Non-Linear Dose-Response Relationships in Biology, Toxicology and Medicine
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.
Competitive inhibition can linearize dose-response and generate a linear rectifier.
Savir, Yonatan; Tu, Benjamin P; Springer, Michael
2015-09-23
Many biological responses require a dynamic range that is larger than standard bi-molecular interactions allow, yet the also ability to remain off at low input. Here we mathematically show that an enzyme reaction system involving a combination of competitive inhibition, conservation of the total level of substrate and inhibitor, and positive feedback can behave like a linear rectifier-that is, a network motif with an input-output relationship that is linearly sensitive to substrate above a threshold but unresponsive below the threshold. We propose that the evolutionarily conserved yeast SAGA histone acetylation complex may possess the proper physiological response characteristics and molecular interactions needed to perform as a linear rectifier, and we suggest potential experiments to test this hypothesis. One implication of this work is that linear responses and linear rectifiers might be easier to evolve or synthetically construct than is currently appreciated.
Competitive inhibition can linearize dose-response and generate a linear rectifier
Savir, Yonatan; Tu, Benjamin P.; Springer, Michael
2015-01-01
Summary Many biological responses require a dynamic range that is larger than standard bi-molecular interactions allow, yet the also ability to remain off at low input. Here we mathematically show that an enzyme reaction system involving a combination of competitive inhibition, conservation of the total level of substrate and inhibitor, and positive feedback can behave like a linear rectifier—that is, a network motif with an input-output relationship that is linearly sensitive to substrate above a threshold but unresponsive below the threshold. We propose that the evolutionarily conserved yeast SAGA histone acetylation complex may possess the proper physiological response characteristics and molecular interactions needed to perform as a linear rectifier, and we suggest potential experiments to test this hypothesis. One implication of this work is that linear responses and linear rectifiers might be easier to evolve or synthetically construct than is currently appreciated. PMID:26495436
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.
IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?
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...
Linearization of dose-response curve of the radiochromic film dosimetry system
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
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.
Cancer risk assessment: Optimizing human health through linear dose-response models.
Calabrese, Edward J; Shamoun, Dima Yazji; Hanekamp, Jaap C
2015-07-01
This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot". Copyright © 2015 Elsevier Ltd. All rights reserved.
Origin of the linearity no threshold (LNT) dose-response concept.
Calabrese, Edward J
2013-09-01
This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673-674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201-213, 1929; Oliver in Science 71:44-46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose-response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide.
Tests of the linear, no-threshold dose-response relationship for high-LET radiation
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.
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.
A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.
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.
A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.
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.
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
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
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.
Ecological versus case-control studies for testing a linear-no threshold dose-response relationship.
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.
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.
Origins of Total-Dose Response Variability in Linear Bipolar Microcircuits
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.
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.
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.
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
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
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
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.
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.
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).
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.
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.
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
Seong, Ki Moon; Seo, Songwon; Lee, Dalnim; Kim, Min-Jeong; Lee, Seung-Sook; Park, Sunhoo; Jin, Young Woo
2016-02-01
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.
NASA Astrophysics Data System (ADS)
Ghelawi, M. A.; Moore, J. S.; Bisby, R. H.; Dodd, N. J. F.
2001-01-01
Food spoilage is caused by infestation by insects, contamination by bacteria and fungi and by deterioration by enzymes. In the third world, it has been estimated that 25% of agricultural products are lost before they reach the market. One way to decrease such losses is by treatment with ionising radiation and maximum permitted doses have been established for treatment of a wide variety of foods. For dates this dose is 2.0 kGy. Detection of irradiated foods is now essential and here we have used ESR to detect and estimate the dose received by a single date. The ESR spectrum of unirradiated date stone contains a single line g=2.0045 (signal A). Irradiation up to 2.0 kGy induces radical formation with g=1.9895, g=2.0159 (signal C) and g=1.9984 (signal B) high field. The lines with g=1.9895 and 2.0159 are readily detected and stable at room temperature for at least 27 months for samples irradiated up to this dose. The yield of the radicals resulting in these lines increase linearly up to a dose of 5.0 kGy as is evidenced by the linear increase in their intensity. In blind trials of 21 unirradiated and irradiated dates we are able to identify with 100% accuracy an irradiated sample and to estimate the dose to which the sample was irradiated to within ˜0.5 kGy.
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
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
Jaikuna, Tanwiwat; Khadsiri, Phatchareewan; Chawapun, Nisa; Saekho, Suwit; Tharavichitkul, Ekkasit
2017-02-01
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. 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). 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. 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.
Non linear processes modulated by low doses of radiation exposure
NASA Astrophysics Data System (ADS)
Mariotti, Luca; Ottolenghi, Andrea; Alloni, Daniele; Babini, Gabriele; Morini, Jacopo; Baiocco, Giorgio
The perturbation induced by radiation impinging on biological targets can stimulate the activation of several different pathways, spanning from the DNA damage processing to intra/extra -cellular signalling. In the mechanistic investigation of radiobiological damage this complex “system” response (e.g. omics, signalling networks, micro-environmental modifications, etc.) has to be taken into account, shifting from a focus on the DNA molecule solely to a systemic/collective view. An additional complication comes from the finding that the individual response of each of the involved processes is often not linear as a function of the dose. In this context, a systems biology approach to investigate the effects of low dose irradiations on intra/extra-cellular signalling will be presented, where low doses of radiation act as a mild perturbation of a robustly interconnected network. Results obtained through a multi-level investigation of both DNA damage repair processes (e.g. gamma-H2AX response) and of the activation kinetics for intra/extra cellular signalling pathways (e.g. NFkB activation) show that the overall cell response is dominated by non-linear processes - such as negative feedbacks - leading to possible non equilibrium steady states and to a poor signal-to-noise ratio. Together with experimental data of radiation perturbed pathways, different modelling approaches will be also discussed.
Wu, Lang; Zhu, Jingjing
2015-09-01
Is there an association between oral contraceptive (OC) use and thyroid cancer risk in females? OC use is inversely associated with the risk of thyroid cancer in females. OC use may be relevant to the risk of thyroid cancer as suggested by some epidemiological studies. However, the findings are inconsistent regarding the effect direction and size. This systematic review and meta-analysis included a total of 1906 patients from about 1.3 million individuals who had participated in 9 prospective cohort studies. The follow-up length ranged 7.5-15.9 years. PubMed (MEDLINE) was searched through to January 2015 for eligible studies. References of relevant review articles were also manually screened. Prospective cohort studies that evaluated the association between OC use and thyroid cancer risk were included. Study characteristics including patients' characteristics, length of the follow-up and risk estimates were extracted. The quality of the studies was also assessed. The included studies were of high methodological quality according to the Newcastle-Ottawa Quality Assessment Scale. After pooling risk estimates from all the studies, there was a significant inverse association between the longest versus shortest duration of OC use and the risk of thyroid cancer [relative risk (RR) = 0.84, 95% confidence interval (CI) 0.73-0.97], with no considerable heterogeneity (I(2) = 26.1%). There was no significant publication bias. The significant association persisted in the subgroup of high-quality studies (RR = 0.84, 95% CI 0.72-0.97). By dose-response analysis, there was a linear relationship (P = 0.0001) between the duration of OC use and thyroid cancer risk. The summary RR for an increment of 1 year of OC use was 0.96 (95% CI 0.94-0.98), with no significant heterogeneity. Individual patient data were unavailable for a more accurate estimation. These results indicate that OC use may decrease the risk of thyroid cancer in females. This may have implications for women
Dose Response Data for Hormonally Active Chemicals ...
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
The road to linearity: why linearity at low doses became the basis for carcinogen risk assessment.
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.
Dose response signal detection under model uncertainty.
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.
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
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.
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.
Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation.
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.
Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation.
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.
A Bayesian Semiparametric Model for Radiation Dose-Response Estimation.
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.
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.
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.
Anthocyanin excretion increases linearly with increasing strawberry dose.
USDA-ARS?s Scientific Manuscript database
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...
Single toxin dose-response models revisited
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
Linear low-dose extrapolation for noncancer heath effects is the exception, not the rule.
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.
Simultaneous measurements of absorbed dose and linear energy transfer in therapeutic proton beams
NASA Astrophysics Data System (ADS)
Granville, Dal A.; Sahoo, Narayan; Sawakuchi, Gabriel O.
2016-02-01
The biological response resulting from proton therapy depends on both the absorbed dose in the irradiated tissue and the linear energy transfer (LET) of the beam. Currently, optimization of proton therapy treatment plans is based only on absorbed dose. However, recent advances in proton therapy delivery have made it possible to vary the LET distribution for potential therapeutic gain, leading to investigations of using LET as an additional parameter in plan optimization. Having a method to measure and verify both absorbed dose and LET as part of a quality assurance program would be ideal for the safe delivery of such plans. Here we demonstrated the potential of an optically stimulated luminescence (OSL) technique to simultaneously measure absorbed dose and LET. We calibrated the ratio of ultraviolet (UV) to blue emission intensities from Al2O3:C OSL detectors as a function of LET to facilitate LET measurements. We also calibrated the intensity of the blue OSL emission for absorbed dose measurements and introduced a technique to correct for the LET-dependent dose response of OSL detectors exposed to therapeutic proton beams. We demonstrated the potential of our OSL technique by using it to measure LET and absorbed dose under new irradiation conditions, including patient-specific proton therapy treatment plans. In the beams investigated, we found the OSL technique to measure dose-weighted LET within 7.9% of Monte Carlo-simulated values and absorbed dose within 2.5% of ionization chamber measurements.
Linear vs. function-based dose algorithm designs.
Stanford, N
2011-03-01
The performance requirements prescribed in IEC 62387-1, 2007 recommend linear, additive algorithms for external dosimetry [IEC. Radiation protection instrumentation--passive integrating dosimetry systems for environmental and personal monitoring--Part 1: General characteristics and performance requirements. IEC 62387-1 (2007)]. Neither of the two current standards for performance of external dosimetry in the USA address the additivity of dose results [American National Standards Institute, Inc. American National Standard for dosimetry personnel dosimetry performance criteria for testing. ANSI/HPS N13.11 (2009); Department of Energy. Department of Energy Standard for the performance testing of personnel dosimetry systems. DOE/EH-0027 (1986)]. While there are significant merits to adopting a purely linear solution to estimating doses from multi-element external dosemeters, differences in the standards result in technical as well as perception challenges in designing a single algorithm approach that will satisfy both IEC and USA external dosimetry performance requirements. The dosimetry performance testing standards in the USA do not incorporate type testing, but rely on biennial performance tests to demonstrate proficiency in a wide range of pure and mixed fields. The test results are used exclusively to judge the system proficiency, with no specific requirements on the algorithm design. Technical challenges include mixed beta/photon fields with a beta dose as low as 0.30 mSv mixed with 0.05 mSv of low-energy photons. Perception-based challenges, resulting from over 20 y of experience with this type of performance testing in the USA, include the common belief that the overall quality of the dosemeter performance can be judged from performance to pure fields. This paper presents synthetic testing results from currently accredited function-based algorithms and new developed purely linear algorithms. A comparison of the performance data highlights the benefits of each
Dose reduction using a dynamic, piecewise-linear attenuator
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
Dose reduction using a dynamic, piecewise-linear attenuator.
Hsieh, Scott S; Fleischmann, Dominik; Pelc, Norbert J
2014-02-01
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. 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. 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 attenuator was relatively
Dose reduction using a dynamic, piecewise-linear attenuator
Hsieh, Scott S.; Fleischmann, Dominik; Pelc, Norbert J.
2014-01-01
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, assuming a 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 without a 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
Linear low-dose extrapolation for noncancer health effects is the exception, not the rule
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
Minimized Doses for Linear Accelerator Radiosurgery of Brainstem Metastasis
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.
Minimized doses for linear accelerator radiosurgery of brainstem metastasis.
Valery, Charles A; Boskos, Christos; Boisserie, Gilbert; Lamproglou, Ioannis; Cornu, Philippe; Mazeron, Jean-Jacques; Simon, Jean-Marc
2011-06-01
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. 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 . 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. Lower doses than previously reported can achieve the same local control and survival rates in brain metastases, with minimal side effects. Copyright © 2011 Elsevier Inc. All rights reserved.
Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal?**
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...
Nonmonotonic Dose-Response Curves and Endocrine-Disrupting Chemicals: Fact or Falderal?**
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...
Exercise dose response in muscle.
Duscha, B D; Annex, B H; Johnson, J L; Huffman, K; Houmard, J; Kraus, W E
2012-03-01
Exercise increases peak VO2 partially through muscle adaptations. However, understanding muscle adaptations related to exercise dose is incomplete. This study investigated exercise training dose on capillaries per fiber and capillaries per area; and citrate synthase from vastus lateralis and related both to changes in peak VO2. This randomized trial compared 3 exercise doses: low amount-moderate intensity (n=40), low amount-high intensity (n=47), high amount-high intensity (n=41), and a control group (n=35). Both measures of capillary supply increased in all exercise groups (p<0.05). Low amount-high intensity and high amount-high intensity improved citrate synthase (p<0.05) and the low amount-moderate intensity citrate synthase approached significance (p=0.059). Muscle improvements were only related to improvements in peak VO2 in high amount-high intensity (citrate synthase, r=0.304; capillaries:fiber, r= - 0.318; p<0.05 and capillaries/mm2 r= - 0.310, p<0.05). These data suggest muscle adaptations occur following both low and high exercise doses, but are only related to improved peak VO2 following high amount-high intensity training. © Georg Thieme Verlag KG Stuttgart · New York.
Exercise Dose Response in Muscle
Duscha, Brian D.; Annex, Brian H.; Johnson, Johanna L.; Huffman, Kim M.; Houmard, Joseph A.; Kraus, William E.
2013-01-01
Exercise increases peak VO2 partially through muscle adaptations. However, understanding muscle adaptations related to exercise dose is incomplete. This study investigated exercise training dose on capillaries per fiber and capillaries per area; and citrate synthase from vastus lateralis and related both to changes in peak VO2. This randomized trial compared 3 exercise doses: low amount-moderate intensity (n = 40), low amount-high intensity (n=47 ), high amount-high intensity (n=41 ), and a control group (n=35). Both measures of capillary supply increased in all exercise groups (p<0.05). Low amount-high intensity and high amount-high intensity improved citrate synthase (p<0.05) and the low amount-moderate intensity citrate synthase approached significance (p=0.059). Muscle improvements were only related to improvements in peak VO2 in high amount-high intensity (citrate synthase, r = 0.308; capillaries: fiber, r = −0.318; p < 0.05 and capillaries/mm2 r= −0.310, p < 0.05 ). These data suggest muscle adaptations occur following both low and high exercise doses, but are only related to improved peak VO2 following high amount-high intensity training. PMID:22261824
Aune, Dagfinn; Sen, Abhijit; Prasad, Manya; Norat, Teresa; Janszky, Imre; Tonstad, Serena; Romundstad, Pål; Vatten, Lars J
2016-05-04
To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease. PubMed and Embase databases searched up to 23 September 2015. Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality. Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models. 230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I(2)=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I(2)=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I(2)=89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I(2)=97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (Pnon-linearity <0.001), and the lowest risk was observed at BMI 23-24 in never smokers, 22-23 in healthy never smokers, and 20-22 in studies of never smokers with ≥20 years' follow-up. In contrast there was a U shaped association between BMI and mortality in analyses with a greater potential for bias including all participants, current, former, or ever smokers, and in studies with a short duration of follow-up (<5 years or <10 years), or with moderate study quality scores. Overweight and obesity is associated with increased risk of all cause mortality and the nadir of the curve
Sen, Abhijit; Prasad, Manya; Norat, Teresa; Janszky, Imre; Tonstad, Serena; Romundstad, Pål; Vatten, Lars J
2016-01-01
Objective To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease. Data sources PubMed and Embase databases searched up to 23 September 2015. Study selection Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality. Data synthesis Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models. Results 230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I2=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I2=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I2=89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I2=97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (Pnon-linearity <0.001), and the lowest risk was observed at BMI 23-24 in never smokers, 22-23 in healthy never smokers, and 20-22 in studies of never smokers with ≥20 years’ follow-up. In contrast there was a U shaped association between BMI and mortality in analyses with a greater potential for bias including all participants, current, former, or ever smokers, and in studies with a short duration of follow-up (<5 years or <10 years), or with moderate study quality scores. Conclusion Overweight and obesity is associated
Optically isolated signal coupler with linear response
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.
Linear ubiquitination signals in adaptive immune responses.
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.
Linear response theory applied to geoengineering
NASA Astrophysics Data System (ADS)
Bodai, Tamas; Lucarini, Valerio
2017-04-01
We investigate in an intermediate-complexity climate model the applicability of linear response theory to a geoengineering problem. Global climate change with respect to an appropriate ensemble average of the surface air temperature ⟨[T]⟩ due to a given rise in carbon dioxide concentration [CO2] is attempted to be canceled out or modulated by an appropriately chosen modulation of the solar forcing. The latter is predicted by linear response theory in frequency-domain as: Δfs(ω) = (Δ⟨[T]⟩(ω) -χCO2(ω)ΔfCO2(ω))/χs(ω), where the χ's are linear susceptibilities. With a doubling of [CO2] the response is nonlinear to a certain degree, but a significant cancellation with respect to (wrt.) [T] is achieved, the asymptotic total response to combined forcing being only 10% of that with [CO2]-doubling alone. We investigate in this geoengineering scenario the response wrt. zonal or regional averages of T too. The nonlinearities have a more severe effect with respect to the predictability of the spatial total response pattern, but in actual fact a significant cancellation is achieved even locally. Similar conclusions can be drawn wrt. the model variable of large scale precipitation. The regional and global response can be characterized by a single dominant multi-year time scale. The spatial pattern of the response time is rather nontrivial.
Regulatory implications of a linear non-threshold (LNT) dose-based risks.
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.
On the dose response of some CVD diamond thermoluminescent detectors.
Marczewska, B; Bilski, P; Olko, P; Nesladek, M; Rebisz, M; Guerrero, M J
2006-01-01
The linearity of dose response of chemical vapour deposition (CVD) diamonds grown at the Institute for Materials Research at Limburg University, Belgium, was investigated over a dose range relevant for radiotherapy. The following CVD diamonds were investigated: (1) a batch of square 3 x 3 mm2 detectors cut from a CVD wafer and (2) an as-grown CVD wafer of 6 cm diameter. A total of 20 CVD square detectors were irradiated with 137Cs gamma rays over the dose range from 200 mGy to 25 Gy. The CVD wafer, used as a large-area thermoluminescent (TL) detector, was exposed to a 226Ra needle. Very few square detectors showed linearity over a limited dose range, followed by saturation of the TL signal. The dose range of linearity was found to be strongly affected by the thermal annealing procedure of the detector. Owing to its high sensitivity and homogeneity of response, the large CVD diamond wafer was found to be very suitable as a large-area detector for 2-D dose mapping of the 226Ra brachytherapy source, possibly for Quality Assurance purposes.
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…
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…
Shared Dosimetry Error in Epidemiological Dose-Response Analyses
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
Shared dosimetry error in epidemiological dose-response analyses
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
Shared dosimetry error in epidemiological dose-response analyses
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.
Shared dosimetry error in epidemiological dose-response analyses.
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.
Shared Dosimetry Error in Epidemiological Dose-Response Analyses
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.
Dose-Response Analysis Using R.
Ritz, Christian; Baty, Florent; Streibig, Jens C; Gerhard, Daniel
2015-01-01
Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides a flexible and versatile infrastructure for dose-response analyses in general. The present version of the package, reflecting extensions and modifications over the last decade, provides a user-friendly interface to specify the model assumptions about the dose-response relationship and comes with a number of extractors for summarizing fitted models and carrying out inference on derived parameters. The aim of the present paper is to provide an overview of state-of-the-art dose-response analysis, both in terms of general concepts that have evolved and matured over the years and by means of concrete examples.
Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens
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...
Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens
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...
A broadly applicable function for describing luminescence dose response
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.
The debate on the use of linear no threshold for assessing the effects of low doses.
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.
Enhanced low dose rate sensitivity (ELDRS) of linear circuits in a space environment
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.
Dose-response-a challenge for allelopathy?
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.
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.
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.
Linear Response Function of Bond-Order
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
Simplified Warfarin Dose-response Pharmacodynamic Models
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
Using machine learning to model dose-response relationships.
Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K
2016-12-01
Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.
Dose-response approaches for nuclear receptor-mediated ...
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 subthreshold doses for a number of receptor-mediated MOPs. 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/PXR, and the PPARa. This paper 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
Dose-response approaches for nuclear receptor-mediated ...
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 subthreshold doses for a number of receptor-mediated MOPs. 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/PXR, and the PPARa. This paper 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
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.
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.
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.
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.
Continuing evaluation of bipolar linear devices for total dose bias dependency and ELDRS effects
NASA Technical Reports Server (NTRS)
McClure, Steven S.; Gorelick, Jerry L.; Yui, Candice; Rax, Bernard G.; Wiedeman, Michael D.
2003-01-01
We present results of continuing efforts to evaluate total dose bias dependency and ELDRS effects in bipolar linear microcircuits. Several devices were evaluated, each exhibiting moderate to significant bias and/or dose rate dependency.
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.
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.
Harderian Gland Tumorigenesis: Low-Dose and LET Response.
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
Harderian Gland Tumorigenesis: Low-Dose and LET Response
Chang, Polly Y.; Cucinotta, Francis A.; Bjornstad, Kathleen A.; Bakke, James; Rosen, Chris J.; Du, Nicholas; Fairchild, David G.; Cacao, Eliedonna; Blakely, Eleanor A.
2016-04-19
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
Ballistic transport in graphene beyond linear response
Rosenstein, B.; Korniyenko, Y.; Lewkowicz, M.; Kao, H. C.
2010-01-15
The process of coherent creation of particle-hole excitations by an electric field in graphene is quantitatively described beyond linear response. We calculate the evolution of current density, number of pairs and energy in ballistic regime for electric field E using the tight-binding model. While for ballistic flight times smaller than t{sub nl}propor toE{sup -1/2} current is linear in E and independent of time, for larger ballistic times the current increases after t{sub nl} as Jpropor toE{sup 3/2}t and finally at yet larger times (t>t{sub B}propor toE{sup -1}) Bloch oscillations set in. It is shown that the number of pairs follows the 2D generalization of the Schwinger's creation rate npropor toE{sup 3/2} only on certain time segments with a prefactor different from that obtained using the asymptotic formula.
Random Response of Linear Hysteretic Damping
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.
Dose-response model for teratological experiments involving quantal responses
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.
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.
Shortcuts to adiabaticity from linear response theory
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
Shortcuts to adiabaticity from linear response theory
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.
Responsive linear-dendritic block copolymers.
Blasco, Eva; Piñol, Milagros; Oriol, Luis
2014-06-01
The combination of dendritic and linear polymeric structures in the same macromolecule opens up new possibilities for the design of block copolymers and for applications of functional polymers that have self-assembly properties. There are three main strategies for the synthesis of linear-dendritic block copolymers (LDBCs) and, in particular, the emergence of click chemistry has made the coupling of preformed blocks one of the most efficient ways of obtaining libraries of LDBCs. In these materials, the periphery of the dendron can be precisely functionalised to obtain functional LDBCs with self-assembly properties of interest in different technological areas. The incorporation of stimuli-responsive moieties gives rise to smart materials that are generally processed as self-assemblies of amphiphilic LDBCs with a morphology that can be controlled by an external stimulus. Particular emphasis is placed on light-responsive LDBCs. Furthermore, a brief review of the biomedical or materials science applications of LDBCs is presented. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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.
A different perception of the linear, nonthreshold hypothesis for low-dose irradiation.
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
A different perception of the linear, nonthreshold hypothesis for low-dose irradiation
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.
CALUX measurements: statistical inferences for the dose-response curve.
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.
Funatogawa, Ikuko; Funatogawa, Takashi
2012-03-15
The assessment of the dose-response relationship is important but not straightforward when the therapeutic agent is administered repeatedly with dose-modification in each patient and a continuous response is measured repeatedly. We recently proposed an autoregressive linear mixed effects model for such data in which the current response is regressed on the previous response, fixed effects, and random effects. The model represents profiles approaching each patient's asymptote, takes into account the past dose history, and provides a dose-response relationship of the asymptote as a summary measure. In an autoregressive model, intermittent missing data mean the missing values in previous responses as covariates. We previously provided the marginal (unconditional on the previous response) form of the proposed model to deal with intermittent missing data. Irregular timings of dose-modification or measurement can also be treated as equally spaced data with intermittent missing values by selecting an adequately small unit of time. The likelihood is, however, expressed by matrices whose sizes depend on the number of observations for a patient, and the computational burden is large. In this study, we propose a state space form of the autoregressive linear mixed effects model to calculate the marginal likelihood without using large matrices. The regression coefficients of the fixed effects can be concentrated out of the likelihood in this model by the same way of a linear mixed effects model. As an illustration of the approach, we analyzed immunologic data from a clinical trial for multiple sclerosis patients and estimated the dose-response curves for each patient and the population mean. Copyright © 2011 John Wiley & Sons, Ltd.
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.
The use of linear programming in optimization of HDR implant dose distributions.
Jozsef, Gabor; Streeter, Oscar E; Astrahan, Melvin A
2003-05-01
The introduction of high dose rate brachytherapy enabled optimization of dose distributions to be used on a routine basis. The objective of optimization is to homogenize the dose distribution within the implant while simultaneously satisfying dose constraints on certain points. This is accomplished by varying the time the source dwells at different locations. As the dose at any point is a linear function of the dwell times, a linear programming approach seems to be a natural choice. The dose constraints are inherently linear inequalities. Homogeneity requirements are linearized by minimizing the maximum deviation of the doses at points inside the implant from a prescribed dose. The revised simplex method was applied for the solution of this linear programming problem. In the homogenization process the possible source locations were chosen as optimization points. To avoid the problem of the singular value of the dose at a source location from the source itself we define the "self-contribution" as the dose at a small distance from the source. The effect of varying this distance is discussed. Test cases were optimized for planar, biplanar and cylindrical implants. A semi-irregular, fan-like implant with diverging needles was also investigated. Mean central dose calculation based on 3D Delaunay-triangulation of the source locations was used to evaluate the dose distributions. The optimization method resulted in homogeneous distributions (for brachytherapy). Additional dose constraints--when applied--were satisfied. The method is flexible enough to include other linear constraints such as the inclusion of the centroids of the Delaunay-triangulation for homogenization, or limiting the maximum allowable dwell time.
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
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.
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.
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.
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.
[Dose response curve of paclitaxel measured by histoculture drug response assay].
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.
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.
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.
Dose-response relationship for breast cancer induction at radiotherapy dose.
Schneider, Uwe; Sumila, Marcin; Robotka, Judith; Gruber, Günther; Mack, Andreas; Besserer, Jürgen
2011-06-08
Cancer induction after radiation therapy is known as a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the patient to be treated including breast cancer. In this work a dose-response relationship for breast cancer is derived based on(i) the analysis of breast cancer induction after Hodgkin's disease,(ii) a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and(iii) the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy,(iv) the breast cancer induction of the A-bomb survivor data. The fitted model parameters for an α/β = 3 Gy were α = 0.067Gy-1 and R = 0.62. The risk for breast cancer is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 20 Gy and drops off only slightly at larger doses. The predicted EAR for breast cancer after radiotherapy of Hodgkin's disease is 11.7/10000PY which can be compared to the findings of several epidemiological studies where EAR for breast cancer varies between 10.5 and 29.4/10000PY. The model was used to predict the impact of the reduction of radiation volume on breast cancer risk. It was estimated that mantle field irradiation is associated with a 3.2-fold increased risk compared with mediastinal irradiation alone, which is in agreement with a published value of 2.7. It was also shown that the modelled age dependency of breast cancer risk is in satisfying agreement with published data. The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients.
Dose Rate Linearity in 4H-SiC Schottky Diode-Based Detectors at Elevated Temperatures
NASA Astrophysics Data System (ADS)
Mohamed, N. S.; Wright, N. G.; Horsfall, A. B.
2017-07-01
The outstanding material properties make silicon carbide radiation hard and this ability has enabled it to be demonstrated in a range of detector structures for deployment in extreme environments, including those where the ability to tolerate high radiation dose is imperative. This includes applications in space and nuclear environments, where the ability to detect highly energetic radiation is important. In contrast, detectors used in medical treatment, such as imaging and radiotherapy, use a range of radiation dose rates and energies for both particulate and photonic radiation. Here, we report the response and dose rate linearity of detectors fabricated from silicon carbide to dose rates in the range of 0.185 mGy · min-1, typical of those used for medical imaging. The data show that the radiation detected current originates within the depletion region of the detector and that the response is linearly dependent on the volume of the space charge region. The realization of a vertical detector structure, coupled with the high quality of epitaxial layers, has resulted in a high dose sensitivity of the detector that is highly linear. The temperature dependence of the characteristics indicates that silicon carbide Schottky diode-based detectors offer a performance suitable for medical applications at temperatures below 100 °C without the need for external cooling.
Dose rate and annealing effects on total dose response of MOS and bipolar circuits
Carriere, T.; Beaucour, J.; Gach, A.; Johlander, B.; Adams, L.
1995-12-01
Different part types of major technology families were irradiated in order to study dose rate and post irradiation annealing effects. Results confirm that degradation of MOS technologies at low dose rates can be predicted from high dose rate and annealing measurements, while this is not possible for bipolar linear IC`s. The ESA/SCC22900 test method is discussed.
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.
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.
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.
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
Formaldehyde dose-response in healthy nonsmokers
Kulle, T.J.; Sauder, L.R.; Hebel, J.R.; Green, D.J.; Chatham, M.D.
1987-08-01
Industrial, commercial, and domestic levels of formaldehydes exposure range from <0.1 to >5.0 ppm. Irritation of the eyes and upper respiratory tract predominate, and bronchoconstriction is described in case reports. However, pulmonary function and irritant symptoms together have not been assessed over a range of HCHO concentrations in a controlled environment. The authors investigated dose response in both symptoms and pulmonary function associated with 3-h exposures to 0.0-3.0 ppm HCHO in a controlled environmental chamber. Ten subjects were randomly exposed to 0.0, 0.5, 1.0, and 2.0 ppm HCHO at rest plus 2.0 ppm HCHO with exercise and nine additional subjects were randomly exposed to 0.0, 1.0, 2.0, and 3.0 ppm HCHO at rest plus 2.0 ppm HCHO with exercise. Significant dose-response relationships in odor and eye irritation were observed (p < 0.05). Nasal flow resistance was increased at 3.0 ppm (p < 0.01), but not at 2.0 ppm HCHO. There were no significant decrements in pulmonary function (FVC, FEV/sub 1/, FEF/sub 25-75%/, SGaw) or increases in bronchial reactivity to methacholine (log PD/sub 35SGaw/) with exposure to 0.5-3.0 ppm HCHO at rest or to 2.0 ppm HCHO with exercise.
Lisinopril dose-response relationship in essential hypertension
Gomez, H. J.; Cirillo, V. J.; Sromovsky, J. A.; Otterbein, E. S.; Shaw, W. C.; Rush, J. E.; Chrysant, S. G.; Gradman, A. H.; Leon, A. S.; MacCarthy, E. P.; Nelson, E. B.; Pool, J.; Vedin, A.
1989-01-01
1 This was a multicentre, double-blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95-115 mm Hg) essential hypertension. 2 After a 4-week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5, 20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks -2, 0, 2, 4, and 6. 3 There was a linear dose-response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day-1 groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day-1 groups. 4 Lisinopril, at doses up to 80 mg day-1, was well tolerated. PMID:2556172
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...
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...
Dose calculation and in-phantom measurement in BNCT using response matrix method.
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%.
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
Dose response relationship in anti-stress gene regulatory networks.
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
Assessment of human exposure doses received by activation of medical linear accelerator components
NASA Astrophysics Data System (ADS)
Lee, D.-Y.; Kim, J.-H.; Park, E.-T.
2017-08-01
This study analyzes the radiation exposure dose that an operator can receive from radioactive components during maintenance or repair of a linear accelerator. This study further aims to evaluate radiological safety. Simulations are performed on 10 MV and 15 MV photon beams, which are the most frequently used high-energy beams in clinics. The simulation analyzes components in order of activity and the human exposure dose based on the amount of neutrons received. As a result, the neutron dose, radiation dose, and human exposure dose are ranked in order of target, primary collimator, flattening filter, multi-leaf collimator, and secondary collimator, where the minimum dose is 9.34E-07 mSv/h and the maximum is 1.71E-02 mSv/h. When applying the general dose limit (radiation worker 20 mSv/year, pubic 1 mSv/year) in accordance with the Nuclear Safety Act, all components of a linear accelerator are evaluated as below the threshold value. Therefore, the results suggest that there is no serious safety issue for operators in maintaining and repairing a linear accelerator. Nevertheless, if an operator recognizes an exposure from the components of a linear accelerator during operation and considers the operating time and shielding against external exposure, exposure of the operator is expected to be minimized.
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.
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.
A model to calculate the induced dose rate around an 18 MV ELEKTA linear accelerator.
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.
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
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 (DDREF_{LSS}). 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.
Confidence bounds for nonlinear dose-response relationships.
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.
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.
Impact of using linear optimization models in dose planning for HDR brachytherapy
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.
Adaptive dose finding based on t-statistic for dose-response trials.
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.
The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery.
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.
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.
Holm, Åsa; Larsson, Torbjörn; Tedgren, Åsa Carlsson
2013-08-01
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. 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. 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. The authors' new model is a viable surrogate to optimizing dosimetric indices and quickly and easily yields high quality dose distributions.
Radiographic response of brain metastasis after linear accelerator radiosurgery.
Rahman, Maryam; Cox, J Bridger; Chi, Yueh-Yun; Carter, Jamal H; Friedman, William A
2012-01-01
Radiographic response of brain metastasis to stereotactic radiosurgery (SRS) over time has not been well characterized. Being able to predict SRS-induced changes in tumor size over time may allow improved counseling of patients and potentially earlier recognition of poor response to SRS. To quantify the rate of change in size of metastatic brain tumors after treatment with a linear accelerator (LINAC) SRS. We performed a retrospective analysis of patients with single metastatic brain tumors treated with LINAC SRS at the University of Florida between 1992 and 2009 who had at least one MRI after treatment. A total of 218 patients with 406 follow-up MRI scans were included in the study. Tumor area was calculated by measuring the largest tumor area on axial imaging and using the equation for area of an ellipse. Primary outcome was percent change in tumor size. The contribution of several factors including gender, primary tumor histology, synchronous or asynchronous presentation, prior treatment, primary tumor control, and SRS dose were examined using multivariate analysis. Mean patient age was 58.3 years (range 4-86), and 48.6% of patients were female. Sixty-three percent of patients had primary tumor control and 70.6% had asynchronous presentation of their brain metastases. SRS peripheral dose range was 1,000-2,250 cGy with a median of 1,750 cGy. The mean percent size change was -22.6% with a mean rate of change of -7.0% per month. The median percent change was -49.7% with a median rate of change of -8.8% per month. The median follow-up was 4.8 months (range 0.3-52.5). Female gender and melanoma histology were found to be significant predictors of an increase in tumor size. Lack of previous surgical resection was a significant predictor of a decrease in tumor size after SRS. Other factors tested with multivariate analysis, including age, synchronicity of presentation, dose, dose volume, Karnofsky performance score, and primary tumor control, were not significant in
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.
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.
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.
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.
Dose-response analyses using restricted cubic spline functions in public health research.
Desquilbet, Loic; Mariotti, François
2010-04-30
Taking into account a continuous exposure in regression models by using categorization, when non-linear dose-response associations are expected, have been widely criticized. As one alternative, restricted cubic spline (RCS) functions are powerful tools (i) to characterize a dose-response association between a continuous exposure and an outcome, (ii) to visually and/or statistically check the assumption of linearity of the association, and (iii) to minimize residual confounding when adjusting for a continuous exposure. Because their implementation with SAS® software is limited, we developed and present here an SAS macro that (i) creates an RCS function of continuous exposures, (ii) displays graphs showing the dose-response association with 95 per cent confidence interval between one main continuous exposure and an outcome when performing linear, logistic, or Cox models, as well as linear and logistic-generalized estimating equations, and (iii) provides statistical tests for overall and non-linear associations. We illustrate the SAS macro using the third National Health and Nutrition Examination Survey data to investigate adjusted dose-response associations (with different models) between calcium intake and bone mineral density (linear regression), folate intake and hyperhomocysteinemia (logistic regression), and serum high-density lipoprotein cholesterol and cardiovascular mortality (Cox model). 2010 John Wiley & Sons, Ltd.
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.
Linear response of zero-resistance states
NASA Astrophysics Data System (ADS)
Breitkreiz, Maxim
2017-08-01
A two-dimensional electron system in the presence of a magnetic field and microwave irradiation can undergo a phase transition towards a zero-resistance state (ZRS). A widely used model predicts the ZRS to be a domain state, which responds to applied dc voltages or dc currents by slightly changing the domain structure. Here we propose an alternative response scenario, according to which the domain pattern remains unchanged. Surprisingly, a fixed domain pattern does not destroy zero-resistance, provided that the resistance is direction independent. Otherwise, if the symmetry of the domain pattern allows a direction dependence of the resistance, the domain state can be dissipative. We give examples for both situations and simulate the response behavior numerically.
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.
Dose-response relationships for carcinogens: a review.
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
Dose-response relationships for carcinogens: a review
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.
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.
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.
Filtration to reduce paediatric dose for a linear slot-scanning digital X-ray machine.
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.
Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses
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
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.
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.
Dose-Response Calculator for ArcGIS
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.
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...
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...
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.
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.
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.
Prenatal intravenous cocaine and the heart rate-orienting response: a dose-response study.
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
Analysis of Transcriptomic Dose Response Data in the ...
Slide presentation at the HESI-HEALTH Canada-McGill Workshop on Transcriptomic Dose Response Data in the Context of Chemical Risk Assessment Slide presentation at the HESI-HEALTH Canada-McGill Workshop on Transcriptomic Dose Response Data in the Context of Chemical Risk Assessment
Neutron dose calculation at the maze entrance of medical linear accelerator rooms.
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.
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.
Lutz, W.K. . E-mail: lutz@toxi.uni-wuerzburg.de; Gaylor, D.W.; Conolly, R.B.; Lutz, R.W.
2005-09-01
Nonlinear and threshold-like shapes of dose-response curves are often observed in tests for carcinogenicity. Here, we present three examples where an apparent threshold is spurious and can be misleading for low dose extrapolation and human cancer risk assessment. Case 1: For experiments that are not replicated, such as rodent bioassays for carcinogenicity, random variation can lead to misinterpretation of the result. This situation was simulated by 20 random binomial samplings of 50 animals per group, assuming a true linear dose response from 5% to 25% tumor incidence at arbitrary dose levels 0, 0.5, 1, 2, and 4. Linearity was suggested only by 8 of the 20 simulations. Four simulations did not reveal the carcinogenicity at all. Three exhibited thresholds, two showed a nonmonotonic behavior with a decrease at low dose, followed by a significant increase at high dose ('hormesis'). Case 2: Logarithmic representation of the dose axis transforms a straight line into a sublinear (up-bent) curve, which can be misinterpreted to indicate a threshold. This is most pronounced if the dose scale includes a wide low dose range. Linear regression of net tumor incidences and intersection with the dose axis results in an apparent threshold, even with an underlying true linear dose-incidence relationship. Case 3: Nonlinear shapes of dose-cancer incidence curves are rarely seen with epidemiological data in humans. The discrepancy to data in rodents may in part be explained by a wider span of individual susceptibilities for tumor induction in humans due to more diverse genetic background and modulation by co-carcinogenic lifestyle factors. Linear extrapolation of a human cancer risk could therefore be appropriate even if animal bioassays show nonlinearity.
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.
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.
Dose-response relationship for rat liver DNA damage caused by 1,2-dimethylhydrazine.
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.
Scott, Bobby R.; Walker, Dale M.; Tesfaigzi, Yohannes; Schöllnberger, Helmut; Walker, Vernon
2003-01-01
The linear nonthreshold (LNT) model plays a central role in low-dose radiation risk assessment for humans. With the LNT model, any radiation exposure is assumed to increase one’s risk of cancer. Based on the LNT model, others have predicted tens of thousands of deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Here, we introduce a mechanism-based model for low-dose, radiation-induced, stochastic effects (genomic instability, apoptosis, mutations, neoplastic transformation) that leads to a LNT relationship between the risk for neoplastic transformation and dose only in special cases. It is shown that nonlinear dose-response relationships for risk of stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected based on known biological mechanisms. Further, for low-dose, low-dose rate, low-LET radiation, large thresholds may exist for cancer induction. We summarize previously published data demonstrating large thresholds for cancer induction. We also provide evidence for low-dose-radiation-induced, protection (assumed via apoptosis) from neoplastic transformation. We speculate based on work of others (Chung 2002) that such protection may also be induced to operate on existing cancer cells and may be amplified by apoptosis-inducing agents such as dietary isothiocyanates. PMID:19330114
Linear optical response of finite systems using multishift linear system solvers
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.
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.
A two-stage sequential linear programming approach to IMRT dose optimization
Zhang, Hao H; Meyer, Robert R; Wu, Jianzhou; Naqvi, Shahid A; Shi, Leyuan; D’Souza, Warren D
2010-01-01
The conventional IMRT planning process involves two stages in which the first stage consists of fast but approximate idealized pencil beam dose calculations and dose optimization and the second stage consists of discretization of the intensity maps followed by intensity map segmentation and a more accurate final dose calculation corresponding to physical beam apertures. Consequently, there can be differences between the presumed dose distribution corresponding to pencil beam calculations and optimization and a more accurately computed dose distribution corresponding to beam segments that takes into account collimator-specific effects. IMRT optimization is computationally expensive and has therefore led to the use of heuristic (e.g., simulated annealing and genetic algorithms) approaches that do not encompass a global view of the solution space. We modify the traditional two-stage IMRT optimization process by augmenting the second stage via an accurate Monte-Carlo based kernel-superposition dose calculations corresponding to beam apertures combined with an exact mathematical programming based sequential optimization approach that uses linear programming (SLP). Our approach was tested on three challenging clinical test cases with multileaf collimator constraints corresponding to two vendors. We compared our approach to the conventional IMRT planning approach, a direct-aperture approach and a segment weight optimization approach. Our results in all three cases indicate that the SLP approach outperformed the other approaches, achieving superior critical structure sparing. Convergence of our approach is also demonstrated. Finally, our approach has also been integrated with a commercial treatment planning system and may be utilized clinically. PMID:20071764
On relating the generalized equivalent uniform dose formalism to the linear-quadratic model.
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.
A single-source photon source model of a linear accelerator for Monte Carlo dose calculation
Glatting, Gerhard; Wenz, Frederik; Fleckenstein, Jens
2017-01-01
Purpose To introduce a new method of deriving a virtual source model (VSM) of a linear accelerator photon beam from a phase space file (PSF) for Monte Carlo (MC) dose calculation. Materials and methods A PSF of a 6 MV photon beam was generated by simulating the interactions of primary electrons with the relevant geometries of a Synergy linear accelerator (Elekta AB, Stockholm, Sweden) and recording the particles that reach a plane 16 cm downstream the electron source. Probability distribution functions (PDFs) for particle positions and energies were derived from the analysis of the PSF. These PDFs were implemented in the VSM using inverse transform sampling. To model particle directions, the phase space plane was divided into a regular square grid. Each element of the grid corresponds to an area of 1 mm2 in the phase space plane. The average direction cosines, Pearson correlation coefficient (PCC) between photon energies and their direction cosines, as well as the PCC between the direction cosines were calculated for each grid element. Weighted polynomial surfaces were then fitted to these 2D data. The weights are used to correct for heteroscedasticity across the phase space bins. The directions of the particles created by the VSM were calculated from these fitted functions. The VSM was validated against the PSF by comparing the doses calculated by the two methods for different square field sizes. The comparisons were performed with profile and gamma analyses. Results The doses calculated with the PSF and VSM agree to within 3% /1 mm (>95% pixel pass rate) for the evaluated fields. Conclusion A new method of deriving a virtual photon source model of a linear accelerator from a PSF file for MC dose calculation was developed. Validation results show that the doses calculated with the VSM and the PSF agree to within 3% /1 mm. PMID:28886048
A single-source photon source model of a linear accelerator for Monte Carlo dose calculation.
Nwankwo, Obioma; Glatting, Gerhard; Wenz, Frederik; Fleckenstein, Jens
2017-01-01
To introduce a new method of deriving a virtual source model (VSM) of a linear accelerator photon beam from a phase space file (PSF) for Monte Carlo (MC) dose calculation. A PSF of a 6 MV photon beam was generated by simulating the interactions of primary electrons with the relevant geometries of a Synergy linear accelerator (Elekta AB, Stockholm, Sweden) and recording the particles that reach a plane 16 cm downstream the electron source. Probability distribution functions (PDFs) for particle positions and energies were derived from the analysis of the PSF. These PDFs were implemented in the VSM using inverse transform sampling. To model particle directions, the phase space plane was divided into a regular square grid. Each element of the grid corresponds to an area of 1 mm2 in the phase space plane. The average direction cosines, Pearson correlation coefficient (PCC) between photon energies and their direction cosines, as well as the PCC between the direction cosines were calculated for each grid element. Weighted polynomial surfaces were then fitted to these 2D data. The weights are used to correct for heteroscedasticity across the phase space bins. The directions of the particles created by the VSM were calculated from these fitted functions. The VSM was validated against the PSF by comparing the doses calculated by the two methods for different square field sizes. The comparisons were performed with profile and gamma analyses. The doses calculated with the PSF and VSM agree to within 3% /1 mm (>95% pixel pass rate) for the evaluated fields. A new method of deriving a virtual photon source model of a linear accelerator from a PSF file for MC dose calculation was developed. Validation results show that the doses calculated with the VSM and the PSF agree to within 3% /1 mm.
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.
Methodology for Estimating Ingestion Dose for Emergency Response at SRS
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.
The dose response of normoxic polymer gel dosimeters measured using X-ray CT.
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.
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.
Dose-Response relationship of luteinizing hormone to luteinizing hormone—releasing hormone in man
Kastin, Abba J.; Schally, Andrew V.; Gual, Carlos; Midgley, A. Rees; Miller, M. Clinton; Cabeza, Angela
1971-01-01
In previous clinical studies with highly purified porcine luteinizing hormone-releasing hormone (LH-RH), administration of the somewhat arbitrarily chosen doses of 700-1500 μg resulted in increased serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The present study determined the minimum effective dose as well as the relationship of the response of serum LH and FSH to the dose of LH-RH administered. Three normal men received i.v. injections of 1.1-810 μg of LH-RH. A dose of 10 μg of LH-RH caused a statistically significant elevation in serum LH. 30 μg of LH-RH significantly increased serum FSH levels. A highly significant linear trend was observed in the log dose-response curve. The results indicate that both LH and FSH release occurs in man with doses of LH-RH much lower than previously used and that a linear log dose-response relationship can be obtained. PMID:4932985
Oligodendroglial response to ionizing radiation: Dose and dose-rate response
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.
Oligodendroglial response to ionizing radiation: Dose and dose-rate response
Levy, Richard 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 γ-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.
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.
VMAT linear accelerator commissioning and quality assurance: dose control and gantry speed tests.
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.
VMAT linear accelerator commissioning and quality assurance: dose control and gantry speed tests.
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.
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.
Curvilinearity in the dose-response curve for cancer in Japanese atomic bomb survivors.
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
The Dose Window for Radiation-Induced Protective Adaptive Responses
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
Learning in higher order Boltzmann machines using linear response.
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.
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.
Rotational IMRT delivery using a digital linear accelerator in very high dose rate 'burst mode'.
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.
Dose calibrator linearity test: 99mTc versus 18F radioisotopes*
Willegaignon, José; Sapienza, Marcelo Tatit; Coura-Filho, George Barberio; Garcez, Alexandre Teles; Alves, Carlos Eduardo Gonzalez Ribeiro; Cardona, Marissa Anabel Rivera; Gutterres, Ricardo Fraga; Buchpiguel, Carlos Alberto
2015-01-01
Objective The present study was aimed at evaluating the viability of replacing 18F with 99mTc in dose calibrator linearity testing. Materials and Methods The test was performed with sources of 99mTc (62 GBq) and 18F (12 GBq) whose activities were measured up to values lower than 1 MBq. Ratios and deviations between experimental and theoretical 99mTc and 18F sources activities were calculated and subsequently compared. Results Mean deviations between experimental and theoretical 99mTc and 18F sources activities were 0.56 (± 1.79)% and 0.92 (± 1.19)%, respectively. The mean ratio between activities indicated by the device for the 99mTc source as measured with the equipment pre-calibrated to measure 99mTc and 18F was 3.42 (± 0.06), and for the 18F source this ratio was 3.39 (± 0.05), values considered constant over the measurement time. Conclusion The results of the linearity test using 99mTc were compatible with those obtained with the 18F source, indicating the viability of utilizing both radioisotopes in dose calibrator linearity testing. Such information in association with the high potential of radiation exposure and costs involved in 18F acquisition suggest 99mTc as the element of choice to perform dose calibrator linearity tests in centers that use 18F, without any detriment to the procedure as well as to the quality of the nuclear medicine service. PMID:25798005
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.
Linear and nonlinear responses to middle latitude surface temperature anomalies
NASA Technical Reports Server (NTRS)
Roads, John O.
1989-01-01
Nonlinear responses to fixed and seasonally varying surface temperature anomalies in a two-level hemispheric time-dependent coupled atmosphere-surface mixed layer model are described. Linear stationary models that are equivalent to the nonlinear time-dependent model are used to analyze these responses. A model linearized around the climatological zonal state of the time dependent model and forced by anomalous surface temperatures does not provide a reasonable estimate for the anomalous reponses, which are considerably underestimated. Better responses are obtained when the anomalous stationary nonlinear eddy fluxes are included in a model linearized around the full climatology. However, this latter model is overly sensitive, and anomalous responses are a small residual balance to the forcing by the surface temperature anomalies and the anomalous transient eddy fluxes. To better understand these linear responses, an eigenanalysis of the climatological state is performed. Seasonal anomalies appear to be dominated by one characteristic pattern near resonance which can be associated with a slowly growing coupled atmosphere-ocean instability.
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
Assessment of leakage doses around the treatment heads of different linear accelerators.
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.
Bayesian Isotonic Regression Dose-response (BIRD) Model.
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.
Endoreversible quantum heat engines in the linear response regime
NASA Astrophysics Data System (ADS)
Wang, Honghui; He, Jizhou; Wang, Jianhui
2017-07-01
We analyze general models of quantum heat engines operating a cycle of two adiabatic and two isothermal processes. We use the quantum master equation for a system to describe heat transfer current during a thermodynamic process in contact with a heat reservoir, with no use of phenomenological thermal conduction. We apply the endoreversibility description to such engine models working in the linear response regime and derive expressions of the efficiency and the power. By analyzing the entropy production rate along a single cycle, we identify the thermodynamic flux and force that a linear relation connects. From maximizing the power output, we find that such heat engines satisfy the tight-coupling condition and the efficiency at maximum power agrees with the Curzon-Ahlborn efficiency known as the upper bound in the linear response regime.
Updating Dosimetry for Emergency Response Dose Projections.
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
Radiation Dose-Response Relationships and Risk Assessment
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
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.
Chaos pass filter: linear response of synchronized chaotic systems.
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.
Cardiotachometer with linear beat-to-beat frequency response
NASA Technical Reports Server (NTRS)
Deboo, G. J.; Pope, J. M.; Smith, D. B. D.
1967-01-01
Cardiotachometer detects and displays the human heart rate during physiological studies. It provides linear response to the heart rate, records heart rate during rest and under heavy stress, provides a beat-to-beat indication of changes in heart rate, and is relatively free of interfering signals from activities other than the heart rate.
NASA Astrophysics Data System (ADS)
Takanashi, Takaoki; Kawamura, Hiraku; Fukasaku, Kazuaki; Sahade, Daniel Antonio; Hamada, Toshimasa
2017-05-01
Absorbed dose-response characteristics of AQUAJOINT®-based polymer gel and PAGAT gel dosimeters were compared using Optical CT and MRI. AQUAJOINT® gel exhibited a relatively good linear dose-response relationship in the radiation dose range of 0-5 Gy.
TESS-based dose-response using pediatric clonidine exposures
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.
Dose-time-response modeling using negative binomial distribution.
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.
[Dose-response relation: relevance for clinical practice].
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.
[Dose-response relationship: relevance for medical practice].
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.
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.
The Emergence of the Dose-Response Concept in Biology and Medicine.
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.
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...
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...
Schneider, Uwe; Sumila, Marcin; Robotka, Judith
2011-07-26
Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three-dimensional inhomogenous dose distribution, cancer risk can be compared by
2011-01-01
Background and Purpose Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Materials and methods For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. Results The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. Conclusions In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three
Buildup region and skin-dose measurements for the Therac 6 Linear Accelerator for radiation therapy
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.
Buildup region and skin-dose measurements for the Therac 6 linear accelerator for radiation therapy.
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.
Dose and linear energy transfer spectral measurements for the supersonic transport program
NASA Technical Reports Server (NTRS)
Philbrick, R. B.
1972-01-01
The purpose of the package, called the high altitude radiation instrumentation system (HARIS), is to measure the radiation hazard to supersonic transport passengers from solar and galactic cosmic rays. The HARIS includes gaseous linear energy transfer spectrometer, a tissue equivalent ionization chamber, and a geiger meuller tube. The HARIS is flown on RB-57F aircraft at 60,000 feet. Data from the HARIS are reduced to give rad and rem dose rates measured by the package during the flights. Results presented include ambient data obtained on background flights, altitude comparison data, and solar flare data.
[Mechanism of cytogenetic adaptive response induced by low dose radiation].
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.
Linear response formalism and ensemble adjoint methods for climate sensitivity
NASA Astrophysics Data System (ADS)
Haine, T.; Eyink, G.; Lea, D.
2003-04-01
Climate sensitivities represent the response of long-time averages of relevant selected variables in geophysical systems to changes in an external forcing. e.g. the response of a global mean temperature averaged over many annual cycles to a change in atmospheric CO2 concentration. Conceptually, such sensitivities are similar to the response of molecular systems to external forcings, such as the Ohmic response of a metallic conductor to an applied electric field. In the latter systems, linear response formalism gives simple "Green-Kubo formulae" for the derivative response or sensitivity matrix, such as the electrical conductivity in Ohm's law. Recently, the linear response formalism has been extended to general chaotic nonlinear dynamical systems, without any assumption of thermal equilibrium statistics [1]. In this generality, the formalism may be applied to geophysical models to calculate climate sensitivities. We show that the resulting "Green-Kubo formulae" can be evaluated by a novel ensemble adjoint technique. The new procedure is compared with a more standard ensemble adjoint method [2,3], in which an average is taken over an ensemble of adjoint calculations of the derivative response for the time-averaged quantity. The two methods are compared for their accuracy, convergence and stability and for their computational requirements on storage and number of model integrations. [1] D. Ruelle, "General linear response formula in statistical mechanics, and the fluctuation-dissipation theorem far from equilibrium." Phys. Letters A 245: 220--224 (1998). [2] D. L. Lea, M. R. Allen, and T. W. N. Haine, "Sensitivity analysis of the climate of a chaotic system," Tellus 52A: 523--532 (2000) [3] D. L. Lea, M. R. Allen, T. W. N. Haine, and J. Hansen, "Sensitivity analysis of the climate of a chaotic ocean circulation model," in press, Q. J. Roy. Met. Soc., 2002.
Dose Response Effects of Hypertonic Saline and Dextran on Cardiovascular Responses in Sheep
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
High-dose fluoroscopy: the administrator's responsibilities.
Archer, Benjamin R
2002-01-01
During the past 15 years, developments in x-ray technologies have substantially improved the ability of practitioners to treat patients using fluoroscopically guided interventional techniques. Many of these procedures require a greater use of fluoroscopy and serial imaging (cine). This has increased the potential for radiation-induced dermatitis, epilation and severe radiation-induced burns to patients. Radiology administrators must realize that these high-dose procedures increase the risk for radiation injury and radiation-induced cancer in personnel as well as in patients. This article discusses particular clinical cases and describes positive, pro-active steps that practitioners and administrators can take to help prevent such injuries in their facilities. Unfortunately, with the exception of radiologists, a large proportion of physicians who use fluoroscopy have effectively no training or credentials in management of radiation or the biological effects associated with its use. In 1994, an FDA advisory warned that training of physicians for modern-day use of the fluoroscope was for the most part insufficient and needed to be expanded. Many prominent medical organizations such as the American College of Cardiology (14) and the American Heart Association (15) have published strongly worded position papers agreeing that there is an urgent need for such training. The consensus is that "rubber-stamp" privileges (16,17) to perform fluoroscopic procedures should no longer be granted. At present, the JCAHO is considering the implementation of a statement regarding JCAHO standards and privileges for practitioners to use fluoroscopic x-ray equipment. Whether or not the JCAHO becomes involved, it is becoming increasingly clear that all practitioners who use fluoroscopic radiation should be required to complete focused training in radiation physics, radiation biology and radiation safety. Training should include the pertinent aspects of radiation management in the clinical
Dose and Radioadaptive Response Analysis of Micronucleus Induction in Mouse Bone Marrow
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
The Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD) Tool
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.
Thermodynamic formalism and linear response theory for nonequilibrium steady states.
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.
DeCarolis, Douglas D; Kim, Grace Miran; Rector, Thomas S; Ishani, Areef
2016-10-01
To compare the change in potassium concentration (dose-response) using the intravenous versus enteral route for potassium replenishment. Cross-sectional analysis of individual potassium chloride doses with resulting changes in plasma potassium concentrations in intensive care patients. Potassium chloride was administered according to potassium replenishment protocols. For inclusion, doses were required to have pre- and post-dose plasma potassium concentrations obtained within 8hours of administration. Medical and surgical intensive care units of a United States Veterans Affairs Medical Center. The primary outcome was the dose-response slope for intravenous versus enteral potassium administration as estimated by linear regression analysis. Multivariable linear regression was employed to adjust for potential confounders. The sample had 278 potassium chloride doses administered to 142 patients. The potassium concentration change per 20mmol of potassium chloride was similar for intravenous and enteral routes, 0.25mmol/L (95% confidence interval 0.16-0.33) versus 0.27mmol/L (0.15-0.39) respectively (p=0.73). Multivariable linear regression did not alter results. The success of achieving a minimum potassium concentration defined by the specific protocol was similar for intravenous (61%) and enteral (59%) administration. Overall, 77% of potassium chloride doses were administered at a time when patients were eligible to receive an enteral dosage form. The enteral route was as effective as the intravenous route in increasing the plasma potassium concentration. The enteral route was widely available for potassium replenishment. Despite enteral route availability and the well-known reliability of potassium chloride absorption, the majority of doses were administered intravenously. Published by Elsevier Ltd.
A linear chromatic mechanism drives the pupillary response.
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
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.
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.
Curious cases: Altered dose-response relationships in addiction genetics.
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. © 2013.
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.
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
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.
In vivo quantification of human lung dose response relationship
NASA Astrophysics Data System (ADS)
O'Dell, Walter; Wang, Peng; Liu, Haisong; Fuller, David; Schell, Michael C.; Okunieff, Paul
2007-03-01
Purpose: To implement a new non-invasive in-vivo assay to compute the dose-response relationship following radiation-induced injury to normal lung tissue, using computed tomography (CT) scans of the chest. Methods and Materials: Follow-up volumetric CT scans were acquired in patients with metastatic tumors to the lung treated using stereotactic radiation therapy. The images reveal a focal region of fibrosis corresponding to the high-dose region and no observable long-term damage in distant sites. For each pixel in the follow-up image the treatment dose and the change in apparent tissue density was compiled. For each of 12 pre-selected dose levels the average pixel tissue density change was computed and fit to a two-parameter dose-response model. The sensitivity of the resulting fits to registration error was also quantified. Results: Complete in vivo dose-response relationships in human normal lung tissue were computed. Increasing radiation sensitivity was found with larger treatment volume. Radiation sensitivity increased also over time up to 12 months, but decreased at later time points. The time-course of dose response correlated with the time-course of levels of circulating IL-1α, TGFβ and MCP-1. The method was found to be robust to registration errors up to 3 mm. Conclusions: This approach for the first time enables the quantification of the full range dose response relationship in human subjects. The method may be used to assess quantitatively the efficacy of various agents thought to illicit radiation protection to the lung.
Dose convolution filter: Incorporating spatial dose information into tissue response modeling
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.
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…
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…
A Generalized QMRA Beta-Poisson Dose-Response Model.
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 0
Optimization of HDR brachytherapy dose distributions using linear programming with penalty costs
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.
Linearity in the response of photopolymers as optical recording media.
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.
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.
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
Maximum likelihood estimation for cytogenetic dose-response curves
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.
Linear response of tripartite entanglement to infinitesimal noise
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.
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.
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.
An analytic linear accelerator source model for GPU-based Monte Carlo dose calculations.
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
Bone, Richard A.; Landrum, John T.
2010-01-01
We conducted a study to determine the effect of different doses of a lutein supplement on serum lutein concentration and macular pigment optical density (MPOD). Lutein is one of the major components of human macular pigment. Eighty seven subjects received daily doses of 5, 10, or 20 mg of lutein, or a placebo, over a 140 day period. Serum lutein concentration was determined by HPLC, and MPOD by heterochromatic flicker photometry (HFP). Serum lutein responded positively, except in the placebo group, reaching a plateau that, averaged for each dosage group, was linearly dependent on dose. Likewise MPOD, on average, increased at a rate that varied linearly with dose. For subjects deemed more proficient at HFP, approximately 29% of the variability in MPOD response could be attributed to a linear dependence on the fractional change in serum lutein concentration. We did not detect any significant influence of age on serum lutein uptake or MPOD response. PMID:20599660
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.
Pseudomonas aeruginosa dose response and bathing water infection.
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.
The Radiation Dose-Response of the Human Spinal Cord
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.
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.
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.
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
Dose-time pattern of the hypercalcemic response to calcium infusion in the dog.
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.
Ranugha, P S S; Mohanan, S; Chandrashekar, L; Basu, D; Thappa, D M; Rajesh, N G
2014-01-01
Epidermolysis bullosa pruriginosa is a rare distinctive variant of dystrophic epidermolysis bullosa characterized by intense pruritus, lichenified plaques in linear distribution, and anonychia. It is a difficult condition to treat and causes a great deal of distress. The present authors report two cases showing good response to low-dose thalidomide, with clinical and symptomatic improvement. The exact mechanism of action is not yet clear. © 2013 Wiley Periodicals, Inc.
Linear-scaling time-dependent density-functional theory in the linear response formalism.
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.
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.
Maximum likelihood estimation for cytogenetic dose-response curves
Frome, E.L; DuFrain, R.J.
1983-10-01
In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and 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.
Transcriptomic Dose-Response Analysis for Mode of Action ...
Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses with minimal replication. Thus, they were not useful in understanding health risks at environmentally-relevant doses. Until the past decade, application of toxicogenomics in dose response assessment and determination of chemical mode of action has been limited. New transcriptomic biomarkers have evolved to detect chemical hazards in multiple tissues together with pathway methods to study biological effects across the full dose response range and critical time course. Comprehensive low dose datasets are now available and with the use of transcriptomic benchmark dose estimation techniques within a mode of action framework, the ability to incorporate informative genomic data into human health risk assessment has substantially improved. The key advantage to applying transcriptomic technology to risk assessment is both the sensitivity and comprehensive examination of direct and indirect molecular changes that lead to adverse outcomes. Book Chapter with topic on future application of toxicogenomics technologies for MoA and risk assessment
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. © 2015. Published by The Company of Biologists Ltd.
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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Response of human fibroblasts to low dose rate gamma irradiation
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.
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.
Dose response of caffeine on 2000-m rowing performance.
Skinner, Tina L; Jenkins, David G; Coombes, Jeff S; Taaffe, Dennis R; Leveritt, Michael D
2010-03-01
To determine whether a dose-response relationship exists between caffeine and 2000-m rowing performance. In this randomized, placebo-controlled, double-blind crossover study, 10 competitive male rowers (mean +/- SD: age = 20.6 +/- 1.4 yr, body mass = 87.7 +/- 10.5 kg, height = 186.8 +/- 6.8 cm, (.)VO2peak = 5.1 +/- 0.6 L x min(-1)) consumed 2, 4, or 6 mg x kg(-1) caffeine or a placebo 60 min before completing a 2000-m time trial on a rowing ergometer. The trials were preceded by a 24-h standardized diet (including a light preexercise meal of 2 g x kg(-1) CHO), and subjects were tested preexercise for hydration, caffeine abstinence, and blood glucose concentrations. Time trial performance was not significantly different across the three caffeine doses or placebo (P = 0.249). After the three caffeine trials, postexercise plasma glucose and lactate concentrations were higher compared with the placebo trial (P < 0.05). Plasma caffeine concentrations after 60 min of ingestion were lower than the values reported previously by others following the same dose, and there was considerable interindividual variation in plasma caffeine concentrations in response to the various caffeine doses. The large interindividual response to the caffeine doses suggests that individual characteristics need to be considered when administering caffeine for performance enhancement. In addition, preexercise feeding may significantly affect plasma caffeine concentrations and the potential for caffeine to improve performance.
Stochastic simulation of anharmonic dissipation. I. Linear response regime
NASA Astrophysics Data System (ADS)
Yan, Yun-An
2016-11-01
Over decades, the theoretical study of the quantum dissipative dynamics was mainly based on the linear dissipation model. The study of the nonlinear dissipative dynamics in condensed phases, where there exist an infinite number of bath modes, is extremely difficult even if not impossible. This work put forward a stochastic scheme for the simulation of the nonlinear dissipative dynamics. In the linear response regime, the second-order cumulant expansion becomes exact to reproduce the effect of the bath on the evolution of the reduced system. Consequently, a Hermitian stochastic Liouville equation is derived without explicit treatment of the bath. Stochastic simulations for an anharmonic model illustrate that the dynamics dissipated by anharmonic bath exhibits substantial difference on temperature dependence compared to that with the Caldeira-Leggett model.
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.
Linearity of Climate Response to Increases in Black Carbon Aerosols
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.
Establishment of a new initial dose plan for vancomycin using the generalized linear mixed model.
Kourogi, Yasuyuki; Ogata, Kenji; Takamura, Norito; Tokunaga, Jin; Setoguchi, Nao; Kai, Mitsuhiro; Tanaka, Emi; Chiyotanda, Susumu
2017-04-08
When administering vancomycin hydrochloride (VCM), the initial dose is adjusted to ensure that the steady-state trough value (Css-trough) remains within the effective concentration range. However, the Css-trough (population mean method predicted value [PMMPV]) calculated using the population mean method (PMM) often deviate from the effective concentration range. In this study, we used the generalized linear mixed model (GLMM) for initial dose planning to create a model that accurately predicts Css-trough, and subsequently assessed its prediction accuracy. The study included 46 subjects whose trough values were measured after receiving VCM. We calculated the Css-trough (Bayesian estimate predicted value [BEPV]) from the Bayesian estimates of trough values. Using the patients' medical data, we created models that predict the BEPV and selected the model with minimum information criterion (GLMM best model). We then calculated the Css-trough (GLMMPV) from the GLMM best model and compared the BEPV correlation with GLMMPV and with PMMPV. The GLMM best model was {[0.977 + (males: 0.029 or females: -0.081)] × PMMPV + 0.101 × BUN/adjusted SCr - 12.899 × SCr adjusted amount}. The coefficients of determination for BEPV/GLMMPV and BEPV/PMMPV were 0.623 and 0.513, respectively. We demonstrated that the GLMM best model was more accurate in predicting the Css-trough than the PMM.
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.
Bayesian penalized log-likelihood ratio approach for dose response clinical trial studies.
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.
A Framework for "Fit for Purpose" Dose Response Assessment
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 ...
A Framework for "Fit for Purpose" Dose Response Assessment
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 ...
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.
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...
Fesoterodine dose response in subjects with overactive bladder syndrome.
Khullar, Vik; Rovner, Eric S; Dmochowski, Roger; Nitti, Victor; Wang, Joseph; Guan, Zhonghong
2008-05-01
To compare the efficacy of fesoterodine 4 mg versus 8 mg in treating subjects with overactive bladder (OAB) syndrome. This is a pooled analysis of data from 2 randomized placebo (PBO)-controlled phase III trials. Eligible subjects with frequency and urgency or urgency urinary incontinence (UUI) were randomized to PBO or fesoterodine 4 or 8 mg for 12 weeks. Subjects assessed efficacy using 3-day bladder diaries recording the time of each void, urgency, and incontinence episode. Endpoints included treatment response (based on a 4-point Treatment Benefit scale) and change from baseline in micturitions, UUI episodes, mean volume voided, urgency episodes, and continent days. We assessed tolerability and safety by evaluating adverse events, residual urine volume, laboratory parameters, and treatment withdrawals. At the end of treatment, both doses of fesoterodine showed statistically significant improvements in all efficacy endpoints versus PBO (P <0.01). These effects were seen 2 weeks after initiation of treatment (the earliest evaluation point) and were sustained throughout the treatment period. Fesoterodine 8 mg performed significantly better than fesoterodine 4 mg in improving all diary variables (P <0.05) except micturition frequency, demonstrating a dose-response relationship. Adverse events reported more frequently with fesoterodine than with PBO included dry mouth, constipation, and urinary tract infection. Both fesoterodine 4 and 8 mg are effective in improving OAB symptoms. The higher 8-mg dose provides additional benefit compared with the lower dose in improving most bladder diary variables, thus offering the possibility of dose flexibility and titration.
Linear control of neuronal spike timing using phase response curves.
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.
Radiation dose reduction with application of non-linear adaptive filters for abdominal CT
Singh, Sarabjeet; Kalra, Mannudeep K; Sung, Mi Kim; Back, Anni; Blake, Michael A
2012-01-01
AIM: To evaluate the effect of non-linear adaptive filters (NLAF) on abdominal computed tomography (CT) images acquired at different radiation dose levels. METHODS: Nineteen patients (mean age 61.6 ± 7.9 years, M:F = 8:11) gave informed consent for an Institutional Review Board approved prospective study involving acquisition of 4 additional image series (200, 150, 100, 50 mAs and 120 kVp) on a 64 slice multidetector row CT scanner over an identical 10 cm length in the abdomen. The CT images acquired at 150, 100 and 50 mAs were processed with the NLAF. Two radiologists reviewed unprocessed and processed images for image quality in a blinded randomized manner. CT dose index volume, dose length product, patient weight, transverse diameters, objective noise and CT numbers were recorded. Data were analyzed using Analysis of Variance and Wilcoxon signed rank test. RESULTS: Of the 31 lesions detected in abdominal CT images, 28 lesions were less than 1 cm in size. Subjective image noise was graded as unacceptable in unprocessed images at 50 and 100 mAs, and in NLAF processed images at 50 mAs only. In NLAF processed images, objective image noise was decreased by 21% (14.4 ± 4/18.2 ± 4.9) at 150 mAs, 28.3% (15.7 ± 5.6/21.9 ± 4) at 100 mAs and by 39.4% (18.8 ± 9/30.4 ± 9.2) at 50 mAs compared to unprocessed images acquired at respective radiation dose levels. At 100 mAs the visibility of smaller structures improved from suboptimal in unprocessed images to excellent in NLAF processed images, whereas diagnostic confidence was respectively improved from probably confident to fully confident. CONCLUSION: NLAF lowers image noise, improves the visibility of small structures and maintains lesion conspicuity at down to 100 mAs for abdominal CT. PMID:22328968
An integrated 6 MV linear accelerator model from electron gun to dose in a water tank.
St Aubin, J; Steciw, S; Kirkby, C; Fallone, B G
2010-05-01
The details of a full simulation of an inline side-coupled 6 MV linear accelerator (linac) from the electron gun to the target are presented. Commissioning of the above simulation was performed by using the derived electron phase space at the target as an input into Monte Carlo studies of dose distributions within a water tank and matching the simulation results to measurement data. This work is motivated by linac-MR studies, where a validated full linac simulation is first required in order to perform future studies on linac performance in the presence of an external magnetic field. An electron gun was initially designed and optimized with a 2D finite difference program using Child's law. The electron gun simulation served as an input to a 6 MV linac waveguide simulation, which consisted of a 3D finite element radio-frequency field solution within the waveguide and electron trajectories determined from particle dynamics modeling. The electron gun design was constrained to match the cathode potential and electron gun current of a Varian 600C, while the linac waveguide was optimized to match the measured target current. Commissioning of the full simulation was performed by matching the simulated Monte Carlo dose distributions in a water tank to measured distributions. The full linac simulation matched all the electrical measurements taken from a Varian 600C and the commissioning process lead to excellent agreements in the dose profile measurements. Greater than 99% of all points met a 1%/1mm acceptance criterion for all field sizes analyzed, with the exception of the largest 40 x 40 cm2 field for which 98% of all points met the 1%/1mm acceptance criterion and the depth dose curves matched measurement to within 1% deeper than 1.5 cm depth. The optimized energy and spatial intensity distributions, as given by the commissioning process, were determined to be non-Gaussian in form for the inline side-coupled 6 MV linac simulated. An integrated simulation of an inline
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).
Bayesian multimodel inference for dose-response studies
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.
Heart rate increases linearly in response to acute isovolemic anemia.
Weiskopf, Richard B; Feiner, John; Hopf, Harriet; Viele, Maurene K; Watson, Jessica J; Lieberman, Jeremy; Kelley, Scott; Toy, Pearl
2003-02-01
The cardiovascular response to acute isovolemic anemia in humans is thought to differ from that of other species. Studies of anesthetized humans have found either no change or a decreased heart rate. A previous study showed that in 32 healthy unmedicated humans, heart rate increased during acute isovolemic anemia. The hypothesis that heart rate in humans increases in response to acute isovolemic anemia and that the increase is affected by gender was tested. Acute isovolemic anemia to a Hb concentration of approximately 5 g per dL in 95 unmedicated healthy humans was produced by simultaneous withdrawal of blood and IV replacement with 5-percent HSA and autologous platelet-rich plasma. The relationship between heart rate and Hb concentration was examined using a mixed-effects linear regression model that allowed each person to have a fitted line with its own slope and intercept. Cubic and quadratic terms were added to determine if these improved the goodness of fit. The effect of gender was tested by including it and its interactions with Hb in the mixed model. The relationship between heart rate and Hb concentration was linear (p < 0.001) and consistent among the population studied: heart rate = 116.0-4.0 [Hb] (slope 95% CI: -4.2 to -3.8 beats/min/g Hb). Adding a cubic or quadratic term did not significantly improve the goodness of fit of the mathematical expression to the data, confirming the linear nature of the relationship between heart rate and Hb concentration. For women, the slope of the heart rate response was significantly greater than it was for males (difference +/- SE: 0.70 +/- 0.23, p < 0.005). In 95 unmedicated, healthy humans, heart rate was a linear function of Hb during acute isovolemic anemia. Females had a significantly greater slope of increase in heart rate with decreasing Hb concentration than did males. The relationship is consistent among individuals, is similar to that reported for conscious dogs, and differs from that found previously in
Hauri, Pascal; Hälg, Roger A; Schneider, Uwe
2017-07-01
The use of X-ray imaging in radiation therapy can give a substantial dose to the patient. A Cobalt machine combined with an magnetic resonance imaging (MRI) was recently introduced to clinical work. One positive aspect of using non-ionizing imaging devices is the reduction of the patient exposure. The purpose of this study was to quantify the difference in out-of-field dose to the patient between the image guided radiation therapy (IGRT) treatment applied with a linear accelerator with cone beam CT (CBCT) equipment and a Cobalt machine combined with an MRI. The treatment of a rhabdomyosarcoma in the prostate was planned and irradiated using different modalities and radiation therapy machines. The whole-body dose was measured for a 3D-conformal radiation therapy (3DCRT), an intensity-modulated radiation therapy (IMRT), and a volumetric-modulated arc therapy plan applied with a conventional linear accelerator operated at 6 MV beam energy. Additionally, the dose of an IMRT plan applied with a (60) Co machine combined with an MRI was measured. Furthermore, the dose of one CBCT scan using the linear accelerator's on-board imaging system was determined. The 3D dose measurements were performed in an anthropomorphic phantom containing 168 slots for thermoluminescence dosimeters (TLDs). A combination of LiF:Mg,Ti (TLD100) and LiF:Mg,Cu,P (TLD100H) was used to accurately determine the in- and out-of-field dose. The plans were rescaled to different fractionation schemes (2 Gy, 3 Gy, and 5 Gy fraction dose) and the dose of one CBCT scan was additionally added to the treatment dose per fraction applied with the linear accelerator. The resulting absorbed doses per fraction of the two machines were compared. In the target region, all measured treatment plans presented the same magnitude of dose, while the CBCT dose was a factor of 100 smaller. Close to the planned target volume (PTV), the dose from the (60) Co machine was a factor of two higher compared with the 3DCRT + CBCT dose
NASA Astrophysics Data System (ADS)
Lu, Chung-hsin; Teng, Jen-hsin; Yang, Yung-muh; Chang, Bor-jing
2010-06-01
In Taiwan the new guides for the nuclear emergency public protective action were laid down by the Atomic Energy Council (AEC) of Executive Yuan, Taiwan, ROC on July 15th, 2005. The main modifications of the guides are that the avertable dose is applied as the intervention levels and suggests the public protective actions. The emergency response dose evaluation system named RPDOSE, which was developed in 2005, was employed in this work to enhance the capability of the avertable dose evaluation for the villages in the emergency planning zone (EPZ). The period of the long-term weather forecasting data was extended from 4 to 8 days to satisfy the requirement of avertable dose computing. According to the intervention levels, the RPDOSE system is used to calculate the avertable dose and suggest appropriate public protective actions such as sheltering, evacuation or iodine prophylaxis as well as the proposed acting times for each village in the EPZ. This system was employed and examined in the annual nuclear emergency exercise of 2008 in the Maanshan nuclear power plant.
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).
Evaluating linear response in active systems with no perturbing field
NASA Astrophysics Data System (ADS)
Szamel, Grzegorz
2017-03-01
We present a method for the evaluation of time-dependent linear response functions for systems of active particles propelled by a persistent (colored) noise from unperturbed simulations. The method is inspired by the Malliavin weights sampling method proposed by Warren and Allen (Phys. Rev. Lett., 109 (2012) 250601) for out-of-equilibrium systems of passive Brownian particles. We illustrate our method by evaluating two linear response functions for a single active particle in an external harmonic potential. As an application, we calculate the time-dependent mobility function and an effective temperature, defined through the Einstein relation between the self-diffusion and mobility coefficients, for a system of many active particles interacting via a screened Coulomb potential. We find that this effective temperature decreases with increasing persistence time of the self-propulsion. Initially, for not too large persistence times, it changes rather slowly, but then it decreases markedly when the persistence length of the self-propelled motion becomes comparable with the particle size.
Non-parametric estimators of a monotonic dose-response curve and bootstrap confidence intervals.
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.
Dose-response effects of oral yohimbine in unrestrained primates.
Rosenblum, L A; Coplan, J D; Friedman, S; Bassoff, T
1991-04-01
Six unrestrained bonnet macaques were each observed after oral administration of four dosages of yohimbine hydrochloride (0.10, 0.25, 0.50, and 0.75 mg/kg) and a placebo. Yohimbine significantly increased episodes of motoric activation and affective response interspersed with intervals of behavioral enervation. Yohimbine scores correlated closely with baseline levels; there was no dose-response relationship. Response to oral yohimbine differed in several ways from subcutaneous and intravenous sodium lactate infusions, including prominent enervative symptoms and the appearance of sexual arousal. In light of the appearance of cyclic enervative episodes, this study suggests limitations to primate models of panic disorder utilizing oral yohimbine.
NASA Astrophysics Data System (ADS)
Inaniwa, Taku; Kanematsu, Nobuyuki; Noda, Koji; Kamada, Tadashi
2017-06-01
The biological effect of charged-particle beams depends on both dose and particle spectrum. As one of the physical quantities describing the particle spectrum of charged-particle beams, we considered the linear energy transfer (LET) throughout this study. We investigated a new therapeutic technique using two or more ion species in one treatment session, which we call an intensity modulated composite particle therapy (IMPACT), for optimizing the physical dose and dose-averaged LET distributions in a patient as its proof of principle. Protons and helium, carbon, and oxygen ions were considered as ion species for IMPACT. For three cubic targets of 4 × 4 × 4, 8 × 8 × 8, and 12 × 12 × 12 cm3, defined at the center of the water phantom of 20 × 20 × 20 cm3, we made IMPACT plans of two composite fields with opposing and orthogonal geometries. The prescribed dose to the target was fixed at 1 Gy, while the prescribed LET to the target was varied from 1 keV µm-1 to 120 keV µm-1 to investigate the range of LET valid for prescription. The minimum and maximum prescribed LETs, (L T_min, L T_max), by the opposing-field geometry, were (3 keV µm-1, 115 keV µm-1), (2 keV µm-1, 84 keV µm-1),and (2 keV µm-1, 66 keV µm-1), while those by the orthogonal-field geometry were (8 keV µm-1, 98 keV µm-1), (7 keV µm-1, 72 keV µm-1), and (8 keV µm-1, 57 keV µm-1) for the three targets, respectively. To show the proof of principle of IMPACT in a clinical situation, we made IMPACT plans for a prostate case. In accordance with the prescriptions, the LETs in prostate, planning target volume (PTV), and rectum could be adjusted at 80 keV µm-1, at 50 keV µm-1, and below 30 keV µm-1, respectively, while keeping the dose to the PTV at 2 Gy uniformly. IMPACT enables the optimization of the dose and the LET distributions in a patient, which will maximize the
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
Shibamoto, Yuta; Otsuka, Shinya; Iwata, Hiromitsu; Sugie, Chikao; Ogino, Hiroyuki; Tomita, Natsuo
2012-01-01
Since the dose delivery pattern in high-precision radiotherapy is different from that in conventional radiation, radiobiological assessment of the physical dose used in stereotactic irradiation and intensity-modulated radiotherapy has become necessary. In these treatments, the daily dose is usually given intermittently over a time longer than that used in conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. This phenomenon is almost universarily observed in vitro. In in vivo tumors, however, this decrease in effect can be counterbalanced by rapid reoxygenation, which has been demonstrated in a laboratory study. Studies on reoxygenation in human tumors are warranted to better evaluate the influence of prolonged radiation delivery. Another issue related to radiosurgery and hypofractionated stereotactic radiotherapy is the mathematical model for dose evaluation and conversion. Many clinicians use the linear-quadratic (LQ) model and biologically effective dose (BED) to estimate the effects of various radiation schedules, but it has been suggested that the LQ model is not applicable to high doses per fraction. Recent experimental studies verified the inadequacy of the LQ model in converting hypofractionated doses into single doses. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when it is used for tumor responses in vivo, since it does not take reoxygenation into account. For normal tissue responses, improved models have been proposed, but, for in vivo tumor responses, the currently available models are not satisfactory, and better ones should be proposed in future studies.
Prediction of the mortality dose-response relationship in man
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.
Zaghian, Maryam; Lim, Gino; Liu, Wei; Mohan, Radhe
2014-01-01
Prescriptions for radiation therapy are given in terms of dose-volume constraints (DVCs). Solving the fluence map optimization (FMO) problem while satisfying DVCs often requires a tedious trial-and-error for selecting appropriate dose control parameters on various organs. In this paper, we propose an iterative approach to satisfy DVCs using a multi-objective linear programming (LP) model for solving beamlet intensities. This algorithm, starting from arbitrary initial parameter values, gradually updates the values through an iterative solution process toward optimal solution. This method finds appropriate parameter values through the trade-off between OAR sparing and target coverage to improve the solution. We compared the plan quality and the satisfaction of the DVCs by the proposed algorithm with two nonlinear approaches: a nonlinear FMO model solved by using the L-BFGS algorithm and another approach solved by a commercial treatment planning system (Eclipse 8.9). We retrospectively selected from our institutional database five patients with lung cancer and one patient with prostate cancer for this study. Numerical results show that our approach successfully improved target coverage to meet the DVCs, while trying to keep corresponding OAR DVCs satisfied. The LBFGS algorithm for solving the nonlinear FMO model successfully satisfied the DVCs in three out of five test cases. However, there is no recourse in the nonlinear FMO model for correcting unsatisfied DVCs other than manually changing some parameter values through trial and error to derive a solution that more closely meets the DVC requirements. The LP-based heuristic algorithm outperformed the current treatment planning system in terms of DVC satisfaction. A major strength of the LP-based heuristic approach is that it is not sensitive to the starting condition. PMID:25506501
Zaghian, Maryam; Lim, Gino; Liu, Wei; Mohan, Radhe
2014-02-01
Prescriptions for radiation therapy are given in terms of dose-volume constraints (DVCs). Solving the fluence map optimization (FMO) problem while satisfying DVCs often requires a tedious trial-and-error for selecting appropriate dose control parameters on various organs. In this paper, we propose an iterative approach to satisfy DVCs using a multi-objective linear programming (LP) model for solving beamlet intensities. This algorithm, starting from arbitrary initial parameter values, gradually updates the values through an iterative solution process toward optimal solution. This method finds appropriate parameter values through the trade-off between OAR sparing and target coverage to improve the solution. We compared the plan quality and the satisfaction of the DVCs by the proposed algorithm with two nonlinear approaches: a nonlinear FMO model solved by using the L-BFGS algorithm and another approach solved by a commercial treatment planning system (Eclipse 8.9). We retrospectively selected from our institutional database five patients with lung cancer and one patient with prostate cancer for this study. Numerical results show that our approach successfully improved target coverage to meet the DVCs, while trying to keep corresponding OAR DVCs satisfied. The LBFGS algorithm for solving the nonlinear FMO model successfully satisfied the DVCs in three out of five test cases. However, there is no recourse in the nonlinear FMO model for correcting unsatisfied DVCs other than manually changing some parameter values through trial and error to derive a solution that more closely meets the DVC requirements. The LP-based heuristic algorithm outperformed the current treatment planning system in terms of DVC satisfaction. A major strength of the LP-based heuristic approach is that it is not sensitive to the starting condition.
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.
Characterization of Statin Dose-response within Electronic Medical Records
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
Biphasic dose response in low level light therapy - an update.
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.
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.
Role of heme Oxygenase-1 in low dose Radioadaptive response
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
Radiation dose detection by imaging response in biological targets.
Jakob, B; Durante, M
2012-04-01
Imaging was one of the earliest techniques to quantify radiation dose. While films and active fluorescent detectors are still commonly used in physical dosimetry, biological imaging is emerging as a new method to visualize and quantify radiation dose in biological targets. Methods for biological imaging are normally based on molecular fluorescent probes, labeling chromatin-conjugated molecules or specific repair proteins. Examples are chromatin-binding coumarin compounds, which become fluorescent under irradiation, or the H2AX histone, which is rapidly phosphorylated at sites of DNA double-strand breaks and can be visualized by immunostaining. Many other DNA repair proteins can be expressed with fluorescent targets, such as green fluorescent protein, thus becoming visible for dose estimation in vivo. The possibility to visualize radiation damage in living biological targets is particularly important for repair kinetic studies, for estimating individual radiation response, and for remote control of living samples exposed to radiation, for instance in robotic space missions. In vivo dose monitoring in particle therapy exploits the production of positron emitters by nuclear interaction of the incident beam in the patient's body. Positron emission tomography (PET) can then be used to visualize and quantify the particle dose in the patient, and it can in principle also be used for radiotherapy with high-energy X rays. Alternatively, prompt γ rays or scattered secondary particles are under study for in vivo dosimetry of ion beams in therapy.
The dose-response curve of the gravitropic reaction: a re-analysis.
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
Brenner, David J.
2008-01-01
The tool most commonly used for quantitative predictions of dose / fractionation dependencies in radiotherapy is the mechanistically-based linear-quadratic (LQ) model. The LQ formalism is now almost universally used for calculating radiotherapeutic isoeffect doses for different fractionation/protraction schemes. In summary, LQ has the following useful properties for predicting isoeffect doses: First, it is a mechanistic, biologically-based model; second, it has sufficiently few parameters to be practical; third, most other mechanistic models of cell killing predict the same fractionation dependencies as does LQ; fourth, it has well documented predictive properties for fractionation/dose-rate effects in the laboratory; fifth, it is reasonably well validated, experimentally and theoretically, up to about 10 Gy / fraction, and would be reasonable for use up to about 18 Gy per fraction. To date, there is no evidence of problems when LQ has been applied in the clinic. PMID:18725109
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.
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.
Fang, Xin; Liang, Chun; Li, Mei; Montgomery, Scott; Fall, Katja; Aaseth, Jan; Cao, Yang
2016-12-01
Although epidemiology studies have reported the relationship, including a dose-response relationship, between dietary magnesium intake and risk of cardiovascular disease (CVD), the risk for CVD mortality is inconclusive and the evidence for a dose-response relationship has not been summarized. We conducted a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the association of dietary magnesium intake with risk of CVD mortality and describe their dose-response relationship. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to August 2015, and reviewed references lists of retrieved articles. We included population-based studies that reported mortality risks, i.e. relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) of CVD mortality or cause-specific CVD death. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. Out of 3002 articles, 9 articles from 8 independent studies met the eligibility criteria. These studies comprised 449,748 individuals and 10,313 CVD deaths. Compared with the lowest dietary magnesium consumption group in the population, the risk of CVD mortality was reduced by 16% in women and 8% in men. No significant linear dose-response relationship was found between increment in dietary magnesium intake and CVD mortality across all the studies. After adjusting for age and BMI, the risk of CVD mortality was reduced by 24-25% per 100mg/d increment in dietary magnesium intake in women of all the participants and in all the US participants. Although the combined data confirm the role of dietary magnesium intake in reducing CVD mortality, the dose-response relationship was only found among women and in US population. Copyright © 2016 Elsevier GmbH. All rights reserved.
Dose-response patterns for vibration-induced white finger
Griffin, M; Bovenzi, M; Nelson, C
2003-01-01
Aims: To investigate alternative relations between cumulative exposures to hand-transmitted vibration (taking account of vibration magnitude, lifetime exposure duration, and frequency of vibration) and the development of white finger (Raynaud's phenomenon). Methods: Three previous studies have been combined to provide a group of 1557 users of powered vibratory tools in seven occupational subgroups: stone grinders, stone carvers, quarry drillers, dockyard caulkers, dockyard boilermakers, dockyard painters, and forest workers. The estimated total operating duration in hours was thus obtained for each subject, for each tool, and for all tools combined. From the vibration magnitudes and exposure durations, seven alternative measurements of cumulative exposure were calculated for each subject, using expressions of the form: dose = ∑amiti, where ai is the acceleration magnitude on tool i, ti is the lifetime exposure duration for tool i, and m = 0, 1, 2, or 4. Results: For all seven alternative dose measures, an increase in dose was associated with a significant increase in the occurrence of vibration-induced white finger, after adjustment for age and smoking. However, dose measures with high powers of acceleration (m > 1) faired less well than measures in which the weighted or unweighted acceleration, and lifetime exposure duration, were given equal weight (m = 1). Dose determined solely by the lifetime exposure duration (without consideration of the vibration magnitude) gave better predictions than measures with m greater than unity. All measures of dose calculated from the unweighted acceleration gave better predictions than the equivalent dose measures using acceleration frequency-weighted according to current standards. Conclusions: Since the total duration of exposure does not discriminate between exposures accumulated over the day and those accumulated over years, a linear relation between vibration magnitude and exposure duration seems appropriate for predicting
How linear features alter predator movement and the functional response
McKenzie, Hannah W.; Merrill, Evelyn H.; Spiteri, Raymond J.; Lewis, Mark A.
2012-01-01
In areas of oil and gas exploration, seismic lines have been reported to alter the movement patterns of wolves (Canis lupus). We developed a mechanistic first passage time model, based on an anisotropic elliptic partial differential equation, and used this to explore how wolf movement responses to seismic lines influence the encounter rate of the wolves with their prey. The model was parametrized using 5 min GPS location data. These data showed that wolves travelled faster on seismic lines and had a higher probability of staying on a seismic line once they were on it. We simulated wolf movement on a range of seismic line densities and drew implications for the rate of predator–prey interactions as described by the functional response. The functional response exhibited a more than linear increase with respect to prey density (type III) as well as interactions with seismic line density. Encounter rates were significantly higher in landscapes with high seismic line density and were most pronounced at low prey densities. This suggests that prey at low population densities are at higher risk in environments with a high seismic line density unless they learn to avoid them. PMID:22419990
Development of a dose-response model for SARS coronavirus.
Watanabe, Toru; Bartrand, Timothy A; Weir, Mark H; Omura, Tatsuo; Haas, Charles N
2010-07-01
In order to develop a dose-response model for SARS coronavirus (SARS-CoV), the pooled data sets for infection of transgenic mice susceptible to SARS-CoV and infection of mice with murine hepatitis virus strain 1, which may be a clinically relevant model of SARS, were fit to beta-Poisson and exponential models with the maximum likelihood method. The exponential model (k= 4.1 x l0(2)) could describe the dose-response relationship of the pooled data sets. The beta-Poisson model did not provide a statistically significant improvement in fit. With the exponential model, the infectivity of SARS-CoV was calculated and compared with those of other coronaviruses. The does of SARS-CoV corresponding to 10% and 50% responses (illness) were estimated at 43 and 280 PFU, respectively. Its estimated infectivity was comparable to that of HCoV-229E, known as an agent of human common cold, and also similar to those of some animal coronaviruses belonging to the same genetic group. Moreover, the exponential model was applied to the analysis of the epidemiological data of SARS outbreak that occurred at an apartment complex in Hong Kong in 2003. The estimated dose of SARS-CoV for apartment residents during the outbreak, which was back-calculated from the reported number of cases, ranged from 16 to 160 PFU/person, depending on the floor. The exponential model developed here is the sole dose-response model for SARS-CoV at the present and would enable us to understand the possibility for reemergence of SARS.
Nonequilibrium thermal transport and its relation to linear response
NASA Astrophysics Data System (ADS)
Karrasch, C.; Ilan, R.; Moore, J. E.
2013-11-01
We study the real-time dynamics of spin chains driven out of thermal equilibrium by an initial temperature gradient TL≠TR using density matrix renormalization group methods. We demonstrate that the nonequilibrium energy current saturates fast to a finite value if the linear-response thermal conductivity is infinite, i.e., if the Drude weight D is nonzero. Our data suggest that a nonintegrable dimerized chain might support such dissipationless transport (D>0). We show that the steady-state value JE of the current for arbitrary TL≠TR is of the functional form JE=f(TL)-f(TR), i.e., it is completely determined by the linear conductance. We argue for this functional form, which is essentially a Stefan-Boltzmann law in this integrable model; for the XXX ferromagnet, f can be computed via the thermodynamic Bethe ansatz in good agreement with the numerics. Inhomogeneous systems exhibiting different bulk parameters as well as Luttinger liquid boundary physics induced by single impurities are discussed briefly.
Finite orbit energetic particle linear response to toroidal Alfven eigenmodes
NASA Astrophysics Data System (ADS)
Berk, H. L.; Breizman, B. N.; Ye, Huanchun
1992-03-01
The linear response of energetic particles of the TAE modes is calculated taking into account their finite orbit excursion from the flux surfaces. The general expression reproduces the previously derived theory for small banana width; when the banana width Δ b is much larger than the mode thickness Δ m, we obtain a new compact expression for the linear power transfer. When Δm/ Δb≪1, the banana orbit effect reduces the power transfer by a factor Δm/ Δb from that predicted by the narrow orbit theory. A comparison is made of the contribution to the TAE growth rate of energetic particles with a slowing-down distribution arising from an isotropic source, and a balanced-injected beam source when the source speed is close to the Alfven speed. For the same stored energy density, the contribution from the principal resonances (| v‖|= vA) is substantially enhanced in the beam case compared to the isotropic case, while the contribution at the higher sidebands (| v‖|= vA/(2 l-1) with l⩾2) is substantially reduced.
Finite orbit energetic particle linear response to toroidal Alfven Eigenmodes
NASA Astrophysics Data System (ADS)
Berk, H. L.; Ye, Huanchun; Breizman, B. N.
1991-07-01
The linear response of energetic particles to the toroidal Alfven eigenmodes (TAE) modes is calculated taking into account their finite orbit excursion from the flux surfaces. The general expression reproduces the previously derived theory for small banana width: when the banana width delta(sub b) is much larger than the mode thickness delta(sub m), we obtain a new compact expression for the linear power transfer. When delta(sub m)/delta(sub b) is much less than 1, the banana orbit effect reduces the power transfer by a factor of delta(sub m)/delta(sub b) from that predicted by the narrow orbit theory. A comparison is made of the contribution to the TAE growth rate of energetic particles with a slowing-down distribution arising from an isotropic source, and a balance-injected beam source when the source speed is close to the Alfven speed. For the same stored energy density, the contribution from the principal resonances (absolute value of upsilon(parallel) = upsilon(sub A) is substantially enhanced in the beam case compared to the isotropic case, while the contribution at the higher sidebands (absolute value of upsilon(parallel) = upsilon(sub A)/(2l - 1) with l greater than or = 2) is substantially reduced.
Finite orbit energetic particle linear response to toroidal Alfven eigenmodes
Berk, H.L.; Ye, Huanchun . Inst. for Fusion Studies); Breizman, B.N. . Inst. Yadernoj Fiziki)
1991-07-01
The linear response of energetic particles to the TAE modes is calculated taking into account their finite orbit excursion from the flux surfaces. The general expression reproduces the previously derived theory for small banana width: when the banana width {triangle}{sub b} is much larger than the mode thickness {triangle}{sub m}, we obtain a new compact expression for the linear power transfer. When {triangle}{sub m}/{triangle}{sub b} {much lt} 1, the banana orbit effect reduces the power transfer by a factor of {triangle}{sub m}/{triangle}{sub b} from that predicted by the narrow orbit theory. A comparison is made of the contribution to the TAE growth rate of energetic particles with a slowing-down distribution arising from an isotropic source, and a balance-injected beam source when the source speed is close to the Alfven speed. For the same stored energy density, the contribution from the principal resonances ({vert bar}{upsilon}{sub {parallel}}{vert bar} = {upsilon}{sub A} is substantially enhanced in the beam case compared to the isotropic case, while the contribution at the higher sidebands ({vert bar}{upsilon}{sub {parallel}}{vert bar}) = {upsilon}{sub A}/(2{ell} {minus} 1) with {ell} {ge} 2) is substantially reduced. 10 refs.
Hyun, Seung Won; Wong, Weng Kee
2016-01-01
We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557
A Transient Response Method for Linear Coupled Substructures
NASA Technical Reports Server (NTRS)
Admire, J. R.; Brunty, J. A.
1989-01-01
A method is presented for determining the transient response of a discrete coordinate model of a linear structural system composed of substructures. The method is applicable to systems consisting of any number of substructures, both determinate and indeterminate interface boundaries, and any topological arrangement of the substructures. The method is simple to implement from a computational point of view because the equations of motion of each of the substructures are solved independently, and the interface boundary compatibility conditions are enforced at each integration time step by a matrix multiplication. The method is demonstrated for a structural system consisting of two beam segments and acted upon by a time dependent force. The numerical results from the demonstration problem validates the accuracy of the method. The application of this method to structural systems with changing interface boundary conditions between substructures is discussed.
Myocardial adrenergic responsiveness after lethal and nonlethal doses of endotoxin
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.
Biphasic dose response in low level light therapy.
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.
Biphasic Dose Response in Low Level Light Therapy
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
Dashwood, R H; Arbogast, D N; Fong, A T; Pereira, C; Hendricks, J D; Bailey, G S
1989-01-01
A number of recent studies have described inhibitor-mediated reductions in the covalent DNA binding and tumorigenicity of various carcinogens, in species such as rats, mice and rainbow trout (Salmo gairdneri). Since inhibitory effects have, in most cases, been reported after testing at one carcinogen and one inhibitor level only, the detailed relationships between carcinogen dose, inhibitor dose, in vivo DNA binding and final tumor response are not well understood in any species. To determine these relationships we have employed the trout model in a combined DNA binding/tumor dose-response protocol using approximately 10,000 animals. Trout were pretreated with one of five different dose-levels of indole-3-carbinol (I3C), a naturally occurring anti-carcinogen found in cruciferous vegetables such as broccoli and cabbage. After 4 weeks, animals received the same dietary level of I3C for a further 2 weeks together with [3H]aflatoxin B1 (AFB1) in the dose-range 10-320 p.p.b. From tanks containing 150 animals (three tanks per I3C-AFB1 dose-point), 15 fish were selected at random in order to assess hepatic AFB1-DNA binding levels. Remaining animals were returned to control diet for determination of tumor response at 12 months. Linear increases in DNA binding occurred with dose of AFB1 at each I3C dose-level. Successive increases in I3C dose gave dose-related decreases in AFB1-DNA binding, resulting in a series of curves of decreasing slope. Shifts in DNA-binding slopes were compared quantitatively with horizontal displacements towards higher carcinogen dose in corresponding tumor dose-response curves. At I3C doses of less than or equal to 2000 p.p.m., the inhibitor-altered tumor response was predicted precisely by changes in dose received (DNA adducts formed) in the target organ. These data constitute the first direct evidence of pure anti-initiating activity by a natural anti-carcinogen found in human diet, where all animals were treated at the same time and under
Liao, Wei-Chih; Tu, Yu-Kang; Wu, Ming-Shiang; Lin, Jaw-Town; Wang, Hsiu-Po; Chien, Kuo-Liong
2015-01-02
To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer. Systematic review and dose-response meta-analysis of prospective observational studies. Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations. Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer. Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer. © Liao et al 2014.
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.
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
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.
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
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.
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...
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...
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
Effects of chewing gum on stress and health: a replication and investigation of dose-response.
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.
A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.
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.
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.
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.
Modeling Effective Dosages in Hormetic Dose-Response Studies
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
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.
Is There a Dose-Response Relationship for Heart Disease With Low-Dose Radiation Therapy?
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.
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
Quantum optimal control theory in the linear response formalism
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.
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.
Characterization of a developmental toxicity dose-response model
Faustman, E.M.; Wellington, D.G.; Smith, W.P.; Kimmel, C.A.
1989-02-01
The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.
Responses of proteins to different ionic environment are linearly interrelated.
Ferreira, Luisa A; Madeira, Pedro P; Uversky, Alexey V; Uversky, Vladimir N; Zaslavsky, Boris Y
2015-03-27
Protein partitioning in aqueous two-phase systems (ATPS) is widely used as a convenient, inexpensive, and readily scaled-up separation technique. Protein partition behavior in ATPS is known to be readily manipulated by ionic composition. However, the available data on the effects of salts and buffer concentrations on protein partitioning are very limited. To fill this gap, partitioning of 15 proteins was examined in dextran-poly(ethylene glycol) ATPSs with different salt additives (Na2SO4, NaClO4, NaSCN, CsCl) in 0.11 M sodium phosphate buffer, pH 7.4. This analysis reveals that there is a linear relationship between the logarithms of the protein partition coefficients determined in the presence of different salts. This relationship suggests that the protein response to ionic environment is determined by the protein structure and type and concentrations of the ions present. Analysis of the differences between protein structures (described in terms of proteins responses to different salts) and that of cytochrome c chosen as a reference showed that the peculiarities of the protein surface structure and B-factor used as a measure of the protein flexibility are the determining parameters. Our results provide better insight into the use of different salts in manipulating protein partitioning in aqueous two-phase systems. These data also demonstrate that the protein responses to different ionic environments are interrelated and are determined by the structural peculiarities of protein surface. It is suggested that changes in ionic microenvironment of proteins may regulate protein transport and behavior in biological systems. Copyright © 2015 Elsevier B.V. All rights reserved.
Curve fitting toxicity test data: Which comes first, the dose response or the model?
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.
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.
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
Cryptosporidium Infection Risk: Results of New Dose-Response Modeling.
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.
Caffeine and sprinting performance: dose responses and efficacy.
Glaister, Mark; Patterson, Stephen D; Foley, Paul; Pedlar, Charles R; Pattison, John R; McInnes, Gillian
2012-04-01
The aims of this study were to evaluate the effects of caffeine supplementation on sprint cycling performance and to determine if there was a dose-response effect. Using a randomized, double-blind, placebo-controlled design, 17 well-trained men (age: 24 ± 6 years, height: 1.82 ± 0.06 m, and body mass(bm): 82.2 ± 6.9 kg) completed 7 maximal 10-second sprint trials on an electromagnetically braked cycle ergometer. Apart from trial 1 (familiarization), all the trials involved subjects ingesting a gelatine capsule containing either caffeine or placebo (maltodextrin) 1 hour before each sprint. To examine dose-response effects, caffeine doses of 2, 4, 6, 8, and 10 mg·kg bm(-1) were used. There were no significant (p ≥ 0.05) differences in baseline measures of plasma caffeine concentration before each trial (grand mean: 0.14 ± 0.28 μg·ml(-1)). There was, however, a significant supplement × time interaction (p < 0.001), with larger caffeine doses producing higher postsupplementation plasma caffeine levels. In comparison with placebo, caffeine had no significant effect on peak power (p = 0.11), mean power (p = 0.55), or time to peak power (p = 0.17). There was also no significant effect of supplementation on pretrial blood lactate (p = 0.58), but there was a significant time effect (p = 0.001), with blood lactate reducing over the 50 minute postsupplementation rest period from 1.29 ± 0.36 to 1.06 ± 0.33 mmol·L(-1). The results of this study show that caffeine supplementation has no effect on short-duration sprint cycling performance, irrespective of the dosage used.
Dose response and factors related to interstitial pneumonitis after bone marrow transplant
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
Th Cell Gene Expression and Function in Response to Low Dose and Acute Radiation
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
TRANSIENT GENOME-WIDE TRANSCRIPTIONAL RESPONSE TO LOW-DOSE IONIZING RADIATION IN VIVO IN HUMANS
Berglund, Susanne R.; Rocke, David M.; Dai, Jian; Schwietert, Chad W.; Santana, Alison; Stern, Robin L.; Lehmann, Joerg; Hartmann Siantar, Christine L.; Goldberg, Zelanna
2009-01-01
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. PMID:17996396
Transient Genome-Wide Transcriptional Response to Low-Dose Ionizing Radiation In Vivo in Humans
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.
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.
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.
Beetroot juice and exercise: pharmacodynamic and dose-response relationships.
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.
GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve.
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.
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.
An analysis of the dose-response relationship at voltage-clamped frog neuromuscular junctions.
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
Mesbahi, Asghar; Jafarzadeh, Vahid; Gharehaghaji, Nahideh
2012-01-01
Background Application of less toxic normoxic polymer gel of N-isopropyl acrylamide (NIPAM) for radiation therapy has been studied in recent years. Aim In the current study the optical and NMR properties of NIPAM were studied for radiation therapy dosimetry application. Materials and methods NIPAM normoxic polymer gel was prepared and irradiated by 9 MV photon beam of a medical linac. The optical absorbance was measured using a conventional laboratory spectrophotometer in different wavelengths ranging from 390 to 860 nm. R2 measurements of NIPAM gels were performed using a 1.5 T scanner and R2–dose curve was obtained. Results Our results showed R2 dose sensitivity of 0.193 ± 0.01 s−1 Gy−1 for NIPAM gel. Both R2 and optical absorbance showed a linear relationship with dose from 1.5 to 11 Gy for NIPAM gel dosimeter. Moreover, absorbance–dose response varied considerably with light wavelength and highest sensitivity was seen for the blue part of the spectrum. Conclusion Our results showed that both optical and NMR approaches have acceptable sensitivity and accuracy for dose determination with NIPAM gel. However, for optical reading of the gel, utilization of an optimum optical wavelength is recommended. PMID:24377016
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.
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.
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.
Pérez-Mañá, Clara; Farré, Magí; Pastor, Antoni; Fonseca, Francina; Torrens, Marta; Menoyo, Esther; Pujadas, Mitona; Frias, Silvia; Langohr, Klaus; de la Torre, Rafael
2017-09-01
Ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs) are non-oxidative metabolites of alcohol that can be detected in conventional and non-conventional biological matrices for longer periods than alcohol. The aim was to describe the time courses of both biomarkers after ingestion of acute low-moderate doses of ethanol. The study design was double-blind, randomized, crossover and controlled with placebo. Participants were distributed in three different cohorts: (a) Cohort-1: two doses of 18 and 30 g of ethanol and placebo were administered to 12 subjects; (b) Cohort-2: two doses of 6 and 12 g of ethanol and placebo were administered to six subjects and (c) Cohort-3: two doses of 24 and 42 g of ethanol and placebo were administered to six subjects. Each participant received two doses of ethanol and placebo. Plasma concentrations (0-6 h) of ethanol and specific FAEEs (palmitic, stearic, linoleic and oleic acid ethyl esters) and urinary concentrations of EtG (0-24 h) were measured. A dose-dependent increase in blood ethanol concentrations was observed. EtG excretion and FAEEs plasmatic concentrations showed a disproportionate increase with the ethanol dose suggesting non-linearity. Area under the curve (AUC0-6h) of ethanol concentrations showed a linear trend with non-oxidative metabolites' concentrations. The formation rate of ethanol non-oxidative biomarkers does not follow a linear trend, explained mainly by a disproportionate increase in AUC0-6h of ethanol concentrations in relation to dose. This observation should be taken into account when interpreting results in biological matrices in clinical and forensic settings. A double-blind, randomized, crossover and controlled study was conducted administering ethanol (6-42 g). Ethyl glucuronide (EtG) excretion and fatty acid ethyl esters (FAEEs) plasmatic concentrations showed a disproportionate increase with the ethanol dose suggesting non-linearity. This observation should be taken into account when
Melatonin entrains free-running blind people according to a physiological dose-response curve.
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.
Motility response of rats to chronic constant-dose treatment with narcotics.
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.
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.
Banks, Siobhan; Van Dongen, Hans P. A.; Maislin, Greg; Dinges, David F.
2010-01-01
Objective: Establish the dose-response relationship between increasing sleep durations in a single night and recovery of neurobehavioral functions following chronic sleep restriction. Design: Intent-to-treat design in which subjects were randomized to 1 of 6 recovery sleep doses (0, 2, 4, 6, 8, or 10 h TIB) for 1 night following 5 nights of sleep restriction to 4 h TIB. Setting: Twelve consecutive days in a controlled laboratory environment. Participants: N = 159 healthy adults (aged 22-45 y), median = 29 y). Interventions: Following a week of home monitoring with actigraphy and 2 baseline nights of 10 h TIB, subjects were randomized to either sleep restriction to 4 h TIB per night for 5 nights followed by randomization to 1 of 6 nocturnal acute recovery sleep conditions (N = 142), or to a control condition involving 10 h TIB on all nights (N = 17). Measurements and Results: Primary neurobehavioral outcomes included lapses on the Psychomotor Vigilance Test (PVT), subjective sleepiness from the Karolinska Sleepiness Scale (KSS), and physiological sleepiness from a modified Maintenance of Wakefulness Test (MWT). Secondary outcomes included psychomotor and cognitive speed as measured by PVT fastest RTs and number correct on the Digit Symbol Substitution Task (DSST), respectively, and subjective fatigue from the Profile of Mood States (POMS). The dynamics of neurobehavioral outcomes following acute recovery sleep were statistically modeled across the 0 h-10 h recovery sleep doses. While TST, stage 2, REM sleep and NREM slow wave energy (SWE) increased linearly across recovery sleep doses, best-fitting neurobehavioral recovery functions were exponential across recovery sleep doses for PVT and KSS outcomes, and linear for the MWT. Analyses based on return to baseline and on estimated intersection with control condition means revealed recovery was incomplete at the 10 h TIB (8.96 h TST) for PVT performance, KSS sleepiness, and POMS fatigue. Both TST and SWE were elevated
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
Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors
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, ...
Adaptive Responses to Prochloraz Exposure That Alter Dose-Response and Time-Course Behaviors
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, ...
A dose-response model for refractory ceramic fibers.
Turim, J; Brown, R C
2003-09-15
Refractory ceramic fibers (RCFs) are man-made vitreous fibers commonly used in insulation applications above 1000 degrees C. Although they have been subjected to considerable toxicologic evaluation, only the pooled results from two rat inhalation studies provide data that may be suitable for performing a numerical risk assessment. Even in these inhalation studies, good evidence exists that the maximum tolerated dose (MTD) was exceeded and that pulmonary overload occurred, a condition that will cause tumors whatever the dust responsible. Indeed, a significant yield of tumors was only obtained at the highest dose tested. If these results are omitted, there is no statistically significant evidence of carcinogenicity within the RCF results. Although there is little evidence that overload-related tumors are relevant to human risk, we adopted a conservative approach to obtain the estimates of risk regardless of overload, using a biologically based model, the two-stage clonal expansion model, as well as various statistical models, including the benchmark dose model. We argue that the data favor the use of a biologically based model, which gives the best fit when the highest dose RCF exposures are omitted. Continuing with this model, we show that available data from the RCF experiment, less outliers, coupled with results from other experiments with man-made mineral fibers (MMVFs), demonstrate that all MMVFs are potentially carcinogenic, with any risk mediated by the fibers' biopersistence. Application of this "all MMVF data set" model yields a maximum likely estimate for RCF excess unit risk of 4.6 x 10(-5) (95% upper confidence limit = 9.2 x 10(-5) per fiber/ml). This implies that the risk from occupational exposure to RCFs at 1 fiber/ml for a typical working lifetime would not exceed 10(-4).
Greene-Schloesser, Dana M; Kooshki, Mitra; Payne, Valerie; D'Agostino, Ralph B; Wheeler, Kenneth T; Metheny-Barlow, Linda J; Robbins, Mike E
2014-09-01
To determine if the brain's response to single doses predicts its response to 'biologically equivalent' fractionated doses. Young adult male Fischer 344 rats were whole-brain irradiated with either single 11, 14, or 16.5 Gy doses of (137)Cs γ rays or their 'biologically equivalent' 20, 30, or 40 Gy fractionated doses (fWBI) delivered in 5 Gy fractions, twice/week for 2, 3, or 4 weeks, respectively. At 2 months post-irradiation, cellular markers of inflammation (total, activated, and newborn microglia) and neurogenesis (newborn neurons) were measured in 40 μm sections of the dentate gyrus (DG). Although the total number of microglia in the DG/hilus was not significantly different (p > 0.7) in unirradiated, single dose, and fWBI rats, single doses produced a significant (p < 0.003) increase in the percent-activated microglia; fWBI did not (p > 0.1). Additionally, single doses produced a significant (p < 0.002) dose-dependent increase in surviving newborn microglia; fWBI did not (p < 0.8). Although total proliferation in the DG was reduced equally by single and fWBI doses, single doses produced a significant dose-dependent (p < 0.02) decrease in surviving newborn neurons; fWBI did not (p > 0.6). These data demonstrate that the rat brain's cellular response to single doses often does not predict its cellular response to 'biologically equivalent' fWBI doses.
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.
Appropriate statistical methods to compare dose responses of methionine sources.
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
Cornelissen, Jan B. W. J.; van der Giessen, Joke W. B.; Takumi, Katsuhisa; Teunis, Peter F. M.; Wisselink, Henk J.
2014-01-01
High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application. PMID:25184619
Exact analysis of dose response for multiple correlated binary outcomes.
Han, Karen E; Catalano, Paul J; Senchaudhuri, Pralay; Mehta, Cyrus
2004-03-01
The neurotoxicity of a substance is often tested using animal bioassays. In the functional observational battery, animals are exposed to a test agent and multiple outcomes are recorded to assess toxicity, using approximately 40 animals measured on up to 30 different items. This design gives rise to a challenging statistical problem: a large number of outcomes for a small sample of subjects. We propose an exact test for multiple binary outcomes, under the assumption that the correlation among these items is equal. This test is based upon an exponential model described by Molenberghs and Ryan (1999, Environmetrics 10, 279-300) and extends the methods developed by Corcoran et al. (2001, Biometrics 57, 941-948) who developed an exact test for exchangeably correlated binary data for groups (clusters) of correlated observations. We present a method that computes an exact p-value testing for a joint dose-response relationship. An estimate of the parameter for dose response is also determined along with its 95% confidence bound. The method is illustrated using data from a neurotoxicity bioassay for the chemical perchlorethylene.
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.
PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT
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...
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...
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...
Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E
2016-01-01
From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.
Klapacz, Joanna; Pottenger, Lynn H.; Engelward, Bevin P.; Heinen, Christopher D.; Johnson, George E.; Clewell, Rebecca A.; Carmichael, Paul L.; Adeleye, Yeyejide; Andersen, Melvin E.
2016-01-01
From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068
New flux based dose-response relationships for ozone for European forest tree species.
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.
Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis.
Di Giuseppe, Daniela; Crippa, Alessio; Orsini, Nicola; Wolk, Alicja
2014-09-30
The association between fish consumption and rheumatoid arthritis (RA) is unclear. The aim of this paper was to summarize the available evidence on the association between fish consumption and risk of RA using a dose-response meta-analysis. Relevant studies were identified by a search of MEDLINE and EMBASE through December 2013, with no restrictions. A random-effects dose-response meta-analysis was conducted to combine study specific relative risks. Potential non-linear relation was investigated using restricted cubic splines. A stratified analysis was conducted by study design. Seven studies (four case-controls and three prospective cohorts) involving a total of 174 701 participants and 3346 cases were included in the meta-analysis. For each one serving per week increment in fish consumption, the relative risk (RR) of RA was 0.96 (95% confidence interval (CI) 0.91 to 1.01). Results did not change when stratifying by study design. No heterogeneity or publication bias was observed. When fish consumption was modeled using restricted cubic splines, the risk of RA was 20 to 24% lower for 1 up to 3 servings per week of fish (RR =0.76, 95% CI: 0.57 to 1.02) as compared to never consumption. Results from this dose-response meta-analysis showed a non-statistically significant inverse association between fish consumption and RA.
Muller's Nobel lecture on dose-response for ionizing radiation: ideology or science?
Calabrese, Edward J
2011-12-01
In his Nobel Prize Lecture of December 12, 1946, Hermann J. Muller argued that the dose-response for radiation-induced germ cell mutations was linear and that there was "no escape from the conclusion that there is no threshold". However, assessment of correspondence between Muller and Curt Stern 1 month prior to his Nobel Prize Lecture reveals that Muller knew the results and implications of a recently completed study at the University of Rochester under the direction of Stern, which directly contradicted his Nobel Prize Lecture. This finding is of historical importance since Muller's Nobel Lecture gained considerable international attention and is a turning point in the acceptance of the linearity model in risk assessment for germ cell mutations and carcinogens.
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.
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.
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.
McKenna, Frederick W; Ahmad, Salahuddin
2011-04-01
The linear quadratic is the standard model for calculating isoeffects in the range of conventional dose per fraction. However, the use of hypofractionation and stereotactic body radiation therapy can call for isoeffect calculations for large doses per fraction. The purpose of this work is to investigate the linear quadratic at large doses per fraction. The linear quadratic is compared to models that incorporate effects such as dose protraction, whose purpose is to extend the useful range of the linear quadratic to larger doses. The linear quadratic and extended linear quadratic models are fit to 4 data sets. The model-predicted isoeffects for these data sets are calculated. It is found that the linear quadratic and extended linear quadratic predict different isoeffect curves for certain data sets. However, for these data sets, by appropriate selection of a α/β ratio, the linear quadratic can well approximate the extended linear quadratic models. In particular, it is found that a α/β ratio of 0.5 well approximates the extended linear quadratic isoeffect curve for 2 prostate cell lines for conventional and moderate doses per fraction.
A trace metal (zinc and iron) study on low dose x-radiation response in rat skin.
Chatterjee, J; Chaudhuri, K; Das, A K; Basu, S K; De, K; Majumdar, S
1997-08-01
There is no reliable bio-dosimeter regarding low dose radiation effects in mammalian systems. In this study, chronic low dose (< 1 cGy) whole body x-irradiated rat skin have shown altered trace metal (zinc and iron) content which clearly indicated the redistribution of these metals in the integumentary system. The decreased zinc to iron ratios suggested enhanced oxidative stress of the tissue. Changes in trace metal content in irradiated rat skin, as a biological response to low dose radiation, were non-linear. Moreover, the lowered zinc content of E2, E3, E4 and E5 dose groups suggested a different steady state, compared to the control. The Zn: Fe ratio decreased with increasing radiation dose.
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.
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
Dale, Roger
2004-06-01
This paper reviews the generalized application of the linear quadratic (LQ) model of radiobiological effect to targeted radiotherapy. Special attention is given to formulations for normal tissue responses and these are applied, in particular, to the kidney. Because it is derived from self-consistent bio-physical principles, the LQ model currently remains the standard formalism for assessing biological responses for the whole range of radiotherapy treatments. A central feature of the model is the derivation of biologically effective doses (BEDs), which may be used to quantify the impact of a treatment on both tumors and normal tissues. BEDs are routinely derived for conventional external-beam treatments. The likely limits of targeted radiotherapy may, thus, be assessed by comparing the expected normal-tissue BEDs for such treatments with those known to be just tolerable in conventional therapy. The main parameters required in the model are defined, and data are provided which demonstrate the tentative link between targeted radiotherapy doses and those used in conventional radiotherapy. The extension of the LQ method to targeted radiotherapy involves using parameters for which the numerical values may not be accurately known at present. This places a restriction on the overall predictive accuracy of the model and the necessary caveats are, therefore, outlined.
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. Published by Elsevier Inc.
Byers, John A
2013-08-01
Dose-response curves of the effects of semiochemicals on neurophysiology and behavior are reported in many articles in insect chemical ecology. Most curves are shown in figures representing points connected by straight lines, in which the x-axis has order of magnitude increases in dosage vs. responses on the y-axis. The lack of regression curves indicates that the nature of the dose-response relationship is not well understood. Thus, a computer model was developed to simulate a flux of various numbers of pheromone molecules (10(3) to 5 × 10(6)) passing by 10(4) receptors distributed among 10(6) positions along an insect antenna. Each receptor was depolarized by at least one strike by a molecule, and subsequent strikes had no additional effect. The simulations showed that with an increase in pheromone release rate, the antennal response would increase in a convex fashion and not in a logarithmic relation as suggested previously. Non-linear regression showed that a family of kinetic formation functions fit the simulated data nearly perfectly (R(2) >0.999). This is reasonable because olfactory receptors have proteins that bind to the pheromone molecule and are expected to exhibit enzyme kinetics. Over 90 dose-response relationships reported in the literature of electroantennographic and behavioral bioassays in the laboratory and field were analyzed by the logarithmic and kinetic formation functions. This analysis showed that in 95% of the cases, the kinetic functions explained the relationships better than the logarithmic (mean of about 20% better). The kinetic curves become sigmoid when graphed on a log scale on the x-axis. Dose-catch relationships in the field are similar to dose-EAR (effective attraction radius, in which a spherical radius indicates the trapping effect of a lure) and the circular EARc in two dimensions used in mass trapping models. The use of kinetic formation functions for dose-response curves of attractants, and kinetic decay curves for
Kalantari, Fereshteh; Ringblom, Joakim; Sand, Salomon; Öberg, Mattias
2017-01-17
Increasingly, dose-response data are being evaluated with the benchmark dose (BMD) approach rather than by the less precise no-observed-adverse-effect-level (NOAEL) approach. However, the basis for designing animal experiments, using equally sized dose groups, is still primed for the NOAEL approach. The major objective here was to assess the impact of using dose groups of unequal size on both the quality of the BMD and overall animal distress. We examined study designs with a total number of 200 animals distributed in four dose groups employing quantal data generated by Monte Carlo simulations. Placing more animals at doses close to the targeted BMD provided an estimate of BMD that was slightly better than the standard design with equally sized dose groups. In situations involving a clear dose-response, this translates into fewer animals receiving high doses and thus less overall animal distress. Accordingly, in connection with risk and safety assessment, animal distress can potentially be reduced by distributing the animals appropriately between dose groups without decreasing the quality of the information obtained. © 2017 Society for Risk Analysis.
Dose-response relationship between light exposure and cycling performance.
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.
Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.
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.
Biological profiling and dose-response modeling tools ...
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
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.
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.
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
Şahiner, Eren
2017-10-01
This paper reports Thermoluminescence (TL) and Optically Stimulated Luminescence (OSL) dose response characteristics of ten different commercial glass samples collected from Turkey. Nowadays, glass samples are widely used mostly in objects of everyday life. The study focuses to both TL and OSL dose responses, through a dose region within 1 and 512Gy. Lowest detectable dose limit (LDDL) as well as the respective linearity features of the corresponding dose response curves were studied for both TL and OSL. Moreover, signal reproducibility and fading behaviors have also been studied in detail. For specific samples, the lowest detectable dose was yielded at 2Gy, making thus these samples appropriate for retrospective dosimetry applications. Nevertheless, based on the features reported in the present study, the majority of the samples could be possibly used effectively for dosimetric applications of higher doses in the UV region emission. Copyright © 2017 Elsevier Ltd. All rights reserved.
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.
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.
Patients who do not respond to the "usual" dose: why Terry fell off the dose-response curve.
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.
Dose-response curve estimation: a semiparametric mixture approach.
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.
Fewer doses of HPV vaccine result in immune response similar to three-dose regimen
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.
Fewer doses of HPV vaccine result in immune response similar to three-dose regimen
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.
The effect of a paraffin screen on the neutron dose at the maze door of a 15 MV linear accelerator.
Krmar, M; Nikolić, D; Kuzmanović, A; Kuzmanović, Z; Ganezer, K
2013-08-01
The purpose of this study was to explore the effects of a paraffin screen located at various positions in the maze on the neutron dose equivalent at the maze door. The neutron dose equivalent was measured at the maze door of a room containing a 15 MV linear accelerator for x-ray therapy. Measurements were performed for several positions of the paraffin screen covering only 27.5% of the cross-sectional area of the maze. The neutron dose equivalent was also measured at all screen positions. Two simple models of the neutron source were considered in which the first assumed that the source was the cross-sectional area at the inner entrance of the maze, radiating neutrons in an isotropic manner. In the second model the reduction in the neutron dose equivalent at the maze door due to the paraffin screen was considered to be a function of the mean values of the neutron fluence and energy at the screen. The results of this study indicate that the equivalent dose at the maze door was reduced by a factor of 3 through the use of a paraffin screen that was placed inside the maze. It was also determined that the contributions to the dosage from areas that were not covered by the paraffin screen as viewed from the dosimeter, were 2.5 times higher than the contributions from the covered areas. This study also concluded that the contributions of the maze walls, ceiling, and floor to the total neutron dose equivalent were an order of magnitude lower than those from the surface at the far end of the maze. This study demonstrated that a paraffin screen could be used to reduce the neutron dose equivalent at the maze door by a factor of 3. This paper also found that the reduction of the neutron dose equivalent was a linear function of the area covered by the maze screen and that the decrease in the dose at the maze door could be modeled as an exponential function of the product φ·E at the screen.
The effect of a paraffin screen on the neutron dose at the maze door of a 15 MV linear accelerator
Krmar, M.; Kuzmanović, A.; Nikolić, D.; Kuzmanović, Z.; Ganezer, K.
2013-08-15
Purpose: The purpose of this study was to explore the effects of a paraffin screen located at various positions in the maze on the neutron dose equivalent at the maze door.Methods: The neutron dose equivalent was measured at the maze door of a room containing a 15 MV linear accelerator for x-ray therapy. Measurements were performed for several positions of the paraffin screen covering only 27.5% of the cross-sectional area of the maze. The neutron dose equivalent was also measured at all screen positions. Two simple models of the neutron source were considered in which the first assumed that the source was the cross-sectional area at the inner entrance of the maze, radiating neutrons in an isotropic manner. In the second model the reduction in the neutron dose equivalent at the maze door due to the paraffin screen was considered to be a function of the mean values of the neutron fluence and energy at the screen.Results: The results of this study indicate that the equivalent dose at the maze door was reduced by a factor of 3 through the use of a paraffin screen that was placed inside the maze. It was also determined that the contributions to the dosage from areas that were not covered by the paraffin screen as viewed from the dosimeter, were 2.5 times higher than the contributions from the covered areas. This study also concluded that the contributions of the maze walls, ceiling, and floor to the total neutron dose equivalent were an order of magnitude lower than those from the surface at the far end of the maze.Conclusions: This study demonstrated that a paraffin screen could be used to reduce the neutron dose equivalent at the maze door by a factor of 3. This paper also found that the reduction of the neutron dose equivalent was a linear function of the area covered by the maze screen and that the decrease in the dose at the maze door could be modeled as an exponential function of the product φ·E at the screen.
GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS
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...
GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS
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...
Predicting nonlinear properties of metamaterials from the linear response.
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.
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.
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.
NASA Astrophysics Data System (ADS)
O'Brien, Ricky T.; Stankovic, Uros; Sonke, Jan-Jakob; Keall, Paul J.
2017-06-01
Four dimensional cone beam computed tomography (4DCBCT) uses a constant gantry speed and imaging frequency that are independent of the patient’s breathing rate. Using a technique called respiratory motion guided 4DCBCT (RMG-4DCBCT), we have previously demonstrated that by varying the gantry speed and imaging frequency, in response to changes in the patient’s real-time respiratory signal, the imaging dose can be reduced by 50-70%. RMG-4DCBCT optimally computes a patient specific gantry trajectory to eliminate streaking artefacts and projection clustering that is inherent in 4DCBCT imaging. The gantry trajectory is continuously updated as projection data is acquired and the patient’s breathing changes. The aim of this study was to realise RMG-4DCBCT for the first time on a linear accelerator. To change the gantry speed in real-time a potentiometer under microcontroller control was used to adjust the current supplied to an Elekta Synergy’s gantry motor. A real-time feedback loop was developed on the microcontroller to modulate the gantry speed and projection acquisition in response to the real-time respiratory signal so that either 40, RMG-4DCBCT40, or 60, RMG-4DCBCT60, uniformly spaced projections were acquired in 10 phase bins. Images of the CIRS dynamic Thorax phantom were acquired with sinusoidal breathing periods ranging from 2 s to 8 s together with two breathing traces from lung cancer patients. Image quality was assessed using the contrast to noise ratio (CNR) and edge response width (ERW). For the average patient, with a 3.8 s breathing period, the imaging time and image dose were reduced by 37% and 70% respectively. Across all respiratory rates, RMG-4DCBCT40 had a CNR in the range of 6.5 to 7.5, and RMG-4DCBCT60 had a CNR between 8.7 and 9.7, indicating that RMG-4DCBCT allows consistent and controllable CNR. In comparison, the CNR for conventional 4DCBCT drops from 20.4 to 6.2 as the breathing rate increases from 2 s to 8 s. With RMG-4DCBCT
O'Brien, Ricky T; Stankovic, Uros; Sonke, Jan-Jakob; Keall, Paul J
2017-06-07
Four dimensional cone beam computed tomography (4DCBCT) uses a constant gantry speed and imaging frequency that are independent of the patient's breathing rate. Using a technique called respiratory motion guided 4DCBCT (RMG-4DCBCT), we have previously demonstrated that by varying the gantry speed and imaging frequency, in response to changes in the patient's real-time respiratory signal, the imaging dose can be reduced by 50-70%. RMG-4DCBCT optimally computes a patient specific gantry trajectory to eliminate streaking artefacts and projection clustering that is inherent in 4DCBCT imaging. The gantry trajectory is continuously updated as projection data is acquired and the patient's breathing changes. The aim of this study was to realise RMG-4DCBCT for the first time on a linear accelerator. To change the gantry speed in real-time a potentiometer under microcontroller control was used to adjust the current supplied to an Elekta Synergy's gantry motor. A real-time feedback loop was developed on the microcontroller to modulate the gantry speed and projection acquisition in response to the real-time respiratory signal so that either 40, RMG-4DCBCT40, or 60, RMG-4DCBCT60, uniformly spaced projections were acquired in 10 phase bins. Images of the CIRS dynamic Thorax phantom were acquired with sinusoidal breathing periods ranging from 2 s to 8 s together with two breathing traces from lung cancer patients. Image quality was assessed using the contrast to noise ratio (CNR) and edge response width (ERW). For the average patient, with a 3.8 s breathing period, the imaging time and image dose were reduced by 37% and 70% respectively. Across all respiratory rates, RMG-4DCBCT40 had a CNR in the range of 6.5 to 7.5, and RMG-4DCBCT60 had a CNR between 8.7 and 9.7, indicating that RMG-4DCBCT allows consistent and controllable CNR. In comparison, the CNR for conventional 4DCBCT drops from 20.4 to 6.2 as the breathing rate increases from 2 s to 8 s. With RMG-4DCBCT, the
Hong, Yazhen; Tan, Yalin; Meng, Yang; Yang, Hao; Zhang, Yu; Warren, Alan; Li, Jiqiu; Lin, Xiaofeng
2017-10-01
Understanding dose-responses is crucial for determining the utility of biomarkers in ecotoxicity assessment. Nitrofurazone is a broad-spectrum antibiotic that is widely used in the aquaculture industry in China despite its detrimental effects on ecosystems. Potential dose-response models were examined for the effect of nitrofurazone on two antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GPx), in the ciliated protozoan Euplotes vannus. This was achieved by measuring enzyme activity and gene expression profiling of SOD and GPx in ciliate cells exposed to nitrofurazone at doses ranging from 0 to 180mgl(-1) for 6h, 12h, 18h and 24h. Dose-response dynamics were characterized by mathematical models. Results showed that: 1) dose-response patterns differed significantly among the tested endpoints, nitrofurazone concentrations and durations of exposure; 2) GPx activity was the best candidate biomarker because of its linear dose-response relationship; 3) SOD activity and mRNA relative expression levels of GPx and SOD are also candidate biomarkers but their dose-responses were non-linear and therefore more difficult to interpret; 4) partitioning the dose-response dynamic model by piecewise function can help to clarify the relationships between biological endpoints. This study demonstrates the utility of dynamic model analysis and the potential of antioxidant enzymes, in particular GPx activity, as a candidate biomarkers for environmental monitoring and risk assessment of nitrofurazone in the aquaculture industry. Copyright © 2017. Published by Elsevier Inc.
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.
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.
Dose response relation to oral theophylline in severe chronic obstructive airways disease.
Chrystyn, H.; Mulley, B. A.; Peake, M. D.
1988-01-01
OBJECTIVE--To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline. DESIGN--Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data. This was followed by random assignment to four consecutive two month treatment periods--placebo and low, medium, and high dose, as assessed by serum concentrations of theophylline. Respiratory function and exercise performance was assessed at the end of each two month period. SETTING--Chest unit in district hospital. PATIENTS--Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited; 33 aged 53-73 years completed the study. INTERVENTIONS--Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted, when 400 mg was given. Targets for the steady state serum theophylline concentrations were 5-10 mg/l in the low dose period, 10-15 mg/l in the medium dose, and 15-20 mg/l in the high dose period. ENDPOINTS--Respiratory function as measured by forced expiratory volume in one second, forced vital capacity, peak expiratory flow rate, slow vital capacity, and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived. Exercise performance assessed by six minute walking test and diary cards using visual analogue scale. MEASUREMENTS AND MAIN RESULTS--The forced expiratory volume in one second, forced vital capacity, and peak expiratory flow rate changed only slightly (about 13%) over the range of doses. There was a linear dose dependent fall of trapped gas volume from 1.84 l (SE 0.157) to 1.42 l (0.152), 1.05 l (0.128), and 0.67 l (0.102) during the placebo and low, medium, and high dose treatment periods. Mean walking distance
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.
Bounding the total-dose response of modern bipolar transistors
Kosier, S.L.; Wei, A.; Schrimpf, R.D.; Combs, W.E.; Fleetwood, D.M.; DeLaus, M.; Pease, R.L.
1994-03-01
The base current in modern bipolar transistors saturates at large total doses once a critical oxide charge is reached. The saturated value of base current is dose-rate independent. Testing implications are discussed.
Ozone as U-Shaped Dose Responses Molecules (Hormetins)
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
Ozone as u-shaped dose responses molecules (hormetins).
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.
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
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
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
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.
Zhu, Hao; Wang, Yaning
2011-12-01
We explored the type I error rate (false positive rate) associated with exposure-response (ER) analyses for two compounds in a fixed-dose combination product through simulations. In the simulations, at least one compound was assumed to be inactive, whereas the active compound followed E(max) model at different concentration ranges. The simulated data were independently evaluated by pre-specified univariate or multivariate linear, log-linear models, and mixed linear log-linear models. The type I error rate was evaluated by comparing the total number of falsely identified significant slope estimates with the total number of models with successful convergence. We demonstrated that ER analyses results based on data from fixed-dose combination products at various dose levels should be interpreted with caution. A univariate analysis, even though is appropriate to guide dose selection, is inadequate to identify the active compound. Multivariate analyses can be applied to determine the active compound only when the underlying ER relationship for each compound (especially for the active compound) has been adequately defined or approximated. The false positive rate in determining a significant ER relationship is elevated, when the underlying ER relationship (especially for the active compound) is erroneously or inadequately defined. Without the assurance of the correct structural models, the identified significant ER relationship does not necessarily indicate that the compound associated with the significant slope estimate is pharmacologically active.
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...
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...
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.
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.
Thomas, Charles; Martin, Jennifer; Devic, Clément; Bräuer-Krisch, Elke; Diserbo, Michel; Thariat, Juliette; Foray, Nicolas
2013-10-01
To ask whether dose-rate influences low-dose hyper- radiosensitivity and induced radioresistance (HRS/IRR) response in rat colon progressive (PRO) and regressive (REG) cells. Clonogenic survival was applied to tumorigenic PRO and non-tumorigenic REG cells irradiated with (60)Co γ-rays at 0.0025-500 mGy.min(-1). Both clonogenic survival and non-homologous end-joining (NHEJ) pathway involved in DNA double-strand breaks (DSB) repair assays were applied to PRO cells irradiated at 25 mGy.min(-1) with 75 kV X-rays only. Irrespective of dose-rates, marked HRS/IRR responses were observed in PRO but not in REG cells. For PRO cells, the doses at which HRS and IRR responses are maximal were dependent on dose-rate; conversely exposure times during which HRS and IRR responses are maximal (t(HRSmax) and t(IRRmax)) were independent of dose-rate. The t(HRSmax) and t(IRRmax) values were 23 ± 5 s and 66 ± 7 s (mean ± standard error of the mean [SEM], n = 7), in agreement with literature data. Repair data show that t(HRSmax) may correspond to exposure time during which NHEJ is deficient while t(IRRmax) may correspond to exposure time during which NHEJ is complete. HRS response may be maximal if exposure times are shorter than t(HRSmax) irrespective of dose, dose-rate and cellular model. Potential application of HRS response in radiotherapy is discussed.
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.
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.
Little, M.P.
2011-01-01
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
Kim, Jin Hyang; Talbot, H Keipp; Mishina, Margarita; Zhu, Yuwei; Chen, Jufu; Cao, Weiping; Reber, Adrian J; Griffin, Marie R; Shay, David K; Spencer, Sarah M; Sambhara, Suryaprakash
2016-08-31
High-dose (HD) influenza vaccine shows improved relative efficacy against influenza disease compared to standard-dose (SD) vaccine in individuals ⩾65years. This has been partially credited to superior serological responses, but a comprehensive understanding of cell-mediated immunity (CMI) of HD vaccine remains lacking. In the current study, a total of 105 participants were randomly administered HD or SD vaccine and were evaluated for serological responses. Subsets of the group (n=12-26 per group) were evaluated for B and T cell responses at days 0, 7, 14 and 28 post-vaccination by flow cytometry or ELISPOT assay. HD vaccine elicited significantly higher hemagglutination inhibition (HI) titers than SD vaccine at d28, but comparable titers at d365 post-vaccination. HD vaccine also elicited higher vaccine-specific plasmablast responses at d7 post-vaccination than SD vaccine. However, long-lived memory B cell induction, cytokine-secreting T cell responses and persistence of serological memory were comparable regardless of vaccine dose. More strategies other than increased Ag amount may be needed to improve CMI in older adults. ClinicalTrials.gov NCT 01189123. Published by Elsevier Ltd.
Kim, Jin Hyang; Talbot, H. Keipp; Mishina, Margarita; Zhu, Yuwei; Chen, Jufu; Cao, Weiping; Reber, Adrian J.; Griffin, Marie R.; Shay, David K.; Spencer, Sarah M.; Sambhara, Suryaprakash
2016-01-01
High-dose (HD) influenza vaccine shows improved relative efficacy against influenza disease compared to standard-dose (SD) vaccine in individuals ≥ 65 years. This has been partially credited to superior serological responses, but a comprehensive understanding of cell-mediated immunity (CMI) of HD vaccine remains lacking. In the current study, a total of 105 participants were randomly administered HD or SD vaccine and were evaluated for serological responses. Subsets of the group (n=12–26 per group) were evaluated for B and T cell responses at days 0, 7, 14 and 28 post-vaccination by flow cytometry or ELISPOT assay. HD vaccine elicited significantly higher hemagglutination inhibition (HI) titers than SD vaccine at d28, but comparable titers at d365 post-vaccination. HD vaccine also elicited higher vaccine-specific plasmablast responses at d7 post-vaccination than SD vaccine. However, long-lived memory B cell induction, cytokine-secreting T cell responses and persistence of serological memory were comparable regardless of vaccine dose. More strategies other than increased Ag amount may be needed to improve CMI in older adults. Trial Registration ClinicalTrials.gov NCT 01189123 PMID:27473306
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
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.
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.
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