  15. Quantifying murine bone marrow and blood radiation dose response following (18)F-FDG PET with DNA damage biomarkers.

    PubMed

    Manning, Grainne; Taylor, Kristina; Finnon, Paul; Lemon, Jennifer A; Boreham, Douglas R; Badie, Christophe

    2014-12-01

    The purpose of this study was to quantify the poorly understood radiation doses to murine bone marrow and blood from whole-body fluorine 18 ((18)F)-fluorodeoxyglucose (FDG) positron emission tomography (PET), by using specific biomarkers and comparing with whole body external low dose exposures. Groups of 3-5 mice were randomly assigned to 10 groups, each receiving either a different activity of (18)F-FDG: 0-37MBq or whole body irradiated with corresponding doses of 0-300mGy X-rays. Blood samples were collected at 24h and at 43h for reticulocyte micronucleus assays and QPCR analysis of gene expression in peripheral blood leukocytes. Blood and bone marrow dose estimates were calculated from injected activities of (18)F-FDG and were based on a recommended ICRP model. Doses to the bone marrow corresponding to 33.43mGy and above for internal (18)F-FDG exposure and to 25mGy and above for external X-ray exposure, showed significant increases in radiation-induced MN-RET formation relative to controls (P<0.05). Regression analysis showed that both types of exposure produced a linear response with linear regression analysis giving R(2) of 0.992 and 0.999 for respectively internal and external exposure. No significant difference between the two data sets was found with a P-value of 0.493. In vivo gene expression dose-responses at 24h for Bbc3 and Cdkn1 were similar for (18)F-FDG and X-ray exposures, with significant modifications occurring for doses over 300mGy for Bbc3 and at the lower dose of 150mGy for Cdkn1a. Both leucocyte gene expression and quantification of MN-RET are highly sensitive biomarkers for reliable estimation of the low doses delivered in vivo to, respectively, blood and bone marrow, following (18)F-FDG PET.

  16. Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies

    PubMed Central

    Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

    2016-01-01

    The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%–13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups. PMID:27869762

  17. Results of animal studies suggest a nonlinear dose-response relationship for benzene effects

    SciTech Connect

    Parodi, S.; Taningher, M. ); Lutz, W.K. ); Colacci, A.; Mazzullo, M.; Grilli, S. )

    1989-07-01

    Considering the very large industrial usage of benzene, studies in risk assessment aimed at the evaluation of carcinogenic risk at low levels of exposure are important. Animal data can offer indications about what could happen in humans and provide more diverse information than epidemiological data with respect to dose-response consideration. The authors have considered experiments investigating metabolism, short-term genotoxicity tests, DNA adduct formation, and carcinogenicity long-term tests. According to the different experiments, a saturation of benzene metabolism and benzene effects in terms of genotoxicity seems evident above 30 to 100 ppm. Below 30 to 60 ppm the initiating effect of benzene seems to be linear for a large interval of dosages, at least judging from DNA adduct formation. Potential lack of a promoting effect of benzene (below 10 ppm) could generate a sublinear response at nontoxic levels of exposure. This possibility was suggested by epidemiological data in humans and is not confirmed or excluded by their observations with animals.

  18. Linear Ordinary Differential Equations with Constant Coefficients. Revisiting the Impulsive Response Method Using Factorization

    ERIC Educational Resources Information Center

    Camporesi, Roberto

    2011-01-01

    We present an approach to the impulsive response method for solving linear constant-coefficient ordinary differential equations based on the factorization of the differential operator. The approach is elementary, we only assume a basic knowledge of calculus and linear algebra. In particular, we avoid the use of distribution theory, as well as of…

  19. [Modeling and simulation of responses from ultrasonic linear phased array].

    PubMed

    He, Wenjing; Zhu, Yuanzhong; Wang, Yufeng; He, Lingli; Lai, Siyu

    2012-10-01

    Phased array transducers are very attractive because the beam generated by the arrays can be electronically focused and steered. The present work characterizes far-field 2D properties of phased array system by functions that are deduced from rectangle source, rectangle line array and phased array based on point source. Results are presented for the distribution of ultrasound intensity on plane xoz and on x-axis by simulation using numerical calculation. It is shown that the shape of response of rectangle line array is modulated by the single array element. It is also demonstrated that the delay time of phased array is the key to steer the beam, sacrificing the value of main lobe and increasing the number of side lobes.

  20. A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

    PubMed Central

    Leonard, Bobby E.

    2008-01-01

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

  1. The Maturing of Hormesis as a Credible Dose-Response Model

    PubMed Central

    Calabrese, Edward J.

    2003-01-01

    Hormesis is a dose-response phenomenon that has received little recognition, credibility and acceptance as evidenced by its absence from major toxicological/risk assessment texts, governmental regulatory dose-response modeling for risk assessment, and non-visibility in major professional toxicological society national meetings. This paper traces the historical evolution of the hormetic dose-response hypothesis, why this model is not only credible but also more common than the widely accepted threshold model in direct comparative evaluation, and how the toxicological community made a critical error in rejecting hormesis, a rejection sustained over 70 years. PMID:19330138

  2. Influence of high doses γ-irradiation on oxygen permeability of linear low-density polyethylene and cast polypropylene films

    NASA Astrophysics Data System (ADS)

    Klepac, Damir; Ščetar, Mario; Baranović, Goran; Galić, Kata; Valić, Srećko

    2014-04-01

    Linear low density polyethylene (PE-LLD) and cast polypropylene (PPcast) films were irradiated in a 60Co γ-source. The total irradiation dose varied from 0 kGy (unirradiated samples) to 200 kGy. Oxygen transport was investigated by a manometric method and the structural changes were studied by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Free radicals decay as a function of time was monitored by electron spin resonance (ESR) spectroscopy. The results show that the γ-irradiation reduces oxygen permeability coefficient in both films. The reduction was associated with an increase in crystallinity. DSC thermograms revealed a decrease in PPcast melting point with increasing irradiation dose, indicating higher degradation compared to PE-LLD. The observed peak in FTIR spectra for both samples at 1716 cm-1 corresponds to the stretching of the carbonyl and carboxylic groups which arise from the reaction of oxygen with the free radicals produced in the polymer matrix as a result of irradiation.

  3. Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure

    PubMed Central

    Johnston, Sara C.; Lin, Kenny L.; Twenhafel, Nancy A.; Raymond, Jo Lynne W.; Shamblin, Joshua D.; Wollen, Suzanne E.; Wlazlowski, Carly B.; Wilkinson, Eric R.; Botto, Miriam A.; Goff, Arthur J.

    2015-01-01

    Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies. PMID:26413900

  4. The effect of anabolic steroids on lean body mass: the dose response curve.

    PubMed

    Forbes, G B

    1985-06-01

    Data from human subjects given various amounts of anabolic steroids show that the resultant increment in lean body mass (LBM) has the features of a typical dose response curve. Low doses produce a very modest effect, while large doses result in a progressive augmentation of the LBM. Endogenous testosterone production during male adolescence is accompanied by a sex differential in LBM that is comparable to the LBM increment generated by exogenous steroids given to adults.

  5. Parameterizing dose-response models to estimate relative potency functions directly.

    PubMed

    Dinse, Gregg E; Umbach, David M

    2012-10-01

    Many comparative analyses of toxicity assume that the potency of a test chemical relative to a reference chemical is constant, but employing such a restrictive assumption uncritically may generate misleading conclusions. Recent efforts to characterize non-constant relative potency rely on relative potency functions and estimate them secondarily after fitting dose-response models for the test and reference chemicals. We study an alternative approach of specifying a relative potency model a priori and estimating it directly using the dose-response data from both chemicals. We consider a power function in dose as a relative potency model and find that it keeps the two chemicals' dose-response functions within the same family of models for families typically used in toxicology. When differences in the response limits for the test and reference chemicals are attributable to the chemicals themselves, the older two-stage approach is the more convenient. When differences in response limits are attributable to other features of the experimental protocol or when response limits do not differ, the direct approach is straightforward to apply with nonlinear regression methods and simplifies calculation of simultaneous confidence bands. We illustrate the proposed approach using Hill models with dose-response data from U.S. National Toxicology Program bioassays. Though not universally applicable, this method of estimating relative potency functions directly can be profitably applied to a broad family of dose-response models commonly used in toxicology.

  6. Quantitative radiation dose-response relationships for normal tissues in man - I. Gustatory tissues response during photon and neutron radiotherapy

    SciTech Connect

    Mossman, K.L.

    1982-08-01

    Quantitative radiation dose-response curves for normal gustatory tissue in man were studied. Taste function, expressed as taste loss, was evaluated in 84 patients who were given either photon or neutron radiotherapy for tumors in the head and neck region. Patients were treated to average tumor doses of 6600 cGy (photon) or 2200 cGy intervals for photon patients and 320-cGy intervals for neutron patients during radiotherapy. The dose-response curves for photons and neutrons were analyzed by fitting a four-parameter logistic equation to the data. Photon and neutron curves differed principally in their relative position along the dose axis. Comparison of the dose-response curves were made by determination of RBE. At 320 cGy, the lowest neutron dose at which taste measurements were made, RBE = 5.7. If this RBE is correct, then the therapeutic gain factor may be equal to or less than 1, indicating no biological advantage in using neutrons over photons for this normal tissue. These studies suggest measurements of taste function and evaluation of dose-response relationships may also be useful in quantitatively evaluating the efficacy of chemical modifiers of radiation response such as hypoxic cell radiosensitizers and radioprotectors.

  7. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

    SciTech Connect

    Sheehan, Daniel M. . E-mail: dansheeh@swbell.net

    2006-01-15

    We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.

  8. Dose response of benzo(a)pyrene-induced mutagenesis using the BigBlue{reg_sign} transgenic mouse assay

    SciTech Connect

    Kotturi, G.; Holcroft, J.; Boer, J. de

    1997-10-01

    To investigate the dose response of benzo(a)pyrene-induced mutagenesis, groups of five BigBlue{reg_sign} transgenic mice were injected with a single intra-peritoneal dose were injected with corn oil containing benzo(a)pyrene to achieve the following concentrations: 0, 62.5, 125, 250, 500 mg/kg. Tissues were harvested after a 14 day expression time and analysed for mutational events. DNA adducts were measured in the liver of mice that were sacrificed 1 day after injection. The mutant frequency in the mouse liver linearly increased from 5.2 to 53.5 x 10{sup -5} in a dose-specific manner from 0 to 500 mg/kg benzo(a)pyrene. Mutants were sequenced to give an estimate of the number of clonal events as a function of benzo(a) pyrene with a total of 20 exposed animals (4 doses and five animals/dose), we established frequently mutated sites or `mutational hotspots` as well as a full mutational spectrum. Various other factors associated with the BigBlue{reg_sign} assay were analysed such as the effect of plating density on the purity of mutant plaques during the phage purification step.

  9. Dose-Response Issues Concerning the Relations between Regular Physical Activity and Health.

    ERIC Educational Resources Information Center

    Rankinen, Tuomo; Bouchard, Claude

    2002-01-01

    This paper categorizes the many benefits of physical activity, offering information concerning the type of dose necessary to get that benefit. In 2000, Health Canada and the United States Centers for Disease Control and Prevention, along with other agencies, sponsored a symposium to determine whether there was a dose-response relationship between…

  10. RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R828035)

    EPA Science Inventory

    Three dose¯response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID50) using a simple cumulative perce...

  11. Development of a biologically based dose response (BBDR) model for arsenic induced cancer

    EPA Science Inventory

    We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action. Expert consultation and literature review are being conducted t...

  12. Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

    NASA Technical Reports Server (NTRS)

    Chappell, Lori J.; Cucinotta, Francis A.

    2010-01-01

    There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies.

  13. Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

    ERIC Educational Resources Information Center

    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.)…

  14. Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors

    EPA Science Inventory

    Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC ...

  15. Implementation of a dose-response curve for γ-radiation in the Portuguese population by use of the chromosomal aberration assay.

    PubMed

    Martins, V; Antunes, A C; Monteiro Gil, O

    2013-01-20

    An in vitro dose-response curve following exposure to γ-radiation was determined at the IST/ITN, by use of the chromosomal aberration assay. This is the first study of this kind carried out among the Portuguese population. Un-irradiated and γ-irradiated peripheral blood lymphocytes from 16 healthy donors were cultured. A total of 22,395 metaphases were analyzed for frequency and distribution of dicentrics and centric rings, as a function of the radiation dose. The dose-response data for dicentrics and dicentrics plus centric rings were fitted by use of a linear-quadratic model: Y(dic)=(0.0011±0.0006)+(0.0105±0.0035)D+(0.0480±0.0019)D(2) and Y(dic+rings)=(0.0011±0.0006)+(0.0095±0.0036)D+(0.0536±0.0020)D(2). Also, calibration curves related to age and gender were determined, but no significant differences were found. Following the establishment of the dose-response curves, a validation experiment was carried out with three individuals. Real and estimated doses, obtained with the dose-response curves, were in agreement. These results give us confidence to apply both dose-response calibration curves in future biological dosimetry requirements.

  16. The use of enriched 6Li and 7Li Lif:Mg,Cu,P glass-rod thermoluminescent dosemeters for linear accelerator out-of-field radiation dose measurements.

    PubMed

    Takam, R; Bezak, E; Liu, G; Marcu, L

    2012-06-01

    (6)LiF:Mg,Cu,P and (7)LiF:Mg,Cu,P glass-rod thermoluminescent dosemeters (TLDs) were used for measurements of out-of-field photon and neutron doses produced by Varian iX linear accelerator. Both TLDs were calibrated using 18-MV X-ray beam to investigate their dose-response sensitivity and linearity. CR-39 etch-track detectors (Luxel+, Landauer) were employed to provide neutron dose data to calibrate (6)LiF:Mg,Cu,P TLDs at various distances from the isocentre. With cadmium filters employed, slow neutrons (<0.5 eV) were distinguished from fast neutrons. The average in-air photon dose equivalents per monitor unit (MU) ranged from 1.5±0.4 to 215.5±94.6 μSv at 100 and 15 cm from the isocentre, respectively. Based on the cross-calibration factors obtained with CR-39 etch-track detectors, the average in-air fast neutron dose equivalents per MU range from 10.6±3.8 to 59.1±49.9 μSv at 100 and 15 cm from the isocentre, respectively. Contribution of thermal neutrons to total neutron dose equivalent was small: 3.1±7.2 μSv per MU at 15 cm from the isocentre.

  17. Linear ordinary differential equations with constant coefficients. Revisiting the impulsive response method using factorization

    NASA Astrophysics Data System (ADS)

    Camporesi, Roberto

    2011-06-01

    We present an approach to the impulsive response method for solving linear constant-coefficient ordinary differential equations based on the factorization of the differential operator. The approach is elementary, we only assume a basic knowledge of calculus and linear algebra. In particular, we avoid the use of distribution theory, as well as of the other more advanced approaches: Laplace transform, linear systems, the general theory of linear equations with variable coefficients and the variation of constants method. The approach presented here can be used in a first course on differential equations for science and engineering majors.

  18. Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose volume outcome relationships

    NASA Astrophysics Data System (ADS)

    El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.

    2006-11-01

    Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

  19. Liposomal amphotericin B and leishmaniasis: dose and response.

    PubMed

    Sundar, Shyam; Chakravarty, Jaya

    2010-05-01

    Liposomal amphotericin B has been used with increasing frequency to treat visceral leishmaniasis (VL). It is the treatment of choice for immunocompetent patients in the Mediterranean region and the preferred drug for HIV/VL co-infection. Although there is a regional variation in the susceptibility of the parasite a total dose of 20 mg/kg is effective in immunocompetent patients. Randomized clinical trials of liposomal amphotericin B in the treatment and secondary prophylaxis of HIV-VL coinfected patients is urgently needed to optimize treatment in this subset. With the availability of Liposomal amphotericin B at a preferential pricing in the endemic areas, short course combination therapy can become a viable alternative.

  20. The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events

    EPA Science Inventory

    The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Act...

  1. Cancer Dose-Response Assessment for Polychlorinated Biphenyls (PCBs) and Application to Environmental Mixtures

    EPA Pesticide Factsheets

    This report updates the cancer dose-response assessment for PCBs and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment.

  2. RASS SOT Webinar - Nonmonotonic Dose Response Curves (NMDRCs) Common after Estrogen or Androgen Signaling Pathway Disruption

    EPA Science Inventory

    The presentation provides the listening and viewing audience with Dr Gray's scientific information on the relevance of nonmonotonic dose response curves to the risk assessment of estrogenic and androgenic chemicals

  3. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats.

    PubMed

    Sullivan, P G; Rabchevsky, A G; Hicks, R R; Gibson, T R; Fletcher-Turner, A; Scheff, S W

    2000-01-01

    Acute neuropathology following experimental traumatic brain injury results in the rapid necrosis of cortical tissue at the site of injury. This primary injury is exacerbated in the ensuing hours and days via the progression of secondary injury mechanism(s) leading to significant neurological dysfunction. Recent evidence from our laboratory demonstrates that the immunosuppressant cyclosporin A significantly ameliorates cortical damage following traumatic brain injury. The present study extends the previous findings utilizing a unilateral controlled cortical impact model of traumatic brain injury in order to establish a dose-response curve and optimal dosing regimen of cyclosporin A. Following injury to adult rats, cyclosporin A was administrated at various dosages and the therapy was initiated at different times post-injury. In addition to examining the effect of cyclosporin A on the acute disruption of the blood-brain barrier following controlled cortical impact, we also assessed the efficacy of cyclosporin A to reduce tissue damage utilizing the fluid percussion model of traumatic brain injury. The findings demonstrate that the neuroprotection afforded by cyclosporin A is dose-dependent and that a therapeutic window exists up to 24h post-injury. Furthermore, the optimal cyclosporin dosage and regimen markedly reduces disruption of the blood-brain barrier acutely following a cortical contusion injury, and similarly affords significant neuroprotection following fluid percussion injury. These findings clearly suggest that the mechanisms responsible for tissue necrosis following traumatic brain injury are amenable to pharmacological intervention.

  4. Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies

    PubMed Central

    Melia, Umberto; Vallverdú, Montserrat; Borrat, Xavier; Valencia, Jose Fernando; Jospin, Mathieu; Jensen, Erik Weber; Gambus, Pedro; Caminal, Pere

    2015-01-01

    The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands. PMID:25901571

  5. Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies.

    PubMed

    Melia, Umberto; Vallverdú, Montserrat; Borrat, Xavier; Valencia, Jose Fernando; Jospin, Mathieu; Jensen, Erik Weber; Gambus, Pedro; Caminal, Pere

    2015-01-01

    The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands.

  6. Comparison of Risk Predicted by Multiple Norovirus Dose-Response Models and Implications for Quantitative Microbial Risk Assessment.

    PubMed

    Van Abel, Nicole; Schoen, Mary E; Kissel, John C; Meschke, J Scott

    2016-06-10

    The application of quantitative microbial risk assessments (QMRAs) to understand and mitigate risks associated with norovirus is increasingly common as there is a high frequency of outbreaks worldwide. A key component of QMRA is the dose-response analysis, which is the mathematical characterization of the association between dose and outcome. For Norovirus, multiple dose-response models are available that assume either a disaggregated or an aggregated intake dose. This work reviewed the dose-response models currently used in QMRA, and compared predicted risks from waterborne exposures (recreational and drinking) using all available dose-response models. The results found that the majority of published QMRAs of norovirus use the 1 F1 hypergeometric dose-response model with α = 0.04, β = 0.055. This dose-response model predicted relatively high risk estimates compared to other dose-response models for doses in the range of 1-1,000 genomic equivalent copies. The difference in predicted risk among dose-response models was largest for small doses, which has implications for drinking water QMRAs where the concentration of norovirus is low. Based on the review, a set of best practices was proposed to encourage the careful consideration and reporting of important assumptions in the selection and use of dose-response models in QMRA of norovirus. Finally, in the absence of one best norovirus dose-response model, multiple models should be used to provide a range of predicted outcomes for probability of infection.

  7. DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES TO PENICILLIUM CHRYSOGENUM

    EPA Science Inventory

    ABSTRACT
    Indoor mold has been associated with development of allergic asthma. Penicillium chrysogenum, a common indoor mold, is known to have several allergens and its viable conidia can induce allergic responses in a mouse model of allergic penicilliosis. The hypothesis o...

  8. The relationship between terazosin dose and blood pressure response in hypertensive patients.

    PubMed

    Achari, R; Hosmane, B; Bonacci, E; O'Dea, R

    2000-10-01

    A double-blind, randomized, placebo-controlled, multicenter study was conducted to describe the dose-response curve for terazosin on blood pressure. A total of 128 patients with mild to moderate essential hypertension (supine diastolic blood pressure, 100 to 114 mmHg) participated in the study. The study consisted of a 4-week single-blind placebo lead-in period and a 14-week double-blind treatment period. Patients were randomized in equal numbers to four parallel treatment groups: terazosin 1, 2, and 5 mg; terazosin 2, 5, and 10 mg; terazosin 20, 40, and 80 mg; and placebo. The 24-hour ambulatory blood pressure measurements were performed at the end of the placebo lead-in period and at the end of each 4-week fixed-dose period. The nonlinear, mixed-effect model computer program was used to analyze the dose-response relationship. There was a strong dose-response relationship between fall in blood pressure and the 1 to 10 mg terazosin dose, as well as a plateauing of response for terazosin doses above 10 mg. The maximum antihypertensive response (Emax) to terazosin was 10.7 mmHg for systolic blood pressure and 8.0 mmHg for diastolic blood pressure. The daily dose of terazosin, which produced 50% of the maximum response (ED50), was 3.0 mg for systolic blood pressure and 1.5 mg for diastolic blood pressure. The results of this study suggest that although some patients may benefit from terazosin doses of greater than 10 mg, doses up to 10 mg will maximize therapeutic benefit for most patients, with acceptable side effects.

  9. Characterizing dose-responses of catalase to nitrofurazone exposure in model ciliated protozoan Euplotes vannus for ecotoxicity assessment: enzyme activity and mRNA expression.

    PubMed

    Li, Jiqiu; Zhou, Liang; Lin, Xiaofeng; Yi, Zhenzhen; Al-Rasheid, Khaled A S

    2014-02-01

    In environmental studies, some biological responses, known as biomarkers, have been used as a powerful bioassay tool for more than four decades. Disparity between enzyme activity and mRNA abundance leads to correlation equivocality, which makes the application of biomarkers for environmental risk assessment more complicated. This study investigates this disparity in the case of catalase when used as a biomarker for detecting ecotoxicity induced by antibiotics in aquatic ecosystems. In particular, dose-responses for catalase activity and mRNA expression abundance were investigated in Euplotes vannus which were exposed to graded doses of nitrofurazone for several discrete durations, and dose-response models were developed to characterize the dose-response dynamics. Significant differences were found in both catalase activity and mRNA expression abundance among the E. vannus treated with nitrofurazone. Catalase activity showed a hormetic-like effect in terms of dose-response, characterized by a biphasic relationship which was more clearly evident after a longer exposure period, while mRNA expression abundance increased linearly with the exposure duration. Additionally, the correlation between catalase activity and mRNA expression abundance reversed along with the duration of exposure to nitrofurazone. Taken together, our results demonstrate that catalase mRNA expression offers a more straightforward dose-response model than enzyme activity. Our findings suggest that both catalase enzyme activity and mRNA expression abundance can be used jointly as bioassay tools for detecting ecotoxicity induced by nitrofurazone in aquatic ecosystems.

  10. Ligand-Induced Protein Responses and Mechanical Signal Propagation Described by Linear Response Theories

    PubMed Central

    Yang, Lee-Wei; Kitao, Akio; Huang, Bang-Chieh; Gō, Nobuhiro

    2014-01-01

    In this study, a general linear response theory (LRT) is formulated to describe time-dependent and -independent protein conformational changes upon CO binding with myoglobin. Using the theory, we are able to monitor protein relaxation in two stages. The slower relaxation is found to occur from 4.4 to 81.2 picoseconds and the time constants characterized for a couple of aromatic residues agree with those observed by UV Resonance Raman (UVRR) spectrometry and time resolved x-ray crystallography. The faster “early responses”, triggered as early as 400 femtoseconds, can be best described by the theory when impulse forces are used. The newly formulated theory describes the mechanical propagation following ligand-binding as a function of time, space and types of the perturbation forces. The “disseminators”, defined as the residues that propagate signals throughout the molecule the fastest among all the residues in protein when perturbed, are found evolutionarily conserved and the mutations of which have been shown to largely change the CO rebinding kinetics in myoglobin. PMID:25229149

  11. A grid algorithm for high throughput fitting of dose-response curve data.

    PubMed

    Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung

    2010-10-21

    We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program's performance in reproducing the actual values that were used to generate the simulated data and compared it with the DRC package for the language and environment R and the XLfit add-in for Microsoft Excel. The Grid program was robust and consistently recovered the actual values for both complete and partial curves with or without noise. Both DRC and XLfit performed well on data without noise, but they were sensitive to and their performance degraded rapidly with increasing noise. The Grid program is automated and scalable to millions of dose-response curves, and it is able to process 100,000 dose-response curves from high throughput screening experiment per CPU hour. The Grid program has the potential of greatly increasing the productivity of large-scale dose-response data analysis and early drug discovery processes, and it is also applicable to many other curve fitting problems in chemical, biological, and medical sciences.

  12. An ultra-high dose of electron radiation response of Germanium Flat Fiber and TLD-100

    NASA Astrophysics Data System (ADS)

    Alawiah, A.; Amin, Y. M.; Abdul-Rashid, H. A.; Abdullah, W. S. Wan; Maah, M. J.; Bradley, D. A.

    2017-01-01

    The thermoluminescence (TL) response of Germanium Flat Fiber (GFF) and TLD-100 irradiated with 2.5 MeV electrons for the doses up to 1 MGy were studied and compared. The aim was to evaluate the TL supralinearity response at an ultra-high dose (UHD) range and to investigate the change in kinetic parameters of the glow peaks, as the doses increases up to 1 MGy. It is found that the critical dose limit (CDL) of GFF is 5 times higher as compared to TLD-100. CDL is determined by the dose at the maximum supralinearity, f(D)max. It is also found that annealing the TLD-100 and GFF with temperature more than 400 °C is required to reset it back to its original condition, following radiation doses up to 1 MGy. It is also noticed the strange behavior of Peak 4 (TLD-100), which tends to be invisible at the lower dose (<10 kGy) and starts to be appeared at the critical dose limit of 10 kGy. This result might be an important clue to understand the behavior of TLD-100 at extremely high dose range. For both samples, it is observed that the TL intensity is not saturated within the UHD range studied.

  13. Radiation effects on livestock: physiological effects, dose response

    SciTech Connect

    Bell, M.C.

    1985-06-01

    Farm livestock show no measurable effects from being exposed to ionizing radiation unless the level is greatly in excess of the natural background radiation. Possible sources of ionizing radiation which might affect livestock or contribute to radioactivity in the food chain to humans are reactor accidents, fuel reprocessing plant accidents and thermonuclear explosions. Most data on ionizing radiation effects on livestock are from whole body gamma doses near the LD 50/60 level. However, grazing livestock would be subjected to added beta exposure from ingested and skin retained radioactive particles. Results of attempts to simulate exposure of the Hereford cattle at Alamogardo, NM show that cattle are more sensitive to ingested fallout radiation than other species. Poultry LD 50/60 for gamma exposure is about twice the level for mammals, and swine appear to have the most efficient repair system being able to withstand the most chronic gamma exposure. Productivity of most livestock surviving an LD 50/60 exposure is temporarily reduced and longterm effects are small. Livestock are good screeners against undesirables in our diet and with the exception of radiosotopes of iodine in milk, very little fission product radioactivity would be expected to be transferred through the food chain in livestock products for humans. Feeding of stored feed or moving livestock to uncontaminated pastures would be the best protective action to follow. 29 references.

  14. Low blood lead level effects on intelligence: can a dose-response curve be determined from the epidemiological data?

    PubMed

    Banner, W; Kahn, C M

    2014-02-01

    CONTEXT. Recent publications have graphically demonstrated a curvilinear relationship between measures of intelligence and blood lead levels at low concentrations (< 10 mcg/dl). This led to speculation that a greater biologic effect occurs at lower concentrations. Critics of this conclusion hypothesized that this graphical relationship may be a function of the underlying distributions of these variables. OBJECTIVE. To study the impact of the distribution of data on the shape of apparent dose-response curves. METHODS. Random data based on varied distributions were constructed to simulate a previous study using a single, randomly generated covariate income (Inc) to demonstrate the impact of normally versus exponentially distributed data on the shape of the graph of intelligence quotient (IQ) versus blood lead. We also used an existing database of US blood lead levels and constructed a similar model of income and IQ using both assumptions of distribution for the intermediate variable income. RESULTS. When both lead and income are exponentially distributed, the graph of lead and IQ will be a curve. CONCLUSION. The apparent shape of a dose-response relationship from simulated epidemiological data is nonlinear when one variable and a covariate are exponentially distributed. A non-linear biological relationship should not be assumed and in fact may be the least likely explanation. The use of observational epidemiological data to discern a dose-response relationship between two variables may be misleading.

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

    PubMed

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

    2017-02-07

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

  16. PREDICTION OF OUTCOME IN SCHIZOPHRENIA USING THE SUBJECTIVE RESPONSE TO A TEST DOSE OF A NEUROLEPTIC

    PubMed Central

    Borde, Milind; Davis, Elizabeth J.B.; Sharma, L.N.

    1991-01-01

    SUMMARY Twenty four patients meeting R.D.C. criteria for schizophrenia were assessed using the B.P.R.S. before starting neuroleptics. They were then given a standardized test dose of haloperidol. Their subjective response to the test dose was assessed 4 hours later by a blind rater. The B.P.R.S. ratings were repeated after 3 weeks of neuroleptic treatment. A dysphoric response to the test dose was associated with a poor therapeutic outcome. The implications of these findings are discussed. PMID:21897458

  17. Dose-response characteristics of ketamine effect on locomotion, cognitive function and central neuronal activity.

    PubMed

    Imre, Gabor; Fokkema, Dirk S; Den Boer, Johan A; Ter Horst, Gert J

    2006-04-14

    The present dose-response study sought to determine the effects of subanesthetic dosages (4-16 mg/kg) of ketamine on locomotion, sensorimotor gating (PPI), working memory, as well as c-fos expression in various limbic regions implicated in the pathogenesis of schizophrenia. In addition, we examined whether ketamine-induced locomotion was influenced by the dark/light cycle. We found that ketamine increased locomotor activity in a dose dependent manner, but found no influence of the dark-light cycle. Additionally, ketamine dose-dependently interrupted PPI, resulting in prepulse facilitation at doses of 8 and 12 mg/kg. The dose of 12 mg/kg also induced impairments in working memory assessed by the discrete-trial delayed-alternation task. C-fos expression indicated that the dose-dependent behavioral effects of ketamine might be related to changes in the activity of limbic regions, notably hippocampus and amygdala.

  18. Tea Consumption and Risk of Bladder Cancer: A Dose-Response Meta-Analysis

    PubMed Central

    Weng, Hong; Zeng, Xian-Tao; Li, Sheng; Kwong, Joey S. W.; Liu, Tong-Zu; Wang, Xing-Huan

    2017-01-01

    Background and Objective: Controversial results of the association between tea (black tea, green tea, mate, and oolong tea) consumption and risk of bladder cancer were reported among epidemiological studies. Thus, we performed a meta-analysis of observational studies to investigate the association. Methods: We searched the PubMed and Embase for studies of tea consumption and bladder cancer that were published in any language up to March, 2016. Cohort or case-control studies were included in the meta-analysis. All statistical analyses were performed in Stata 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationship between tea consumption and risk of bladder cancer. Results: Totally, 25 case-control studies (15 643 cases and 30 795 controls) and seven prospective cohort studies (1807 cases and 443 076 participants) were included. The meta-analysis showed that tea consumption was not significantly associated with bladder cancer risk (OR = 0.96, 95% CI 0.86–1.06) (in a comparison of highest vs. lowest category). No non-linearity association was observed between tea consumption and bladder cancer risk (P = 0.51 for non-linearity). Specific analysis for black tea, green tea, and mate yielded similar results. The dose-response analysis showed the summary OR for an increment of 1 cup/day of tea consumption was 1.01 (95% CI 0.97–1.05). Conclusion: Results based on current meta-analysis indicated that no significant association was observed between tea consumption and risk of bladder cancer. PMID:28167914

  19. Tea Consumption and Risk of Bladder Cancer: A Dose-Response Meta-Analysis.

    PubMed

    Weng, Hong; Zeng, Xian-Tao; Li, Sheng; Kwong, Joey S W; Liu, Tong-Zu; Wang, Xing-Huan

    2016-01-01

    Background and Objective: Controversial results of the association between tea (black tea, green tea, mate, and oolong tea) consumption and risk of bladder cancer were reported among epidemiological studies. Thus, we performed a meta-analysis of observational studies to investigate the association. Methods: We searched the PubMed and Embase for studies of tea consumption and bladder cancer that were published in any language up to March, 2016. Cohort or case-control studies were included in the meta-analysis. All statistical analyses were performed in Stata 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relationship between tea consumption and risk of bladder cancer. Results: Totally, 25 case-control studies (15 643 cases and 30 795 controls) and seven prospective cohort studies (1807 cases and 443 076 participants) were included. The meta-analysis showed that tea consumption was not significantly associated with bladder cancer risk (OR = 0.96, 95% CI 0.86-1.06) (in a comparison of highest vs. lowest category). No non-linearity association was observed between tea consumption and bladder cancer risk (P = 0.51 for non-linearity). Specific analysis for black tea, green tea, and mate yielded similar results. The dose-response analysis showed the summary OR for an increment of 1 cup/day of tea consumption was 1.01 (95% CI 0.97-1.05). Conclusion: Results based on current meta-analysis indicated that no significant association was observed between tea consumption and risk of bladder cancer.

  20. Dose-response relationship between sleep duration and human psychomotor vigilance and subjective alertness

    NASA Technical Reports Server (NTRS)

    Jewett, M. E.; Dijk, D. J.; Kronauer, R. E.; Dinges, D. F.

    1999-01-01

    Although it has been well documented that sleep is required for human performance and alertness to recover from low levels after prolonged periods of wakefulness, it remains unclear whether they increase in a linear or asymptotic manner during sleep. It has been postulated that there is a relation between the rate of improvement in neurobehavioral functioning and rate of decline of slow-wave sleep and/or slow-wave activity (SWS/SWA) during sleep, but this has not been verified. Thus, a cross-study comparison was conducted in which dose-response curves (DRCs) were constructed for Stanford Sleepiness Scale (SSS) and Psychomotor Vigilance Task (PVT) tests taken at 1000 hours by subjects who had been allowed to sleep 0 hours, 2 hours, 5 hours or 8 hours the previous night. We found that the DRCs to each PVT metric improved in a saturating exponential manner, with recovery rates that were similar [time constant (T) approximately 2.14 hours] for all the metrics. This recovery rate was slightly faster than, though not statistically significantly different from, the reported rate of SWS/SWA decline (T approximately 2.7 hours). The DRC to the SSS improved much more slowly than psychomotor vigilance, so that it could be fit equally well by a linear function (slope = -0.26) or a saturating exponential function (T = 9.09 hours). We conclude that although SWS/SWA, subjective alertness, and a wide variety of psychomotor vigilance metrics may all change asymptotically during sleep, it remains to be determined whether the underlying physiologic processes governing their expression are different.

  1. Antibody response of an elderly population to a supplemental dose of influenza B vaccine.

    PubMed

    Peters, N L; Meiklejohn, G; Jahnigen, D W

    1988-07-01

    Recent reports have suggested that the antibody response of elderly persons to standard doses of influenza vaccine is depressed. We examined the effect of an additional threefold dose of influenza B vaccine on the antibody response in elderly, ambulatory veterans. One hundred thirty-one male subjects aged 70 years and older were randomized to receive one of three influenza vaccine regimens: Group I received standard trivalent influenza vaccine containing 15 micrograms of B/USSR/100/83 in one arm and placebo in the other; Group II received standard trivalent vaccine in one arm and a supplemental dose of 45 micrograms of B/USSR in the other; Group III received the same dose as group II combined in one arm with a placebo in the other. Antibody levels were measured at baseline, 1 month, and 5 months. Nearly 80% of the participants achieved levels of antibody to B/USSR considered protective; seroconversion rates varied from 40% to 61%. No significant differences in antibody response to B/USSR occurred among the vaccine groups, and there were more side effects at higher doses. The higher dose groups did, however, achieve greater antibody levels to the drifted influenza B virus which circulated during the year of the study. Response to the influenza A components of the vaccine, however, may have been blunted in Group III which received a large dose of A and B antigens all at one site.

  2. The Key Events Dose-Response Framework: A Cross-Disciplinary Mode-of-Action Based Approach to Examining Dose-Response and Thresholds

    PubMed Central

    JULIEN, ELIZABETH; BOOBIS, ALAN R.; OLIN, STEPHEN S.

    2009-01-01

    The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents—food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework—the Key Events Dose-Response Framework (KEDRF)—for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents. PMID:19690994

  3. Bystander responses in low dose irradiated cells treated with plasma from gamma irradiated blood

    NASA Astrophysics Data System (ADS)

    Acheva, A.; Georgieva, R.; Rupova, I.; Boteva, R.; Lyng, F.

    2008-02-01

    There are two specific low-dose radiation-induced responses that have been the focus of radiobiologists' interest in recent years. These are the bystander effect in non-irradiated cells and the adaptive response to a challenge dose after prior low dose irradiation. In the present study we have investigated if plasma from irradiated blood can act as a 'challenge dose' on low dose irradiated reporter epithelial cells (HaCaT cell line). The main aim was to evaluate the overall effect of low dose irradiation (0.05 Gy) of reporter cells and the influence of bystander factors in plasma from 0.5 Gy gamma irradiated blood on these cells. The effects were estimated by clonogenic survival of the reporter cells. We also investigated the involvement of reactive oxygen species (ROS) as potential factors involved in the bystander signaling. Calcium fluxes and mitochondrial membrane potential (MMP) depolarization were also examined as a marker for initiation of apoptosis in the reporter cells. The results show that there are large individual differences in the production of bystander effects and adaptive responses between different donors. These may be due to the specific composition of the donor plasma. The observed effects generally could be divided into two groups: adaptive responses and additive effects. ROS appeared to be involved in the responses of the low dose pretreated reporter cells. In all cases there was a significant decrease in MMP which may be an early event in the apoptotic process. Calcium signaling also appeared to be involved in triggering apoptosis in the low dose pretreated reporter cells. The heterogeneity of the bystander responses makes them difficult to be modulated for medical uses. Specific plasma characteristics that cause these large differences in the responses would need to be identified to make them useful for radiotherapy.

  4. Response of V79 cells to low doses of X-rays and negative pi-mesons: clonogenic survival and DNA strand breaks.

    PubMed

    Marples, B; Adomat, H; Koch, C J; Skov, K A

    1996-10-01

    Mammalian cells are hypersensitive to very low doses of X-rays (< 0.2 Gy), a response which is followed by increased radioresistance up to 1 Gy. Increased radioresistance is postulated to be a response to DNA damage, possibly single-strand breaks, and it appears to be a characteristic of low linear energy transfer (LET) radiation. Here we demonstrate a correspondence between the extent of the increased radioresistance and linear energy transfer of 250 kVp X-rays and plateau and Bragg peak negative pi-mesons. The results support our hypothesis since the size of the increased radioresistant response appears to correspond to the number of radiation induced single-strand breaks. Furthermore, since survival prior to the increased radioresistant response (< 0.2 Gy) was LET-independent, these data support the notion that the increased radioresistant response may dictate the overall survival response to higher doses. However, while these data provide further circumstantial evidence for the involvement of DNA strand breaks in the triggering of increased radioresistance, more direct conclusions cannot be made. The data are not accurate enough to detect structure in the single-strand break profiles, the production of single-strand breaks being apparently linear with dose.

  5. Activation of Bone Remodeling after Fatigue: Differential Response to Linear Microcracks and Diffuse Damage

    PubMed Central

    Herman, B.C.; Cardoso, L.; Majeska, R.J.; Jepsen, K.J.; Schaffler, M.B

    2010-01-01

    Recent experiments point to two predominant forms of fatigue microdamage in bone: linear microcracks (tens to a few hundreds microns in length) and “diffuse damage” (patches of diffuse stain uptake in fatigued bone comprised of clusters of sublamellar-sized cracks). The physiological relevance of diffuse damage in activating bone remodeling is not known. In this study microdamage amount and type were varied to assess whether linear or diffuse microdamage have similar effects on the activation of intracortical resorption. Activation of resorption was correlated to the number of linear microcracks (Cr.Dn) in the bone (R2=0.60, p<0.01). In contrast, there was no activation of resorption in response to diffuse microdamage alone. Furthermore, there was no significant change in osteocyte viability in response to diffuse microdamage, suggesting that osteocyte apoptosis, which is know to activate remodeling at typical linear microcracks in bone, does not result from sublamellar damage. These findings indicate that inability of diffuse microdamage to activate resorption may be due to lack of a focal injury response. Finally, we found that duration of loading does not affect the remodeling response. In conclusion, our data indicate that osteocytes activate resorption in response to linear microcracks but not diffuse microdamage, perhaps due to lack of a focal injury-induced apoptotic response. PMID:20633708

  6. Development of Noise Dose/Visitor Response Relationships for the National Parks Overflight Rule: Bryce Canyon National Park Study

    DTIC Science & Technology

    1998-07-01

    National Rule). The foundation of the research program for the National Rule is the performance of noise dose/visitor response ( dose - response ) studies in...several National Parks. This document summarizes the results of a dose - response study conducted along two separate segments of a frontcountry, short

  7. Explicit solvent simulations of the aqueous oxidation potential and reorganization energy for neutral molecules: gas phase, linear solvent response, and non-linear response contributions.

    PubMed

    Guerard, Jennifer J; Tentscher, Peter R; Seijo, Marianne; Samuel Arey, J

    2015-06-14

    First principles simulations were used to predict aqueous one-electron oxidation potentials (Eox) and associated half-cell reorganization energies (λaq) for aniline, phenol, methoxybenzene, imidazole, and dimethylsulfide. We employed quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations of the oxidized and reduced species in an explicit aqueous solvent, followed by EOM-IP-CCSD computations with effective fragment potentials for diabatic energy gaps of solvated clusters, and finally thermodynamic integration of the non-linear solvent response contribution using classical MD. A priori predicted Eox and λaq values exhibit mean absolute errors of 0.17 V and 0.06 eV, respectively, compared to experiment. We also disaggregate Eox into several well-defined free energy properties, including the gas phase adiabatic free energy of ionization (7.73 to 8.82 eV), the solvent-induced shift in the free energy of ionization due to linear solvent response (-2.01 to -2.73 eV), and the contribution from non-linear solvent response (-0.07 to -0.14 eV). The linear solvent response component is further apportioned into contributions from the solvent-induced shift in vertical ionization energy of the reduced species (ΔVIEaq) and the solvent-induced shift in negative vertical electron affinity of the ionized species (ΔNVEAaq). The simulated ΔVIEaq and ΔNVEAaq are found to contribute the principal sources of uncertainty in computational estimates of Eox and λaq. Trends in the magnitudes of disaggregated solvation properties are found to correlate with trends in structural and electronic features of the solute. Finally, conflicting approaches for evaluating the aqueous reorganization energy are contrasted and discussed, and concluding recommendations are given.

  8. Association between vitamin C intake and lung cancer: a dose-response meta-analysis

    PubMed Central

    Luo, Jie; Shen, Li; Zheng, Di

    2014-01-01

    Epidemiological studies evaluating the association between the intake of vitamin C and lung cancer risk have produced inconsistent results. We conducted a meta-analysis to assess the association between them. Pertinent studies were identified by a search of PubMed, Web of Knowledge and Wan Fang Med Online through December of 2013. Random-effect model was used to combine the data for analysis. Publication bias was estimated using Begg's funnel plot and Egger's regression asymmetry test. Eighteen articles reporting 21 studies involving 8938 lung cancer cases were included in this meta-analysis. Pooled results suggested that highest vitamin C intake level versus lowest level was significantly associated with the risk of lung cancer [summary relative risk (RR) = 0.829, 95%CI = 0.734–0.937, I2 = 57.8%], especially in the United States and in prospective studies. A linear dose-response relationship was found, with the risk of lung cancer decreasing by 7% for every 100 mg/day increase in the intake of vitamin C [summary RR = 0.93, 95%CI = 0.88–0.98]. No publication bias was found. Our analysis suggested that the higher intake of vitamin C might have a protective effect against lung cancer, especially in the United States, although this conclusion needs to be confirmed. PMID:25145261

  9. Dose response of a new phytase on dry matter, calcium, and phosphorus digestibility in weaned piglets.

    PubMed

    Bento, M H L; Pedersen, C; Plumstead, P W; Salmon, L; Nyachoti, C M; Bikker, P

    2012-12-01

    The present study evaluated the dose response of Buttiauxella phytase on apparent total tract digestibility (ATTD) of DM, Ca, and P in weaned pigs at 2 locations. Experimental diets fed to weaned pigs were a positive control (PC), a negative control (NC), and NC supplemented with increasing levels of Buttiauxella phytase. In Trial A, ATTD of P was 57.2% for PC, 32.5% for NC, and 59.4, 62.0, 63.8, 66.0, and 67.3% for 250, 500, 750, 1000, and 2000 phytase units (FTU) added to NC, respectively. In Trial B, ATTD of P was 45.2% for PC, 28.4% for NC, and 58.7, 64.1, 67.9, and 70.9% for 250, 500, 1000, and 2000 FTU added to NC, respectively. In both studies, the reduction in P in the NC diets reduced (P < 0.01) ATTD of P when compared with the PC diets. Phytase supplementation linearly and quadratically increased (P < 0.01) ATTD of P at all inclusion levels to the NC diet. In conclusion, the average digestible P increase from Buttiauxella phytase (vs. the NC diet) was 1.3, 1.5, 1.6, and 1.7 g digestible P/kg feed for 250, 500, 1000, and 2000 FTU/kg, respectively.

  10. Linear attenuation coefficient and buildup factor of MCP-96 alloy for dose accuracy, beam collimation, and radiation protection.

    PubMed

    Hopkins, Deidre N; Maqbool, Muhammad; Islam, Mohammed S

    2012-07-01

    The linear attenuation coefficients and buildup factor of MCP-96 alloy were determined for (60)Co, (54)Mn, and (137)Cs gamma emitters and a NaI detector. The thickness of the MCP-96 attenuator was varied from 1 to 4 cm. A collimated beam of gamma rays was allowed to pass through various thicknesses of the MCP-96 alloy. The attenuated beam was detected by a NaI detector, and data were recorded by a multichannel analyzer. The run was repeated without the collimator for broad-beam geometry. For each run, the attenuated beam intensity was normalized by the intensity of the unattenuated incident beam obtained by removing the attenuators. Linear attenuation coefficients were determined by plotting of the intensity of the collimated beam against the attenuator thickness. For every thickness of the alloy, the ratio of the attenuated to the unattenuated beam was found to be higher in broad-beam geometry as compared to the same ratio in narrow-beam geometry. We used the difference in these ratios in broad and narrow-beam geometries to calculate the buildup factor. The buildup factor was found to increase with beam energy and attenuator thickness. Variation in the source-to-detector distance gave a lower value of the buildup factor for a small and a large distance and a higher value for an intermediate distance. The buildup factor was found to be greater than 1 in all cases. We conclude that the buildup factor must be calculated and incorporated for dose correction and precision when the MCP-96 alloy is used for tissue compensation or radiation shielding and protection purposes.

  11. Dose--response of initial G2-chromatid breaks induced in normal human fibroblasts by heavy ions

    NASA Technical Reports Server (NTRS)

    Kawata, T.; Durante, M.; Furusawa, Y.; George, K.; Takai, N.; Wu, H.; Cucinotta, F. A.; Dicello, J. F. (Principal Investigator)

    2001-01-01

    PURPOSE: To investigate initial chromatid breaks in prematurely condensed G2 chromosomes following exposure to heavy ions of different LET. MATERIAL AND METHODS: Exponentially growing human fibroblast cells AG1522 were irradiated with gamma-rays, energetic carbon (13 keV/ microm, 80 keV/microm), silicon (55 keV/microm) and iron (140 keV/microm, 185keV/microm, 440keV/microm) ions. Chromosomes were prematurely condensed using calyculin-A. Initial chromatid-type and isochromatid breaks in G2 cells were scored. RESULTS: The dose response curves for total chromatid breaks were linear regardless of radiation type. The relative biological effectiveness (RBE) showed a LET-dependent increase, peaking around 2.7 at 55-80keV/microm and decreasing at higher LET. The dose response curves for isochromatid-type breaks were linear for high-LET radiations, but linear-quadratic for gamma-rays and 13 keV/microm carbon ions. The RBE for the induction of isochromatid breaks obtained from linear components increased rapidly between 13keV/microm (about 7) and 80keV/microm carbon (about 71), and decreased gradually until 440 keV/microm iron ions (about 66). CONCLUSIONS: High-LET radiations are more effective at inducing isochromatid breaks, while low-LET radiations are more effective at inducing chromatid-type breaks. The densely ionizing track structures of heavy ions and the proximity of sister chromatids in G2 cells result in an increase in isochromatid breaks.

  12. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans.

    PubMed Central

    Greer, Monte A; Goodman, Gay; Pleus, Richard C; Greer, Susan E

    2002-01-01

    Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect

  13. Micro RNA responses to chronic or acute exposures to low dose ionizing radiation

    PubMed Central

    Chaudhry, M. Ahmad; Omaruddin, Romaica A.; Kreger, Bridget; de Toledo, Sonia M.; Azzam, Edouard I.

    2014-01-01

    Human health risks of exposure to low dose ionizing radiation remain ambiguous and are the subject of intense debate. A wide variety of biological effects are induced after cellular exposure to ionizing radiation, but the underlying molecular mechanism(s) remain to be completely understood. We hypothesized that low dose c-radiation-induced effects are controlled by the modulation of micro RNA (miRNA) that participate in the control of gene expression at the posttranscriptional level and are involved in many cellular processes. We monitored the expression of several miRNA in human cells exposed to acute or chronic low doses of 10 cGy or a moderate dose of 400 cGy of 137Cs γ-rays. Dose, dose rate and time dependent differences in the relative expression of several miRNA were investigated. The expression patterns of many miRNA differed after exposure to either chronic or acute 10 cGy. The expression of miRNA let-7e, a negative regulator of RAS oncogene, and the c-MYC miRNA cluster were upregulated after 10 cGy chronic dose but were downregulated after 3 h of acute 10 cGy. The miR-21 was upregulated in chronic or acute low dose and moderate dose treated cells and its target genes hPDCD4, hPTEN, hSPRY2, and hTPM1 were found to be downregulated. These findings provide evidence that low dose and dose rate c-irradiation dictate the modulation of miRNA, which can result in a differential cellular response than occurs at high doses. This information will contribute to understanding the risks to human health after exposure to low dose radiation. PMID:22367372

  14. Kinetic Modeling Reveals the Roles of Reactive Oxygen Species Scavenging and DNA Repair Processes in Shaping the Dose-Response Curve of KBrO₃-Induced DNA Damage.

    PubMed

    Spassova, Maria A; Miller, David J; Nikolov, Alexander S

    2015-01-01

    We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical KBrO3 which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits KBrO3-caused oxidative damage. Our modeling revealed that sustained exposure to KBrO3 can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical's toxicity dose dependence based on the dose-response of early genotoxic events.

  15. Dicentric chromosomes and gamma-H2AX foci formation in lymphocytes of human blood samples exposed to a CT scanner: a direct comparison of dose response relationships.

    PubMed

    Golfier, Sven; Jost, Gregor; Pietsch, Hubertus; Lengsfeld, Philipp; Eckardt-Schupp, Friederike; Schmid, Ernst; Voth, Matthias

    2009-02-01

    Experiments using the induction of dicentric chromosomes (dicentrics) as well as the gamma-H2AX foci formation in lymphocytes of blood samples from a healthy donor were performed to directly evaluate the radiation sensitivity of both biological endpoints. For computed tomography scans at dose levels from 0.025 to 1 Gy, a linear-quadratic dose-response relationship for dicentrics and a linear dose-response relationship for gamma-H2AX foci were obtained. The coefficients of the dose-response relationship for dicentrics are alpha = (3.76 +/- 0.29) x 10(-2) Gy(-1) and beta = (5.54 +/- 0.45) x 10(-2) Gy(-2), the linear coefficient for gamma-H2AX foci is (7.38 +/- 0.11) Gy(-1). The findings indicate that scoring of dicentrics as well as microscopic analysis of gamma-H2AX foci are sensitive methods to quantify a radiation-induced biological damage at low doses. However, since gamma-H2AX foci can be partially repaired within a few hours, biological damages present for days or even months, which constitute the clinically relevant endpoints, can only be quantified reliably by scoring of chromosome aberrations. Thus currently the quantification of dicentrics or reciprocal translocations remains the recommended method for estimating the effect of exposures to low dose levels of radiation ('biological dosimetry'). However, owing to the high radiation sensitivity of the gamma-H2AX foci assay observed in the present study, further investigations on the effectiveness of low-linear energy transfer radiation qualities in producing gamma-H2AX foci in lymphocytes from healthy donors should be performed.

  16. The spin polarized linear response from density functional theory: Theory and application to atoms

    SciTech Connect

    Fias, Stijn Boisdenghien, Zino; De Proft, Frank; Geerlings, Paul

    2014-11-14

    Within the context of spin polarized conceptual density functional theory, the spin polarized linear response functions are introduced both in the [N, N{sub s}] and [N{sub α}, N{sub β}] representations. The mathematical relations between the spin polarized linear response functions in both representations are examined and an analytical expression for the spin polarized linear response functions in the [N{sub α}, N{sub β}] representation is derived. The spin polarized linear response functions were calculated for all atoms up to and including argon. To simplify the plotting of our results, we integrated χ(r, r′) to a quantity χ(r, r{sup ′}), circumventing the θ and ϕ dependence. This allows us to plot and to investigate the periodicity throughout the first three rows in the periodic table within the two different representations. For the first time, χ{sub αβ}(r, r{sup ′}), χ{sub βα}(r, r{sup ′}), and χ{sub SS}(r, r{sup ′}) plots have been calculated and discussed. By integration of the spin polarized linear response functions, different components to the polarisability, α{sub αα}, α{sub αβ}, α{sub βα}, and α{sub ββ} have been calculated.

  17. A review of linear response theory for general differentiable dynamical systems

    NASA Astrophysics Data System (ADS)

    Ruelle, David

    2009-04-01

    The classical theory of linear response applies to statistical mechanics close to equilibrium. Away from equilibrium, one may describe the microscopic time evolution by a general differentiable dynamical system, identify nonequilibrium steady states (NESS) and study how these vary under perturbations of the dynamics. Remarkably, it turns out that for uniformly hyperbolic dynamical systems (those satisfying the 'chaotic hypothesis'), the linear response away from equilibrium is very similar to the linear response close to equilibrium: the Kramers-Kronig dispersion relations hold, and the fluctuation-dispersion theorem survives in a modified form (which takes into account the oscillations around the 'attractor' corresponding to the NESS). If the chaotic hypothesis does not hold, two new phenomena may arise. The first is a violation of linear response in the sense that the NESS does not depend differentiably on parameters (but this nondifferentiability may be hard to see experimentally). The second phenomenon is a violation of the dispersion relations: the susceptibility has singularities in the upper half complex plane. These 'acausal' singularities are actually due to 'energy nonconservation': for a small periodic perturbation of the system, the amplitude of the linear response is arbitrarily large. This means that the NESS of the dynamical system under study is not 'inert' but can give energy to the outside world. An 'active' NESS of this sort is very different from an equilibrium state, and it would be interesting to see what happens for active states to the Gallavotti-Cohen fluctuation theorem.

  18. Association between dietary vitamin C intake and risk of esophageal cancer: A dose-response meta-analysis.

    PubMed

    Bo, Yacong; Lu, Yan; Zhao, Yan; Zhao, Erjiang; Yuan, Ling; Lu, Weiquan; Cui, Lingling; Lu, Quanjun

    2016-04-15

    While several epidemiological studies have investigated the association between vitamin C and risk of esophageal cancer, the results remain inconsistent. In the present study, a meta-analysis was conducted to assess the impact of dietary vitamin C intake on esophageal cancer risk. Online databases were searched up to March 29, 2015, for studies on the association between dietary vitamin C intake and esophageal cancer risk. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Dose-response analyses were performed using the method of restricted cubic splines with four knots at percentiles of 5, 35, 65 and 95% of the distribution. Publication bias was estimated using Egger's tests and funnel plots. In all, 15 articles were included in this meta-analysis, including 20 studies, containing 7063 controls and 3955 cases of esophageal cancer. By comparing the highest vs. the lowest categories of vitamin C intake, we found that vitamin C was inversely associated with the risk of esophageal cancer [overall OR = 0.58, 95% CI = 0.49-0.68, I(2) = 56%]. A linear dose-response relationship was found. With an increase in dietary vitamin C intake of 50 mg/day, the risk of esophageal cancer statistically decreased by 13% (OR = 0.87, 95% CI = 0.80-0.93, p(linearity) = 0.0002). In conclusion, our analysis suggested that the higher intake of dietary vitamin C might have a protective effect against esophageal cancer.

  19. Length of surgery and pressure ulcers risk in cardiovascular surgical patients: a dose-response meta-analysis.

    PubMed

    Chen, Hong-Lin; Shen, Wang-Qin; Liu, Peng; Liu, Kun

    2017-03-02

    The aim of this study was to assess the relationship between length of surgery (LOS) and pressure ulcer (PU) risk in cardiovascular surgery patients. PubMed and Web of Science were systematically searched. We compared LOS difference between PU (+) group and PU (-) group. We also examined the dose-response effect of this relationship. The mean LOS in the PU(+) groups ranged from 252·5 to 335·7 minutes, compared with 233·0 to 298·3 minutes in PU(-) groups. The LOS was higher in PU(+) groups compared with PU(-) groups [weighted mean difference (WMD) = 36·081 minutes; 95% CI: 21·640-50·522 minutes; Z = 4·90, P = 0·000]. The funnel plot showed no publication bias. A significant dose-response association was also found between the LOS and the risk of surgery-related pressure ulcers (SRPU, model χ(2)  = 9·29, P = 0·000). In the linear model, the PU OR was 1·296 (95% CI 1·097-1·531) for a 60-minute increase in the LOS intervals and 13·344 (95% CI 2·521-70·636) for a 600-minute increase. In a spline model, the OR of PU increased almost linearly along with the LOS. Our meta-analysis indicated that LOS was an important risk factor for pressure ulcers in cardiovascular surgical patients.

  20. Dose-Response Evaluation of Braslet-M Occlusion Cuffs

    NASA Technical Reports Server (NTRS)

    Ebert, Douglas; Garcia, Kathleen; Sargsyan, Ashot E.; Ham, David; Hamilton, Douglas; Dulchavsky, Scott A.

    2010-01-01

    Introduction: Braslet-M is a set of special elasticized thigh cuffs used by the Russian space agency to reduce the effects of the head-ward fluid shift during early adaptation to microgravity by sequestering fluid in the lower extremities. Currently, no imaging modalities are used in the calibration of the device, and the pressure required to produce a predictable physiological response is unknown. This investigation intends to relate the pressure exerted by the cuffs to the extent of fluid redistribution and commensurate physiological effects. Materials and Methods: Ten healthy subjects with standardized fluid intake participated in the study. Data collection included femoral and internal jugular vein imaging in two orthogonal planes, pulsed Doppler of cervical and femoral vessels and middle cerebral artery, optic nerve imaging, and echocardiography. Braslet-M cuff pressure was monitored at the skin interface using pre-calibrated pressure sensors. Using 6 and 30 head-down tilt in two separate sessions, the effect of Braslet-M was assessed while incrementally tightening the cuffs. Cuffs were then simultaneously released to document the resulting hemodynamic change. Results: Preliminary analysis shows correlation between physical pressure exerted by the Braslet-M device and several parameters such as jugular and femoral vein cross-sections, resistivity of the lower extremity vascular bed, and others. A number of parameters reflect blood redistribution and will be used to determine the therapeutic range of the device and to prevent unsafe application. Conclusion: Braslet-M exerts a physical effect that can be measured and correlated with many changes in central and peripheral hemodynamics. Analysis of the full data set will be required to make definitive recommendations regarding the range of safe therapeutic application. Objective data and subjective responses suggest that a safer and equally effective use of Braslet can be achieved when compared with the current

  1. Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

    SciTech Connect

    Hall, Matthew D.; Schultheiss, Timothy E.; Smith, David D.; Nguyen, Khanh H.; Wong, Jeffrey Y.C.

    2015-01-01

    Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the

  2. Dose-Response Relationship between Alanine Aminotransferase Levels within the Reference Interval and Metabolic Syndrome in Chinese Adults

    PubMed Central

    Wu, Peipei; Chen, Qicai; Chen, Lili; Zhang, Pengpeng; Xiao, Juan; Chen, Xiaoxiao; Liu, Meng

    2017-01-01

    Purpose Elevation in serum alanine aminotransferase (ALT) levels is a biomarker for metabolic syndrome (MS); however, the relationship has not been fully investigated within the reference interval of ALT levels. Our objective was to explore the relationship between serum ALT levels within the reference interval and MS in Chinese adults. Materials and Methods This cross-sectional study included 16028 adults, who attended routine health check-ups at Shengli Oilfield Central Hospital from January 2006 to March 2012. The reference interval of serum ALT level was defined as less than 40 U/L. Logistic regression models and restricted cubic spline were used to evaluate the association of ALT with MS. Results The prevalence of MS in the total population was 13.7% (6.4% for females and 18.4% for males). Multiple logistic regression showed that ALT levels were positively associated with MS after adjustment for potential confounding factors. The odds ratio of MS in the top quartile was 4.830 [95% confidence interval (CI): 2.980–7.829] in females and 3.168 (95% CI: 2.649–3.790) in males, compared with the ALT levels in the bottom quartile. The restricted cubic spline models revealed a positive non-linear dose-response relationship between ALT levels and the risk of MS in women (p for nonlinearity was 0.0327), but a positive linear dose-response relationship in men (p for nonlinearity was 0.0659). Conclusion Serum ALT levels within the reference interval are positively associated with MS in a dose-response manner. Elevated ALT levels, even within the reference interval, may reflect early dysmetabolic changes. PMID:27873509

  3. Establishment of a Dose-response Curve for X-ray-Induced Micronuclei in Human Lymphocytes.

    PubMed

    Lusiyanti, Yanti; Alatas, Zubaidah; Syaifudin, Mukh; Purnami, Sofiati

    2016-01-01

    The cytokinesis-block micronucleus assay in peripheral blood lymphocytes is an established technique for biodosimetry. The aim of this project was to generate a X-ray induced micronuclei (MN) curve for peripheral blood lymphocytes taken from five healthy donors. The blood samples were irradiated with X-rays of 122 KeV at a dose rate of 0.652 Gy/min to doses of 0.5, 1, 2, 3, and 4 Gy. The blood samples were then cultured for 72 h at 37°C and processed following the International Atomic Energy Agency standard procedure with slight modifications. The result showed that the yields of MN frequencies were increased with the increase of radiation dose. Reconstruction of the relationship of MN with dose was fitted to a linear-quadratic model using Chromosome Aberration Calculation Software version 2.0. Due to their advantages, mainly, the dependence on radiation dose and dose rate, despite their limitation, these curves will be useful as alternative method for in vitro dose reconstruction and can support the preparedness for public or occupational radiation overexposure and protection. The results reported here also give us confidence to apply the obtained calibration curve of MN for future biological dosimetry requirements in Indonesia.

  4. Establishment of a Dose-response Curve for X-ray-Induced Micronuclei in Human Lymphocytes

    PubMed Central

    Lusiyanti, Yanti; Alatas, Zubaidah; Syaifudin, Mukh; Purnami, Sofiati

    2016-01-01

    The cytokinesis-block micronucleus assay in peripheral blood lymphocytes is an established technique for biodosimetry. The aim of this project was to generate a X-ray induced micronuclei (MN) curve for peripheral blood lymphocytes taken from five healthy donors. The blood samples were irradiated with X-rays of 122 KeV at a dose rate of 0.652 Gy/min to doses of 0.5, 1, 2, 3, and 4 Gy. The blood samples were then cultured for 72 h at 37°C and processed following the International Atomic Energy Agency standard procedure with slight modifications. The result showed that the yields of MN frequencies were increased with the increase of radiation dose. Reconstruction of the relationship of MN with dose was fitted to a linear-quadratic model using Chromosome Aberration Calculation Software version 2.0. Due to their advantages, mainly, the dependence on radiation dose and dose rate, despite their limitation, these curves will be useful as alternative method for in vitro dose reconstruction and can support the preparedness for public or occupational radiation overexposure and protection. The results reported here also give us confidence to apply the obtained calibration curve of MN for future biological dosimetry requirements in Indonesia. PMID:28217283

  5. Quasilaminar regime in the linear response of a turbulent flow to wall waviness

    NASA Astrophysics Data System (ADS)

    Luchini, Paolo; Charru, François

    2017-01-01

    The linear response of the wall-shear stress of a turbulent flow to wall waviness is analyzed in the context of a comparison between existing experiments, direct numerical simulations, and analytical approximations. The spectral region where the response is largest is found to be amenable to a simplified quasilaminar analysis. The end result is a parameterless description of this phenomenon that completely captures its physics in a single analytical formula, a Padé approximation of the response function.

  6. Dose response of selected solid state detectors in applied homogeneous transverse and longitudinal magnetic fields

    SciTech Connect

    Reynolds, M.; Fallone, B. G.; Rathee, S.

    2014-09-15

    Purpose: MR-Linac devices under development worldwide will require standard calibration, commissioning, and quality assurance. Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is therefore evaluated in varying transverse and longitudinal magnetic fields for this purpose. Methods: The Monte Carlo code PENELOPE was used to model irradiation of a PTW 60003 diamond detector and IBA PFD diode detector in the presence of a magnetic field. The field itself was varied in strength, and oriented both transversely and longitudinally with respect to the incident photon beam. The long axis of the detectors was oriented either parallel or perpendicular to the photon beam. The dose to the active volume of each detector in air was scored, and its ratio to dose with zero magnetic field strength was determined as the “dose response” in magnetic field. Measurements at low fields for both detectors in transverse magnetic fields were taken to evaluate the accuracy of the simulations. Additional simulations were performed in a water phantom to obtain few representative points for beam profile and percent depth dose measurements. Results: Simulations show significant dose response as a function of magnetic field in transverse field geometries. This response can be near 20% at 1.5 T, and it is highly dependent on the detectors’ relative orientation to the magnetic field, the energy of the photon beam, and detector composition. Measurements at low transverse magnetic fields verify the simulations for both detectors in their relative orientations to radiation beam. Longitudinal magnetic fields, in contrast, show little dose response, rising slowly with magnetic field, and reaching 0.5%–1% at 1.5 T regardless of detector orientation. Water tank and in air simulation results were the same within simulation uncertainty where lateral electronic equilibrium is present and expectedly

  7. Linear-response calculation in the time-dependent density functional theory

    SciTech Connect

    Nakatsukasa, Takashi; Inakura, Tsunenori; Avogadro, Paolo; Ebata, Shuichiro; Sato, Koichi; Yabana, Kazuhiro

    2012-11-12

    Linear response calculations based on the time-dependent density-functional theory are presented. Especially, we report results of the finite amplitude method which we have recently proposed as an alternative and feasible approach to the (quasiparticle-)random-phase approximation. Calculated properties of the giant resonances and low-energy E1 modes are discussed. We found a universal linear correlation between the low-energy E1 strength and the neutron skin thickness.

  8. High dose and low dose Lactobacilli acidophilus exerted differential immune modulating effects on T cell immune responses induced by an oral human rotavirus vaccine in gnotobiotic pigs

    PubMed Central

    Wen, Ke; Li, Guohua; Bui, Tammy; Liu, Fangning; Li, Yanru; Kocher, Jacob; Lin, Lin; Yang, Xingdong; Yuan, Lijuan

    2011-01-01

    Background Strain-specific effects of probiotics in pro- or anti-inflammatory immune responses have been well recognized. Several proinflammatory Lactobacillus strains have been shown to act as adjuvants to enhance the immunogenicity of vaccines. However, dose effects of probiotics in modulating immune responses are not clearly understood. This study examined the dose effects of Lactobacillus acidophilus (LA) NCFM strain on T cell immune responses to rotavirus vaccination in a gnotobiotic (Gn) pig model. Methods Frequencies of IFN-γ producing CD4+ and CD8+ T cell and IL-10 and TGF-β producing CD4+CD25+ and CD4+CD25- regulatory T (Treg) cell responses were determined in the intestinal and systemic lymphoid tissues of Gn pigs vaccinated with an oral human rotavirus vaccine in conjunction with low dose (5 feedings; up to 106 colony forming units [CFU]/dose) or high dose (14 feedings; up to 109 CFU/dose) or without LA feeding. Results Low dose LA significantly promoted IFN-γ producing T cell responses and down-regulated Treg cell responses and their TGF-β and IL-10 productions in all the tissues compared to the high dose LA and control groups. To the contrary, high dose LA increased the frequencies of Treg cells in most of the tissues compared to the control groups. The dose effects of LA on IFN-γ producing T cell and CD4+CD25- Treg cell immune responses were similar in the intestinal and systemic lymphoid tissues and were independent from the vaccination. Conclusion Thus the same probiotic strain in different doses can either promote or suppress IFN-γ producing T cell or Treg cell immune responses. These findings have significant implications in the use of probiotic lactobacilli as immunostimulatory versus immunoregulatory agents. Probiotics can be ineffective or even detrimental if not used at the optimal dosage for the appropriate purposes. PMID:22178726

  9. Dose-Responsive Gene Expression in Suberoylanilide Hydroxamic Acid (SAHA) Treated Resting CD4+ T Cells

    PubMed Central

    Reardon, Brian; Beliakova-Bethell, Nadejda; Spina, Celsa A.; Singhania, Akul; Margolis, David M.; Richman, Douglas R.; Woelk, Christopher H.

    2015-01-01

    Design Persistent latently infected CD4+ T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a proposed activation therapy. However, off-target effects on expression in host immune cells are poorly understood. We hypothesized that HDACi-modulated genes would be best identified with dose-response analysis. Methods Resting primary CD4+ T cells were treated with 0.34, 1, 3, or 10 μM of the HDACi, SAHA, for 24 hours and subjected to microarray gene expression analysis. Genes with dose-correlated expression were filtered to identify a subset with consistent up or downregulation at each SAHA dose. Histone modifications were characterized in 6 SAHA dose-responsive genes by chromatin immunoprecipitation (ChIP-RT-qPCR). Results A large number of genes were shown to be up (N=657) or downregulated (N=725) by SAHA in a dose-responsive manner (FDR p-value < 0.05, fold change ≥ |2|). Several genes (CTNNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in vivo biomarkers of SAHA activity. SAHA dose-responsive genes included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV. Pathway analysis suggested net downregulation of T cell activation with increasing SAHA dose. Histone acetylation was not correlated with host gene expression, but plausible alternative mechanisms for SAHA-modulated gene expression were identified. Conclusions Numerous genes in CD4+ T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone modification, and altered expression and activity of transcription factors. PMID:26258524

  10. Estimating the predictive quality of dose-response after model selection.

    PubMed

    Hu, Chuanpu; Dong, Yingwen

    2007-07-20

    Prediction of dose-response is important in dose selection in drug development. As the true dose-response shape is generally unknown, model selection is frequently used, and predictions based on the final selected model. Correctly assessing the quality of the predictions requires accounting for the uncertainties caused by the model selection process, which has been difficult. Recently, a new approach called data perturbation has emerged. It allows important predictive characteristics be computed while taking model selection into consideration. We study, through simulation, the performance of data perturbation in estimating standard error of parameter estimates and prediction errors. Data perturbation was found to give excellent prediction error estimates, although at times large Monte Carlo sizes were needed to obtain good standard error estimates. Overall, it is a useful tool to characterize uncertainties in dose-response predictions, with the potential of allowing more accurate dose selection in drug development. We also look at the influence of model selection on estimation bias. This leads to insights into candidate model choices that enable good dose-response prediction.

  11. (Dose and dose-rate effects on radiation response): Foreign trip report, May 5--13, 1989

    SciTech Connect

    Selby, P.B.

    1989-05-25

    The traveler attended the thirty-eighth session of UNSCEAR where he took part in the meetings of the Biological Subgroup and the Working Group of the entire UNSCEAR Committee. He was responsible for the correction of several major errors in the draft version of the document entitled ''Dose and Dose-Rate Effects on Radiation Response. '' He also played a key role in bringing about UNSCEAR's decision to prepare a document on hereditary defects in the current cycle. To a large extent, it was because of the traveler's arguments that UNSCEAR reversed the Secretariat's decision not to reevaluate genetic risk in this cycle and decided that a genetics report was among its highest priorities. Important contacts were made with many internationally prominent scientists involved in radiation protection and risk evaluation. It was apparent how important it is to ORNL, to DOE, to the United States Government, and to UNSCEAR itself to have a representative from the United States present who has firsthand familiarity with the mouse data that are used to such an important extent in genetic risk estimation. Many of these data were collected in the Biology Division of ORNL.

  12. Development of the dose-response relationship for human toxoplasma gondii infection associated with meat consumption

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States.A substantial portion of human T. gondii infections may be acquired through the consumption of meats. The dose-response relationship for human exposure...

  13. AN EXTRACT OF PENICILLIUM CHRYSOGENUM INDUCES DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES IN MICE

    EPA Science Inventory

    Rationale: Penicillium chrysogenum, a common indoor mold, is known to have several allergens and can induce allergic responses in a mouse model of allergic penicilliosis. Our hypothesis is that soluble components of P. chrysogenum (PCE) can dose-dependently induce responses typ...

  14. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  15. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

  16. Dose-response curve for anaesthetics based on the Monod-Wyman-Changeux model.

    PubMed

    Iwai, T; Kihara, H; Imaiand, K; Uchida, M

    1996-10-01

    We have analysed the dose-response curve for halothane and isoflurane according to the Monod-Wyman-Changeux (MWC) model. This model describes the nature of the physiological data reported by Wakamori, Ikemoto and Akaike for inhibitory Cl currents induced by GABA or glycine in dissociated rat brain neurones and by Herrington and colleagues for Ca2+ currents in clonal pituitary cells. With some assumptions on the difference in response to anaesthetics between patients, the model is applicable in vivo, and it also describes well the human dose-response curve for isoflurane reported by Mather, Raftery and Prys-Roberts. However, the steeply sigmoidal dose-response curve in humans for halothane presented by deJong and Eger is difficult to understand with the same model, because it gives rise to unrealistic MWC variables.

  17. Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

    PubMed

    Shi, J Q; Wang, B; Will, E J; West, R M

    2012-11-20

    We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.

  18. Improved anamnestic response among adolescents boosted with a higher dose of the hepatitis B vaccine.

    PubMed

    Chaves, Sandra S; Groeger, Justina; Helgenberger, Louisa; Auerbach, Steven B; Bialek, Stephanie R; Hu, Dale J; Drobeniuc, Jan

    2010-04-01

    Some hepatitis B vaccine booster studies have suggested waning of vaccine-induced immunity in adolescents vaccinated starting at birth. Those studies, however, used a pediatric formulation of the hepatitis B vaccine as a booster to detect anamnestic response. We compared adolescents boosted with an adult dose of hepatitis B vaccine with those boosted with a pediatric dose. Among adolescents who had lost protective antibody levels against hepatitis B, a higher proportion had an anamnestic response when boosted with the adult dose (60.0% vs. 43.8%). Thus, higher antigen concentrations may be required to elicit an adequate immune memory response. Despite improved anamnestic response, our study still raises concerns about whether children immunized in early infancy will remain protected from hepatitis B as they age into adulthood.

  19. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    PubMed

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

  20. Linear response theory for symmetry improved two particle irreducible effective actions

    NASA Astrophysics Data System (ADS)

    Brown, Michael J.; Whittingham, Ian B.; Kosov, Daniel S.

    2016-05-01

    We investigate the linear response of an O (N ) scalar quantum field theory subject to external perturbations using the symmetry-improved two-particle irreducible effective action (SI-2PIEA) formalism [A. Pilaftsis and D. Teresi, Nucl. Phys. B874, 594 (2013)]. Despite satisfactory equilibrium behavior, we find a number of unphysical effects at the linear response level. Goldstone boson field fluctuations are overdetermined, with the only consistent solution being to set the fluctuations and their driving sources to zero, except for momentum modes where the Higgs and Goldstone self-energies obey a particular relationship. Also Higgs field fluctuations propagate masslessly, despite the Higgs propagator having the correct mass. These pathologies are independent of any truncation of the effective action and still exist even if we relax the overdetermining Ward identities, so long as the constraint is formulated O (N ) covariantly. We discuss possible reasons for the apparent incompatibility of the constraints and linear response approximation and possible ways forward.

  1. Determining the continuous family of quantum Fisher information from linear-response theory

    NASA Astrophysics Data System (ADS)

    Shitara, Tomohiro; Ueda, Masahito

    2016-12-01

    The quantum Fisher information represents a continuous family of metrics on the space of quantum states and places the fundamental limit on the accuracy of quantum state estimation. We show that the entire family of quantum Fisher information can be determined from linear-response theory through generalized covariances. We derive the generalized fluctuation-dissipation theorem that relates linear-response functions to generalized covariances and hence allows us to determine the quantum Fisher information from linear-response functions, which are experimentally measurable quantities. As an application, we examine the skew information, which is a quantum Fisher information, of a harmonic oscillator in thermal equilibrium, and show that the equality of the skew-information-based uncertainty relation holds.

  2. Dielectric function beyond the random-phase approximation: kinetic theory versus linear response theory.

    PubMed

    Reinholz, H; Röpke, G

    2012-03-01

    Calculating the frequency-dependent dielectric function for strongly coupled plasmas, the relations within kinetic theory and linear response theory are derived and discussed in comparison. In this context, we give a proof that the Kohler variational principle can be extended to arbitrary frequencies. It is shown to be a special case of the Zubarev method for the construction of a nonequilibrium statistical operator from the principle of the extremum of entropy production. Within kinetic theory, the commonly used energy-dependent relaxation time approach is strictly valid only for the Lorentz plasma in the static case. It is compared with the result from linear response theory that includes electron-electron interactions and applies for arbitrary frequencies, including bremsstrahlung emission. It is shown how a general approach to linear response encompasses the different approximations and opens options for systematic improvements.

  3. Habitual Chocolate Consumption May Increase Body Weight in a Dose-Response Manner

    PubMed Central

    Greenberg, James A.; Buijsse, Brian

    2013-01-01

    Objective Habitual chocolate intake was recently found to be associated with lower body weight in three cross-sectional epidemiological studies. Our objective was to assess whether these cross-sectional results hold up in a more rigorous prospective analysis. Methods We used data from the Atherosclerosis Risk in Communities cohort. Usual dietary intake was assessed by questionnaire at baseline (1987–98), and after six years. Participants reported usual chocolate intake as the frequency of eating a 1-oz (∼28 g) serving. Body weight and height were measured at the two visits. Missing data were replaced by multiple imputation. Linear mixed-effects models were used to evaluate cross-sectional and prospective associations between chocolate intake and adiposity. Results Data were from 15,732 and 12,830 participants at the first and second visit, respectively. More frequent chocolate consumption was associated with a significantly greater prospective weight gain over time, in a dose-response manner. For instance, compared to participants who ate a chocolate serving less often than monthly, those who ate it 1–4 times a month and at least weekly experienced an increase in Body Mass Index (kg/m2) of 0.26 (95% CI 0.08, 0.44) and 0.39 (0.23, 0.55), respectively, during the six-year study period. In cross-sectional analyses the frequency of chocolate consumption was inversely associated with body weight. This inverse association was attenuated after excluding participants with preexisting obesity-related illness. Compared to participants without such illness, those with it had higher BMI and reported less frequent chocolate intake, lower caloric intake, and diets richer in fruits and vegetables. They tended to make these dietary changes after becoming ill. Conclusions Our prospective analysis found that a chocolate habit was associated with long-term weight gain, in a dose-response manner. Our cross-sectional finding that chocolate intake was associated with lower body

  4. Application of Low Dose Radiation Adaptive Response to Control Aging-Related Disease

    SciTech Connect

    Doss, Mohan

    2013-11-01

    Oxidative damage has been implicated in the pathogenesis of most aging-related diseases including neurodegenerative diseases. Antioxidant supplementation has been found to be ineffective in reducing such diseases, but increased endogenous production of antioxidants from the adaptive response due to physical and cognitive exercises (which increase oxidative metabolism and oxidative stress) has been effective in reducing some of the diseases. Low dose radiation (LDR), which increases oxidative stress and results in adaptive response of increased antioxidants, may provide an alternative method of controlling the aging-related diseases. We have studied the effect of LDR on the induction of adaptive response in rat brains and the effectiveness of the LDR in reducing the oxidative damage caused by subsequent high dose radiation. We have also investigated the effect of LDR on apomorphine-induced rotations in the 6-hydroxydopamine (6-OHDA) unilaterally-lesioned rat model of Parkinson?s disease (PD). LDR was observed to initiate an adaptive response in the brain, and reduce the oxidative damage from subsequent high dose radiation exposure, confirming the effectiveness of LDR adaptive response in reducing the oxidative damage from the free radicals due to high dose radiation. LDR resulted in a slight improvement in Tyrosine hydroxylase expression on the lesioned side of substantia nigra (indicative of its protective effect on the dopaminergic neurons), and reduced the behavioral symptoms in the 6-OHDA rat model of PD. Translation of this concept to humans, if found to be applicable, may be a possible approach for controlling the progression of PD and other neurodegenerative diseases. Since any translation of the concept to humans would be hindered by the currently prevalent carcinogenic concerns regarding LDR based on the linear no-threshold (LNT) model, we have also studied the justifications for the use of the LNT model. One of the shortcomings of the LNT model is that it

  5. Cerebellar lobules and dentate nuclei mirror cortical force-related-BOLD responses: Beyond all (linear) expectations.

    PubMed

    Alahmadi, Adnan A S; Pardini, Matteo; Samson, Rebecca S; Friston, Karl J; Toosy, Ahmed T; D'Angelo, Egidio; Gandini Wheeler-Kingshott, Claudia A M

    2017-02-27

    The relationship between the BOLD response and an applied force was quantified in the cerebellum using a power grip task. To investigate whether the cerebellum responds in an on/off way to motor demands or contributes to motor responses in a parametric fashion, similarly to the cortex, five grip force levels were investigated under visual feedback. Functional MRI data were acquired in 13 healthy volunteers and their responses were analyzed using a cerebellum-optimized pipeline. This allowed us to evaluate, within the cerebellum, voxelwise linear and non-linear associations between cerebellar activations and forces. We showed extensive non-linear activations (with a parametric design), covering the anterior and posterior lobes of the cerebellum with a BOLD-force relationship that is region-dependent. Linear responses were mainly located in the anterior lobe, similarly to the cortex, where linear responses are localized in M1. Complex responses were localized in the posterior lobe, reflecting its key role in attention and executive processing, required during visually guided movement. Given the highly organized responses in the cerebellar cortex, a key question is whether deep cerebellar nuclei show similar parametric effects. We found positive correlations with force in the ipsilateral dentate nucleus and negative correlations on the contralateral side, suggesting a somatotopic organization of the dentate nucleus in line with cerebellar and cortical areas. Our results confirm that there is cerebellar organization involving all grey matter structures that reflect functional segregation in the cortex, where cerebellar lobules and dentate nuclei contribute to complex motor tasks with different BOLD response profiles in relation to the forces. Hum Brain Mapp, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

  6. A study of the shape of dose-response curves for acute lethality at low response: a megadaphnia study'

    SciTech Connect

    Sebaugh, J.L.; Wilson, J.D.; Tucker, M.W.; Adams, W.J. )

    1991-12-01

    Dose-response curves were developed for the immobilization response in Daphnia magna to four toxicants. The purpose of this work was to study the effect of the form of the model and the number of concentration levels used on the estimates of typical low-dose effective concentrations (1%, 5%, 10%). The generalized four-parameter logistic model was used as the reference. When using 12 concentration levels, one of the logistic family two- or three-parameter models was shown reliably to represent each of these various sets of dose-response data, and to provide adequate estimates of EC01 and EC05, as well as EC10 and EC50. For two of the toxicants, an asymmetric model was required. When reducing the number of concentrations to five, the EC10 and EC50 were well estimated by the probit model, with acceptable results at the EC05 level.

  7. The effect of measurement error on the dose-response curve

    SciTech Connect

    Yoshimura, I. )

    1990-07-01

    In epidemiological studies for an environmental risk assessment, doses are often observed with errors. However, they have received little attention in data analysis. This paper studies the effect of measurement errors on the observed dose-response curve. Under the assumptions of the monotone likelihood ratio on errors and a monotone increasing dose-response curve, it is verified that the slope of the observed dose-response curve is likely to be gentler than the true one. The observed variance of responses are not so homogeneous as to be expected under models without errors. The estimation of parameters in a hockey-stick type dose-response curve with a threshold is considered on line of the maximum likelihood method for a functional relationship model. Numerical examples adaptable to the data in a 1986 study of the effect of air pollution that was conducted in Japan are also presented. The proposed model is proved to be suitable to the data in the example cited in this paper.

  8. Immune response to 1 and 2 dose regimens of measles vaccine in Pakistani children.

    PubMed

    Hussain, Hamidah; Akram, Dure Samin; Chandir, Subhash; Khan, Aamir J; Memon, Ashraf; Halsey, Neal A

    2013-12-01

    Measles is a significant problem in Pakistan despite vaccine coverage rates reported at 80%. The purpose of this study was to determine the serologic response in children after one dose of measles vaccine at 9 mo versus two doses at 9 and 15 mo of age. From March through December 2006, children were enrolled from immunization clinics and squatter settlements in Karachi. Blood samples were taken from children in Group A at 9-10 mo of age prior to measles vaccine and 8 to 11 weeks later; from children in Group B at 16-17 mo of age after receiving 2 doses of measles vaccine; and from children in Group C who had received at least one dose of measles vaccine by 5 y of age. After the first dose of measles vaccine, 107/147 (73%) of children in Group A were seropositive, 157/180 (87%) of children in Group B were seropositive after two doses and 126/200 (63%) of children in Group C were seropositive at 5 y of age. The post-vaccination geometric mean antibody concentrations were higher in females than males in groups A (irrespective of pre-vaccination antibody levels) and B. The serologic response to one and two doses of measles vaccine was lower in children in Karachi than has been reported in many other countries. Two doses of vaccine were significantly better than one dose. An in-depth investigation is needed to determine the reason for the lower-than-expected protection rates. Differences in immunogenicity between genders need to be further studied. Recent introduction of supplemental measles vaccine doses should help control measles in Pakistan.

  9. Low-dose total-body γ irradiation modulates immune response to acute proton radiation.

    PubMed

    Luo-Owen, Xian; Pecaut, Michael J; Rizvi, Asma; Gridley, Daila S

    2012-03-01

    Health risks due to exposure to low-dose/low-dose-rate radiation alone or when combined with acute irradiation are not yet clearly defined. This study quantified the effects of protracted exposure to low-dose/low-dose-rate γ rays with and without acute exposure to protons on the response of immune and other cell populations. C57BL/6 mice were irradiated with ⁵⁷Co (0.05 Gy at 0.025 cGy/h); subsets were subsequently exposed to high-dose/high-dose-rate proton radiation (250 MeV; 2 or 3 Gy at 0.5 Gy/min). Analyses were performed at 4 and 17 days postexposure. Spleen and thymus masses relative to body mass were decreased on day 4 after proton irradiation with or without pre-exposure to γ rays; by day 17, however, the decrease was attenuated by the priming dose. Proton dose-dependent decreases, either with or without pre-exposure to γ rays, occurred in white blood cell, lymphocyte and granulocyte counts in blood but not in spleen. A similar pattern was found for lymphocyte subpopulations, including CD3+ T, CD19+ B, CD4+ T, CD8+ T and NK1.1+ natural killer (NK) cells. Spontaneous DNA synthesis by leukocytes after proton irradiation was high in blood on day 4 and high in spleen on day 17; priming with γ radiation attenuated the effect of 3 Gy in both body compartments. Some differences were also noted among groups in erythrocyte and thrombocyte characteristics. Analysis of splenocytes activated with anti-CD3/anti-CD28 antibodies showed changes in T-helper 1 (Th1) and Th2 cytokines. Overall, the data demonstrate that pre-exposure of an intact mammal to low-dose/low-dose-rate γ rays can attenuate the response to acute exposure to proton radiation with respect to at least some cell populations.

  10. Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

    SciTech Connect

    Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H. )

    1990-05-01

    Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.

  11. Application of linear response theory to magnetotransport properties of dense plasmas

    SciTech Connect

    Adams, J. R.; Redmer, R.; Reinholz, H.

    2010-03-15

    Linear response theory, as developed within the Zubarev formalism, is a quantum statistical approach for describing systems out of but close to equilibrium, which has been successfully applied to a wide variety of plasmas in an external electric field and/or containing a temperature gradient. We present here an extension of linear response theory to include the effects of an external magnetic field. General expressions for the complete set of relevant transport properties are given. In particular, the Hall effect and the influence of a magnetic field on the dc electrical conductivity are discussed. Low-density limits including electron-electron scattering are presented as well as results for arbitrary degeneracy.

  12. Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

    SciTech Connect

    Little, Mark P.; Kleinerman, Ruth A.; Stovall, Marilyn; Smith, Susan A.; Mabuchi, Kiyohiko

    2012-12-01

    Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  13. Dose-response trend tests for tumorigenesis, adjusted for body weight.

    PubMed

    Gaylor, D W; Kodell, R L

    1999-06-01

    Several studies have demonstrated a relationship between rodent body weight and tumor incidence for some tissue/organ sites. It is not uncommon for a chemical tested for carcinogenicity to also affect body weight. In such cases, comparisons of tumor incidence may be biased by body-weight differences across dose groups. A simple procedure was investigated for reducing this bias. This procedure divides the animals into a few groups based on body weight. Body weight at 12 months was used, before the appearance of a tumor was likely to affect body weight. Statistics for dose-response trend tests are calculated within body weight strata and pooled to obtain an overall dose-response trend test. This procedure is analogous to that currently used, of stratifying animals, based on their age at the time of removal from a study. Age stratification is used to account for differences in animal age across dose groups, which can affect comparisons of tumor incidence. Several examples were investigated where the high-dose group had reduced body weights and associated reductions in tumor incidence. When the data were analyzed by body-weight strata, some positive dose-response trends for tumor incidence were demonstrated. In one case, the weight-adjusted analysis indicated that a negative dose-response trend in tumor incidence was a real effect, in addition to a body weight reduction. These examples indicate that it is important to consider the effects of body weight changes as low as 10%, and perhaps below, that were caused by chemicals in 2-year bioassays for carcinogenesis. The simple procedure of analyzing tumor incidence within body-weight strata can reduce the bias introduced by weight differences across dose groups.

  14. Time and dose-response effects of honokiol on UVB-induced skin cancer development.

    PubMed

    Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

    2012-06-01

    Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

  15. Magnetization transfer proportion: a simplified measure of dose response for polymer gel dosimetry

    NASA Astrophysics Data System (ADS)

    Whitney, Heather M.; Gochberg, Daniel F.; Gore, John C.

    2008-12-01

    The response to radiation of polymer gel dosimeters has most often been described by measuring the nuclear magnetic resonance transverse relaxation rate as a function of dose. This approach is highly dependent upon the choice of experimental parameters, such as the echo spacing time for Carr-Purcell-Meiboom-Gill-type pulse sequences, and is difficult to optimize in imaging applications where a range of doses are applied to a single gel, as is typical for practical uses of polymer gel dosimetry. Moreover, errors in computing dose can arise when there are substantial variations in the radiofrequency (B1) field or resonant frequency, as may occur for large samples. Here we consider the advantages of using magnetization transfer imaging as an alternative approach and propose the use of a simplified quantity, the magnetization transfer proportion (MTP), to assess doses. This measure can be estimated through two simple acquisitions and is more robust in the presence of some sources of system imperfections. It also has a dependence upon experimental parameters that is independent of dose, allowing simultaneous optimization at all dose levels. The MTP is shown to be less susceptible to B1 errors than are CPMG measurements of R2. The dose response can be optimized through appropriate choices of the power and offset frequency of the pulses used in magnetization transfer imaging.

  16. Optimal design of clinical trials with biologics using dose-time-response models.

    PubMed

    Lange, Markus R; Schmidli, Heinz

    2014-12-30

    Biologics, in particular monoclonal antibodies, are important therapies in serious diseases such as cancer, psoriasis, multiple sclerosis, or rheumatoid arthritis. While most conventional drugs are given daily, the effect of monoclonal antibodies often lasts for months, and hence, these biologics require less frequent dosing. A good understanding of the time-changing effect of the biologic for different doses is needed to determine both an adequate dose and an appropriate time-interval between doses. Clinical trials provide data to estimate the dose-time-response relationship with semi-mechanistic nonlinear regression models. We investigate how to best choose the doses and corresponding sample size allocations in such clinical trials, so that the nonlinear dose-time-response model can be precisely estimated. We consider both local and conservative Bayesian D-optimality criteria for the design of clinical trials with biologics. For determining the optimal designs, computer-intensive numerical methods are needed, and we focus here on the particle swarm optimization algorithm. This metaheuristic optimizer has been successfully used in various areas but has only recently been applied in the optimal design context. The equivalence theorem is used to verify the optimality of the designs. The methodology is illustrated based on results from a clinical study in patients with gout, treated by a monoclonal antibody.

  17. A Hypothesis Concerning the Biphasic Dose-response of Tumors to Angiostatin and Endostatin.

    PubMed

    Parris, George E

    2015-01-01

    This manuscript proposes a hypothesis to explain the U-shaped dose-response observed for angiostatin and other high-molecular-weight drugs in various anti-cancer bio-assays. The dose-response curves for angiostatin and endostatin (measured as suppression of tumor growth) go through an optimum (i.e., minimum tumor growth) and then becomes less effective at higher doses. The literature suggests that at lower doses the primary action of these high-molecular-weight drugs is to counteract the angiogenic effects of vascular endothelial growth factor (VEGF). To do this, the drugs must pass out of the blood vessel and enter the extra-cellular matrix (ECM) where VEGF induces the growth and fusion of tip cells. Ironically, VEGF actually facilitates access of the drugs to the ECM by making the vascular endothelium leaky. At higher doses, the high-molecular-weight drugs seem to reverse VEGF-induced permeability of the endothelium. Thus, at high dose rates, it is hypothesized that the drugs are not able to enter the ECM and block the angiogenic effects of VEGF there. As a result, high doses of the drugs do not suppress vascularization of the tumor or tumor growth. Moreover, if the permeability of the vessels is suppressed, the VEGF released by the stroma is concentrated in the ECM where it amplifies the angiogenic activity around the tumor.

  18. Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams.

    PubMed

    Castriconi, Roberta; Ciocca, Mario; Mirandola, Alfredo; Sini, Carla; Broggi, Sara; Schwarz, Marco; Fracchiolla, Francesco; Martišíková, Mária; Aricò, Giulia; Mettivier, Giovanni; Russo, Paolo

    2017-01-21

    We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.

  19. Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams

    NASA Astrophysics Data System (ADS)

    Castriconi, Roberta; Ciocca, Mario; Mirandola, Alfredo; Sini, Carla; Broggi, Sara; Schwarz, Marco; Fracchiolla, Francesco; Martišíková, Mária; Aricò, Giulia; Mettivier, Giovanni; Russo, Paolo

    2017-01-01

    We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.

  20. Near-linear response of mean monsoon strength to a broad range of radiative forcings.

    PubMed

    Boos, William R; Storelvmo, Trude

    2016-02-09

    Theoretical models have been used to argue that seasonal mean monsoons will shift abruptly and discontinuously from wet to dry stable states as their radiative forcings pass a critical threshold, sometimes referred to as a "tipping point." Further support for a strongly nonlinear response of monsoons to radiative forcings is found in the seasonal onset of the South Asian summer monsoon, which is abrupt compared with the annual cycle of insolation. Here it is shown that the seasonal mean strength of monsoons instead exhibits a nearly linear dependence on a wide range of radiative forcings. First, a previous theory that predicted a discontinuous, threshold response is shown to omit a dominant stabilizing term in the equations of motion; a corrected theory predicts a continuous and nearly linear response of seasonal mean monsoon strength to forcings. A comprehensive global climate model is then used to show that the seasonal mean South Asian monsoon exhibits a near-linear dependence on a wide range of isolated greenhouse gas, aerosol, and surface albedo forcings. This model reproduces the observed abrupt seasonal onset of the South Asian monsoon but produces a near-linear response of the mean monsoon by changing the duration of the summer circulation and the latitude of that circulation's ascent branch. Thus, neither a physically correct theoretical model nor a comprehensive climate model support the idea that seasonal mean monsoons will undergo abrupt, nonlinear shifts in response to changes in greenhouse gas concentrations, aerosol emissions, or land surface albedo.

  1. Effects of ozone on pulmonary function: the relationship of response to dose

    SciTech Connect

    Kleinman, M.T. )

    1991-07-01

    A dose-response relationship for the effects of ozone on pulmonary function in humans has been derived using the concept of internal thoracic dose. This quantity, which represents the dose of inhaled pollutant capable of reaching and affecting target sites in the lower respiratory tract, was estimated using a mathematical model derived in part from theory and in part from data obtained using human and animal subjects. The model was applied to ozone exposures of individuals ranging in age from infants to adults over age 65 and for exercise conditions ranging from rest to heavy exercise (greater than 6 times resting minute ventilation). The dose model was successfully used to compare results from clinical studies in which subjects were exposed under disparate conditions of exercise, exposure concentration and exposure duration. The model can also be applied to estimate doses to populations exposed to ambient pollution. The effects of ozone on pulmonary function in adults and children were evaluated using the model. On the basis of dose of ozone (micrograms O3 per kg body mass), children, aged 8 to 15 years, and adults were equally sensitive. When dose is analyzed as a function of age, the data suggest that children, under the age of 6 years, receive greater doses to respiratory tract tissues than do older children or adults, under equivalent conditions of exposure.

  2. Beneficial effects of low dose radiation in response to the oncogenic KRAS induced cellular transformation