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Sample records for statistically significant dose-response

  1. Statistical and low dose response

    The low dose response and the lower limit of detection of the Hanford dosimeter depend upon may factors, including the energy of the radiation, whether the exposure is to be a single radiation or mixed fields, annealing cycles, environmental factors, and how well various batches of TLD materials are matched in the system. A careful statistical study and sensitivity analysis were performed to determine how these factors influence the response of the dosimeter system. Estimates have been included in this study of the standard deviation of calculated dose for various mixed field exposures from 0 to 1000 mrem

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

    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. PMID:26952004

  3. Standard error of inverse prediction for doseresponse relationship: approximate and exact statistical inference

    Demidenko, Eugene; Williams, Benjamin B.; Flood, Ann Barry; Swartz, Harold M.

    2012-01-01

    This paper develops a new metric, the standard error of inverse prediction (SEIP), for a doseresponse relationship (calibration curve) when dose is estimated from response via inverse regression. SEIP can be viewed as a generalization of the coefficient of variation to regression problem when x is predicted using y-value. We employ nonstandard statistical methods to treat the inverse prediction, which has an infinite mean and variance due to the presence of a normally distributed variable in...

  4. Standard error of inverse prediction for dose-response relationship: approximate and exact statistical inference.

    Demidenko, Eugene; Williams, Benjamin B; Flood, Ann Barry; Swartz, Harold M

    2013-05-30

    This paper develops a new metric, the standard error of inverse prediction (SEIP), for a dose-response relationship (calibration curve) when dose is estimated from response via inverse regression. SEIP can be viewed as a generalization of the coefficient of variation to regression problem when x is predicted using y-value. We employ nonstandard statistical methods to treat the inverse prediction, which has an infinite mean and variance due to the presence of a normally distributed variable in the denominator. We develop confidence intervals and hypothesis testing for SEIP on the basis of the normal approximation and using the exact statistical inference based on the noncentral t-distribution. We derive the power functions for both approaches and test them via statistical simulations. The theoretical SEIP, as the ratio of the regression standard error to the slope, is viewed as reciprocal of the signal-to-noise ratio, a popular measure of signal processing. The SEIP, as a figure of merit for inverse prediction, can be used for comparison of calibration curves with different dependent variables and slopes. We illustrate our theory with electron paramagnetic resonance tooth dosimetry for a rapid estimation of the radiation dose received in the event of nuclear terrorism. PMID:23124816

  5. Statistically significant relational data mining :

    Berry, Jonathan W.; Leung, Vitus Joseph; Phillips, Cynthia Ann; Pinar, Ali; Robinson, David Gerald; Berger-Wolf, Tanya; Bhowmick, Sanjukta; Casleton, Emily; Kaiser, Mark; Nordman, Daniel J.; Wilson, Alyson G.

    2014-02-01

    This report summarizes the work performed under the project (3z(BStatitically significant relational data mining.(3y (BThe goal of the project was to add more statistical rigor to the fairly ad hoc area of data mining on graphs. Our goal was to develop better algorithms and better ways to evaluate algorithm quality. We concetrated on algorithms for community detection, approximate pattern matching, and graph similarity measures. Approximate pattern matching involves finding an instance of a relatively small pattern, expressed with tolerance, in a large graph of data observed with uncertainty. This report gathers the abstracts and references for the eight refereed publications that have appeared as part of this work. We then archive three pieces of research that have not yet been published. The first is theoretical and experimental evidence that a popular statistical measure for comparison of community assignments favors over-resolved communities over approximations to a ground truth. The second are statistically motivated methods for measuring the quality of an approximate match of a small pattern in a large graph. The third is a new probabilistic random graph model. Statisticians favor these models for graph analysis. The new local structure graph model overcomes some of the issues with popular models such as exponential random graph models and latent variable models.

  6. Statistical Estimation of Dose-response Functions of Respiratory Diseases and Societal Costs of Haze-related Air Pollution in Brunei Darussalam

    Anaman, K. A.; Ibrahim, N.

    - The effects on human health resulting from the January to April 1998 haze-related air pollution episode in Brunei Darussalam were analysed for five groups of diseases of the respiratory system. The analysis concentrated on the statistical estimation of dose-response functions which related the number of cases of respiratory diseases to the level of quality of ambient environment as measured by the pollutants standards index (PSI) and other environmental variables. The total number of cases of the five groups of diseases was shown to be significantly related to PSI and temperature. Societal costs were also estimated. The results showed that societal costs were significantly related to PSI, temperature and relative humidity. Societal costs increased with higher PSI and relative humidity but decreased with increasing temperature.

  7. Self-play: statistical significance

    Haworth, Guy McCrossan

    2003-01-01

    Heinz recently completed a comprehensive experiment in self-play using the FRITZ chess engine to establish the ‘decreasing returns’ hypothesis with specific levels of statistical confidence. This note revisits the results and recalculates the confidence levels of this and other hypotheses. These appear to be better than Heinz’ initial analysis suggests.

  8. Statistical issues in radiation dose-response analysis of employees of the nuclear industry in Oak Ridge, Tennessee

    Poisson regression methods are used to describe dose-response relations for cancer mortality for a subcohort of 28,347 white male radiation workers. Age specific baseline rates are described using both internal and external (US white male) rates. Regression analyses are based on an analytic data structure (ADS) that consists of a table of observed deaths, expected deaths, and person-years at risk for each combination of levels of seven risk factors. The factors are socioeconomic status, length of employment, birth cohort, age at risk, facility, internal exposure, and external exposure. Each observation in the ADS consists of the index value of each of the stratifying factors, the observed deaths, the expected deaths, the person-years, and the ten year lagged average cumulative dose. Regression diagnostics show that a linear exponential relative risk model is not appropriate for these data. Results are presented using a main effects model for factors other than external radiation, and an excess relative risk term for cumulative external radiation dose

  9. Social significance of community structure: Statistical view

    Li, Hui-Jia; Daniels, Jasmine J.

    2015-01-01

    Community structure analysis is a powerful tool for social networks that can simplify their topological and functional analysis considerably. However, since community detection methods have random factors and real social networks obtained from complex systems always contain error edges, evaluating the significance of a partitioned community structure is an urgent and important question. In this paper, integrating the specific characteristics of real society, we present a framework to analyze the significance of a social community. The dynamics of social interactions are modeled by identifying social leaders and corresponding hierarchical structures. Instead of a direct comparison with the average outcome of a random model, we compute the similarity of a given node with the leader by the number of common neighbors. To determine the membership vector, an efficient community detection algorithm is proposed based on the position of the nodes and their corresponding leaders. Then, using a log-likelihood score, the tightness of the community can be derived. Based on the distribution of community tightness, we establish a connection between p -value theory and network analysis, and then we obtain a significance measure of statistical form . Finally, the framework is applied to both benchmark networks and real social networks. Experimental results show that our work can be used in many fields, such as determining the optimal number of communities, analyzing the social significance of a given community, comparing the performance among various algorithms, etc.

  10. Statistical Significance of Modular Structure Detection

    Yu-Teng Chang

    2011-10-01

    Full Text Available Human brain functional modules organize hierarchically and their structure changes with several factors, including normal aging, adolescence, and certain diseases. A large number of methods have been proposed to identify natural divisions of networks into groups. Perhaps the most popular is modularity [1], which compares the network against a null model and favors within module connections when edges are stronger than their expected values. Divisions that increase modularity are preferred because they lead to modules with high community structure. Random networks can exhibit high modularity because of incidental concentration of edges, even though they have no underlying organizational structure [2]. This is even more evident in large networks where the number of possible divisions increases rapidly with the network size [3]. Therefore, significant divisions of a network should have higher modularity than random graphs [2, 4]. We propose a statistical procedure to test the significance of a community structure based on its modularity value. As a surrogate of modularity, we use the largest eigenvalue of the difference between the affinity matrices of the network and its null model. Based on previous work on null models [5], we show that the distribution of the largest eigenvalue can be well approximated with a Gamma distribution (Fig. 1a. We derive an empirical formula for the parameters of the Gamma distribution with respect to the size of the network and the variance of its edges (Fig. 1b. Based on this distribution we compute a p-value for the community structure, which can be used as a threshold criterion when partitioning a graph. We demonstrate our method with simulated networks and structural brain networks (Fig. 2.

  11. Significant Statistics: Viewed with a Contextual Lens

    Tait-McCutcheon, Sandi

    2010-01-01

    This paper examines the pedagogical and organisational changes three lead teachers made to their statistics teaching and learning programs. The lead teachers posed the research question: What would the effect of contextually integrating statistical investigations and literacies into other curriculum areas be on student achievement? By finding the…

  12. Social significance of community structure: Statistical view

    Li, Hui-Jia

    2015-01-01

    Community structure analysis is a powerful tool for social networks, which can simplify their topological and functional analysis considerably. However, since community detection methods have random factors and real social networks obtained from complex systems always contain error edges, evaluating the significance of community structure partitioned is an urgent and important question. In this paper, integrating the specific characteristics of real society, we present a novel framework analyzing the significance of social community specially. The dynamics of social interactions are modeled by identifying social leaders and corresponding hierarchical structures. Instead of a direct comparison with the average outcome of a random model, we compute the similarity of a given node with the leader by the number of common neighbors. To determine the membership vector, an efficient community detection algorithm is proposed based on the position of nodes and their corresponding leaders. Then, using log-likelihood sco...

  13. Social significance of community structure: Statistical view

    Li, Hui-Jia; Daniels, J J

    2015-01-01

    Community structure analysis is a powerful tool for social networks, which can simplify their topological and functional analysis considerably. However, since community detection methods have random factors and real social networks obtained from complex systems always contain error edges, evaluating the significance of community structure partitioned is an urgent and important question. In this paper, integrating the specific characteristics of real society, we present a novel framework analy...

  14. Effect size as a supplement to statistical significance testing

    Gašper Cankar; Boštjan Bajec

    2003-01-01

    Researchers in the field of psychology often face the situation that the statistical significance depends largely on the sample size and its statistical power. Effect size is a statistical measure that can offer some solutions for constructive research, since it can overcome the problems that are connected to the sample size. This article presents statistical significance testing we meet in psychology and the usage of smaller group of the effect size measures – measures of the standardi...

  15. Caveats for using statistical significance tests in research assessments

    Schneider, Jesper Wiborg

    2013-01-01

    This article raises concerns about the advantages of using statistical significance tests in research assessments as has recently been suggested in the debate about proper normalization procedures for citation indicators by Opthof and Leydesdorff (2010). Statistical significance tests are highly ...... important or not. On the contrary their use may be harmful. Like many other critics, we generally believe that statistical significance tests are over- and misused in the empirical sciences including scientometrics and we encourage a reform on these matters....

  16. Nonlinearity of dose responses in thermoluminescence dosimetry

    All of dose responses in thermoluminescence (TL) dosimetry can be described by a dose response function derived from statistical Poisson distribution. Two characteristic parameters in this function, one hit factor R and characteristic dose D0, can be used to analyze the nonlinearity of TL responses. The one hit factor R indicates whether there is a linear region in the dose responses, and that the responses are linear-sublinear or linear-supralinear-sublinear. The characteristic dose D0 is used to compare the range of linear region in responses and sensitivity of TLD. When coupling with physical mechanisms in the TL process, the dominant features of the TL nonlinear behavior observed in experiments can be explained. (8 refs., 7 figs., 1 tab.)

  17. Caveats for using statistical significance tests in research assessments

    Schneider, Jesper W

    2011-01-01

    This paper raises concerns about the advantages of using statistical significance tests in research assessments as has recently been suggested in the debate about proper normalization procedures for citation indicators. Statistical significance tests are highly controversial and numerous criticisms have been leveled against their use. Based on examples from articles by proponents of the use statistical significance tests in research assessments, we address some of the numerous problems with such tests. The issues specifically discussed are the ritual practice of such tests, their dichotomous application in decision making, the difference between statistical and substantive significance, the implausibility of most null hypotheses, the crucial assumption of randomness, as well as the utility of standard errors and confidence intervals for inferential purposes. We argue that applying statistical significance tests and mechanically adhering to their results is highly problematic and detrimental to critical thinki...

  18. Statistical significance test for transition matrices of atmospheric Markov chains

    Vautard, Robert; Mo, Kingtse C.; Ghil, Michael

    1990-01-01

    Low-frequency variability of large-scale atmospheric dynamics can be represented schematically by a Markov chain of multiple flow regimes. This Markov chain contains useful information for the long-range forecaster, provided that the statistical significance of the associated transition matrix can be reliably tested. Monte Carlo simulation yields a very reliable significance test for the elements of this matrix. The results of this test agree with previously used empirical formulae when each cluster of maps identified as a distinct flow regime is sufficiently large and when they all contain a comparable number of maps. Monte Carlo simulation provides a more reliable way to test the statistical significance of transitions to and from small clusters. It can determine the most likely transitions, as well as the most unlikely ones, with a prescribed level of statistical significance.

  19. On detection and assessment of statistical significance of Genomic Islands

    Chaudhuri Probal

    2008-04-01

    Full Text Available Abstract Background Many of the available methods for detecting Genomic Islands (GIs in prokaryotic genomes use markers such as transposons, proximal tRNAs, flanking repeats etc., or they use other supervised techniques requiring training datasets. Most of these methods are primarily based on the biases in GC content or codon and amino acid usage of the islands. However, these methods either do not use any formal statistical test of significance or use statistical tests for which the critical values and the P-values are not adequately justified. We propose a method, which is unsupervised in nature and uses Monte-Carlo statistical tests based on randomly selected segments of a chromosome. Such tests are supported by precise statistical distribution theory, and consequently, the resulting P-values are quite reliable for making the decision. Results Our algorithm (named Design-Island, an acronym for Detection of Statistically Significant Genomic Island runs in two phases. Some 'putative GIs' are identified in the first phase, and those are refined into smaller segments containing horizontally acquired genes in the refinement phase. This method is applied to Salmonella typhi CT18 genome leading to the discovery of several new pathogenicity, antibiotic resistance and metabolic islands that were missed by earlier methods. Many of these islands contain mobile genetic elements like phage-mediated genes, transposons, integrase and IS elements confirming their horizontal acquirement. Conclusion The proposed method is based on statistical tests supported by precise distribution theory and reliable P-values along with a technique for visualizing statistically significant islands. The performance of our method is better than many other well known methods in terms of their sensitivity and accuracy, and in terms of specificity, it is comparable to other methods.

  20. More accurate tests for the statistical significance of result differences

    Yeh, Alexander

    2000-01-01

    Statistical significance testing of differences in values of metrics like recall, precision and balanced F-score is a necessary part of empirical natural language processing. Unfortunately, we find in a set of experiments that many commonly used tests often underestimate the significance and so are less likely to detect differences that exist between different techniques. This underestimation comes from an independence assumption that is often violated. We point out some useful tests that do ...

  1. Test for the statistical significance of differences between ROC curves

    A test for the statistical significance of observed differences between two measured Receiver Operating Characteristic (ROC) curves has been designed and evaluated. The set of observer response data for each ROC curve is assumed to be independent and to arise from a ROC curve having a form which, in the absence of statistical fluctuations in the response data, graphs as a straight line on double normal-deviate axes. To test the significance of an apparent difference between two measured ROC curves, maximum likelihood estimates of the two parameters of each curve and the associated parameter variances and covariance are calculated from the corresponding set of observer response data. An approximate Chi-square statistic with two degrees of freedom is then constructed from the differences between the parameters estimated for each ROC curve and from the variances and covariances of these estimates. This statistic is known to be truly Chi-square distributed only in the limit of large numbers of trials in the observer performance experiments. Performance of the statistic for data arising from a limited number of experimental trials was evaluated. Independent sets of rating scale data arising from the same underlying ROC curve were paired, and the fraction of differences found (falsely) significant was compared to the significance level, α, used with the test. Although test performance was found to be somewhat dependent on both the number of trials in the data and the position of the underlying ROC curve in the ROC space, the results for various significance levels showed the test to be reliable under practical experimental conditions

  2. Systematic reviews of anesthesiologic interventions reported as statistically significant

    Imberger, Georgina; Gluud, Christian; Boylan, John; Wetterslev, Jørn

    2015-01-01

    may be implemented by an anesthesiologist during the perioperative period. We randomly selected 50 meta-analyses that reported a statistically significant dichotomous outcome in their abstract. We applied TSA to these meta-analyses by using 2 main TSA approaches: relative risk reduction 20% and...... number of participants with the outcome was 202 (IQR, 96-443). By using both of our main TSA approaches, only 12% (95% CI, 5%-25%) of the meta-analyses had power ≥80%, and only 32% (95% CI, 20%-47%) of the meta-analyses preserved the risk of type 1 error <5%. CONCLUSIONS: Most nominally statistically...

  3. Dose response relationship and Alara

    In this paper, it will be shown how dose-response relationships allow to give quantitative figures for the detriment of irradiation. At this stage, the detriment is expressed directly as a certain number of health effects, whose valuation is not dealt with here. The present tools for quantifying, their weaknesses and their strenghts, and their scientific basis will be developed

  4. Mahalanobis distance and variable selection to optimize dose response

    A battery of statistical techniques are combined to improve detection of low-level dose response. First, Mahalanobis distances are used to classify objects as normal or abnormal. Then the proportion classified abnormal is regressed on dose. Finally, a subset of regressor variables is selected which maximizes the slope of the dose response line. Use of the techniques is illustrated by application to mouse sperm damaged by low doses of x-rays

  5. The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

    A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings

  6. The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview.

    Calabrese, Edward J; Blain, Robyn

    2005-02-01

    A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings. PMID:15667834

  7. Increasing the statistical significance of entanglement detection in experiments

    Entanglement is often verified by a violation of an inequality like a Bell inequality or an entanglement witness. Considerable effort has been devoted to the optimization of such inequalities in order to obtain a high violation. We demonstrate theoretically and experimentally that such an optimization does not necessarily lead to a better entanglement test, if the statistical error is taken into account. Theoretically, we show for different error models that reducing the violation of an inequality can improve the significance. We show this to be the case for an error model in which the variance of an observable is interpreted as its error and for the standard error model in photonic experiments. Specifically, we demonstrate that the Mermin inequality yields a Bell test which is statistically more significant than the Ardehali inequality in the case of a photonic four-qubit state that is close to a GHZ state. Experimentally, we observe this phenomenon in a four-photon experiment, testing the above inequalities for different levels of noise.

  8. Large SDSS quasar groups and their statistical significance

    Park, Changbom; Einasto, Maret; Lietzen, Heidi; Heinamaki, Pekka

    2015-01-01

    We use a volume-limited sample of quasars in the Sloan Digital Sky Survey (SDSS) DR7 quasar catalog to identify quasar groups and address their statistical significance. This quasar sample has a uniform selection function on the sky and nearly a maximum possible contiguous volume that can be drawn from the DR7 catalog. Quasar groups are identified by using the Friend-of-Friend algorithm with a set of fixed comoving linking lengths. We find that the richness distribution of the richest 100 quasar groups or the size distribution of the largest 100 groups are statistically equivalent with those of randomly-distributed points with the same number density and sky coverage when groups are identified with the linking length of 70 h-1Mpc. It is shown that the large-scale structures like the huge Large Quasar Group (U1.27) reported by Clowes et al. (2013) can be found with high probability even if quasars have no physical clustering, and does not challenge the initially homogeneous cosmological models. Our results are...

  9. Lexical Co-occurrence, Statistical Significance, and Word Association

    Chaudhari, Dipak; Laxman, Srivatsan

    2010-01-01

    Lexical co-occurrence is an important cue for detecting word associations. We present a theoretical framework for discovering statistically significant lexical co-occurrences from a given corpus. In contrast with the prevalent practice of giving weightage to unigram frequencies, we focus only on the documents containing both the terms (of a candidate bigram). We detect biases in span distributions of associated words, while being agnostic to variations in global unigram frequencies. Our framework has the fidelity to distinguish different classes of lexical co-occurrences, based on strengths of the document and corpuslevel cues of co-occurrence in the data. We perform extensive experiments on benchmark data sets to study the performance of various co-occurrence measures that are currently known in literature. We find that a relatively obscure measure called Ochiai, and a newly introduced measure CSA capture the notion of lexical co-occurrence best, followed next by LLR, Dice, and TTest, while another popular m...

  10. Skull base chordomas: analysis of dose-response characteristics

    Objective: To extract dose-response characteristics from dose-volume histograms and corresponding actuarial survival statistics for 115 patients with skull base chordomas. Materials and Methods: We analyzed data for 115 patients with skull base chordoma treated with combined photon and proton conformal radiotherapy to doses in the range 66.6Gy - 79.2Gy. Data set for each patient included gender, histology, age, tumor volume, prescribed dose, overall treatment time, time to recurrence or time to last observation, target dose-volume histogram, and several dosimetric parameters (minimum/mean/median/maximum target dose, percent of the target volume receiving the prescribed dose, dose to 90% of the target volume, and the Equivalent Uniform Dose (EUD). Data were analyzed using the Kaplan-Meier survivor function estimate, the proportional hazards (Cox) model, and parametric modeling of the actuarial probability of recurrence. Parameters of dose-response characteristics were obtained using the maximum likelihood method. Results: Local failure developed in 42 (36%) of patients, with actuarial local control rates at 5 years of 59.2%. The proportional hazards model revealed significant dependence of gender on the probability of recurrence, with female patients having significantly poorer prognosis (hazard ratio of 2.3 with the p value of 0.008). The Wilcoxon and the log-rank tests of the corresponding Kaplan-Meier recurrence-free survival curves confirmed statistical significance of this effect. The Cox model with stratification by gender showed significance of tumor volume (p=0.01), the minimum target dose (p=0.02), and the EUD (p=0.02). Other parameters were not significant at the α level of significance of 0.05, including the prescribed dose (p=0.21). Parametric analysis using a combined model of tumor control probability (to account for non-uniformity of target dose distribution) and the Weibull failure time model (to account for censoring) allowed us to estimate parameters of the time-dose-response relationship for the analyzed group of patients. For example, the maximum likelihood estimates of surviving fraction at 2Gy (SF2) are 0.47 with 95% confidence limits of [0.45-0.49] for male and 0.53 [0.51-0.55] for female, with the coefficient of inter-patient variation in SF2 of 4.3%. The density of clonogens was estimated to be 108.2 clonogens per cubic centimeter. In effect, the slope of the dose-response curve, γ50, was estimated to be 2.7 [1.9-3.2] for both male and female, and the ED50 doses to be 67Gy and 73Gy respectively. Skull base chordomas of the female patients seemed to be not only more resistant to radiation but also recurring faster than that for male patients (the maximum likelihood estimates of the Weibull shape parameter β are 2.6 for female and 1.7 for male patients). Conclusions: This analysis revealed several clinically important characteristics of radioresponsiveness of skull base chordomas. The comprehensive patient data obtained using three-dimensional treatment planning system allowed us to demonstrate and quantify the existence of dose-response and dose-volume relationships. In consequence, we are able to estimate prospectively the individual's probability of staying recurrence-free and her/his overall survival characteristics as a function of the applied three-dimensional dose distribution and time after treatment. Based on the analysis our treatment protocols have been modified to account for differences in radiosensitivity between female and male patients

  11. The statistical significance of the superhump signal in U Gem

    Schreiber, M R

    2007-01-01

    Although its well determined mass ratio of $q=\\Msec/\\Mwd=0.357\\pm0.007$ should avoid superoutbursts according to the thermal tidal instability model, the prototypical dwarf nova U Gem experienced in 1985 an extraordinary long outburst resembling very much superoutbursts observed in SU UMa systems. Recently, the situation for the model became even worse as superhump detections have been reported for the 1985 outburst of U Gem. The superhump signal is noisy and the evidence provided by simple periodograms seems to be weak. Therefore and because of the importance for our understanding of superoutbursts and superhumps, we determine the statistical significance of the recently published detection of superhumps in the AAVSO light curve of the famous long 1985 outburst of U Gem. Using Lomb-Scargle periodograms, analysis of variance (AoV), and Monte-Carlo methods we analyse the 160 visual magnitudes obtained by the AAVSO during the outburst and relate our analyse to previous superhump detections. The 160 data points ...

  12. Statistical controversies in clinical research: statistical significance-too much of a good thing ….

    Buyse, M; Hurvitz, S A; Andre, F; Jiang, Z; Burris, H A; Toi, M; Eiermann, W; Lindsay, M-A; Slamon, D

    2016-05-01

    The use and interpretation of P values is a matter of debate in applied research. We argue that P values are useful as a pragmatic guide to interpret the results of a clinical trial, not as a strict binary boundary that separates real treatment effects from lack thereof. We illustrate our point using the result of BOLERO-1, a randomized, double-blind trial evaluating the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line therapy for HER2+ advanced breast cancer. In this trial, the benefit of everolimus was seen only in the predefined subset of patients with hormone receptor-negative breast cancer at baseline (progression-free survival hazard ratio = 0.66, P = 0.0049). A strict interpretation of this finding, based on complex 'alpha splitting' rules to assess statistical significance, led to the conclusion that the benefit of everolimus was not statistically significant either overall or in the subset. We contend that this interpretation does not do justice to the data, and we argue that the benefit of everolimus in hormone receptor-negative breast cancer is both statistically compelling and clinically relevant. PMID:26861602

  13. Statistical downscaling rainfall using artificial neural network: significantly wetter Bangkok?

    Vu, Minh Tue; Aribarg, Thannob; Supratid, Siriporn; Raghavan, Srivatsan V.; Liong, Shie-Yui

    2015-08-01

    Artificial neural network (ANN) is an established technique with a flexible mathematical structure that is capable of identifying complex nonlinear relationships between input and output data. The present study utilizes ANN as a method of statistically downscaling global climate models (GCMs) during the rainy season at meteorological site locations in Bangkok, Thailand. The study illustrates the applications of the feed forward back propagation using large-scale predictor variables derived from both the ERA-Interim reanalyses data and present day/future GCM data. The predictors are first selected over different grid boxes surrounding Bangkok region and then screened by using principal component analysis (PCA) to filter the best correlated predictors for ANN training. The reanalyses downscaled results of the present day climate show good agreement against station precipitation with a correlation coefficient of 0.8 and a Nash-Sutcliffe efficiency of 0.65. The final downscaled results for four GCMs show an increasing trend of precipitation for rainy season over Bangkok by the end of the twenty-first century. The extreme values of precipitation determined using statistical indices show strong increases of wetness. These findings will be useful for policy makers in pondering adaptation measures due to flooding such as whether the current drainage network system is sufficient to meet the changing climate and to plan for a range of related adaptation/mitigation measures.

  14. Statistically significant data base of rock properties for geothermal use

    Koch, A.; Jorand, R.; Clauser, C.

    2009-04-01

    The high risk of failure due to the unknown properties of the target rocks at depth is a major obstacle for the exploration of geothermal energy. In general, the ranges of thermal and hydraulic properties given in compilations of rock properties are too large to be useful to constrain properties at a specific site. To overcome this problem, we study the thermal and hydraulic rock properties of the main rock types in Germany in a statistical approach. An important aspect is the use of data from exploration wells that are largely untapped for the purpose of geothermal exploration. In the current project stage, we have been analyzing mostly Devonian and Carboniferous drill cores from 20 deep boreholes in the region of the Lower Rhine Embayment and the Ruhr area (western North Rhine Westphalia). In total, we selected 230 core samples with a length of up to 30 cm from the core archive of the State Geological Survey. The use of core scanning technology allowed the rapid measurement of thermal conductivity, sonic velocity, and gamma density under dry and water saturated conditions with high resolution for a large number of samples. In addition, we measured porosity, bulk density, and matrix density based on Archimedes' principle and pycnometer analysis. As first results we present arithmetic means, medians and standard deviations characterizing the petrophysical properties and their variability for specific lithostratigraphic units. Bi- and multimodal frequency distributions correspond to the occurrence of different lithologies such as shale, limestone, dolomite, sandstone, siltstone, marlstone, and quartz-schist. In a next step, the data set will be combined with logging data and complementary mineralogical analyses to derive the variation of thermal conductivity with depth. As a final result, this may be used to infer thermal conductivity for boreholes without appropriate core data which were drilled in similar geological settings.

  15. Exploring the dose response of radiochromic dosimeters

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

  16. Exploring the dose response of radiochromic dosimeters

    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.

  17. Distinguishing between statistical significance and practical/clinical meaningfulness using statistical inference.

    Wilkinson, Michael

    2014-03-01

    Decisions about support for predictions of theories in light of data are made using statistical inference. The dominant approach in sport and exercise science is the Neyman-Pearson (N-P) significance-testing approach. When applied correctly it provides a reliable procedure for making dichotomous decisions for accepting or rejecting zero-effect null hypotheses with known and controlled long-run error rates. Type I and type II error rates must be specified in advance and the latter controlled by conducting an a priori sample size calculation. The N-P approach does not provide the probability of hypotheses or indicate the strength of support for hypotheses in light of data, yet many scientists believe it does. Outcomes of analyses allow conclusions only about the existence of non-zero effects, and provide no information about the likely size of true effects or their practical/clinical value. Bayesian inference can show how much support data provide for different hypotheses, and how personal convictions should be altered in light of data, but the approach is complicated by formulating probability distributions about prior subjective estimates of population effects. A pragmatic solution is magnitude-based inference, which allows scientists to estimate the true magnitude of population effects and how likely they are to exceed an effect magnitude of practical/clinical importance, thereby integrating elements of subjective Bayesian-style thinking. While this approach is gaining acceptance, progress might be hastened if scientists appreciate the shortcomings of traditional N-P null hypothesis significance testing. PMID:24248505

  18. Lack-of-fit tests for assessing mean structures for continuous dose-response data

    Ritz, Christian; Martinussen, Torben

    2011-01-01

    We review a range of lack-of-fit tests suitable for assessing the appropriateness of the mean function in dose-response models. The review encompasses both well-known tests and new tests based on recent developments in statistics, which we have extended to the dose-response case. We argue that the...

  19. Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

    Little, Mark P., E-mail: mark.little@nih.gov [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States); Kleinerman, Ruth A. [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States); Stovall, Marilyn; Smith, Susan A. [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mabuchi, Kiyohiko [Radiation Epidemiology Branch, National Cancer Institute, Executive Plaza South, Rockville, Maryland (United States)

    2012-12-01

    Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. There were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  20. Understanding the Sampling Distribution and Its Use in Testing Statistical Significance.

    Breunig, Nancy A.

    Despite the increasing criticism of statistical significance testing by researchers, particularly in the publication of the 1994 American Psychological Association's style manual, statistical significance test results are still popular in journal articles. For this reason, it remains important to understand the logic of inferential statistics. A…

  1. Perception and annoyance due to wind turbine noise--a dose-response relationship.

    Pedersen, Eja; Waye, Kerstin Persson

    2004-12-01

    Installed global wind power increased by 26% during 2003, with U.S and Europe accounting for 90% of the cumulative capacity. Little is known about wind turbines' impact on people living in their vicinity. The aims of this study were to evaluate the prevalence of annoyance due to wind turbine noise and to study dose-response relationships. Interrelationships between noise annoyance and sound characteristics, as well as the influence of subjective variables such as attitude and noise sensitivity, were also assessed. A cross-sectional study was performed in Sweden in 2000. Responses were obtained through questionnaires (n = 351; response rate 68.4%), and doses were calculated as A-weighted sound pressure levels for each respondent. A statistically significant dose-response relationship was found, showing higher proportion of people reporting perception and annoyance than expected from the present dose-response relationships for transportation noise. The unexpected high proportion of annoyance could be due to visual interference, influencing noise annoyance, as well as the presence of intrusive sound characteristics. The respondents' attitude to the visual impact of wind turbines on the landscape scenery was found to influence noise annoyance. PMID:15658697

  2. A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

    Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P?1 of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI ?0.002, 0.119), and 1.087 (95% CI ?0.018, 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  3. Influence of microdosimetric quantities on observed dose-response relationships in radiation therapy

    The steepness of dose-response curves in radiation therapy depends to a large extent on the statistics of cell killing. This is so if the last few clonogenic tumor cells have to be hit or eradicated by other means to cure the patient. The steepness is dependent on the number of clonogenic cells in the tumor and the possible variation in their sensitivity. However, the uniformity of the dose distribution is also important and a decreased slope may result when the delivery of the dose is nonuniform or statistically uncertain. The variance in the energy imparted at the microdosimetric level to individual cell nuclei constitutes the ultimate limit of the variance in delivered dose at a given mean tumor dose. Considering all dosimetric variances it is shown that for low-LET beams the conventional microdosimetric variance will dominate, while in neutron and high-LET beams in general the microdosimetric variance may contribute significantly to the observed dose-response relationship. As a result the normalized slope of the dose-response curve for tumor control and normal tissue complications with neutrons and other high-LET beams will be reduced compared to that with photons. This conclusion is found to be in quantitative agreement with available data from clinical trials with neutron therapy. Finally, it is pointed out that for beams with a very high RBE and LET it may be favorable to deliver a fraction of the total dose in the form of conventional low-LET radiation. This addition of low-LET radiation may be desirable to ensure a dose to all clonogenic tumor cell nuclei that is sufficiently high and uniform to achieve a high probability of tumor control

  4. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: Evidence for the prolonged effects of radiation on the thyroid

    The risk of developing thyroid cancer and other thyroid neoplasms after radiation exposure is well known, but specific modifiers of the dose-response relationship are not. The authors have identified 4,296 subjects who received treatment before their sixteenth birthday with orthovoltage radiation for benign conditions in the head and neck area. Individual thyroid dose estimates were calculated for 3,843 subjects. Of the 2,634 subjects who have been found, 1,043 have developed thyroid nodules of all types, and 309 have developed thyroid cancer. The radiation dose-response relationship was consistent with a linear excess relative risk model for thyroid cancer and thyroid nodules within the range of observed doses. Women developed thyroid cancer and thyroid nodules at a higher rate, but the slopes of the dose-response curves were the same for men and women. Age at radiation exposure was a significant factor of the risk, with a lower age at exposure associated with a higher risk. To determine the effect of the wide publicity and the screening program, which began in 1974, the authors compared the dose-response relationship for cases diagnosed before and after 1974. The overall rates increased dramatically after 1974, but the estimates of the slopes of the dose-response curves were not statistically different. The slope of the dose-response curve for thyroid neoplasms appears to have reached a maximum 25-29 yr after radiation exposure, but the dose response continued to be elevated at the end of follow-up. These data are consistent with the tumorigenic effects of radiation lasting at least 40 yr

  5. A New Method for Synthesizing Radiation Dose-Response Data From Multiple Trials Applied to Prostate Cancer

    Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, γ50, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies. Results: Nonrandomized studies produced a statistically significantly higher γ50 than randomized studies for intermediate- to high-risk patients (γ50 = 1.63 vs. γ50 = 0.93, p = 0.03) and a borderline significantly higher (γ50 = 1.78 vs. γ50 = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in γ50 was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of γ50 = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.

  6. Inhalation Anthrax: Dose Response and Risk Analysis

    Coleman, Margaret E.; Thran, Brandolyn; Morse, Stephen S.; Hugh-Jones, Martin; Massulik, Stacey

    2008-01-01

    The notion that inhalation of a single Bacillus anthracis spore is fatal has become entrenched nearly to the point of urban legend, in part because of incomplete articulation of the scientific basis for microbial risk assessment, particularly dose-response assessment. Risk analysis (ie, risk assessment, risk communication, risk management) necessitates transparency: distinguishing scientific facts, hypotheses, judgments, biases in interpretations, and potential misinformation. The difficulty ...

  7. The orthopaedic trauma literature: an evaluation of statistically significant findings in orthopaedic trauma randomized trials

    Tornetta Paul; Siegel Judith; Sung Jinsil; Bhandari Mohit

    2008-01-01

    Abstract Background Evidence-based medicine posits that health care research is founded upon clinically important differences in patient centered outcomes. Statistically significant differences between two treatments may not necessarily reflect a clinically important difference. We aimed to quantify the sample sizes and magnitude of treatment effects in a review of orthopaedic randomized trials with statistically significant findings. Methods We conducted a comprehensive search (PubMed, Cochr...

  8. Statistical Significance Does Not Equal Geological Significance: Reply to Comments on “Lies, Damned Lies, and Statistics (in Geology)”

    Vermeesch, Pieter

    2011-02-01

    In my Eos Forum of 24 November 2009 (90(47), 443), I used the chi-square test to reject the null hypothesis that earthquakes occur independent of the weekday to make the point that statistical significance should not be confused with geological significance. Of the five comments on my article, only the one by Sornette and Pisarenko [2011] disputes this conclusion, while the remaining comments take issue with certain aspects of the geophysical case study. In this reply I will address all of these points, after providing some necessary further background about statistical tests. Two types of error can result from a hypothesis test. A Type I error occurs when a true null hypothesis is erroneously rejected by chance. A Type II error occurs when a false null hypothesis is erroneously accepted by chance. By definition, the p value is the probability, under the null hypothesis, of obtaining a test statistic at least as extreme as the one observed. In other words, the smaller the p value, the lower the probability that a Type I error has been made. In light of the exceedingly small p value of the earthquake data set, Tseng and Chen's [2011] assertion that a Type I error has been committed is clearly wrong. How about Type II errors?

  9. Codon Deviation Coefficient: A novel measure for estimating codon usage bias and its statistical significance

    Zhang, Zhang

    2012-03-22

    Background: Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB). Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis.Results: Here we propose a novel measure--Codon Deviation Coefficient (CDC)--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance.Conclusions: As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions. 2012 Zhang et al; licensee BioMed Central Ltd.

  10. Codon Deviation Coefficient: a novel measure for estimating codon usage bias and its statistical significance

    Zhang Zhang

    2012-03-01

    Full Text Available Abstract Background Genetic mutation, selective pressure for translational efficiency and accuracy, level of gene expression, and protein function through natural selection are all believed to lead to codon usage bias (CUB. Therefore, informative measurement of CUB is of fundamental importance to making inferences regarding gene function and genome evolution. However, extant measures of CUB have not fully accounted for the quantitative effect of background nucleotide composition and have not statistically evaluated the significance of CUB in sequence analysis. Results Here we propose a novel measure--Codon Deviation Coefficient (CDC--that provides an informative measurement of CUB and its statistical significance without requiring any prior knowledge. Unlike previous measures, CDC estimates CUB by accounting for background nucleotide compositions tailored to codon positions and adopts the bootstrapping to assess the statistical significance of CUB for any given sequence. We evaluate CDC by examining its effectiveness on simulated sequences and empirical data and show that CDC outperforms extant measures by achieving a more informative estimation of CUB and its statistical significance. Conclusions As validated by both simulated and empirical data, CDC provides a highly informative quantification of CUB and its statistical significance, useful for determining comparative magnitudes and patterns of biased codon usage for genes or genomes with diverse sequence compositions.

  11. Comparison of the dose-response relationships for chromosome aberration frequencies between the T65D and DS86 dosimetries

    Cytogenetic data, derived from cultured lymphocytes of atomic bomb survivors and controls in the ABCC-RERF Adult Health Study cohort, have been analyzed to determine differences in the dose-response relationships for chromosome aberrations between the T65D and DS86 dose estimates and to assess differences between Hiroshima and Nagasaki. For a linear dose-response model, the average percentage of cells with at least one chromosome aberration increases less rapidly with dose in Nagasaki than in Hiroshima. The magnitude of the intercity difference in the percentage of cells with aberrations per gray is less for DS86 than for T65D, though the difference is statistically significant for both kerma and bone marrow dose with either dosimetry. The percentage of cells with aberrations per gray for DS86 kerma estimates is about 60 % greater than the corresponding T65D slope. Analyses to test nonlinearity in the dose-response function indicate significant departures (p<.001) from linearity, using both dosimetries for both kerma and marrow dose. Therefore, comparative results are presented for a range of RBE relationships under various linear (L) and linearquadratic linear (LQ-L) models. As an illustrative result, if one assumes an LQ-L model similar to models reported in the cytogenetic literature, with a limiting RBE of 20 at zero dose, the DS86 slope (the percentage of cells with aberrations per sievert) is 120 % greater than the corresponding T65D value. (J.P.N.)

  12. Confidence intervals permit, but don't guarantee, better inference than statistical significance testing

    FionaFidler

    2010-07-01

    Full Text Available A statistically significant result, and a non-significant result may differ little, although significance status may tempt an interpretation of difference. Two studies are reported that compared interpretation of such results presented using null hypothesis significance testing (NHST, or confidence intervals (CIs. Authors of articles published in psychology, behavioural neuroscience, and medical journals were asked, via email, to interpret two fictitious studies that found similar results, one statistically significant, and the other non-significant. Responses from 330 authors varied greatly, but interpretation was generally poor, whether results were presented as CIs or using NHST. However, when interpreting CIs respondents who mentioned NHST were 60% likely to conclude, unjustifiably, the two results conflicted, whereas those who interpreted CIs without reference to NHST were 95% likely to conclude, justifiably, the two results were consistent. Findings were generally similar for all three disciplines. An email survey of academic psychologists confirmed that CIs elicit better interpretations if NHST is not invoked. Improved statistical inference can result from encouragement of meta-analytic thinking and use of CIs but, for full benefit, such highly desirable statistical reform requires also that researchers interpret CIs without recourse to NHST.

  13. Does Statistical Significance Help to Evaluate Predictive Performance of Competing Models?

    Levent Bulut

    2016-04-01

    Full Text Available In Monte Carlo experiment with simulated data, we show that as a point forecast criterion, the Clark and West's (2006 unconditional test of mean squared prediction errors does not reflect the relative performance of a superior model over a relatively weaker one. The simulation results show that even though the mean squared prediction errors of a constructed superior model is far below a weaker alternative, the Clark- West test does not reflect this in their test statistics. Therefore, studies that use this statistic in testing the predictive accuracy of alternative exchange rate models, stock return predictability, inflation forecasting, and unemployment forecasting should not weight too much on the magnitude of the statistically significant Clark-West tests statistics.

  14. A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

    Little, Mark P., E-mail: mark.little@nih.gov [Radiation Epidemiology Branch, National Cancer Institute, Rockville, Maryland (United States); Stovall, Marilyn; Smith, Susan A. [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kleinerman, Ruth A. [Radiation Epidemiology Branch, National Cancer Institute, Rockville, Maryland (United States)

    2013-02-01

    Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy{sup -1} of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018, 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.

  15. Statistical significance of trends in monthly heavy precipitation over the US

    Mahajan, Salil

    2011-05-11

    Trends in monthly heavy precipitation, defined by a return period of one year, are assessed for statistical significance in observations and Global Climate Model (GCM) simulations over the contiguous United States using Monte Carlo non-parametric and parametric bootstrapping techniques. The results from the two Monte Carlo approaches are found to be similar to each other, and also to the traditional non-parametric Kendall\\'s τ test, implying the robustness of the approach. Two different observational data-sets are employed to test for trends in monthly heavy precipitation and are found to exhibit consistent results. Both data-sets demonstrate upward trends, one of which is found to be statistically significant at the 95% confidence level. Upward trends similar to observations are observed in some climate model simulations of the twentieth century, but their statistical significance is marginal. For projections of the twenty-first century, a statistically significant upwards trend is observed in most of the climate models analyzed. The change in the simulated precipitation variance appears to be more important in the twenty-first century projections than changes in the mean precipitation. Stochastic fluctuations of the climate-system are found to be dominate monthly heavy precipitation as some GCM simulations show a downwards trend even in the twenty-first century projections when the greenhouse gas forcings are strong. © 2011 Springer-Verlag.

  16. A critical discussion of null hypothesis significance testing and statistical power analysis within psychological research

    Jones, Allan; Sommerlund, Bo

    2007-01-01

    The uses of null hypothesis significance testing (NHST) and statistical power analysis within psychological research are critically discussed. The article looks at the problems of relying solely on NHST when dealing with small and large sample sizes. The use of power-analysis in estimating the...

  17. Interpreting Statistical Significance Test Results: A Proposed New "What If" Method.

    Kieffer, Kevin M.; Thompson, Bruce

    As the 1994 publication manual of the American Psychological Association emphasized, "p" values are affected by sample size. As a result, it can be helpful to interpret the results of statistical significant tests in a sample size context by conducting so-called "what if" analyses. However, these methods can be inaccurate unless "corrected" effect…

  18. Recent Literature on Whether Statistical Significance Tests Should or Should Not Be Banned.

    Deegear, James

    This paper summarizes the literature regarding statistical significant testing with an emphasis on recent literature in various discipline and literature exploring why researchers have demonstrably failed to be influenced by the American Psychological Association publication manual's encouragement to report effect sizes. Also considered are…

  19. Statistical Significance, Effect Size, and Replication: What Do the Journals Say?

    DeVaney, Thomas A.

    2001-01-01

    Studied the attitudes of representatives of journals in education, sociology, and psychology through an electronic survey completed by 194 journal representatives. Results suggest that the majority of journals do not have written policies concerning the reporting of results from statistical significance testing, and most indicated that statistical…

  20. Statistical Significance of the Contribution of Variables to the PCA Solution: An Alternative Permutation Strategy

    Linting, Marielle; van Os, Bart Jan; Meulman, Jacqueline J.

    2011-01-01

    In this paper, the statistical significance of the contribution of variables to the principal components in principal components analysis (PCA) is assessed nonparametrically by the use of permutation tests. We compare a new strategy to a strategy used in previous research consisting of permuting the columns (variables) of a data matrix…

  1. Quantitative Dose-Response Curves from Subcellular Lipid Multilayer Microarrays

    Kusi-Appiah, A. E.; Lowry, T. W.; Darrow, E. M.; Wilson, K.; Chadwick, B. P.; Davidson, M. W.; Lenhert, S.

    2015-01-01

    The dose-dependent bioactivity of small molecules on cells is a crucial factor in drug discovery and personalized medicine. Although small-molecule microarrays are a promising platform for miniaturized screening, it has been a challenge to use them to obtain quantitative dose-response curves in vitro, especially for lipophilic compounds. Here we establish a small-molecule microarray assay capable of controlling the dosage of small lipophilic molecules delivered to cells by varying the sub-cellular volumes of surface supported lipid micro- and nanostructure arrays fabricated with nanointaglio. Features with sub-cellular lateral dimensions were found necessary to obtain normal cell adhesion with HeLa cells. The volumes of the lipophilic drug-containing nanostructures were determined using a fluorescence microscope calibrated by atomic-force microscopy. We used the surface supported lipid volume information to obtain EC-50 values for the response of HeLa cells to three FDA-approved lipophilic anticancer drugs, docetaxel, imiquimod and triethylenemelamine, which were found to be significantly different from neat lipid controls. No significant toxicity was observed on the control cells surrounding the drug/lipid patterns, indicating lack of interference or leakage from the arrays. Comparison of the microarray data to dose-response curves for the same drugs delivered liposomally from solution revealed quantitative differences in the efficacy values, which we explain in terms of cell-adhesion playing a more important role in the surface-based assay. The assay should be scalable to a density of at least 10,000 dose response curves on the area of a standard microtiter plate. PMID:26167949

  2. Statistical significance for hierarchical clustering in genetic association and microarray expression studies

    Yang Yaning

    2003-12-01

    Full Text Available Abstract Background With the increasing amount of data generated in molecular genetics laboratories, it is often difficult to make sense of results because of the vast number of different outcomes or variables studied. Examples include expression levels for large numbers of genes and haplotypes at large numbers of loci. It is then natural to group observations into smaller numbers of classes that allow for an easier overview and interpretation of the data. This grouping is often carried out in multiple steps with the aid of hierarchical cluster analysis, each step leading to a smaller number of classes by combining similar observations or classes. At each step, either implicitly or explicitly, researchers tend to interpret results and eventually focus on that set of classes providing the "best" (most significant result. While this approach makes sense, the overall statistical significance of the experiment must include the clustering process, which modifies the grouping structure of the data and often removes variation. Results For hierarchically clustered data, we propose considering the strongest result or, equivalently, the smallest p-value as the experiment-wise statistic of interest and evaluating its significance level for a global assessment of statistical significance. We apply our approach to datasets from haplotype association and microarray expression studies where hierarchical clustering has been used. Conclusion In all of the cases we examine, we find that relying on one set of classes in the course of clustering leads to significance levels that are too small when compared with the significance level associated with an overall statistic that incorporates the process of clustering. In other words, relying on one step of clustering may furnish a formally significant result while the overall experiment is not significant.

  3. Dose-response curves and cell killing

    In the literature on dose-response curves (drc) for radiation-induced cancer, it is customary to include an exponential term to describe the downturn of drcs at high doses. This term is supposed to describe the effect of cell killing on the frequency of radiation-induced cancers. A closer look at the point estimates, which are fit by mathematical models, reveals that most authors plot frequency estimates without considerations of time since exposure and of competing risks. The authors suggest plots of the estimated frequency of tumor appearance corrected for independent competing risks at a fixed and equal time since exposure against dose to correct these short comings and demonstrate with several examples (e.g. /sup 239/Pu in beagles and /sup 226/Ra in man) the disappearance of the downtrend in such plots. Application of Ockham's razor suggests, therefore, the abandonment of the cell killing hypothesis as the complete explanation of the downturn

  4. Radiation dose-response of human tumors

    Purpose: The dose of radiation that locally controls human tumors treated electively or for gross disease is rarely well defined. These doses can be useful in understanding the dose requirements of novel therapies featuring inhomogeneous dosimetry and in an adjuvant setting. The goal of this study was to compute the dose of radiation that locally controls 50% (TCD50) of tumors in human subjects. Methods and Materials: Logit regression was used with data collected from single institutions or from combinations of local control data accumulated from several institutions treating the same disease. Results: 90 dose response curves were calculated; 62 of macroscopic tumor therapy, 28 of elective therapy with surgery for primary control. The mean and median TCD50 for gross disease were 50.0 and 51.9 Gy, respectively. The mean and median TCD50 for microscopic disease control were 39.3 and 37.9 Gy, respectively. At the TCD50, an additional dose of 1 Gy controlled an additional 2.5% (median) additional patients with macroscopic disease and 4.2% (median) additional patients with microscopic disease. For both macro- and microscopic disease, an increase of 1% of dose at the TCD50 increased control rates ? 1% (median) or 2-3% (mean). A predominance of dose response curves had shallow slopes accounting for the discrepancy between mean and median values. Conclusion: Doses to control microscopic disease are approximately 12 Gy less than that required to control macroscopic disease, and are about 79% of the dose required to control macroscopic disease. The percentage increase in cures expected for a 1% increase in dose is similar for macroscopic and microscopic disease, with a median value of ? 1%/% and a mean of ? 2.7%/%

  5. Cognitive Constructivism and the Epistemic Significance of Sharp Statistical Hypotheses in Natural Sciences

    Stern, J M

    2010-01-01

    This book presents our case in defense of a constructivist epistemological framework and the use of compatible statistical theory and inference tools. The basic metaphor of decision theory is the maximization of a gambler's expected fortune, according to his own subjective utility, prior beliefs an learned experiences. This metaphor has proven to be very useful, leading the development of Bayesian statistics since its XX-th century revival, rooted on the work of de Finetti, Savage and others. The basic metaphor presented in this text, as a foundation for cognitive constructivism, is that of an eigen-solution, and the verification of its objective epistemic status. The FBST - Full Bayesian Significance Test - is the cornerstone of a set of statistical tolls conceived to assess the epistemic value of such eigen-solutions, according to their four essential attributes, namely, sharpness, stability, separability and composability. We believe that this alternative perspective, complementary to the one ofered by dec...

  6. Non-Linear Dose Response Relationships in Biology, Toxicology, and Medicine (June 8-10, 2004). Final Report

    The conference attracts approximately 500 scientists researching in the area of non-linear low dose effects. These scientists represent a wide range of biological/medical fields and technical disciplines. Observations that biphasic dose responses are frequently reported in each of these areas but that the recognition of similar dose response relationships across disciplines is very rarely appreciated and exploited. By bringing scientist of such diverse backgrounds together who are working on the common area of non-linear dose response relationships this will enhance our understanding of the occurrence, origin, mechanism, significance and practical applications of such dose response relationships

  7. Dose response from pharmacological interventions for CBF changes in a baboon model using 99Tcm-HMPAO and SPECT

    This study assesses the sensitivity of the baboon model under anaesthesia to determine by single photon emission computed tomography (SPECT) and 99Tcm-hexamethylpropyleneamine oxime (HMPAO) dose responses from drugs (acetazolamide) with known regional cerebral blood flow (rCBF) effects on humans. Three dosages of acetazolamide were chosen: 250, 500 and 750 mg. The effects of these were studied by conventional SPECT 5 min after intravenous (i.v.) administration and compared to previous studies of rCBF with the baboons under anaesthesia only. An additional study concerned the effect of 500 mg acetazolamide at 15 min after administration. Haemodynamic parameters and blood gases were also monitored. No statistically significant regional effects were noted. The largest increase in CBF (39%) was observed from 500 mg acetazolamide after 5 min. This was statistically significantly different from control values only at a 10% level of confidence; then following a 27% increase above control values after 750 mg (5 min). At 15 min 500 mg yielded values lower by 10% than the high dose. No effects were observed from 250 mg acetazolamide; only pO2 showed changes which largely confirm the CBF findings. The model did not give significant results at a 5% level of confidence but large fluctuations were observed, also in the haemodynamic and blood gas values. At a 10% level a significant dose response was confirmed for acetazolamide. (author)

  8. The orthopaedic trauma literature: an evaluation of statistically significant findings in orthopaedic trauma randomized trials

    Tornetta Paul

    2008-01-01

    Full Text Available Abstract Background Evidence-based medicine posits that health care research is founded upon clinically important differences in patient centered outcomes. Statistically significant differences between two treatments may not necessarily reflect a clinically important difference. We aimed to quantify the sample sizes and magnitude of treatment effects in a review of orthopaedic randomized trials with statistically significant findings. Methods We conducted a comprehensive search (PubMed, Cochrane for all randomized controlled trials between 1/1/95 to 12/31/04. Eligible studies include those that focused upon orthopaedic trauma. Baseline characteristics and treatment effects were abstracted by two reviewers. Briefly, for continuous outcome measures (ie functional scores, we calculated effect sizes (mean difference/standard deviation. Dichotomous variables (ie infection, nonunion were summarized as absolute risk differences and relative risk reductions (RRR. Effect sizes >0.80 and RRRs>50% were defined as large effects. Using regression analysis we examined the association between the total number of outcome events and treatment effect (dichotomous outcomes. Results Our search yielded 433 randomized controlled trials (RCTs, of which 76 RCTs with statistically significant findings on 184 outcomes (122 continuous/62 dichotomous outcomes met study eligibility criteria. The mean effect size across studies with continuous outcome variables was 1.7 (95% confidence interval: 1.43–1.97. For dichotomous outcomes, the mean risk difference was 30% (95%confidence interval:24%–36% and the mean relative risk reduction was 61% (95% confidence interval: 55%–66%; range: 0%–97%. Fewer numbers of total outcome events in studies was strongly correlated with increasing magnitude of the treatment effect (Pearson's R = -0.70, p Conclusion Our review suggests that statistically significant results in orthopaedic trials have the following implications-1 On average large risk reductions are reported 2 Large treatment effects (>50% relative risk reduction are correlated with few number of total outcome events. Readers should interpret the results of such small trials with these issues in mind.

  9. The Effects of Electrode Impedance on Data Quality and Statistical Significance in ERP Recordings

    Kappenman, Emily S.; Luck, Steven. J.

    2010-01-01

    To determine whether data quality is meaningfully reduced by high electrode impedance, EEG was recorded simultaneously from low- and high-impedance electrode sites during an oddball task. Low-frequency noise was found to be increased at high-impedance sites relative to low-impedance sites, especially when the recording environment was warm and humid. The increased noise at the high-impedance sites caused an increase in the number of trials needed to obtain statistical significance in analyses...

  10. The null hypothesis significance test in health sciences research (1995-2006): statistical analysis and interpretation

    Fernández-Somoano Ana; Suárez-Gil Patricio; Silva-Ayçaguer Luis

    2010-01-01

    Abstract Background The null hypothesis significance test (NHST) is the most frequently used statistical method, although its inferential validity has been widely criticized since its introduction. In 1988, the International Committee of Medical Journal Editors (ICMJE) warned against sole reliance on NHST to substantiate study conclusions and suggested supplementary use of confidence intervals (CI). Our objective was to evaluate the extent and quality in the use of NHST and CI, both in Englis...

  11. Identification of Microorganisms by High Resolution Tandem Mass Spectrometry with Accurate Statistical Significance

    Alves, Gelio; Wang, Guanghui; Ogurtsov, Aleksey Y.; Drake, Steven K.; Gucek, Marjan; Suffredini, Anthony F.; Sacks, David B.; Yu, Yi-Kuo

    2016-02-01

    Correct and rapid identification of microorganisms is the key to the success of many important applications in health and safety, including, but not limited to, infection treatment, food safety, and biodefense. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is challenging correct microbial identification because of the large number of choices present. To properly disentangle candidate microbes, one needs to go beyond apparent morphology or simple `fingerprinting'; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptidome profiles of microbes to better separate them and by designing an analysis method that yields accurate statistical significance. Here, we present an analysis pipeline that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using MS/MS data of 81 samples, each composed of a single known microorganism, that the proposed pipeline can correctly identify microorganisms at least at the genus and species levels. We have also shown that the proposed pipeline computes accurate statistical significances, i.e., E-values for identified peptides and unified E-values for identified microorganisms. The proposed analysis pipeline has been implemented in MiCId, a freely available software for Microorganism Classification and Identification. MiCId is available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html.

  12. On determining the statistical significance of discontinuities within ordered ecological data

    Current ecological theory hypothesizes that boundaries between adjacent ecosystem units are important in determining ecosystem structure and function across heterogeneous landscapes, and that such boundaries are potentially important sites for early detection of global climate change effects. Yet traditional data analysis methods focus primarily on homogeneous units rather than on the boundaries between them; thus, new methods are being developed for detecting, characterizing and classifying boundaries, e.g., split moving-window boundary analysis (SMW). SMW is a simple yet sensitive method for locating discontinuities that may exist within multivariate, serial data at various scales relative to the length of the data series. However, SMW is subjective and relative, and therefore locates apparent discontinuities even within random, serial data. In this paper they present two nonparametric methods for determining the statistical significance of discontinuities detected by SMW. First, they describe a Monte Carlo method for determining the statistical significance of scale-dependent discontinuities. Second, they propose a nonparametric, scale-independent method that is more appropriate for locating statistically significant discontinuities that separate different, relatively homogeneous groups of varying size along a series. They examine the robustness of these two methods using computer-generated data having varying intensities of imposed discontinuities, and illustrate their application to locating boundaries between vegetation samples collected at systematic intervals across a desert landscape in southern New Mexico

  13. Identification of Microorganisms by High Resolution Tandem Mass Spectrometry with Accurate Statistical Significance.

    Alves, Gelio; Wang, Guanghui; Ogurtsov, Aleksey Y; Drake, Steven K; Gucek, Marjan; Suffredini, Anthony F; Sacks, David B; Yu, Yi-Kuo

    2016-02-01

    Correct and rapid identification of microorganisms is the key to the success of many important applications in health and safety, including, but not limited to, infection treatment, food safety, and biodefense. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is challenging correct microbial identification because of the large number of choices present. To properly disentangle candidate microbes, one needs to go beyond apparent morphology or simple 'fingerprinting'; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptidome profiles of microbes to better separate them and by designing an analysis method that yields accurate statistical significance. Here, we present an analysis pipeline that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using MS/MS data of 81 samples, each composed of a single known microorganism, that the proposed pipeline can correctly identify microorganisms at least at the genus and species levels. We have also shown that the proposed pipeline computes accurate statistical significances, i.e., E-values for identified peptides and unified E-values for identified microorganisms. The proposed analysis pipeline has been implemented in MiCId, a freely available software for Microorganism Classification and Identification. MiCId is available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html . Graphical Abstract ᅟ. PMID:26510657

  14. Identification of Microorganisms by High Resolution Tandem Mass Spectrometry with Accurate Statistical Significance

    Alves, Gelio; Wang, Guanghui; Ogurtsov, Aleksey Y.; Drake, Steven K.; Gucek, Marjan; Suffredini, Anthony F.; Sacks, David B.; Yu, Yi-Kuo

    2015-10-01

    Correct and rapid identification of microorganisms is the key to the success of many important applications in health and safety, including, but not limited to, infection treatment, food safety, and biodefense. With the advance of mass spectrometry (MS) technology, the speed of identification can be greatly improved. However, the increasing number of microbes sequenced is challenging correct microbial identification because of the large number of choices present. To properly disentangle candidate microbes, one needs to go beyond apparent morphology or simple `fingerprinting'; to correctly prioritize the candidate microbes, one needs to have accurate statistical significance in microbial identification. We meet these challenges by using peptidome profiles of microbes to better separate them and by designing an analysis method that yields accurate statistical significance. Here, we present an analysis pipeline that uses tandem MS (MS/MS) spectra for microbial identification or classification. We have demonstrated, using MS/MS data of 81 samples, each composed of a single known microorganism, that the proposed pipeline can correctly identify microorganisms at least at the genus and species levels. We have also shown that the proposed pipeline computes accurate statistical significances, i.e., E-values for identified peptides and unified E-values for identified microorganisms. The proposed analysis pipeline has been implemented in MiCId, a freely available software for Microorganism Classification and Identification. MiCId is available for download at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/downloads.html .

  15. Testing statistical significance scores of sequence comparison methods with structure similarity

    Leunissen Jack AM

    2006-10-01

    Full Text Available Abstract Background In the past years the Smith-Waterman sequence comparison algorithm has gained popularity due to improved implementations and rapidly increasing computing power. However, the quality and sensitivity of a database search is not only determined by the algorithm but also by the statistical significance testing for an alignment. The e-value is the most commonly used statistical validation method for sequence database searching. The CluSTr database and the Protein World database have been created using an alternative statistical significance test: a Z-score based on Monte-Carlo statistics. Several papers have described the superiority of the Z-score as compared to the e-value, using simulated data. We were interested if this could be validated when applied to existing, evolutionary related protein sequences. Results All experiments are performed on the ASTRAL SCOP database. The Smith-Waterman sequence comparison algorithm with both e-value and Z-score statistics is evaluated, using ROC, CVE and AP measures. The BLAST and FASTA algorithms are used as reference. We find that two out of three Smith-Waterman implementations with e-value are better at predicting structural similarities between proteins than the Smith-Waterman implementation with Z-score. SSEARCH especially has very high scores. Conclusion The compute intensive Z-score does not have a clear advantage over the e-value. The Smith-Waterman implementations give generally better results than their heuristic counterparts. We recommend using the SSEARCH algorithm combined with e-values for pairwise sequence comparisons.

  16. EasyGene a prokaryotic gene finder that ranks ORFs by statistical significance

    Larsen, Thomas Schou; Krogh, Anders Strmose

    2003-01-01

    Background: Contrary to other areas of sequence analysis, a measure of statistical significance of a putative gene has not been devised to help in discriminating real genes from the masses of random Open Reading Frames (ORFs) in prokaryotic genomes. Therefore, many genomes have too many short ORF...... exceeds other methods. The entire pipeline of computer processing from the raw input of a genome or set of contigs to a list of putative genes with significance is automated, making it easy to apply EasyGene to newly sequenced organisms....

  17. Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

    Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

    2012-01-01

    Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

  18. Testing statistical significance of trends in learning, ageing and safety indicators

    Viertaevae, Janne [Colenco Power Engineering Ltd., Taefernstrasse 26, 5405 Baden-Daettvil (Switzerland); Vaurio, Jussi K. [Lappeenranta University of Technology and Prometh Solutions, Hiihtaejaenkuja 3K, 06100 Porvoo (Finland)], E-mail: jussi.vaurio@pbezone.net

    2009-06-15

    A relatively new subject for probabilistic safety methodology is statistical analysis of trends in observed failures and other safety indicators reflecting ageing or learning in operational and maintenance experience at industrial facilities. Random variations of the indicators can mask real changes or cause false alarms. Methodology is proposed for testing statistical significance of apparent trends in safety indicators. Improved methods are developed for detecting both monotonic and non-monotonic trends, some demonstrated by simulation studies and real examples to be more powerful than those known so far. An effective way to use standard trend tests with transformed data for testing exponentiality of data is also demonstrated and found superior to a well-known Lilliefors' goodness-of-fit test.

  19. Testing statistical significance of trends in learning, ageing and safety indicators

    A relatively new subject for probabilistic safety methodology is statistical analysis of trends in observed failures and other safety indicators reflecting ageing or learning in operational and maintenance experience at industrial facilities. Random variations of the indicators can mask real changes or cause false alarms. Methodology is proposed for testing statistical significance of apparent trends in safety indicators. Improved methods are developed for detecting both monotonic and non-monotonic trends, some demonstrated by simulation studies and real examples to be more powerful than those known so far. An effective way to use standard trend tests with transformed data for testing exponentiality of data is also demonstrated and found superior to a well-known Lilliefors' goodness-of-fit test

  20. Review of dose-response curves for acute antimigraine drugs

    Hougaard, Anders; Tfelt-Hansen, Peer

    2015-01-01

    INTRODUCTION: Dose-response curves for efficacy and tolerability are the important determinants for the choice of doses of acute migraine drugs. Areas covered: Dose-response curves for the efficacy of seven triptans (5-HT1B/1D receptor agonists), a 5-HT1F receptor agonist (lasmiditan) and four oral...... calcitonin-gene related peptide receptor antagonists (telcagepant, MK-3207, BI 44370 TA and BMS-927711) in placebo-controlled trials were reviewed. In addition, dose-response curves for adverse events (AEs) were reviewed. Expert opinion: For most triptans, the dose-response curve for efficacy is flat...

  1. Dose-response in stereotactic irradiation of lung tumors

    The dose-response for local tumor control after stereotactic radiotherapy of 92 pulmonary tumors (36 NSCLC and 56 metastases) was evaluated. Short course irradiation of 1-8 fractions with different fraction doses was used. After a median follow-up of 14 months (2-85 months) 11 local recurrences were observed with significant advantage for higher doses. When normalization to a biologically effective dose (BED) is used a dose of 94 Gy at the isocenter and 50 Gy at the PTV-margin are demonstrated to give 50% probability of tumor control (TCD50). Multivariate analysis revealed the dose at the PTV-margin as the only significant factor for local control

  2. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods

    Jakobsen, Janus Christian; Wetterslev, Jorn; Winkel, Per; Lange, Theis; Gluud, Christian

    2014-01-01

    Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: We propose an eight-step procedure for better validation of meta-analytic results in systematic reviews (1) Obtain the 95% confidence intervals and the P-values from both fixed-effect and random-effects meta-analyses and report the most......BACKGROUND: Thresholds for statistical significance when assessing meta-analysis results are being insufficiently demonstrated by traditional 95% confidence intervals and P-values. Assessment of intervention effects in systematic reviews with meta-analysis deserves greater rigour. METHODS...... proposed eight-step procedure will increase the validity of assessments of intervention effects in systematic reviews of randomised clinical trials....

  3. Statistically Significant Strings are Related to Regulatory Elements in the Promoter Regions of Saccharomyces cerevisiae

    Hu, R; Hu, Rui; Wang, Bin

    2000-01-01

    Finding out statistically significant words in DNA and protein sequences forms the basis for many genetic studies. By applying the maximal entropy principle, we give one systematic way to study the nonrandom occurrence of words in DNA or protein sequences. Through comparison with experimental results, it was shown that patterns of regulatory binding sites in Saccharomyces cerevisiae(yeast) genomes tend to occur significantly in the promoter regions. We studied two correlated gene family of yeast. The method successfully extracts the binding sites varified by experiments in each family. Many putative regulatory sites in the upstream regions are proposed. The study also suggested that some regulatory sites are a ctive in both directions, while others show directional preference.

  4. Confidence bounds for nonlinear dose-response relationships

    Baayen, C; Hougaard, P

    2015-01-01

    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...

  5. Biological dosimetry in radiological protection: dose response curves elaboration for 60Co and 137Cs

    Ionizing radiation sources for pacific uses are being extensively utilized by modern society and the applications of these sources have raised the probability of the occurrence of accidents. The accidental exposition to radiation creates a necessity of the development of methods to evaluate dose quantity. This data could be obtained by the measurement of damage caused by radiation in the exposed person. The radiation dose can be estimated in exposed persons through physical methods (physical dosimetry) but the biological methods can't be dispensed, and among them, the cytogenetic one that makes use of chromosome aberrations (dicentric and centric ring) formed in peripheral blood lymphocytes (PBL) exposed to ionizing radiation. This method correlates the frequency of radioinduced aberrations with the estimated absorbed dose, as in vitro as in vivo, which is called cytogenetic dosimetry. By the introduction of improved new techniques in culture, in the interpretation of aberrations in the different analysers of slides and by the adoption of different statistical programs to analyse the data, significant differences are observed among laboratories in dose-response curves (calibration curves). The estimation of absorbed dose utilizing other laboratory calibration curves may introduce some uncertainties, so the International Atomic Energy Agency (IAEA) advises that each laboratory elaborates your own dose-response curve for cytogenetic dosimetry. The results were obtained from peripheral blood lymphocytes of the healthy and no-smoking donors exposed to 60Co and 137Cs radiation, with dose rate of 5 cGy.min.-1. Six points of dose were determined 20,50,100,200,300,400 cGy and the control not irradiated. The analysed aberrations were of chromosomic type, dicentric and centric ring. The dose response curve for dicentrics were obtained by frequencies weighted in liner-quadratic mathematic model and the equation resulted were for 60Co: Y = (3 46 +- 2.14)10-4 cGy-1 + (3.45 +- 0.64)10-6 cGy''-2 and for 137Cs'Cs: Y = (7.69 +- 2.33)10-4 cGy-1 + (l,96 +- 0,58)10-6 cGy-2. (author)

  6. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response

    Purpose: The purpose of this paper is to use the outcome of a dose escalation protocol for three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer to study the dose-response for late rectal toxicity and to identify anatomic, dosimetric, and clinical factors that correlate with late rectal bleeding in multivariate analysis. Methods and Materials: Seven hundred forty-three patients with T1c-T3 prostate cancer were treated with 3D-CRT with prescribed doses of 64.8 to 81.0 Gy. The 5-year actuarial rate of late rectal toxicity was assessed using Kaplan-Meier statistics. A retrospective dosimetric analysis was performed for patients treated to 70.2 Gy (52 patients) or 75.6 Gy (119 patients) who either exhibited late rectal bleeding (RTOG Grade 2/3) within 30 months after treatment (i.e., 70.2 Gy--13 patients, 75.6 Gy--36 patients) or were nonbleeding for at least 30 months (i.e., 70.2 Gy--39 patients, 75.6 Gy--83 patients). Univariate and multivariate logistic regression was performed to correlate late rectal bleeding with several anatomic, dosimetric, and clinical variables. Results: A dose response for ≥ Grade 2 late rectal toxicity was observed. By multivariate analysis, the following factors were significantly correlated with ≥ Grade 2 late rectal bleeding for patients prescribed 70.2 Gy: 1) enclosure of the outer rectal contour by the 50% isodose on the isocenter slice (i.e., Iso50) (p max (p max

  7. 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.

  8. Scalable detection of statistically significant communities and hierarchies: message-passing for modularity

    Zhang, Pan

    2014-01-01

    Modularity is a popular measure of community structure. However, maximizing the modularity can lead to many competing partitions with almost the same modularity that are poorly correlated to each other; it can also overfit, producing illusory "communities" in random graphs where none exist. We address this problem by using the modularity as a Hamiltonian, and computing the marginals of the resulting Gibbs distribution. If we assign each node to its most-likely community under these marginals, we claim that, unlike the ground state, the resulting partition is a good measure of statistically-significant community structure. We propose an efficient Belief Propagation (BP) algorithm to compute these marginals. In random networks with no true communities, the system has two phases as we vary the temperature: a paramagnetic phase where all marginals are equal, and a spin glass phase where BP fails to converge. In networks with real community structure, there is an additional retrieval phase where BP converges, and ...

  9. Henry Eyring: Statistical Mechanics, Significant Structure Theory, and the Inductive-Deductive Method

    Henderson, Douglas

    2010-01-01

    Henry Eyring was, and still is, a towering figure in science. Some aspects of his life and science, beginning in Mexico and continuing in Arizona, California, Wisconsin, Germany, Princeton, and finally Utah, are reviewed here. Eyring moved gradually from quantum theory toward statistical mechanics and the theory of liquids, motivated in part by his desire to understand reactions in condensed matter. Significant structure theory, while not as successful as Eyring thought, is better than his critics realize. Eyring won many awards. However, most chemists are surprised, if not shocked, that he was never awarded a Nobel Prize. He joined Lise Meitner, Rosalind Franklin, John Slater, and others, in an even more select group, those who should have received a Nobel Prize but did not.

  10. Historical blunders: how toxicology got the dose-response relationship half right.

    Calabrese, E J

    2005-12-14

    Substantial evidence indicates that reliable examples of hormetic dose responses in the toxicological literature are common and generalizable across biological model, endpoint measured and chemical class. Further evaluation revealed that the hormetic dose response model is more common than the threshold dose response model in objective, head-to-head comparisons. Nonetheless, the field of toxicology made a profound error by rejecting the use of the hormetic dose response model in its teaching, research, risk assessment and regulatory activities over nearly the past century. This paper argues that the hormetic dose response model (formerly called the Arndt-Schulz Law) was rejected principally because of its close historical association with the medical practice of homeopathy as a result of the prolonged and bitter feud between traditional medicine and homeopathy. Opponents of the concept of hormesis, making use of strong appeals to authority, were successful in their misrepresentation of the scientific foundations of hormesis and in their unfair association of it with segments of the homeopathic movement with extreme and discreditable views. These misrepresentations became established and integrated within the pharmacology and toxicology communities as a result of their origins in and continuities with traditional medicine and subsequently profoundly impacted a broad range of governmental risk assessment activities further consolidating the rejection of hormesis. This error of judgment was reinforced by toxicological hazard assessment methods using only high and few doses that were unable to assess hormetic responses, statistical modeling processes that were constrained to deny the possibility of hormetic dose response relationships and by the modest nature of the hormetic stimulatory response itself, which required more rigorous study designs to evaluate possible hormetic responses. PMID:16359616

  11. There's more than one way to conduct a replication study: Beyond statistical significance.

    Anderson, Samantha F; Maxwell, Scott E

    2016-03-01

    As the field of psychology struggles to trust published findings, replication research has begun to become more of a priority to both scientists and journals. With this increasing emphasis placed on reproducibility, it is essential that replication studies be capable of advancing the field. However, we argue that many researchers have been only narrowly interpreting the meaning of replication, with studies being designed with a simple statistically significant or nonsignificant results framework in mind. Although this interpretation may be desirable in some cases, we develop a variety of additional "replication goals" that researchers could consider when planning studies. Even if researchers are aware of these goals, we show that they are rarely used in practice-as results are typically analyzed in a manner only appropriate to a simple significance test. We discuss each goal conceptually, explain appropriate analysis procedures, and provide 1 or more examples to illustrate these analyses in practice. We hope that these various goals will allow researchers to develop a more nuanced understanding of replication that can be flexible enough to answer the various questions that researchers might seek to understand. (PsycINFO Database Record PMID:26214497

  12. Estimates of statistical significance for comparison of individual positions in multiple sequence alignments

    Sadreyev Ruslan I

    2004-08-01

    Full Text Available Abstract Background Profile-based analysis of multiple sequence alignments (MSA allows for accurate comparison of protein families. Here, we address the problems of detecting statistically confident dissimilarities between (1 MSA position and a set of predicted residue frequencies, and (2 between two MSA positions. These problems are important for (i evaluation and optimization of methods predicting residue occurrence at protein positions; (ii detection of potentially misaligned regions in automatically produced alignments and their further refinement; and (iii detection of sites that determine functional or structural specificity in two related families. Results For problems (1 and (2, we propose analytical estimates of P-value and apply them to the detection of significant positional dissimilarities in various experimental situations. (a We compare structure-based predictions of residue propensities at a protein position to the actual residue frequencies in the MSA of homologs. (b We evaluate our method by the ability to detect erroneous position matches produced by an automatic sequence aligner. (c We compare MSA positions that correspond to residues aligned by automatic structure aligners. (d We compare MSA positions that are aligned by high-quality manual superposition of structures. Detected dissimilarities reveal shortcomings of the automatic methods for residue frequency prediction and alignment construction. For the high-quality structural alignments, the dissimilarities suggest sites of potential functional or structural importance. Conclusion The proposed computational method is of significant potential value for the analysis of protein families.

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

    Alber, Markus; Belka, Claus [Universitaetsklinikum Tuebingen, Radioonkologische Uniklinik, Hoppe-Seyler-Strasse 3, D-72076 Tuebingen (Germany)

    2006-01-07

    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.

  14. Temporal analysis of a dose-response relationship leukemia mortality in atomic bomb survivors

    A data analysis, which incorporates time dependencies, is demonstrated for the dose response of leukemia mortality in the atomic bomb survivors. The time dependencies are initially left unspecified and the data are used to infer them. Two principal findings based on the T65 revised dose estimates are obtained. First, it is shown that the fits to the data of constant risk L-Q-L, L-L, and Q-L dose-response models are significantly improved (p < .001) by using time-dependent dose-response models. Second, it is shown that the increased risk of leukemia mortality due to gamma irradiation decreases in time at an exponential-like rate, while the increased risk due to neutron exposure changes very little, if at all, in time. Consequently, the relative biological effectiveness of neutrons is shown to increase in time (p = .002). Finally, it is conjectured that these findings will remain valid with a reappraisal of dosimetry. (author)

  15. Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

    Appelt, A. L.; Ploen, J.; Vogelius, I. R.; Bentzen, S. M.; Jakobsen, A.

    2013-01-01

    significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D-50,D-TRG1 = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), gamma(50,TRG1) = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D-50,D-TRG1&2 = 72.1 Gy (CI 65.3-94.0 Gy...... dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered. (C) 2013 Elsevier Inc....

  16. Defining a dose-response relationship with radiotherapy for prostate cancer: is more really better?

    Purpose: Data were reviewed addressing the association between radiation therapy (RT) dose and treatment outcome for localized prostate cancer to help clarify the existence of a potential dose-response relationship. Methods and Materials: Articles were identified through the MEDLINE database, CancerLit database, and reference lists of relevant articles. Studies were categorized into four groups based upon the endpoint analyzed, including biochemical control (BC), local control (LC), pathologic control (PC), and cause-specific survival (CSS). The impact of increasing RT dose with each endpoint was recorded. Results: Twenty-two trials involving a total of 11,297 patients were identified. Of the 11 trials addressing the association of RT dose with LC, 9 showed statistically significant improvements. Of the 12 trials that reported BC with RT dose, all showed statistically significant improvements. Two out of 4 studies analyzing PC with increasing dose showed a positive correlation. Finally, 3 out of 9 studies addressing RT dose with CSS showed statistically significant improvements. Despite inconclusive results, patients with poor risk features (e.g., prostate-specific antigen [PSA] ≥10, Gleason score [GS] ≥7, or tumor stage ≥T2b) were most likely to benefit from increasing dose with respect to each endpoint. However, the optimal RT dose and the magnitude of benefit of dose escalation could not be identified. Conclusions: Although RT dose appears to correlate with various measures of treatment outcome, objective, high-quality data addressing this critical issue are still lacking. At the present time, the absolute improvement in outcome due to dose escalation, the subset of patients benefiting most, and the optimal dose remain to be defined

  17. Pulmonary inflammation and crystalline silica in respirable coal mine dust: dose-response

    E D Kuempel; M D Attfield; V Vallyathan; N L Lapp; J M Hale; R J Smith; V Castranova

    2003-02-01

    This study describes the quantitative relationships between early pulmonary responses and the estimated lungburden or cumulative exposure of respirable-quartz or coal mine dust. Data from a previous bronchoalveolar lavage (BAL) study in coal miners ( = 20) and nonminers ( = 16) were used including cell counts of alveolar macrophages (AMs) and polymorphonuclear leukocytes (PMNs), and the antioxidant superoxide dismutase (SOD) levels. Miners’ individual working lifetime particulate exposures were estimated from work histories and mine air sampling data, and quartz lung-burdens were estimated using a lung dosimetry model. Results show that quartz, as either cumulative exposure or estimated lung-burden, was a highly statistically significant predictor of PMN response ( < 0.0001); however cumulative coal dust exposure did not significantly add to the prediction of PMNs ( = 0.2) above that predicted by cumulative quartz exposure ( < 0.0001). Despite the small study size, radiographic category was also significantly related to increasing levels of both PMNs and quartz lung burden (-values < 0.04). SOD in BAL fluid rose linearly with quartz lung burden ( < 0.01), but AM count in BAL fluid did not ( > 0.4). This study demonstrates dose-response relationships between respirable crystalline silica in coal mine dust and pulmonary inflammation, antioxidant production, and radiographic small opacities.

  18. Dose-response relationship for prophylactic cranial irradiation in small cell lung cancer

    Purpose: To determine the dose-response relationship for prophylactic cranial irradiation (PCI) in small cell lung cancer, to quantify the growth kinetics of subclinical metastases, and to determine the influence of time-delay in initiating PCI on its utility. Methods and Materials: Published reports of brain relapse rates in small cell lung cancer with and without PCI were collected. The reduction in brain relapse rate as a function of radiation dose was analyzed. The time interval between treatment of the primary tumor and the initiation of PCI was analyzed as a factor potentially influencing dose-response. Results: A shallow dose-response curve without any threshold in the dose intercept was demonstrated for control of subclinical brain metastases in 'early PCI' (delay between initiation of treatment for primary tumor and PCI less than 60 days). By contrast 'late PCI' (delay over 60 days) was associated with a significant displacement of the dose intercept. Doses over 30-35 Gy in 2-Gy fractions did not result in a further reduction in brain relapse rate, but there were too few high-dose studies to draw any definite conclusion. Conclusions: The nearly linear dose-response relationship for reduction in brain relapses demonstrated for 'early PCI' in the range of doses from zero up to 35 Gy given in 2-Gy fractions supports the model of a fairly logarithmically uniform distribution of metastatic cell number within a series of patients. When PCI is delayed, a significant threshold in dose-response was observed, consistent with a fast growth rate of untreated subclinical brain metastases from small cell lung cancer. The exact shape and locations of dose-response curves is not well established by this retrospective analysis of diverse data. A high probability of eliminating brain relapses following PCI requires a dose of about 30-35 Gy in 2-Gy fractions. Control rates in brain can be enhanced if PCI is applied early

  19. Scalable detection of statistically significant communities and hierarchies, using message passing for modularity.

    Zhang, Pan; Moore, Cristopher

    2014-12-23

    Modularity is a popular measure of community structure. However, maximizing the modularity can lead to many competing partitions, with almost the same modularity, that are poorly correlated with each other. It can also produce illusory ''communities'' in random graphs where none exist. We address this problem by using the modularity as a Hamiltonian at finite temperature and using an efficient belief propagation algorithm to obtain the consensus of many partitions with high modularity, rather than looking for a single partition that maximizes it. We show analytically and numerically that the proposed algorithm works all of the way down to the detectability transition in networks generated by the stochastic block model. It also performs well on real-world networks, revealing large communities in some networks where previous work has claimed no communities exist. Finally we show that by applying our algorithm recursively, subdividing communities until no statistically significant subcommunities can be found, we can detect hierarchical structure in real-world networks more efficiently than previous methods. PMID:25489096

  20. Model for dose-response with alternative change of sign

    A new mathematical model of dose-response relationships is proposed, suitable for calculating stochastic effects of low level exposure. The corresponding differential equations are presented as well as their solution. (A.K.)

  1. A Method to Evaluate Hormesis in Nanoparticle Dose-Responses

    Nascarella, Marc A.; Calabrese, Edward J

    2012-01-01

    The term hormesis describes a dose-response relationship that is characterized by a response that is opposite above and below the toxicological or pharmacological threshold. Previous reports have shown that this relationship is ubiquitous in the response of pharmaceuticals, metals, organic chemicals, radiation, and physical stressor agents. Recent reports have also indicated that certain nanoparticles (NPs) may also exhibit a hormetic dose-response. We describe the application of three previo...

  2. Effect of Cesium–137 Gamma Rays and High-Energy Electrons on Dose Response of Glycine Dosimeter

    Santosh H Shinde; T. Mukherjee

    2010-01-01

    Glycine (50 mg / 10 mL FX) system can be used in the dose range of 500 to 4000 Gy for Cobalt-60 gamma rays. The energy dependency study for the glycine system was carried out by comparing its dose response for Cesium–137 gamma rays and 7 MeV electron beam with the dose response for Cobalt-60 gamma rays. It was found that for both the radiations viz.: Cesium-137 gamma rays and electrons, there is no significant change in dose response as compared with that for Cobalt-60.

  3. Pharmacogenetic Predictors of Methylphenidate Dose-Response in Attention-Deficit/Hyperactivity Disorder

    Froehlich, Tanya E.; Epstein, Jeffery N.; Nick, Todd G.; Melguizo Castro, Maria S.; Stein, Mark A.; Brinkman, William B.; Graham, Amanda J.; Langberg, Joshua M.; Kahn, Robert S.

    2011-01-01

    Objective: Because of significant individual variability in attention-deficit/hyperactivity disorder (ADHD) medication response, there is increasing interest in identifying genetic predictors of treatment effects. This study examined the role of four catecholamine-related candidate genes in moderating methylphenidate (MPH) dose-response. Method:…

  4. Cumulative lognormal distributions of dose-response vs. dose distributions

    A review of the author's findings over four decades will show that the lognormal probability density function can be fit to many types of positive-variate radiation measurement and response data. The cumulative lognormal plot on probability vs. logarithmic coordinate graph paper can be shown to be useful in comparing trends in exposure distributions or responses under differing conditions or experimental parameters. For variates that can take on only positive values, such a model is more natural than the 'normal' (Gaussian) model. Such modeling can also be helpful in elucidating underlying mechanisms that cause the observed data distributions. It is important, however, to differentiate between the cumulative plot of a dose distribution, in which successive percentages of data are not statistically independent, and the plots of dose-response data for which independent groups of animals or persons are irradiated or observed for selected doses or dose intervals. While independent response points can often be best fitted by appropriate regression methods, the density functions for cumulative dose or concentration distributions must be fit by particular maximum likelihood estimates from the data. Also, as indicated in the texts by D.J. Finney and by R.O. Gilbert, for example, a simple plot of such data on available probability (or probit) vs. log scale graph paper will quickly show whether an adequate representation of the data is a lognormal function. Processes that naturally generate lognormal variates are sometimes estimated by statistics that follow the lognormal straight line for a cumulative plot on a probability vs. log scale; on the other hand, sometimes the statistics of interpretation follow such a line only over a certain range. Reported examples of lognormal occupational exposure distributions include those in some facilities in which roundoff biases were removed for some years. However, for a number of exposure distributions at licensed facilities in the United States, the cumulative exposure distributions curved upward above about 1 rem, showing the pressure of the 5 rem limit in constraining the natural' distribution of occupational exposure. The United Nations Scientific Committee (UNSCEAR) adopted this type of display in some of its reports. Kumazawa and associates (1981, 1982) fitted some of these distributions by a function named 'the hybrid lognormal', which has been used to describe exposure distributions in Canada (Sont and Ashmore 1988). Examples of the suitability of the lognormal dose-response function for animal data on lethality and carcinogenesis have been reported earlier by the author. In 1998, the close representation of a lognormal fit to the excess absolute mortality from solid cancers was reported by the author for the Hiroshima-Hagasaki cohorts reported by UNSCEAR. The close representation of a two-stage model of carcinogenesis by families of lognormal functions has also been reported. In 1999, the author showed that the deviation (in the low range) from lognormality of plutonium in urine measured by fission track analysis can be explained as the result of convoluting observed lognormal human sample data with the randomly varying and also lognormally distributed tracks of the subtracted reagent blanks. The sum or difference of two lognormally distributed variates is not lognormal; yet, in the higher range of interpreted plutonium activity in urine samples - well above the range of variation of the blanks - the 'true' lognormality of excreted plutonium can be exhibited. Thus, reasons for the departure from an actual lognormal distribution of a fundamental quantity of interest can often be explained by examining the actual measurements and calculations leading to the interpreted results. A sample of these phenomena, as observed by the author, are presented and discussed in this paper. (author)

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

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

  6. FES Training in Aging: interim results show statistically significant improvements in mobility and muscle fiber size

    Helmut Kern

    2012-03-01

    Full Text Available Aging is a multifactorial process that is characterized by decline in muscle mass and performance. Several factors, including reduced exercise, poor nutrition and modified hormonal metabolism, are responsible for changes in the rates of protein synthesis and degradation that drive skeletal muscle mass reduction with a consequent decline of force generation and mobility functional performances. Seniors with normal life style were enrolled: two groups in Vienna (n=32 and two groups in Bratislava: (n=19. All subjects were healthy and declared not to have any specific physical/disease problems. The two Vienna groups of seniors exercised for 10 weeks with two different types of training (leg press at the hospital or home-based functional electrical stimulation, h-b FES. Demografic data (age, height and weight were recorded before and after the training period and before and after the training period the patients were submitted to mobility functional analyses and muscle biopsies. The mobility functional analyses were: 1. gait speed (10m test fastest speed, in m/s; 2. time which the subject needed to rise from a chair for five times (5x Chair-Rise, in s; 3. Timed Up-Go- Test, in s; 4. Stair-Test, in s; 5. isometric measurement of quadriceps force (Torque/kg, in Nm/kg; and 6. Dynamic Balance in mm. Preliminary analyses of muscle biopsies from quadriceps in some of the Vienna and Bratislava patients present morphometric results consistent with their functional behaviors. The statistically significant improvements in functional testings here reported demonstrates the effectiveness of h-b FES, and strongly support h-b FES, as a safe home-based method to improve contractility and performances of ageing muscles.

  7. Time-dose-response relationships in postoperatively irradiated patients with head and neck squamous cell carcinomas

    Background and purpose: To define the influence of the dose and time on the response to treatment in postoperatively irradiated head and neck cancer patients and to establish a good prediction of failure. Methods and materials: From January 1985 to December 1995, 214 patients with histologically proven head and neck squamous cell carcinomas were irradiated after radical surgery or single tumour resection according to surgical and histopathological findings. The total doses given ranged between 50 and 75 Gy to the primary bed tumour and between 42 and 56 Gy to the neck with fraction sizes of 1.7-2 Gy/day. The median length of the time interval between surgery and radiotherapy, time of irradiation and total treatment time were 81, 59 and 139 days, respectively. The end-point analyzed was the local-regional tumour control rate at the primary tumour bed and neck for 5 years from the beginning of radiotherapy. Univariate and multivariate analyses were used to determine predictors of failure from among the following studied variables: (i), clinical stage (T/N) of the patients; (ii), tumour grade; (iii), neck surgery; (iv), tumour margins; (v), histological tumour nodal extension; (vi), chemotherapy; (vii), normalized total dose; (viii), time interval between surgery and radiotherapy; (ix), time of irradiation; and (x), total treatment time. Results: The actuarial 5-year tumour control rate for the entire group was 72%, and 92% of the patients who achieved local control are currently alive without disease. Tumour control was inversely related to T stage (83% for T2 vs. 57% for T4) and the probability of local control within each stage was dependent on the N status (≥71% for T3-T4/N0 vs. 31-44% for T3-T4/N1-N3). Histological N status and tumour margins, but not tumour grade, impacted significantly on tumour control. When local control was analyzed as a function of the dose to the primary, a non-significant negative dose-response relationship was found. The total treatment time was a significant prognostic factor, and the time interval between surgery and irradiation proved to be an independent predictor of failure. Conclusions: Despite the absence of a statistically significant dose-response relationship, the present results suggest that postoperative irradiation treatment given to patients with head and neck squamous cell carcinomas should not be unduly prolonged, in order to minimize the amount of tumour cell proliferation. In these patients, nodal involvement, positive margins of the resected specimens and time interval between surgery and irradiation were the most important prognostic factors

  8. Evaluation of significantly modified water bodies in Vojvodina by using multivariate statistical techniques

    Vujović Svetlana R.; Kolaković Srđan R.; Bečelić-Tomin Milena R.

    2013-01-01

    This paper illustrates the utility of multivariate statistical techniques for analysis and interpretation of water quality data sets and identification of pollution sources/factors with a view to get better information about the water quality and design of monitoring network for effective management of water resources. Multivariate statistical techniques, such as factor analysis (FA)/principal component analysis (PCA) and cluster analysis (CA), were applied...

  9. Evaluation of significantly modified water bodies in Vojvodina by using multivariate statistical techniques

    Vujović Svetlana R.

    2013-01-01

    Full Text Available This paper illustrates the utility of multivariate statistical techniques for analysis and interpretation of water quality data sets and identification of pollution sources/factors with a view to get better information about the water quality and design of monitoring network for effective management of water resources. Multivariate statistical techniques, such as factor analysis (FA/principal component analysis (PCA and cluster analysis (CA, were applied for the evaluation of variations and for the interpretation of a water quality data set of the natural water bodies obtained during 2010 year of monitoring of 13 parameters at 33 different sites. FA/PCA attempts to explain the correlations between the observations in terms of the underlying factors, which are not directly observable. Factor analysis is applied to physico-chemical parameters of natural water bodies with the aim classification and data summation as well as segmentation of heterogeneous data sets into smaller homogeneous subsets. Factor loadings were categorized as strong and moderate corresponding to the absolute loading values of >0.75, 0.75-0.50, respectively. Four principal factors were obtained with Eigenvalues >1 summing more than 78 % of the total variance in the water data sets, which is adequate to give good prior information regarding data structure. Each factor that is significantly related to specific variables represents a different dimension of water quality. The first factor F1 accounting for 28 % of the total variance and represents the hydrochemical dimension of water quality. The second factor F2 accounting for 18% of the total variance and may be taken factor of water eutrophication. The third factor F3 accounting 17 % of the total variance and represents the influence of point sources of pollution on water quality. The fourth factor F4 accounting 13 % of the total variance and may be taken as an ecological dimension of water quality. Cluster analysis (CA is an objective technique to identify natural groupings in the set of data. CA divides a large number of objects into smaller number of homogenous groups on the basis of their correlation structure. CA combines the data objects together to form the natural groups involving objects with similar cluster properties and separates the objects with different cluster properties. CA showed similarities and dissimilarities among the sampling sites and explain the observed clustering in terms of affected conditions. Using FA/PCA and CA have been identified water bodies that are under the highest pressure. With regard to the factors identified water bodies are: for factor F1 (Plazović, Bosut, Studva, Zlatica, Stari Begej, Krivaja, for factor F2 (Krivaja, Kereš, for factor F3 (Studva, Zlatica, Tamiš, Krivaja i Kereš and for factor F4 (Studva, Zlatica, Krivaja, Kereš.

  10. Accelerator driven reactors, - the significance of the energy distribution of spallation neutrons on the neutron statistics

    In order to make correct predictions of the second moment of statistical nuclear variables, such as the number of fissions and the number of thermalized neutrons, the dependence of the energy distribution of the source particles on their number should be considered. It has been pointed out recently that neglecting this number dependence in accelerator driven systems might result in bad estimates of the second moment, and this paper contains qualitative and quantitative estimates of the size of these efforts. We walk towards the requested results in two steps. First, models of the number dependent energy distributions of the neutrons that are ejected in the spallation reactions are constructed, both by simple assumptions and by extracting energy distributions of spallation neutrons from a high-energy particle transport code. Then, the second moment of nuclear variables in a sub-critical reactor, into which spallation neutrons are injected, is calculated. The results from second moment calculations using number dependent energy distributions for the source neutrons are compared to those where only the average energy distribution is used. Two physical models are employed to simulate the neutron transport in the reactor. One is analytical, treating only slowing down of neutrons by elastic scattering in the core material. For this model, equations are written down and solved for the second moment of thermalized neutrons that include the distribution of energy of the spallation neutrons. The other model utilizes Monte Carlo methods for tracking the source neutrons as they travel inside the reactor material. Fast and thermal fission reactions are considered, as well as neutron capture and elastic scattering, and the second moment of the number of fissions, the number of neutrons that leaked out of the system, etc. are calculated. Both models use a cylindrical core with a homogenous mixture of core material. Our results indicate that the number dependence of the energy distribution of the spallation neutrons leads to second moments that differ significantly from the ones calculated with the average energy distribution only. With the most realistic model of the energy distributions, the second moment of the number of fissions was underestimated with 12-16%

  11. Bounding the total-dose response of modern bipolar transistors

    The excess base current in an irradiated BJT increases super-linearly with total dose at low-total-dose levels. In this regime, the excess base current depends on the particular charge-trapping properties of the oxide that covers the emitter-base junction. The device response is dose-rate-, irradiation-bias-, and technology-dependent in this regime. However, once a critical amount of charge has accumulated in the oxide, the excess base current saturates at a value that is independent of how the charge accumulated. This saturated excess base current depends on the device layout, bulk lifetime in the base region, and the measurement bias. In addition to providing important insight into the physics of bipolar-transistor total-dose response, these results have significant circuit-level implications. For example, in some circuits, the transistor gain that corresponds to the saturated excess base current is sufficient to allow reliable circuit operation. For cases in which the saturated value of current gain is acceptable, and where other circuit elements permit such over-testing, this can greatly simplify hardness assurance for space applications

  12. Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy

    Purpose: In this era of dose escalation, the benefit of higher radiation doses for low-risk prostate cancer remains controversial. For intermediate-risk patients, the data suggest a benefit from higher doses. However, the quantitative characterization of the benefit for these patients is scarce. We investigated the radiation dose-response relation of tumor control probability in low-risk and intermediate-risk prostate cancer patients treated with radiotherapy alone. We also investigated the differences in the dose-response characteristics using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition vs. an alternative biochemical failure definition. Methods and materials: This study included 235 low-risk and 387 intermediate-risk prostate cancer patients treated with external beam radiotherapy without hormonal treatment between 1987 and 1998. The low-risk patients had 1992 American Joint Committee on Cancer Stage T2a or less disease as determined by digital rectal examination, prostate-specific antigen (PSA) levels of ≤10 ng/mL, and biopsy Gleason scores of ≤6. The intermediate-risk patients had one or more of the following: Stage T2b-c, PSA level of ≤20 ng/mL but >10 ng/mL, and/or Gleason score of 7, without any of the following high-risk features: Stage T3 or greater, PSA >20 ng/mL, or Gleason score ≥8. The logistic models were fitted to the data at varying points after treatment, and the dose-response parameters were estimated. We used two biochemical failure definitions. The ASTRO PSA failure was defined as three consecutive PSA rises, with the time to failure backdated to the mid-point between the nadir and the first rise. The second biochemical failure definition used was a PSA rise of ≥2 ng/mL above the current PSA nadir (CN + 2). The failure date was defined as the time at which the event occurred. Local, nodal, and distant relapses and the use of salvage hormonal therapy were also failures. Results: On the basis of the ASTRO definition, at 5 years after radiotherapy, the dose required for 50% tumor control (TCD50) for low-risk patients was 57.3 Gy (95% confidence interval [CI], 47.6-67.0). The γ50 was 1.4 (95% CI, -0.1 to 2.9) around 57 Gy. A statistically significant dose-response relation was found using the ASTRO definition. However, no dose-response relation was noted using the CN + 2 definition for these low-risk patients. For the intermediate-risk patients, using the ASTRO definition, the TCD50 was 67.5 Gy (95% CI, 65.5-69.5) Gy and the γ50 was 2.2 (95% CI, 1.1-3.2) around TCD50. Using the CN + 2 definition, the TCD50 was 57.8 Gy (95% CI, 49.8-65.9) and the γ50 was 1.4 (95% CI, 0.2-2.5). Recursive partitioning analysis identified two subgroups within the low-risk group, as well as the intermediate-risk group: PSA level 78 Gy for these patients. A dose-response relation was noted for the intermediate-risk patients using either the CN + 2 or ASTRO definition. Most of the benefit from the higher doses also derived from the intermediate-risk patients with higher PSA levels. Some room for improvement appears to exist with additional dose increases in this group

  13. Study on relationship of dose-response using the ultraviolet plus Giemsa technology

    To detect the rate of lymphocyte Chromosome aberration by conventional chromosome production and ultraviolet plus Giemsa technology (UpG), after the human peripheral blood irradiated by 60Co γ-ray, and the dose-response relationship of the rate of chromosome aberration was discussed. The feasibility of UpG applied in dose estimation was discussed. The results show that the rate of chromosome aberration is closely related to dose (P<0.05). Compared the conventional method to UpG, the result of UpG is higher, and a extremely statistically difference was observed between two methods (P<0.05). These results show that a well relationship of dose-response can be established by UpG, and accurate and sensitive. (authors)

  14. A methodology for testing for statistically significant differences between fully 3D PET reconstruction algorithms

    We present a practical methodology for evaluating 3D PET reconstruction methods. It includes generation of random samples from a statistically described ensemble of 3D images resembling those to which PET would be applied in a medical situation, generation of corresponding projection data with noise and detector point spread function simulating those of a 3D PET scanner, assignment of figures of merit appropriate for the intended medical applications, optimization of the reconstruction algorithms on a training set of data, and statistical testing of the validity of hypotheses that say that two reconstruction algorithms perform equally well (from the point of view of a particular figure of merit) as compared to the alternative hypotheses that say that one of the algorithms outperforms the other. Although the methodology was developed with the 3D PET in mind, it can be used, with minor changes, for other 3D data collection methods, such as fully 3D CT or SPECT. (Author)

  15. Statistically significant contrasts between EMG waveforms revealed using wavelet-based functional ANOVA

    McKay, J. Lucas; Welch, Torrence D. J.; Vidakovic, Brani; Ting, Lena H.

    2012-01-01

    We developed wavelet-based functional ANOVA (wfANOVA) as a novel approach for comparing neurophysiological signals that are functions of time. Temporal resolution is often sacrificed by analyzing such data in large time bins, increasing statistical power by reducing the number of comparisons. We performed ANOVA in the wavelet domain because differences between curves tend to be represented by a few temporally localized wavelets, which we transformed back to the time domain for visualization. ...

  16. Optimal experimental designs for dose-response studies with continuous endpoints.

    Holland-Letz, Tim; Kopp-Schneider, Annette

    2015-11-01

    In most areas of clinical and preclinical research, the required sample size determines the costs and effort for any project, and thus, optimizing sample size is of primary importance. An experimental design of dose-response studies is determined by the number and choice of dose levels as well as the allocation of sample size to each level. The experimental design of toxicological studies tends to be motivated by convention. Statistical optimal design theory, however, allows the setting of experimental conditions (dose levels, measurement times, etc.) in a way which minimizes the number of required measurements and subjects to obtain the desired precision of the results. While the general theory is well established, the mathematical complexity of the problem so far prevents widespread use of these techniques in practical studies. The paper explains the concepts of statistical optimal design theory with a minimum of mathematical terminology and uses these concepts to generate concrete usable D-optimal experimental designs for dose-response studies on the basis of three common dose-response functions in toxicology: log-logistic, log-normal and Weibull functions with four parameters each. The resulting designs usually require control plus only three dose levels and are quite intuitively plausible. The optimal designs are compared to traditional designs such as the typical setup of cytotoxicity studies for 96-well plates. As the optimal design depends on prior estimates of the dose-response function parameters, it is shown what loss of efficiency occurs if the parameters for design determination are misspecified, and how Bayes optimal designs can improve the situation. PMID:25155192

  17. Statistically significant performance results of a mine detector and fusion algorithm from an x-band high-resolution SAR

    Williams, Arnold C.; Pachowicz, Peter W.

    2004-09-01

    Current mine detection research indicates that no single sensor or single look from a sensor will detect mines/minefields in a real-time manner at a performance level suitable for a forward maneuver unit. Hence, the integrated development of detectors and fusion algorithms are of primary importance. A problem in this development process has been the evaluation of these algorithms with relatively small data sets, leading to anecdotal and frequently over trained results. These anecdotal results are often unreliable and conflicting among various sensors and algorithms. Consequently, the physical phenomena that ought to be exploited and the performance benefits of this exploitation are often ambiguous. The Army RDECOM CERDEC Night Vision Laboratory and Electron Sensors Directorate has collected large amounts of multisensor data such that statistically significant evaluations of detection and fusion algorithms can be obtained. Even with these large data sets care must be taken in algorithm design and data processing to achieve statistically significant performance results for combined detectors and fusion algorithms. This paper discusses statistically significant detection and combined multilook fusion results for the Ellipse Detector (ED) and the Piecewise Level Fusion Algorithm (PLFA). These statistically significant performance results are characterized by ROC curves that have been obtained through processing this multilook data for the high resolution SAR data of the Veridian X-Band radar. We discuss the implications of these results on mine detection and the importance of statistical significance, sample size, ground truth, and algorithm design in performance evaluation.

  18. Dose-response relationship with radiotherapy: an evidence?

    The dose-response relationship is a fundamental basis of radiobiology. Despite many clinical data, difficulties remain to demonstrate a relation between dose and local control: relative role of treatment associated with radiation therapy (surgery, chemotherapy, hormonal therapy), tumor heterogeneity, few prospective randomized studies, uncertainty of local control assessment. Three different situations are discussed: tumors with high local control probabilities for which dose effect is demonstrated by randomized studies (breast cancer) or sound retrospective data (soft tissues sarcomas), tumors with intermediate local control probabilities for which dose effect seems to be important according to retrospective studies and ongoing or published phase III trials (prostate cancer), tumors with low local control probabilities for which dose effect appears to be modest beyond standard doses, and inferior to the benefit of concurrent chemotherapy (lung and oesophageal cancer). For head and neck tumors, the dose-response relationship has been explored through hyperfractionation and accelerated radiation therapy and a dose effect has been demonstrated but must be compared to the benefit of concurrent chemotherapy. Last but not least, the development of conformal radiotherapy allow the exploration of the dose response relationship for tumors such as hepatocellular carcinomas traditionally excluded from the field of conventional radiation therapy. In conclusion, the dose-response relationship remains a sound basis of radiation therapy for many tumors and is a parameter to take into account for further randomized studies. (author)

  19. Alcohol and cirrhosis: dose--response or threshold effect?

    Kamper-Jørgensen, Mads; Grønbaek, Morten; Tolstrup, Janne; Becker, Ulrik

    2004-01-01

    of death from alcoholic cirrhosis when exceeding an average daily number of five drinks (>60 g/alcohol) in neither men nor women. CONCLUSIONS: The results indicate that alcohol has a threshold effect rather than a dose-response effect on mortality from alcoholic cirrhosis in alcohol misusers....

  20. Characteristics of dose-response relationships for late radiation effects

    The dose-response characteristics were analysed for late skin telangiectasia in patients for 1, 2 and 5 fractions/week and 3-4 dose levels per schedule. Altogether 286 fields were used. Skin telangiectasia was scored on an arbitrary scale and dose-response analysis was performed at 10 year's follow-up for various degrees of telangiectasia, score >=1 to>=4. The following parameters were determined for each schedule and the equivalent single dose-response curves for each endpoint using probit analysis: the ED50, the absolute steepness, measured as the probit width, K, the relative steepness, K/ED50, and the normalised effect gradient, γ50. The inverse radiosensitivity, D0eff or D0, was estimated using the Poisson and LQ-models for tissue response. The α/β value was found to be independent of the degree of telangiectasia used as endpoint. The absolute steepness of the dose-incidence curve increased with increasing dose per fraction when the dose-response curve was generated by a fixed dose per fraction, and was less than if generated by a fixed number of fractions. The relative steepness increased with higher degree of damage. D0eff decreased with increasing dose per fraction, and also with higher degree of telangiectasia. The highest steepness determined for telangiectasia score >=4 (partially confluent or more) at 10 years correspond to K=0.8 Gy, K/ED50=5 percent, γ50=7 and D0=0.7 Gy. The dose-response characteristics found for late skin telangiectasia score >=2 to >=4 were consistent with those determined for necrosis and fatal complications 5 years after radiotherapy to head and neck tumours in our department. (author). 23 refs.; 1 fig.; 9 tabs

  1. Radiation Dose-Response Relationships and Risk Assessment

    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. The chapter ends with conclusions and recommendations.

  2. Statistical significance of hair analysis of clenbuterol to discriminate therapeutic use from contamination.

    Krumbholz, Aniko; Anielski, Patricia; Gfrerer, Lena; Graw, Matthias; Geyer, Hans; Schänzer, Wilhelm; Dvorak, Jiri; Thieme, Detlef

    2014-01-01

    Clenbuterol is a well-established β2-agonist, which is prohibited in sports and strictly regulated for use in the livestock industry. During the last few years clenbuterol-positive results in doping controls and in samples from residents or travellers from a high-risk country were suspected to be related the illegal use of clenbuterol for fattening. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to detect low clenbuterol residues in hair with a detection limit of 0.02 pg/mg. A sub-therapeutic application study and a field study with volunteers, who have a high risk of contamination, were performed. For the application study, a total dosage of 30 µg clenbuterol was applied to 20 healthy volunteers on 5 subsequent days. One month after the beginning of the application, clenbuterol was detected in the proximal hair segment (0-1 cm) in concentrations between 0.43 and 4.76 pg/mg. For the second part, samples of 66 Mexican soccer players were analyzed. In 89% of these volunteers, clenbuterol was detectable in their hair at concentrations between 0.02 and 1.90 pg/mg. A comparison of both parts showed no statistical difference between sub-therapeutic application and contamination. In contrast, discrimination to a typical abuse of clenbuterol is apparently possible. Due to these findings results of real doping control samples can be evaluated. PMID:25388545

  3. A New Method for Assessing the Statistical Significance in the Differential Functioning of Items and Tests (DFIT) Framework

    Oshima, T. C.; Raju, Nambury S.; Nanda, Alice O.

    2006-01-01

    A new item parameter replication method is proposed for assessing the statistical significance of the noncompensatory differential item functioning (NCDIF) index associated with the differential functioning of items and tests framework. In this new method, a cutoff score for each item is determined by obtaining a (1-alpha ) percentile rank score

  4. Improved Monte Carlo estimation of statistical significance for tests of trend in rates or proportions

    Asymptotic significance levels of tests for monotone trends in rates or proportions can be profoundly anticonservative when applied to small numbers of events and when distributions of exposure to risk are highly skewed. In such cases Monte Carlo (MC) estimation of observed levels of significance (''p-values'') can be very useful. We describe a simple technique of importance sampling (IS) which can greatly improve the efficiency of MC estimation in this setting. Implementation of the IS technique is described, and the variance of the IS estimator is derived. It is shown that, in many situations likely to occur in practice, the variance is substantially less than that of a simple MC estimator proposed earlier. Generalizations beyond the case of survival data without ties are described, and the use of IS is illustrated with data regarding mortality among atomic bomb survivors. (author)

  5. The statistical interpretation of pilot trials: should significance thresholds be reconsidered?

    Lee, E C; Whitehead, A. L.; Jacques, R.M.; Julious, S A

    2014-01-01

    Background In an evaluation of a new health technology, a pilot trial may be undertaken prior to a trial that makes a definitive assessment of benefit. The objective of pilot studies is to provide sufficient evidence that a larger definitive trial can be undertaken and, at times, to provide a preliminary assessment of benefit. Methods We describe significance thresholds, confidence intervals and surrogate markers in the context of pilot studies and how Bayesian methods can be used in pilot tr...

  6. Similarity criterion analysis of dose-response curves in biological assay and radioimmunoassay of hormones

    The difficulties involved in the control of biological and radioimmunological assay systems, and in the maintenance of standard, as well as, the usual heterogeneity of assayed samples require some evidence of similarity between the dose-response curves obtained with the standard and the sample. Nowadays the parallelism test is used to provide such evidence. However, some indications of non-normal errors distribution, such as the presence of out layers, render the parallelism test both conceptually implausible and statistically inefficient. In such a manner we suggest the non-parametric 'frequencial' test as a more sounding option. (author)

  7. Dose response in prostate cancer with 8-12 years' follow-up

    Purpose: This communication reports the long-term results of the original group of prostate cancer patients who participated in the first prospective Fox Chase Cancer Center radiation dose escalation study for which 8-12 years of follow-up is now available. Methods and Materials: Between March 1, 1989 and October 31, 1992, 232 patients with clinically localized prostate cancer received three-dimensional conformal radiotherapy only at Fox Chase Cancer Center in a prospective dose-escalation study. Of these patients, 229 were assessable. The 8-, 10-, and 12-year actuarial rates of biochemical control (biochemically no evidence of disease [bNED]), freedom from distant metastasis (FDM), and morbidity were calculated. The Cox proportional hazards model was used to assess multivariately the predictors of bNED control and FDM, including pretreatment prostate-specific antigen (PSA) level (continuous), tumor stage (T1/T2a vs. T2b/T3), Gleason score (2-6 vs. 7-10), and radiation dose (continuous). The median total dose for all patients was 74 Gy (range 67-81). The median follow-up for living patients was 110 months (range 89-147). bNED control was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Results: The actuarial bNED control for all patients included in this series was 55% at 5 years, 48% at 10 years, and 48% at 12 years. Patients with pretreatment PSA levels of 10-20 ng/mL had statistically significant differences (19% vs. 31% vs. 84%, p=0.0003) in bNED control when stratified by dose (75.6 Gy, respectively) on univariate analysis. For the 229 patients with follow-up, 124 (54%) were clinically and biochemically without evidence of disease. Sixty-nine patients were alive at the time of last follow-up, and 55 patients were dead of intercurrent disease. On multivariate analysis, radiation dose was a statistically significant predictor of bNED control for all patients and for unfavorable patients with a pretreatment PSA 20 ng/mL, although large numbers of patients are required to demonstrate a difference. The radiation dose, Gleason score, and palpation T stage were significant predictors for the entire patient set, as well as for those with pretreatment PSA levels between 10 and 20 ng/mL. The FDM rate for all patients included in this series was 89%, 83%, and 83% at 5, 10, and 12 years, respectively. For patients with pretreatment PSA levels 9 years of median follow-up confirm the existence of a dose response for both bNED control and FDM. The dose response in prostate cancer is real, and the absence of biochemical recurrence after 8 years demonstrates the lack of late failure and suggests cure

  8. Statistical significance of the relationship between X-ray luminosity and variability timescale in active galactic nuclei; and reply

    The paper examines the work of Barr and Mushotzky [Nature 320, 421-3(1985)] on the relationship between x-ray luminosity and the timescale of x-ray variability for seyfert galaxies and quasars, with respect to the method of analysis and its statistical significance. Criticisms are given of the least squares fitting procedure employed, and a more general approach is recommended by the present authors. Application of this generalized fit to the same data set led to results significantly different from that found by Barr and Mushotzsky, and more acceptable in terms of goodness of the fit. When judged on the basis of their statistical significance, both results are too weak to be conclusive, and physical conclusions drawn from them are debatable. (UK)

  9. Cancer dose-response analysis of the radium dial workers

    Bone (46 deaths) and head (19 deaths) cancers have been analyzed using Cox proportional hazard models with cumulative dose treated as a time dependent covariate. For bone cancers, the best models separate the 226Ra and 228Ra isotopes and use a single linear dose-response function with a threshold dose at about 9Gy. Covariates for age-at-first exposure and a tumour latency of 5 years were also important. Head carcinomas depend only on 226Ra, and the best-fitted dose-response function is linear with a threshold at about 5 Gy. For head carcinomas, the inclusion of covariates for age-at-first exposure and tumour latency into the model was not necessary. (orig.)

  10. Model Averaging Software for Dichotomous Dose Response Risk Estimation

    Matthew W. Wheeler

    2008-02-01

    Full Text Available Model averaging has been shown to be a useful method for incorporating model uncertainty in quantitative risk estimation. In certain circumstances this technique is computationally complex, requiring sophisticated software to carry out the computation. We introduce software that implements model averaging for risk assessment based upon dichotomous dose-response data. This software, which we call Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD, fits the quantal response models, which are also used in the US Environmental Protection Agency benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates. The software fulfills a need for risk assessors, allowing them to go beyond one single model in their risk assessments based on quantal data by focusing on a set of models that describes the experimental data.

  11. Myths and Misconceptions Revisited - What are the (Statistically Significant) methods to prevent employee injuries

    A company's overall safety program becomes an important consideration to continue performing work and for procuring future contract awards. When injuries or accidents occur, the employer ultimately loses on two counts - increased medical costs and employee absences. This paper summarizes the human and organizational components that contributed to successful safety programs implemented by WESKEM, LLC's Environmental, Safety, and Health Departments located in Paducah, Kentucky, and Oak Ridge, Tennessee. The philosophy of 'safety, compliance, and then production' and programmatic components implemented at the start of the contracts were qualitatively identified as contributing factors resulting in a significant accumulation of safe work hours and an Experience Modification Rate (EMR) of <1.0. Furthermore, a study by the Associated General Contractors of America quantitatively validated components, already found in the WESKEM, LLC programs, as contributing factors to prevent employee accidents and injuries. Therefore, an investment in the human and organizational components now can pay dividends later by reducing the EMR, which is the key to reducing Workers' Compensation premiums. Also, knowing your employees' demographics and taking an active approach to evaluate and prevent fatigue may help employees balance work and non-work responsibilities. In turn, this approach can assist employers in maintaining a healthy and productive workforce. For these reasons, it is essential that safety needs be considered as the starting point when performing work. (authors)

  12. Statistics

    Hayslett, H T

    1991-01-01

    Statistics covers the basic principles of Statistics. The book starts by tackling the importance and the two kinds of statistics; the presentation of sample data; the definition, illustration and explanation of several measures of location; and the measures of variation. The text then discusses elementary probability, the normal distribution and the normal approximation to the binomial. Testing of statistical hypotheses and tests of hypotheses about the theoretical proportion of successes in a binomial population and about the theoretical mean of a normal population are explained. The text the

  13. Dose-response relationship between sleep duration and human psychomotor vigilance and subjective alertness

    Jewett, M. E.; Dijk, D. J.; Kronauer, R. E.; Dinges, D. F.

    1999-01-01

    Although it has been well documented that sleep is required for human performance and alertness to recover from low levels after prolonged periods of wakefulness, it remains unclear whether they increase in a linear or asymptotic manner during sleep. It has been postulated that there is a relation between the rate of improvement in neurobehavioral functioning and rate of decline of slow-wave sleep and/or slow-wave activity (SWS/SWA) during sleep, but this has not been verified. Thus, a cross-study comparison was conducted in which dose-response curves (DRCs) were constructed for Stanford Sleepiness Scale (SSS) and Psychomotor Vigilance Task (PVT) tests taken at 1000 hours by subjects who had been allowed to sleep 0 hours, 2 hours, 5 hours or 8 hours the previous night. We found that the DRCs to each PVT metric improved in a saturating exponential manner, with recovery rates that were similar [time constant (T) approximately 2.14 hours] for all the metrics. This recovery rate was slightly faster than, though not statistically significantly different from, the reported rate of SWS/SWA decline (T approximately 2.7 hours). The DRC to the SSS improved much more slowly than psychomotor vigilance, so that it could be fit equally well by a linear function (slope = -0.26) or a saturating exponential function (T = 9.09 hours). We conclude that although SWS/SWA, subjective alertness, and a wide variety of psychomotor vigilance metrics may all change asymptotically during sleep, it remains to be determined whether the underlying physiologic processes governing their expression are different.

  14. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

    2015-02-01

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

  15. Diethylene glycol-induced toxicities show marked threshold dose response in rats

    Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury

  16. Investigating quartz optically stimulated luminescence dose-response curves at high doses

    Despite the general expectation that optically stimulated luminescence (OSL) growth should be described by a simple saturating exponential function, an additional high dose component is often reported in the dose response of quartz. Although often reported as linear, it appears that this response is the early expression of a second saturating exponential. While some studies using equivalent doses that fall in this high dose region have produced ages that correlate well with independent dating, others report that it results in unreliable age determinations. Two fine grain sedimentary quartz samples that display such a response were used to investigate the origin of this additional high dose component: three experiments were conducted to examine their dose-response up to >1000 Gy. The high dose rates provided by laboratory irradiation were found not to induce a sensitivity change in the response to a subsequent test dose, with the latter not being significantly different from those generated following naturally acquired doses. The relative percentage contributions of the fast and medium OSL components remained fixed throughout the dose-response curve, suggesting that the electron traps that give rise to the initial OSL do not change with dose. An attempt was made to investigate a change in luminescence centre recombination probability by monitoring the depletion of the '325 oC' thermoluminescence (TL) during the optical stimulation that would result in depletion of the OSL signal. The emissions measured through both the conventional ultraviolet (UV), and a longer wavelength violet/blue (VB) window, displayed similar relative growth with dose, although it was not possible to resolve the origin of the VB emissions. No evidence was found to indicate whether the additional component at high doses occurs naturally or is a product of laboratory treatment. However, it appears that these samples display an increased sensitivity of quartz OSL to high doses that is not recorded by the sensitivity to a subsequent test dose, and which results in a change in the sensitivity-corrected dose-response curve.

  17. Dose-response relationship for light intensity and ocular and electroencephalographic correlates of human alertness

    Cajochen, C.; Zeitzer, J. M.; Czeisler, C. A.; Dijk, D. J.

    2000-01-01

    Light can elicit both circadian and acute physiological responses in humans. In a dose response protocol men and women were exposed to illuminances ranging from 3 to 9100 lux for 6.5 h during the early biological night after they had been exposed to Light exerted an acute alerting response as assessed by a reduction in the incidence of slow-eye movements, a reduction of EEG activity in the theta-alpha frequencies (power density in the 5-9 Hz range) as well as a reduction in self-reported sleepiness. This alerting response was positively correlated with the degree of melatonin suppression by light. In accordance with the dose response function for circadian resetting and melatonin suppression, the responses of all three indices of alertness to variations in illuminance were consistent with a logistic dose response curve. Half of the maximum alerting response to bright light of 9100 lux was obtained with room light of approximately 100 lux. This sensitivity to light indicates that variations in illuminance within the range of typical, ambient, room light (90-180 lux) can have a significant impact on subjective alertness and its electrophysiologic concomitants in humans during the early biological night.

  18. Determination of dose- response relationship in cultured human by lymphocytes for biological dosimetry

    Background: lymphocyte- dicentric assay is the most generally accepted method for biological dosimetry of overexposed individuals. In this study, the frequency of unstable chromosome aberration in blood lymphocytes was used to estimate radiation dose received by individuals. Evaluation of dose using a calibration curve produced elsewhere may have a significant uncertainty; therefore, experiments were performed to produce a dose-response curve using an established protocol of international atomic energy agency. Materials and methods: lymphocytes in whole peripheral blood obtained from healthy individuals, were exposed to various doses of gamma radiation (0.25-4 Gy). Then after 1 hour of incubation in 37digC , were cultured in complete RPMI-1640 medium. 500 mitoses were analyzed for the presence or absence of unstable chromosomal aberrations for each radiation dose after the standard metaphase preparation and staining slides. Results and conclusion: Intercellular distribution chromosomes at each radiation dose has been used to contrast a dose- response curve. It seems that dose-effect relationship follows with the linear-quadratic model. There is a good agreement between our dose- response curves with similar published studies by other laboratories

  19. Temporal analysis of a dose-response relationship: leukemia mortality in atomic bomb survivors

    A data analysis that incorporates time dependencies is demonstrated for the dose response of leukemia mortality in the atomic bomb survivors. The time dependencies are initially left unspecified and the data on leukemia mortality, up to the end of 1978, are used to infer them. Several findings based on T65 revised doses (T65DR) are obtained. First, it is shown that the fits to the data of time-independent L (linear in ? dose)-Q (quadratic in ? dose)-L (linear in nuetron dose, L-L, and Q-L dose-response models are significantly improved by using the corresponding time-dependent dose-response models. Second, it is shown that the increased risk of leukemia mortality due to ? irradiation decreases in time while the increased risk due to neutron exposure decreases more slowly, if at all, in time. Consequently, relative biological effectiveness (RBE) of neutrons is shown to increase in time and the current definition of RBE as a time-dependent quantity is therefore challenged. It is demonstrated with time-dependent models that the L-L model has a poor fit to the data for the first 7 years of study, but has an adequate fit for the remaining 21 years. In contrast the Q-L model has an adequate fit for the entire follow-up period

  20. Statistics

    Links to sources of cancer-related statistics, including the Surveillance, Epidemiology and End Results (SEER) Program, SEER-Medicare datasets, cancer survivor prevalence data, and the Cancer Trends Progress Report.

  1. Dose responses of two pea lines to ultraviolet-B radiation (280-315 nm)

    UV-B dose responses of two lines of pea were quantified at 2.3, 4.6, 6.9 and 9.2 kJ m?2 day?1 UV-B (weighted according to Caldwell's generalised plant action spectrum) in controlled environments providing near-field doses of photosynthetic radiation. Increasing UV-B significantly increased UV-B absorbing compounds in both lines. In the UV-B sensitive line, JI1389, increasing UV-B significantly inhibited most aspects of plant morphology and biomass. In the more UV-B-tolerant line, Scout, increasing UV-B significantly reduced foliage area but had no effect on above-ground biomass, although root biomass was significantly increased. Reduced plant height in JI1389 was caused by shorter internodes, in turn due to reduced cell number but not cell length. UV-B had no significant effects on photosynthesis in either line. Significant dose responses were linear for the growth of the main stem in JI1389 but remaining significant dose responses were better fitted by quadratics with maximum UV-B effects occurring in the range 57 kJ m?2 day?1 PAS300, due to stimulation of branch growth at the highest dose. However, growth stimulation by UV-B was confined to PAS300 doses which at temperate latitudes would result only from rather extreme ozone depletions. We conclude that investigations using relatively low UV-B doses, rather than those well above the current maximum, may be the best approach to both understanding of the fundamental mechanisms of plant responses to UV-B and quantifying the magnitude of responses to stratospheric ozone depletion. (author)

  2. Youth suicide attempts and the dose-response relationship to parental risk factors: a population-based study

    Christiansen, E; Goldney, R D; Beautrai, A L; Agerbo, E

    2011-01-01

    BACKGROUND: There is a lack of specific knowledge about the dose-response effect of multiple parental risk factors for suicide attempts among children and adolescents. The aim of this study was to determine the dose-response effect of multiple parental risk factors on an offspring's risk for...... illness and low level of income were all significant independent risk factors for offspring's suicide attempts. CONCLUSIONS: Knowledge of the effect of multiple risk factors on the likelihood of suicide attempts in children and adolescents is important for risk assessment. Dose-response effects of...... multiple parental risk factors are multiplicative, but it is rare for children and adolescents to be exposed to multiple parental risk factors simultaneously. Nevertheless, they should be considered along with the offspring's own multiple risk factors in determining the overall risk of a suicide attempt...

  3. Dose Response of Alanine Detectors Irradiated with Carbon Ion Beams

    Herrmann, Rochus; Jäkel, Oliver; Palmans, Hugo; Sharpe, Peter; Bassler, Niels

    2011-01-01

    Purpose: The dose response of the alanine detector shows a dependence on particle energy and type, when irradiated with ion beams. The purpose of this study is to investigate the response behaviour of the alanine detector in clinical carbon ion beams and compare the results with model predictions....... Methods: Alanine detectors have been irradiated with carbon ions with an energy range of 89-400 MeV/u. The relative effectiveness of alanine has been measured in this regime. Pristine and spread out Bragg peak depth-dose curves have been measured with alanine dosimeters. The track-structure based alanine...... detector geometry implemented in the Monte Carlo simulations....

  4. Anti-irritants I: Dose-response in acute irritation

    Andersen, Flemming; Hedegaard, Kathryn; Petersen, Thomas Kongstad; Bindslev-Jensen, Carsten; Fullerton, Ann; Andersen, Klaus Ejner

    2006-01-01

    induced acute irritation in healthy volunteers. Each AI was used in 3 concentrations. Acute irritation was induced by occlusive tests with 1% sodium lauryl sulfate and 20% nonanoic acid in N-propanol. The irritant reactions were treated twice daily with AI-containing formulations from the time of removal...... of the patches. Evaluation of skin irritation and efficacy of treatments were performed daily for 4 days using clinical scoring, evaporimetry (transepidermal water loss), hydration measurement and colourimetry. Only glycerol showed dose-response and effects potentially better than no treatment. There...

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

    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 LD05, LD10, LD25, LD50, LD75, LD90, and LD95, for dose rates ranging from 1 to 50 R/min. 6 refs., 5 tabs

  6. Statistics

    For the years 2004 and 2005 the figures shown in the tables of Energy Review are partly preliminary. The annual statistics published in Energy Review are presented in more detail in a publication called Energy Statistics that comes out yearly. Energy Statistics also includes historical time-series over a longer period of time (see e.g. Energy Statistics, Statistics Finland, Helsinki 2004.) The applied energy units and conversion coefficients are shown in the back cover of the Review. Explanatory notes to the statistical tables can be found after tables and figures. The figures presents: Changes in GDP, energy consumption and electricity consumption, Carbon dioxide emissions from fossile fuels use, Coal consumption, Consumption of natural gas, Peat consumption, Domestic oil deliveries, Import prices of oil, Consumer prices of principal oil products, Fuel prices in heat production, Fuel prices in electricity production, Price of electricity by type of consumer, Average monthly spot prices at the Nord pool power exchange, Total energy consumption by source and CO2-emissions, Supplies and total consumption of electricity GWh, Energy imports by country of origin in January-June 2003, Energy exports by recipient country in January-June 2003, Consumer prices of liquid fuels, Consumer prices of hard coal, natural gas and indigenous fuels, Price of natural gas by type of consumer, Price of electricity by type of consumer, Price of district heating by type of consumer, Excise taxes, value added taxes and fiscal charges and fees included in consumer prices of some energy sources and Energy taxes, precautionary stock fees and oil pollution fees

  7. 2-D radiation therapy dosimetry using EPIDs: Dose response variation between 3 siemens electronic portal imaging devices (EPIDs)

    Prerequisite for any new clinical dosimeter is a detailed understanding of the detector’s dose response behavior. The purpose of the present study was to investigate the level of variability in dose response characteristics of 3 siemens EPIDs for both 6 and 18 MV photons. Dose response tests for linearity, field size, short- and long-term reproducibilities, ghosting effects and dose rate dependence were undertaken for three different model Siemens EPIDs on three dosimetrically matched linear accelerators. All three EPIDs showed a linear dose response above 20 monitor units. The pixel sensitivity for EPID2 and EPID3 agreed to within 0.5%. EPID1 was 6.3% (6 MV) and 2.3% (18 MV) greater than for EPID2 and EPID3. The field size response and dose rate response agreed within 1% for all three EPIDs. The short-term and long-term reproducibilities for all EPIDs were within 0.5% and 1% respectively. The maximum increase in relative response due to the ghosting effect was 0.5%. The off-axis profiles from uncorrected gain files agreed to within 2% for EPID2 and EPID3 at 6 MV and 18 MV respectively. The off-axis profiles for EPID1 had more pronounced horns. The different dose response behavior of EPID1 is due to a thicker phosphor scintillator compared to EPID2 and EPID3. EPID1 was significantly more sensitive to dose and energy variations and would require separate calibration data for EPID dosimetry. EPIDs with the same phosphor had no significant difference in dose response. Differences in EPID/phosphor design must be considered when commissioning EPIDs for clinical dosimetry.

  8. Dose response of selected solid state detectors in applied homogeneous transverse and longitudinal magnetic fields

    Purpose: MR-Linac devices under development worldwide will require standard calibration, commissioning, and quality assurance. Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is therefore evaluated in varying transverse and longitudinal magnetic fields for this purpose. Methods: The Monte Carlo code PENELOPE was used to model irradiation of a PTW 60003 diamond detector and IBA PFD diode detector in the presence of a magnetic field. The field itself was varied in strength, and oriented both transversely and longitudinally with respect to the incident photon beam. The long axis of the detectors was oriented either parallel or perpendicular to the photon beam. The dose to the active volume of each detector in air was scored, and its ratio to dose with zero magnetic field strength was determined as the “dose response” in magnetic field. Measurements at low fields for both detectors in transverse magnetic fields were taken to evaluate the accuracy of the simulations. Additional simulations were performed in a water phantom to obtain few representative points for beam profile and percent depth dose measurements. Results: Simulations show significant dose response as a function of magnetic field in transverse field geometries. This response can be near 20% at 1.5 T, and it is highly dependent on the detectors’ relative orientation to the magnetic field, the energy of the photon beam, and detector composition. Measurements at low transverse magnetic fields verify the simulations for both detectors in their relative orientations to radiation beam. Longitudinal magnetic fields, in contrast, show little dose response, rising slowly with magnetic field, and reaching 0.5%–1% at 1.5 T regardless of detector orientation. Water tank and in air simulation results were the same within simulation uncertainty where lateral electronic equilibrium is present and expectedly differed at the beam edge in transverse field orientations only. Due to the difference in design, the two detectors behaved differently. Conclusions: When transverse magnetic fields are present, great care must be taken when using diamond or diode detectors. Dose response varies with relative detector orientation, magnetic field strength, and between detectors. This response can be considerable (∼20% for both detectors). Both detectors in longitudinal fields exhibit little to no dose response as a function of magnetic field. Water tank simulations seem to suggest that the diode detector is better suited to general beam commissioning, and each detector must be investigated separately

  9. Statistics

    For the year 1999 and 2000, part of the figures shown in the tables of the Energy Review are preliminary or estimated. The annual statistics of the Energy Review appear in more detail from the publication Energiatilastot - Energy Statistics issued annually, which also includes historical time series over a longer period (see e.g., Energiatilastot 1998, Statistics Finland, Helsinki 1999, ISSN 0785-3165). The inside of the Review's back cover shows the energy units and the conversion coefficients used for them. Explanatory notes to the statistical tables can be found after tables and figures. The figures presents: Changes in the volume of GNP and energy consumption, Changes in the volume of GNP and electricity, Coal consumption, Natural gas consumption, Peat consumption, Domestic oil deliveries, Import prices of oil, Consumer prices of principal oil products, Fuel prices for heat production, Fuel prices for electricity production, Carbon dioxide emissions, Total energy consumption by source and CO2-emissions, Electricity supply, Energy imports by country of origin in January-March 2000, Energy exports by recipient country in January-March 2000, Consumer prices of liquid fuels, Consumer prices of hard coal, natural gas and indigenous fuels, Average electricity price by type of consumer, Price of district heating by type of consumer, Excise taxes, value added taxes and fiscal charges and fees included in consumer prices of some energy sources and Energy taxes and precautionary stock fees on oil products

  10. Dose responses of alkaline-earth sulfate doped with rare earth ions

    Thermoluminescence (TL) and optical stimulated luminescence (OSL) dose response curves of alkaline-earth sulfate doped with rare earth ions were measured. The non-linear dose response parameters were obtained by using the composite action dose response model. It is concluded that the linearity of dose response is relative to the species of rare earth ions and the defect structure. The one-hit factors (R) are closes to 1 in sulfate phosphors doped with Eu ions, which means that the dose responses are sublinear. But the dose responses are supralinear since R<0.5 when sulfate phosphors were doped with Tm or Dy ions. The value of R decreases with the increasing of TL peak temperatures, which means that contribution to dose response from the two-hit events is increased. The experiments also show that the dose response parameters of OSL are similar to those to TL. (authors)

  11. Maximum likelihood estimation for cytogenetic dose-response curves

    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[γd + g(t, tau)d2], where t is the time and d is dose. The coefficient of the d2 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

  12. Maximum likelihood estimation for cytogenetic dose-response curves

    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

  13. Statistical significance of rising and oscillatory trends in global ocean and land temperature in the past 160 years

    L. Østvand

    2014-03-01

    Full Text Available Various interpretations of the notion of a trend in the context of global warming are discussed, contrasting the difference between viewing a trend as the deterministic response to an external forcing and viewing it as a slow variation which can be separated from the background spectral continuum of long-range persistent climate noise. The emphasis in this paper is on the latter notion, and a general scheme is presented for testing a multi-parameter trend model against a null hypothesis which models the observed climate record as an autocorrelated noise. The scheme is employed to the instrumental global sea-surface temperature record and the global land temperature record. A trend model comprising a linear plus an oscillatory trend with period of approximately 70 yr, and the statistical significance of the trends, are tested against three different null models: first-order autoregressive process, fractional Gaussian noise, and fractional Brownian motion. The parameters of the null models are estimated from the instrumental record, but are also checked to be consistent with a Northern Hemisphere temperature reconstruction prior to 1750 for which an anthropogenic trend is negligible. The linear trend in the period 1850–2010 AD is significant in all cases, but the oscillatory trend is insignificant for ocean data and barely significant for land data. However, by using the significance of the linear trend to constrain the null hypothesis, the oscillatory trend in the land record appears to be statistically significant. The results suggest that the global land record may be better suited for detection of the global warming signal than the ocean record.

  14. SU-E-J-51: Dose Response of Common Solid State Detectors in Homogeneous Transverse and Longitudinal Magnetic Fields

    Purpose: Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is evaluated in varying transverse and longitudinal magnetic fields for eventual use in MR-Linac devices. Methods: A PTW 60003 and IBA PFD detector were modeled in the Monte Carlo code PENELOPE, incorporating a magnetic field which was varied in strength and oriented both transversely and longitudinally with respect to the incident photon beam. The detectors' long axis was in turn oriented either parallel or perpendicular to the photon beam. Dose to the active volume of each detector was scored, and its ratio to dose with zero magnetic field strength (dose response) was determined. Accuracy of the simulations was evaluated by measurements using both chambers taken at low field with a small electromagnet. Simulations were also performed in a water phantom to compare to the in air results. Results: Significant dose response was found in transverse field geometries, nearing 20% at 1.5T. The response is highly dependent on relative orientations to the magnetic field and photon beam, and on detector composition. Low field measurements confirm these results. In the presence of longitudinal magnetic fields, the detectors exhibit little dose response, reaching 0.51% at 1.5T regardless of detector orientation. Water tank simulations compared well to the in air simulations when not at the beam periphery, where in transverse magnetic fields only, the water tank simulations differed from the in air results. Conclusion: Transverse magnetic fields can cause large deviations in dose response, and are highly position orientation dependent. Comparatively, longitudinal magnetic fields exhibit little to no dose response in each detector as a function of magnetic field strength. Water tank simulations show longitudinal fields are generally easier to work with, but each detector must be evaluated separately

  15. Statistics

    For the year 2002, part of the figures shown in the tables of the Energy Review are partly preliminary. The annual statistics of the Energy Review also includes historical time-series over a longer period (see e.g. Energiatilastot 2001, Statistics Finland, Helsinki 2002). The applied energy units and conversion coefficients are shown in the inside back cover of the Review. Explanatory notes to the statistical tables can be found after tables and figures. The figures presents: Changes in GDP, energy consumption and electricity consumption, Carbon dioxide emissions from fossile fuels use, Coal consumption, Consumption of natural gas, Peat consumption, Domestic oil deliveries, Import prices of oil, Consumer prices of principal oil products, Fuel prices in heat production, Fuel prices in electricity production, Price of electricity by type of consumer, Average monthly spot prices at the Nord pool power exchange, Total energy consumption by source and CO2-emissions, Supply and total consumption of electricity GWh, Energy imports by country of origin in January-June 2003, Energy exports by recipient country in January-June 2003, Consumer prices of liquid fuels, Consumer prices of hard coal, natural gas and indigenous fuels, Price of natural gas by type of consumer, Price of electricity by type of consumer, Price of district heating by type of consumer, Excise taxes, value added taxes and fiscal charges and fees included in consumer prices of some energy sources and Excise taxes, precautionary stock fees on oil pollution fees on energy products

  16. Statistics

    For the year 2003 and 2004, the figures shown in the tables of the Energy Review are partly preliminary. The annual statistics of the Energy Review also includes historical time-series over a longer period (see e.g. Energiatilastot, Statistics Finland, Helsinki 2003, ISSN 0785-3165). The applied energy units and conversion coefficients are shown in the inside back cover of the Review. Explanatory notes to the statistical tables can be found after tables and figures. The figures presents: Changes in GDP, energy consumption and electricity consumption, Carbon dioxide emissions from fossile fuels use, Coal consumption, Consumption of natural gas, Peat consumption, Domestic oil deliveries, Import prices of oil, Consumer prices of principal oil products, Fuel prices in heat production, Fuel prices in electricity production, Price of electricity by type of consumer, Average monthly spot prices at the Nord pool power exchange, Total energy consumption by source and CO2-emissions, Supplies and total consumption of electricity GWh, Energy imports by country of origin in January-March 2004, Energy exports by recipient country in January-March 2004, Consumer prices of liquid fuels, Consumer prices of hard coal, natural gas and indigenous fuels, Price of natural gas by type of consumer, Price of electricity by type of consumer, Price of district heating by type of consumer, Excise taxes, value added taxes and fiscal charges and fees included in consumer prices of some energy sources and Excise taxes, precautionary stock fees on oil pollution fees

  17. Detecting multiple periodicities in observational data with the multi-frequency periodogram. I. Analytic assessment of the statistical significance

    Baluev, Roman V

    2013-01-01

    We consider the "multi-frequency" periodogram, in which the putative signal is modelled as a sum of two or more sinusoidal harmonics with idependent frequencies. It is useful in the cases when the data may contain several periodic components, especially when their interaction with each other and with the data sampling patterns might produce misleading results. Although the multi-frequency statistic itself was already constructed, e.g. by G. Foster in his CLEANest algorithm, its probabilistic properties (the detection significance levels) are still poorly known and much of what is deemed known is unrigourous. These detection levels are nonetheless important for the data analysis. We argue that to prove the simultaneous existence of all $n$ components revealed in a multi-periodic variation, it is mandatory to apply at least $2^n-1$ significance tests, among which the most involves various multi-frequency statistics, and only $n$ tests are single-frequency ones. The main result of the paper is an analytic estima...

  18. 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.

  19. Multifraction dose response of growing and resting phase hair follicles

    It has been established in both the clinic and the laboratory that there is a differentiation response to changes in dose per fraction in early and late responding tissues. To study one possible biological reason for differences in early and late responses. The authors selected one kind of cellular entity, the hair follicle, in two different phases of mitotic activity. The follicles are usually in a resting phase (7-12 wks), but mitotic activity can be initiated by plucking the club hairs. This was done on one half of the thorax and then exposing mice to doses of radiation (cesium gamma-ray). Dose responses for epilation between growing (early) and resting (late) follicles were compared for the same mouse. The fractionated response was studied by reducing the dose down to 2.5 Gy/fx. As the literature suggests, the total dose tolerated by a resting (late) follicle increased more than that for a growing (early) follicle

  20. Proposal of a probabilistic dose-response model

    A biologically updated dose-response model is presented as an alternative to the linear-quadratic model currently in use for cancer risk assessment. The new model is based on the probability functions for misrepair and/or unrepair of DNA lesions, in terms of the radiation damage production rate in the cell (supposedly, a stem cell) and its repair-rate constant. The model makes use, interpreting it on the basis of misrepair probabilities, of the ''dose and dose-rate effectiveness factor'' of ICRP, and provides the way for a continuous extrapolation between the high and low dose-rate regions, ratifying the ''linear non-threshold hypothesis'' as the main option. Anyhow, the model throws some doubts about the additive property of the dose. (author)

  1. Anti-irritants I: Dose-response in acute irritation

    Andersen, Flemming; Hedegaard, Kathryn; Petersen, Thomas Kongstad; Bindslev-Jensen, Carsten; Fullerton, Ann; Andersen, Klaus Ejner

    2006-01-01

    The term 'anti-irritant' (AI) was coined in 1965 by Goldemberg to describe a diverse group of topical product ingredients, which were able to reduce the irritation potential of other more irritating ingredients in the same product. 'AIs' are being added to cosmetic formulations in order, allegedly......, to benefit tolerability of the products and allow claims such as 'soothing' and 'healing' ingredients. Limited documentation in favour of the efficacy of AIs is published. We studied the dose-related effect of 4 alleged AIs (nifedipine, (-)-alpha-bisabolol, canola oil and glycerol) on experimentally...... of the patches. Evaluation of skin irritation and efficacy of treatments were performed daily for 4 days using clinical scoring, evaporimetry (transepidermal water loss), hydration measurement and colourimetry. Only glycerol showed dose-response and effects potentially better than no treatment. There...

  2. Dose response curves for effects of low-level radiation

    The linear dose-response model used by international committees to assess the genetic and carcinogenic hazards of low-level radiation appears to be the most reasonable interpretation of the available scientific data that are relevant to this topic. There are, of course, reasons to believe that this model may overestimate radiation hazards in certain instances, a fact acknowledged in recent reports of these committees. The linear model is now also being utilized to estimate the potential carcinogenic hazards of other agents such as asbestos and polycyclic aromatic hydrocarbons. This model implies that there is no safe dose for any of these agents and that potential health hazards will increase in direct proportion to total accumulated dose. The practical implication is the recommendation that all exposures should be kept 'as low as reasonably achievable, economic and social factors being taken into account'. (auth)

  3. Combined Statistical Analyses of Peptide Intensities and Peptide Occurrences Improves Identification of Significant Peptides from MS-based Proteomics Data

    Webb-Robertson, Bobbie-Jo M.; McCue, Lee Ann; Waters, Katrina M.; Matzke, Melissa M.; Jacobs, Jon M.; Metz, Thomas O.; Varnum, Susan M.; Pounds, Joel G.

    2010-11-01

    Liquid chromatography-mass spectrometry-based (LC-MS) proteomics uses peak intensities of proteolytic peptides to infer the differential abundance of peptides/proteins. However, substantial run-to-run variability in peptide intensities and observations (presence/absence) of peptides makes data analysis quite challenging. The missing abundance values in LC-MS proteomics data are difficult to address with traditional imputation-based approaches because the mechanisms by which data are missing are unknown a priori. Data can be missing due to random mechanisms such as experimental error, or non-random mechanisms such as a true biological effect. We present a statistical approach that uses a test of independence known as a G-test to test the null hypothesis of independence between the number of missing values and the experimental groups. We pair the G-test results evaluating independence of missing data (IMD) with a standard analysis of variance (ANOVA) that uses only means and variances computed from the observed data. Each peptide is therefore represented by two statistical confidence metrics, one for qualitative differential observation and one for quantitative differential intensity. We use two simulated and two real LC-MS datasets to demonstrate the robustness and sensitivity of the ANOVA-IMD approach for assigning confidence to peptides with significant differential abundance among experimental groups.

  4. Modeling silicon diode dose response factors for small photon fields

    Eklund, Karin; Ahnesjoe, Anders [Section of Oncology, Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala (Sweden)

    2010-12-21

    The dosimetry of small fields is important for the use of high resolution photon radiotherapy. Silicon diodes yield a high signal from a small detecting volume which makes them suitable for use in small fields and high dose gradients. Unshielded diodes used in large fields are known to give a varying dose response depending on the proportion of low energy scattered photons in the field. Response variations in small fields can be caused by both spectral variations, and disturbances of the local level of lateral electron equilibrium. We present a model that includes the effects from lack of charged particle equilibrium. The local spectra are calculated by use of fluence pencil kernels and divided into a low and a high energy component. The low energy part is treated with large cavity theory and the high energy part with the Spencer-Attix small cavity theory. Monte Carlo-derived correction factors are used to account for both the local level of electron equilibrium in the field, and deviations from this level in the silicon disk cavity. Results for field sizes ranging from 0.5 x 0.5 to 20 x 20 cm{sup 2} are compared to data from full Monte Carlo simulations and measurements. The achieved dose response accuracy is for the smallest fields 1-2%, and for larger fields 0.5%. Spectral variations were of little importance for the small field response, implying that volume averaging, and to some extent interface transient effects, are of importance for use of unshielded diodes in non-equilibrium conditions. The results indicate that diodes should preferably be designed to have the thin layer of active volume padded in between inactive layers of the silicon base material.

  5. The dose-response relationship for UV-tumorigenesis

    The main objective of the investigations was to extend the knowledge on experimental UV-carcinogenesis and to use the experimental results as guidelines for developing a dose-response model for UV-carcinogenesis. The animal experiments carried out were all long-term ones. It was decided that - in anticipation of the data to be obtained - a model for such an assessment should be developed using the experimental results available at the start of the present study (1977). This initial study is presented. The results of two animal experiments are presented, which show that UV radiation is capable of inducing a systemic effect that enhances the de novo formation of UV induced tumors. The results of the main experiment are presented. In this experiment groups of mice were subjected to daily exposure to a certain dose of UV radiation in order to find the dose-response relationship. The relation between the daily dose and the duration of the treatment till the appearance of tumors (for instance, as measured by the yield) was ascertained for tumors of different sizes. It appears that the growth of a tumor is dose-independent, and, therefore, only the initiation of a tumor is dose-dependent. Finally an experiment is presented in which it was measured that, if a mouse is subjected to daily UV exposure, the transmission of the epidermis in the shortwave UV region decreases continuously. This decrease is due to hyperplasia of the epidermis, i.e., thickening of the epidermis by an increase in the number of cells per unit surface area. (Auth.)

  6. Dose-response relationships for radium-induced bone sarcomas

    The incidence of bone sarcomas among 3055 female radium-dial workers who entered the dial industry before 1950 was used to determine dose-response relationships for the induction of bone sarcomas by radium. Two subpopulations were analyzed: all measured cases who survived at last five years after the start of employment and all cases who survived at least two years after first measurement. The first constituted a group based on year of entry; it contained 1468 women who experienced 42 bone sarcomas; the expected number was 0.4. The second comprised a group based on first measurement; it contained 1257 women who experienced 13 bone sarcomas; the expected number was 0.2. The dose-response function, I = (C + αD + #betta#D2)e/sup -#betta#D/, and simplifications of this general form, were fit to each data set. Two functions, I = (C + αD + #betta#D2)e/sup -#betta#D/ and I = (C + #betta#D2)e/sup -#betta#D/, fit the data for year of entry (p greater than or equal to 0.05); both these functions and I = (C + αD) fit the data for first measurement. The function I = (C + #betta#D2)e/sup -#betta#D/ was used to predict the number of bone sarcomas in all other pre-1950 radium cases (medical, laboratory, and other exposure); fewer were actually observed than the fit of this function to the female dial workers predicted

  7. Application of Dempster–Shafer theory in dose response outcome analysis

    The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) reviews summarize the currently available three-dimensional dose/volume/outcome data from multi-institutions and numerous articles to update and refine the normal tissue dose/volume tolerance guidelines. As pointed out in the review, the data have limitations and even some inconsistency. However, with the help of new physical and statistical techniques, the information in the review could be updated so that patient care can be continually improved. The purpose of this work is to demonstrate the application of a mathematical theory, the Dempster–Shafer theory, in dose/volume/outcome data analysis. We applied this theory to the original data obtained from published clinical studies describing dose response for radiation pneumonitis. Belief and plausibility concepts were introduced for dose response evaluation. We were also able to consider the uncertainty and inconsistency of the data from these studies with Yager's combination rule, a special methodology of Dempster–Shafer theory, to fuse the data at several specific doses. The values of belief and plausibility functions were obtained at the corresponding doses. Then we applied the Lyman–Kutcher–Burman (LKB) model to fit these values and a belief–plausibility range was obtained. This range could be considered as a probability range to assist physicians and treatment planners in determining acceptable dose–volume constraints. Finally, the parameters obtained from the LKB model fitting were compared with those in Emami and Burman's papers and those from other frequentist statistics methods. We found that Emami and Burman's parameters are within the belief–plausibility range we calculated by the Dempster–Shafer theory. (paper)

  8. Linear dose response curves in fungi and tradescantia

    Tradescantia Clone 02 data suggests that linear non-threshold dose responses are expected to the lowest doses and dose rates of low linear energy transfer (LET) radiation. This is likely to be true for other living organisms even though Clone 02 is radiation sensitive. It is concluded that Clone 02 is partially defective in the RAD 6 pathway for the repair of DNA interstrand cross-links (ISCL) and other loss of coding damage (LCD), based on its cross sensitivities to EMS and ionizing radiation. Tradescantia Clone 02 data showing linear non-threshold induction of somatic genetic events in part reflects the repair deficiency of this Clone. More DNA damage is repaired by recombinational mechanisms in Clone 02 than would occur in a wild-type strain. Two important classes of DNA lesions are induced by ionizing radiation in DNA - double strand breaks (DSB) which are repaired by recombination mechanisms, and loss of coding information damage (LCD), which is repaired by error prone mechanisms but may also be a substrate for recombinational repair. Based on data from yeast, there are two different repair pathways which deal with these differing lesions with different somatic genetic consequences. From yeast, yield cross sections can be derived and applied to DNA damage and repair in Tradescantia. For Clone 02, per lesion, more visible genetic events are scored than in wild-type strains. In a radiation-derived sub-clone, Clone 0106, which is more variable than Clone 02, even more events occur per lesion. This derivative clone, plus breeding experiments, indicate that Clone 02 is heterozygous, or a 'carrier' for a mutant version of a gene in the Tradescantia RAD 6 repair pathway. Clone 02 is, therefore, much like a Fanconi's anemia carrier in a human population, while the Clone 0106 derivative is much like a homozygous Fanconi's anemia patient, with respect to its response to ionizing radiation damage. Two anomalies in its dose response curves for 'pink' loss of heterozygosity (LOH) events occur because Clone 02 repairs both DSB and LCD by recombination. Clone 02 has a linear dose response for high LET radiation. Starting from the same initial yieId frequency, wild-types have a sublinear response. The sublinear response reflects a smoothly decreasing probability that 'pinks' are generated as a function of increasing high LET dose for wild-type but not Clone 02. This smoothly decreasing response would be expected for LOH in 'wild-type' humans. It reflects an increasing proportion of DNA damage being repaired by non-recombinational pathways and/or an increasing probability of cell death with increasing dose. Clone 02 at low doses and low dose rates of low LET radiation has a linear dose response, reflecting a 1/16 probability of a lesion leading to LOH, relative to high LET lesions. This differential is held to reflect: microdosimetric differences in energy deposition and, therefore, DNA damage by low and high LET radiations; the effects of lesion clustering after high LET on the probability of generating the end wild-types. While no observations have been made at very low doses and dose rates in wild-types, there is no reason to suppose that the low LET linear non-threshold dose response of Clone 02 is abnormal. The importance of the LOH somatic genetic end-point is that it reflects cancer risk in humans. The linear non-threshold low dose low LET response curves reflects either the probability that recombinational Holliday junctions are occasionally cleaved in a rare orientation to generate LOH, or the probability that low LET lesions include a small proportion of clustered events similar to high LET ionization or both. Calculations of the Poisson probability that two or more low LET lesions will be induced in the same target suggest that dose rate effects depend upon the coincidence of DNA lesions in the same target, and that the probability of LOH depends upon lesion and repair factors. But the slope of LOH in Clone 02 and all other strains never approaches the expected slope of predicted for two hit events. This suggests that only particular combinations of coincident LCD and DSB lesions lead, on repair, to LOH. All the evidence suggests that DNA damage induction is linear to the lowest doses. The evidence suggests that even at the lowest doses and dose rates of low LET radiation, there is a constant probability of LOH arising from repair. The effects on cancer risk of this LOH will depend upon the genotype of the individual, and further selective mechanisms which may ameliorate or intensify the effects of the original LOH event. Radiation LOH mechanisms and organismic selective screens can be tested using mice with a defined genetic back-ground, and with genes involved in DNA repair and cancer risk, inactivated or knocked out to produce 'heterozygotes'. By selecting cancers within or outside the selective screen of the immune system the effects of immunological surveillance on the risks associated with LOH of a cancer risk gene can be measured. By knocking out genes in the RAD 52 or RAD 6 pathways, the differential effects of low and high LET radiations, the effects of repair deficiencies on RBE, and dose rate effects can be measured in heterozygotes. The interest in heterozygotes arises because they are expected to be present in the population at approximately four times the square root of the frequency of homozygotes, and because in terms of Knudson's multi-step theory of cancer risk, they have already inherited the first 'hit' from their parents in the form of one abnormal cancer risk gene. Clone 02 is abnormal, but in the same way that a heterozygous carrier of a Fanconi's anemia gene would be. As 1/77 of South African Afrikaans speakers are carriers of a Fanconi's anemia mutant gene, the Clone 02 results can be extrapolated to real human populations. It would, therefore, be expected that real humans would show linear non-threshold radiation-induced LOH and potentially cancer risk. (author)

  9. Statistical significance of rising and oscillatory trends in global ocean and land temperature in the past 160 years

    Østvand, Lene; Rypdal, Martin

    2013-01-01

    Various interpretations of the notion of a trend in the context of global warming are discussed, contrasting the difference between viewing a trend as the deterministic response to an external forcing and viewing it as a slow variation which can be separated from the background spectral continuum of long-range persistent climate noise. The emphasis in this paper is on the latter notion, and a general scheme is presented for testing a multi-parameter trend model against a null hypothesis which models the observed climate record as an autocorrelated noise. The scheme is employed to the instrumental global sea-surface temperature record and the global land-temperature record. A trend model comprising a linear plus an oscillatory trend with period of approximately 60 yr, and the statistical significance of the trends, are tested against three different null models: first-order autoregressive process, fractional Gaussian noise, and fractional Brownian motion. The linear trend is significant in all cases, but the o...

  10. Investigating quartz optically stimulated luminescence dose-response curves at high doses

    Lowick, Sally E., E-mail: lowick@geo.unibe.c [Institut fuer Geologie, Universitaet Bern, Baltzerstrasse 1-3, 3012 Bern (Switzerland); Preusser, Frank [Institut fuer Geologie, Universitaet Bern, Baltzerstrasse 1-3, 3012 Bern (Switzerland); Wintle, Ann G. [Institute of Geography and Earth Sciences, Aberystwyth University, AberystwythSY23 3DB (United Kingdom)

    2010-10-15

    Despite the general expectation that optically stimulated luminescence (OSL) growth should be described by a simple saturating exponential function, an additional high dose component is often reported in the dose response of quartz. Although often reported as linear, it appears that this response is the early expression of a second saturating exponential. While some studies using equivalent doses that fall in this high dose region have produced ages that correlate well with independent dating, others report that it results in unreliable age determinations. Two fine grain sedimentary quartz samples that display such a response were used to investigate the origin of this additional high dose component: three experiments were conducted to examine their dose-response up to >1000 Gy. The high dose rates provided by laboratory irradiation were found not to induce a sensitivity change in the response to a subsequent test dose, with the latter not being significantly different from those generated following naturally acquired doses. The relative percentage contributions of the fast and medium OSL components remained fixed throughout the dose-response curve, suggesting that the electron traps that give rise to the initial OSL do not change with dose. An attempt was made to investigate a change in luminescence centre recombination probability by monitoring the depletion of the '325 {sup o}C' thermoluminescence (TL) during the optical stimulation that would result in depletion of the OSL signal. The emissions measured through both the conventional ultraviolet (UV), and a longer wavelength violet/blue (VB) window, displayed similar relative growth with dose, although it was not possible to resolve the origin of the VB emissions. No evidence was found to indicate whether the additional component at high doses occurs naturally or is a product of laboratory treatment. However, it appears that these samples display an increased sensitivity of quartz OSL to high doses that is not recorded by the sensitivity to a subsequent test dose, and which results in a change in the sensitivity-corrected dose-response curve.

  11. Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer

    Background and purpose: We fit phenomenological tumor control probability (TCP) models to biopsy outcome after three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer patients to quantify the local dose-response of prostate cancer. Materials and methods: We analyzed the outcome after photon beam 3D-CRT of 103 patients with stage T1c-T3 prostate cancer treated at Memorial Sloan-Kettering Cancer Center (MSKCC) (prescribed target doses between 64.8 and 81 Gy) who had a prostate biopsy performed ≥2.5 years after end of treatment. A univariate logistic regression model based on Dmean (mean dose in the planning target volume of each patient) was fit to the whole data set and separately to subgroups characterized by low and high values of tumor-related prognostic factors T-stage (6), and pre-treatment prostate-specific antigen (PSA) (≤10 ng/ml vs. >10 ng/ml). In addition, we evaluated five different classifications of the patients into three risk groups, based on all possible combinations of two or three prognostic factors, and fit bivariate logistic regression models with Dmean and the risk group category to all patients. Dose-response curves were characterized by TCD50, the dose to control 50% of the tumors, and γ50, the normalized slope of the dose-response curve at TCD50. Results: Dmean correlates significantly with biopsy outcome in all patient subgroups and larger values of TCD50 are observed for patients with unfavorable compared to favorable prognostic factors. For example, TCD50 for high T-stage patients is 7 Gy higher than for low T-stage patients. For all evaluated risk group definitions, Dmean and the risk group category are independent predictors of biopsy outcome in bivariate analysis. The fit values of TCD50 show a clear separation of 9-10.6 Gy between low and high risk patients. The corresponding dose-response curves are steeper (γ50=3.4-5.2) than those obtained when all patients are analyzed together (γ50=2.9). Conclusions: Dose-response of prostate cancer, quantified by TCD50 and γ50, varies by prognostic subgroup. Our observations are consistent with the hypothesis that the shallow nature of clinically observed dose-response curves for local control result from a patient population that is a heterogeneous mixture of sub-populations with steeper dose-response curves and varying values of TCD50. Such results may eventually help to identify patients, based on their individual pre-treatment prognostic factors, that would benefit most from dose-escalation, and to guide dose prescription

  12. A universal doseresponse curve for radiochromic films

    Purpose: This paper presents a model for doseresponse curves of radiochromic films. It is based on a modified version of single-hit model to take into account the growth experienced by lithium salt of pentacosa-10,12-diynoic acid polymers after irradiation. Methods: Polymer growth in radiochromic films is a critical phenomenon that can be properly described by means of percolation theory to provide an appropriate distribution function for polymer sizes. Resulting functional form is a power function featuring a critical exponent and two adjustable parameters. Moreover, these parameters act as scaling factors setting a natural scale for sensitometric curves where the dependence on channel sensitivity is removed. A unique reduced response curve is then obtained from all the color channels describing film behavior independently of film dosimetry system. Results: Resulting functional form has been successfully tested in several sensitometric curves from different Gafchromic EBT models, providing excellent agreement with experimental data in a wide dose range up to about 40 Gy and low dose uncertainty. Conclusions: The model presented in this paper describes accurately the sensitometric curves of radiochromic films in wide dose ranges covering all typical ranges used in external radiotherapy. Resulting dose uncertainty is low enough to render a reasonably good performance in clinical applications. Due to cross-correlation, only one of the adjustable parameters is totally independent and characterizes film batches

  13. Nonlinear dose-response relationships and inducible cellular defence mechanisms

    With the inclusion of inducible radioprotective mechanisms in a radiobiological state-vector model it was possible to explain plateaus in dose-response relationships for neoplastic transformation produced by in vitro irradiation of different cell lines with low-LET irradiation at high dose rates. The current study repeated the simulation of one data set that contains a plateau at mid doses. In contrast to earlier studies, the new one did not model the repair of double-strand breaks (DSBs) located in bulk DNA (likely via non-homologous end joining) as being inducible. Repair of specific DSBs located in actively transcribed genes was assumed to occur via homologous recombination and was considered to be inducible. This reduced the number of parameters that have to be determined by fitting the model to data. In addition, all types of radical scavengers were formerly considered to be inducible by radiation. This was redefined in the current work and the effectiveness of scavengers was implemented in a refined way. The current work investigated whether these and other model adjustments lead to an improved fit of the data set. (author)

  14. On the dose response of some CVD diamond thermoluminescent detectors

    The linearity of dose response of chemical vapour deposition (CVD) diamonds grown at the Inst. for Materials Research at Limburg Univ. (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. (authors)

  15. Optimal dose-response relationships in voice therapy.

    Roy, Nelson

    2012-10-01

    Like other areas of speech-language pathology, the behavioural management of voice disorders lacks precision regarding optimal dose-response relationships. In voice therapy, dosing can presumably vary from no measurable effect (i.e., no observable benefit or adverse effect), to ideal dose (maximum benefit with no adverse effects), to doses that produce toxic or harmful effects on voice production. Practicing specific vocal exercises will inevitably increase vocal load. At ideal doses, these exercises may be non-toxic and beneficial, while at intermediate or high doses, the same exercises may actually be toxic or damaging to vocal fold tissues. In pharmacology, toxicity is a critical concept, yet it is rarely considered in voice therapy, with little known regarding "effective" concentrations of specific voice therapies vs "toxic" concentrations. The potential for vocal fold tissue damage related to overdosing on specific vocal exercises has been under-studied. In this commentary, the issue of dosing will be explored within the context of voice therapy, with particular emphasis placed on possible "overdosing". PMID:22574765

  16. Fast neutron dose response of a commercial polycarbonate

    Souto, E. B.; Campos, L. L.

    2007-09-01

    A commercial polycarbonate produced in Brazil is being studied to be used as neutron detector material using Solid State Nuclear Track Detection (SSNTD) method replacing the well-known detector materials Makrofol and CR-39. This technique is based on the damage (tracks) registration of charged particles produced by the interaction of neutrons with carbon and oxygen atoms of some dielectric materials. The IPEN dosimeter prototype is composed by 30101.5 mm 3 polycarbonate piece inserted between two Polymethyl Methacralate (PMMA) plates 2 mm thick. The prototypes were irradiated placed on an ISO slab phantom using an isotropic 241AmBe source at LN/LNMRI (Neutrons Laboratory of the National Laboratory of Ionizing Radiation Metrology). To study the dose response groups of five prototypes were irradiated with Hp(10) from 0.5 to 20 mSv with normal incidence and to investigate the angular incidence effect with Hp(10) = 5 mSv with incidence angles of 15, 45, 60, 75, 85 and 90. The detectors were revealed by chemical etching with the solution PEW-40 during 3 h. The track density of the detector surface was determined by the average of track counting of five fields ( 200.1 mm 2). The track response to equivalent dose Hp(10) showed a good agreement with linear fit in the studied interval. The track density strongly decreases for incidence angles higher than 45.

  17. Development of free statistical software enabling researchers to calculate confidence levels, clinical significance curves and risk-benefit contours

    Confidence levels, clinical significance curves, and risk-benefit contours are tools improving analysis of clinical studies and minimizing misinterpretation of published results, however no software has been available for their calculation. The objective was to develop software to help clinicians utilize these tools. Excel 2000 spreadsheets were designed using only built-in functions, without macros. The workbook was protected and encrypted so that users can modify only input cells. The workbook has 4 spreadsheets for use in studies comparing two patient groups. Sheet 1 comprises instructions and graphic examples for use. Sheet 2 allows the user to input the main study results (e.g. survival rates) into a 2-by-2 table. Confidence intervals (95%), p-value and the confidence level for Treatment A being better than Treatment B are automatically generated. An additional input cell allows the user to determine the confidence associated with a specified level of benefit. For example if the user wishes to know the confidence that Treatment A is at least 10% better than B, 10% is entered. Sheet 2 automatically displays clinical significance curves, graphically illustrating confidence levels for all possible benefits of one treatment over the other. Sheet 3 allows input of toxicity data, and calculates the confidence that one treatment is more toxic than the other. It also determines the confidence that the relative toxicity of the most effective arm does not exceed user-defined tolerability. Sheet 4 automatically calculates risk-benefit contours, displaying the confidence associated with a specified scenario of minimum benefit and maximum risk of one treatment arm over the other. The spreadsheet is freely downloadable at www.ontumor.com/professional/statistics.htm A simple, self-explanatory, freely available spreadsheet calculator was developed using Excel 2000. The incorporated decision-making tools can be used for data analysis and improve the reporting of results of any comparison between two patient groups

  18. Exposuredoseresponse of Anadara trapezia to metal contaminated estuarine sediments. 1. Cadmium spiked sediments

    Highlights: ? We describe an exposuredoseresponse approach for assessing cadmium exposure in Anadara trapezia. ? Accumulated cadmium was detoxified in metallothionein like proteins or as active metal in mitochondria. ? Increased cadmium dose resulted in a reduction in total antioxidant capacity, decreased lysosomal stability and genotoxic damage. ? Elevated sediment cadmium concentrations can lead to increased biologically active cadmium and cellular impairment of A. trapezia. - Abstract: The relationship between cadmium exposure dose and response was investigated in Anadara trapezia exposed to cadmium spiked sediment (10 ?g/g and 50 ?g/g dry mass) for 56 days. A. trapezia reached an equilibrium cadmium tissue concentration (13 ?g/g and 25 ?g/g, respectively) by day 42. Gills accumulated significantly more cadmium than the hepatopancreas and haemolymph. After 56 days exposure between 46 and 73% of accumulated gill and hepatopancreas cadmium was detoxified and in the metallothionein like protein fraction. Approximately half of the biologically active cadmium in both tissues was in the mitochondrial fraction which has the potential to cause dysfunction in mitochondrial activity. Cadmium exposed A. trapezia generally had reduced GPx activity with an associated increase in total glutathione concentrations and reduced GSH:GSSG ratios due to a build up of oxidised glutathione. The changes in the glutathione pathway were reflected in the total antioxidant capacity of cadmium exposed A. trapezia which were significantly reduced compared to control organisms. There was a trend of increased lipid peroxidation with increased cadmium exposure but this was not significant. Increased cadmium exposure resulted in significant lysosomal destabilisation and increased frequency of micronuclei. The significant exposuredoseresponse relationship for A. trapezia exposed to cadmium enriched sediments indicates that elevated sediment cadmium concentrations have the potential to lead to increased biologically active cadmium burdens and impairment of individual A. trapezia at cellular and subcellular levels.

  19. Exposure-dose-response of Anadara trapezia to metal contaminated estuarine sediments. 1. Cadmium spiked sediments

    Taylor, Anne M., E-mail: anne.taylor@canberra.edu.au [Ecochemistry Laboratory, Institute for Applied Ecology, Faculty of Applied Science, University of Canberra, ACT 2601 (Australia); Maher, William A. [Ecochemistry Laboratory, Institute for Applied Ecology, Faculty of Applied Science, University of Canberra, ACT 2601 (Australia)

    2012-03-15

    Highlights: Black-Right-Pointing-Pointer We describe an exposure-dose-response approach for assessing cadmium exposure in Anadara trapezia. Black-Right-Pointing-Pointer Accumulated cadmium was detoxified in metallothionein like proteins or as active metal in mitochondria. Black-Right-Pointing-Pointer Increased cadmium dose resulted in a reduction in total antioxidant capacity, decreased lysosomal stability and genotoxic damage. Black-Right-Pointing-Pointer Elevated sediment cadmium concentrations can lead to increased biologically active cadmium and cellular impairment of A. trapezia. - Abstract: The relationship between cadmium exposure dose and response was investigated in Anadara trapezia exposed to cadmium spiked sediment (10 {mu}g/g and 50 {mu}g/g dry mass) for 56 days. A. trapezia reached an equilibrium cadmium tissue concentration (13 {mu}g/g and 25 {mu}g/g, respectively) by day 42. Gills accumulated significantly more cadmium than the hepatopancreas and haemolymph. After 56 days exposure between 46 and 73% of accumulated gill and hepatopancreas cadmium was detoxified and in the metallothionein like protein fraction. Approximately half of the biologically active cadmium in both tissues was in the mitochondrial fraction which has the potential to cause dysfunction in mitochondrial activity. Cadmium exposed A. trapezia generally had reduced GPx activity with an associated increase in total glutathione concentrations and reduced GSH:GSSG ratios due to a build up of oxidised glutathione. The changes in the glutathione pathway were reflected in the total antioxidant capacity of cadmium exposed A. trapezia which were significantly reduced compared to control organisms. There was a trend of increased lipid peroxidation with increased cadmium exposure but this was not significant. Increased cadmium exposure resulted in significant lysosomal destabilisation and increased frequency of micronuclei. The significant exposure-dose-response relationship for A. trapezia exposed to cadmium enriched sediments indicates that elevated sediment cadmium concentrations have the potential to lead to increased biologically active cadmium burdens and impairment of individual A. trapezia at cellular and subcellular levels.

  20. Exposure dose response relationships of the freshwater bivalve Hyridella australis to cadmium spiked sediments

    Highlights: The exposuredoseresponse approach was used to assess cadmium exposure and toxicity. Accumulated cadmium in H. australis reflected the sediment cadmium exposure. Spill over of cadmium into the biologically active pool was observed. Increased cadmium resulted in measurable biological effects. H. australis has the potential to be a cadmium biomonitor in freshwater environments. - Abstract: To understand how benthic biota may respond to the additive or antagonistic effects of metal mixtures in the environment it is first necessary to examine their responses to the individual metals. In this context, laboratory controlled single metal-spiked sediment toxicity tests are useful to assess this. The exposuredoseresponse relationships of Hyridella australis to cadmium-spiked sediments were, therefore, investigated in laboratory microcosms. H. australis was exposed to individual cadmium spiked sediments (<0.05 (control), 4 0.3 (low) and 15 1 (high) ?g/g dry mass) for 28 days. Dose was measured as cadmium accumulation in whole soft body and individual tissues at weekly intervals over the exposure period. Dose was further examined as sub-cellular localisation of cadmium in hepatopancreas tissues. The biological responses in terms of enzymatic and cellular biomarkers were measured in hepatopancreas tissues at day 28. H. australis accumulated cadmium from spiked sediments with an 8-fold (low exposure organisms) and 16-fold (high exposure organisms) increase at day 28 compared to control organisms. The accumulated tissue cadmium concentrations reflected the sediment cadmium exposure at day 28. Cadmium accumulation in high exposure organisms was inversely related to the tissue calcium concentrations. Gills of H. australis showed significantly higher cadmium accumulation than the other tissues. Accumulated cadmium in biologically active and biologically detoxified metal pools was not significantly different in cadmium exposed organisms, which suggests that H. australis has some tolerance to cadmium. The metallothionein like protein fraction played an important role in the sequestration and detoxification of cadmium and the amount sequestered in this fraction increased with increased cadmium exposure. The highest percentage of biologically active cadmium was associated with the lysosome + microsome and mitochondrial fractions. Cadmium concentrations in these two fractions of cadmium exposed organisms were significantly higher with respect to controls. Total antioxidant capacity decreased with increased cadmium exposure and tissue dose. Lipid peroxidation increased and lysosomal membrane stability decreased significantly with increased cadmium exposure and tissue dose. Based on exposuredoseresponse analysis in this study, H. australis would be a suitable organism for assessing cadmium sediment exposure and toxicity

  1. Dose-response behavior of the bacterium Vibrio fischeri exposed to pharmaceuticals and personal care products.

    Ortiz de García, Sheyla; García-Encina, Pedro A; Irusta-Mata, Rubén

    2016-01-01

    The presence of pharmaceuticals and personal care products (PPCPs) in the environment has become a real and widespread concern in recent years. Therefore, the primary goal of this study was to investigate 20 common and widely used PPCPs to assess their individual and combined effect on an important species in one trophic level, i.e., bacteria. The ecotoxicological effects of PPCPs at two different concentration ranges were determined in the bacterium Vibrio fischeri using Microtox(®) and were statistically analyzed using three models in the GraphPad Prism 6 program for Windows, v.6.03. A four-parameter model best fit the majority of the compounds. The half maximal effective concentration (EC50) of each PPCP was estimated using the best-fitting model and was compared with the results from a recent study. Comparative analysis indicated that most compounds showed the same level of toxicity. Moreover, the stimulatory effects of PPCPs at environmental concentrations (low doses) were assessed. These results indicated that certain compounds have traditional inverted U- or J-shaped dose-response curves, and 55% of them presented a stimulatory effect below the zero effect-concentration point. Effective concentrations of 0 (EC0), 5 (EC5) and 50% (EC50) were calculated for each PPCP as the ecotoxicological points. All compounds that presented narcosis as a mode of toxic action at high doses also exhibited stimulation at low concentrations. The maximum stimulatory effect of a mixture was higher than the highest stimulatory effect of each individually tested compound. Moreover, when the exposure time was increased, the hormetic effect decreased. Hormesis is being increasingly included in dose-response studies because this may have a harmful, beneficial or indifferent effect in an environment. Despite the results obtained in this research, further investigations need to be conducted to elucidate the behavior of PPCPs in aquatic environments. PMID:26518677

  2. Test of significant toxicity: a statistical application for assessing whether an effluent or site water is truly toxic.

    Denton, Debra L; Diamond, Jerry; Zheng, Lei

    2011-05-01

    The U.S. Environmental Protection Agency (U.S. EPA) and state agencies implement the Clean Water Act, in part, by evaluating the toxicity of effluent and surface water samples. A common goal for both regulatory authorities and permittees is confidence in an individual test result (e.g., no-observed-effect concentration [NOEC], pass/fail, 25% effective concentration [EC25]), which is used to make regulatory decisions, such as reasonable potential determinations, permit compliance, and watershed assessments. This paper discusses an additional statistical approach (test of significant toxicity [TST]), based on bioequivalence hypothesis testing, or, more appropriately, test of noninferiority, which examines whether there is a nontoxic effect at a single concentration of concern compared with a control. Unlike the traditional hypothesis testing approach in whole effluent toxicity (WET) testing, TST is designed to incorporate explicitly both α and β error rates at levels of toxicity that are unacceptable and acceptable, given routine laboratory test performance for a given test method. Regulatory management decisions are used to identify unacceptable toxicity levels for acute and chronic tests, and the null hypothesis is constructed such that test power is associated with the ability to declare correctly a truly nontoxic sample as acceptable. This approach provides a positive incentive to generate high-quality WET data to make informed decisions regarding regulatory decisions. This paper illustrates how α and β error rates were established for specific test method designs and tests the TST approach using both simulation analyses and actual WET data. In general, those WET test endpoints having higher routine (e.g., 50th percentile) within-test control variation, on average, have higher method-specific α values (type I error rate), to maintain a desired type II error rate. This paper delineates the technical underpinnings of this approach and demonstrates the benefits to both regulatory authorities and permitted entities. PMID:21305584

  3. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    Stram, Daniel; Preston, D. L.; Sokolnkov, Mikhail; Napier, Bruce A.; Kopecky, Kenneth; Boice, John; Beck, Harold L.; Till, John E.; Bouville, A.

    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.

  4. A randomized trial in a massive online open course shows people dont know what a statistically significant relationship looks like, but they can learn

    Fisher, Aaron; Anderson, G. Brooke; Peng, Roger

    2014-01-01

    Scatterplots are the most common way for statisticians, scientists, and the public to visually detect relationships between measured variables. At the same time, and despite widely publicized controversy, P-values remain the most commonly used measure to statistically justify relationships identified between variables. Here we measure the ability to detect statistically significant relationships from scatterplots in a randomized trial of 2,039 students in a statistics massive open online course (MOOC). Each subject was shown a random set of scatterplots and asked to visually determine if the underlying relationships were statistically significant at the P < 0.05 level. Subjects correctly classified only 47.4% (95% CI [45.1%49.7%]) of statistically significant relationships, and 74.6% (95% CI [72.5%76.6%]) of non-significant relationships. Adding visual aids such as a best fit line or scatterplot smooth increased the probability a relationship was called significant, regardless of whether the relationship was actually significant. Classification of statistically significant relationships improved on repeat attempts of the survey, although classification of non-significant relationships did not. Our results suggest: (1) that evidence-based data analysis can be used to identify weaknesses in theoretical procedures in the hands of average users, (2) data analysts can be trained to improve detection of statistically significant results with practice, but (3) data analysts have incorrect intuition about what statistically significant relationships look like, particularly for small effects. We have built a web tool for people to compare scatterplots with their corresponding p-values which is available here: http://glimmer.rstudio.com/afisher/EDA/. PMID:25337457

  5. A randomized trial in a massive online open course shows people don't know what a statistically significant relationship looks like, but they can learn.

    Fisher, Aaron; Anderson, G Brooke; Peng, Roger; Leek, Jeff

    2014-01-01

    Scatterplots are the most common way for statisticians, scientists, and the public to visually detect relationships between measured variables. At the same time, and despite widely publicized controversy, P-values remain the most commonly used measure to statistically justify relationships identified between variables. Here we measure the ability to detect statistically significant relationships from scatterplots in a randomized trial of 2,039 students in a statistics massive open online course (MOOC). Each subject was shown a random set of scatterplots and asked to visually determine if the underlying relationships were statistically significant at the P < 0.05 level. Subjects correctly classified only 47.4% (95% CI [45.1%-49.7%]) of statistically significant relationships, and 74.6% (95% CI [72.5%-76.6%]) of non-significant relationships. Adding visual aids such as a best fit line or scatterplot smooth increased the probability a relationship was called significant, regardless of whether the relationship was actually significant. Classification of statistically significant relationships improved on repeat attempts of the survey, although classification of non-significant relationships did not. Our results suggest: (1) that evidence-based data analysis can be used to identify weaknesses in theoretical procedures in the hands of average users, (2) data analysts can be trained to improve detection of statistically significant results with practice, but (3) data analysts have incorrect intuition about what statistically significant relationships look like, particularly for small effects. We have built a web tool for people to compare scatterplots with their corresponding p-values which is available here: http://glimmer.rstudio.com/afisher/EDA/. PMID:25337457

  6. Volume and heterogeneity dependence of the dose response relationship for head and neck tumours

    Based on the Poisson statistics of cell kill a model for the response of heterogeneous tumours to non-uniform dose delivery have been developed. The five parameters required to characterize the response are the 50% response dose, D50, the normalized dose-response gradient, ?, the tumour heterogeneity factor, h, the relative volume, y and the extra daily dose required to counteract the tumour cell proliferation, ?. The model has been fitted to data from a number of clinical investigations to allow the derivation of clinically relevant radiation response parameters for head and neck tumours. The D50 value for T2 larynx cancers is 59.9 Gy in 41 days with a relative standard deviation of 2.1 Gy and the ? value is 2.9 with a relative standard deviation of 0.3. The value of ?, which is most consistent with the clinical data for laryngeal tumours, is 0.35 Gy/day and this value should be used if the treatment time is changed from the 41 days normalization. The heterogeneity factor, h, is close to zero for laryngeal tumours which indicates that their response is basically governed by Poisson statistics. Nasopharyngeal tumours, on the other hand, exhibit h values around 0.2 which indicates that these tumours are more heterogeneous in their internal organization and so are their responses to radiation. (orig.)

  7. The dose-response of canine focal gastric mucosal blood flow to misoprostol

    Gana, T.J.; Pherson, B.R.; Koo, J. (Alberta Univ., Edmonton, AB (Canada))

    1989-01-01

    The dose-response of focal gastric mucosal blood flow was measured simultaneously by laser-Doppler flowmetry and hydrogen gas clearance in the canine chambered gastric segment to topical misoprostol. Simultaneously obtained mucosal blood flow values showed a highly significant linear correlation in the basal but not misoprostol periods between the two techniques. Laser-Doppler flowmetry measured a dose-dependent increase in blood flow, while in contrast, hydrogen gas clearance showed a gradual decline in blood flow after misoprostol administration throughout all experiments. It is concluded that misoprostol dose-dependently and transiently increases focal gastric mucosal blood flow. However, only laser-Doppler flowmetry is sensitive enough to detect it. Although it can measure steady-state blood flow, owing to the duration of one measurement, hydrogen gas clearance is incapable of detecting rapid flow changes.

  8. The dose-response of canine focal gastric mucosal blood flow to misoprostol

    The dose-response of focal gastric mucosal blood flow was measured simultaneously by laser-Doppler flowmetry and hydrogen gas clearance in the canine chambered gastric segment to topical misoprostol. Simultaneously obtained mucosal blood flow values showed a highly significant linear correlation in the basal but not misoprostol periods between the two techniques. Laser-Doppler flowmetry measured a dose-dependent increase in blood flow, while in contrast, hydrogen gas clearance showed a gradual decline in blood flow after misoprostol administration throughout all experiments. It is concluded that misoprostol dose-dependently and transiently increases focal gastric mucosal blood flow. However, only laser-Doppler flowmetry is sensitive enough to detect it. Although it can measure steady-state blood flow, owing to the duration of one measurement, hydrogen gas clearance is incapable of detecting rapid flow changes

  9. Dose-response of acute urinary toxicity of long-course preoperative chemoradiotherapy for rectal cancer

    Appelt, Ane L.; Bentzen, Søren M.; Jakobsen, Anders; Vogelius, Ivan R.

    2015-01-01

    BACKGROUND: Long-course preoperative chemoradiotherapy (chemo-RT) improves outcomes for rectal cancer patients, but acute side effects during treatment may cause considerable patient discomfort and may compromise treatment compliance. We developed a dose-response model for acute urinary toxicity...... based on a large, single-institution series. MATERIAL AND METHODS: In total 345 patients were treated with (chemo-)RT for primary rectal cancer from January 2007 to May 2012. Urinary toxicity during RT was scored prospectively using the CTCAE v 3.0 cystitis score (grade 0-5). Clinical variables and...... (dose cut-off model, Vx). The optimal dose metric was chosen using the Akaike Information Criterion (AIC). RESULTS: Grade 1 cystitis was experienced by 138 (40%), grade 2 by 39 (11%) and grade 3 by two (1%) patients, respectively. Dose metrics were significantly correlated with toxicity in all models...

  10. ENDOCRINE ACTIVE SUBSTANCES AND DOSE-RESPONSE FOR INDIVIDUALS AND POPULATIONS

    Endocrine Active Substances and Dose-Response for Individuals and PopulationsHugh A. BartonAbstract for IUPAC-SCOPE articleDose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ec...

  11. Marginal iodide deficiency and thyroid function: Dose-response analysis for quantitative pharmacokinetic modeling

    Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 ?g/kg I to the base diet (?25 ?g I/kg chow) to produce 5 nominal I levels, ranging from excess (basal + added I, Treatment 1: 1000 ?g I/kg chow) to deficient (Treatment 5: 25 ?g I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation.

  12. Dose response study using micronucleus cytome assay-useful tool for biodosimetry application

    The in vitro cytokinesis-block micronucleus cytome (CBMN-cytome) assay is a modified CBMN assay based on the assessment of micronuclei (MNi) in nucleated cells that have completed only one nuclear division. Along with micronucleus measurement, the CBMN cytome assay allows to assess relevant biodosimetric markers like nucleoplasmic bridges (NPBs), nuclearbuds (NBUDs), apoptotic and necrotic cells. The present study is aimed at obtaining in vitro dose response data for the induction of MNi, NPBs, NBUDs, apoptotic and necrotic cells in human lymphocytes using 60Co-gamma rays. An attempt has been made to validate possibility of applying NPBs and NBUDs as new biodosimetry endpoints. The 60Co gamma chamber with dose rate 1.2 Gy was used for irradiation. The dose range was selected was 0 to 6 Gy. A total of 1000 binucleated cells per dose were evaluated for the frequency of MNi, NPBs, NBUDs, apoptotic and necrotic cells. The MN induction was found to be linear quadratic and the dose response relationship can be represented by Y(MNi) = (0.04 0.016) + (0.041 0.014) D + (0.038 0.002) D2 (with R2=0.998, and p < 0.0001). The NPBs are narrow DNA-containing bridges linking the two daughter nuclei, and represent an indicator of dicentric chromosomes resulting from mis-repaired DNA breaks or telomere end fusions, which can be a useful tool for biodosimetry. The results show a linear quadratic increase in NPBs with the radiation dose, and the dose response relation can be written as Y(NPBs) = (0.002 8.57 x 10-4 ) + (0.0026 8.57 x 10-5) D + (0.00243 5.4 x 10-4 ) D2 (with R2=0.99, and p = 0.0046). The study concludes that NPBs frequency against radiation dose can be used for biodosimetry application, where as NBUDs frequency does not vary significantly with the radiation dose. (author)

  13. Dose-response relationship of neutrons and ? rays to leukemia incidence among atomic bomb survivors in Hiroshima and Nagasaki by type of leukemia, 1950--1971

    The incidence of leukemia during 1950 to 1971 in a fixed mortality sample of atomic bomb survivors in Hiroshima and Nagasaki was analyzed as a function of neutron and ? kerma and marrow doses. Two dose-response models were tested for acute leukemia, chronic granulocytic leukemia, and all types of leukemia, respectively. Each model postulates that the leukemia incidence depends upon the sum of separate risks imposed by ? and neutron doses. In Model I the risk from both types of radiation is assumed to be directly proportional to the respective doses, while Model II assumes that whereas the risk from neutrons is directly proportional to the dose, the risk from ? rays is proportional to dose-squared. The analysis demonstrated that the dose-response of the two types of leukemia differed by type of radiation. The data suggested that the response of acute leukemia was best explained by Model II, while the response of chronic granulocytic leukemia depended almost linearly upon neutron dose alone, because the regression coefficients associated with ? radiation for both Models I and II were not significant. The relative biological effectiveness (RBE) of neutrons in relation to ? rays for incidence of acute leukemia was estimated to be approximately 30/(Dn)/sup 1/2/ [95% confidence limits; 17/(Dn)/sup 1/2/ approx. 54/(Dn)/sup 1/2/] for kerma and 32/(Dn)/sup 1/2/ [95% confidence limits; 18/(Dn)/sup 1/2/ approx. 58/(Dn)/sup 1/2/] for marrow dose (Dn = neutron dose). If acute and chronic granulocytic leukemias are considered together as all types of leukemia, Model II appears to fit the data slightly better than Model I, but neither model is statistically rejected by the data

  14. Follicular and endocrine dose responses according to anti-Müllerian hormone levels in IVF patients treated with a novel human recombinant FSH (FE 999049)

    Bosch, Ernesto; Nyboe Andersen, Anders; Barri, Pedro; García-Velasco, Juan Antonio; de Sutter, Petra; Fernández-Sánchez, Manuel; Visnova, Hana; Klein, Bjarke M; Mannaerts, Bernadette; Arce, Joan-Carles

    2015-01-01

    : Follicular development and endocrine parameters during controlled ovarian stimulation (COS) with rhFSH. RESULTS: Serum FSH levels increased with increasing rhFSH doses and steady-state levels for each dose were similar in both AMH strata. In the whole study population, significant (P < 0·001) positive dose...... responses were observed for the number of follicles ≥12 mm, and serum levels of oestradiol, inhibin B, inhibin A and progesterone at end of stimulation. In comparison with the higher AMH stratum, patients in the lower AMH stratum had significantly different slopes of the dose-response curves for these...

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

    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. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26365692

  16. The Shape of the Dose-Response Relationship between Sugars and Caries in Adults.

    Bernab, E; Vehkalahti, M M; Sheiham, A; Lundqvist, A; Suominen, A L

    2016-02-01

    Dental caries is considered a diet-mediated disease, as sugars are essential in the caries process. However, some gaps in knowledge about the sugars-caries relationship still need addressing. This longitudinal study aimed to explore 1) the shape of the dose-response association between sugars intake and caries in adults, 2) the relative contribution of frequency and amount of sugars intake to caries levels, and 3) whether the association between sugars intake and caries varies by exposure to fluoride toothpaste. We used data from 1,702 dentate adults who participated in at least 2 of 3 surveys in Finland (Health 2000, 2004/05 Follow-up Study of Adults' Oral Health, and Health 2011). Frequency and amount of sugars intake were measured with a validated food frequency questionnaire. The DMFT index was the repeated outcome measure. Data were analyzed with fractional polynomials and linear mixed effects models. None of the 43 fractional polynomials tested provided a better fit to the data than the simpler linear model. In a mutually adjusted linear mixed effects model, the amount of, but not the frequency of, sugars intake was significantly associated with DMFT throughout the follow-up period. Furthermore, the longitudinal association between amount of sugars intake and DMFT was weaker in adults who used fluoride toothpaste daily than in those using it less often than daily. The findings of this longitudinal study among Finnish adults suggest a linear dose-response relationship between sugars and caries, with amount of intake being more important than frequency of ingestion. Also, daily use of fluoride toothpaste reduced but did not eliminate the association between amount of sugars intake and dental caries. PMID:26553884

  17. Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

    Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H. (National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (USA))

    1990-05-01

    Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.

  18. Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

    Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose, a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time

  19. Ecophysiological significance of scale-dependent patterns in prokaryotic genomes unveiled by a combination of statistic and genometric analyses.

    Garcia, Juan A L; Bartumeus, Frederic; Roche, David; Giraldo, Jess; Stanley, H Eugene; Casamayor, Emilio O

    2008-06-01

    We combined genometric (DNA walks) and statistical (detrended fluctuation analysis) methods on 456 prokaryotic chromosomes from 309 different bacterial and archaeal species to look for specific patterns and long-range correlations along the genome and relate them to ecological lifestyles. The position of each nucleotide along the complete genome sequence was plotted on an orthogonal plane (DNA landscape), and fluctuation analysis applied to the DNA walk series showed a long-range correlation in contrast to the lack of correlation for artificially generated genomes. Different features in the DNA landscapes among genomes from different ecological and metabolic groups of prokaryotes appeared with the combined analysis. Transition from hyperthermophilic to psychrophilic environments could have been related to more complex structural adaptations in microbial genomes, whereas for other environmental factors such as pH and salinity this effect would have been smaller. Prokaryotes with domain-specific metabolisms, such as photoautotrophy in Bacteria and methanogenesis in Archaea, showed consistent differences in genome correlation structure. Overall, we show that, beyond the relative proportion of nucleotides, correlation properties derived from their sequential position within the genome hide relevant phylogenetic and ecological information. This can be studied by combining genometric and statistical physics methods, leading to a reduction of genome complexity to a few useful descriptors. PMID:18420375

  20. Threshold estimation based on a p-value framework in dose-response and regression settings

    Mallik, Atul; Banerjee, Moulinath; Michailidis, George

    2011-01-01

    We use p-values to identify the threshold level at which a regression function takes off from its baseline value, a problem motivated by applications in toxicological and pharmacological dose-response studies and environmental statistics. We study the problem in two sampling settings: one where multiple responses can be obtained at a number of different covariate-levels and the other the standard regression setting involving limited number of response values at each covariate. Our procedure involves testing the hypothesis that the regression function is at its baseline at each covariate value and then computing the potentially approximate p-value of the test. An estimate of the threshold is obtained by fitting a piecewise constant function with a single jump discontinuity, otherwise known as a stump, to these observed p-values, as they behave in markedly different ways on the two sides of the threshold. The estimate is shown to be consistent and its finite sample properties are studied through simulations. Ou...

  1. A dose-response analysis for classical Kaposi's sarcoma management by radiotherapy

    Objective was to evaluate the dose-response relationship in classical Kaposi's sarcoma CKS patients treated with external beam radiotherapy. Between 1993 and 2004, patients with CKS treated at the Department of Radiation Oncology, Gulhane Military Medical School, Ankara, Turkey were evaluated in this retrospective study. The median age at initial presentation was 60 years. First we analyzed the overall response rates for normalized total dose2Gy NTD2Gy of 20Gy. Secondly we searched for whether better response rates could be obtained with the NTD2Gy of >/=20Gy compared to the NTD2Gy of /20Gy and 64% and 24%for NDT2Gyof 20< Gy and these were statistically different p=0.001. Late side effects of radiation therapy were acceptable in all but 4 patients with fibrosis and edema. This retrospective analysis showed that radiotherapy schedules with an NDT2Gy of 20 Gy and above by using local irradiation fields are effective in terms of complete response rates in the management of CKS compared to NDT2Gy of < 20 Gy. (author)

  2. Analysis/plot generation code with significance levels computed using Kolmogorov-Smirnov statistics valid for both large and small samples

    Kurtz, S.E.; Fields, D.E.

    1983-10-01

    This report describes a version of the TERPED/P computer code that is very useful for small data sets. A new algorithm for determining the Kolmogorov-Smirnov (KS) statistics is used to extend program applicability. The TERPED/P code facilitates the analysis of experimental data and assists the user in determining its probability distribution function. Graphical and numerical tests are performed interactively in accordance with the user's assumption of normally or log-normally distributed data. Statistical analysis options include computation of the chi-square statistic and the KS one-sample test statistic and the corresponding significance levels. Cumulative probability plots of the user's data are generated either via a local graphics terminal, a local line printer or character-oriented terminal, or a remote high-resolution graphics device such as the FR80 film plotter or the Calcomp paper plotter. Several useful computer methodologies suffer from limitations of their implementations of the KS nonparametric test. This test is one of the more powerful analysis tools for examining the validity of an assumption about the probability distribution of a set of data. KS algorithms are found in other analysis codes, including the Statistical Analysis Subroutine (SAS) package and earlier versions of TERPED. The inability of these algorithms to generate significance levels for sample sizes less than 50 has limited their usefulness. The release of the TERPED code described herein contains algorithms to allow computation of the KS statistic and significance level for data sets of, if the user wishes, as few as three points. Values computed for the KS statistic are within 3% of the correct value for all data set sizes.

  3. Comparison of Dose Response Models for Predicting Normal Tissue Complications from Cancer Radiotherapy: Application in Rat Spinal Cord

    Adamus-Górka, Magdalena; Mavroidis, Panayiotis, E-mail: panayiotis.mavroidis@ki.se; Lind, Bengt K.; Brahme, Anders [Department of Medical Radiation Physics, Karolinska Institutet and Stockholm University, Stockholm S-17176 (Sweden)

    2011-05-18

    Seven different radiobiological dose-response models have been compared with regard to their ability to describe experimental data. The first four models, namely the critical volume, the relative seriality, the inverse tumor and the critical element models are mainly based on cell survival biology. The other three models: the Lyman (Gaussian distribution), the parallel architecture and the Weibull distribution models are semi-empirical and rather based on statistical distributions. The maximum likelihood estimation was used to fit the models to experimental data and the χ{sup 2}-distribution, AIC criterion and F-test were applied to compare the goodness-of-fit of the models. The comparison was performed using experimental data for rat spinal cord injury. Both the shape of the dose-response curve and the ability of handling the volume dependence were separately compared for each model. All the models were found to be acceptable in describing the present experimental dataset (p > 0.05). For the white matter necrosis dataset, the Weibull and Lyman models were clearly superior to the other models, whereas for the vascular damage case, the Relative Seriality model seems to have the best performance although the Critical volume, Inverse tumor, Critical element and Parallel architecture models gave similar results. Although the differences between many of the investigated models are rather small, they still may be of importance in indicating the advantages and limitations of each particular model. It appears that most of the models have favorable properties for describing dose-response data, which indicates that they may be suitable to be used in biologically optimized intensity modulated radiation therapy planning, provided a proper estimation of their radiobiological parameters had been performed for every tissue and clinical endpoint.

  4. PCBS: CANCER DOSE-RESPONSE ASSESSMENT AND APPLICATION TO ENVIRONMENTAL MIXTURES (1996)

    This report updates the cancer dose-response assessment for polychlorinated biphenyls (PCBs) and shows how information on toxicity, disposition, and environmental processes can be considered together to evaluate health risks from PCB mixtures in the environment. Processes that ch...

  5. Development of a Biologically Based Dose Response (BBDR) Model for Arsenic Induced Cancer (S)

    Discuss the development of a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action.

  6. Hydrothermal synthesis of ZnO nanorods: a statistical determination of the significant parameters in view of reducing the diameter

    In this paper a 28-4 fractional factorial design of experiments is applied to identify the important parameters that affect the average diameter of ZnO rods, synthesized by means of a hydrothermal procedure. A water-based Zn2+ precursor is used for the formation of one-dimensional ZnO particles, without the presence of an organic additive. Results indicate that, at the investigated levels, four of the parameters have a significant effect on the mean diameter. These are the temperature, the heating rate, stirring and an ultrasonic pre-treatment of the precursor solution. Experiments carried out with zinc acetate and zinc chloride do not show a significant difference in rod diameter. Other parameters that do not show a significant effect are the concentration of Zn2+, the molar ratio between the hydroxyl and the zinc ions, and the reaction time. Interactions are observed between stirring and an ultrasonic pre-treatment and between the zinc concentration and the OH:Zn ratio. By fixing the significant factors at their optimal value it is possible to decrease the mean diameter. The particles are characterized by means of x-ray diffraction (XRD) and transmission electron microscopy (TEM).

  7. Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment

    Lagarde, Fabien; Belcher, Scott M; Belzunces, Luc; Emond, Claude; Guerbet, Michel; Rousselle, Christophe

    2014-01-01

    Experimental studies investigating the effects of endocrine disruptors frequently identify potential unconventional dose-response relationships called non-monotonic dose-response (NMDR) relationships. Standardized approaches for investigating NMDR relationships in a risk assessment context are missing. The aim of this work was to develop criteria for assessing the strength of NMDR relationships. A literature search was conducted to identify published studies that report NMDR relationships wit...

  8. The Importance of Integrating Clinical Relevance and Statistical Significance in the Assessment of Quality of Care –Illustrated Using the Swedish Stroke Register

    Lindmark, Anita; van Rompaye, Bart; Goetghebeur, Els; Glader, Eva-Lotta; Eriksson, Marie

    2016-01-01

    Background When profiling hospital performance, quality inicators are commonly evaluated through hospital-specific adjusted means with confidence intervals. When identifying deviations from a norm, large hospitals can have statistically significant results even for clinically irrelevant deviations while important deviations in small hospitals can remain undiscovered. We have used data from the Swedish Stroke Register (Riksstroke) to illustrate the properties of a benchmarking method that integrates considerations of both clinical relevance and level of statistical significance. Methods The performance measure used was case-mix adjusted risk of death or dependency in activities of daily living within 3 months after stroke. A hospital was labeled as having outlying performance if its case-mix adjusted risk exceeded a benchmark value with a specified statistical confidence level. The benchmark was expressed relative to the population risk and should reflect the clinically relevant deviation that is to be detected. A simulation study based on Riksstroke patient data from 2008–2009 was performed to investigate the effect of the choice of the statistical confidence level and benchmark value on the diagnostic properties of the method. Results Simulations were based on 18,309 patients in 76 hospitals. The widely used setting, comparing 95% confidence intervals to the national average, resulted in low sensitivity (0.252) and high specificity (0.991). There were large variations in sensitivity and specificity for different requirements of statistical confidence. Lowering statistical confidence improved sensitivity with a relatively smaller loss of specificity. Variations due to different benchmark values were smaller, especially for sensitivity. This allows the choice of a clinically relevant benchmark to be driven by clinical factors without major concerns about sufficiently reliable evidence. Conclusions The study emphasizes the importance of combining clinical relevance and level of statistical confidence when profiling hospital performance. To guide the decision process a web-based tool that gives ROC-curves for different scenarios is provided. PMID:27054326

  9. Dose - response relationship between noise exposure and the risk of occupational injury

    Jin-Ha Yoon

    2015-01-01

    Full Text Available Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers′ Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively. Workplace dust exposure was classified as 90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals derived from a logistic regression model were 1.68 (1.27-2.24 and 3.42 (2.26-5.17 at 80-89 dB and ≥90 dB versus <80 dB. These associations remained significant when in a separate analysis according to high or low dust exposure level. Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury.

  10. [Significance of a single tattoo in dyssocial probands. Statistical comparison of socially maladjustment, male delinquents with and without tattoos].

    Knecht, T

    1998-01-01

    Although tattooing is not confined to the circle of sociopaths and delinquents, it is widely known, that criminal offenders always had heightened tendencies towards this kind of body ornamentation. The author makes an attempt to clarify the significance of a single tattoo in a sample of male delinquents by comparing the tattooed and the non-tattooed individuals. In spite of the popular prejudice, the results of this trial show, that delinquents with one tattoo stem from comparatively more favourable familiar backgrounds, are less loaded with mental disorders and delinquency among blood relatives, show better scholastic and professional accomplishments. However, tendencies toward addictive and delinquent behavior were comparable in the two groups. PMID:9541718

  11. The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

    Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a 60Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions

  12. The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

    Schmitz, T., E-mail: schmito@uni-mainz.de [Institute for nuclear chemistry, Johannes Gutenberg-University, Mainz D-55128 (Germany); Bassler, N. [Department of Physics and Astronomy, Aarhus University, Ny Munkegade 120, Aarhus C, Aarhus 8000 (Denmark); Blaickner, M. [AIT Austrian Institute of Technology GmbH, Vienna A-1220 (Austria); Ziegner, M. [AIT Austrian Institute of Technology GmbH, Vienna A-1220, Austria and TU Wien, Vienna University of Technology, Vienna A-1020 (Austria); Hsiao, M. C. [Insitute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Liu, Y. H. [Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Koivunoro, H. [Department of Physics, University of Helsinki, POB 64, FI-00014, Finland and HUS Medical Imaging Center, Helsinki University Central Hospital, FI-00029 HUS (Finland); Auterinen, I.; Serén, T.; Kotiluoto, P. [VTT Technical Research Centre of Finland, Espoo (Finland); Palmans, H. [National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington TW11 0LW, United Kingdom and Medical Physics Group, EBG MedAustron GmbH, Wiener Neustadt A-2700 (Austria); Sharpe, P. [National Physical Laboratory, Acoustics and Ionising Radiation Division, Teddington TW11 0LW (United Kingdom); Langguth, P. [Department of Pharmacy and Toxicology, University of Mainz, Mainz D-55128 (Germany); Hampel, G. [Institut für Kernchemie, Johannes Gutenberg-Universität, Mainz D-55128 (Germany)

    2015-01-15

    Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.

  13. Application of Monte Carlo-based statistical significance determinations to the Beta Cephei stars V400 Car, V401 Car, V403 Car and V405 Car

    Engelbrecht, C. A.; Frescura, F. A. M.; Frank, B. S.

    2009-01-01

    We have used Lomb-Scargle periodogram analysis and Monte Carlo significance tests to detect periodicities above the 3-sigma level in the Beta Cephei stars V400 Car, V401 Car, V403 Car and V405 Car. These methods produce six previously unreported periodicities in the expected frequency range of excited pulsations: one in V400 Car, three in V401 Car, one in V403 Car and one in V405 Car. One of these six frequencies is significant above the 4-sigma level. We provide statistical significances for...

  14. Health effects of low doses at low dose rates: dose-response relationship modeling in a cohort of workers of the nuclear industry

    The aim of this thesis is to contribute to a better understanding of the health effects of chronic external low doses of ionising radiation. This work is based on the French cohort of CEA-AREVA NC nuclear workers. The mains stages of this thesis were (1) conducting a review of epidemiological studies on nuclear workers, (2) completing the database and performing a descriptive analysis of the cohort, (3) quantifying risk by different statistical methods and (4) modelling the exposure-time-risk relationship. The cohort includes monitored workers employed more than one year between 1950 and 1994 at CEA or AREVA NC companies. Individual annual external exposure, history of work, vital status and causes of death were reconstructed for each worker. Standardized mortality ratios using French national mortality rates as external reference were computed. Exposure-risk analysis was conducted in the cohort using the linear excess relative risk model, based on both Poisson regression and Cox model. Time dependent modifying factors were investigated by adding an interaction term in the model or by using exposure time windows. The cohort includes 36, 769 workers, followed-up until age 60 in average. During the 1968- 2004 period, 5, 443 deaths, 2, 213 cancers, 62 leukemia and 1, 314 cardiovascular diseases were recorded. Among the 57% exposed workers, the mean cumulative dose was 21.5 milli-sieverts (mSv). A strong Healthy Worker Effect is observed in the cohort. Significant elevated risks of pleura cancer and melanoma deaths were observed in the cohort but not associated with dose. No significant association was observed with solid cancers, lung cancer and cardiovascular diseases. A significant dose-response relationship was observed for leukemia excluding chronic lymphatic leukemia, mainly for doses received less than 15 years before and for yearly dose rates higher than 10 mSv. This PhD work contributes to the evaluation of risks associated to chronic external radiation exposure. Our study finds a risk of leukemia associated with chronic external exposure and allows taking into account modifying factors of this relation. Additional follow-up allows to improve the precision of the estimated dose-response relationship. A combined analysis including the present cohort and other nuclear cohorts could quantify more precisely the risks associated with low doses at low dose rates, in order to validate current underlying hypotheses of the radiation protection system. (author)

  15. Dose - response relationship between noise exposure and the risk of occupational injury.

    Yoon, Jin-Ha; Hong, Jeong-Suk; Roh, Jaehoon; Kim, Chi-Nyon; Won, Jong-Uk

    2015-01-01

    Many workers worldwide experience fatality and disability caused by occupational injuries. This study examined the relationship between noise exposure and occupational injuries at factories in Korea. A total of 1790 factories located in northern Gyeonggi Province, Korea was evaluated. The time-weighted average levels of dust and noise exposure were taken from Workplace Exposure Assessment data. Apart occupational injuries, sports events, traffic accidents, and other accidents occurring outside workplaces were excluded. The incidences of occupational injury in each factory were calculated by data from the Korea Workers' Compensation and Welfare Services. Workplaces were classified according to the incidence of any occupational injuries (incident or nonincident workplaces, respectively). Workplace dust exposure was classified as noise exposure as 90 dB. Workplaces with high noise exposure were significantly associated with being incident workplaces, whereas workplaces with high dust exposure were not. The odds ratios (95% confidence intervals) derived from a logistic regression model were 1.68 (1.27-2.24) and 3.42 (2.26-5.17) at 80-89 dB and ≥ 90 dB versus Noise exposure increases the risk of occupational injury in the workplace. Furthermore, the risk of occupational injury increases with noise exposure level in a dose-response relationship. Therefore, strategies for reducing noise exposure level are required to decrease the risk of occupational injury. PMID:25599757

  16. Comparison of US and FRG post-irradiation examination procedures to measure statistically significant failure fractions of irradiated coated-particle fuels

    Two methods for measuring failure fraction on irradiated coated-particle fuels have been developed, one in the United States (the IMGA system - Irradiated-Microsphere Gamma Analyzer) and one in the Federal Republic of Germany (FRG) (the PIAA procedure - Postirradiation Annealing and Beta Autoradiography). A comparison of the two methods on two standardized sets of irradiated particles was undertaken to evaluate the accuracy, operational procedures, and expense of each method in obtaining statistically significant results. From the comparison, the postirradiation examination method employing the IMGA system was found to be superior to the PIAA procedure for measuring statistically significant failure fractions. Both methods require that the irradiated fuel be in the form of loose particles, each requires extensive remote hot-cell facilities, and each is capable of physically separating failed particles from unfailed particles. Important differences noted in the comparison are described

  17. Biphasic dose responses in biology, toxicology and medicine: Accounting for their generalizability and quantitative features

    The most common quantitative feature of the hormetic-biphasic dose response is its modest stimulatory response which at maximum is only 3060% greater than control values, an observation that is consistently independent of biological model, level of organization (i.e., cell, organ or individual), endpoint measured, chemical/physical agent studied, or mechanism. This quantitative feature suggests an underlying upstream mechanism common across biological systems, therefore basic and general. Hormetic dose response relationships represent an estimate of the peak performance of integrative biological processes that are allometrically based. Hormetic responses reflect both direct stimulatory or overcompensation responses to damage induced by relatively low doses of chemical or physical agents. The integration of the hormetic dose response within an allometric framework provides, for the first time, an explanation for both the generality and the quantitative features of the hormetic dose response. -- Highlights: The hormetic stimulation is at maximum 3060% greater than control responses. Hormesis is a measure of biological performance and plasticity. The hormetic response is evolutionary based and highly generalizable. -- This paper provides a biologically based explanation for the generalizability/quantitative features of the hormetic dose response, representing a fundamental contribution to the field

  18. Non-linear least squares curve fitting of a simple theoretical model to radioimmunoassay dose-response data using a mini-computer

    Using the simple univalent antigen univalent-antibody equilibrium model the dose-response curve of a radioimmunoassay (RIA) may be expressed as a function of Y, X and the four physical parameters of the idealised system. A compact but powerful mini-computer program has been written in BASIC for rapid iterative non-linear least squares curve fitting and dose interpolation with this function. In its simplest form the program can be operated in an 8K byte mini-computer. The program has been extensively tested with data from 10 different assay systems (RIA and CPBA) for measurement of drugs and hormones ranging in molecular size from thyroxine to insulin. For each assay system the results have been analysed in terms of (a) curve fitting biases and (b) direct comparison with manual fitting. In all cases the quality of fitting was remarkably good in spite of the fact that the chemistry of each system departed significantly from one or more of the assumptions implicit in the model used. A mathematical analysis of departures from the model's principal assumption has provided an explanation for this somewhat unexpected observation. The essential features of this analysis are presented in this paper together with the statistical analyses of the performance of the program. From these and the results obtained to date in the routine quality control of these 10 assays, it is concluded that the method of curve fitting and dose interpolation presented in this paper is likely to be of general applicability. (orig.)

  19. Multi-spectral detection of statistically significant components in pre-seismic electromagnetic emissions related with Athens 1999, M = 5.9 earthquake

    Kalimeris, A.; Potirakis, S. M.; Eftaxias, K.; Antonopoulos, G.; Kopanas, J.; Nomikos, C.

    2016-05-01

    A multi-spectral analysis of the kHz electromagnetic time series associated with Athens' earthquake (M = 5.9, 7 September 1999) is presented here, that results to the reliable discrimination of the fracto-electromagnetic emissions from the natural geo-electromagnetic field background. Five spectral analysis methods are utilized in order to resolve the statistically significant variability modes of the studied dynamical system out of a red noise background (the revised Multi-Taper Method, the Singular Spectrum Analysis, and the Wavelet Analysis among them). The performed analysis reveals the existence of three distinct epochs in the time series for the period before the earthquake, a "quiet", a "transitional" and an "active" epoch. Towards the end of the active epoch, during a sub-period which is approximately starting two days before the earthquake, the dynamical system passes into a high activity state, where electromagnetic signal emissions become powerful and statistically significant almost in all time-scales. The temporal behavior of the studied system in each one of these epochs is further searched through mathematical reconstruction in the time domain of those spectral features that were found to be statistically significant. The transition of the system from the quiet to the active state proved to be detectable first in the long time-scales and afterwards in the short scales. Finally, a Hurst exponent analysis revealed persistent characteristics embedded in the two strong EM bursts observed during the "active" epoch.

  20. Statistical trend analysis and extreme distribution of significant wave height from 1958 to 1999 – an application to the Italian Seas

    G. Martucci

    2010-06-01

    Full Text Available The study is a statistical analysis of sea states timeseries derived using the wave model WAM forced by the ERA-40 dataset in selected areas near the Italian coasts. For the period 1 January 1958 to 31 December 1999 the analysis yields: (i the existence of a negative trend in the annual- and winter-averaged sea state heights; (ii the existence of a turning-point in late 80's in the annual-averaged trend of sea state heights at a site in the Northern Adriatic Sea; (iii the overall absence of a significant trend in the annual-averaged mean durations of sea states over thresholds; (iv the assessment of the extreme values on a time-scale of thousand years. The analysis uses two methods to obtain samples of extremes from the independent sea states: the r-largest annual maxima and the peak-over-threshold. The two methods show statistical differences in retrieving the return values and more generally in describing the significant wave field. The r-largest annual maxima method provides more reliable predictions of the extreme values especially for small return periods (<100 years. Finally, the study statistically proves the existence of decadal negative trends in the significant wave heights and by this it conveys useful information on the wave climatology of the Italian seas during the second half of the 20th century.

  1. Dairy consumption and incidence of hypertension: a dose-response meta-analysis of prospective cohort studies.

    Soedamah-Muthu, Sabita S; Verberne, Lisa D M; Ding, Eric L; Engberink, Marille F; Geleijnse, Johanna M

    2012-11-01

    Observational and clinical studies suggest that dairy intake, particularly low-fat dairy, could have a beneficial effect on blood pressure. We performed a dose-response meta-analysis of prospective cohort studies on dairy intake and risk of hypertension in the general population. A systematic literature search for eligible studies was conducted until July 2011, using literature databases and hand search. Study-specific dose-response associations were computed according to the generalized least squares for trend estimation method, and linear and piecewise regression models were created. Random-effects models were performed with summarized dose-response data. We included 9 studies with a sample size of 57 256, a total of 15 367 incident hypertension cases, and a follow-up time between 2 and 15 years. Total dairy (9 studies; range of intake, ?100-700 g/d), low-fat dairy (6 studies; ?100-500 g/d), and milk (7 studies; ?100-500 g/d) were inversely and linearly associated with a lower risk of hypertension. The pooled relative risks per 200 g/d were 0.97 (95% CI, 0.95-0.99) for total dairy, 0.96 (95% CI, 0.93-0.99) for low-fat dairy, and 0.96 (95% CI, 0.94-0.98) for milk. High-fat dairy (6 studies), total fermented dairy (4 studies), yogurt (5 studies), and cheese (8 studies) were not significantly associated with hypertension incidence (pooled relative risks of ?1). This meta-analysis of prospective cohort studies suggests that low-fat dairy and milk could contribute to the prevention of hypertension, which needs confirmation in randomized controlled trials. PMID:22987924

  2. Radiation dose and leukaemia risk: general relative risk techniques for dose-response models in a matched case-control study

    Generalized relative risk functions were used to model radiation dose-response information from a large matched case-control study of leukaemia occurring after treatment for cervical cancer. Models suggested by radiobiological theory were investigated and compared to standard analyses of categorical dose-response to the linear model. Local radiation doses to each of fourteen bone marrow compartments for each patient were incorporated into the models, and the corresponding risks were summed. Conditional maximum likelihood methods were used to estimate risk parameters. Unique features of the analysis include modelling both induction and reduction of risk as a function of radiation dose absorbed by different parts of the body within individuals. Detailed statistical aspects of these analyses are presented and discussed. (author)

  3. Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes

    Torekov, Signe Srensen; Kipnes, M S; Harley, R E; Holst, J J; Ehlers, M R

    2011-01-01

    To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles.......To evaluate the dose-response relationship of the recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered by continuous subcutaneous infusion (CSCI) in subjects with type 2 diabetes, with respect to reductions in fasting, postprandial and 11-h serum glucose profiles....

  4. Limitations in dose-response and surrogate species methodologies for risk assessment of Cry toxins on arthropod natural enemies.

    Paula, Débora P; Andow, David A; Bellinati, André; Timbó, Renata Velozo; Souza, Lucas M; Pires, Carmen S S; Sujii, Edison R

    2016-04-01

    Dose-response assays and surrogate species are standard methods for risk analysis for environmental chemicals. These assume that individuals within a species have unimodal responses and that a surrogate species can predict responses of other related taxa. We exposed immature individuals of closely related aphidophagous coccinellid predators, Cycloneda sanguinea and Harmonia axyridis, to Cry1Ac and Cry1F toxins through uniform and constant artificial tritrophic exposure through Myzus persicae aphids. Both toxins were detected in coccinellid pupae, with individual and interspecific variation. Uptake was significantly higher in H. axyridis than in C. sanguinea, both in the proportion of individuals and the concentrations per individual. We also observed bimodal uptake of the Cry toxins by H. axyridis, which indicated that some individuals had low bioaccumulation and some had high bioaccumulation. This suggests that standard dose-response assays need to be interpreted with caution and future assays should examine the modality of the responses. In addition, the similarity in the biological effects of the Cry toxins in the two predators was due to different biological exposure mechanisms. The majority of H. axyridis were exposed both internally and in the gut, while C. sanguinea was exposed primarily in the gut. Thus, despite their close phylogenetic relatedness, these species would not be good surrogates for each other and the surrogate species methodology should be tested more rigorously. PMID:26846212

  5. Statistics Related Self-Efficacy A Confirmatory Factor Analysis Demonstrating a Significant Link to Prior Mathematics Experiences for Graduate Level Students

    Karen Larwin

    2014-02-01

    Full Text Available The present study examined students' statistics-related self-efficacy, as measured with the current statistics self-efficacy (CSSE inventory developed by Finney and Schraw (2003. Structural equation modeling was used to check the confirmatory factor analysis of the one-dimensional factor of CSSE. Once confirmed, this factor was used to test whether a significant link to prior mathematics experiences exists. Additionally a new post-structural equation modeling (SEM application was employed to compute error-free latent variable score for CSSE in an effort to examine the ancillary effects of gender, age, ethnicity, department, degree level, hours completed, expected course grade, number of college-level math classes, current GPA on students' CSSE scores. Results support the one-dimensional construct and as expected, the model demonstrated a significant link between CSSE scores and prior mathematics experiences to CSSE. Additionally the students' department, expected grade, and number of prior math classes were found to have a significant effect on student's CSSE scores.

  6. Longitudinal evaluation of dose-response relationships for environmental exposures and pulmonary function in swine production workers.

    Reynolds, S J; Donham, K J; Whitten, P; Merchant, J A; Burmeister, L F; Popendorf, W J

    1996-01-01

    Studies describing respiratory health hazards for workers in swine production facilities have been published in the United States, Sweden, Canada, the Netherlands, and Denmark. Up to 50% of these workers experience bronchitis, organic dust toxic syndrome, hyper-reactive airways disease, chronic mucous membrane irritation, and other respiratory effects. These studies clearly point to the fact that this occupational environment poses a significant health risk hazard, and that control methods are needed to protect the worker. Before precise control strategies can be developed, implemented, and evaluated, dose-response studies are required to determine acceptable target levels for exposure. A previous manuscript described the development of multiple regression equations characterizing the relationships between environmental exposures and pulmonary response in a cohort of 207 swine producers. Baseline pulmonary function was included as a significant predictor of cross-shift decrements in pulmonary function in addition to personal measurements of dust, endotoxin, and ammonia concentrations. These equations were then used to predict specific exposure levels of dust and ammonia that could be expected to elicit significant decrements in cross-shift pulmonary function. This paper presents the results from analysis of follow-up data obtained on this same cohort 2 years after the initial measurements. At the second measurement period of the study (time-2), swine workers were found to have a mean cross-shift decrease in FEV1 of 2%. Cross-shift change in FEV1 was significantly correlated with personal exposures to total dust, total endotoxin, respirable endotoxin, and ammonia. The magnitude of the decrease in FEV1 was associated with increasing airborne concentrations of these environmental parameters thus confirming the dose-response relationship observed in the initial study (time-1). The correlation of dust with FEV1 changes in workers with more than 6 years of exposure (time-1 data) and more than 10 years of exposure (time-2 data) suggests that dust exposure is an important factor in chronic respiratory disease. Additionally, the correlation of endotoxins with FEV1 changes in the group with less than 6 years exposure (time-2 data) suggests endotoxins may have more significance for subacute respiratory effects. The agreement between observed cross-shift FEV1 changes measured in time-2 with changes predicted using regression equations derived from time-1 data demonstrates a consistent dose-response relationship over time for this cohort of swine production workers. This finding provides further support for conclusions of the previous study that levels of 2.5 mg/m3 (total dust) and 7.5 ppm (ammonia) are reasonable guidelines for occupational exposure limits in this environment. PMID:8808040

  7. Dose-Response Curve of Chromosome Aberrations in Human Lymphocytes Induced by Gamma-Rays

    Y. Lusiyanti

    2013-12-01

    Full Text Available Chromosome aberration is a biomarker to predict the level of cell damage caused by exposure to ionizing radiation on human body. Dicentric chromosome is a specific chromosome aberration caused by ionizing radiation and is used as a gold standard biodosimetry of individuals over exposed to ionizing radiation. In radiation accident the dicentric assays has been applied as biological dosimetry to estimate radiation absorbed dose and also to confirm the radiation dose received to radiation workers.The purpose of this study was to generate a dose response curve of chromosome aberration (dicentric in human lymphocyte induced by gamma radiation. Peripheral blood samples from three non smoking healthy volunteers aged between 25-48 years old with informed consent were irradiated with dose between 0.1-4.0 Gy and a control using gamma teletherapy source. The culture procedure was conducted following the IAEA standard procedures with slight modifications. Analysis of dose-response curves used was LQ model Y = a + ?D + ?D2. The result showed that ? and ? values of the curve obtained were 0.018 0.006 and 0.013 0.002, respectively. Dose response calibration curve for dicentric chromosome aberrations in human lymphocytes induced by gamma-radiation fitted to linear quadratic model. In order to apply the dose response curve of chromosome aberration disentric for biodosimetry, this standar curve still need to be validated.

  8. Development of the dose-response relationship for human toxoplasma gondii infection associated with meat consumption

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States.A substantial portion of human T. gondii infections may be acquired through the consumption of meats. The dose-response relationship for human exposure...

  9. EXPERIMENTAL DESIGN STRATEGY FOR THE WEIBULL DOSE RESPONSE MODEL (JOURNAL VERSION)

    The objective of the research was to determine optimum design point allocation for estimation of relative yield losses from ozone pollution when the true and fitted yield-ozone dose response relationship follows the Weibull. The optimum design is dependent on the values of the We...

  10. Dose-response information and environmental damage assessments: an economic perspective

    Adams, R.M.; Crocker, T.D.

    1982-10-01

    The concept of a dose-response function is central to the assessment of biological damages associated with air pollution. Dose-response information is also important to the economist who wishes to assess the bioeconomic consequences of such pollution. The need for informed communication between the biological scientist and the economist in pollution research was enhanced in 1981 by President Reagan's Executive Order 12291, which explicitly requires the application of benefit-cost procedures to most rules a federal agency wishes to promulgate. One major determinant of the usefulness of dose-response information has since become the degree to which it contributes to improving the economic efficiency basis of environmental policy decisions. This paper suggests some criteria or guidelines concerning response surface experimental design, estimation, and choice of models which may assist the biologist in acquiring economically informative dose-response data. Also pointed out are some plausible sources of discrepancies between experimentally derived surfaces and those generated under field conditions as a source of estimation bias which may effect benefits assessments.

  11. Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms

    Urbain, Paul; Jakobsen, Jette

    2015-01-01

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of...

  12. Cytogenetics dosimetry: dose-response curve for low doses of X-ray

    The purpose of this study was to conduct a preliminary study for the standardization in the future, the dose-response curve for low doses of X-rays, through the analysis of in vitro cultures of peripheral blood samples of 3 men and 3 women occupationally not exposed to artificial sources of ionizing radiation, age 18-40 years, where possible nonsmokers

  13. Dose-Response Curve of Chromosome Aberrations in Human Lymphocytes Induced by Gamma-Rays

    Chromosome aberration is a bio marker to predict the level of cell damage caused by exposure to ionizing radiation on human body. Dicentric chromosome is a specific chromosome aberration caused by ionizing radiation and is used as a gold standard bio dosimetry of individuals over exposed to ionizing radiation. In radiation accident the dicentric assays has been applied as biological dosimetry to estimate radiation absorbed dose and also to confirm the radiation dose received to radiation workers.The purpose of this study was to generate a dose response curve of chromosome aberration (dicentric) in human lymphocyte induced by gamma radiation. Peripheral blood samples from three non smoking healthy volunteers aged between 25-48 years old with informed consent were irradiated with dose between 0.1-4.0 Gy and a control using gamma teletherapy source. The culture procedure was conducted following the IAEA standard procedures with slight modifications. Analysis of dose-response curves used was LQ model Y = a + ?D + ?D2. The result showed that ? and ? values of the curve obtained were 0.018 0.006 and 0.013 0.002, respectively. Dose response calibration curve for dicentric chromosome aberrations in human lymphocytes induced by gamma-radiation fitted to linear quadratic model. In order to apply the dose response curve of chromosome aberration dicentric for bio dosimetry, this standard curve still need to be validated. (author)

  14. Development of a biologically based dose response (BBDR) model for arsenic induced cancer

    We are developing a biologically based dose response (BBDR) model for arsenic carcinogenicity in order to reduce uncertainty in estimates of low dose risk by maximizing the use of relevant data on the mode of action. Expert consultation and literature review are being conducted t...

  15. Mechanistic interpretation of radiation dose-response relationship for subclinical metastasis

    To use a biophysical model based on the kinetics of metastatic formation to interpret radiation dose-response relationship for subclinical metastasis, and compare with what is predicted by the empirical model of Withers et al.. Methods: The metastases control probability (MCP) was formulated as a function of radiation dose and metastatic cell burden (MCB). The MCB was expressed to be log-uniformly distributed, as suggested by Withers et al.. In the mechanistic model, it was derived from the kinetics of primary tumor growth and subsequent metastatic colony formation and growth. A limiting resolution for clinical detection of metastasis (e.g. 109 cells) was assumed, and heterogeneous distributions for various biological parameters were considered. Mathematical expressions for both empirical and mechanistic models were solved analytically, and numerical simulations were performed using Mathcad software. Results: Withers et al. had presented clinical data to support a sigmoid-shaped MCP curve with a slope that is flatter than the control probability for gross tumor. This was verified by assuming the MCB to be log-uniformly distributed from 1 to 109 cells, provided that patients without subclinical metastasis are excluded. However, for patients diagnosed to have localized primary tumor, whether or not subclinical metastases are present remains unknown. This difficulty is alleviated in the mechanistic model, as an explicit expression for the metastasis-free cohort was obtained by subjecting all patients to undergo the Poisson process of metastatic establishment. Numerical simulations confirmed that the sigmoid MCP curve has a shallower slope if heterogeneity in metastatic rate is considered using log-normal distribution. Heterogeneity in metastatic growth rate with Gaussian distribution also resulted in significant flattening from an otherwise sharply-rising deterministic MCP curve. Conclusion: The mechanistic model of metastatogenesis appears to be more versatile for clinical application than the empirical model. It may help in formulating appropriate therapeutic strategy for subclinical metastases

  16. Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs

    Koplovitz, I.; Menton, R.; Matthews, C.; Shutz, M.; Nalls, C.

    1995-12-31

    H1-6 (1-2-hydrnxyiminomethyl-1 pyridino-3-(4-carbameyl- 1--pyddino)-2- oxaprnpane dichioride) has been evaluated as an oxime alternative to pralidoxime, and toxogonin in the treatment of organophosphorus (OP) poisoning. The dose response effects of atropine (ATR) and HI-6 were investigated to more fully explore the interaction of these compounds in the treatment of OP poisoning. ATR, HI-6 and various combinations of the two drugs were evaluated against lethal poisoning by soman (GD) and tabun (GA) in guinea pigs. The effect of adjunctive diazepam treatment on the efficacy of atropine and HI-6 against soman was also investigated. Animals of either sex were challenged s.c. with OP and treated i.m. 1 min later with ATR and/or HI-6. When used, diazepam was injected immediately after ATR+HI6. LD50s of each treatment were calculated from probit models based on 24-hour survival against 5 levels of nerve agent and 6 animals per challenge level. A protective index (PI) was calculated by dividing the nerve agent LD50 in the presence of treatment by the LD50 in the absence of treatment. Treatment with HI-6 alone had little effect on the toxicity of either OP. Treatment with ATR alone was more effective than HI-6 alone and was significantly more effective against soman than against tabun. When used in combination atropine and HI-6 had a strong synergistic effect against both agents. The dose of atropine used with HI-6 was critical in determining the efficacy of HI-6 against either agent. The slopes of the dose-lethality curves were minimally affected by the dose of ATR or HI-6. Adjunctive treatment with diazepam enhanced the efficacy of HI-6 and atropine against soman.

  17. Acute aerobic exercise and affect: current status, problems and prospects regarding dose-response.

    Ekkekakis, P; Petruzzello, S J

    1999-11-01

    One of the assumptions underlying recent physical activity recommendations is that lower doses of activity (i.e. intensity and duration) are more enjoyable for the average person, thus leading to higher involvement and adherence rates. However, the veracity of this hypothesis can be questioned, since little is actually known regarding the association between activity doses and affective responses. The few preliminary attempts at the conceptual delineation of the dose-response relationship, all centred around an 'inverted-U' notion, are reviewed and criticised as lacking empirical foundation. Available meta-analyses, as well as the empirical literature on the role of exercise intensity and duration, are examined. Increased intensity appears to be associated with reduced positivity of affect during and immediately following an exercise bout. Intensity effects appear to be attenuated during recovery. Fitness and training status appear to become significant mediators of the exercise-affect relationship only at high intensities. With intensity being kept constant, different exercise bout durations have not been shown to have a differential impact on pre- to post-exercise affective changes. Recommendations for future research include: (i) a shift from categorical to dimensional conceptualisations and operationalisations of affect; (ii) the examination of psychological theories on the association between activation and affect (e.g. extraversion-introversion, sensation seeking, type A behaviour pattern and related self-evaluative tendencies, reversal theory, optimal stimulation theory, multidimensional activation theory and self-efficacy); (iii) the systematic and theory-based examination of in-task and post-exercise affective responses; (iv) the incorporation of the parameter of fitness and/or activity status in research designs; and (v) the re-evaluation of methods for selecting exercise intensity levels. PMID:10593646

  18. Intracoronary irradiation: dose response for the prevention of restenosis in swine

    Purpose: Restenosis after percutaneous transluminal coronary angioplasty represents, in part, a proliferative response of vascular smooth muscle at the site of injury. We have previously shown that high-dose radiation (20 Gy), delivered via an intracoronary 192Ir source, causes focal medial fibrosis and markedly impairs the restenosis process after balloon angioplasty in swine. This study sought to delineate the dose-response characteristics of this effect. Methods and Materials: Forty juvenile swine underwent coronary angiography; a segment of the left coronary artery was chosen as a target for balloon injury. In 30 swine, a 2 cm ribbon of 192Ir was positioned at the target segment and 20, 15, or 10 Gy were delivered to the vessel wall (10 animals/dose). Subsequently, overdilatation balloon angioplasty was performed at the irradiated segment. In 10 control swine, overdilatation balloon angioplasty was performed without previous irradiation. Thirty-eight animals survived until sacrifice at 30 ± 3 days. Histopathological analysis was performed by a pathologist in a blinded manner. The area of maximal luminal compromise within the target segment was analyzed via computer-assisted planimetry. Results: Neointimal area was decreased by 71.4% at 20 Gy and by 58.3% at 15 Gy compared with control animals (p < 0.05 for both). A stimulatory effect on smooth muscle cell proliferation was noted at 10 Gy, with a 123% increase in neointimal area compared with controls (p < 0.05). Mean percent area stenosis was also reduced by 63% at 20 Gy and by 74.8% at 15 Gy compared with controls (p < 0.05 for both). Conclusions: Intracoronary irradiation prior to overstretch balloon angioplasty markedly reduces neointima formation; this effect is dose dependent, with evidence of a significant stimulatory effect at 10 Gy. The effective therapeutic dose range for the prevention of restenosis in this model begins at approximately 15 Gy delivered to the vessel wall

  19. Dose-response relationship between sports activity and musculoskeletal pain in adolescents.

    Kamada, Masamitsu; Abe, Takafumi; Kitayuguchi, Jun; Imamura, Fumiaki; Lee, I-Min; Kadowaki, Masaru; Sawada, Susumu S; Miyachi, Motohiko; Matsui, Yuzuru; Uchio, Yuji

    2016-06-01

    Physical activity has multiple health benefits but may also increase the risk of developing musculoskeletal pain (MSP). However, the relationship between physical activity and MSP has not been well characterized. This study examined the dose-response relationship between sports activity and MSP among adolescents. Two school-based serial surveys were conducted 1 year apart in adolescents aged 12 to 18 years in Unnan, Japan. Self-administered questionnaires were completed by 2403 students. Associations between time spent in organized sports activity and MSP were analyzed cross-sectionally (n = 2403) and longitudinally (n = 374, students free of pain and in seventh or 10th grade at baseline) with repeated-measures Poisson regression and restricted cubic splines, with adjustment for potential confounders. The prevalence of overall pain, defined as having pain recently at least several times a week in at least one part of the body, was 27.4%. In the cross-sectional analysis, sports activity was significantly associated with pain prevalence. Each additional 1 h/wk of sports activity was associated with a 3% higher probability of having pain (prevalence ratio = 1.03, 95% confidence interval = 1.02-1.04). Similar trends were found across causes (traumatic and nontraumatic pain) and anatomic locations (upper limbs, lower back, and lower limbs). In longitudinal analysis, the risk ratio for developing pain at 1-year follow-up per 1 h/wk increase in baseline sports activity was 1.03 (95% confidence interval = 1.02-1.05). Spline models indicated a linear association (P adolescents played sports, the more likely they were to have and develop pain. PMID:26894915

  20. Association between dietary vitamin C intake and risk of esophageal cancer: A dose-response meta-analysis.

    Bo, Yacong; Lu, Yan; Zhao, Yan; Zhao, Erjiang; Yuan, Ling; Lu, Weiquan; Cui, Lingling; Lu, Quanjun

    2016-04-15

    While several epidemiological studies have investigated the association between vitamin C and risk of esophageal cancer, the results remain inconsistent. In the present study, a meta-analysis was conducted to assess the impact of dietary vitamin C intake on esophageal cancer risk. Online databases were searched up to March 29, 2015, for studies on the association between dietary vitamin C intake and esophageal cancer risk. Pooled risk ratios (RRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Dose-response analyses were performed using the method of restricted cubic splines with four knots at percentiles of 5, 35, 65 and 95% of the distribution. Publication bias was estimated using Egger's tests and funnel plots. In all, 15 articles were included in this meta-analysis, including 20 studies, containing 7063 controls and 3955 cases of esophageal cancer. By comparing the highest vs. the lowest categories of vitamin C intake, we found that vitamin C was inversely associated with the risk of esophageal cancer [overall OR = 0.58, 95% CI = 0.49-0.68, I(2)  = 56%]. A linear dose-response relationship was found. With an increase in dietary vitamin C intake of 50 mg/day, the risk of esophageal cancer statistically decreased by 13% (OR = 0.87, 95% CI = 0.80-0.93, plinearity  = 0.0002). In conclusion, our analysis suggested that the higher intake of dietary vitamin C might have a protective effect against esophageal cancer. PMID:26355388

  1. SU-F-BRD-05: Dosimetric Comparison of Protocol-Based SBRT Lung Treatment Modalities: Statistically Significant VMAT Advantages Over Fixed- Beam IMRT

    Purpose: The purpose of this study is to inter-compare and find statistically significant differences between flattened field fixed-beam (FB) IMRT with flattening-filter free (FFF) volumetric modulated arc therapy (VMAT) for stereotactic body radiation therapy SBRT. Methods: SBRT plans using FB IMRT and FFF VMAT were generated for fifteen SBRT lung patients using 6 MV beams. For each patient, both IMRT and VMAT plans were created for comparison. Plans were generated utilizing RTOG 0915 (peripheral, 10 patients) and RTOG 0813 (medial, 5 patients) lung protocols. Target dose, critical structure dose, and treatment time were compared and tested for statistical significance. Parameters of interest included prescription isodose surface coverage, target dose heterogeneity, high dose spillage (location and volume), low dose spillage (location and volume), lung dose spillage, and critical structure maximum- and volumetric-dose limits. Results: For all criteria, we found equivalent or higher conformality with VMAT plans as well as reduced critical structure doses. Several differences passed a Student's t-test of significance: VMAT reduced the high dose spillage, evaluated with conformality index (CI), by an average of 9.4%±15.1% (p=0.030) compared to IMRT. VMAT plans reduced the lung volume receiving 20 Gy by 16.2%±15.0% (p=0.016) compared with IMRT. For the RTOG 0915 peripheral lesions, the volumes of lung receiving 12.4 Gy and 11.6 Gy were reduced by 27.0%±13.8% and 27.5%±12.6% (for both, p<0.001) in VMAT plans. Of the 26 protocol pass/fail criteria, VMAT plans were able to achieve an average of 0.2±0.7 (p=0.026) more constraints than the IMRT plans. Conclusions: FFF VMAT has dosimetric advantages over fixed beam IMRT for lung SBRT. Significant advantages included increased dose conformity, and reduced organs-at-risk doses. The overall improvements in terms of protocol pass/fail criteria were more modest and will require more patient data to establish difference trends of more statistical significance

  2. Spatial and doseresponse analysis of fibrotic lung changes after stereotactic body radiation therapy

    Purpose: Stereotactic body radiation therapy (SBRT) is becoming the standard of care for early stage nonoperable lung cancers. Accurate doseresponse modeling is challenging for SBRT because of the decreased number of clinical toxicity events. As a surrogate for a clinical toxicity endpoint, studies have proposed to use radiographic changes in follow up computed tomography (CT) scans to evaluate lung SBRT normal tissue effects. The purpose of the current study was to use local fibrotic lung regions to spatially and dosimetrically evaluate lung changes in patients that underwent SBRT.Methods: Forty seven SBRT patients treated at our institution from 2003 to 2009 were used for the current study. Our patient cohort had a total of 148 follow up CT scans ranging from 3 to 48 months post-therapy. Post-treatment scans were binned into intervals of 3, 6, 12, 18, 24, 30, and 36 months after the completion of treatment. Deformable image registration was used to align the follow up CT scans with the pretreatment CT and dose distribution. Areas of visible fibrotic changes were contoured. The centroid of each gross tumor volume (GTV) and contoured fibrosis volume was calculated and the fibrosis volume location and movement (magnitude and direction) relative to the GTV and 30 Gy isodose centroid were analyzed. To perform a doseresponse analysis, each voxel in the fibrosis volume was sorted into 10 Gy dose bins and the average CT number value for each dose bin was calculated. Doseresponse curves were generated by plotting the CT number as a function of dose bin and time posttherapy.Results: Both fibrosis and GTV centroids were concentrated in the upper third of the lung. The average radial movement of fibrosis centroids relative to the GTV centroids was 2.6 cm with movement greater than 5 cm occurring in 11% of patients. Evaluating doseresponse curves revealed an overall trend of increasing CT number as a function of dose. The authors observed a CT number plateau at doses ranging from 30 to 50 Gy for the 3, 6, and 12 months posttherapy time points. There was no evident plateau for the doseresponse curves generated using data from the 18, 24, 30, and 36 months posttherapy time points.Conclusions: Regions of local fibrotic lung changes in patients that underwent SBRT were evaluated spatially and dosimetrically. The authors found that the average fibrosis movement was 2.6 cm with movement greater than 5 cm possible. Evaluating doseresponse curves revealed an overall trend of increasing CT number as a function of dose. Furthermore, our doseresponse data also suggest that one of the possible explanations of the CT number plateau effect may be the time posttherapy of the acquired data. Understanding normal tissue doseresponse is important for reducing toxicity after SBRT, especially in cases where larger tumors are treated. The methods presented in the current work build on prior quantitative studies and further enhance the understanding of normal lung doseresponse after SBRT

  3. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular response to radiation could be sex and age dependent. The early hippocampal vascular dose-response could predict late neurocognitive dysfunction. (Support: NIH-RO1NS064973)

  4. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y [University of Michigan, Ann Arbor, MI (United States)

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular response to radiation could be sex and age dependent. The early hippocampal vascular dose-response could predict late neurocognitive dysfunction. (Support: NIH-RO1NS064973)

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

    Chung, Eugene [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Corbett, James R. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Moran, Jean M. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Griffith, Kent A. [Department of Biostatistics, University of Michigan, Ann Arbor, Michigan (United States); Marsh, Robin B.; Feng, Mary; Jagsi, Reshma; Kessler, Marc L. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States); Ficaro, Edward C. [Division of Nuclear Medicine, Department of Radiology, University of Michigan, Ann Arbor, Michigan (United States); Pierce, Lori J., E-mail: ljpierce@umich.edu [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    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.

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

    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

  7. Dose-response study of thimerosal-induced murine systemic autoimmunity

    The organic compound ethylmercurithiosalicylate (thimerosal), which is primarily present in the tissues as ethylmercury, has caused illness and several deaths due to erroneous handling when used as a disinfectant or as a preservative in medical preparations. Lately, possible health effects of thimerosal in childhood vaccines have been much discussed. Thimerosal is a well-known sensitizing agent, although usually of no clinical relevance. In rare cases, thimerosal has caused systemic immune reactions including acrodynia. We have studied if thimerosal might induce the systemic autoimmune condition observed in genetically susceptible mice after exposure to inorganic mercury. A.SW mice were exposed to 1.25-40 mg thimerosal/l drinking water for 70 days. Antinucleolar antibodies, targeting the 34-kDa protein fibrillarin, developed in a dose-related pattern and first appeared after 10 days in the two highest dose groups. The lowest observed adverse effect level (LOAEL) for antifibrillarin antibodies was 2.5 mg thimerosal/l, corresponding to an absorbed dose of 147 μg Hg/kg bw and a concentration of 21 and 1.9 μg Hg/g in the kidney and lymph nodes, respectively. The same LOAEL was found for tissue immune-complex deposits. The total serum concentration of IgE, IgG1, and IgG2a showed a significant dose-related increase in thimerosal-treated mice, with a LOAEL of 5 mg thimerosal/l for IgG1 and IgE, and 20 mg thimerosal/l for IgG2a. The polyclonal B-cell activation showed a significant dose-response relationship with a LOAEL of 10 mg thimerosal/l. Therefore, thimerosal induces in genetically susceptible mice a systemic autoimmune syndrome very similar to that seen after treatment with inorganic mercury, although a higher absorbed dose of Hg is needed using thimerosal. The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury

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

    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...

  9. Statistics of regional surface temperatures post year 1900. Long-range versus short-range dependence, and significance of warming trends.

    Løvsletten, Ola; Rypdal, Martin; Rypdal, Kristoffer; Fredriksen, Hege-Beate

    2015-04-01

    We explore the statistics of instrumental surface temperature records on 5°× 5°, 2°× 2°, and equal-area grids. In particular, we compute the significance of determinstic trends against two parsimonious null models; auto-regressive processes of order 1, AR(1), and fractional Gaussian noises (fGn's). Both of these two null models contain a memory parameter which quantifies the temporal climate variability, with white noise nested in both classes of models. Estimates of the persistence parameters show significant positive serial correlation for most grid cells, with higher persistence over occeans compared to land areas. This shows that, in a trend detection framework, we need to take into account larger spurious trends than what follows from the frequently used white noise assumption. Tested against the fGn null hypothesis, we find that ~ 68% (~ 47%) of the time series have significant trends at the 5% (1%) significance level. If we assume an AR(1) null hypothesis instead, then the result is that ~ 94% (~ 88%) of the time series have significant trends at the 5% (1%) significance level. For both null models, the locations where we do not find significant trends are mostly the ENSO regions and the North-Atlantic. We try to discriminate between the two null models by means of likelihood-ratios. If we at each grid point choose the null model preferred by the model selection test, we find that ~ 82% (~ 73%) of the time series have significant trends at the 5% (1%). We conclude that there is emerging evidence of significant warming trends also at regional scales, although with a much lower signal-to-noise ratio compared to global mean temperatures. Another finding is that many temperature records are consistent with error models for internal variability that exhibit long-range dependence, whereas the temperature fluctuations of the tropical oceans are strongly influenced by the ENSO, and therefore seemingly more consistent with random processes with short-range dependence. Four different data products, HADCRUT4, NOAA mlost, GISS and Berkely Earth, are analyzed in this project, with similar results in all cases.

  10. The role of variability of dose in dose-response relationships for alpha emitting radionuclides

    Radiation protection requires predictions of the effects of radiation at low mean organ doses. Since epidemiological data are restricted to moderate to high doses, extrapolation functions must be developed. The present paper derives such a function from theoretical considerations of the ability of radiation to initiate, promote and kill cells. The resulting function, however, is unable to account for the continued increase in cancer incidence amongst uranium miners and 224Ra cases at mean organ doses of several tens of grays. This failure is ascribed to the use of mean organ dose as an appropriate variable in dose-response equations. By an explicit incorporation of variability in cellular doses, the model developed here is shown to display the general features of the epidemiological data when model parameters are made consistent with findings from cellular radiobiology. This indicates that variability of cellular dose may play an essential role in determining the shape of epidemiologically based dose-response curves. (author)

  11. Aspartame tablets-gamma dose response and usability for routine radiation processing dosimetry using spectrophotometry

    Shinde, S.H. [Radiation Safety Systems Division, Bhabha Atomic Research Centre, Mumbai 400 085 (India)]. E-mail: shs_barc@yahoo.com; Mukherjee, T. [Radiation Safety Systems Division, Chemistry Group, Bhabha Atomic Research Centre, Mumbai 400 085 (India)

    2007-02-15

    Aspartame tablets were studied for gamma dose response, using spectrophotometric read-out method. The optimum concentration for ferrous ions was 2x10{sup -4}moldm{sup -3} and xylenol orange with 2.5x10{sup -1}moldm{sup -3} of sulphuric acid for the optimum acidity in FX solution. Wavelength of maximum absorbance is 548nm. Post-irradiation stability is appreciable i.e. for not less than one month. Dose response is non-linear with third order polynomial fit, in the dose range of 1000-10000Gy. This system of aspartame was further used for carrying out relative percentage dose profile measurement in Gamma Cell-220. Results obtained were inter-compared with that of a glutamine dosimeter, which showed that maximum difference between the values of aspartame and glutamine systems is within +/-10%.

  12. Aspartame tablets-gamma dose response and usability for routine radiation processing dosimetry using spectrophotometry

    Aspartame tablets were studied for gamma dose response, using spectrophotometric read-out method. The optimum concentration for ferrous ions was 2x10-4moldm-3 and xylenol orange with 2.5x10-1moldm-3 of sulphuric acid for the optimum acidity in FX solution. Wavelength of maximum absorbance is 548nm. Post-irradiation stability is appreciable i.e. for not less than one month. Dose response is non-linear with third order polynomial fit, in the dose range of 1000-10000Gy. This system of aspartame was further used for carrying out relative percentage dose profile measurement in Gamma Cell-220. Results obtained were inter-compared with that of a glutamine dosimeter, which showed that maximum difference between the values of aspartame and glutamine systems is within +/-10%

  13. Dose-response relation for chromosomal aberrations in irradiated human lymphocytes

    The linear-quadratic equation (LQE) was fitted to the frequency of dicentrics and rings produced by gamma irradiation in human lymphocytes in different dose ranges. It was found that at higher doses the linear term of the LQE increased whereas the quadratic term decreased. The same regularity was observed when the results of other authors were subjected to the same analysis. This result questioned the validity of the 'dual theory' for interpretation of the production of chromosomal abberations, and the LQE appeared to be inadequate for extrapolation of effect to low doses. The dose-response relation was studied experimentally at low doses using a sufficient number of doses and cells. An anomalous response at low doses, not predicted by the existing theories, was found. The mechanism underlying the shape of the dose-response curves is discussed. (author)

  14. Single-dose-response curves of murine gastrointestinal crypt stem cells

    Dose-response curves for the reproductive capacity of crypt stem cells of murine colonic, jejunal, and gastric mucosae exposed in situ to multifractionated gamma ray exposures were analyzed and single-dose-survival curves of these cells were constructed. The following conclusions were drawn: (1) The single-dose-response curves bend downward over a dose range of approximately 200 to 1500 rad; (2) cell death seems to be due to nonrepairable damage at doses less than 250 rad for colon, and 220 rad for jejunum; (3) there are 21, 110, and 140 stem cells per crypt of gastric, colonic, and jejunal mucosa, respectively; and (4) jejunal stem cells are the most radiosensitive and gastric mucosal stem cells are the most resistant

  15. 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. PMID:22496105

  16. The nickel doseresponse relationship by filaggrin genotype (FLG)

    Ross-Hansen, Katrine; Johansen, Jeanne D; Vlund, Aage; Menn, Torkil; Thyssen, Jacob P

    2014-01-01

    BACKGROUND: On skin contact, nickel accumulates in the stratum corneum, where it is probably bound to proteins and amino acids. One probable contributor is filaggrin, which binds nickel avidly. Filaggrin gene (FLG) null mutations lead to a complete lack of filaggrin production from the affected......-sensitized female patients, seven heterozygous mutation carriers and six non-mutation carriers (genotyped for R501X, 2282del4, or R2447X), were patch tested and performed a repeated open application test (ROAT) with a nickel sulfate dilution series. Logistic threshold dose-response analyses were used to test for...... differences between the two groups. RESULTS: No difference was found in the dose-response relationship between FLG mutation and non-mutation carriers. CONCLUSIONS: On the basis of this small patient study, it appears that the elicitation threshold level for nickel is independent of FLG null mutation single...

  17. An Interlaboratory Validation of the Radiation Dose Response Relationship (DRR) for H-ARS in the Rhesus Macaque.

    Thrall, Karla D; Love, Ruschelle; OʼDonnell, Kyle C; Farese, Ann M; Manning, Ronald; MacVittie, Thomas J

    2015-11-01

    The Medical Countermeasures against Radiological Threats (MCART) consortium has established a dose response relationship for the hematopoietic acute radiation syndrome (HARS) in the rhesus macaque conducted under an individualized supportive care protocol, including blood transfusions. Application of this animal model as a platform for demonstrating efficacy of candidate medical countermeasures is significantly strengthened when the model is independently validated at multiple institutions. The study reported here describes implementation of standard operating procedures at an institute outside the consortium in order to evaluate the ability to establish an equivalent radiation dose response relationship in a selected species. Validation of the animal model is a significant component for consideration of the model protocol as an FDA-recommended drug development tool in the context of the "Animal Rule." In the current study, 48 male rhesus macaques (4-8 kg) were exposed to total-body irradiation (TBI) using 6 MV photon energy at a dose rate of approximately 0.8 Gy min. Results show that onset and duration of the hematological response, including anemia, neutropenia, and thrombocytopenia, following TBI ranging from 6.25 to 8.75 Gy correlate well with previously reported findings. The lethality values at 60 d following TBI were estimated to be 6.88 Gy (LD30/60), 7.43 Gy (LD50/60), and 7.98 Gy (LD70/60). These values are equivalent to those published previously of 7.06 Gy (LD30/60), 7.52 Gy (LD50/60), and 7.99 Gy (LD70/60); the DRR slope (p = 0.68) and y-intercepts show agreement along the complete dose range for HARS. The ability to replicate the previously established institutional lethality profile (PROBIT) and model outcomes through careful implementation of defined procedures is a testament to the robustness of the model and highlights the need for consistency in procedures. PMID:26425909

  18. Extent of exposure to environmental tobacco smoke (ETS and its dose-response relation to respiratory health among adults

    Ward Kenneth D

    2005-02-01

    Full Text Available Abstract Background There is a dearth of standardized studies examining exposure to environmental tobacco smoke (ETS and its relationship to respiratory health among adults in developing countries. Methods In 2004, the Syrian Center for Tobacco Studies (SCTS conducted a population-based survey using stratified cluster sampling to look at issues related to environmental health of adults aged 1865 years in Aleppo (2,500,000 inhabitants. Exposure to ETS was assessed from multiple self-reported indices combined into a composite score (maximum 22, while outcomes included both self-report (symptoms/diagnosis of asthma, bronchitis, and hay fever, and objective indices (spirometric assessment of FEV1 and FVC. Logistic and linear regression analyses were conducted to study the relation between ETS score and studied outcomes, whereby categorical (tertiles and continuous scores were used respectively, to evaluate the association between ETS exposure and respiratory health, and explore the dose-response relationship of the association. Results Of 2038 participants, 1118 were current non-smokers with breath CO levels ? 10 ppm (27.1% men, mean age 34.7 years and were included in the current analysis. The vast majority of study participants were exposed to ETS, whereby only 3.6% had ETS score levels ? 2. In general, there was a significant dose-response pattern in the relationship of ETS score with symptoms of asthma, hay fever, and bronchitis, but not with diagnoses of these outcomes. The magnitude of the effect was in the range of twofold increases in the frequency of symptoms reported in the high exposure group compared to the low exposure group. Severity of specific respiratory problems, as indicated by frequency of symptoms and health care utilization for respiratory problems, was not associated with ETS exposure. Exposure to ETS was associated with impaired lung function, indicative of airflow limitation, among women only. Conclusions This study provides evidence for the alarming extent of exposure to ETS among adult non-smokers in Syria, and its dose-response relationship with respiratory symptoms of infectious and non-infectious nature. It calls for concerted efforts to increase awareness of this public health problem and to enforce regulations aimed at protecting non-smokers.

  19. Variation through the cell cycle in the dose-response of DNA neutral filter elution in X-irradiated synchronous CHO-cells

    Dose-response curves for DNA neutral (pH 9.6) filter elution were obtained with synchronized CHO cells exposed to X-rays at various phases of cell cycle. The dose response was similar in synchronized and plateau-phase G1 cells, as well as in cells arrested at the G1/S border using aphidicolin; it flattened as cells progressed into S phase and reached a minimum in the middle of this phase. An increase in DNA elution dose response, to values only slightly lower than those obtained with G1 cells, was observed as cells entered G2 phase. Significant alterations in the sedimentation properties of the DNA during S phase were also observed in Ehrlich ascites tumor cells using the neutral sucrose gradient centrifugation technique. A significant proportion of the DNA from S cells irradiated with 10 Gy sedimented at speeds (350S-700S) well above the maximum sedimentation speed expected for free sedimenting DNA molecules (ssub(max) = 350S), indicating the formation of a DNA complex. DNA from G1, G1/S, or G2 + M cells sedimented as expected for free sedimenting molecules. (author)

  20. Does a dose-response relation exist between spinal pain and temporomandibular disorders?

    Englund Erling; Malker Hans; Wiesinger Birgitta; Wnman Anders

    2009-01-01

    Abstract Background The aim of this study was to test whether a reciprocal dose-response relation exists between frequency/severity of spinal pain and temporomandibular disorders (TMD). Methods A total of 616 subjects with varying severity of spinal pain or no spinal pain completed a questionnaire focusing on symptoms in the jaw, head and spinal region. A subset of the population (n = 266) were sampled regardless of presence or absence of spinal pain. We used two different designs, one with f...

  1. A comparison of dose-response models for death from hematological depression

    Many radiation-induced lethality experiments that have been published for various mammalian species have been compiled into a database suitable to study interspecific variability of radiosensitivity, dose-rate dependence of sensitivity, dose-response behavior within each experiment, etc. The data compiled were restricted to continuous and nearly continuous exposures to photon radiations having source energies above 100 keV. Also, photon source energy, exposure geometry, and body weight considerations were used to select studies where the dose to hematopoietic marrow was nearly uniform, i.e., < +- 20%. The data base reflects 13 mammalian test species ranging from mouse to cattle. Some 211 studies were compiled but only 105 were documented in adequate detail to be useful in development and evaluation of dose-response models of interest to practical human exposures. Of the 105 studies, 70 were for various rodent species, and 35 were for nonrodent groups ranging from standard laboratory primates (body weight ∼5 kg) to cattle (body weight 375 kg). This paper considers seven different dose-response models which are tested for validity against those 105 studies. The dose-response models included: a right-skewed extreme value, a left-skewed extreme value model, log-logistic, log-probit, logistic, probit, and Weibull models. In general, the log transformed models did not improve model performance and the extreme value models did not seem consistent with the preponderance of the data. Overall, the probit and the logistic models seemed preferable over the Weibull model. 30 refs., 8 tabs

  2. Dose response severity functions for acoustic disturbance in cetaceans using recurrent event survival analysis

    Harris, C. M.; Sadykova, D.; DeRuiter, S.L.; Tyack, P. L.; Miller, P.J.O.; Kvadsheim, P. H.; Lam, F.P.A.; L. Thomas

    2015-01-01

    Behavioral response studies (BRSs) aim to enhance our understanding of the behavior changes made by animals in response to specific exposure levels of different stimuli, often presented in an increasing dosage. Here, we focus on BRSs that aim to understand behavioral responses of free-ranging whales and dolphins to manmade acoustic signals (although the methods are applicable more generally). One desired outcome of these studies is dose-response functions relevant to different species, signal...

  3. Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation

    Yuece, Ulkue Rabia, E-mail: ulkuyuce@hotmail.co [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Meric, Niyazi, E-mail: meric@ankara.edu.t [Ankara University, Faculty of Engineering, Department of Engineering Physics, 06100, Tandogan - Ankara (Turkey); Atakol, Orhan, E-mail: atakol@science.ankara.edu.t [Ankara University, Science Faculty, Department of Chemistry, 06100, Tandogan - Ankara (Turkey); Yasar, Fusun, E-mail: ab121310@adalet.gov.t [Council of Forensic Medicine, Ankara Branch, Ankara (Turkey)

    2010-08-15

    The beta dose response and Optically Stimulated Luminescence (OSL) signal stability characteristics of human tooth enamel deproteinated by hydrazine reagent under blue photon stimulation are reported. Removal of the protein organic component of tooth enamel resulted in a higher OSL sensitivity and slower fading of OSL signals. The effect of chemical sample preparation on the enamel sample sensitivity is discussed and further steps to make this deproteinization treatment suitable for in vitro dose reconstruction studies are suggested.

  4. Dose-response data for X-ray induced translocations in spermatogonia of rhesus monkeys

    The yields of translocations in spermatocytes after irradiation of spermatogonia of Rhesus monkeys with doses of 100, 220, or 300 rad X-rays were low and consistent with a humped dose-response curve with a peak at about 200 rad. Such a curve would agree well with earlier results on the marmoset and man, but the yields at any dose in the Rhesus monkey were lower

  5. Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients

    Purpose: To study the incidence of various forms of late normal tissue injuries to determine the latency and dose-response relationships. Methods: We retrospectively analyzed the clinical records of 150 breast cancer patients treated with radiotherapy after mastectomy in the mid to late 1960s. None of the patients had received chemotherapy as a part of their primary treatment. Radiotherapy was delivered to the parasternal, axillary, and supraclavicular lymph node regions. Almost all the patients continued to be checked at regular 3-month to 1-year intervals at our Oncology Department. Detailed records were available for the entire 34 years of the follow-up period. The patients were divided into 3 groups. The prescribed dose was either 11x4 Gy (treated with 60Co photons) or 11x4 Gy or 14-15x3 Gy (treated with both 60Co photons and electrons). The dose recalculation at the brachial plexus where the axillary and supraclavicular beams overlapped was performed in the early 1970s and expressed in cumulative radiation effect (CRE) units. It varied widely among the individual patients. The received dose has now been converted to biologic effective dose3 units, and from that into the equivalent dose in 2-Gy fractions to plot the dose-response relationships. Results: We present a comparison of the latency and frequency of fibrosis, edema, brachial plexus neuropathy, and paralysis in the three different subgroups and the total group. Dose-response relationships are shown at 5, 10, and 30 years after irradiation. Conclusion: The use of large daily fractions, combined with hotspots from overlapping fields, was the cause of the complications. Clear dose-response curves were seen for late radiation injuries. The incidence seen at 5 years did not represent the full spectrum of injuries. Doses that seem safe at 5 years can lead to serious complications later

  6. Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

    Jeffrey B. Blumberg; Vita, Joseph A.; C. -Y. Oliver Chen

    2015-01-01

    Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid c...

  7. Radiation-induced heart disease: review of experimental data on dose response and pathogenesis

    Clinical and experimental heart irradiation can cause a variety of sequelae. A single dose of ? 15 Gy leads to a reversible exudative pericarditis, occurring in dogs, rabbits or rats at around 100 days. Its time-course is very similar in all species investigated, but there are considerable species and strain differences in severity and incidence. After longer, dose-dependent latency times chronic congestive myocardial failure develops. The paper reviews experimental data concerning dose response and pathogenesis. (author)

  8. Non-targeted effects and the dose response for heavy ion tumor induction

    Non-targeted effects (NTE), including bystander effects in neighbor cells of cells directly hit by radiation tracks and genomic instability in the progeny of irradiated cells, challenge traditional radiation protection paradigms on Earth. It is thus of interest to understand how NTE could impact our understanding of cancer risks from galactic cosmic rays (GCR), which are comprised of high-energy protons and heavy ions. The most comprehensive data set for tumor induction by heavy ions is the induction of Harderian gland tumors in mice by high-energy protons, helium, neon, iron and niobium ions after doses of 0.05 to several Gy. We report on an analysis of these data that compares a dose response model motivated by the conventional targeted effects (TE) model to one which includes a dose response term descriptive of non-targeted effects (NTE) in cell culture. Results show that a NTE model provides an improved fit to the Harderian gland data over the TE model. Relative biological effectiveness (RBE) factors are shown to have much larger values at low doses based on a NTE model than the maximum RBE estimates based on estimates of the ratio of initial linear slopes of heavy ions compared to γ-rays in the TE model. Our analysis provides important in vivo support for the deviation from linear dose responses at low doses for high LET radiation, which are best explained by a NTE model.

  9. The shape of the cancer mortality dose-response curve for atomic bomb survivors

    The shape of the cancer mortality dose-response in the atomic bomb survivor data is analyzed in the context of linear-quadratic (LQ) models. Results are given for all cancers except leukemia as a group, for leukemia, and for combined inferences assuming common curvature. Since there is substantial information aside from these data suggesting a dose-response concave from above, the emphasis here is not on estimating the best-fitting dose-response curve, but rather on assessing the maximal extent of curvature under LQ models which is consistent with the data. Such inferences are substantially affected by imprecision in the dose estimates, and methods are applied which make explicit allowances for biases due to this. The primary means used here to express the extent of curvature is the factor by which linear risk estimates should be divided to arrive at appropriate low-dose risk estimates. In the past, influential committees have recommended ranges of 2-10 and of 1.5-3 for such a factor. Results here suggest that values greater than about 2 are at least moderately inconsistent with these data, within the context of LQ models. It is emphasized, however, that there is little direct information in these data regarding low-dose risks; the inferences here depend strongly on the link between low-dose and high-dose risks provided by the assumption of an LQ model. (author)

  10. Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships

    Jeffrey B. Blumberg

    2015-12-01

    Full Text Available Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD, blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages.

  11. Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships.

    Blumberg, Jeffrey B; Vita, Joseph A; Chen, C-Y Oliver

    2015-12-01

    Pure fruit juices provide nutritional value with evidence suggesting some of their benefits on biomarkers of cardiovascular disease risk may be derived from their constituent polyphenols, particularly flavonoids. However, few data from clinical trials are available on the dose-response relationship of fruit juice flavonoids to these outcomes. Utilizing the results of clinical trials testing single doses, we have analyzed data from studies of 100% Concord grape juice by placing its flavonoid content in the context of results from randomized clinical trials of other polyphenol-rich foods and beverages describing the same outcomes but covering a broader range of intake. We selected established biomarkers determined by similar methods for measuring flow-mediated vasodilation (FMD), blood pressure, platelet aggregation, and the resistance of low density lipoprotein cholesterol (LDL) to oxidation. Despite differences among the clinical trials in the treatment, subjects, and duration, correlations were observed between the dose and FMD. Inverse dose-response relationships, albeit with lower correlation coefficients, were also noted for the other outcomes. These results suggest a clear relationship between consumption of even modest serving sizes of Concord grape juice, flavonoid intake, and effects on risk factors for cardiovascular disease. This approach to dose-response relationships may prove useful for testing other individual foods and beverages. PMID:26633488

  12. Human evidence on the shape of the dose-response curves for radiation carcinogenesis

    The carcinogenic effects of high levels of ionizing radiation are better understood than those of any other environmental agent. However, the somatic risk from low doses is highly disputed. The uncertainties stem from the fact that a direct estimation of small risks requires impracticably large samples. Therefore, risk estimates for low doses have to be derived indirectly by extrapolation from high exposure data and are heavily dependent on assumptions about the form of the dose-response curve. Although radiobiological theories tested on in vitro systems predict a quadratic term in the dose-response equation which should, at least for sparsely ionizing radiation, dominate the shape of the curve, the epidemiological data available cannot exclude the possibility of a pure linear relationship. In some cases, apparent thresholds may result from latent periods inversely related to dose. Besides depending on the quality of the radiation, the shape seems also to differ with the type of cancer induced. Studies on uranium miners, atomic bomb survivors and on irradiated patients are reviewed with emphasis on the shape of the dose-response. The credibility of the most publicized reports claiming a large cancer risk from low levels of radiation is assessed. The feasibility of a new study in an area of high natural background is explored. Finally, the influence of the uncertainties concerning the effect of low level radiation on future exposure limits set by regulatory bodies is discussed. (Auth.)

  13. A comparison of dose-response models for death from hematological depression in different species

    A database has been completed suitable to study interspecific variability of radiosensitivity, dose-rate dependence of sensitivity, dose-response behaviour within each experiment, etc. Data compiled were restricted to continuous and nearly continuous exposures to photon radiations having source energies above 100 keV. Photon source energy, exposure geometry, and body weight considerations were used to select studies where dose to hematopoietic tissue was approximately uniform. The database reflects 13 mammalian species ranging in size from mouse to cattle. Some 211 studies were compiled, but only 105 were documented in adequate detail to be useful in development and evaluation of dose-response models of interest to human exposures. Of the 105 studies, 70 were for rodent species, 35 for non-rodent groups ranging from standard laboratory primates (body weight ∼ 5 kg) to cattle (body weight ∼ 375 kg). Seven different dose-response models are tested for validity against the 105 studies. In general, log transformation models did not improve model performance and extreme value models did not seem consistent with the preponderance of the data. Probit and the logistic models seemed preferable over the Weibull model. (author)

  14. Dose-response relationship analysis for cancer and circulatory system disease mortality risks among uranium miners

    The relation between lung cancer risk and radon exposure has been clearly established, especially from the studies on uranium miner cohorts. But the association between radon exposure and extrapulmonary cancers and non-cancer diseases remains not well known. Moreover, the health risks associated with the other mining-related ionizing radiation exposures are still under consideration. The aim of this thesis is to contribute to the estimation of the radio-induced health risks at low-doses through the analysis of the kidney cancer and Circulatory System Disease (CSD) mortality risks among uranium miners. Kidney cancer mortality risk analyses were performed from the French cohort of uranium miners (n=5086; follow-up period: 1946-2007), the post-55 cohort (n=3,377; follow-up period: 1957-2007) and the German cohort of the Wismut (n=58,986; follow-up period: 1946-2003) which included 24, 11 and 174 deaths from kidney cancer, respectively. The exposures to radon and its short-lived progeny (expressed in Working Level Month WLM), to uranium ore dust (kBqh.m-3) and to external gamma rays (mSv) were estimated for each miners and the equivalent kidney dose was calculated. The dose-response relation was refined considering two responses: the instantaneous risk of kidney cancer mortality (corresponding to the classical analysis, Cause specific Hazard Ratio (CSHR) estimated with the Cox model) and its occurrence probability during the followup (Sub-distribution Hazard Ratio (SHR) estimated with the Fine and Gray model). An excess of kidney cancer mortality was observed only in the French cohort (SMR = 1.62 CI95%[1.04; 2.41]). In the Wismut cohort, a decrease of the kidney cancer mortality was observed (0.89 [0.78; 0.99]). For these three cohorts, the occupational radiological exposures (or the equivalent kidney dose) were significantly associated neither with the risk of kidney cancer mortality (e.g. CSHRWismut-radon/100 WLM=1.023 [0.993; 1.053]), nor with its occurrence probability during the follow-up (e.g. SHRWismut-radon /100 WLM=1.012 [0.983; 1.042]). CSD mortality risk analyses in the French cohort showed a significant increase of the risks of mortality from CSD (n=442, CSHR/100 WLM=1.11 [1.01; 1.22]) and from Cerebrovascular Disease (MCeV, n=105, CSHR/100 WLM=1.25 [1.09; 1.43]) with radon exposure. A case-control study nested in the French cohort was set up to collect the information related to CSD risk factors (overweight, hypertension, diabetes...) from the medical records of 313 miners (76 deaths from CSD (including 26 from Ischemic Heart Disease (IHD) and 16 from MCeV) and 237 controls). For the three radiological exposures, the exposure-risk relation was analyzed in a pseudo-cohort (n=1,644 pseudo-individuals, obtained from the weighting of the observations by their inverse selection probability) with the Cox model, adjusted for the CSD risk factors. The association between the radiological exposure and the risk of mortality from CSD, IHD or MCeV was not significant (e.g. CSHRCSD-radon/100 WLM=1.43 [0.71; 2.87]). The adjustment for CSD risk factors did not substantially change the exposure-risk relation. The lack of a significant dose-response relation suggests that the excess of kidney cancer mortality among the French uranium miners may be induced by other risk factors, unavailable for this study. The small change of the coefficients observed after adjustment for CSD risk factors in the nested case-control study supports the assumption of the existence of the MCeV mortality risk increase associated with radon exposure in the French cohort of uranium miners. Future analyses based on further follow-up updates should allow to confirm or not these results. (author)

  15. Comparison of the dose-response relationship of radiation-induced apoptosis in the hippocampal dentate gyrus and intestinal crypt of adult mice

    The present study compared the dose-response curves for the frequency of apoptosis in mouse hippocampal dentate gyrus (DG) and intestinal crypt using whole-body gamma irradiation. The incidence of gamma-ray-induced apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end-labelling (TUNEL) method. TUNEL-positive apoptotic nuclei in the DG and intestinal crypt were increased in a dose-dependent pattern (0-2 Gy). The dose-response curves were linear-quadratic, with a significant relationship between the appearance of apoptosis and irradiation dose. The slopes of the dose-response curves in the DG were much steeper (∼5-6-fold) than those in the intestinal crypt within the range of 0-1 Gy exposure. Hippocampal DG might be a more effective and sensitive evaluation structure than the intestinal crypt to estimate the degree of radiation exposure in damaged organs of adult mice exposed to low irradiation dose. copy; The Author 2011. Published by Oxford Univ. Press. All rights reserved. (authors)

  16. The influence of tube voltage and phantom size in computed tomography on the dose-response relationship of dicentrics in human blood samples

    The aim of this study was to investigate the dose response relationship of dicentrics in human lymphocytes after CT scans at tube voltages of 80 and 140 kV. Blood samples from a healthy donor placed in tissue equivalent abdomen phantoms of standard, pediatric and adipose sizes were exposed at dose levels up to 0.1 Gy using a 64-slice CT scanner. It was found that both the tube voltage and the phantom size significantly influenced the CT scan-induced linear dose-response relationship of dicentrics in human lymphocytes. Using the same phantom (standard abdomen), 80 kV CT x-rays were biologically more effective than 140 kV CT x-rays. However, it could also be determined that the applied phantom size had much more influence on the biological effectiveness. Obviously, the increasing slopes of the CT scan-induced dose response relationships of dicentrics in human lymphocytes obtained in a pediatric, a standard and an adipose abdomen have been induced by scattering effects of photons, which strongly increase with increasing phantom size.

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

    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 60Co gamma-rays. A dose-dependent increase of aberration yield was accompanied by a tendency to the under dispersion 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 0.098-0.129xcell-1xGy-1 and 0.039-0.034xcell-1xGy-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. (authors)

  18. Dose-response curves for fish MFO induction: How do we interpret different maxima and slopes?

    Induction of hepatic mixed function oxygenase (MFO) activity has been useful for screening effluents from pulp mills and oil refineries. Effluents and pure compounds can be assessed by direct fish exposure or by concentration with semipermeable membrane devices (SPMDs) and by measuring MFO in fish liver cell lines exposed to SPMD extracts. In these experiments, both fish and fish cells showed differences in slopes of dose-response curves, and in the maximal ethoxyresorufin-O-deethylase (EROD) activity. For example, TCDD elicits an EROD maxima of over 500 pmol/mg/min in PLHC-1 (Poeciliopsis lucida hepatocellular carcinoma cell line), while pulp mill and oil refinery effluent extracts showed maxima of 40 to 200 pmol/mg/min. Substituted phenanthrenes caused induction maxima of 100 pmol/mg/min. Similarly, in rainbow trout in vivo, TCDD and other chlorinated dioxins and furans induced up to 500 pmol/mg/min, whereas pulp mill and refinery effluents and substituted phenanthrenes produced EROD maxima of up to 100 pmol/mg/min. Differences in the slopes of dose-response curves were also common. In the current assessment of potencies, these diverse response curves are boiled-down to one number, the EC50 or other threshold-type of concentration. Comparisons of EC50s cannot express these differences and instead, ignore them. However, the authors realize there must be a better approach that takes into account these large differences in dose-response curve shape, slope and maxima. Interaction and discussions with modelers in the session will allow them to discuss various approaches to expressing the potencies of MFO inducers in fish

  19. Dose-response models and methods of risk prediction and causation estimation

    Dose-response models are mathematical expressions that describe the relationship between absorbed dose and radiogenic effects. The limited quality and quantity of human dose-response data make it necessary to use fairly simplistic models. Most current low-LET data support the linear-quadratic model in which radiogenic effects are linearly dependent at low doses and then become quadratically curved at higher doses. Some types of effects never exhibit a quadratic component, remaining linear over a wide range of absorbed dose. Future progress in developing more refined dose-response models is more likely to come from a better understanding of the fundamentals of radiation carcinogenesis rather than better data or better curve-fitting techniques. The risk of radiation injury is a prospective estimation of the probability that some harm will result in the future as a consequence of having been irradiated. Quantitative risk estimates for the carcinogenic, genetic, and fetal effects of low level radiation that have been determined by national and international organizations are of the order of magnitude of one chance fatality in 10,000/rem. Causation estimation is the retrospective analysis of the probability that cancer observed in an irradiated individual was caused by radiation as opposed to some other agent. Depending on the dose type of cancer, gender, age at time of irradiation, and time since irradiation, the probability of causation can range from 0% to 100%. Methods for calculation of the probability of causation for certain types of cancer and irradiation circumstances have been developed recently by the National Institutes of Health

  20. An assessment of non-linear dose response in chemiluminescence dosimetry

    Sugar and sorbite are well known to be convenient and suitable materials for chemiluminescence (CL) as well as electron spin resonance (ESR) dosimetry, in particular for retrospective dose assessment in an emergency and/or accident situation, mainly because of their close tissue-equivalence. In practice, however, the dose-CL response of those materials are not always shown to be satisfactorily linear. An attempt was made in this study to evaluate and correct the early supralinear dose-CL relationship appeared in the sugar and sorbite samples irradiated to gamma-ray doses of 0.5 to 10 Gy. In consideration of a similarity of the non-linear CL-dose relationship with the initial supralinearity shown in TL-dose response as depicted by Aitken, several recently proposed methods of expressing non-linear dose responses of TL, ESR or CL outputs were examined and investigated in order to look for a fittest means for the assessment of our supralinear dose-CL response of sugar and sorbite. As a result of an extensive study, merits and demerits of each method of representing non-linear dose response could be figured out in the light of our particular dose-CL relationship appeared in the sugar and sorbite samples. It is concluded that the 'supralinearity index', f(D), defined as a function of dose by Chen and McKeever is the most suitable function for expressing and correcting the non-linear dose-CL response shown in the initial low dose range of our irradiated sugar sorbite samples. The CL outputs corrected by use of f(D) are compared with those uncorrected, and the resultant CL sensitivities of the samples are numerically given together with re-evaluated dispersion of the sensitivities in terms of standard deviation. (author)

  1. Dose-response-time modelling: Second-generation turnover model with integral feedback control

    Andersson, R.; Jirstrand, M.; Peletier, L.; Chappell, M. J.; Evans, N.D.; Gabrielsson, J.

    2016-01-01

    This study presents a dose-response-time (DRT) analysis based on a large preclinical biomarker dataset on the interaction between nicotinic acid (NiAc) and free fatty acids (FFA). Data were collected from studies that examined different rates, routes, and modes of NiAc provocations on the FFA time course. All information regarding the exposure to NiAc was excluded in order to demonstrate the utility of a DRT model. Special emphasis was placed on the selection process of the biophase model. An...

  2. Dose response curve of the unsterilized products and the survival on the products

    Using the microbial radiation resistance distribution given by AAMI, the unsterilized fraction of the products was calculated at various bioburden levels, and the results obtained were shown in the dose response curves. With increasing microbical bioburden, the shoulder of the curves is becoming more remarkable. The appearance of the curves is resembled to that of multi-targets survival curves, and this fact can be realized from the analogy that the microbes on the products are to be the targets and the products are to be the cells in the target theory. (author)

  3. Dose response curve of the unsterilized products and the survival on the products

    Oka, Mitsuru; Hosobuchi, Kazunari.

    1988-11-01

    Using the microbial radiation resistance distribution given by AAMI, the unsterilized fraction of the products was calculated at various bioburden levels, and the results obtained were shown in the dose response curves. With increasing microbical bioburden, the shoulder of the curves is becoming more remarkable. The appearance of the curves is resembled to that of multi-targets survival curves, and this fact can be realized from the analogy that the microbes on the products are to be the targets and the products are to be the cells in the target theory.

  4. Uncertainty analysis in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cancer dose-response for three occupational cohorts.

    Dong, Zhaomin; Yuan, Guanxiang; Hu, Jianying

    2016-03-01

    While the U.S. EPA has issued a draft report with a 1% TCDD effective dose (ED01) of 87.9pg/kg/day based on continuous integration of key scientific evidence, a detailed and comprehensive uncertainty analysis has not been well documented. In this study, a new estimate for ED01 was derived based on uncertainty analysis by quantitatively assessing the potential bias arising from the selection of kinetic models, dose-response models and cohorts. The cumulative serum lipid concentration (CSLC) and cumulative body burden (CBB) were reconstructed as dose metrics using a concentration- and age-dependent pharmacokinetic model (CADM), physiologically based pharmacokinetic model (PBPK), and age-dependent half-life model (FV), and the reconstructed dose metrics based on CADM and PBPK were generally higher than those based on the FV model. Three dose-response curves (linear, multiplicative and power) were used to link dose metrics and cancer risk to estimate ED01, and the linear model resulted in the lowest ED01, followed by the power model and multiplicative model, for the same cohort. Meanwhile, ED01 based on the CADM model was the highest, followed by those based on the PBPK model and first-order model. Finally, the ED01 was estimated to be 17.03±7.83pg/kg/day by statistically analyzing the distribution of ED01 values based on various kinetic models, cohorts and dose-response models. The study presented here strengthens the scientific basis for understanding the potential health implications of TCDD exposure. PMID:26708281

  5. Dose-response of micronuclei frequency in lymphoblast cells irradiated with different LET rays and combination of α-particles and γ-rays

    Objective: To investigate the dose-response of micronuclei (MN) frequency in the lymphocytes irradiated with or without combination of α-particles and γ-rays. Methods: Human lymphoblast cells HMy2. CIR were irradiated with 0-1 Gy of α-particles, 0-5 Gy of γ-rays,and 0.025-0.5 Gy of α-particles followed by different doses of γ-rays,respectively. The micronuclei (MN) in the irradiated cells were measured with the cytokinesis block technique,and the dose-responses of MN were established under different irradiation conditions. Results: For γ-ray irradiation, the dose-response of MN was well-fit by the linear-quadratic model with an equation Y =c + αD + βD2. For α-particle irradiation, the MN induction increased linearly with the dose less than 0.250 Gy. But when the dose of α-particles increased continually, the dose-response curve bended and could be well fit with the BaD model Y=c + αD + σ [1 - exp(-δD)] exp (-βD) where radiation-induced bystander effect (RIBE) was indicated. For the combined exposure, the dose-response of MN was similar to that of γ-irradiation when the dose of α-particles was lower than 0.1 Gy, but it was similar to that of α-irradiation when the dose of α-particles was higher. When the dose of α-particles was 0.2 and 0.5 Gy, MN induced by the mixed radiation were significantly higher than the sum of corresponding irradiation alone (t=5.22-11.86, P<0.05). Conclusions: The radiation damage of α-particles differs from that of γ-rays, where RIBE may be involved. The combination irradiation of α-particles and γ-rays has a synergistic effect on radiation damage of lymphoblast cells. (authors)

  6. Equivalent dose determination in foraminifera: analytical description of the CO{sub 2}{sup -}-signal dose-response curve

    Hoffmann, D. E-mail: dirk.hoffmann@iup.uni-heidelberg.de; Woda, C.; Mangini, A

    2003-02-01

    The dose-response of the CO{sub 2}{sup -}signal (g=2.0006) in foraminifera with ages between 19 and 300 ka is investigated. The sum of two exponential saturation functions is an adequate function to describe the dose-response curve up to an additional dose of 8000 Gy. It yields excellent dating results but requires an artificial doses of at least 5000 Gy. For small additional doses of about 500 Gy the single exponential saturation function can be used to calculate a reliable equivalent dose D{sub E}, although it does not describ the dose-response for higher doses. The CO{sub 2}{sup -}-signal dose-response indicates that the signal has two components of which one is less stable than the other.

  7. Dose-response efficacy and long-term effect of the hypocholesterolemic effect of octadecylpectinamide in rats.

    Marounek, Milan; Volek, Zdeněk; Dušková, Dagmar; Tůma, Jan; Taubner, Tomáš

    2013-09-12

    The dose-response efficiency and long-term effect of the hypocholesterolemic effect of octadecylpectinamide was examined in female rats fed diets containing cholesterol at 10 g/kg. In our first experiment, amidated pectin supplied at 20 g/kg, 40 g/kg and 60 g/kg significantly decreased serum cholesterol from 3.32 μmol/ml (control) to 1.23 μmol/ml in a dose-dependent manner. In a second experiment, the hypocholesterolemic effect of amidated pectin supplied at 20 g/kg persisted after 3 months of feeding. In both experiments, the amidated pectin significantly decreased the concentrations of cholesterol in hepatic tissue and triacylglycerols in serum. The serum concentration of aspartate aminotransferase significantly increased in rats fed amidated pectin at 60 g/kg for 4 weeks, and at 20 g/kg for 3 months. In conclusion, amidated pectin at a low dose and used for a period shorter than 3 months might be considered as an effective hypocholesterolemic and lipid-lowering agent that may substitute typical antilipidemic drugs. PMID:23911514

  8. Specific accumulation of orally administered redox nanotherapeutics in the inflamed colon reducing inflammation with dose-response efficacy.

    Vong, Long Binh; Mo, John; Abrahamsson, Bertil; Nagasaki, Yukio

    2015-07-28

    Although current medications for ulcerative colitis (UC) are effective to some extent, there are still some limitation of their use due to the non-specific distribution, drug metabolism in the gastrointestinal tract, and severe adverse effects. In our previous studies, we developed oral redox nanoparticles (RNP(O)) that specifically accumulated and scavenged overproduced reactive oxygen species (ROS) in an inflamed colon. However, the mechanism leading to specific accumulation of RNP(O) in an inflamed colon is still unclear. In this study, we investigated the cellular uptake of RNP(O) into ROS-treated epithelial colonic cells in vitro, and compared to the untreated cells, found a significantly increased uptake in ROS-treated cells. In vivo, we discovered that orally administered RNP(O) were not internalized into the cells of a normal colon. A significant amount of disintegrated RNP(O) was detected in the cells of an inflamed colon of dextran sodium sulfate (DSS)-induced colitis mice, resulting in scavenging of ROS and suppression of inflammation with low adverse effects. Furthermore, we confirmed a significant reduction of disease activity and a robust dose response efficacy following RNP(O) treatment in acute DSS-induced colitis mice, outperforming the positive control 5-aminosalicylic acid. Oral administration of RNP(O) is a promising approach to develop a new therapy for UC disease. PMID:25998050

  9. Dose response in radiation-induced human carcinogenesis: accumulated data do not yet solve the enigma

    The carcinogenic effects of high levels of ionizing radiation are better understood than those of any other environmental agent. However, the somatic risk from low doses is highly disputed. The uncertainties stem from the fact that due to a multitude of confounding factors a direct estimation of small risks requires impracticably large samples. Therefore, risk estimates for low doses have to be derived indirectly by extrapolation from high-exposure data and are heavily dependent on assumptions about the shape of the dose-response curve. Although radiobiological theories tested mostly on in vitro systems predict a quadratic term in the dose-response equation, which should dominate the shape of the curve at least for sparsely ionizing radiation, the epidemiological data available are not yet sufficient to exclude the possibility of a purely linear relationship. In some cases, apparent thresholds may result from latent periods inversely related to dose. Besides depending on the quality of the radiation, the shape also seems to differ with the type of cancer induced. The huge epidemiological data base on atomic bomb survivors, irradiated patients, miners, and other exposed groups can most consistently be fitted to a linear quadratic model. For lung cancer in miners resulting from high linear energy transfer alpha radiation and for female breast cancer, the linear component seems to be dominant

  10. Dose - Response Curves for Dicentrics and PCC Rings: Preparedness for Radiological Emergency in Thailand

    Establishing in-vitro dose calibration curves is important for reconstruction of radiation dose in the exposed individuals. The aim of this pioneering work in Thailand was to generate dose-response curves using conventional biological dosimetry: dicentric chromosome assay (DCA) and premature chromosome condensation (PCC) assay. The peripheral blood lymphocytes were irradiated with 137Cs at a dose rate of 0.652 Gy/min to doses of 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4 and 5 Gy for DCA technique, and 5, 10, 15, 20 and 25 Gy for PCC technique. The blood samples were cultured and processed following the standard procedure given by the IAEA with slight modifications. At least 500-1,000 metaphases or 100 dicentrics/ PCC rings were analyzed using an automated metaphase finder system. The yield of dicentrics with dose was fitted to a linear quadratic model using Chromosome Aberration Calculation Software (CABAS, version 2.0), whereas the dose-response curve of PCC rings was fitted to a linear relationship. These curves will be useful for in-vitro dose reconstruction and can support the preparedness for radiological emergency in the country.

  11. Dose response of F center optical absorption in LiF:Mg,Ti (TLD-100)

    Optical absorption (OA) of nominally pure single crystal LiF following beta irradiation was measured in order to estimate, the energy and width of the dominant F-band with minimum interference from dopant-related bands. The OA dose response of LiF:Mg,Ti was measured to 30,000 Gy, a level of dose sufficiently high to observe total saturation of the F band, which, we believe, reduces uncertainty in the estimation of the dose filling constant. The dose filling constants for the OA bands associated with the trapping center (4 eV) and competitive center (5.45 eV) responsible for the major dosimetric TL glow peak 5 were also determined. The results of these studies will be used in the framework of a kinetic model which includes the effects of radiation created defects and which will aid in the investigation of the capability of Track Structure Theory to predict OA heavy charged particle (HCP) relative efficiencies. - Highlights: • The energy and width of the F-band in LiF are estimated. • OA dose response was extended to high levels of dose including deconvolution. • Dose filling constants of the major OA bands were determined

  12. Non-linear dose response of a few plant taxa to acute gamma radiation

    Micronuclei induction serves as an essential biomarker of radiation stress in a living system, and the simplicity of its detection technique has made it a widely used indicator of radiation damage. The present study was conducted to reveal the cytological dose-response of a few plant taxa, viz., Allium cepa var. aggregatum Linn., Allium sativum Linn., Chlorophytum comosum (Thunb.) Jacques and Eichhornia crassipes (Mart.) Solms, to low LET gamma radiation with special emphasis on the pattern of micronuclei induced across low and high dose regimes. A tri-phasic non-linear dose-response pattern was observed in the four taxa studied, characterized by a low dose linear segment, a plateau and a high dose linear segment. Despite a similar response trend, the critical doses where the phase transitions occurred varied amongst the plant taxa, giving an indication to their relative radiosensitivities. E. crassipes and A. sativum, with their lower critical doses for slope modifications of phase transitions, were concluded as being more radiosensitive as compared to C. comosum and A. cepa, which had relatively higher critical doses. (author)

  13. Thermoluminescence from igneous and natural hydrothermal vein quartz: dose response after optical bleaching

    We studied optical bleaching and gamma dose response of primary quartz isolated from volcanic and granitic host rocks as well as from pegmatites and hydrothermal veins using thermoluminescence (TL). We attempted to isolate the TL signature of these individual types of quartz so that improved analysis of the TL behaviour of composite sedimentary quartz mixtures is possible. We have identified the following aspects of quartz TL in these samples: (1) large variation in TL residuals after extensive bleaching; (2) shifts in glow curve peak temperatures during bleaching and gamma dose apparently related to 2nd order TL kinetics; (3) differences in TL sensitivity to gamma dose among samples; (4) supralinear dose response of both a 230oC TL peak and a germanium EPR signal only in the pegmatitic quartz samples; and (5) the volcanic and pegmatitic samples had generally higher TL sensitivity to gamma dose than did the granitic or hydrothermal samples. We concluded that (1), (2) and (3) could contribute to enhanced scatter in routine TL dating of sediments composed of mixed fractions of different quartz types, but that none of the effects observed appear to introduce any unforeseen sources of error into ED determinations using any of the standard sediment dating methods. (author)

  14. Dose-Response Model for Chest Wall Tolerance of Stereotactic Body Radiation Therapy.

    Kimsey, Frank; McKay, Jesse; Gefter, Jeffrey; Milano, Michael T; Moiseenko, Vitali; Grimm, Jimm; Berg, Ronald

    2016-04-01

    Many recent studies have described rib fractures and chest wall pain following stereotactic body radiation therapy (SBRT). Although these toxicities generally are not life-threatening, the chest wall and ribs are considered dose-limiting tissues because of the potential effect on patients׳ quality of life. Few studies have reported dose-response models that can provide quantitative estimates of risk as a function of dose and volume. Notably, Memorial Sloan Kettering Cancer Center (Mutter et al(8)) analyzed grade 2 or higher chest wall toxicity in a cohort of 126 patients treated with linear accelerator-based SBRT; the authors provided detailed dose-volume histogram (DVH) data to allow for pooled analyses. We pooled these 126 patients with an additional 44 patients treated with CyberKnife at the Erlanger Medical Center to create an updated dose-response model for chest wall tolerance. In the aggregate analysis, the 10% risk level for grade 2 or higher complications for D70cc was 16.2Gy in 4 fractions, and the 50% risk level was D70cc = 65.1Gy in 4 fractions. For D2cc, the 10% and 50% risk levels in 4 fractions were 43.0Gy and 87.9Gy, respectively. These dose-tolerance limits may help quantify chest wall toxicity risks. Further research continues to determine more accurate estimates of grade 3 risk levels. PMID:27000509

  15. Application of the Key Events Dose-response Framework to Folate Metabolism.

    Hu, Jing; Wang, Bing; Sahyoun, Nadine R

    2016-06-10

    Folate is a vitamin that plays a role as a cofactor and coenzyme in many essential reactions. These reactions are interrelated and any change in folate homeostasis could affect other reactions. With food fortified with folic acid, and use of multivitamin, unmetabolized folic acid (UMFA) has been detected in blood circulation, particularly among older adults. This has raised concern about the potential harmful effect of high folic acid intake and UMFA on health conditions such as cognitive dysfunction and cancer. To examine what is known about folate metabolism and the release of circulating UMFA, the Key Events Dose-Response Framework (KEDRF) was used to review each of the major key events, dose-response characteristics and homeostatic mechanisms of folate metabolism. The intestine, liver and kidneys each play essential roles in regulating body folate homeostasis. But the determining event in folate metabolism leading to the release of UMFA in circulation appears to be the saturation of dihydrofolate reductase in the liver. However, at each of the key events in folate metabolism, limited information is available on threshold, homeostatic regulation and intracellular effects of folic acid. More studies are needed to fill in the knowledge gaps for quantitatively characterizing the dose-effect relationship especially in light of the call for extending folate fortification to other foods. PMID:25674817

  16. Dose-response relationships between mouse allergen exposure and asthma morbidity among urban children and adolescents.

    Torjusen, E N; Diette, G B; Breysse, P N; Curtin-Brosnan, J; Aloe, C; Matsui, E C

    2013-08-01

    Home mouse allergen exposure is associated with asthma morbidity, but little is known about the shape of the dose-response relationship or the relevance of location of exposure within the home. Asthma outcome and allergen exposure data were collected every 3 months for 1 year in 150 urban children with asthma. Participants were stratified by mouse sensitization, and relationships between continuous measures of mouse allergen exposure and outcomes of interest were analyzed. Every tenfold increase in the bed mouse allergen level was associated with an 87% increase in the odds of any asthma-related health care use among mouse-sensitized [Odds Ratio (95% CI): 1.87 (1.21-2.88)], but not non-mouse-sensitized participants. Similar relationships were observed for emergency department visit and unscheduled doctor visit among mouse-sensitized participants. Kitchen floor and bedroom air mouse allergen concentrations were also associated with greater odds of asthma-related healthcare utilization; however, the magnitude of the association was less than that observed for bed mouse allergen concentrations. In this population of urban children with asthma, there is a linear dose-response relationship between mouse allergen concentrations and asthma morbidity among mouse-sensitized asthmatics. Bed and bedroom air mouse allergen exposure compartments may have a greater impact on asthma morbidity than other compartments. PMID:23067271

  17. Taxol-induced cell cycle arrest and apoptosis: dose-response relationship in lung cancer cells of different wild-type p53 status and under isogenic condition.

    Das, G C; Holiday, D; Gallardo, R; Haas, C

    2001-04-26

    The effective dose, schedule, molecular basis of the cytotoxicity of taxol and their dependence on the genetic background in tumor cells are still not well understood. Here, we examined how the dose-response relationship for taxol varies in lung cancer cells with different p53 status and under isogenic conditions. DNA content analyses in A 549 (p53, +/+) and H 1299 (p53, -/-) cells, showed that taxol progressively induced G2/M arrest in both cell lines in a concentration-dependent manner, which was accompanied by a parallel decrease in the G1 population. G2/M arrest, however, occurred at a lower concentration in A 549 cell lines than in H 1299 cells. The S-phase population in A 549 cells was not significantly changed up to 0.025 microM, but dropped by six-fold at 1.0 microM taxol, in contrast to that in H 1299 cells. A sub-G1 apoptotic population was present at 24 h, even at 0.002 microM taxol, when G2/M arrest was not appreciably detected. In both cell lines, the maximum apoptosis of about 28% was achieved at 0.025 microM taxol, implicating that wild-type p53 does not modulate the level of taxol-induced apoptosis. When we examined the role of the wild-type p53 in isogenic cell lines developed in a H 1299 background, the maximum level of apoptosis was in the range of 28-34% at a drug concentration around 0.03 microM, not significantly different from that observed in parental H 1299 cells. We conclude that taxol is effective in inducing apoptosis at very low doses (0.020-0.035 microM), and that the presence or absence of the wild-type p53 does not make a statistically significant difference in the level of apoptotic cell death in these lung cancer cell lines, but the maximum is attained at a lower drug concentration in the presence of p53. PMID:11275363

  18. The doseresponse of the anal sphincter region An analysis of data from the MRC RT01 trial

    Purpose: Most studies investigating the doseresponse of the rectum focus on rectal bleeding. However, it has been reported that other symptoms such as urgency or sphincter control have a large impact on quality-of-life and that different symptoms are related to the dose to different parts of the anorectal wall. In this study correlations between the 3D dose distribution to the anal-sphincter region and radiation-induced side-effects were quantified. Materials and methods: Dosesurface maps of the anal canal were generated. Next, longitudinal and lateral extent and eccentricity were calculated at different dose levels; DSHs and DVHs were also determined. Correlations between these dosimetric measures and seven clinically relevant endpoints were determined by assessing dosimetric constraints. Furthermore, an LKB model was generated. The study was performed using the data of 388 prostate patients from the RT01 trial (ISRCTN 47772397). Results: Subjective sphincter control was significantly correlated with the dose to the anal surface. The strongest correlations were found for lateral extent at 53 Gy (p = 0.01). Outcome was also significantly correlated with the DSH and the mean dose to the anal surface. Conclusions: The dose to the anal sphincter region should be taken into account when generating treatment-plans. This could be done using shape-based tools, DSH/DVH-based tools or an NTCP model.

  19. Effect of processing time delay on the dose response of Kodak EDR2 film

    Kodak EDR2 film is a widely used two-dimensional dosimeter for intensity modulated radiotherapy (IMRT) measurements. Our clinical use of EDR2 film for IMRT verifications revealed variations and uncertainties in dose response that were larger than expected, given that we perform film calibrations for every experimental measurement. We found that the length of time between film exposure and processing can affect the absolute dose response of EDR2 film by as much as 4%-6%. EDR2 films were exposed to 300 cGy using 6 and 18 MV 10x10 cm2 fields and then processed after time delays ranging from 2 min to 24 h. An ion chamber measured the relative dose for these film exposures. The ratio of optical density (OD) to dose stabilized after 3 h. Compared to its stable value, the film response was 4%-6% lower at 2 min and 1% lower at 1 h. The results of the 4 min and 1 h processing time delays were verified with a total of four different EDR2 film batches. The OD/dose response for XV2 films was consistent for time periods of 4 min and 1 h between exposure and processing. To investigate possible interactions of the processing time delay effect with dose, single EDR2 films were irradiated to eight different dose levels between 45 and 330 cGy using smaller 3x3 cm2 areas. These films were processed after time delays of 1, 3, and 6 h, using 6 and 18 MV photon qualities. The results at all dose levels were consistent, indicating that there is no change in the processing time delay effect for different doses. The difference in the time delay effect between the 6 and 18 MV measurements was negligible for all experiments. To rule out bias in selecting film regions for OD measurement, we compared the use of a specialized algorithm that systematically determines regions of interest inside the 10x10 cm2 exposure areas to manually selected regions of interest. There was a maximum difference of only 0.07% between the manually and automatically selected regions, indicating that the use of a systematic algorithm to determine regions of interest in large and fairly uniform areas is not necessary. Based on these results, we recommend a minimum time of 1 h between exposure and processing for all EDR2 film measurements

  20. Systematic overview of preoperative (neoadjuvant) chemoradiotherapy trials in oesophageal cancer: Evidence of a radiation and chemotherapy dose response

    Background and purpose: Numerous trials have shown that pathological complete response (pCR) following preoperative chemoradiotherapy (CRT) and surgery for oesophageal cancer is associated with improved survival. However, different radiotherapy doses and fractionations and chemotherapy drugs, doses and scheduling were used, which may account for the differences in observed pCR and survival rates. A dose-response relationship may exist between radiotherapy and chemotherapy dose and pCR. Patients and methods: Trials using a single radiotherapy and chemotherapy regimen (5FU, cisplatin or mitomycin C-based) and providing information on patient numbers, age, resection and pCR rates were eligible. The endpoint used was pCR and the covariates analysed were prescribed radiotherapy dose, radiotherapy dosexdose per fraction, radiotherapy treatment time, prescribed chemotherapy (5FU, cisplatin and mitomycin C) dose and median age of patients within the trial. The model used was a multivariate logistic regression. Results: Twenty-six trials were included (1335 patients) in which 311 patients (24%) achieved pCR. The probability of pCR improved with increasing dose of radiotherapy (P=0.006), 5FU (P=0.003) and cisplatin (P=0.018). Increasing radiotherapy treatment time (P=0.035) and increasing median age (P=0.019) reduced the probability of pCR. The estimated ?/? ratio of oesophageal cancer was 4.9 Gy (95% confidence interval (CI) 1.5-17 Gy) and the estimated radiotherapy dose lost per day was 0.59 Gy (95% CI 0.18-0.99 Gy). One gram per square metre of 5FU was estimated to be equivalent to 1.9 Gy (95% CI 0.8-5.2 Gy) of radiation and 100 mg/m2 of cisplatin was estimated to be equivalent to 7.2 Gy (95% CI 2.1-28 Gy). Mitomycin C dose did not appear to influence pCR rates (P=0.60). Conclusions: There was evidence of a dose-response relationship between increasing protocol prescribed radiotherapy, 5FU and cisplatin dose and pCR. Additional significant factors were radiotherapy treatment time and median age of patients within the trial

  1. The Enigma of Linear/Supralinear Thermoluminescence Dose Response Mixed Localized/Delocalized Recombination describes a Solution

    Kinetic models of thermoluminescence (TL) dose response have recently been proposed which propose to solve the long-standing conundrumconcerning the dependence of the TL dose response on ionization density. Many TL materials exhibit an initially linear dose response over several decades of dose which then turns supralinear before entering into saturation. LiF:Mg,Ti is perhaps the most outstanding and widely studied example. The dose response of the major dosimetric glow peak is strictly linear from the lowest level of dose measurable of ~10-4 Gy to ~ 1 Gy and then turns supralinear reaching maximum values of the normalized TL dose response f(D) of 3-5 at levels of dose between 300 -500 Gy .This behaviour coupled with the dependence of the supralinearity on particle type and energy (i.e., on ionization density) has presented a formidable challenge to conventional kinetic theories of dose response. It has been gradually recognized over the past decade that this behaviour in LiF:Mg,Ti requires both nanodosimetric input coupled with a mixture of both localized and delocalized recombination mechanisms. This due to the complex nature of the trapping structure giving rise to the TL. Following irradiation the trapping center (TC)- luminescent center (LC) can be populated by a locally trapped electron-hole (e-h) or an electron (e) only. The former giving rise to geminate (localized) recombination the latter to mainly delocalized recombination via charge transfer migration in the conduction band. The relative concentrations of these configurations are dependent on ionization density. In this paper we present the latest developments in which we attempt to simulate the linear/supralinear dose response, the dependence of the supralinearity on electron energy and the shape of composite glow peak 5 as a function of electron energy. In order to predict all three characteristics the simulations require the incorporation of band tail states allowing semi-localized recombination from the e-only configuration

  2. A Dose Response Study of Magnesium Sulfate in Suppressing Cardiovascular Responses to Laryngoscopy & Endotracheal Intubation

    K Montazeri

    2005-03-01

    Full Text Available Background: The effects of pretreatment with magnesium on cardiovascular responses associated with intubation have been studied previously. In this study we wanted to find optimal dose of magnesium that causes decreased cardiovascular responses after laryngoscopy & endotracheal intubation. Methods: In a double-blind , randomized, clinical trial ,120 ASA-1 patients with ages between 15-50 years old , who were candidates for elective surgery, were selected and classified in 6 groups (20 patients in each . The pulse rate and arterial blood pressure were measured and recorded at 5 minutes before taking any drug then, according to different groups, patients took magnesium sulfate (10, 20, 30, 40, 50mg/kg and lidocaine (1.5 mg/kg. The induction of anesthesia was same in all groups and the pulse rate and arterial blood pressure were measured and recorded just before intubation and also at 1, 3 , and 5 minutes after intubation (before surgical incision . Statistical analysis was performed by use of ANOVA, Post Hoc test (Duncan, Pearson correlation, and Chi square test. Results: there were no statistically significant differences in blood pressure, pulse rate, Train Of Four (TOF, and complications between groups who received magnesium but the significant differences in these parameters were seen between magnesium and lidocaine groups. Conclusion: We concluded that pretreatment with different doses of magnesium sulfate have a safe decreasing effect on cardiovascular responses that is more effective than pretreatment with lidocaine. Keywords: magnesium sulfate, cardiovascular responses, lidocaine.

  3. Relative radiation sensitivity of the integumentary system: Dose response of the epidermal, microvascular, and dermal populations

    This presentation lists gross and histologic changes produced by irradiation of the skin that have been quantified. It examines available cell kinetic radiobiological and morphological variables to identify interactions that occur between component populations. The dose response data of the hair and epidermal, fibrocytic, and endothelial cell populations are examined and a rank ordering is attempted. The contribution of the radiosensitivity of these populations to defining the dose tolerance of the skin is discussed. Future clinical needs are considered. The intent is to quantify or define tissue population changes in the irradiated skin so that the data may serve as guidelines to aid the radiation therapist to select therapy schedules that preserve skin function while improving cancer control

  4. The influence of parameters of A-type carbonated apatites synthesis on radiation dose response

    The aim of this work is the investigation of dose response of A-type carbonated apatites prepared in different conditions. Irradiated samples prepared with carbonate content of 1.45 to 4.84% are studied by using electron paramagnetic resonance (EPR). The EPR spectra are mainly constituted of lines associated to axial CO2- species (gperp = 2.0028 and g// = 1.9973) and CO3- species (g1 = 2,0170, g2 = 2,0090 e g3 = 2,0041). The production of CO2- species on gamma irradiation depends on the carbonate concentration and the hydroxyapatite stoichiometry. The lowest dose detection limit was achieved with stoichiometric samples and carbonate content around of 3.7%. (author)

  5. Dose-response relationships after incorporation of ?-active radionuclides by mycobacteria

    Experimental and theoretical studies have been carried out to overcome the problems encountered in the dosimetry of the intracellular ?-decay of different radionuclides in mycobacteria (BCG). The absorbed dose can be calculated theoretically if the activity is homogeneously distributed in spherical-symmetrical sections. The radiobiologic criteria determined were on the one hand the radioactivity content, and on the other hand the inactivation and the radiation-induced resistance of the bacteria to Isoniazid. On the basis of the dose-response curves the following conclusions have been drawn: The absorbed dose concept is applicable to the intracellular 3H-decay. It is the nucleus dose which determines the mutagenic effect, while inactivation is also caused by the energy deposit in the cell plasma. However, no clear correlation has been found between dose and response with regard to the local effects (transmutation, recoil energy) resulting from intracellular 35S- and 32P-decay. (orig.)

  6. Dose-response regressions for algal growth and similar continuous endpoints: Calculation of effective concentrations

    Christensen, Erik R.; Kusk, Kresten Ole; Nyholm, Niels

    2009-01-01

    We derive equations for the effective concentration giving 10% inhibition (EC10) with 95% confidence limits for probit (log-normal), Weibull, and logistic dose -responsemodels on the basis of experimentally derived median effective concentrations (EC50s) and the curve slope at the central point (50......-4-(trifluoromethyl)phenoxy-phenol) with ranges of representative slopes at 50% response (0.54-2.62) and EC50s (2.20-357 mg/L) were selected. Reference EC50s and EC10s with 95% confidence limits using probit or Weibull models are calculated by nonlinear regression on the whole dataset using a dose - response...... regression program with variance weighting and proper inverse estimation. The Weibull model provides the best fit to the data for all four chemicals. Predicted EC10s (95% confidence limits) from our derived equations are quite accurate; for example, with 4-4-(trifluoromethyl)phenoxy-phenol and the probit...

  7. Childhood adversity specificity and dose-response effect in non-affective first-episode psychosis

    Trauelsen, Anne Marie; Bendall, Sarah; Jansen, Jens Einar; Nielsen, Hanne-Grethe Lyse; Pedersen, Marlene Buch; Trier, Christopher Høier; Haahr, Ulrik H; Simonsen, Erik

    2015-01-01

    BACKGROUND: Reviews conclude that childhood and adolescence sexual, physical, emotional abuse and emotional and physical neglect are all risk factors for psychosis. However, studies suggest only some adversities are associated with psychosis. Dose-response effects of several adversities on risk of......-clinical control persons matched by gender, age and parents' socio-economic status. Assessment included the Childhood Trauma Questionnaire and parts of the Childhood Experience of Care and Abuse Questionnaire. RESULTS: Eighty-nine percent of the FEP group reported one or more adversities compared to 37% of the...... control group. Childhood and adolescent sexual, physical, emotional abuse, and physical and emotional neglect, separation and institutionalization were about four to 17 times higher for the FEP group (all p<0.01). The risk of psychosis increased two and a half times for each additional adversity. All...

  8. Summary of dosimetry, pathology, and dose response for bone sarcomas in beagles injected with radium-226

    In the completed 226Ra portion of a 30-year-long experiment to determine the relative radiotoxicity of injected 226Ra and 239Pu, 42 of 116 animals injected with 226Ra developed 63 bone sarcomas; none were observed in 44 controls. Average alpha plus beta dose to the skeleton to death was calculated on the basis of mathematical functions developed from sequential measurements of radium and radon retention in each dog. Bone sarcomas were identified radiographically or clinically, with subsequent histopathological confirmation and classification. Most primary bone tumors were classified as osteosarcomas if osteoid arose from a malignant stroma. The dose-response curve over the six lowest injected dose levels fits well to a linear, no-threshold, least squares fit, through a control incidence of 0.8%, and with a slope of 0.042% incidence per rad. 19 refs., 5 figs., 2 tabs

  9. Dose response characteristics of polymethacrylic acid gel (PMAAG) for a polymerization-based dosimeter using NMR.

    Iskandar, S M; Elias, S; Jumiah, H; Asri, M T M; Masrianis, A; Ab Rahman, M Z; Taiman, K; Abdul Rashid, M Y

    2004-05-01

    The radiation-response characteristics of polymetharylic acid gel dosimeter prepared with different concentrations of monomer and cross-linker is described in these studies. The dosimeters were prepared under the hypoxic condition in a glove box and were then irradiated with gamma-rays produced by Co-60 radionuclide that was generated at 1.25MeV energy. The irradiation took place at different doses ranged from 0Gy to 19Gy. Due to the radiation activities, chain-reaction polymerisation processes had taken place in the formation of polymethacrylic acid (PMAA) gel, which cause the dose response mechanism increased in the NMR relaxation rates of protons. It has been observed that for higher concentration of monomer and cross-linker, the polymerization rate was increased. PMID:15468893

  10. Dose response of xylitol and sorbitol for epr retrospective dosimetry with applications to chewing gum

    The purpose of this investigation was to study the radiation-induced electron paramagnetic resonance signal in sweeteners xylitol and sorbitol for use in retrospective dosimetry. For both sweeteners and chewing gum, the signal changed at an interval of 1-84 d after irradiation with minimal changes after 4-8 d. A dependence on storage conditions was noticed and the exposure of the samples to light and humidity was therefore minimised. Both the xylitol and sorbitol signals showed linearity with dose in the measured dose interval, 0-20 Gy. The dose-response measurements for the chewing gum resulted in a decision threshold of 0.38 Gy and a detection limit of 0.78 Gy. A blind test illustrated the possibility of using chewing gums as a retrospective dosemeter with an uncertainty in the dose determination of 0.17 Gy (1 SD). (authors)

  11. SO/sub 2/ dose-response sensitivity classification data for crops and natural vegetation species

    Irving, P.M.; Ballou, S.W.

    1980-09-01

    Over the past several years studies have been made on the interaction of sulfur dioxide (SO/sub 2/) and vegetation by performing field research and by developing analytical procedures for applying field observation data to energy impact assessments. As a result of this work, numerous reports have been prepared on crop-pollutant interactions, such as dose-response data; on the applications of such data to screening approaches for identifying crops at risk; and on models that predict crop yield reductions from point source emissions of SO/sub 2/. Data that were used for these studies, such as the crop-at-risk screening procedure, are presented in this report. Maps are also presented that show the national distribution of SO/sub 2/-sensitive crops and natural vegetation.

  12. Study on the dose-response relation of premature chromosome condensation induced by Okadaic acid

    In order to study the effect-dosage relationship between the PCC induced by Okadaic acid and the IR dosages, human peripheral blood in vitro was irradiated by X-rays at different doses (0, 0.5, 1.0, 2.0, 3.0, 5.0Gy) cultivated for 48 hours and added with Okadaic acid two hours before the end of culture. Chromosome aberrations frequencies was analyzed and compared with that induced by the conventional chromosome assay and their dose-response curves were fitted. The results show that the mitotic index of the PCC induced by Okadaic acid is higher than that of the conventional chromosome assay. And the fragment rate of chromosome condensation induced by Okadaic acid has a favorable linearity relationship with external radiation doses. (authors)

  13. Radiation dose response correlation between thermoluminescence and optically stimulated luminescence in quartz

    Oniya, E.O. [Archaeometry Laboratory, Cultural and Educational Technology Institute (C.E.T.I.), R.C. ' Athena' , Tsimiski 58, GR-67100 Xanthi (Greece); Physics and Electronics Department, Adekunle Ajasin University, PMB 01, Akungba Akoko (Nigeria); Polymeris, G.S.; Tsirliganis, N.C. [Archaeometry Laboratory, Cultural and Educational Technology Institute (C.E.T.I.), R.C. ' Athena' , Tsimiski 58, GR-67100 Xanthi (Greece); Kitis, G., E-mail: gkitis@auth.gr [Aristotle University of Thessaloniki, Nuclear Physics Laboratory, 54124 Thessaloniki (Greece)

    2012-07-15

    The fast, linearly modulated optically stimulated luminescence (LM-OSL) component in quartz is the main dosimetric signal used for the dating applications of this material. Since the blue light stimulation (470 nm, 40 mW cm {sup -2}) time needed to obtain the fast LM-OSL component is less than 50 s the electron trapping levels responsible for it are still highly populated. In this way an active radiation history is created which could play an important role in the dosimetric characteristics of the fast OSL signal. In the present work the dose response behavior of the fast OSL signal is investigated in quartz samples with an annealed radiation history and quartz samples possessing an artificial radiation history. A computerized curve de-convolution analysis of the LM-OSL curves for 50 s stimulation time showed that it consists of three individual OSL components. The faster component C{sub 1} with peak maximum time around 5 s has a linear dose response in virgin samples, which turns to a slight superlinearity as a function of the artificial radiation history. On the other hand the component C{sub 2} with peak maximum time at 12 s is slightly superlinear which turns into strong superlinearity as a function of artificial radiation history. Finally, component C{sub 3} with peak maximum time at about 45 s is strongly superlinear for both virgin samples and as a function of artificial radiation history. The implications to practical application are discussed. - Highlights: Black-Right-Pointing-Pointer The fast OSL component consists of three components. Black-Right-Pointing-Pointer The linearity of first fast component does not depend on radiation history. Black-Right-Pointing-Pointer The linearity of second and third components depend on radiation history. Black-Right-Pointing-Pointer The TL between 180 and 300 Degree-Sign C is the major source of OSL.

  14. Influence of image slice thickness on rectal dose-response relationships following radiotherapy of prostate cancer

    Olsson, C.; Thor, M.; Liu, M.; Moissenko, V.; Petersen, S.E.; Hyer, M; Apte, A.; Deasy, J.O.

    2016-01-01

    When pooling retrospective data from different cohorts, slice thicknesses of acquired computed tomography (CT) images used for treatment planning may vary between cohorts. It is, however, not known if varying slice thickness influences derived dose-response relationships. We investigated this for rectal bleeding using dose-volume histograms (DVHs) of the rectum and rectal wall for dose distributions superimposed on images with varying CT slice thicknesses. We used dose and endpoint data from two prostate cancer cohorts treated with 3D-CRT to either 74 Gy (N=159) or 78 Gy (N=159) @ 2 Gy per fraction. The rectum was defined as the whole organ with content, and the morbidity cut-off was Grade ?2 late rectal bleeding. Rectal walls were defined as 3-mm inner margins added to the rectum. DVHs for simulated slice thicknesses from 3 to 13 mm were compared to DVHs for the originally acquired slice thicknesses at 3 and 5 mm. Volumes, mean, and maximum doses were assessed from the DVHs, and gEUD values were calculated. For each organ and each of the simulated slice thicknesses, we performed predictive modeling of late rectal bleeding using the Lyman-Kutcher-Burman (LKB) model. For the most coarse slice thickness, rectal volumes increased (?18%), whereas maximum and mean doses decreased (?0.8 Gy and ?4.2 Gy, respectively). For all a values, the gEUD for the simulated DVHs were ?1.9 Gy different than the gEUD for the original DVHs. The best-fitting LKB model parameter values with 95% CIs were consistent between all DVHs. In conclusion, we found that the investigated slice thickness variations had minimal impact on rectal dose-response estimations. From the perspective of predictive modeling, our results suggest that variations within 10 mm in slice thickness between cohorts are unlikely to be a limiting factor when pooling multi-institutional rectal dose data that include slice thickness variations within this range. PMID:24936956

  15. Dose-response relationship for breast cancer induction at radiotherapy dose

    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

  16. Dose-response relationship for breast cancer induction at radiotherapy dose

    Gruber Günther

    2011-06-01

    Full Text Available Abstract Purpose 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. Materials and methods 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. Results 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. Conclusions The dose-response relationship obtained in this report can be used for the prediction of radiation induced secondary breast cancer of radiotherapy patients.

  17. A dose-response study on opening of imidazole ring of adenine in DNA by ionizing radiation

    A dose-response relationship between γ-irradiation and the cleavage of the imidazole ring of adenine in DNA to form formamidopyrimidine has been demonstrated. When the DNA aqueous solution was irradiated with 0.1 Gy under N2O there is little evidence of imidazole ring cleavage. A significant increase in cleavage begins to be noticed above 1 Gy reaching a plateau at 1000 Gy. No formamidopyrimidine was formed when 2'-deoxyadenosine was irradiated with up to 1000 Gy. A dose of 100 Gy converts 18 per cent of adenine in DNA to formamidopyrimidine. In irradiated DNA aqueous solution 1000 Gy convert 25 per cent of adenine to formamidopyrimidine under N2O. Some of the adenine was converted to 7,8-dihydro-8-oxoadenine but in amount that is 20 per cent of that converted to formamidopyrimidine under N2O. There was more adenine in DNA converted to formamidopyrimidine under N2O than under N2. (author)

  18. Use of three-dimensional lognormal dose-response surfaces in lifetime studies of radiation-induced cancer

    The three-dimensional lognormal cumulative probability power function was used to provide a unifying dose-response description of the lifetime cancer risk for chronic exposure of experimental animals and people, for risk evaluation, and for scaling between species. Bone tumor fatilities, primarily from alpha irradiation of the skeleton in lifetime studies of beagles injected with 226Ra, were shown to be well described by this function. This function described cancer risk in lifetime studies as a curved smooth surface depending on radiation exposure rate and elapsed time, such that the principal risk at low dose rates occurred near the end of the normal life span without significant life shortening. Essentially identical functions with the median value of the power function displaced with respect to appropriate RBE values were shown to describe bone-cancer induction primarily from alpha irradiation of the skeleton in lifetime beagle studies with injected 226Ra, 228Th, 239Pu and 241Am, and with inhaled 238Pu. Application of this model to human exposures to 226Ra yielded a response ratio of 3.6; that is, the time required for development of bone cancer in people was 3.6 times longer than for beagles at the same average skeletal dose rate. It was suggested that similar techniques were appropriate to other carcinogens and other critical organs. 20 refs., 8 figs., 3 tabs

  19. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies.

    Zhou, Quan; Luo, Mei-Ling; Li, Hui; Li, Min; Zhou, Jian-Guo

    2015-01-01

    This is a dose-response (DR) meta-analysis to evaluate the association of coffee consumption on endometrial cancer (EC) risk. A total 1,534,039 participants from 13 published articles were added in this meta-analysis. The RR of total coffee consumption and EC were 0.80 (95% CI: 0.74-0.86). A stronger association between coffee intake and EC incidence was found in patients who were never treated with hormones, 0.60 (95% CI: 0.50-0.72), and subjects with a BMI ≥25 kg/m(2), 0.57 (95% CI: 0.46-0.71). The overall RRs for caffeinated and decaffeinated coffee were 0.66 (95% CI: 0.52-0.84) and 0.77 (95% CI: 0.63-0.94), respectively. A linear DR relationship was seen in coffee, caffeinated coffee, decaffeinated coffee and caffeine intake. The EC risk decreased by 5% for every 1 cup per day of coffee intake, 7% for every 1 cup per day of caffeinated coffee intake, 4% for every 1 cup per day of decaffeinated intake of coffee, and 4% for every 100 mg of caffeine intake per day. In conclusion, coffee and intake of caffeine might significantly reduce the incidence of EC, and these effects may be modified by BMI and history of hormone therapy. PMID:26302813

  20. Generation of dose-response relationships to assess the effects of acidity in precipitation on growth and productivity of vegetation

    Experiments were performed with several plant species in natural environments as well in a greenhouse and/or tissue culture facilities to establish dose-response functions of plant responses to simulated acidic rain in order to determine environmental risk assessments to ambient levels of acidic rain. Response functions of foliar injury, biomass of leaves and seed of soybean and pinto beans, root yields of radishes and garden beets, and reproduction of bracken fern are considered. The dose-response function of soybean seed yields with the hydrogen ion concentration of simulated acidic rainfalls was expressed by the equation y = 21.06-1.01 log x where y = seed yield in grams per plant and x = the hydrogen concentration if ?eq l-1. The correlation coefficient of this relationship was -0.90. A similar dose-response function was generated for percent fertilization of ferns in a forest understory. When percent fertilization is plotted on logarithmic scale with hydrogen ion concentration of the simulated rain solution, the Y intercept is 51.18, slope -0.041 with a correlation coefficient of -0.98. Other dose-response functions were generated that assist in a general knowledge as to which plant species and which physiological processes are most impacted by acidic precipitation. Some responses did not produce convenient dose-response relationships. In such cases the responses may be altered by other environmental factors or there may be no differences among treatment means

  1. Generation of dose-response relationships to assess the effects of acidity in precipitation on growth and productivity of vegetation

    Evans, L.S.

    1981-01-01

    Experiments were performed with several plant species in natural environments as well in a greenhouse and/or tissue culture facilities to establish dose-response functions of plant responses to simulated acidic rain in order to determine environmental risk assessments to ambient levels of acidic rain. Response functions of foliar injury, biomass of leaves and seed of soybean and pinto beans, root yields of radishes and garden beets, and reproduction of bracken fern are considered. The dose-response function of soybean seed yields with the hydrogen ion concentration of simulated acidic rainfalls was expressed by the equation y = 21.06-1.01 log x where y = seed yield in grams per plant and x = the hydrogen concentration if ..mu..eq l/sup -1/. The correlation coefficient of this relationship was -0.90. A similar dose-response function was generated for percent fertilization of ferns in a forest understory. When percent fertilization is plotted on logarithmic scale with hydrogen ion concentration of the simulated rain solution, the Y intercept is 51.18, slope -0.041 with a correlation coefficient of -0.98. Other dose-response functions were generated that assist in a general knowledge as to which plant species and which physiological processes are most impacted by acidic precipitation. Some responses did not produce convenient dose-response relationships. In such cases the responses may be altered by other environmental factors or there may be no differences among treatment means.

  2. Statistical behavior and geological significance of the geochemical distribution of trace elements in the Cretaceous volcanics Cordoba and San Luis, Argentina

    Statistical analysis of trace elements in volcanics research s, allowed to distinguish two independent populations with the same geochemical environment. For each component they have variable index of homogeneity resulting in dissimilar average values that reveal geochemical intra telluric phenomena. On the other hand the inhomogeneities observed in these rocks - as reflected in its petrochemical characters - could be exacerbated especially at so remote and dispersed location of their pitches, their relations with the enclosing rocks for the ranges of compositional variation, due differences relative ages

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

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

  4. Maximum likelihood estimation of dose-response parameters for therapeutic operating characteristic (TOC) analysis of carcinoma of the nasopharynx

    A Therapeutic Operating Characteristic (TOC) curve for radiation therapy plots, for all possible treatment doses, the probability of tumor ablation as a function of the probability of radiation-induced complication. Application of this analysis to actual therapeutic situation requires that dose-response curves for ablation and for complication be estimated from clinical data. We describe an approach in which ''maximum likelihood estimates'' of these dose-response curves are made, and we apply this approach to data collected on responses to radiotherapy for carcinoma of the nasopharynx. TOC curves constructed from the estimated dose-response curves are subject to moderately large uncertainties because of the limitations of available data.These TOC curves suggest, however, that treatment doses greater than 1800 rem may substantially increase the probability of tumor ablation with little increase in the risk of radiation-induced cervical myelopathy, especially for T1 and T2 tumors

  5. Dose-response relationship in locoregional control for patients with stage II-III esophageal cancer treated with concurrent chemotherapy and radiotherapy

    Purpose: To evaluate the correlation between radiation dose and locoregional control (LRC) for patients with Stage II-III unresectable esophageal cancer treated with concurrent chemotherapy and radiotherapy. Methods and materials: The medical records of 69 consecutive patients with clinical Stage II or III esophageal cancer treated with definitive chemoradiotherapy at the University of Texas M. D. Anderson Cancer Center between 1990 and 1998 were retrospectively reviewed. Of the 69 patients, 43 had received ?51 Gy (lower dose group) and 26 >51 Gy (higher dose group). The median dose in the lower and higher dose groups was 30 Gy (range, 30-51 Gy) and 59.4 Gy (range, 54-64.8 Gy), respectively. Two fractionation schedules were used: rapid fractionation, delivering 30 Gy at 3 Gy/fraction within 2 weeks, and standard fractionation, delivering ?45 Gy at 1.8-2 Gy/fraction daily. Total doses of 5% (46.2% vs. 23.3%). The lower dose group had more N1 tumors, but the tumor classification and stage grouping were similar in the two groups. The median follow-up time for all patients was 22 months (range, 2-56 months). Patients in the higher dose group had a statistically significant better 3-year local control rate (36% vs. 19%, p = 0.011), disease-free survival rate (25% vs. 10%, p = 0.004), and overall survival rate (13% vs. 3%, p = 0.054). A trend toward a better distant-metastasis-free survival rate was noted in the higher dose group (72% vs. 59%, p = 0.12). The complete clinical response rate was significantly greater in the higher dose group (46% vs. 23%, p = 0.048). In both groups, the most common type of first failure was persistence of the primary tumor. Significantly fewer patients in the higher dose group had tumor persistence after treatment (p = 0.02). No statistically significant difference was found between the two groups in the pattern of locoregional or distant failure. The long-term side effects of chemoradiotherapy were similar in the two groups, although it was difficult to assess the side effects accurately in a retrospective fashion. On multivariate analysis, Stage II (vs. III) disease and radiation dose >51 Gy were independent predictors of improved LRC, and locoregional failure was an independent predictor of worse overall survival. Conclusion: Our data suggested a positive correlation between radiation dose and LRC in the population studied. A higher radiation dose was associated with increased LRC and survival in the dose range studied. The data also suggested that better LRC was associated with a lower rate of distant metastasis. A threshold of tumor response to radiation dose might be present, as suggested by the flattened slope in the high-dose area on the dose-response curve. A carefully designed dose-escalation study is required to confirm this assumption

  6. Pregabalin versus gabapentin in partial epilepsy: a meta-analysis of dose-response relationships

    Thompson Sally

    2010-11-01

    Full Text Available Abstract Background To compare the efficacy of pregabalin and gabapentin at comparable effective dose levels in patients with refractory partial epilepsy. Methods Eight randomized placebo controlled trials investigating the efficacy of pregabalin (4 studies and gabapentin (4 studies over 12 weeks were identified with a systematic literature search. The endpoints of interest were "responder rate" (where response was defined as at least a 50% reduction from baseline in the number of seizures and "change from baseline in seizure-free days over the last 28 days (SFD". Results of all trials were analyzed using an indirect comparison approach with placebo as the common comparator. The base-case analysis used the intention-to-treat last observation carried forward method. Two sensitivity analyses were conducted among completer and responder populations. Results The base-case analysis revealed statistically significant differences in response rate in favor of pregabalin 300 mg versus gabapentin 1200 mg (odds ratio, 1.82; 95% confidence interval, 1.02, 3.25 and pregabalin 600 mg versus gabapentin 1800 mg (odds ratio, 2.52; 95% confidence interval, 1.21, 5.27. Both sensitivity analyses supported the findings of the base-case analysis, although statistical significance was not demonstrated. All dose levels of pregabalin (150 mg to 600 mg were more efficacious than corresponding dosages of gabapentin (900 mg to 2400 mg in terms of SFD over the last 28 days. Conclusion In patients with refractory partial epilepsy, pregabalin is likely to be more effective than gabapentin at comparable effective doses, based on clinical response and the number of SFD.

  7. Research toward the development of a biologically based dose response assessment for inorganic arsenic carcinogenicity: A progress report

    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 adequate biologically based dose response (BBDR) model that could provide a quantitative basis for an alternative nonlinear approach. This paper describes elements of an ongoing collaborative research effort between the CIIT Centers for Health Research, the U.S. Environmental Protection Agency, ENVIRON International, and EPRI to develop BBDR modeling approaches that could be used to inform a nonlinear cancer dose response assessment for inorganic arsenic. These efforts are focused on: (1) the refinement of physiologically based pharmacokinetic (PBPK) models of the kinetics of inorganic arsenic and its metabolites in the mouse and human; (2) the investigation of mathematical solutions for multi-stage cancer models involving multiple pathways of cell transformation; (3) the review and evaluation of the literature on the dose response for the genomic effects of arsenic; and (4) the collection of data on the dose response for genomic changes in the urinary bladder (a human target tissue for arsenic carcinogenesis) associated with in vivo drinking water exposures in the mouse as well as in vitro exposures of both mouse and human cells. An approach is proposed for conducting a biologically based margin of exposure risk assessment for inorganic arsenic using the in vitro dose response for the expression of genes associated with the obligatory precursor events for arsenic tumorigenesis

  8. Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences

    This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted. - The quantitative features of the hormetic dose/response are described and placed within the context of toxicology

  9. Paradigm lost, paradigm found: The re-emergence of hormesis as a fundamental dose response model in the toxicological sciences

    Calabrese, Edward J. [Environmental Health Sciences, School of Public Health, Morrill I, N344, University of Massachusetts, Amherst, MA 01003 (United States)]. E-mail: edwardc@schoolph.umass.edu

    2005-12-15

    This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted. - The quantitative features of the hormetic dose/response are described and placed within the context of toxicology.

  10. Patch test dose-response study: polysensitized individuals do not express lower elicitation thresholds than single/double-sensitized individuals

    Carlsen, B C; Fischer, Louise Arup; Sosted, H; Vølund, A; Menné, T; Johansen, J D

    2009-01-01

    compare elicitation dose-response curves and elicitation thresholds in a polysensitized vs. a single/double-sensitized group for allergens to which the test subjects were already sensitized. PATIENTS/METHODS: Fifty-one patients (13 polysensitized and 38 single/double-sensitized) were patch tested with...... nickel sulphate, methyldibromo glutaronitrile (MDBGN) and p-phenylenediamine (PPD) in dilution series. The ratio between the doses eliciting a response in 50% of patients in the two groups was used as the measure for relative sensitivity. RESULTS: The dose-response curves of the polysensitized group for...

  11. Consequences of dose response curves for tumor control and normal tissue injury on the precision necessary in patient management

    This paper is concerned with an analysis of the relationship between dose response curves, treatment precision, and treatment outcome. The approach that is taken is first to define the term ''treatment precision'' as it is used in this paper and then to compare the expected treatment outcomes for two treatment systems with different levels of precision. The treatment outcomes will be calculated using assumed dose response curves for tumor control and for severe normal tissue injury. This approach is admittedly theoretical and is not intended to provide any quantitative conclusions concerning the treatment of patients. The approach will, however, provide valuable insight into the relationship between treatment precision and outcome

  12. Nano-silver induces dose-response effects on the nematode Caenorhabditis elegans.

    Ellegaard-Jensen, Lea; Jensen, Keld Alstrup; Johansen, Anders

    2012-06-01

    Toxicity of nano-formulated silver to eukaryotes was assessed by exposing nematodes (Caenorhabditis elegans) to two types of silver nanoparticles (AgNPs): with average primary particle diameters of 1 nm (AgNP1) and 28nm (AgNP28, PVP coated), respectively. Tests were performed with and without presence of Escherichia coli to evaluate how the presence of a food bacterium affects the AgNP toxicity. A pre-exposure experiment was also conducted with nematodes pre-exposed to 0 and 1mgAgNPL(-1), respectively, for 20 h prior to exposure at higher concentrations of AgNP. Both AgNP1 and AgNP28 showed adverse dose-response effects and mortality on C. elegans. LC(50) for AgNP28 was lower than for AgNP1 and, hence, at the present test conditions the PVP-coated AgNP28 was more toxic than AgNP1. Including E. coli in the test medium as a food source increased AgNPs toxicity towards nematodes compared to when bacteria were not present. Pre-exposure to a low-level AgNP1 concentration made the nematodes slightly more sensitive to further exposure at higher concentrations compared to no pre-exposure, indicating that nematodes have no efficient physiological ability to counteract nano-silver toxicity by acclimation. The amount of dissolved Ag(+) was 0.18 to 0.21 mg L(-1) after 20 h at the highest AgNP1 (10 mg L(-1)) and AgNP28 (3 mg L(-1)) doses in the exposure medium, respectively. The upper limit of Ag(+) solubility cannot immediately explain the dose-response-related toxic effects of the AgNP nor the difference between AgNP1 and AgNP28. Higher toxicity of AgNP28 than AgNP1 may be explained by a combination of effects of coating, Ag-solubility and higher uptake rates due to agglomeration into μm-size agglomerates in the exposure medium. PMID:22475389

  13. 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 [Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada) and Department of Radiation Oncology, SMBD Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2 (Canada); Executive Administration for Radiation Protection and Safety Medical Devices Sector, Saudi Food and Drug Authority, Riyadh, Kingdom of Saudi Arabia 13312 (Saudi Arabia); Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada) and Department of Radiation Oncology, SMBD Jewish General Hospital, McGill University, Montreal, Quebec H3T 1E2 (Canada); Medical Physics Unit, McGill University, Montreal, Quebec H3G 1A4 (Canada); Department of Medical Physics, Memorial Sloan-Kettering Cancer Center Basking Ridge, New Jersey 07920 (United States); Ashland Inc., Wayne, New Jersey 07470 (United States)

    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 found that criteria of 3%/3 mm for an IMRT QA plan and 3%/2 mm for a brachytherapy QA plan are passing 95% gamma function points. Conclusions: In this paper, we demonstrate the use of functional argument to linearize the inherently nonlinear response of a radiochromic film based reference dosimetry system. In this way, relative dosimetry can be conveniently performed using radiochromic film dosimetry system without the need of establishing calibration curve.

  14. Different thresholds of tissue-specific dose-responses to growth hormone in short prepubertal children

    Decker Ralph

    2012-11-01

    Full Text Available Abstract Background In addition to stimulating linear growth in children, growth hormone (GH influences metabolism and body composition. These effects should be considered when individualizing GH treatment as dose-dependent changes in metabolic markers have been reported. Hypothesis: There are different dose-dependent thresholds for metabolic effects in response to GH treatment. Method A randomized, prospective, multicentre trial TRN 98-0198-003 was performed for a 2-year catch-up growth period, with two treatment regimens (a individualized GH dose including six different dose groups ranging from 17100 ?g/kg/day (n=87 and (b fixed GH dose of 43 ?g/kg/day (n=41. The individualized GH dose group was used for finding doseresponse effects, where the effective GH dose (ED 50% required to achieve 50% ? effect was calculated with piecewise linear regressions. Results Different thresholds for the GH dose were found for the metabolic effects. The GH dose to achieve half of a given effect (ED 50%, with 90% confidence interval was calculated as 33(24.4 ?g/kg/day for ? left ventricular diastolic diameter (cm, 39(24.5 ?g/kg/day for ? alkaline phosphatase (?kat/L, 47(43.5 ?g/kg/day for ? lean soft tissue (SDS, 48(35.7 ?g/kg/day for ? insulin (mU/L, 51(47.6 ?g/kg/day for ? height (SDS, and 57(52.7 ?g/kg/day for ? insulin-like growth factor I (IGF-I SDS. Even though lipolysis was seen in all subjects, there was no doseresponse effect for ? fat mass (SDS or ? leptin ng/ml in the dose range studied. None of the metabolic effects presented here were related to the dose selection procedure in the trial. Conclusions Dose-dependent thresholds were observed for different GH effects, with cardiac tissue being the most responsive and level of IGF-I the least responsive. The level of insulin was more responsive than that of IGF-I, with the threshold effect for height in the interval between.

  15. Kinetic modeling of Fluorine vacancy/F center creation in LiF:Mg,Ti including vacancy-interstitial recombination: Evaluating the factors leading to the lack of supralinearity in the optical absorption F center concentration dose response

    Kinetic model simulations of charge carrier transport following irradiation of LiF:Mg,Ti (TLD-100) including Fluorine vacancy/F center creation by the radiation and dose-dependent vacancy-interstitial recombination are presented which describe the experimentally measured linear/exponentially saturating optical absorption dose response of the electron trapping centers at 4.0 eV, 4.77 eV, 5.08 eV (F band) and 5.45 eV. Linear/exponentially saturating dose response is commonly observed for centers which are not created by the radiation. The creation of Fluorine vacancies by the radiation could therefore be expected to lead to a supralinear dose response of the F center before the onset of saturation. Nonetheless, the dose response is linear from 10 Gy to 500 Gy and can be fitted with a dose-filling constant β = 6.1 · 10−5 Gy−1 corresponding to a 5% and 25% decrease from linearity at 103 Gy and 5 · 103 Gy respectively. The model attempts to resolve a central question concerning the mechanisms leading to the linear/exponentially saturating dose response of the F band even though Fluorine vacancies are being continuously created during the irradiation. The electron-trapping characteristics of the created vacancies are assumed to differ somewhat from the vacancies originally present in un-irradiated samples due to differences in their immediate environment. Vacancy-interstitial recombination for separation distances less than a critical distance, dc is demonstrated to be significant for D > 500 Gy (dc = 36 Å) and is an important mechanism contributing to the F center saturation at high dose-levels. The kinetic model accurately simulates the experimentally observed F center dose response over the entire investigated dose range of 10–105 Gy under the following conditions: (i) The concentration of vacancies initially present is unexpectedly high at ∼1023 m−3, possibly due to the highly doped, non-crystalline and hot-pressed nature of the LiF:Mg,Ti samples. (ii) The transition probability, An4o, for electron capture into the initially-present vacancies is ∼40 times greater than An4, the transition probability for the radiation-created vacancies. These two factors marginalize the effect of the created vacancies at low dose resulting in a linear dose response

  16. Kinetic modeling of Fluorine vacancy/F center creation in LiF:Mg,Ti including vacancy-interstitial recombination: Evaluating the factors leading to the lack of supralinearity in the optical absorption F center concentration dose response

    Eliyahu, I., E-mail: ilan.eliyahu@gmail.com [Ben Gurion University of the Negev, Beersheva 84105 (Israel); Soreq Nuclear Research Center, Yavne 81800 (Israel); Horowitz, Y.S. [Ben Gurion University of the Negev, Beersheva 84105 (Israel); Oster, L. [Sami Shamoon College of Engineering, Beersheva 84100 (Israel); Mardor, I. [Soreq Nuclear Research Center, Yavne 81800 (Israel); Druzhyna, S. [Ben Gurion University of the Negev, Beersheva 84105 (Israel); Biderman, S. [Nuclear Research Center Negev, Beersheva 84100 (Israel)

    2015-01-15

    Kinetic model simulations of charge carrier transport following irradiation of LiF:Mg,Ti (TLD-100) including Fluorine vacancy/F center creation by the radiation and dose-dependent vacancy-interstitial recombination are presented which describe the experimentally measured linear/exponentially saturating optical absorption dose response of the electron trapping centers at 4.0 eV, 4.77 eV, 5.08 eV (F band) and 5.45 eV. Linear/exponentially saturating dose response is commonly observed for centers which are not created by the radiation. The creation of Fluorine vacancies by the radiation could therefore be expected to lead to a supralinear dose response of the F center before the onset of saturation. Nonetheless, the dose response is linear from 10 Gy to 500 Gy and can be fitted with a dose-filling constant ? = 6.1 10{sup ?5} Gy{sup ?1} corresponding to a 5% and 25% decrease from linearity at 10{sup 3} Gy and 5 10{sup 3} Gy respectively. The model attempts to resolve a central question concerning the mechanisms leading to the linear/exponentially saturating dose response of the F band even though Fluorine vacancies are being continuously created during the irradiation. The electron-trapping characteristics of the created vacancies are assumed to differ somewhat from the vacancies originally present in un-irradiated samples due to differences in their immediate environment. Vacancy-interstitial recombination for separation distances less than a critical distance, d{sub c} is demonstrated to be significant for D > 500 Gy (d{sub c} = 36 ) and is an important mechanism contributing to the F center saturation at high dose-levels. The kinetic model accurately simulates the experimentally observed F center dose response over the entire investigated dose range of 1010{sup 5} Gy under the following conditions: (i) The concentration of vacancies initially present is unexpectedly high at ?10{sup 23} m{sup ?3}, possibly due to the highly doped, non-crystalline and hot-pressed nature of the LiF:Mg,Ti samples. (ii) The transition probability, A{sub n4o}, for electron capture into the initially-present vacancies is ?40 times greater than A{sub n4}, the transition probability for the radiation-created vacancies. These two factors marginalize the effect of the created vacancies at low dose resulting in a linear dose response.

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

    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. - Highlights: • Neutron dose response was determined for embryos of the zebrafish, Danio rerio. • Neutron doses of 0.6, 1 and 2.5 mGy led to neutron hormetic effects. • Neutron doses of 70 and 100 mGy accompanied by gamma rays led to gamma-ray hormesis

  18. Nano-silver induces dose-response effects on the nematode Caenorhabditis elegans

    Ellegaard-Jensen, Lea; Alstrup Jensen, Keld; Johansen, Anders

    2012-01-01

    presence of Escherichia coil to evaluate how the presence of a food bacterium affects the AgNP toxicity. A pre-exposure experiment was also conducted with nematodes pre-exposed to 0 and 1 mg AgNP L-1, respectively, for 20 h prior to exposure at higher concentrations of AgNP. Both AgNP1 and AgNP28 showed...... adverse dose-response effects and mortality on C. elegans. LC50 for AgNP28 was lower than for AgNP1 and, hence, at the present test conditions the PVP-coated AgNP28 was more toxic than AgNP1. Including E. coil in the test medium as a food source increased AgNPs toxicity towards nematodes compared to when...... AgNP1 and AgNP28. Higher toxicity of AgNP28 than AgNP1 may be explained by a combination of effects of coating, Ag-solubility and higher uptake rates due to agglomeration into mu m-size agglomerates in the exposure medium. (C) 2012 Elsevier Inc. All rights reserved....

  19. Digitoxin medication and cancer; case control and internal dose-response studies

    Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents

  20. Dose response to cancerogenic and mutagenic treatments. [X radiation, gamma radiation, alpha particles

    Totter, J.R.; Finamore, F.J.

    1978-01-01

    Thirty-seven dose-response curves involving animal and plant material, subjected to treatment with cancerogenic chemicals and low-energy-transfer ionizing radiation, have been gathered from the literature. In addition, one experiment in which a nutritional factor was used has beeen included in the results. Our calculations indicate that all the responses appear to fit the equation f = (D/sup n/)/(K/sup n/ + D/sup n/) where f is the fraction of subjects affected, D is the dose applied, and K is a constant characteristic of the cancerogen or treatment. Both of these parameters are raised to the nth power and result in a family of curves. The values of n were found to range between 0.33 and 3.13 with a value close to 1.00 (linear at low doses) in only three cases. Data from these 38 reports are displayed in a logarithmic plot on a single graph. In addition to the values of n and K, as well as the dosages and responses needed to construct this graph, are presented in two tables. Our mathematical treatment of the published data shows an unexpected universality of biological behavior that may be helpful in the extrapolation of experimental data to humans.

  1. Dose-response relationships for female radium dial workers: A new look

    The values of initial systemic intake and of skeletal dose for all of the U.S. radium cases have recently been revised. This revision was required following the demonstrations by Rundo and by Keane that humans who were exposed to radium as adults lost radium at a rate that depended on the quantity of radium originally deposited within their bodies. These new values have been used to define new dose-response relationships for both the bone sarcomas and the carcinomas arising in the paranasal sinuses and mastoid air cells induced by internally deposited radium. The population examined was employed in the U.S. dial painting industry prior to 1950 and consisted of 1530 female dial workers for whom radium body burden measurements were available. By the end of 1990, 46 cases of bone sarcomas and 19 cases of head carcinomas had been diagnosed in this cohort. The head carcinoma incidence can be adequately fitted by a simple linear function, as was found in previous analyses. The bone sarcoma cases were previously fitted by a dose-squared-exponential function. With the revised values of systemic intake, the sarcoma results could not be satisfactorily fitted with this expression. When the exponent on D was increased to larger values, excellent fits were obtained

  2. A two phase dose-response relationship at low dose rates

    With a new model concerning the dose-effect relation, the Random Coincidence Model (RCM), it is possible to explain the radiobiological effect of a two phase dose-response relationship. This model describes the formation of cancer caused by a multistep series of fixed lesions in the critical regions of tumor associated genes such as proto-oncogenes or tumor-suppressor genes. It is the central thesis of the model that in the case of spontaneously occurring mutations mainly the random coincidence of two base lesions or two single strand breaks of complementary DNA bases (strands) during the repair time of the first base lesion or single strand break leads to a fixation. In that case the stimulation of detoxification and repair systems by radiation reduces the mutation rate to a large extend. On the other hand the energy transfer of radiation generates a large number of radicals at each single point of interaction, so that the cloud of radicals can neither be reduced by detoxification to a large extend nor is there any possibility to repair in between the interaction with the DNA; a so called causal coincidence leads to a fixation. (author)

  3. 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. PMID:26164201

  4. Dose-response for bone regeneration after single doses of 60Co irradiation

    The Bone Growth Chamber (BGC) methodology was used to establish a dose-response relationship for regeneration of mature bone tissue after irradiation of 5, 8, 11, 15 and 25 Gy single dose 60Co. The BGC, which is a titanium implant, was inserted in the proximal tibial metaphyses, bilaterally, of a rabbit immediately following local irradiation to one tibia. Each animal thus served as its own control. During a healing period of 4 weeks, the two canals penetrating the implant became filled with more or less newly formed bone. At the end of the healing period, the implants were removed and taken apart and the newly formed bone was collected and its volume measured by microradiography and microdensitometry. It was found that in the dose range of 5 to 8 Gy bone regeneration was reduced by about 20% as compared to non-irradiated controls. Between 8 and 11 Gy, there was a critical range in that a small increase in dose resulted in a greatly reduced bone formation. At 11 Gy and above, the depression in bone formation, as compared to non-irradiated controls, was about 65 to 75%

  5. Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels.

    Hyun, Seung Won; Wong, Weng Kee

    2015-11-01

    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

  6. Dose-response curve for chromosome translocations induced by low dose rate 137Cs gamma rays

    A calibration curve for chronic exposure to 137Cs gamma rays is required for biological dosimetry of individuals exposed in connection with Chernobyl and other radiation accidents involving radiocaesium. Here, chromosome painting was used to measure the frequencies of reciprocal translocations in human lymphocytes following protracted exposures in vitro to 0.29, 0.62, and 0.95 Gy of 137Cs gamma rays. The exposures were delivered continuously during 48 h. A reliable measure of the linear slope (α coefficient) of the dose-response curve was obtained by analysing 18.389 metaphase lymphocytes in the irradiated samples and 25,067 in the controls. The α-coefficients were measured to be 0.030 ± 0.003 translocation per cell near Gy when fitting the data with a linear model using a weighted least square method and a very similar 0.029 ± 0.009 translocation per cell per Gy when fitted with a weighted least square linear-quadratic model. These results provide a calibration curve for biodosimetry involving protracted or low dose exposures to 137Cs gamma rays, where the α coefficient defines the induced translocation frequency. (Author)

  7. Using plant biomonitors and flux modelling to develop O3 dose-response relationships in Catalonia

    We used tobacco Bel-W3 biomonitoring data and ozone flux modelling (WINDEP model) with the aim of developing the absorbed dose-response relationship, and comparing this approach with the most commonly used AOT40 (the sum of hourly ozone concentrations above a cut-off of 40 ppb during daylight hours, when global radiation exceeds 50 W m-2) in the estimation of exposure-damage curves. Leaf damage values were more related to OAD15days,potential (potential ozone absorbed dose calculated over 15 consecutive days) than to AOT40 in all the studied stations. An OAD15days,potential of 180 mg m-2 was found to be the threshold for damage to the most sensitive species in this region under well watered conditions. The results show the applicability of the flux approach for risk assessment at the local scale, the improvement of the ozone damage estimation when the potential absorbed dose is modelled and used instead of just the ozone exposure, and finally, the possibilities opened by the use of biomonitoring networks. - Modelling of biomonitors ozone absorbed dose improves damage estimation in comparison with exposure indices such as AOT40

  8. High-LET dose-response characteristics by track structure theory of heavy charged particles

    The track structure theory developed by Katz and co-workers ascribes the effect of high-LET radiation to the highly inhomogeneous dose distribution due to low energy Δ-rays ejected from the particle track. The theory predicts the effectiveness of high-LET radiation by using the ion parameters zsub(eff') effective charge of the ion, and β = v/c, the relative ion velocity, together with the characteristic dose D37 derived from low-LET dose-response characteristic of the detector and the approximate size asub(0) of the sensitive element of the detector. 60Co gamma-irradiation is used as a reference low-LET radiation, while high-LET radiation ranging from 16 MeV protons to 4 MeV/amu 160-ions covering an initial LET range of 30-5500 MeVcm2/g is obtained from a tandem Van de Graaff accelerator. A thin film (5mg/cm2) radiochromic dye cyanide plastic dosemeter was used as detector with the characteristic dose of 16.8 Mrad and a sensitive element size of 10-7 cm. Theoretical and experimental effectiveness, RBE, agreed within 10 to 25% depending on LET. (author)

  9. Dose-Response Relationship Of Chromosome Aberration Induced By Low Doses Gamma Rays

    The detection method of chromosome aberration is highly valuable as a biological dosimeter to support physical dosimeter. Dicentric is a specific type of chromosome aberration caused by ionizing radiation exposure that can be detected from a radiation dose of 0.2 Gy. To prove this presumption, a research had been conducted by exposing lymphocyte cell of peripheral blood taken from four male donors to Co-60 gamma rays at doses of 0 (control), 0.2, 0.4, 0.6, 0.8, and 1 Gy. The blood samples were cultured with standard procedures. The results showed that dicentric type can be detected starting from 0.2 Gy dose, i.e. 0.002 + 0.001/cell. The higher radiation dose the higher dicentric chromosome induced. The equation of dose-response curve obtained with linier quadratic model is Y = 0.678 x 10-3 - 0.166 x 10-4 X + 0.147 x 10-5 X2 with corellation value R of 0.969

  10. Estimation and uncertainty analysis of dose response in an inter-laboratory experiment

    Toman, Blaza; Rösslein, Matthias; Elliott, John T.; Petersen, Elijah J.

    2016-02-01

    An inter-laboratory experiment for the evaluation of toxic effects of NH2-polystyrene nanoparticles on living human cancer cells was performed with five participating laboratories. Previously published results from nanocytoxicity assays are often contradictory, mostly due to challenges related to producing a reliable cytotoxicity assay protocol for use with nanomaterials. Specific challenges include reproducibility preparing nanoparticle dispersions, biological variability from testing living cell lines, and the potential for nano-related interference effects. In this experiment, such challenges were addressed by developing a detailed experimental protocol and using a specially designed 96-well plate layout which incorporated a range of control measurements to assess multiple factors such as nanomaterial interference, pipetting accuracy, cell seeding density, and instrument performance. Detailed data analysis of these control measurements showed that good control of the experiments was attained by all participants in most cases. The main measurement objective of the study was the estimation of a dose response relationship between concentration of the nanoparticles and metabolic activity of the living cells, under several experimental conditions. The dose curve estimation was achieved by imbedding a three parameter logistic curve in a three level Bayesian hierarchical model, accounting for uncertainty due to all known experimental conditions as well as between laboratory variability in a top-down manner. Computation was performed using Markov Chain Monte Carlo methods. The fit of the model was evaluated using Bayesian posterior predictive probabilities and found to be satisfactory.

  11. EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY

    Effects of Prenatal Testosterone Propionate on Sexual Development of Male and Female Rats: A Dose-Response StudyCynthia Wolf1,2, Joe Ostby1*, Andrew Hotchkiss3, Gerald LeBlanc2, and L. Earl Gray, Jr.11USEPA, NHEERL, Reproductive Toxicology Division, RTP, NC; 2Dept. of To...

  12. EFFECTS OF PRENATAL TESTOSTERONE PROPIONATE ON THE SEXUAL DEVELOPMENT OF MALE AND FEMALE RATS: A DOSE-RESPONSE STUDY

    Effects of Prenatal Testosterone Propionate on the Sexual Development of Male and Female Rats: A Dose-Response Study Cynthia J. Wolf1,2, Andrew Hotchkiss3, Joseph S. Ostby1, Gerald A. LeBlanc2 and L. Earl Gray1,4, Jr.ABSTRACTTestosterone plays a major role in ...

  13. Glyphosate resistant and susceptible soybean (Glycine max) and canola (Brassica napus) dose response and metabolism relationships with glyphosate

    Experiments were conducted to determine 1) dose response of glyphosate-resistant (GR) and –susceptible (non-GR) soybean [Glycine max (L.) Merr.] and canola (Brassica napus L.) to glyphosate, 2) if differential metabolism of glyphosate to aminomethylphosphonic acid (AMPA) is the underlying mechanism ...

  14. Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

    Marino, Dale J.; Clewell, Harvey J.; Gentry, P. Robinan; Covington, Tammie R.; Hack, C. Eric; David, Raymond M.; Morgott, David A.

    2006-01-01

    KEYWORDS - CLASSIFICATION: analysis;Animals;Bayes Theorem;chemically induced;Carcinogens;Dose-Response Relationship,Drug;Environment;Inhalation Exposure;metabolism;methods;Markov Chains;mechanisms of carcinogenesis;Methylene Chloride;Mice;Models,Biological;Monte Carlo Method;Neoplasms;pharmacokinetics;Risk Assessment;Safety.

  15. Pancreatic beta cell function increases in a linear dose-response manner following exercise training in adults with prediabetes

    Malin, Steven K; Solomon, Thomas; Blaszczak, Alecia; Finnegan, Stephen; Filion, Julianne; Kirwan, John P

    2013-01-01

    While some studies suggest that a linear dose-response relationship exists between exercise and insulin sensitivity, the exercise dose required to enhance pancreatic beta-cell function is unknown. Thirty-five older, obese adults with prediabetes underwent a progressive 12-week supervised exercise...

  16. Biological Stress Response Terminology: Integrating the Concepts of Adaptive Response and Preconditioning Stress Within a Hormetic Dose-Response Framework

    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 stres...

  17. Dose response evaluation of gene expression profiles in the skin of K6/ODC mice exposed to sodium arsenite

    Chronic drinking water exposure to inorganic arsenic and its metabolites increases tumor frequency in the skin of K6/ODC transgenic mice. To identify potential biomarkers and modes of action for this skin tumorigenicity, we characterized gene expression profiles from analysis of K6/ODC mice administered 0, 0.05, 0.25, 1.0 and 10 ppm sodium arsenite in their drinking water for 4 weeks. Following exposure, total RNA was isolated from mouse skin and processed to biotin-labeled cRNA for microarray analyses. Skin gene expression was analyzed with Affymetrix Mouse Genome 430A 2.0 GeneChips (registered) , and pathway analysis was conducted with DAVID (NIH), Ingenuity (registered) Systems and MetaCore's GeneGo. Differential expression of several key genes was verified through qPCR. Only the highest dose (10 ppm) resulted in significantly altered KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways, including MAPK, regulation of actin cytoskeleton, Wnt, Jak-Stat, Tight junction, Toll-like, phosphatidylinositol and insulin signaling pathways. Approximately 20 genes exhibited a dose response, including several genes known to be associated with carcinogenesis or tumor progression including cyclin D1, CLIC4, Ephrin A1, STAT3 and DNA methyltransferase 3a. Although transcription changes in all identified genes have not previously been linked to arsenic carcinogenesis, their association with carcinogenesis in other systems suggests that these genes may play a role in the early stages of arsenic-induced skin carcinogenesis and can be considered potential biomarkers

  18. Effects of the pre-irradiation storage procedure on the dose response of a Fricke xylenol orange gel dosimeter

    Liosi Giulia Maria

    2015-09-01

    Full Text Available The Fricke xylenol orange (FX gel system is a chemical dosimeter characterized by good sensitivity, linear dose response, tissue equivalence, no toxicity, easy preparation, reproducibility and low cost. Thanks to the presence of the gelatinous matrix, the system is particularly suitable to perform reliable 3D mapping of the absorbed dose spatial distribution via magnetic resonance imaging (MRI or optical techniques. The aim of this work is to study in a systematic way the influence of the pre-irradiation storage procedure upon sensitivity, dose response stability and lifetime of use of a FX gel system made with gelatin from porcine skin subjected to homogeneous irradiation. For this purpose, different pre-irradiation storage procedures, in terms of temperature and duration of each storage step, were investigated. In order to evaluate the dose response stability, the optical analyses of the samples were performed up to 6 hours after irradiation. Moreover, the samples were irradiated at time intervals of 24 hours for up to 7 days after preparation in order to evaluate the system lifetime of use. Regardless of their thermal and temporal life, the samples show linear dose responses in the investigated dose range (3-24 Gy and an increase of sensitivity with the time elapsed between preparation and irradiation. Among the three pre-irradiation storage procedures considered here, a procedure that provides the best dose response stability and lifetime of use was identified and recommended for further use. The analyzed dosimetric system possesses good properties that make it promising for medical application, particularly concerning the evaluation of pre-treatment plan quality assurance within the conformational external beam radiotherapy

  19. Dose-response model of murine typhus (Rickettsia typhi: time post inoculation and host age dependency analysis

    Tamrakar Sushil B

    2012-03-01

    Full Text Available Abstract Background Rickettsia typhi (R. mooseri is the causative agent of murine typhus. It is one of the most widely distributed flea-borne diseases with a relatively mild febrile initial illness with six to 14 days of incubation period. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through fleabites or via contact with infected feces. This paper develops dose-response models of different routes of exposure for typhus in rodents. Methods Data from published articles were analyzed using parametric dose-response relationship models. Dose-response relationships were fit to data using the method of maximum likelihood estimation (MLE. Results Dose-response models quantifying the effects of different ages of rats and time post inoculation in BALB/c mice were analyzed in the study. Both the adult rats (inoculated intradermally and newborn rats (inoculated subcutaneously were best fit by exponential models and both distributions could be described by a single dose-response relationship. The BALB/C mice inoculated subcutaneously were best fit by Beta-Poisson models. The time post inoculation analysis showed that there was a definite time and response relationship existed in this case. Conclusions Intradermally or subcutaneously inoculated rats (adult and newborn models suggest that less than 1 plaque-forming unit (PFU (1.33 to 0.38 in 95% confidence limits of the pathogen is enough to seroconvert 50% of the exposed population on average. For the BALB/c mouse time post inoculation model, an average dose of 0.28 plaque-forming units (PFU (0.75 to 0.11 in 95% confidence limits will seroconvert 50% of the exposed mice.

  20. Development of Dose-Response Models to Predict the Relationship for Human Toxoplasma gondii Infection Associated with Meat Consumption.

    Guo, Miao; Mishra, Abhinav; Buchanan, Robert L; Dubey, Jitender P; Hill, Dolores E; Gamble, H Ray; Jones, Jeffrey L; Du, Xianzhi; Pradhan, Abani K

    2016-05-01

    Toxoplasma gondii is a protozoan parasite that is responsible for approximately 24% of deaths attributed to foodborne pathogens in the United States. It is thought that a substantial portion of human T. gondii infections is acquired through the consumption of meats. The dose-response relationship for human exposures to T. gondii-infected meat is unknown because no human data are available. The goal of this study was to develop and validate dose-response models based on animal studies, and to compute scaling factors so that animal-derived models can predict T. gondii infection in humans. Relevant studies in literature were collected and appropriate studies were selected based on animal species, stage, genotype of T. gondii, and route of infection. Data were pooled and fitted to four sigmoidal-shaped mathematical models, and model parameters were estimated using maximum likelihood estimation. Data from a mouse study were selected to develop the dose-response relationship. Exponential and beta-Poisson models, which predicted similar responses, were selected as reasonable dose-response models based on their simplicity, biological plausibility, and goodness fit. A confidence interval of the parameter was determined by constructing 10,000 bootstrap samples. Scaling factors were computed by matching the predicted infection cases with the epidemiological data. Mouse-derived models were validated against data for the dose-infection relationship in rats. A human dose-response model was developed as P (d) = 1-exp (-0.0015 × 0.005 × d) or P (d) = 1-(1 + d × 0.003 / 582.414)(-1.479) . Both models predict the human response after consuming T. gondii-infected meats, and provide an enhanced risk characterization in a quantitative microbial risk assessment model for this pathogen. PMID:26477997

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

    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 set and with different background tumor incidences. We considered different experimental designs with varying number of doses and varying low doses dependant on the LET of the radiation. The optimal design to detect a NTE for an individual ion had 4 doses equally spaced below a maximal dose where bending due to cell sterilization was < 2%. For example at 100 keV/micron we would irradiate at 0.03 Gy, 0.065 Gy, 0.13 Gy, and 0.26 Gy and require 850 mice including a control dose for a sensitivity to detect NTE with 80% power. Sample sizes could be improved by combining ions similar to the methods used with the Harderian Gland data.

  2. Interaction of dietary protein level on dose response relationships during aflatoxicosis in young chickens.

    Richardson, K E; Nelson, L A; Hamilton, P B

    1987-06-01

    It is well known that the effect of aflatoxin is enhanced by a low protein diet, but whether this is associated with a lower apparent minimum effective dose, increased slope of response curves, or both has not been investigated previously. Aflatoxin at 12 dosages ranging from 0 to 2.34 micrograms/g of feed was fed to eight groups of 10 young chickens per treatment consuming a 10.00 or 12.75% protein diet for 3 weeks. The body weights, liver weights relative to body weights, and total lipid content of the livers were determined. Mathematical models were fitted to the data and from the appropriate equations the dose-response curves were predicted as continuous functions of aflatoxin concentration. A quadratic polynomial fit body weight data on the 12.75% protein diet whereas a plateau-linear model fit body weight data on the 10.00% protein diet. This implies that in a low protein diet aflatoxin affects only one of the factors controlling growth. Plateau-linear models fit liver relative weight and liver lipid content data on both 10.00 and 12.75% diets. For both variables the lower protein diet decreased the apparent minimum effective dose and increased the positive slope of the linear response. The apparent minimum effective doses (micrograms of aflatoxin per gram of feed) in this experimental system were calculated from the modeling approach to be 1.21 and 2.00 for body weight, 1.08 and 1.65 for liver lipids, and 1.45 and 2.34 for liver relative weight in 10.00 and 12.75% protein diets, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3658888

  3. Effect of Relative Humidity on Dose Response of Effervescent Glycine Pellet Dosimeters

    Santosh H Shinde

    2013-07-01

    Full Text Available Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} Glycine pellet dosimeter based on spectrophotometric read-out method has a useful dose range of 100 to 1000 Gy and is apt for routine dosimetry in low dose applications of radiation processing. The read-out method requires dissolution of these pellets in acidified solution of ferrous ammonium sulphate and xylenol orange, but due to appreciable hardness of these pellets it is required to stir the solution for complete dissolution which is generally not preferable. Hence fast dissolving pellets were fabricated using sodium bicarbonate as an effervescent agent. As sodium bicarbonate is hygroscopic, study of effect of relative humidity on dose response of these pellets was carried out in the present work.

  4. Energy crop (Sida hermaphrodita) fertilization using digestate under marginal soil conditions: A dose-response experiment

    Nabel, Moritz; Bueno Piaz Barbosa, Daniela; Horsch, David; Jablonowski, Nicolai David

    2014-05-01

    The global demand for energy security and the mitigation of climate change are the main drivers pushing energy-plant production in Germany. However, the cultivation of these plants can cause land use conflicts since agricultural soil is mostly used for plant production. A sustainable alternative to the conventional cultivation of food-based energy-crops is the cultivation of special adopted energy-plants on marginal lands. To further increase the sustainability of energy-plant cultivation systems the dependency on synthetic fertilizers needs to be reduced via closed nutrient loops. In the presented study the energy-plant Sida hermaphrodita (Malvaceae) will be used to evaluate the potential to grow this high potential energy-crop on a marginal sandy soil in combination with fertilization via digestate from biogas production. With this dose-response experiment we will further identify an optimum dose, which will be compared to equivalent doses of NPK-fertilizer. Further, lethal doses and deficiency doses will be observed. Two weeks old Sida seedlings were transplanted to 1L pots and fertilized with six doses of digestate (equivalent to a field application of 5, 10, 20, 40, 80, 160t/ha) and three equivalent doses of NPK-fertilizer. Control plants were left untreated. Sida plants will grow for 45 days under greenhouse conditions. We hypothesize that the nutrient status of the marginal soil can be increased and maintained by defined digestate applications, compared to control plants suffering of nutrient deficiency due to the low nutrient status in the marginal substrate. The dose of 40t/ha is expected to give a maximum biomass yield without causing toxicity symptoms. Results shall be used as basis for further experiments on the field scale in a field trial that was set up to investigate sustainable production systems for energy crop production under marginal soil conditions.

  5. Digitoxin medication and cancer; case control and internal dose-response studies

    Spigset Olav

    2001-08-01

    Full Text Available Abstract Background Digitoxin induces apoptosis in different human malignant cell lines in vitro. In this paper we investigated if patients taking digitoxin for cardiac disease have a different cancer incidence compared to the general population. Methods Computer stored data on digitoxin concentrations in plasma from 9271 patients with cardiac disease were used to define a user population. Age and sex matched controls from the Norwegian Cancer Registry were used to calculate the number of expected cancer cases. Results The population on digitoxin showed a higher incidence of cancer compared to the control population. However, an additional analysis showed that the population on digitoxin had a general increased risk of cancer already, before the start on digitoxin. Leukemia/lymphoma were the cancer types which stood out with the highest risk in the digitoxin population before starting on digitoxin. This indicates that yet unknown risk factors exist for cardiovascular disease and lymphoproliferative cancer. An internal dose-response analysis revealed a relationship between high plasma concentration of digitoxin and a lower risk for leukemia/lymphoma and for cancer of the kidney/urinary tract. Conclusion Morbidity and mortality are high in the population on digitoxin, due to high age and cardiac disease.These factors disturb efforts to isolate an eventual anticancer effect of digitoxin in this setting. Still, the results may indicate an anticancer effect of digitoxin for leukemia/lymphoma and kidney/urinary tract cancers. Prospective clinical cancer trials have to be done to find out if digitoxin and other cardiac glycosides are useful as anticancer agents.

  6. Dose-response relationship of octylphenol and radiation evaluated by tradescantia-micronucleus assay

    Kim, J. K.; Cheon, K. J.; Lee, B. H. [KAERI, Taejon (Korea, Republic of); Shin, H. S.; Lee, J. H. [Chungnam National Univ., Taejon (Korea, Republic of)

    2002-05-01

    Many kinds of synthetic chemicals have been being used for various purposes. Some of them are called 'Endocrine Disruptor's because they can disturb the endocrine system of organisms. Presently no technique is established for the quantitative assessment of biological risk of the environmental hormones. The pollen mother cells (PMC) of Tradescantia are very sensitive to chemical toxicants or ionizing radiation, and thus can be used as a biological end-point assessing their effect. Micronucleus frequencies in PMC showed a good dose- and concentration-response relationship for radiation, bisphenol A and octylphenol. A parallel series of experiment using five increasing doses of gamma-ray at 10, 20, 30, 40 and 50 cGy was conducted. The MCN frequencies of 12.0, 25.2, 41.7, 76 and 83 MCN/100 tetrads were observed from each of the increasing gamma-ray dosage groups, respectively. Lenear regression analysis of the gamma-ray data MCN frequencies yielded a correlation coefficient of 0.95. the MCN frequencies in pollen mother cells treated with bisphenol a and octylphenol showed dose-response relationship in a concentration of 0, 1, 2, 4 {mu}M and 0, 4, 10, 20 {mu}M. the MCN frequency for the bisphenol a and octylphenol group yields 2.33, 8.06, 12.7 and 19.6 MCN/100 tetrads for the bisphenol a and 2.33, 2.33, 11.47, 17.6 MCN/100 tetrads for the octylphenol. The MCN frequency of the control was 2.33 MCN/100 tetrads. It is known from the result that Trad-MCN assay can be an excellent tool for detection of biological risk due to environmental toxicants or synthetic chemicals.

  7. Study of Cell Line and Dose-response of Human Leukemic Cells

    M. Idrish Miah

    2003-01-01

    Full Text Available Cell type studied in this work is human leukemic cell Jurkat. In order to identify the exponential growth phase, the better time for sampling the population, the cell line was evaluated by monitoring the proliferation and viability of the cells in a 7-days long culture adding no medium to the cells. It was found that the culture within the cellular concentration from 6x105-2.7x106 cells/ml was in the exponential or log phase, where the viability and reproduction for the cells were high. The lag time and population doubling time were calculated and found to be 1 and 5 days respectively. The density dependent survival of cells in culture was remained constant, with the exception at very higher cell densities where it was found to decrease slightly. The viability of the cells was found to remain within 96-97% at incubation temperature range 10-500C, with a maximum at 35-400C. The cells were then incubated with 1 mM ALA at different temperatures and irradiated with different light doses. The dose-response curves were studied and modeled. The cell survival for incubation temperatures 10-370C were modeled as sigmoidal Boltzmann curves, whereas the survival for temperatures 39-500C were modeled as the second-order exponential decay curves. The efficiency for cell inactivation was calculated as the light dose or exposure time required for 50% of cell survival, and it was found that the efficiency was higher at higher temperatures.

  8. Ondansetron: A newer aspect of dose response relationship on ileal smooth muscles of rabbit.

    Afzal, Ayesha; Khan, Bushra Tayyaba; Bakhtiar, Salman

    2016-01-01

    There are several life threatening deadly diseases in our world but ‘Cancer’ out powers them all in recent years. Chemotherapy may be used on its own or an adjunct to other forms of therapy. Despite the advancement in cytotoxic drug therapy and supportive treatment almost 70% of patient suffer from chemotherapy induced nausea and vomiting (CINV). Ondansetron, a 5-HT(3) receptor antagonist has now become a gold standard in the treatment of chemotherapy induced nausea and vomiting. The central actions of ondansetron are well established but its peripheral actions are not well recognized. The aim of our study was to explore the peripheral actions of ondansetron. Experiments were performed in five groups (n=6) and ileal smooth muscles activity was recorded on power lab (USA). The effects of increasing concentrations of acetylcholine, serotonin & ondansetron alone was observed in first three groups. In the next two groups effects of acetylcholine and serotonin pretreated with fixed concentration (1ml) of ondansetron (10¯ϖ M)were studied. The maximum response obtained by acetylcholine served as a control for our study. Maximum response with acetylcholine was taken as 100% and with serotonin was 177 percent of control. Cumulative dose response curve with ondansetron was triphasic. At 10¯ψM it was 28.8%, whereas with 10¯ξM the amplitude decreased to 16.87%, it reached to plateau at 10¯ϖ M. Response of acetylcholine & serotonin was decreased to 57% and 78% respectively in the presence of fixed concentration of ondansetron (10¯ϖ M). Ondansetron reduces the acetylcholine and serotonin induced gastrointestinal motility. Our study has indicated that ondansetron apart from having central action also has marked peripheral actions that play an important role in CINV and may act as a partial agonist. PMID:26826825

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

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

    2016-05-01

    Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment. PMID:26152227

  10. Dose-response relationship of octylphenol and radiation evaluated by tradescantia-micronucleus assay

    Many kinds of synthetic chemicals have been being used for various purposes. Some of them are called 'Endocrine Disruptor's because they can disturb the endocrine system of organisms. Presently no technique is established for the quantitative assessment of biological risk of the environmental hormones. The pollen mother cells (PMC) of Tradescantia are very sensitive to chemical toxicants or ionizing radiation, and thus can be used as a biological end-point assessing their effect. Micronucleus frequencies in PMC showed a good dose- and concentration-response relationship for radiation, bisphenol A and octylphenol. A parallel series of experiment using five increasing doses of gamma-ray at 10, 20, 30, 40 and 50 cGy was conducted. The MCN frequencies of 12.0, 25.2, 41.7, 76 and 83 MCN/100 tetrads were observed from each of the increasing gamma-ray dosage groups, respectively. Lenear regression analysis of the gamma-ray data MCN frequencies yielded a correlation coefficient of 0.95. the MCN frequencies in pollen mother cells treated with bisphenol a and octylphenol showed dose-response relationship in a concentration of 0, 1, 2, 4 μM and 0, 4, 10, 20 μM. the MCN frequency for the bisphenol a and octylphenol group yields 2.33, 8.06, 12.7 and 19.6 MCN/100 tetrads for the bisphenol a and 2.33, 2.33, 11.47, 17.6 MCN/100 tetrads for the octylphenol. The MCN frequency of the control was 2.33 MCN/100 tetrads. It is known from the result that Trad-MCN assay can be an excellent tool for detection of biological risk due to environmental toxicants or synthetic chemicals

  11. Demonstration of brachytherapy boost dose-response relationships in glioblastoma multiforme

    Purpose: To evaluate brachytherapy dose-response relationships in adults with glioblastoma undergoing temporary 125I implant boost after external beam radiotherapy. Methods and Materials: Since June 1987, orthogonal radiographs using a fiducial marker box have been used to verify brain implant source positions and generate dose-volume histograms at the University of California, San Francisco. For adults who underwent brachytherapy boost for glioblastoma from June 1987 through December 1992, tumor volumes were reoutlined to ensure consistency and dose-volume histograms were recalculated. Univariate and multivariate analyses of various patient and treatment parameters were performed evaluating for influence of dose on freedom from local failure (FFLF) and actuarial survival. Results: Of 102 implant boosts, 5 were excluded because computer plans were unavailable. For the remaining 97 patients, analyses with adjustment for known prognostic factors (age, KPS, extent of initial surgical resection) and prognostic factors identified on univariate testing (adjuvant chemotherapy) showed that higher minimum brachytherapy tumor dose was strongly associated with improved FFLF (p = 0.001). A quadratic relationship was found between total biological effective dose and survival, with a trend toward optimal survival probability at 47 Gy minimum brachytherapy tumor dose (corresponding to about 65 Gy to 95% of the tumor volume); survival decreased with lower or higher doses. Two patients expired and one requires hospice care because of brain necrosis after brachytherapy doses > 63 Gy to 95% of the tumor volume with 60 Gy to > 18 cm3 of normal brain. Conclusion: Although higher minimum brachytherapy tumor dose was strongly associated with better local control, a brachytherapy boost dose > 50-60 Gy may result in life-threatening necrosis. We recommend careful conformation of the prescription isodose line to the contrast enhancing tumor volume, delivery of a minimum brachytherapy boost dose of 45-50 Gy in conjunction with convectional external beam radiotherapy, and reoperation for symptomatic necrosis.

  12. Which cities produce worldwide more excellent papers than can be expected? A new mapping approach--using Google Maps--based on statistical significance testing

    Bornmann, Lutz

    2011-01-01

    The methods presented in this paper allow for a spatial analysis revealing centers of excellence around the world using programs that are freely available. Based on Web of Science data, field-specific excellence can be identified in cities where highly-cited papers were published. Compared to the mapping approaches published hitherto, our approach is more analytically oriented by allowing the assessment of an observed number of excellent papers for a city against the expected number. With this feature, this approach can not only identify the top performers in output but the "true jewels." These are cities locating authors who publish significantly more top cited papers than can be expected. As the examples in this paper show for physics, chemistry, and psychology, these cities do not necessarily have a high output of excellent papers.

  13. An Estimation of the Likelihood of Significant Eruptions During 2000-2009 Using Poisson Statistics on Two-Point Moving Averages of the Volcanic Time Series

    Wilson, Robert M.

    2001-01-01

    Since 1750, the number of cataclysmic volcanic eruptions (volcanic explosivity index (VEI)>=4) per decade spans 2-11, with 96 percent located in the tropics and extra-tropical Northern Hemisphere. A two-point moving average of the volcanic time series has higher values since the 1860's than before, being 8.00 in the 1910's (the highest value) and 6.50 in the 1980's, the highest since the 1910's peak. Because of the usual behavior of the first difference of the two-point moving averages, one infers that its value for the 1990's will measure approximately 6.50 +/- 1, implying that approximately 7 +/- 4 cataclysmic volcanic eruptions should be expected during the present decade (2000-2009). Because cataclysmic volcanic eruptions (especially those having VEI>=5) nearly always have been associated with short-term episodes of global cooling, the occurrence of even one might confuse our ability to assess the effects of global warming. Poisson probability distributions reveal that the probability of one or more events with a VEI>=4 within the next ten years is >99 percent. It is approximately 49 percent for an event with a VEI>=5, and 18 percent for an event with a VEI>=6. Hence, the likelihood that a climatically significant volcanic eruption will occur within the next ten years appears reasonably high.

  14. Dose response and adaptive response of Non-Homologous End Joining (NHEJ) repair genes and proteins in resting human peripheral blood mononuclear cells exposed to gamma radiation

    Ionizing radiation (IR) induces single strand breaks, double strand breaks (DSB), base damages in human cell. Double strand breaks are the most deleterious and if not repaired may lead to genomic instability and cell death. DSB can be repaired through Non-Homologous End Joining (NHEJ) pathway in resting lymphocytes. In the present study, radiation induced NHEJ genes and proteins were studied in resting Peripheral Blood Mononuclear Cells (PBMC) exposed to various doses of gamma radiation. Dose response, time point kinetics and adaptive response studies were conducted in irradiated PBMC and various end points such as DNA damage quantitation, transcription and protein expression profile were studied. Venous blood samples were collected from 20 random, normal, and healthy donors with written informed consent. PBMC was separated and irradiated with various doses between 0.1 Gy to 2.0 Gy (60Co-γ source) for dose response study. Repair kinetics of DNA damage and time point changes in expression of genes and proteins were studied in post-irradiated PBMC at 2.0 Gy at various time points up to 240 min. Adaptive response study was conducted with a priming dose of 0.1 Gy followed by a challenging dose of 2.0 Gy after 4 h incubation. Our results revealed that significant increase in DNA double strand breaks at higher doses. Both slow and fast repair kinetics were observed among the donors. DNA double strand break recognizing Ku proteins (Ku70 and Ku80), XLF and Ligase IV were significantly up regulated at transcript as well as protein expression level, indicating the active role of NHEJ pathway in repairing and rejoining DNA DSBs. Radio-adaptive study also showed significant up regulation of Ku70, Ku80, DNA-PKcs, XRCC4 and Ligase IV suggesting the involvement of NHEJ proteins in radio-adaptive response in human PBMC at G0/G1, which has important implications to human health. (author)

  15. Experimental determination of the lateral dose response functions of detectors to be applied in the measurement of narrow photon-beam dose profiles

    Poppinga, D.; Meyners, J.; Delfs, B.; Muru, A.; Harder, D.; Poppe, B.; Looe, HK

    2015-12-01

    This study aims at the experimental determination of the detector-specific 1D lateral dose response function K(x) and of its associated rotational symmetric counterpart K(r) for a set of high-resolution detectors presently used in narrow-beam photon dosimetry. A combination of slit-beam, radiochromic film, and deconvolution techniques served to accomplish this task for four detectors with diameters of their sensitive volumes ranging from 1 to 2.2 mm. The particular aim of the experiment was to examine the existence of significant negative portions of some of these response functions predicted by a recent Monte-Carlo-simulation (Looe et al 2015 Phys. Med. Biol. 60 6585-607). In a 6 MV photon slit beam formed by the Siemens Artiste collimation system and a 0.5 mm wide slit between 10 cm thick lead blocks serving as the tertiary collimator, the true cross-beam dose profile D(x) at 3 cm depth in a large water phantom was measured with radiochromic film EBT3, and the detector-affected cross-beam signal profiles M(x) were recorded with a silicon diode, a synthetic diamond detector, a miniaturized scintillation detector, and a small ionization chamber. For each detector, the deconvolution of the convolution integral M(x)  =  K(x)  ∗  D(x) served to obtain its specific 1D lateral dose response function K(x), and K(r) was calculated from it. Fourier transformations and back transformations were performed using function approximations by weighted sums of Gaussian functions and their analytical transformation. The 1D lateral dose response functions K(x) of the four types of detectors and their associated rotational symmetric counterparts K(r) were obtained. Significant negative curve portions of K(x) and K(r) were observed in the case of the silicon diode and the diamond detector, confirming the Monte-Carlo-based prediction (Looe et al 2015 Phys. Med. Biol. 60 6585-607). They are typical for the perturbation of the secondary electron field by a detector with enhanced electron density compared with the surrounding water. In the cases of the scintillation detector and the small ionization chamber, the negative curve portions of K(x) practically vanish. It is planned to use the measured functions K(x) and K(r) to deconvolve clinical narrow-beam signal profiles and to correct the output factor values obtained with various high-resolution detectors.

  16. Dose-response relationship of γ-ray-induced reciprocal translocations at low doses in spermatogonia of the crab-eating monkey (Macaca fascicularis)

    The yield of translocations induced by acute γ-irradiation at low doses in the crab-eating monkey's (Macaca fascicularis) spermatogonia was examined. Over the low dose range from 0 to 1 Gy, the dose-response relationship for translocation yield was a linear one. To estimate the sensitivity to the induction of translocations in the crab-eating monkey's spermatogonia, the slope of the regression line was compared with those in other mammalian species. Consequently, over the low dose range below 1 Gy, the sensitivity of the crab-eating monkey's spermatogonia to translocation induction was similar to several mammalian species, the mouse, Chinese hamster, and the rabbit, but significantly higher than that of the rhesus monkey and lower than that of the marmoset. (Auth.)

  17. Critical dose threshold for TL dose response non-linearity: Dependence on the method of analysis: It’s not only the data

    It is demonstrated that the method of data analysis, i.e., the method of the phenomenological/theoretical interpretation of dose response data, can greatly influence the estimation of the onset of deviation from dose response linearity of the high temperature thermoluminescence in LiF:Mg,Ti (TLD-100).

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

    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 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. PMID:21636557

  19. Dose-response relationship of cytogenetic damage and adaptive response of mammalian cells under low dose irradiation

    Dose response relationship of cytogenetic damage after single dose γ-irradiation at the dose range of 0.1-2 Gy and adaptive response after double-dose irradiation were studied on chinese hamster and human melanoma cells in culture using cytogenetic criteria. Non-linear dose dependencies were found for the induction of chromosome aberrations with decrease in cell radiosensitivity in the definite dose range. This decrease started at 10 and 20 cGy for melanoma and Chinese hamster cells respectively. Maximal adaptive response was induced at 1 cGy for melanoma cells and at 20 cGy for Chinese hamster cells. It can be supposed that the same inducible repair processes are responsible for non-linearity of dose-response curves and induction of the adaptive response. These processes are similar in mechanisms and different in quantitative proportion for different cell types

  20. Joint action of chemicals in algal toxicity tests: Influence of response level and dose-response regression model

    Christensen, E.R.; Chen, D.; Nyholm, Niels; Kusk, Kresten Ole

    2001-01-01

    The joint toxicity of nonylamine and decylamine and of atrazine and decylamine was evaluated in assays with the green alga Selenastrum capricornutum based on an isobologram method. In this method, curves of constant response, isoboles, are plotted versus concentrations of two toxicants. The...... response parameter was growth rate based on biomass, and several response levels were used. Doseresponse curves were developed for dilution series using fixed ratios between concentrations in toxic units of the compounds. Probit and Weibull doseresponse curves were then determined by nonlinear regression....... A model for isoboles for partially similar action was used when applicable. The no-effect concentration (NEC or EC0) was estimated based on a newly proposed model containing median effective concentration (EC50) and EC0 as explicit variables. Results show that nonylamine and decylamine are nearly...

  1. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation

    Van Dongen, Hans P A.; Maislin, Greg; Mullington, Janet M.; Dinges, David F.

    2003-01-01

    OBJECTIVES: To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation. DESIGN: The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days. SETTING: Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring. PARTICIPANTS: A total of n = 48 healthy adults (ages 21-38) participated in the experiments. INTERVENTIONS: Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited. RESULTS: Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness were near-linearly related to the cumulative duration of wakefulness in excess of 15.84 h (s.e. 0.73 h). CONCLUSIONS: Since chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation, it appears that even relatively moderate sleep restriction can seriously impair waking neurobehavioral functions in healthy adults. Sleepiness ratings suggest that subjects were largely unaware of these increasing cognitive deficits, which may explain why the impact of chronic sleep restriction on waking cognitive functions is often assumed to be benign. Physiological sleep responses to chronic restriction did not mirror waking neurobehavioral responses, but cumulative wakefulness in excess of a 15.84 h predicted performance lapses across all four experimental conditions. This suggests that sleep debt is perhaps best understood as resulting in additional wakefulness that has a neurobiological "cost" which accumulates over time.

  2. The capacity of short-chain fructo-oligosaccharides to stimulate faecal bifidobacteria: a dose-response relationship study in healthy humans

    Simoneau Guy

    2006-03-01

    Full Text Available Abstract Background Short-chain fructo-oligosaccharides (scFOS are well-known for their bifidogenicity. In a large study comprising 200 healthy volunteers, we determined the bifidogenic properties of 7 non-digestible carbohydrates administered at a dose of 10 g/d in the diet; we analysed dose-response relationships of the bifidogenic substrates at doses ranging from 2.5 to 10 g/d in comparison with a placebo. The aim of this presentation is to give more details about the dose-response effects of short-chain fructo-oligosaccharides (scFOS. Methods Forty healthy volunteers (18 males, 22 females eating their usual diets were randomly divided into 5 groups of 8 subjects and received scFOS at a dose of 2.5, 5.0, 7.5 and 10 g/d or a placebo for 7 d. Stools were collected before (day (d 8 and at the end (day (d 15 of sugar consumption, and tolerance was evaluated using a daily chart. Results (m SEM Bifidobacteria counts increase was higher in scFOS than in placebo group for all doses tested [2.5 g/d (from 9.15 0.59 to 9.39 0.70; P = 0.02; 5 g/d (from 10.21 0.21 to 10.67 0.22; P = 0.03; 7.5 g/d (from 9.28 0.49 to 9.85 0.35;P = 0.01; 10 g/d (from 9.00 0.81 to 10.18 0.60; P = 0.003]. A significant correlation between the ingested dose of scFOS and faecal bifidobacteria counts was observed at d15 (r2 = 0.307, P Conclusion This study showed that scFOS is bifidogenic and well tolerated at doses ranging from 2.5 to 10 g/d, and that there is a dose-response relationship in healthy volunteers.

  3. Dose-response studies on the spermatogonial stem cells of the rhesus monkey (Macaca mulatta) after X irradiation

    Studies of the dose response of the spermatogonial stem cells in the rhesus monkey were performed at intervals of 130 and 160 days after graded doses of X irradiation. The D0 of the spermatogonial stem cells was established using the total numbers of the type A spermatogonia that were present at 130 and 160 days after irradiation and was found to be 1.07 Gy; the 95% confidence interval was 0.90-1.34 Gy

  4. Red and processed meat consumption and risk of ovarian cancer: a dose-response meta-analysis of prospective studies

    Wallin, A.; Orsini, N; Wolk, A

    2011-01-01

    Background: During the last decade, the epidemiological evidence on consumption of meat and risk of ovarian cancer has accumulated. Methods: We assessed the relationship between red and processed meat consumption and risk of ovarian cancer with a dose-response meta-analysis. Relevant prospective cohort studies were identified by searching the PubMed and EMBASE databases through 21 January 2011, and by reviewing the reference lists of retrieved articles. Study-specific relative risk (RR) estim...

  5. Dose Response Effects of Dermally applied Diethanolamine on Neurogenesis in Fetal Mouse Hippocampus and Potential Exposure of Humans

    Craciunescu, Corneliu N; Niculescu, Mihai D.; Guo, Zhong; Johnson, Amy R; Fischer, Leslie; Zeisel, Steven H.

    2008-01-01

    Diethanolamine (DEA) is a common ingredient of personal care products. Dermal administration of DEA diminishes hepatic stores of the essential nutrient choline and alters brain development. We previously reported that 80 mg/kg/day of DEA during pregnancy in mice reduced neurogenesis and increased apoptosis in the fetal hippocampus. This study was designed to establish the dose-response relationships for this effect of DEA. Timed-pregnant C57BL/6 mouse dams were dosed dermally from gestation d...

  6. Developing guidelines for economic evaluation of environmental impacts in EIAs. Part II: Case studies and dose-response literature

    NONE

    2005-07-01

    This Part II of the report contains full versions of the case studies for air, water and land (Chapters 2-4), which were only summarised in Part I. In addition, during the work the research team has collected a large amount of literature and information on dose response relationships for air and water pollution relevant to China. This information is included as Chapters 5 and 6.

  7. A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

    Leonard, Bobby E.

    2008-01-01

    Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends t...

  8. Developing guidelines for economic evaluation of environmental impacts in EIAs. Part II: Case studies and dose-response literature

    This Part II of the report contains full versions of the case studies for air, water and land (Chapters 2-4), which were only summarised in Part I. In addition, during the work the research team has collected a large amount of literature and information on dose response relationships for air and water pollution relevant to China. This information is included as Chapters 5 and 6

  9. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol

    Ruth Gallily; Zhannah Yekhtin; Lumír Ondřej Hanuš

    2015-01-01

    Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect. However, when given either intraperitoneally or orally as a purified product, a bell-shaped dose-response was observed, which limits its clinical use. In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the Cannabis sativa L., clone 202, wh...

  10. Dose-response relationships and risk estimates for the induction of cancer due to low doses of low-LET radiation

    Risk estimates for radiation-induced cancer at low doses can be obtained only by extrapolation from the known effects at high doses and high dose rates, using a suitable dose-response model. The applicability of three different models, linear, sublinear and supralinear, are discussed in this paper. Several experimental studies tend to favour a sublinear dose-response model (linear-quadratic model) for low-LET radiation. However, human epidemiological studies do not exclude any of the dose-response relationships. The risk estimates based on linear and linear quadratic dose-response models are compared and it is concluded that, for low-LET radiation, the linear dose-response model would probably over-estimate the actual risk of cancer by a factor of two or more. (author)

  11. Statistical Significance of the Netflix Challenge

    Feuerverger, Andrey; HE Yu; Khatri, Shashi

    2012-01-01

    Inspired by the legacy of the Netflix contest, we provide an overview of what has been learned---from our own efforts, and those of others---concerning the problems of collaborative filtering and recommender systems. The data set consists of about 100 million movie ratings (from 1 to 5 stars) involving some 480 thousand users and some 18 thousand movies; the associated ratings matrix is about 99% sparse. The goal is to predict ratings that users will give to movies; systems which can do this ...

  12. Evaluation of the Linear-Nonthreshold Dose-Response Model for Ionizing Radiation (NCRP Report No 136)

    National Council on Radiation Protection and Measurements MD: NCRP (2001) 287 pp, $50.00 Lively debate continues on the nature of the dose-response relationship for the excess risk of cancer following exposure to ionising radiation at low doses and/or low dose rates. Clearly, these are the exposure conditions of principal importance to radiological protection. Presently, for the purposes of radiological protection, the assumption is made that the underlying dose-response relationship is linear-quadratic with no threshold, and that in the low dose and/or low dose rate region this curve can be approximated by a straight line with a gradient half that of the linear relationship which (for cancers other than leukaemia) is appropriate for moderate to high doses received at high dose rates. This, in essence, is the 'linear-nonthreshold (LNT) dose-response model' referred to in the title of NCRP Report No 136. The report begins by examining the way in which radiation energy is deposited in cells. It concludes that at low doses and low dose rates the relevant biological damage would be produced by a 'single hit' because of the spatial and temporal sparseness of the events causing the damage. Since cancer is considered to be monoclonal (single cell) in origin, this suggests that the dose-response is linear at low doses with no threshold. However, it is possible that the whole organism may be more capable of repairing damage at low doses and low dose rates, whic h would modify the dose-response to a sub-linear curve. The extent of such modification, if it exists, is unknown as is whether it could be 100% effective as implied by a threshold in the dose-response at some non-zero dose. The evidence for the modification of the dose-response curve at low doses is considered in the report in four chapters dealing with various biological manifestations of the fundamental damage caused by ionising radiation. The chapter on DNA repair and processing concludes that it is likely that exposure of humans to low doses and low dose rates does result in permanent alterations in DNA sequences, which points away from a threshold. However, many steps are required between these events and clinical cancer and it is not known how this progression might differ after low dose irradiation. The next chapter discusses radiation-induced mutations. All types of mutations commonly seen in human cancers can be induced by ionising radiation. There is no direct evidence for a threshold in the dose-response obtained from in vitro studies. Genomic instability may contribute to radiation-induced carcinogenesis and produce a non-linear dose-response, but insufficient is known about this process at the moment. The misrepair of DNA lesions can also give rise to chromosome aberrations and this is considered in the next chapter. While the existing data do not exclude the possibility that a threshold for the induction of chromosome aberrations may exist in the mSv dose range, there is no body of data supporting such a possibility nor would such a threshold be consistent with current understanding of the mechanisms of chromosome aberration formation at low doses. Oncogenic transformation in vitro and genomic instability are considered in the following chapter. The dose-response curve for neoplastic transformation is complex in shape and subject to variation depending upon the particular cells and experimental conditions under investigation. The report identifies the principal research need as being the development of transformation assays based on human cells. The experimental findings concerning carcinogenic effects in laboratory animals (next chapter) permit few generalisations concerning the shapes of the dose-response curves. The variations in the dose-response relationships for different cancers point to differences in causal mechanisms which are not yet understood. However, it is clear that cancer induction in vivo is a multi-stage process. The epidemiological evidence for carcinogenic effects in human populations is considered in a large chapter within the report. '

  13. Construction of dose response calibration curves for dicentrics and micronuclei for X radiation in a Serbian population.

    Pajic, J; Rakic, B; Jovicic, D; Milovanovic, A

    2014-10-01

    Biological dosimetry using chromosome damage biomarkers is a valuable dose assessment method in cases of radiation overexposure with or without physical dosimetry data. In order to estimate dose by biodosimetry, any biological dosimetry service have to have its own dose response calibration curve. This paper reveals the results obtained after irradiation of blood samples from fourteen healthy male and female volunteers in order to establish biodosimetry in Serbia and produce dose response calibration curves for dicentrics and micronuclei. Taking into account pooled data from all the donors, the resultant fitted curve for dicentrics is: Ydic=0.0009 (±0.0003)+0.0421 (±0.0042)×D+0.0602 (±0.0022)×D(2); and for micronuclei: Ymn=0.0104 (±0.0015)+0.0824 (±0.0050)×D+0.0189 (±0.0017)×D(2). Following establishment of the dose response curve, a validation experiment was carried out with four blood samples. Applied and estimated doses were in good agreement. On this basis, the results reported here give us confidence to apply both calibration curves for future biological dosimetry requirements in Serbia. PMID:25308702

  14. Data mining-based statistical analysis of biological data uncovers hidden significance: clustering Hashimoto's thyroiditis patients based on the response of their PBMC with IL-2 and IFN-γ secretion to stimulation with Hsp60.

    Tonello, Lucio; Conway de Macario, Everly; Marino Gammazza, Antonella; Cocchi, Massimo; Gabrielli, Fabio; Zummo, Giovanni; Cappello, Francesco; Macario, Alberto J L

    2015-03-01

    The pathogenesis of Hashimoto's thyroiditis includes autoimmunity involving thyroid antigens, autoantibodies, and possibly cytokines. It is unclear what role plays Hsp60, but our recent data indicate that it may contribute to pathogenesis as an autoantigen. Its role in the induction of cytokine production, pro- or anti-inflammatory, was not elucidated, except that we found that peripheral blood mononucleated cells (PBMC) from patients or from healthy controls did not respond with cytokine production upon stimulation by Hsp60 in vitro with patterns that would differentiate patients from controls with statistical significance. This "negative" outcome appeared when the data were pooled and analyzed with conventional statistical methods. We re-analyzed our data with non-conventional statistical methods based on data mining using the classification and regression tree learning algorithm and clustering methodology. The results indicate that by focusing on IFN-γ and IL-2 levels before and after Hsp60 stimulation of PBMC in each patient, it is possible to differentiate patients from controls. A major general conclusion is that when trying to identify disease markers such as levels of cytokines and Hsp60, reference to standards obtained from pooled data from many patients may be misleading. The chosen biomarker, e.g., production of IFN-γ and IL-2 by PBMC upon stimulation with Hsp60, must be assessed before and after stimulation and the results compared within each patient and analyzed with conventional and data mining statistical methods. PMID:25408301

  15. Validity of bioeffect dose response models for normal tissue early and late complications of the skin

    Background: The bioeffect of a physical dose depends on the nature of the tissue, fractionation scheme, dose rate and treatment time. Certainly, experienced radiotherapists are convinced of the existence of patient-to-patient variability in normal tissue response to radiotherapy for malignant tumours. The absorbed dose needs to be translated into a bioeffect dose, which takes into account treatment variables and the radiobiological characteristics of the relevant tissue. Various bioeffect models such as NSD, CRE, TDF and BED have been proposed to predict the biological effect of radiotherapy treatments. Aim: This study was aimed at deriving tolerance bioeffect dose values for normal tissue complication rate. Materials/Methods: Compiled clinical data of time dose fractionation schedules and incidence of erythema, desquamation and telangiectasia were used for the present analysis. Results: For erythema and desquamation the radiation dose varied from 23.9 to 55.1 Gy in 04 to 50 fractions (dose per fraction 1.1 to 7.3 Gy) in 11 to 40 days. For telangiectasia (score .1 at 3 years) the radiation dose varied from 25.8 to 55.1 Gy in 04 to 50 fractions (dose per fraction 1.1 to 7.3 Gy) in 11 to 40 days. For telangiectasia (score .2 at 5 years) the radiation dose varied from 25.8 to 63.0 Gy in 04 to 50 fractions (dose per fraction 1.1 to 7.3 Gy) in 11 to 68 days. For telangiectasia (score .1, .2, .3, .4 at 10 years) the radiation dose varied from 25.8 to 63.0 Gy in 04 to 35 fractions (dose per fraction 1.7 to 7.3 Gy) in 22 to 68 days. TDF and LQF values for erythema, desquamation and telangiectasia were evaluated with a/b values of 7.5 Gy, 11.2 Gy and 2.8 Gy respectively. TDF and LQF had a statistically significant correlation with probability of erythema, desquamation and telangiectasia (p<0.001). Conclusions: TDF and LQF values should be limited to 60 and 86 Gy in order to limit the probability of telangiectasia. (authors)

  16. Glyphosate-resistant and -susceptible soybean (Glycine max) and canola (Brassica napus) dose response and metabolism relationships with glyphosate.

    Nandula, Vijay K; Reddy, Krishna N; Rimando, Agnes M; Duke, Stephen O; Poston, Daniel H

    2007-05-01

    Experiments were conducted to determine (1) dose response of glyphosate-resistant (GR) and -susceptible (non-GR) soybean [Glycine max (L.) Merr.] and canola (Brassica napus L.) to glyphosate, (2) if differential metabolism of glyphosate to aminomethyl phosphonic acid (AMPA) is the underlying mechanism for differential resistance to glyphosate among GR soybean varieties, and (3) the extent of metabolism of glyphosate to AMPA in GR canola and to correlate metabolism to injury from AMPA. GR50 (glyphosate dose required to cause a 50% reduction in plant dry weight) values for GR (Asgrow 4603RR) and non-GR (HBKC 5025) soybean were 22.8 kg ae ha-1 and 0.47 kg ha-1, respectively, with GR soybean exhibiting a 49-fold level of resistance to glyphosate as compared to non-GR soybean. Differential reduction in chlorophyll by glyphosate was observed between GR soybean varieties, but there were no differences in shoot fresh weight reduction. No significant differences were found between GR varieties in metabolism of glyphosate to AMPA, and in shikimate levels. These results indicate that GR soybean varieties were able to outgrow the initial injury from glyphosate, which was previously caused at least in part by AMPA. GR50 values for GR (Hyola 514RR) and non-GR (Hyola 440) canola were 14.1 and 0.30 kg ha-1, respectively, with GR canola exhibiting a 47-fold level of resistance to glyphosate when compared to non-GR canola. Glyphosate did not cause reduction in chlorophyll content and shoot fresh weight in GR canola, unlike GR soybean. Less glyphosate (per unit leaf weight) was recovered in glyphosate-treated GR canola as compared to glyphosate-treated GR soybean. External application of AMPA caused similar injury in both GR and non-GR canola. The presence of a bacterial glyphosate oxidoreductase gene in GR canola contributes to breakdown of glyphosate to AMPA. However, the AMPA from glyphosate breakdown could have been metabolized to nonphytotoxic metabolites before causing injury to GR canola. Injury in GR and non-GR canola from exogenous application of AMPA was similar. PMID:17417871

  17. Dose-response association between hepatitis B surface antigen levels and liver cancer risk in Chinese men and women.

    Yang, Yang; Gao, Jing; Li, Hong-Lan; Zheng, Wei; Yang, Gong; Zhang, Wei; Ma, Xiao; Tan, Yu-Ting; Rothman, Nathaniel; Gao, Yu-Tang; Chow, Wong-Ho; Shu, Xiao-Ou; Xiang, Yong-Bing

    2016-07-15

    We aimed at evaluating the risk of liver cancer in different levels of HBsAg among Chinese men and women. We carried out a nested case-control study including 363 cases and 3,511 controls in two population-based cohorts in Shanghai. Plasma samples collected at enrollment were quantified for HBsAg levels using the Architect QT assay. Conditional logistic regression was performed to estimate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for liver cancer, with adjustment for potential confounders. HBsAg was detected in 6.29% of control subjects overall (7.02% in men and 4.98% in women). HBsAg levels were positively associated with liver cancer risk in a dose-response manner (ptrend  < 0.001). Such association showed a significant gender disparity. With increasing levels of HBsAg, liver cancer risks rose more steeply in men than in women. In men, the adjusted ORs increased from 7.27 (95% CI: 3.49-15.15) at the lowest detectable level of HBsAg (5-9 IU/ml) to 7.16 (95% CI: 3.21-15.96), 34.30 (95% CI: 16.94-69.44), and 47.33 (95% CI: 23.50-95.34) at the highest level of HBsAg (≥1,000 IU/ml) compared to those negative for HBsAg. The corresponding ORs were much lower for women, from 1.37 (95% CI: 0.25-7.47), 3.81 (95% CI: 1.09-13.28), 7.36 (95% CI: 2.41-22.46) and 16.86 (95% CI: 7.24-39.27), respectively. HBsAg quantification has potential to distinguish individuals at different risks of liver cancer. Men with the lowest detectable level of HBsAg should still pay attention to their liver cancer risks, but those with a higher level may be given a higher priority in future liver cancer surveillance program. PMID:26990915

  18. Nonlinearity and thresholds in dose-response relationships for carcinogenicity due to sampling variation, logarithmic dose scaling, or small differences in individual susceptibility

    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

  19. PSOD: an interactive Fortran program to simulate the radiation dose response of membrane populations

    Program PSOD was written to simulate the distribution in responses of membrane populations subjected to random radiation doses and dose rates. It computes the response (damage) according to one of three formulas selected by the user, and outputs statistical results to the terminal. It will plot simulated dose- and response-frequency distributions in two or three dimensions. Doses and dose rates are selected from the log normal distribution; other distributions can be incorporated as the need arises. A true log normal curve with defined mean and standard deviation can also be generated. The purpose of this documentation is to provide a complete operating manual for the program. A user guide is available on-line after initiating a session of PSOD. Detailed examinations of the statistical validity of various steps have been included to aid future modifications and updating

  20. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

    Berrington de Gonzalez, Amy, E-mail: berringtona@mail.nih.gov [Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States); Gilbert, Ethel; Curtis, Rochelle; Inskip, Peter; Kleinerman, Ruth; Morton, Lindsay; Rajaraman, Preetha; Little, Mark P. [Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (United States)

    2013-06-01

    Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.

  1. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review

    Chronic arsenic (As) poisoning has become a worldwide public health issue. Most human As exposure occurs from consumption of drinking water containing high amounts of inorganic As (iAs). In this paper, epidemiological studies conducted on the dose-response relationships between iAs exposure via the drinking water and related adverse health effects are reviewed. Before the review, the methods for evaluation of the individual As exposure are summarized and classified into two types, that is, the methods depending on As concentration of the drinking water and the methods depending on biological monitoring for As exposure; certain methods may be applied as optimum As exposure indexes to study dose-response relationship based on various As exposure situation. Chronic effects of iAs exposure via drinking water include skin lesions, neurological effects, hypertension, peripheral vascular disease, cardiovascular disease, respiratory disease, diabetes mellitus, and malignancies including skin cancer. The skin is quite sensitive to arsenic, and skin lesions are some of the most common and earliest nonmalignant effects related to chronic As exposure. The increase of prevalence in the skin lesions has been observed even at the exposure levels in the range of 0.005-0.01 mg/l As in drinking waters. Skin, lung, bladder, kidney, liver, and uterus are considered as sites As-induced malignancies, and the skin is though to be perhaps the most sensitive site. Prospective studies in large area of endemic As poisoning, like Bangladesh or China, where the rate of malignancies is expected to increase within the next several decades, will help to clarify the dose-response relationship between As exposure levels and adverse health effects with enhanced accuracy

  2. Dose-response curve slope is a missing dimension in the analysis of HIV-1 drug resistance.

    Sampah, Maame Efua S; Shen, Lin; Jilek, Benjamin L; Siliciano, Robert F

    2011-05-01

    HIV-1 drug resistance is a major clinical problem. Resistance is evaluated using in vitro assays measuring the fold change in IC(50) caused by resistance mutations. Antiretroviral drugs are used at concentrations above IC(50), however, and inhibition at clinical concentrations can only be predicted from IC(50) if the shape of the dose-response curve is also known. Curve shape is influenced by cooperative interactions and is described mathematically by the slope parameter or Hill coefficient (m). Implicit in current analysis of resistance is the assumption that mutations shift dose-response curves to the right without affecting the slope. We show here that m is altered by resistance mutations. For reverse transcriptase and fusion inhibitors, single resistance mutations affect both slope and IC(50). For protease inhibitors, single mutations primarily affect slope. For integrase inhibitors, only IC(50) is affected. Thus, there are fundamental pharmacodynamic differences in resistance to different drug classes. Instantaneous inhibitory potential (IIP), the log inhibition of single-round infectivity at clinical concentrations, takes into account both slope and IC(50), and thus provides a direct measure of the reduction in susceptibility produced by mutations and the residual activity of drugs against resistant viruses. The standard measure, fold change in IC(50), does not correlate well with changes in IIP when mutations alter slope. These results challenge a fundamental assumption underlying current analysis of HIV-1 drug resistance and suggest that a more complete understanding of how resistance mutations reduce antiviral activity requires consideration of a previously ignored parameter, the dose-response curve slope. PMID:21502494

  3. Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

    Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques

  4. Low dose effects and non-monotonic dose responses for endocrine active chemicals: Science to practice workshop: Workshop summary

    Beausoleil, Claire; Ormsby, Jean-Nicolas; Gies, Andreas; Hass, Ulla; Heindel, Jerrold J.; Holmer, Marie Louise; Nielsen, Pia Juul; Munn, Sharon; Schoenfelder, Gilbert

    2013-01-01

    A workshop was held in Berlin September 12–14th 2012 to assess the state of the science of the data supporting low dose effects and non-monotonic dose responses (“low dose hypothesis”) for chemicals with endocrine activity (endocrine disrupting chemicals or EDCs). This workshop consisted of...... lectures to present the current state of the science of EDC action and also the risk assessment process. These lectures were followed by breakout sessions to integrate scientists from various backgrounds to discuss in an open and unbiased manner the data supporting the “low dose hypothesis”. While no...

  5. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Qiang Liu; Bing Wang; Takanori Katsube; Sai Jun Fan; Fei-Yue Fan; Hui Zhao; Xu (Kevin) Su; Jian Xiang Liu; Jia Cao; Li Qing Du; Chang Xu; Yan Wang

    2013-01-01

    Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001). A time-response relationship was also found within 72 h after irradiation (p < 0.001). The curves for DNA double-strand bre...

  6. Effects of Folic Acid Supplementation on Serum Folate and Plasma Homocysteine Concentrations in Older Adults: A Dose-Response Trial

    Anderson, Cheryl A. M.; Jee, Sun Ha; Charleston, Jeanne; Narrett, Matthew; APPEL, LAWRENCE J.

    2010-01-01

    The authors’ objective in this study was to estimate the changes in serum folate and homocysteine concentration that resulted from 6 weeks of supplementation with folic acid. A randomized, double-blind, placebo-controlled, dose-response trial with a parallel-group design was conducted. A total of 133 participants aged 60–90 years (70% female, 19% nonwhite) were assigned to receive 0, 100, 400, 1,000, or 2,000 μg/day of folic acid for 6 weeks. Data were collected in the United States between J...

  7. Low dose radiation induced adaptive response upon salt stress and vacuum stress: a possible mechanism for the effect of saddle-like dose response curve

    To explore mechanism for the effect of saddle-like dose-response curve, the relationship of irradiation-vacuum stress, and irradiation-salt stress, was investigated with rice seeds irradiated to 60-560 Gy by 60Co ?-rays. The dose-response curve was simulated based on seedling height data, which showed obedient to linear-quadratic model. During germination,the irradiated rice seeds were stressed by 10-3 Pa vacuum, or by NaCl in different concentrations. After that, the dose-response curve manifested a saddle-like shape. The results indicate that while low dose irradiation could retard seedling growth synergistically with vacuum stress and salt stress, it could also induce adaptive response upon vacuum stress and salt stress. Low dose irradiation induced adaptive response upon environmental adverse factors could contribute to the mechanism for the effect of saddle-like dose-response curve. (authors)

  8. SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

    Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receiving radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for use in dose-response studies. We would like to thank the Engineering and Physical Sciences Research Council for funding. We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. RayStatation was used under an evaluation agreement with RaySearch Laboratories AB

  9. SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

    Dean, J; Welsh, L; Gulliford, S; Harrington, K; Nutting, C [The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London (United Kingdom)

    2014-06-01

    Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receiving radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for use in dose-response studies. We would like to thank the Engineering and Physical Sciences Research Council for funding. We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. RayStatation was used under an evaluation agreement with RaySearch Laboratories AB.

  10. Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment

    Al-Mayah, Adil; Moseley, Joanne; Hunter, Shannon; Brock, Kristy

    2015-11-01

    Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D).

  11. An in vitro dynamic microcosm biofilm model for caries lesion development and antimicrobial dose-response studies.

    Maske, T T; Brauner, K V; Nakanishi, L; Arthur, R A; van de Sande, F H; Cenci, M S

    2016-03-01

    Some dynamic biofilm models for dental caries development are limited as they require multiple experiments and do not allow independent biofilm growth units, making them expensive and time-consuming. This study aimed to develop and test an in vitro dynamic microcosm biofilm model for caries lesion development and for dose-response to chlorhexidine. Microcosm biofilms were grown under two different protocols from saliva on bovine enamel discs for up to 21 days. The study outcomes were as follows: the percentage of enamel surface hardness change, integrated hardness loss, and the CFU counts from the biofilms formed. The measured outcomes, mineral loss and CFU counts showed dose-response effects as a result of the treatment with chlorhexidine. Overall, the findings suggest that biofilm growth for seven days with 0.06 ml min(-1) salivary flow under exposure to 5% sucrose (3 × daily, 0.25 ml min(-1), 6 min) was suitable as a pre-clinical model for enamel demineralization and antimicrobial studies. PMID:26905384

  12. Dose response and post-irradiation characteristics of the Sunna 535-nm photo-fluorescent film dosimeter

    Murphy, M. K.; Kovcs, A.; Miller, S. D.; McLaughlin, W. L.

    2003-12-01

    Results of characterization studies on one of the first versions of the Sunna photo-fluorescent dosimeter have previously been reported, and the performance of the red fluorescence component described. This present paper describes dose response and post-irradiation characteristics of the green fluorescence component from the same dosimeter film ( Sunna Model ?), which is manufactured using the injection molding technique. This production method may supply batch sizes on the order of 1 million dosimeter film elements while maintaining a signal precision (1 ?) on the order of 1% without the need to correct for variability of film thickness. The dosimeter is a 1 cm3 cm polymeric film of 0.5-mm thickness that emits green fluorescence at intensities increasing almost linearly with dose. The data presented include dose response, post-irradiation growth, heat treatment, dosimeter aging, dose rate dependence, energy dependence, dose fractionation, variation of response within a batch, and the stability of the fluorimeter response. The results indicate that, as a routine dosimeter, the green signal provides a broad range of response at food irradiation (0.3-5 kGy), medical sterilization (5-40 kGy), and polymer cross-linking (40-250 kGy) dose levels.

  13. The dose-response-relation of erythema of the domestic pig induced by UVC-radiation (254 nm)

    For domestic pigs the time-course and the dose-response-relationship of erythemal effective UVC-radiation was investigated. By the chromameter CR 300 (Minolta) the redness of the skin was measured, using the international L*a*b*-system. As UVC-source a germicidal lamp (TUV, Philips) was housed in a tube. The irradiance of the 10 zylindric holes were attenuated by a wire mash, changing the intensity along a logarithmic decrement. For the experiment 10 pigs were used. Each pig could be irradiated with 40 dose-steps. The redness of the marked skin-areas was not only determined once before the irradiation but also several times within 36 hours. The reaction of the skin of the pigs to UVC-radiation was different to human's. The time-course of the UVC-erythema was biphasical. The second erythema-maximum could not be explained by the pigmentation, which had just begun, but by an new increase of the reddening of the skin. No dose-response-correlation like the human's UVC-erythema could be detected. Therefore, the domestic pig can not be used as a human's photo-biological model for UVC. (author)

  14. Thyroid nodules in the population living around semipalatinsk nuclear test site. Possible implications for dose-response relationships study

    The risk of radiation-induced nodules is higher than the risk for radiation-induced cancer. Risk factors and specific modifiers of the dose-response relationship may vary among different populations and not be well recognized. Many thyroid studies have considered thyroid nodularity itself, but not specific morphological types of thyroid nodules. There are many specific types of thyroid nodules which follow a morphological classification of thyroid lesions, including some congenital and tumor-like conditions. Modern equipment and technique can help us to identify particular specific types of thyroid nodules. In this study we report some results of a clinically applicable approach to materials derived from three studies. From 1999 through 2002, we have screened 571 current residents from 4 exposed and 1 control village near the Semipalatinsk Nuclear Test Site area, who were of similar ages (<20) at the time of major radiation fallout events at the Semipalatinsk Nuclear Test Site (SNTS). Prevalent nodules were identified by ultrasound and fine-needle aspiration biopsy, cytopathology results. Analysis of ultrasound images and cytopathology of thyroid lesions among exposed and non-exposed population allowed us to distinguish some interesting ultrasound features for specific types of thyroid nodules. We believe that it would be interesting and possibly more informative for thyroid dosimetry studies to consider specific morphological types of thyroid nodules. We need more detailed research to clarify the feasibility of applying these findings for study of the dose-response relationship. (author)

  15. Effect of inorganic salts and glucose additives on dose-response, melting point and mass density of genipin gel dosimeters.

    Al-Jarrah, A M; Abdul Rahman, Azhar; Shahrim, Iskandar; Razak, Nik Noor Ashikin Nik Ab; Ababneh, Baker; Tousi, Ehsan Taghizadeh

    2016-01-01

    Genipin gel dosimeters are hydrogels infused with a radiation-sensitive material which yield dosimetric information in three dimensions (3D). The effect of inorganic salts and glucose on the visible absorption dose-response, melting points and mass density of genipin gel dosimeters has been experimentally evaluated using 6-MV LINAC photons. As a result, the addition of glucose with optimum concentration of 10% (w/w) was found to improve the thermal stability of the genipin gel and increase its melting point (Tm) by 6 °C accompanied by a slight decrease of dose-response. Furthermore, glucose helps to adjust the gel mass density to obtain the desired tissue-equivalent properties. A drop of Tm was observed when salts were used as additives. As the salt concentration increased, gel Tm decreased. The mass density and melting point of the genipin gel could be adjusted using different amounts of glucose that improved the genipin gel suitability for 3D dose measurements without introducing additional toxicity to the final gel. PMID:26494156

  16. Possible uses of animal databases for further statistical evaluation and modeling

    Many studies have been performed in animals which mimic potential exposures of people in order to understand how factors modify radiation dose-response relationships. Cooperative analyses by investigators in different laboratories have a large potential for strengthening the conclusions that can be drawn from individual studies. When information on each animal is combined, then formal tests can be made to demonstrate that apparent consistencies or inconsistencies are statistically significant. Statistical methods must be carefully chosen so that differences between laboratories or studies can be controlled or described as part of the analysis in the interpretation of the conclusions. In this report, the example of bone cancer of the large number of studies of modifying factors for bone cancer available from studies in US and European laboratories

  17. Ingestion risks of metals in groundwater based on TIN model and dose-response assessment - A case study in the Xiangjiang watershed, central-south China

    Groundwater samples were collected in the Xiangjiang watershed in China from 2002 to 2008 to analyze concentrations of arsenic, cadmium, chromium, copper, iron, lead, mercury, manganese, and zinc. Spatial and seasonal trends of metal concentrations were then discussed. Combined with geostatistics, an ingestion risk assessment of metals in groundwater was performed using the dose-response assessment method and the triangulated irregular network (TIN) model. Arsenic concentration in groundwater had a larger variation from year to year, while the variations of other metal concentrations were minor. Meanwhile, As concentrations in groundwater over the period of 2002-2004 were significantly higher than that over the period of 2005-2007, indicating the improvement of groundwater quality within the later year. The hazard index (HI) in 2002 was also significantly higher than that in 2005, 2006, 2007 and 2008. Moreover, more than 80% of the study area recorded an HI of more than 1.0 for children, suggesting that some people will experience deleterious health effects from drinking groundwater in the Xiangjiang watershed. Arsenic and manganese were the largest contributors to human health risks (HHRs). This study highlights the value of long-term health risk evaluation and the importance of geographic information system (GIS) technologies in the assessment of watershed-scale human health risk.

  18. Transformation of C3H 10T1/2 cells by low doses of ionising radiation: a collaborative study by six European laboratories strongly supporting a linear dose-response relationship

    Mill, A.J. [Faculty of Applied Sciences, Frenchay Campus, University of the West of England, Coldharbour Lane, Bristol BS16 1QY (United Kingdom); Radiobiology Laboratory, Berkeley Centre, Magnox Electric plc, Berkeley, Gloucestershire GL13 9PB (United Kingdom); Frankenberg, D.; Frankenberg-Schwager, M. [Klinische Strahlenbiologie und Klinische Strahlenphysik, Georg-August-Universitaet Goettingen, von Siebold-Stra 3, 3400 Goettingen (Germany); Bettega, D.; Calzolari, P.; Tallone, L. [Dipartimento di Fisica, Universita degli Studi di Milano, Via Celoria, 16, I-20133 Milano (Italy); Hieber, L. [Institut fuer Strahlenbiologie, GSF - Forschungzentrum, Ingolstadter Landstra 1, 85764 Oberschleissheim, Muenchen (Germany); Saran, A.; Pariset, L.; Pazzaglia, S. [Ente per le Nuove Tecnologie, l' Energia e l' Ambiente, CRE-Casaccia, Settore AMB-BIO, C.P. 2400, 00100 Roma (Italy); Allen, L.A. [Radiobiology Laboratory, Berkeley Centre, Magnox Electric plc, Berkeley, Gloucestershire GL13 9PB (United Kingdom); Lehane, M.M. [Radiobiology Laboratory, Berkeley Centre, Magnox Electric plc, Berkeley, Gloucestershire GL13 9PB (United Kingdom); Paediatric and Neuro-oncology Laboratories, Frenchay Hospital, Bristol BS16 1LE (United Kingdom); Morgan, G.R.; Roberts, C.J. [Biotechnology Services, AEA Technology plc, 353 Harwell Laboratory, Didcot, Oxfordshire OX11 0RA (United Kingdom)

    1998-06-01

    For the assessment of radiation risk at low doses, it is presumed that the shape of the low-dose-response curve in humans for cancer induction is linear. Epidemiological data alone are unlikely to ever have the statistical power needed to confirm this assumption. Another approach is to use oncogenic transformation in vitro as a surrogate for carcinogenesis in vivo. In mid-1990, six European laboratories initiated such an approach using C3H 10T1/2 mouse cells. Rigid standardisation procedures were established followed by collaborative measurements of transformation down to absorbed doses of 0.25 Gy of x-radiation resulting in a total of 759 transformed foci. The results clearly support a linear dose-response relationship for cell transformation in vitro with no evidence for a threshold dose or for an enhanced, supralinear response at doses {approx}200-300 mGy. For radiological protection this represents a large dose, and the limitations of this approach are apparent. Only by understanding the fundamental mechanisms involved in radiation carcinogenesis will further knowledge concerning the effects of low doses become available. These results will, however, help to validate new biologically based models of radiation cancer risk thus providing increased confidence in the estimation of cancer risk at low doses. (author)

  19. Trial sequential analysis may be insufficient to draw firm conclusions regarding statistically significant treatment differences using observed intervention effects: a case study of meta-analyses of multiple myeloma trials.

    Miladinovic, Branko; Kumar, Ambuj; Hozo, Iztok; Mahony, Helen; Djulbegovic, Benjamin

    2013-03-01

    Trial sequential analysis (TSA) has been proposed as a method to assess the risk of random error in cumulative meta-analysis (MA), which increases due to repeated significance testing. The aim of TSA is to assist researchers from wrongly concluding treatment differences in the absence of a benefit (i.e. true versus false positive). Similar to monitoring boundaries applied in individual randomized controlled trials, recent literature has advocated the use of TSA for assessing the conclusiveness of results from MAs to determine the requirement for future studies in case of true positive results. While this may be desirable, we present empirical evidence from a recent systematic review to demonstrate that the use of TSA may lead to a premature declaration of statistically significant treatment difference, when further accumulated evidence suggested otherwise. Using all apparently conclusive MAs in multiple-myeloma, we empirically studied under what thresholds for the risk ratio reduction and power a true positive result becomes false positive. We recommend that the conclusion of significant treatment differences in cumulative MA should be weighed against acceptable thresholds regarding the type I error, power and apriori specified clinically meaningful treatment difference. PMID:23274403

  20. Dose response behaviour of water scarcity towards genetical and morphological traits in spring wheat

    Combining ability was studied in a Line * Tester mating fashion in wheat (Tricticum aestivum L.). Significant differences were observed for all the yield and yield contributing traits. GCA and SCA components of variation were found significant for most of the traits. Under water stressed conditions among lines the genotype Kohistan-97 revealed significant GCA effects for all the traits except spike length. Among testers, the genotype V08172 showed significant effects for the traits spike length, 1000-grain weight and flag leaf area. Based on desirable SCA effects and mean performance the cross combinations Kohistan-97 * V08172, Chakwal-86 * Punjab-81, Fsd-2008 * Punjab-81, Sehar-2006 * V08172 and Chakwal-86 * V08172 behaved best combiner to tolerate the water stress. Results of genetic analysis offered over dominance type of gene action that remained unchanged with the change in water provision for the traits like 1000 grain weight and economic yield. Similarly additive gene action was observed for the trait plant height under both normal irrigation and water stress conditions. However the cumulative genetic effects to control the expression of yield and yield components was shifted due to the changed environments. The study was concluded that due to presence of additive variance, selection could be practiced in early generation whereas in the presence of recessiveness the selection may be delayed up to the later generations. Plant traits associated with water stress tolerance having high heritability and with additive gene action may be used as indirect selection criteria for early selection of water stress tolerant genotypes. The information generated as a result of this study on genetic analysis of important economic traits of wheat under contrasting water availability positions will be of great value to the wheat breeders to design future breeding programmes. (author)

  1. Dose-response study with ibuprofen in rheumatoid arthritis: clinical and pharmacokinetic findings.

    Grennan, D M; Aarons, L; Siddiqui, M; Richards, M; Thompson, R.; Higham, C

    1983-01-01

    Clinical response and plasma pharmacokinetics were studied in 20 rheumatoid patients receiving three dosages of ibuprofen. There was a significant response to 1600 mg daily of ibuprofen by all three clinical measurements but increasing the daily dosage to 2400 mg produced no overall increase in response. The AUC increased with increasing daily drug dosages from 800 to 2400 mg daily and the dose normalised AUC fell by 15% over the same dosage range. The fraction of ibuprofen not bound to plasm...

  2. Prenatal irradiation and spatial memory in mice: investigation of dose-response relationship

    Pregnant CD1 mice were exposed on gestational day 18 to 250 kV X-rays at 0.1, 0.25, 0.35 and 0.5 Gy. The performances of 10 adult male offspring from each exposure condition were investigated on a spatial discrimination learning task in a radial arm maze. An impairment in the performance of this task was found which showed a correlation with dose. Compared with sham exposed control mice, performance was not significantly affected with irradiation at 0.1 Gy and was slightly but non-significantly reduced at 0.25 Gy. Irradiation at 0.35 Gy caused a significant impairment in performance, and exposure at 0.5 Gy resulted in a still larger impairment. The overall association between dose and behavioural impairment was best described by a linear relationship without a threshold, although at doses lower than about 0.25 Gy any impairment would appear to be too small to be detectable. (Author)

  3. Dose-response studies of depletion and repopulation of rat intestinal mucosal mast cells after irradiation

    Sedgwick, D.M.; Ferguson, A. (Western General Hospital, Edinburgh (United Kingdom))

    1994-04-01

    The effects of radiation on gut mucosal mast cells (MMC) and tissue eosinophils were examined. Groups of rats were given single doses of whole-body irradiation from 0.5 to 5 Gy. Serum rat mast cell protease II (RMCPII) concentration showed a significant dose-dependent fall after 1 Gy on day 3 and 1.5 Gy on day 7. MMC counts and tissue RMCPII values on day 7 decreased significantly by 70% after 1 Gy and were undetectable with larger doses. Rats with normal and expanded MMC populations were irradiated or given anaphylaxis. Serum RMCPII concentrations did not change after irradiation, but there was a 10-fold increase in RMCPII after anaphylaxis. Tissue eosinophils in jejunum were 50% of control at 7 days after 2 Gy, and this effect was progressively more marked with higher doses. Similar effects on MMC and eosinophils were demonstrated in ileum, ascending colon and rectum. After 4.5 Gy, repopulation of the gut with MMC did not occur until week 3-4 postirradiation and MMC counts were still 50% below those of controls at 5 weeks postirradiation. Counts of tisse eosinophils 5 weeks after 4.5 Gy irradiation had returned to control levels in jejunum but were still significantly depleted in colon. (Author).

  4. Dose-response studies of depletion and repopulation of rat intestinal mucosal mast cells after irradiation

    The effects of radiation on gut mucosal mast cells (MMC) and tissue eosinophils were examined. Groups of rats were given single doses of whole-body irradiation from 0.5 to 5 Gy. Serum rat mast cell protease II (RMCPII) concentration showed a significant dose-dependent fall after 1 Gy on day 3 and 1.5 Gy on day 7. MMC counts and tissue RMCPII values on day 7 decreased significantly by 70% after 1 Gy and were undetectable with larger doses. Rats with normal and expanded MMC populations were irradiated or given anaphylaxis. Serum RMCPII concentrations did not change after irradiation, but there was a 10-fold increase in RMCPII after anaphylaxis. Tissue eosinophils in jejunum were 50% of control at 7 days after 2 Gy, and this effect was progressively more marked with higher doses. Similar effects on MMC and eosinophils were demonstrated in ileum, ascending colon and rectum. After 4.5 Gy, repopulation of the gut with MMC did not occur until week 3-4 postirradiation and MMC counts were still 50% below those of controls at 5 weeks postirradiation. Counts of tisse eosinophils 5 weeks after 4.5 Gy irradiation had returned to control levels in jejunum but were still significantly depleted in colon. (Author)

  5. Exposure dose response relationships of the freshwater bivalve Hyridella australis to cadmium spiked sediments

    Marasinghe Wadige, Chamani P.M., E-mail: chamani.marasinghe.wadige@canberra.edu.au; Maher, William A.; Taylor, Anne M.; Krikowa, Frank

    2014-07-01

    Highlights: • The exposure–dose–response approach was used to assess cadmium exposure and toxicity. • Accumulated cadmium in H. australis reflected the sediment cadmium exposure. • Spill over of cadmium into the biologically active pool was observed. • Increased cadmium resulted in measurable biological effects. • H. australis has the potential to be a cadmium biomonitor in freshwater environments. - Abstract: To understand how benthic biota may respond to the additive or antagonistic effects of metal mixtures in the environment it is first necessary to examine their responses to the individual metals. In this context, laboratory controlled single metal-spiked sediment toxicity tests are useful to assess this. The exposure–dose–response relationships of Hyridella australis to cadmium-spiked sediments were, therefore, investigated in laboratory microcosms. H. australis was exposed to individual cadmium spiked sediments (<0.05 (control), 4 ± 0.3 (low) and 15 ± 1 (high) μg/g dry mass) for 28 days. Dose was measured as cadmium accumulation in whole soft body and individual tissues at weekly intervals over the exposure period. Dose was further examined as sub-cellular localisation of cadmium in hepatopancreas tissues. The biological responses in terms of enzymatic and cellular biomarkers were measured in hepatopancreas tissues at day 28. H. australis accumulated cadmium from spiked sediments with an 8-fold (low exposure organisms) and 16-fold (high exposure organisms) increase at day 28 compared to control organisms. The accumulated tissue cadmium concentrations reflected the sediment cadmium exposure at day 28. Cadmium accumulation in high exposure organisms was inversely related to the tissue calcium concentrations. Gills of H. australis showed significantly higher cadmium accumulation than the other tissues. Accumulated cadmium in biologically active and biologically detoxified metal pools was not significantly different in cadmium exposed organisms, which suggests that H. australis has some tolerance to cadmium. The metallothionein like protein fraction played an important role in the sequestration and detoxification of cadmium and the amount sequestered in this fraction increased with increased cadmium exposure. The highest percentage of biologically active cadmium was associated with the lysosome + microsome and mitochondrial fractions. Cadmium concentrations in these two fractions of cadmium exposed organisms were significantly higher with respect to controls. Total antioxidant capacity decreased with increased cadmium exposure and tissue dose. Lipid peroxidation increased and lysosomal membrane stability decreased significantly with increased cadmium exposure and tissue dose. Based on exposure–dose–response analysis in this study, H. australis would be a suitable organism for assessing cadmium sediment exposure and toxicity.

  6. Health effects of low doses at low dose rates: dose-response relationship modeling in a cohort of workers of the nuclear industry; Effets sanitaires des faibles doses a faibles debits de dose: modelisation de la relation dose-reponse dans une cohorte de travailleurs du nucleaire

    Metz-Flamant, Camille

    2011-09-19

    The aim of this thesis is to contribute to a better understanding of the health effects of chronic external low doses of ionising radiation. This work is based on the French cohort of CEA-AREVA NC nuclear workers. The mains stages of this thesis were (1) conducting a review of epidemiological studies on nuclear workers, (2) completing the database and performing a descriptive analysis of the cohort, (3) quantifying risk by different statistical methods and (4) modelling the exposure-time-risk relationship. The cohort includes monitored workers employed more than one year between 1950 and 1994 at CEA or AREVA NC companies. Individual annual external exposure, history of work, vital status and causes of death were reconstructed for each worker. Standardized mortality ratios using French national mortality rates as external reference were computed. Exposure-risk analysis was conducted in the cohort using the linear excess relative risk model, based on both Poisson regression and Cox model. Time dependent modifying factors were investigated by adding an interaction term in the model or by using exposure time windows. The cohort includes 36, 769 workers, followed-up until age 60 in average. During the 1968- 2004 period, 5, 443 deaths, 2, 213 cancers, 62 leukemia and 1, 314 cardiovascular diseases were recorded. Among the 57% exposed workers, the mean cumulative dose was 21.5 milli-sieverts (mSv). A strong Healthy Worker Effect is observed in the cohort. Significant elevated risks of pleura cancer and melanoma deaths were observed in the cohort but not associated with dose. No significant association was observed with solid cancers, lung cancer and cardiovascular diseases. A significant dose-response relationship was observed for leukemia excluding chronic lymphatic leukemia, mainly for doses received less than 15 years before and for yearly dose rates higher than 10 mSv. This PhD work contributes to the evaluation of risks associated to chronic external radiation exposure. Our study finds a risk of leukemia associated with chronic external exposure and allows taking into account modifying factors of this relation. Additional follow-up allows to improve the precision of the estimated dose-response relationship. A combined analysis including the present cohort and other nuclear cohorts could quantify more precisely the risks associated with low doses at low dose rates, in order to validate current underlying hypotheses of the radiation protection system. (author)

  7. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Wang, Yan; Xu, Chang; Du, Li Qing; Cao, Jia; Liu, Jian Xiang; Su, Xu; Zhao, Hui; Fan, Fei-Yue; Wang, Bing; Katsube, Takanori; Fan, Sai Jun; Liu, Qiang

    2013-01-01

    Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001). A time-response relationship was also found within 72 h after irradiation (p < 0.001). The curves for DNA double-strand breaks and DNA repair in vitro of human lymphocytes presented a nice model, and a smooth, three-dimensional plane model was obtained when the two curves were combined. PMID:24240807

  8. High-Throughput Dose-Response Measurement Using a Label-Free Microarray-in-Microplate Assay Platform.

    Landry, J P; Malovichko, G; Zhu, X D

    2015-06-01

    Microarray-based binding assays facilitate the discovery of protein ligands from large collections of small molecules. Hundreds of ligands can be identified, yet only a small portion of them have interfering effects (competitive or noncompetitive) on a specific protein-receptor binding reaction. Further efficient screening of ligands for those with specific modifying effect is needed in order to take the full advantage of throughputs of microarray-based assays for drug discovery. We report a label-free "microarray-in-microplate" assay platform for simultaneous acquisition of at least 32 dose-response curves in a single experiment, each curve having 12 concentration points. When combined with ligand discovery, this makes the microarray-based platform a true high-throughout means of finding inhibitors to specific protein-receptor reactions starting from a large collection of small-molecule libraries. PMID:25921700

  9. Evaluation of the Comet Assay for Assessing the Dose-Response Relationship of DNA Damage Induced by Ionizing Radiation

    Qiang Liu

    2013-11-01

    Full Text Available Dose- and time-response curves were combined to assess the potential of the comet assay in radiation biodosimetry. The neutral comet assay was used to detect DNA double-strand breaks in lymphocytes caused by γ-ray irradiation. A clear dose-response relationship with DNA double-strand breaks using the comet assay was found at different times after irradiation (p < 0.001. A time-response relationship was also found within 72 h after irradiation (p < 0.001. The curves for DNA double-strand breaks and DNA repair in vitro of human lymphocytes presented a nice model, and a smooth, three-dimensional plane model was obtained when the two curves were combined.

  10. Dose-response evaluation after Yttrium-90 resin microsphere radio-embolization of breast cancer liver metastases

    Full text of publication follows. Aim: Yttrium-90 resin microsphere radio-embolization is a valuable therapeutic option in metastatic breast cancer patients with progressive disease refractory to chemotherapy. The goal of this study was to evaluate the dose-response relationship of liver metastasis based on a 3D voxelized 90Y PET dosimetry. Materials and methods: we studied the dose-response relationship of twelve hepatic lesions in four selected patients with metastatic breast cancer who underwent 90Y radio-embolization (Sirtex SIR-Spheres Pty Ltd.). The administered activity ranged from 1 to 1.3 GBq. Ten days before treatment, patients underwent a baseline 18F-FDG PET/CT. The determination of the 90Y-microsphere activity to administer for treatment was based on the BSA method refined with the partition model derived from a 99mTc-MAA SPECT/CT performed a week prior to radio-embolization. Within 24 hours after treatment, 90Y TOF PET/CT imaging was performed. A follow-up 18F-FDG PET/CT was performed 1 month after the treatment to evaluate the response to radio-embolization. For each patient, 3D voxelized dose-maps were obtained from the post-treatment 90Y TOF PET/CT. A volume of interest (VOI) was drawn for each selected hepatic lesion using the baseline 18F-FDG PET/CT. To obtain dose-volume histogram (DVH) for each lesion, image co-registration and VOI masks were generated using the PMOD 3.4 software and then exported in Matlab for dose calculation. Furthermore, the average absorbed dose in lesions was corrected for PVE effects by multiplication for appropriate (phantom-based) recovery coefficients according to the lesion size. Early metabolic lesion response was assessed in terms of variation in the maximum standard uptake value (ΔSUVmax) between baseline and follow-up 18F-FDG PET/CT. The average absorbed dose for each lesion was associated with the respective metabolic response. Results: for the 12 selected lesions, the average volume was 35 cm3 (range 8-147 cm3) and the average absorbed dose was 92 Gy (range 32-137 Gy). We observed a reduced average absorbed dose as the volume of the lesion increased. Metabolic response was observed for all lesions with a measured average ΔSUVmax of -66% (range -28% to -83%). The observed dose-response relationship suggests that better metabolic response was obtained in lesions receiving the higher dose. Conclusions: three-dimensional voxelized dose-map based on 90Y TOF PET/CT imaging is an effective tool for assessing tumor dose-response relationship. Patients with breast cancer liver metastases showed good short-term metabolic responses with average absorbed doses to lesions ranging between 32 and 137 Gy. A trend showing improved metabolic response in lesions receiving higher doses was observed. (authors)

  11. Coffee consumption and risk of endometrial cancer: a dose-response meta-analysis of prospective cohort studies

    Quan Zhou; Mei-Ling Luo; Hui Li; Min Li; Jian-Guo Zhou

    2015-01-01

    This is a dose-response (DR) meta-analysis to evaluate the association of coffee consumption on endometrial cancer (EC) risk. A total 1,534,039 participants from 13 published articles were added in this meta-analysis. The RR of total coffee consumption and EC were 0.80 (95% CI: 0.74–0.86). A stronger association between coffee intake and EC incidence was found in patients who were never treated with hormones, 0.60 (95% CI: 0.50–0.72), and subjects with a BMI ≥25 kg/m2, 0.57 (95% CI: 0.46–0.71...

  12. Comment on the treatment of dose-response relationship for the epidemiological data of atomic bomb survivors

    As for the dose-response relationship for solid cancer incidence rate at low dose radiation, the epidemiological study of atomic bomb survivors by RERF have been regarded to be the most important and authentic, and ICRP has its conceptual basis in the policy of radiation protection on this data for adopting the linear, non-threshold (LNT) model. However, we have found that there are two fundamental problems in the way of treatment of the data, and we believe it may bring an important modification on the validity of the LNT model for the interpretation of the radiation effect at low dose. The first point is that in estimating the exposure dose of the survivors, the chronic dose received by them should be considered in addition to the acute dose calculated by T65D or DS86, which only estimates the dose at the instant of explosion of the bomb. It seems there are ample evidences that the survivors received additional chronic dose due to the radioactivity contained both in the fallout and in the induced radioactivity by the neutron bombardment of the environmental materials. For example, it is a well-known fact that there was a heavy temporary shower (so to speak ''black rain'') in a wide region of the city after the bomb explosion, which contained much radioactivity due to the fission products. According to a literature, in the case of residents at Nishiyama District in Nagasaki, which is located 3 km from the explosion center but is shielded by a mountain from the instantaneous bomb explosion, the cumulative dose received by 280 residents there was estimated to be as much as 0.2 Gy, which caused an abnormal increase in the number of leukocytes for most of the residents. For the case of Hiroshima, a literature reports that the dose due to the black rain was about 0.03-0.04 Gy. In both cities, a substantial percentage of the survivors had stayed for considerable time in the contaminated area in the city after bombing, such as for the purpose of searching their families and relatives, and they must have received additional chronic dose due to the residual radioactivity remained in the city. Thus, as to the values to be used for the abscissa of the dose-response curve, not only the instantaneous radiation dose, those added by the chronic dose should be used. If this additional chronic dose for all survivors is regarded to be on the average, say, as 0.05 Gy, the dose-response curve shall shift rightward by this value, thus the dose-response relationship should show a threshold of ca 0.05 Gy. The second aspect for the treatment of the data is the fact that the doses for the exposed group below 0.01 Gy has until 1996 been treated as ''zero dose group'', and the data for this group was used as ''control''. (Since 1996 the zero group has become the cohort of <0.005 Gy.) If a hormetic effect actually had occurred in this cohort of the lowest dose level, every other value observed at higher dose groups, referred to this control, which may have inherently negative incidence rate, will show as if there is only the positive risk, as the presently available data. The consideration above, along with other recent experimental findings at low dose radiation, supports the proposal that the LNT model should be abandoned for the fundamental policy of radiation protection, as several other researchers claim. (author)

  13. Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition

    Falgreen, Steffen; Laursen, Maria Bach; Bdker, Julie Stve; Kjeldsen, Malene Krag; Schmitz, Alexander; Nyegaard, Mette; Johnsen, Hans Erik; Dybkr, Karen; Bgsted, Martin

    2014-01-01

    BACKGROUND: In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves' dependency on drug exposure time and growth kinetics. This may...... lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. RESULTS: First, a mathematical model for drug induced cell growth inhibition was...... cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an...

  14. Revised assessment of cancer risk to dichloromethane: part I Bayesian PBPK and dose-response modeling in mice.

    Marino, Dale J; Clewell, Harvey J; Gentry, P Robinan; Covington, Tammie R; Hack, C Eric; David, Raymond M; Morgott, David A

    2006-06-01

    The current USEPA cancer risk assessment for dichloromethane (DCM) is based on deterministic physiologically based pharmacokinetic (PBPK) modeling involving comparative metabolism of DCM by the GST pathway in the lung and liver of humans and mice. Recent advances in PBPK modeling include probabilistic methods and, in particular, Bayesian inference to quantitatively address variability and uncertainty separately. Although Bayesian analysis of human PBPK models has been published, no such efforts have been reported specifically addressing the mouse, apart from results included in the OSHA final rule on DCM. Certain aspects of the OSHA model, however, are not consistent with current approaches or with the USEPA's current DCM cancer risk assessment. Therefore, Bayesian analysis of the mouse PBPK model and dose-response modeling was undertaken to support development of an improved cancer risk assessment for DCM. A hierarchical population model was developed and prior parameter distributions were selected to reflect parameter values that were considered the most appropriate and best available. Bayesian modeling was conducted using MCSim, a publicly available software program for Markov Chain Monte Carlo analysis. Mean posterior values from the calibrated model were used to develop internal dose metrics, i.e., mg DCM metabolized by the GST pathway/L tissue/day in the lung and liver using exposure concentrations and results from the NTP mouse bioassay, consistent with the approach used by the USEPA for its current DCM cancer risk assessment. Internal dose metrics were 3- to 4-fold higher than those that support the current USEPA IRIS assessment. A decrease of similar magnitude was also noted in dose-response modeling results. These results show that the Bayesian PBPK model in the mouse provides an improved basis for a cancer risk assessment of DCM. PMID:16442684

  15. Association between physical activity and all cancer mortality: Dose-response meta-analysis of cohort studies.

    Li, Yingjun; Gu, Mengjia; Jing, Fangyuan; Cai, Shaofang; Bao, Chengzhen; Wang, Jianbing; Jin, Mingjuan; Chen, Kun

    2016-02-15

    The relationship between physical activity (PA) before cancer diagnosis and all cancer mortality among the general population is not well defined because of inconsistent results from published studies. Thus, the lack of a meta-analysis that addresses that issue prompted the current report. We conducted a literature search of PubMed and Web of Science to identify all relevant epidemiological studies published before February 28, 2015. We performed categorical and dose-response meta-analyses to evaluate and quantify the association between pre-diagnosis PA and all cancer mortality. A total of 32 prospective cohort studies involving 59,362 cancer deaths were included in this meta-analysis. The pooled relative risks (RRs) of all cancer mortality were 0.80 [95% confidence interval (CI)?=?0.76-0.85)] for highest versus lowest PA group and 0.85 (95% CI?=?0.82-0.88) for PA versus non/occasional PA group. Dose-response analysis showed that the increment in pre-diagnosis PA level was associated with a decreased risk of cancer death continuously. Moreover, an increment of 10 MET-h/week was related to a 7% lower risk for all cancer mortality (RR?=?0.93, 95% CI?=?0.91-0.95). In conclusion, the present meta-analysis provides evidence of an inverse association between pre-diagnosis PA and all cancer mortality among the general population. High-quality epidemiological studies that employ standardized PA assessments and unified definitions of PA levels should be developed in future. PMID:26317834

  16. Dose-response curve for blood exposed to gamma-neutron mixed field by conventional cytogenetic method

    There is increasing concern about airline crew members (about one million worldwide) are exposed to measurable neutrons doses. Historically, cytogenetic biodosimetry assays have been based on quantifying asymmetrical chromosome alterations (dicentrics, centric rings and acentric fragments) in mytogen-stimulated T-lymphocytes in their first mitosis after radiation exposure. Increased levels of chromosome damage in peripheral blood lymphocytes are a sensitive indicator of radiation exposure and they are routinely exploited for assessing radiation absorbed dose after accidental or occupational exposure. Since radiological accidents are not common, not all nations feel that it is economically justified to maintain biodosimetry competence. However, dependable access to biological dosimetry capabilities is completely critical in event of an accident. In this paper the dose-response curve was measured for the induction of chromosomal alterations in peripheral blood lymphocytes after chronic exposure in vitro to neutron-gamma mixes field. Blood was obtained from one healthy donor and exposed to two neutron-gamma mixed field from sources 241AmBe (20 Ci) at the Neutron Calibration Laboratory (NCL-CRCN/NE-PE-Brazil). The evaluated absorbed doses were 0.2 Gy; 1.0 Gy and 2.5 Gy. The dicentric chromosomes were observed at metaphase, following colcemid accumulation and 1000 well-spread metaphase figures were analyzed for the presence of dicentrics by two experienced scorers after painted by giemsa 5%. Our preliminary results showed a linear dependence between radiations absorbed dose and dicentric chromosomes frequencies. Dose-response curve described in this paper will contribute to the construction of calibration curve that will be used in our laboratory for biological dosimetry. (author)

  17. Dose--response of initial G2-chromatid breaks induced in normal human fibroblasts by heavy ions

    Kawata, T.; Durante, M.; Furusawa, Y.; George, K.; Takai, N.; Wu, H.; Cucinotta, F. A.; Dicello, J. F. (Principal Investigator)

    2001-01-01

    PURPOSE: To investigate initial chromatid breaks in prematurely condensed G2 chromosomes following exposure to heavy ions of different LET. MATERIAL AND METHODS: Exponentially growing human fibroblast cells AG1522 were irradiated with gamma-rays, energetic carbon (13 keV/ microm, 80 keV/microm), silicon (55 keV/microm) and iron (140 keV/microm, 185keV/microm, 440keV/microm) ions. Chromosomes were prematurely condensed using calyculin-A. Initial chromatid-type and isochromatid breaks in G2 cells were scored. RESULTS: The dose response curves for total chromatid breaks were linear regardless of radiation type. The relative biological effectiveness (RBE) showed a LET-dependent increase, peaking around 2.7 at 55-80keV/microm and decreasing at higher LET. The dose response curves for isochromatid-type breaks were linear for high-LET radiations, but linear-quadratic for gamma-rays and 13 keV/microm carbon ions. The RBE for the induction of isochromatid breaks obtained from linear components increased rapidly between 13keV/microm (about 7) and 80keV/microm carbon (about 71), and decreased gradually until 440 keV/microm iron ions (about 66). CONCLUSIONS: High-LET radiations are more effective at inducing isochromatid breaks, while low-LET radiations are more effective at inducing chromatid-type breaks. The densely ionizing track structures of heavy ions and the proximity of sister chromatids in G2 cells result in an increase in isochromatid breaks.

  18. A comparison of natural- and laboratory-generated dose response curves for quartz optically stimulated luminescence signals from Chinese Loess

    It has previously been observed that laboratory-generated quartz optically stimulated luminescence (OSL) signals from different samples have similar dose response curves (DRCs) after they are normalized using a test dose. It therefore seems likely that growth of the normalized signal due to natural irradiation of quartz may also follow a general dose response curve. The existence of such a curve is investigated by constructing a natural DRC from the test dose-normalized natural OSL signals of seven samples from the Luochuan section of the Chinese Loess Plateau. The same aliquots are then used to build single aliquot regenerative (SAR) DRCs, making it possible to compare the natural and laboratory constructed curves. Two main differences are observed. Firstly, the laboratory-generated DRCs are best fitted with double saturating exponential functions whereas the natural DRC is equally well fitted with a single saturating function. Secondly, in the laboratory-generated DRCs the normalized OSL signal continues to increase at high laboratory doses (>500 Gy), whereas no growth is seen at these doses in the equivalent natural DRC. These differences between natural- and laboratory-generated DRCs are still apparent even if data are manipulated to isolate the fast component, or if a sensitivity corrected multiple aliquot regenerative (SC-MAR) dose procedure is used. This suggests that the observed differences are not due to the influence of different components or inter-regenerative dose cycle sensitivity changes. The divergence between the natural- and laboratory-generated DRC means that the current maximum limit of quartz OSL dating at the Luochuan section is 150 Gy, as De estimates above this value are likely to be underestimations.

  19. Dose Response Of TLDs AT Energy And Dose Ranges Applied In Clinical Radiology

    The study aimed to investigate the performance of lithium fluoride thermoluminescent dosimeters (TLD-700) to photon beams applied in clinical radiology in energy range 75 KVp to 15 MV at variable dose ranges. The study extended to evaluate the implication of sorting multiple crystals per reading on its response. Annealing and TL reading procedures were done using thermolyne furnace and Victoreen reader, respectively. Irradiation at 75 KVp X-rays was done using Philips PC 2000 diagnostic machine and Philips SLS-9 fluoroscopic RT-Simulator. Theratron 780 C, Co-60 machine, was used as a reference gamma ray beam as well as Philips SL-75 and Elekta Precise TM linear accelerators were used for irradiations at 6 and 15 MV X-rays, respectively. Perspex phantom (PMMA) was used as a medium of TLD-irradiation and 0.6 cc farmer chamber with PTW electrometer were used for the purposes of output dose rate measurements. Several experiments of irradiation and measurement were performed to evaluate the sensitivity, reproducibility, energy response and linearity of TLDs. The implication of sorting multiple crystals per data point was investigated in comparison with individual crystal measurements.TLD-700 employed in this study was selected in such a way that its sensitivity did not differ by more than 5% of the average. The selected crystals exhibit good homogeneity with relative sensitivity ranged between 0.99 and 1.00 and acceptable stability ranged between 3.36 and 4.42% over 5 reuse cycles of irradiation and measurements at Co-60 gamma rays. Non-significant variations were found in TLD responses at photon energy ranging 75 KVp to 15 MV. The TLDs showed good linearity over dose range 0.2-4 cGy at 75 KVp and 1-1100 cGy for Co-60 gamma rays as well as 6 and 15 MV for X-rays. The results of measuring multiple crystals per TL reading showed good linearity of TLD response with the number of sorted crystals ranged 1-8 crystals. Non-significant difference was recorded in TLD sensitivity of individual and three sorted crystals over energy range employed in this study.The results showed that TLD-700 had high sensitivity, good reproducibility, wide range linearity and non-significant variation in response over a range of energies typically used in clinical investigations. Sorting multiple crystals up to 8 per TL readout didn't affect the performance attainable with TLD-700 and exhibited good linearity with the number of crystals per reading. This sorting technique provides a simple, convenient, precise and accurate method for TLD measurements.

  20. Low-Level Laser Therapy Attenuates the Myeloperoxidase Activity and Inflammatory Mediator Generation in Lung Inflammation Induced By Gut Ischemia and Reperfusion: A Dose-Response Study

    Aimbire, Flvio; Miranda, Humberto; Vieira, Rodolfo de Paula; de Oliveira, Ana Paula Ligeiro; Albertini, Regiane

    2014-01-01

    Introduction: Intestinal ischemia and reperfusion (i-I/R) is an insult associated with acute respiratory distress syndrome (ARDS). Herein we evaluate the dose-response effect of low-level laser therapy (LLLT) on lung inflammation induced by i-I/R. Methods: Mice were subjected to mesenteric artery occlusion (45 min) and killed after clamp release and intestinal reperfusion (2h). Increasing doses (1, 3, 5 and 7,5 J/cm2) of laser irradiation (660 nm) was carried out on the mice skin over the upper bronchus for 5 min after initiating reperfusion. Neutrophils activation was determined by myeloperoxidase (MPO) activity. The mRNA expression and protein concentration of inflammatory mediators IL-1?, IL-6, TNF and IL-10 in lung were measured by RT-PCR and ELISA, respectively. Results: With exception of 1J/cm2, LLLT reduced MPO activity as well as IL-1? levels in the lungs from inflamed mice. LLLT was also markedly effective in reducing both IL-6 and TNF expression and levels in the lungs from mice submitted to i-I/R in all laser doses studied. Otherwise, LLLT significantly increased the protein levels of IL-10 in inflamed mice by i-I/R; however only in the dose of 1J/cm2. Conclusion: We conclude that the LLLT is able to control the neutrophils activation and proinflammatorycytokines release into the lungs in a model of i-I/R in mice. PMID:25653801

  1. Fluctuating asymmetry in Bobwhite quail chicks (Colinus virginianus) does not follow a predictable dose-response relationship following maternal exposure to four different herbicides

    Knopper, Loren D.; Mineau, Pierre

    2004-09-01

    Most biomonitoring studies that have investigated the relationship between fluctuating asymmetry (FA) and anthropogenic stressors have measured organisms from polluted ecosystems and compared them to organisms at reference sites. What has received little attention is whether FA follows a dose-response relationship with stress, a key criterion of a useful biomarker. Using chicks from currently mandated avian reproductive tests we tested whether a composite index of FA (FA{sup C}), was related to the dose or duration of exposure of their parents to one of four different herbicides, and if FA{sup C} was indeed a more sensitive marker of stress than standard reproductive endpoints measured from this test. We found no consistent relationship between FA{sup C} and dose or duration of herbicide exposure in any of the four studies. Exposure to one of the four pesticides did result in significant reproductive toxicity but this was not accompanied or foreshadowed by higher levels of FA{sup C}. Our results do not support the hypothesis that FA is a reliable general biomarker of pesticide exposure.

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

    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.

  3. DOSE-RESPONSE OF PORCINE OVARIAN GRANULOSA CELLS TO AMYGDALIN TREATMENT COMBINED WITH DEOXYNIVALENOL

    Marek Halenár

    2014-02-01

    Full Text Available Amygdalin is one of many nitrilosides, which are natural cyanide-containing substances abundant in the seeds of apricots, almond, peaches, apples, and other rosaceous plants. It is a controversial anti-tumor natural product that has been used as an alternative cancer drug for many years. On the other hand, one of the most widely distributed mycotoxin contaminating food and animal feed is deoxynivalenol (DON. Deoxynivalenol has adverse effects on humans, animals, and crops that result in illnesses. The aim of the in vitro study was to investigated the effect of natural substance amygdalin at the selected doses (1, 10, 100, 1000, 10 000 µg/mL in combination with deoxynivalenol (1000 ng/mL on secretion of steroid hormones (progesterone and estradiol by ovarian granulosa cells (GCs from cyclic pigs. Our results showed that the releasing of progesterone and estradiol by ovarian granulosa cells was affected by amygdalin plus DON addition. The secretion of progesterone by ovarian GCs was significantly (P≤0.05 affected by administration of both compounds in all experimental groups. Similarly, estradiol releasing by GCs was significantly (P≤0.05 increased in experimental groups with amygdalin (10, 100 and 10 000 µg/mL plus DON (1000 ng/mL addition. Amygdalin treatment combined with DON caused increase of steroid hormones release by ovarian granulosa cells. Our findings suggest possible involvement of these natural substances (amygdalin and deoxynivalenol in the regulation process of steroidogenesis. In conclusion, results from this experiment contribute to knowledge about interaction between two different natural compounds and their positive or negative interferences with ovarian functions.

  4. Dose response of red imported fire ant colonies to Solenopsis invicta virus 3.

    Valles, Steven M; Porter, Sanford D

    2015-10-01

    Baiting tests were conducted to evaluate the effect of increasing Solenopsis invicta virus 3 (SINV-3) dose on fire ant colonies. Actively growing early-stage fire ant (Solenopsis invicta Buren) laboratory colonies were pulse-exposed for 24 hours to six concentrations of SINV-3 (10(1), 10(3), 10(5), 10(7), 10(9) genome equivalents/μl) in 1 ml of a 10 % sucrose bait and monitored regularly for two months. SINV-3 concentration had a significant effect on colony health. Brood rating (proportion of brood to worker ants) began to depart from the control group at 19 days for the 10(9) concentration and 26 days for the 10(7) concentration. At 60 days, brood rating was significantly lower among colonies treated with 10(9), 10(7), and 10(5) SINV-3 concentrations. The intermediate concentration, 10(5), appeared to cause a chronic, low-level infection with one colony (n = 9) supporting virus replication. Newly synthesized virus was not detected in any fire ant colonies treated at the 10(1) concentration, indicating that active infections failed to be established at this level of exposure. The highest bait concentration chosen, 10(9), appeared most effective from a control aspect; mean colony brood rating at this concentration (1.1 ± 0.9 at the 60 day time point) indicated poor colony health with minimal brood production. No clear relationship was observed between the quantity of plus genome strand detected and brood rating. Conversely, there was a strong relationship between the presence of the replicative genome strand and declining brood rating, which may serve as a predictor of disease severity. Recommendations for field treatment levels to control fire ants with SINV-3 are discussed. PMID:26162304

  5. Detector dose response in megavoltage small photon beams. I. Theoretical concepts

    Purpose: To explain the reasons for significant quality correction factors in megavoltage small photon fields and clarify the underlying concepts relevant to dosimetry under such conditions. Methods: The validity of cavity theory and the requirement of charged particle equilibrium (CPE) are addressed from a theoretical point of view in the context of nonstandard beams. Perturbation effects are described into four main subeffects, explaining their nature and pointing out their relative importance in small photon fields. Results: It is demonstrated that the failure to meet classical cavity theory requirements, such as CPE, is not the reason for significant quality correction factors. On the contrary, it is shown that the lack of CPE alone cannot explain these corrections and that what matters most, apart from volume averaging effects, is the relationship between the lack of CPE in the small field itself and the density of the detector cavity. The density perturbation effect is explained based on Fano’s theorem, describing the compensating effect of two main contributions to cavity absorbed dose. Using the same approach, perturbation effects arising from the difference in atomic properties of the cavity medium and the presence of extracameral components are explained. Volume averaging effects are also discussed in detail. Conclusions: Quality correction factors of small megavoltage photon fields are mainly due to differences in electron density between water and the detector medium and to volume averaging over the detector cavity. Other effects, such as the presence of extracameral components and differences in atomic properties of the detection medium with respect to water, can also play an accentuated role in small photon fields compared to standard beams

  6. Dose-response relationship of cadmium or radiation-induced embryotoxicity in mouse whole embryo culture

    Nakashima, Kiyohito; Kawamata, Akitoshi; Matsuoka, Masato; Wakisaka, Takashi; Fujiki, Yoshishige (Asahi University School of Dentistry, Gifu (Japan))

    1988-12-01

    Mouse embryos of B6C3F/sub 1/ strain were exposed in vitro to 1.2 to 2.2 {mu}M cadmium chloride (Cd) or to 100 to 320 R x-rays, and the effects of the exposure on development were examined after 39 h of culture. Development of embryos was assessed from lethality, formation of the neural tube defect, diameter and protein of yolk sac, crown-rump and head lengths, embryonic protein, and number of somites. Incidence of the neural tube defect increased from 3.4 to 100% by 1.2 to 2.0 {mu}M Cd, while embryo deaths increased from 13.8 to 93.3% by 2.0 to 2.2 {mu}M Cd. Embryonic protein was significantly reduced at the teratogenic range, but the number of somites was only affected by 1.6 to 2.0 {mu}M Cd. X-irradiation at 100 to 320 R induced the neural tube defect in 2.9 to 72.7% of the embryos. An embryolethal effect was observed only at the 320 R dose. Crown-rump and head lengths and embryonic protein were significantly affected at the teratogenic range, but the diameter and protein of yolk sac and number of somites were hardly affected. Cadmium- or radiation-induced response data of both teratogenicity and endpoints indicating inhibition of embryonic development were acceptably fitted to a linear log-probit regression. These regressions suggest that as an estimation of interference in development of embryos, embryonic protein and head length are sensitive endpoints while the number of somites is an insensitive criterion. (author).

  7. Dose-response relationship of cadmium or radiation-induced embryotoxicity in mouse whole embryo culture

    Mouse embryos of B6C3F1 strain were exposed in vitro to 1.2 to 2.2 ?M cadmium chloride (Cd) or to 100 to 320 R x-rays, and the effects of the exposure on development were examined after 39 h of culture. Development of embryos was assessed from lethality, formation of the neural tube defect, diameter and protein of yolk sac, crown-rump and head lengths, embryonic protein, and number of somites. Incidence of the neural tube defect increased from 3.4 to 100% by 1.2 to 2.0 ?M Cd, while embryo deaths increased from 13.8 to 93.3% by 2.0 to 2.2 ?M Cd. Embryonic protein was significantly reduced at the teratogenic range, but the number of somites was only affected by 1.6 to 2.0 ?M Cd. X-irradiation at 100 to 320 R induced the neural tube defect in 2.9 to 72.7% of the embryos. An embryolethal effect was observed only at the 320 R dose. Crown-rump and head lengths and embryonic protein were significantly affected at the teratogenic range, but the diameter and protein of yolk sac and number of somites were hardly affected. Cadmium- or radiation-induced response data of both teratogenicity and endpoints indicating inhibition of embryonic development were acceptably fitted to a linear log-probit regression. These regressions suggest that as an estimation of interference in development of embryos, embryonic protein and head length are sensitive endpoints while the number of somites is an insensitive criterion. (author)

  8. Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

    Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the combined data analyzed here. Although data were limited to articles with 5-year actuarial estimates, the development of radiation-induced cataracts extends beyond this time

  9. Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

    Hall, Matthew D. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Schultheiss, Timothy E., E-mail: schultheiss@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Smith, David D. [Division of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Nguyen, Khanh H. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Department of Radiation Oncology, Bayhealth Cancer Center, Dover, Delaware (United States); Wong, Jeffrey Y.C. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States)

    2015-01-01

    Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the combined data analyzed here. Although data were limited to articles with 5-year actuarial estimates, the development of radiation-induced cataracts extends beyond this time.

  10. Analysis of bias effects on the total ionizing dose response in a 180 nm technology

    Liu Zhangli, E-mail: liuzhangli@mail.sim.ac.cn [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China); Graduate University of the Chinese Academy of Sciences, Beijing 100039 (China); Hu Zhiyuan [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China); Graduate University of the Chinese Academy of Sciences, Beijing 100039 (China); Zhang, Zhengxuan; Shao Hua [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China); Chen Ming [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China); Graduate University of the Chinese Academy of Sciences, Beijing 100039 (China); Bi Dawei [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China); Ning Bingxu [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China); Graduate University of the Chinese Academy of Sciences, Beijing 100039 (China); Zou Shichang [State Key Laboratory of Functional Materials for Informatics, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050 (China)

    2011-07-11

    The effects of gamma ray irradiation on the shallow trench isolation (STI) leakage current in a 180 nm technology are investigated. The radiation response is strongly influenced by the bias modes, gate bias during irradiation, substrate bias during irradiation and operating substrate bias after irradiation. We found that the worst case occurs under the ON bias condition for the ON, OFF and PASS bias mode. A positive gate bias during irradiation significantly enhances the STI leakage current, indicating the electric field influence on the charge buildup process during radiation. Also, a negative substrate bias during irradiation enhances the STI leakage current. However a negative operating substrate bias effectively suppresses the STI leakage current, and can be used to eliminate the leakage current produced by the charge trapped in the deep STI oxide. Appropriate substrate bias should be introduced to alleviate the total ionizing dose (TID) response, and lead to acceptable threshold voltage shift and subthreshold hump effect. Depending on the simulation results, we believe that the electric field distribution in the STI oxide is the key parameter influencing bias effects on the radiation response of transistor. - Highlights: > ON bias is the worst bias condition for the ON, PASS and OFF bias modes. > Larger gate bias during irradiation leads to more pronounced characteristic degradation. > TID induced STI leakage can be suppressed by negative operating substrate bias voltage. > Negative substrate bias during irradiation leads to larger increase of off-state leakage. > Electric field in the STI oxide greatly influences the device's radiation effect.

  11. Plastic packaging and burn-in effects on ionizing dose response in CMOS microcircuits

    Results are reported from an investigation of the effects of packaging and burn-in on the post-irradiation performance of National Semiconductor 54AC02 Quad 2-input NOR gates. The test population was drawn from a single wafer fabricated in the National process qualified under Mil-Prf-38535 to an ionizing radiation hardness of 100 krads(Si). The test sample was divided between plastic and ceramic packages. Additionally, half of the plastic samples and half of the two ceramic samples received a 168 hour/125 C burn-in. Two irradiation schemes were used. The first followed Mil-Std-883 Method 1019.4 (dose rate = 50 rads(Si)/s). The second used a low dose rate (0.1 rads(Si)/s). AC, DC, transfer function and functional behavior were monitored throughout the tests. Significant differences among the package types and burn-in variations were noted with the plastic, burned-in components demonstrating enhanced degradation. They show the worst post-irradiation parameter values as well as very broad post-irradiation parameter distributions. Degradation is highly dependent upon dose rate and anneal conditions. Two different radiation induced leakage paths have been identified, and their characteristics have been correlated to variations in high dose rate and low dose rate circuit performance. Caution is recommended for system developers to ensure that radiation hardness characterization is performed for the same package/burn-in configuration to be used in the system

  12. Bone cancer from radium: canine dose response explains data for mice and humans

    Analysis of lifetime studies of 243 beagles with skeletal burdens of radium-226 shows that the distribution of bone cancers clusters about a linear function of the logarithms of radiation dose rate to the skeleton and time from exposure until death. Similar relations displaced by species-dependent response ratios also provide satisfactory descriptions of the reported data on deaths from primary bone cancers in people and mice exposed to radium-226. The median cumulative doses (or times) leading to death from bone tumors are 2.9 times larger for dogs than for mice and 3.6 times larger for people than for dogs. These response ratios are well correlated with the normal life expectancies. The cumulative radiation dose required to give significant risk of bone cancer is found to be much less at lower dose rates than at higher rates, but the time required for the tumors to be manifested is longer. At low dose rates, this time exceeds the normal life-span and appears as a practical threshold, which for bone cancer is estimated to occur at an average cumulative radiation dose to the skeleton of about 50 to 110 rads for the three species

  13. Dose-response relationships for resetting of human circadian clock by light

    Boivin, D. B.; Duffy, J. F.; Kronauer, R. E.; Czeisler, C. A.

    1996-01-01

    Since the first report in unicells, studies across diverse species have demonstrated that light is a powerful synchronizer which resets, in an intensity-dependent manner, endogenous circadian pacemakers. Although it is recognized that bright light (approximately 7,000 to 13,000 lux) is an effective circadian synchronizer in humans, it is widely believed that the human circadian pacemaker is insensitive to ordinary indoor illumination (approximately 50-300 lux). It has been proposed that the relationship between the resetting effect of light and its intensity follows a compressive nonlinear function, such that exposure to lower illuminances still exerts a robust effect. We therefore undertook a series of experiments which support this hypothesis and report here that light of even relatively low intensity (approximately 180 lux) significantly phase-shifts the human circadian pacemaker. Our results clearly demonstrate that humans are much more sensitive to light than initially suspected and support the conclusion that they are not qualitatively different from other mammals in their mechanism of circadian entrainment.

  14. Arc Statistics

    Meneghetti, M; Dahle, H; Limousin, M

    2013-01-01

    The existence of an arc statistics problem was at the center of a strong debate in the last fifteen years. With the aim to clarify if the optical depth for giant gravitational arcs by galaxy clusters in the so called concordance model is compatible with observations, several studies were carried out which helped to significantly improve our knowledge of strong lensing clusters, unveiling their extremely complex internal structure. In particular, the abundance and the frequency of strong lensing events like gravitational arcs turned out to be a potentially very powerful tool to trace the structure formation. However, given the limited size of observational and theoretical data-sets, the power of arc statistics as a cosmological tool has been only minimally exploited so far. On the other hand, the last years were characterized by significant advancements in the field, and several cluster surveys that are ongoing or planned for the near future seem to have the potential to make arc statistics a competitive cosmo...

  15. Ingestion dose response to the deposition date in the first year after radionuclide deposition

    Mueck, K.; Suda, M.; Gerzabek, M.; Kunsch, B. (Oesterreichisches Forschungszentrum Seibersdorf GmbH (Austria))

    1992-01-01

    To facilitate emergency planning, the ingestion dose following large scale radionuclide contamination was evaluated relative to the date of deposition. The radiological prediction model OECOSYS, a version of ECOSYS adapted to Austrian conditions, was used and the calculations were based on a standard deposition of 1 kBq.m[sup -2] (0.98 kBq.m[sup -2] by wet deposition) of the radiologically most important radionuclides [sup 90]Sr, [sup 131]I, [sup 134]Cs, and [sup 137]Cs. The results were derived for a moderate climatic zone with seasonal variations of plant growth typical for the alpine foothills of central Europe. For purposes of comparison, the dose by purely dry deposition was also evaluated. As expected, the highest first year ingestion dose was derived for fallout events in the summer period. For [sup 90]Sr at the beginning of August an ingestion dose of 102 [mu]Sv results from a deposition of 1 kBq.m[sup -2], while in November the calculated dose was approximately 28 times lower. For [sup 137]Cs the peak value of 124 [mu]Sv per unit deposition results at the beginning of July. Lower soil-to-plant transfer factors for [sup 137]Cs result in a more significant decline by a factor of about 200 in November. Dose values for the 5 y old child are approximately 55% ([sup 90]Sr) and 30% ([sup 137]Cs) of the adult values. Much lower dose values result for 1 kBq.m[sup -2] deposition of [sup 131]I (3.1 [mu]Sv for the adult and 6.5 [mu]Sv for the 5 y child for a deposition date at the beginning of August), but the reduction from summer to winter is comparable to [sup 137]Cs. (Author).

  16. Rats avoid exposure to HVdc electric fields: a dose response study.

    Creim, J A; Lovely, R H; Weigel, R J; Forsythe, W C; Anderson, L E

    1993-01-01

    Rats, given the choice, avoid exposure to alternating current (ac) 60-Hz electric fields at intensities > or = 75 kV/m. This study investigated the generality of this behavior by studying the response of rats when exposed to high voltage direct current (HVdc) electric fields. Three hundred eighty male Long Evans rats were studied in 9 experiments with 40 rats per experiment and in one experiment with 20 rats to determine 1) if rats avoid exposure to HVdc electric fields of varying field strengths, and 2) if avoidance did occur, what role, if any, the concentration of air ions would have on the avoidance behavior. In all experiments a three-compartment glass shuttlebox was used; either the left or right compartment could be exposed to a combination of HVdc electric fields and air ions while the other compartment remained sham-exposed. The third, center compartment was a transition zone between exposure and sham-exposure. In each experiment, the rats were individually assessed in 1-h sessions where half of the rats (n = 20) had the choice to locomote between the two sides being exposed or sham-exposed, while the other half of the rats (n = 20) were sham-exposed regardless of their location, except in one experiment where there was no sham-exposed group. The exposure levels for the first six experiments were 80, 55, 42.5, 30, -36, and -55 kV/m, respectively. The air ion concentration was constant at 1.4 x 10(6) ions/cc for the four positive exposure levels and -1.4 x 10(6) ions/cc for the two negative exposure levels. Rats having a choice between exposure and non-exposure relative to always sham-exposed control animals significantly reduced the amount of time spent on the exposed side at 80 kV/m (P HVdc exposure level was held constant at either -55 kV/m (for three experiments) or -55 kV/m (for 1 experiment) while the air ion concentration was varied between experiments at 2.5 x 10(5) ions/cc, 1.0 x 10(4) for two of the experiments and was below the measurement limit (< +/- 2 x 10(3) ions/cc) for the other two experiments at 55 and -55 kV/m.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8216386

  17. The scientific basis for the establishment of threshold levels and dose response relationships of carcinogenesis

    Over the last one and a half decades the variety of radiosterilized articles has increased to such an extent that it is almost impossible to present a complete list. They include disposable surgical and medical instruments and devices, laboratory equipment, sutures and other temporary and permanent implants, medicaments and pharmaceutical starting materials, biological tissues for transplantation and other biological preparations. A large volume of radiation-sterilized hermetically sealed, ready-to-use medical supplies are imported by many non-producer countries to supplement their public health care services. During the recent years this trend is increasing and several developing countries are even planning to introduce this technology in the near future, while some have already done so through the provision of expertise and funding by the IAEA and UNDP. Unlike the technologically advanced countries, the medical care services in most of the developing countries are inadequate still today. Against the figure of one doctor per 500 people in the most highly advanced countries the corresponding figure in some developing countries stands as one doctor per 60,000 people. The available limited number of hospitals in many such countries are located only in the urban areas, while the preponderance of rural populations are served through non-equipped mobile dispensaries and camp health centres. Based upon these factors, many developing countries are opting to introduce the technology and practices of radiation sterilization of medical products even if the products cost slightly more. During the last ten years the Agency's programme has attached great importance to encouraging this development of peaceful application of atomic energy in the form of accumulation of relevant technical information through co-ordinated research and its early dissemination by holding international meetings. The Agency's second symposium on Ionizing Radiation for Sterilization of Medical Products and Biological Tissues was held in Bombay, India, in December 1974, to summarize and critically review all the current information and experiences on the practices including the regulatory aspects of the processes involved as well as the safety assurance of the final products. The topics of discussion during the symposium were carried out under the following sessions: (i) Microbiological control aspects of radiation sterilization (ii) Dosimetry aspects of radiation sterilization (iii) Effects of sterilizing radiation dose on the constituents of medical products (iv) Application of radiation sterilization on medical products of biological origin (v) Application on Pharmaceuticals (vi) Technological aspects of radiation sterilization facilities (vii) Review of the current status of radiation sterilization of medical products in the developing and developed Member States. mportant considerations on the microbiological control aspects of radiation sterilization focussed on the role of pre-sterilization contamination levels, radio-resistance of the contaminants, choice of sterilizing radiation dose, the use of standardized microbiological indicators, and the feasibility of combination radiation treatments with heat and hydrostatic pressure. The data were presented in support of the model for application of sub-sterilizing radiation dose in the routine control and safety assurance determination for medical products. The practical dosimetry systems for the process calibration and control were evaluated as supported by the data from the various national experiences. Suitability of application of radiation sterilization method for the Pharmaceuticals and biological tissue preparations were reviewed. esigning and operations of radiation sterilization facilities in keeping with the conditions (market size, nature of products and volume, available technical expertise) of the developing countries were discussed and appropriate steps recommended. ince its inception the radiation-sterilized medical supplies have increasingly been introduced in the markets of the countrie s beyond their national boundary of manufacturing. An early acceptance of such products of public health significance continue to rely on the international standardization of the partices concerned. Agency's document on the Recommended Practice for Radiation Sterilization of Medical Products was discussed and reviewed by the participants in order to revise and up-date in the light of the current experiences. The Recommendations continue to serve as a guide in the formulation of the national standards and specifications by the Member States. (author)

  18. Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery.

    Hiniker, Susan M; Modlin, Leslie A; Choi, Clara Y; Atalar, Banu; Seiger, Kira; Binkley, Michael S; Harris, Jeremy P; Liao, Yaping Joyce; Fischbein, Nancy; Wang, Lei; Ho, Anthony; Lo, Anthony; Chang, Steven D; Harsh, Griffith R; Gibbs, Iris C; Hancock, Steven L; Li, Gordon; Adler, John R; Soltys, Scott G

    2016-04-01

    Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus. PMID:27000505

  19. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total body irradiation (TBI) with 250 kVp or 2 MeV x radiation, Co gamma radiation and reactor- and nuclear weapon-derived mixed gamma: neutron-radiation, delivered at various dose rates from a total body, bilateral, rotational, or unilateral exposure aspect. The DRRs established by a probit analysis vs. linear dose relationship were characterized by two main parameters or dependent variables: a slope and LD50/30. Respective LD50/30 values for studies that used 250 kVp x radiation (five primary studies combined, n = 338), 2 MeV x radiation, Co gamma radiation, and steady-state reactor-derived mixed gamma:neutron radiation for total body uniform exposures were 521 rad [498, 542], 671 rad [632, 715], 644 rad [613, 678], and 385 rad [357, 413]. The respective slopes were steep and ranged from 0.738 to 1.316. The DRR, LD50/30 values and slopes were also determined for total body, non-uniform, unilateral, pulse-rate exposures of mixed gamma:neutron radiation derived at reactor and nuclear weapon detonations. The LD50/30 values were, respectively, 395 rad [337, 432] and 412 rad [359, 460]. Secondary data sets of limited studies that did not describe a DRR were used to support the mid-to-high lethal dose range for the H-ARS and the threshold dose range for the concurrent acute GI ARS. The available evidence provided a reliable and extensive database that characterized the DRR for the H-ARS in young rhesus macaques exposed to 250 kVp uniform total body x radiation without the benefit of medical management. A less substantial but consistent database demonstrated the DRR for total body exposure of differing radiation quality, dose rate and non-uniform exposure. The DRR for the H-ARS is characterized by steep slopes and relative LD50/30 values that reflect the radiation quality, exposure aspect, and dose rate over a range in time from 1954-2012. PMID:26425897

  20. Steepness of the dose-response curve as a function of volume in an experimental tumor irradiated under ambient or hypoxic conditions

    Purpose: Radiation dose-response curves play a fundamental role in the attempts to optimize radiotherapy, and it is a major task in clinical and experimental radiation research to characterize and quantify the factors that determine the position and shape of dose-response curves. A convenient measure of the steepness of radiation dose-response curves is the normalized dose-response gradient, y, which represents the increase in response, in percentage points, for a 1 % increase in dose. Theoretically, the normalized dose-response gradient should increase with increasing clonogenic cell number or, assuming a constant clonogen density, with increasing tumor volume. The aim of this study was to test this hypothesis over a range of tumor volumes and to study how this relationship is affected by heterogeneity in tumor oxygenation. Methods and Materials: A C3H mouse mammary carcinoma implanted in the feet of female CDF1 mice was used. Groups of tumors with various volumes were irradiated with single graded radiation doses in air or after making them artificially hypoxic by clamping. The end point used was tumor control defined as complete absence of a macroscopic relapse within 90 days after irradiation. A Poisson dose-response model was assumed to describe tumor control probability in each volume group. The dose needed to control 37% of the tumors (D37) and the normalized dose-response gradient at this dose (y37) were estimated by the maximum likelihood method. In another group of animals with tumors in the same volume range, oxygenation status was assessed by a polarographic needle electrode. The percentage of pO2 values 37 values increased as a function of tumor volume under both clamped and ambient conditions. For tumors irradiated under clamped conditions, y37 increased with increasing tumor volume throughout the range of volumes studied. However, for tumors irradiated under ambient conditions, there was an initial increase in y37 with tumor volume up to 100 mm3 with no further increase beyond that volume. As the tumor volume increased, both the level of hypoxia and the tumor-to-tumor heterogeneity in that level increased. Conclusions: This study has confirmed the hypothesis that y37 increases with increasing tumor volume when tumors are irradiated under clamped condition. The increased heterogeneity of the hypoxic volume fraction with increasing tumor volume could explain why the steepness of the dose-response curve did not increase with increasing tumor volume when irradiation was done under ambient condition

  1. Autoradiographic in vitro studies for the determination of the dose-response relationship between erythropoietin and the proliferation kinetics of erythroblasts in nephrectomised rats

    Until now there have not been any experimental studies on the question of the dose-response relationship between erythropoietin and the proliferation kinetics of erythroblasts in a short-time study. The goal of this work was to test a dose-response relationship in the bone marrow of rats with the help of autoradiographic in vitro methods. For this determinations of the incorporation rate of the radioactive thymidine in the DNA of erythroblast nuclei, of the length of DNA synthesis in erythroblasts under the influence of variously high doses of erythropoietin were carried out. Autologous serums were used. (orig./MG)

  2. Doseresponse relationship with clinical outcome for lung stereotactic body radiotherapy (SBRT) delivered via online image guidance

    Purpose: To examine potential doseresponse relationships with various non-small-cell lung cancer (NSCLC) SBRT fractionation regimens delivered with online CT-based image guidance. Methods: 505 tumors in 483 patients with clinical stage T1-T2N0 NSCLC were treated with SBRT using on-line cone-beam-CT-based image guidance at 5 institutions (19982010). Median maximum tumor dimension was 2.6 cm (range 0.98.5 cm). Dose fractionation prescription was according to each institutions protocol with the most common schedules of 1820 GyX3, 12 GyX4, 12 GyX5, 12.5 GyX3, 7.5 GyX8 (median = 54 Gy, 3 fractions). Median prescription (Rx) BED10 = 132 Gy (50.4180). Median values (Gy) of 3D planned doses for BED10 were GTVmin = 164.1, GTVmean = 188.4, GTVmax = 205.9, PTVmin = 113.9, PTV D99 = 123.9, PTVmean = 164.7, PTV D1 = 197.3, PTVmax = 210.7. Mean follow-up = 1.6 years. Results: 26 cases (5%) had local recurrence (LR) for a 2-year rate of 6% and 3-year rate of 9%. All BED10 GTV and PTV endpoints were associated with LR as continuous variables on univariate analysis (p < 0.05). Rx and PTVmean dose appeared to have the highest correlation with LR with area under ROC curve of 0.69 and 0.65 respectively and optimal cut points of 105 and 125 Gy, respectively. 2-year LR was 4% for PTVmean > 125 vs 17% for <125 Gy (p < 0.01) with sensitivity = 84% and specificity = 57% for predicting LR. 2-year LR for Rx BED10 > 105 was 4% vs 15% for <105 Gy (p < 0.01). Longer treatment duration (?11 elapsed days) demonstrated a 2-year LR of 14% vs 4% for ?10 days (p < 0.01). GTV size was associated with LR on univariate analysis as a continuous variable (p = 0.02) with 2-year LR = 3% for <2.7 cm vs 9% for ?2.7 cm (p = 0.03). BED10 (p = 0.01) and elapsed days during RT (p = 0.05) were independent predictors on multivariate analysis as continuous variables. Conclusions: There is a substantial doseresponse relationship for local control of NSCLC following image-guided SBRT with optimal PTVmean BED10 > 125 Gy. Shorter treatment duration was also associated with better local control in this dataset

  3. Artria radial versus veia safena para revascularizao do miocrdio: metanlise (no houve diferena estatisticamente significante Radial artery versus saphenous vein to myocardial revascularization: meta-analysis (there is no statistically significant difference

    Rafael Fagionato Locali

    2006-09-01

    Full Text Available OBJETIVO: Comparar a efetividade do enxerto de artria radial com o enxerto de veia safena para revascularizao do miocrdio, em associao com a artria torcica interna. MTODO: Realizou-se uma reviso sistemtica da literatura, utilizando uma estratgia de busca de artigos aplicada s bases de dados da MEDLINE e LILACS. Dois pesquisadores independentes realizaram a seleo dos artigos identificados, avaliando criteriosamente a metodologia dos artigos considerados relevantes para o tema. Somente os ensaios clnicos controlados e randomizados com adequado sistema de aleatorizao foram includos. Em todas as situaes em que ocorreu discordncia entre os pesquisadores, foi realizada uma reunio de consenso. No foi estipulada restrio quanto ao perodo ps-operatrio para avaliao angiogrfica do enxerto, o vaso tratado cirurgicamente e as caractersticas dos pacientes includos. Os resultados so expressos como Risco Relativo (RR, com 95% de Intervalo de Confiana (CI, da comparao da efetividade entre a artria radial e a veia safena. RESULTADOS: Com base nesses critrios foram includos trs estudos. No foi detectada diferena estatstica entre a perviabilidade dos enxertos estudados (RR 0,53 [95% IC 0,13 - 2,18]. CONCLUSO: Apesar dos estudos serem de boa qualidade metodolgica, no houve resultado estatisticamente significativo beneficiando um dos enxertos. O poder estatstico da metanlise baixo. Portanto, so necessrios novos ensaios clnicos controlados e randomizados, com tamanho de amostra adequado para detectar possveis diferenas entre os tratamentos propostos.OBJECTIVE: To compare the effectiveness of radial artery graft with saphenous vein graft to myocardial revascularization, in association with the internal thoracic artery. METHODS: We made a systematic review of literature, using a strategy to search articles applied to MEDLINE and LILACS databases. Two independent researchers have carried through the election of identified articles, evaluating carefully the methodology of articles considered excellent for the subject. Only the randomized controlled trials, with adjusted randomization system have been enclosed. All the situations where the researchers didn't agree there was a consensus meeting. It hasn't been stipulated restriction for postoperative period to graft angiographic evaluation, the vessel treated and enclosed patient's characteristics. The results have been expressed as Risk Relative (RR, with 95% of Confidence Interval (CI, to comparison the effectiveness between the radial artery and the saphenous vein. RESULTS: Based in these criteria three studies have been enclosed. We couldn't find statistic difference between grafts' patency studied (RR 0.53 [95% IC 0.13 - 2.18]. CONCLUSION: Despite of the studies have good methodological quality, we have not observed a result significant statistically benefiting one of the grafts. The statistical power of the meta-analysis is low, therefore, it's necessary more randomized controlled trials, with adjusted sample size to detect possible differences between the considered treatments.

  4. Dose-response relationships

    Japanese bomb survivor experience has shown that a single, very brief radiation exposure, a few tens of seconds in duration, is able to induce a considerable variety of different kinds of malignant disease. Why then should it be assumed, as it often is, that radiation carcinogenesis must involve a sequence of causative steps? Only, it seems, as a consequence of assumptions and analogies that are not necessarily valid. A long latent period of 20 to 40 years is thought to be impossible to reconcile with a single-step cause because cancer cells are ''known'' to divide too rapidly. The progressive increase in natural cancer frequency with increase in age is often regarded as demonstrating that ''natural'' cancer requires several causal steps and by analogy so should radiation-induced cancer. If a brief exposure is sufficient of itself, such a framework of explanation suggests that one of the sequence of several causal steps is likely to be the radiation-sensitive step. But attempts to demonstrate this are conspicuous by their infrequency and inconclusiveness

  5. Analyses of dose-response in radiotherapy for patients with mature T/NK-cell lymphomas according to the WHO classification

    Background and purpose: This study was conducted to analyze the influence of radiotherapy doses and chemotherapy doses and clinical parameters on in-field disease control in order to assess the optimal radiation doses for treatment of mature T/NK-cell lymphomas according to the newly proposed WHO classification. Patients and methods: Subjects consisted of 62 patients with mature T/NK-cell lymphomas treated with radiotherapy at four Japanese institutions between 1983 and 2002. We reevaluated all histopathological specimens of non-Hodgkin's lymphomas (NHL), using the WHO classification. Radiation therapy was usually delivered to the involved field. The majority of patients also received adriamycin-based chemotherapy such as CHOP, modified CHOP, or more intensive chemotherapy. Results: There were no significant differences in radiosensitivity among subtypes of mature T/NK-cell lymphomas, at least between extranodal NK/T-cell lymphomas, nasal type and peripheral T-cell lymphomas, unspecified. There was a radiation dose-response in non-bulky mature T/NK-cell lymphomas, indicating that radiation doses of more than 52 Gy may be required to obtain in-field control. However, it was difficult to obtain local control of bulky T-cell lymphomas, even with high doses of irradiation. Conclusions: Mature T/NK-cell lymphomas were more radioresistant than B-cell lymphomas such as diffuse large B-cell lymphomas (DLBCL). The chemotherapy including adriamycin did not improve the in-field control of mature T/NK-cell lymphomas. These results were obtained by using non-randomized data and the significance of these results is limited by bias in data. However, our results suggest that the treatment strategy which is usually used for DLBCL, that is, a combined modality of CHOP and around 40 Gy of radiotherapy, may not be sufficiently effective for mature T/NK-cell lymphomas

  6. Identification of low-dose responsive metabolites in X-irradiated human B lymphoblastoid cells and fibroblasts

    Ionizing radiation (IR) induces cellular stress responses, such as signal transduction, gene expression, protein modification, and metabolite change that affect cellular behavior. We analyzed X-irradiated human Epstein-Barr virus-transformed B lymphoblastoid cells and normal fibroblasts to search for metabolites that would be suitable IR-responsive markers by Liquid Chromotography–Mass spectrometry (LC–MS). Mass spectra, as analyzed with principal component analysis, showed that the proportion of peaks with IR-induced change was relatively small compared with the influence of culture time. Dozens of peaks that had either been upregulated or downregulated by IR were extracted as candidate IR markers. The IR-changed peaks were identified by comparing mock-treated groups to 100 mGy-irradiated groups that had recovered after 10 h, and the results indicated that the metabolites involved in nucleoside synthesis increased and that some acylcarnitine levels decreased in B lymphoblastoids. Some peaks changed by as much as 20 mGy, indicating the presence of an IR-sensitive signal transduction/metabolism control mechanism in these cells. On the other hand, we could not find common IR-changed peaks in fibroblasts of different origin. These data suggest that cell phenotype-specific pathways exist, even in low-dose responses, and could determine cell behavior. (author)

  7. Dose-response analysis of heavy metal toxicants in man: Direct in vivo assessment of body burden

    Differences in uptake, metabolism, and excretion of heavy metals makes selection of a suitable biological media as a monitor of body burden very difficult. Exposure assessments based on body fluid levels can provide, at best, only general population estimates. The most frequently monitored media are blood, urine, nail or hair clippings, sweat, and saliva. Unfortunately each of these tissues can be influenced by recent exposure conditions and are not accurate indices of the total dose or body burden. Direct in vivo measurements of body burden in humans, however, have recently been performed. This nuclear technique has focused on the measurements of kidney and liver cadmium (Cd) by neutron activation analysis and bone lead (Pb) determinations using x-ray fluorescence. The dose-response relationship for renal dysfunction based on the direct in vivo body burden for Cd is presented. The most probable Cd value for the kidney associated with renal impairment is approximately 35 mg. Approximately 100% of the subjects with 20 mg Cd in the kidney will have moderately elevated β2-microglobulin, an early indicator of potential renal functional changes

  8. Understanding the lateral dose response functions of high-resolution photon detectors by reverse Monte Carlo and deconvolution analysis.

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

    2015-08-21

    The purpose of the present study is to understand the mechanism underlying the perturbation of the field of the secondary electrons, which occurs in the presence of a detector in water as the surrounding medium. By means of 'reverse' Monte Carlo simulation, the points of origin of the secondary electrons contributing to the detector's signal are identified and associated with the detector's mass density, electron density and atomic composition. The spatial pattern of the origin of these secondary electrons, in addition to the formation of the detector signal by components from all parts of its sensitive volume, determines the shape of the lateral dose response function, i.e. of the convolution kernel K(x,y) linking the lateral profile of the absorbed dose in the undisturbed surrounding medium with the associated profile of the detector's signal. The shape of the convolution kernel is shown to vary essentially with the electron density of the detector's material, and to be attributable to the relative contribution by the signal-generating secondary electrons originating within the detector's volume to the total detector signal. Finally, the representation of the over- or underresponse of a photon detector by this density-dependent convolution kernel will be applied to provide a new analytical expression for the associated volume effect correction factor. PMID:26267311

  9. Assessing bioavailability of the solubilization of organic compound in nonionic surfactant micelles by dose-response analysis.

    Dai, Zewen; Wang, Zhilong; Xu, Jian-He; Qi, Hanshi

    2010-09-01

    It is uncertain in some extent that organic compounds solubilized in micelles of a nonionic surfactant aqueous solution are bioavailable directly by the microbes in an extractive microbial transformation or biodegradation process. In this work, a dose-response method, where a bioequivalence concept is introduced to evaluate the synergic toxicity of the nonionic surfactants and the organic compounds, was applied to analyze the inhibition effect of organic compounds (naphthalene, phenyl ether, 2-phenylethanol, and 1-butanol) in nonionic surfactant Triton X-100 micelle aqueous solutions and Triton X-114 in aqueous solutions forming cloud point systems. Based on the result, a mole solubilization ratio of organic compounds in micelle was also determined, which consisted very well with those of classic semi-equilibrium dialysis experiments. The results exhibit that bioavailability of organic compounds solubilized in micelles to microbial cells is negligible, which provides a guideline for application of nonionic surfactant micelle aqueous solutions or cloud point systems as novel media for microbial transformations or biodegradations. PMID:20607232

  10. ESTIMATING A DOSE-RESPONSE RELATIONSHIP BETWEEN LENGTH OF STAY AND FUTURE RECIDIVISM IN SERIOUS JUVENILE OFFENDERS.

    Loughran, Thomas A; Mulvey, Edward P; Schubert, Carol A; Fagan, Jeffrey; Piquero, Alex R; Losoya, Sandra H

    2009-01-01

    The effect of sanctions on subsequent criminal activity is of central theoretical importance in criminology. A key question for juvenile justice policy is the degree to which serious juvenile offenders respond to sanctions and/or treatment administered by the juvenile court. The policy question germane to this debate is finding the level of confinement within the juvenile justice system that maximizes the public safety and therapeutic benefits of institutional confinement. Unfortunately, research on this issue has been limited with regard to serious juvenile offenders. We use longitudinal data from a large sample of serious juvenile offenders from two large cities to 1) estimate a causal treatment effect of institutional placement, as opposed to probation, on future rate of rearrest and 2) investigate the existence of a marginal effect (i.e., benefit) for longer length of stay once the institutional placement decision had been made. We accomplish the latter by determining a dose-response relationship between the length of stay and future rates of rearrest and self-reported offending. The results suggest that an overall null effect of placement exists on future rates of rearrest or self-reported offending for serious juvenile offenders. We also find that, for the group placed out of the community, it is apparent that little or no marginal benefit exists for longer lengths of stay. Theoretical, empirical, and policy issues are outlined. PMID:20052309

  11. ESTIMATING A DOSE-RESPONSE RELATIONSHIP BETWEEN LENGTH OF STAY AND FUTURE RECIDIVISM IN SERIOUS JUVENILE OFFENDERS*

    Loughran, Thomas A.; Mulvey, Edward P.; Schubert, Carol A.; Fagan, Jeffrey; Piquero, Alex R.; Losoya, Sandra H.

    2009-01-01

    The effect of sanctions on subsequent criminal activity is of central theoretical importance in criminology. A key question for juvenile justice policy is the degree to which serious juvenile offenders respond to sanctions and/or treatment administered by the juvenile court. The policy question germane to this debate is finding the level of confinement within the juvenile justice system that maximizes the public safety and therapeutic benefits of institutional confinement. Unfortunately, research on this issue has been limited with regard to serious juvenile offenders. We use longitudinal data from a large sample of serious juvenile offenders from two large cities to 1) estimate a causal treatment effect of institutional placement, as opposed to probation, on future rate of rearrest and 2) investigate the existence of a marginal effect (i.e., benefit) for longer length of stay once the institutional placement decision had been made. We accomplish the latter by determining a dose-response relationship between the length of stay and future rates of rearrest and self-reported offending. The results suggest that an overall null effect of placement exists on future rates of rearrest or self-reported offending for serious juvenile offenders. We also find that, for the group placed out of the community, it is apparent that little or no marginal benefit exists for longer lengths of stay. Theoretical, empirical, and policy issues are outlined. PMID:20052309

  12. Dose response relationship of disturbed migration of Purkinje cells in the cerebellum due to X-irradiation

    Pregnant rats were exposed to 2.0, 2.25 or 2.5 Gy X-irradiation on gestation day 21. Pups were sacrificed 12 hr after exposure, and on postnatal day 5 (P5), P7 and P9. Their cerebella were observed immunohistochemically using anti-inositol 1,4,5 triphosphate (IP3) receptor antibody to identify Purkinje cells. These cells were disturbed to migrate and remained in the internal granular layer and white matter of the cerebellum. They had short dendrites, and some showed an abnormal direction of dendrites in rats exposed to 2.25 or 2.5 Gy. Alignment of Purkinje cells was also disturbed when examined either on P5, P7 or P9 especially by doses of 2.25 and 2.5 Gy. There was a relationship between X-ray doses and the number of cells piling up in the Purkinje cell layer of the cerebellum. The dose-response relationship with the number of ectopic Purkinje cells was noted in the anterior lobes of the cerebellum. (author)

  13. Study of the dose response of the system ferrous ammonium sulfate-sucrose-xylenol orange in acid aqueous solution

    Juarez-Calderon, J. M.; Negron-Mendoza, A.; Ramos-Bernal, S.

    2014-11-01

    An aqueous solution of ammonium ferrous sulfate-sucrose-xylenol orange in sulfuric acid (FSX) is proposed as a dosimetric system for the processes of gamma irradiation in a range between 0.3 and 6 Gy. This system is based on the indirect oxidation of ferrous ion by an organic compound (sucrose) to ferric ion and on the formation of a color complex of Fe3+ in an acidic medium with xylenol orange (a dye). After gamma radiation, an observable change occurs in the color of the system. Irradiation was executed at three different temperatures (13 C, 22 C, and 40 C). A spectrometric readout method at 585 nm was employed to evaluate the system's dose response. In all of the cases analyzed, the responses had a linear behavior, and a slight effect of irradiation temperature was observed. Post-irradiation response was also evaluated and showed the stability of the solutions 24 h after the irradiation. The results obtained suggest that FSX might be used as a dosimeter for low doses of gamma irradiation because it provides a stable signal, good reproducibility, and an accessible technique for analysis.

  14. Deriving ozone dose-response of photosynthesis in adult forest trees from branch-level cuvette gas exchange assessment

    Branch-level gas exchange provided the basis for assessing ozone flux in order to derive the dose-response relationship between cumulative O3 uptake (COU) and carbon gain in the upper sun crown of adult Fagus sylvatica. Fluxes of ozone, CO2 and water vapour were monitored simultaneously by climatized branch cuvettes. The cuvettes allowed branch exposure to an ambient or twice-ambient O3 regime, while tree crowns were exposed to the same O3 regimes (twice-ambient generated by a free-air canopy O3 exposure system). COU levels higher than 20 mmol m-2 led to a pronounced decline in carbon gain under elevated O3. The limiting COU range is consistent with findings on neighbouring branches exposed to twice-ambient O3 through free-air fumigation. The cuvette approach allows to estimate O3 flux at peripheral crown positions, where boundary layers are low, yielding a meso-scale within-crown resolution of photosynthetic foliage sensitivity under whole-tree free-air O3 fumigation. - Branch-level O3 dose dependence of photosynthesis derived from cuvette assessment yields sun-crown foliage sensitivity under whole-tree free-air O3 fumigation

  15. Study of the dose response of the system ferrous ammonium sulfate–sucrose–xylenol orange in acid aqueous solution

    An aqueous solution of ammonium ferrous sulfate–sucrose–xylenol orange in sulfuric acid (FSX) is proposed as a dosimetric system for the processes of gamma irradiation in a range between 0.3 and 6 Gy. This system is based on the indirect oxidation of ferrous ion by an organic compound (sucrose) to ferric ion and on the formation of a color complex of Fe3+ in an acidic medium with xylenol orange (a dye). After gamma radiation, an observable change occurs in the color of the system. Irradiation was executed at three different temperatures (13 °C, 22 °C, and 40 °C). A spectrometric readout method at 585 nm was employed to evaluate the system's dose response. In all of the cases analyzed, the responses had a linear behavior, and a slight effect of irradiation temperature was observed. Post-irradiation response was also evaluated and showed the stability of the solutions 24 h after the irradiation. The results obtained suggest that FSX might be used as a dosimeter for low doses of gamma irradiation because it provides a stable signal, good reproducibility, and an accessible technique for analysis. - Highlights: • The system ferrous-sucrose-xylenol is reproducibility with less than 5% error. • The dosimeter has low cost and easy readout using UV-vis spectrometry, and the response is stable for several days. • The system proposed is suitable for low irradiation doses

  16. Non-monotonic dose-response effect of bisphenol A on rare minnow Gobiocypris rarus ovarian development.

    Zhang, Yingying; Tao, Shiyu; Yuan, Cong; Liu, Yan; Wang, Zaizhao

    2016-02-01

    Bisphenol A (BPA) is widely spread in the environment, and can cause various reproductive disrupting effects on different organisms, including fish. Our previous published study showed that BPA has non-monotonic (inverted U-shaped) dose-response effect on rare minnow Gobiocypris rarus ovarian weight at different concentrations. To investigate the potential mechanism, we exposed female rare minnow to 1, 15 and 225 µg L(-1) BPA for 7 days in the present study. The levels of vitellogenin (Vtg), sex hormones, hydrogen peroxide (H2O2), glutathione (GSH) and triglyceride (TG) were measured. RNA-seq of ovary tissues was also performed. Result showed that Vtg, sex hormone and TG levels showed an inverted U-shaped increased response, while H2O2 and GSH levels showed a U-shaped inhibited response. RNA-seq data showed that many genes involved in lipid metabolism, oxidative stress, and proteolysis processes were altered. The change of Vtg, H2O2, GSH and TG levels was possibly related to the altered sex hormone levels. Sex hormone's direct effect, Vtg accumulation, TG accumulation and oxidative stress induced proteolysis may contribute to the change of ovary weight. PMID:26364221

  17. The incidence of radioepidermitis and the dose-response relationship in parotid gland cancer patients treated with 125I seed brachytherapy. Incidence of radioepidermitis and the dose-response relationship

    We studied the incidence and dose-response relationship of radioepidermitis in parotid gland carcinoma patients treated with [125I] seed brachytherapy in the hopes of designing an optimized pre-implant treatment plan that would reduce the incidence and severity of radioepidermitis in patients receiving this therapy. Between January 2007 and May 2010, 100 parotid gland cancer patients were treated postoperatively with [125I] seed brachytherapy. The matched peripheral dose (MPD) was 80-140 Gy, and [125I] seed activity was 0.7-0.8 mCi. The mean dose delivered to the skin was calculated in the post-implant CT on day 0 following implantation. Grades of acute and late dermatitis were evaluated at 2, 6, 12, and 18 months post-implantation. Most patients experienced grade 0-2 acute and late skin side effects (86 and 97 %, respectively), though a small subset developed severe complications. Most grade 1-3 effects resolved within 6 months of implantation, though some grade 1-3 effects and all grade 4 effects remained unchanged throughout the 18-month follow-up period. Grade 3 and 4 effects were most prominent (75 and 25 %, respectively) with doses of 110-140 Gy; doses higher than 140 Gy produced only grade 4 effects. [125I] seed brachytherapy produced acceptable levels of acute and late radioepidermitis with a good clinical outcome. A mean dose under 100 Gy delivered to the skin was safe, though doses of 110-140 Gy should be given with caution and extra monitoring; doses greater than 140 Gy are dangerous and likely to produce grade 4-5 effects. (orig.)

  18. A dose-response of consuming high fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults

    National Health and Nutrition Examination Survey data show increased risk of cardiovascular disease (CVD) mortality with increased intake of added sugar across quintiles. Objective: To determine the dose response effects of consuming beverages sweetened with high fructose corn syrup (HFCS) at zero, ...

  19. DOSE-RESPONSE FOR UV-INDUCED IMMUNE SUPPRESSION IN PEOPLE OF COLOR: DIFFERENCES BASED ON ERYTHEMAL REACTIVITY RATHER THAN SKIN PIGMENTATION

    Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation...

  20. Cytogenetics dosimetry: dose-response curve for low doses of X-ray; Dosimetria citogenetica: curva dosis-respuesta para bajas dosis de rayos-X

    Lara, Virginia E. Noval; Pineda Bolivar, William R.; Riano, Victor M. Pabon, E-mail: venovall.15@hotmail.com, E-mail: wrpineda@misena.edu.co, E-mail: vmpabonr@udistrital.edu.co [Universidad Distrital Francisco Jose de Caldas (UD), Bogota (Colombia). Grupo de Investigacion en Ciencia y Tecnologia Nuclear; Ureana, Cecilia Crane, E-mail: cecicrane@yahoo.com [Instituto Nacional de Salud (INS), Bogota (Colombia). Laboratorio de Genetica

    2013-07-01

    The purpose of this study was to conduct a preliminary study for the standardization in the future, the dose-response curve for low doses of X-rays, through the analysis of in vitro cultures of peripheral blood samples of 3 men and 3 women occupationally not exposed to artificial sources of ionizing radiation, age 18-40 years, where possible nonsmokers.

  1. Health risks from arsenic-contaminated soil in Flin Flon-Creighton, Canada: Integrating geostatistical simulation and dose-response model

    Elevated concentrations of arsenic were detected in surface soils adjacent to a smelting complex in northern Canada. We evaluated the cancer risks caused by exposure to arsenic in two communities through combining geostatistical simulation with demographic data and dose-response models in a framework. Distribution of arsenic was first estimated using geostatistical circulant-embedding simulation method. We then evaluated the exposures from inadvertent ingestion, inhalation and dermal contact. Risks of skin caner and three internal cancers were estimated at both grid scale and census-unit scale using parametric dose-response models. Results indicated that local residents could face non-negligible cancer risks (skin cancer and liver cancer mainly). Uncertainties of risk estimates were discussed from the aspects of arsenic concentrations, exposed population and dose-response model. Reducing uncertainties would require additional soil sampling, epidemic records as well as complementary studies on land use, demographic variation, outdoor activities and bioavailability of arsenic. - Cancer risks induced by arsenic in soil were evaluated using geostatistical simulation and dose-response model.

  2. Dose response screening of free and encapsulated ellagic Acid against 7,12-Dimethylbenz(aanthracene induced oxidative stress on hamster buccal pouch carcinogenesis

    Arulmozhi V

    2012-08-01

    Full Text Available Ellagic acid, a phenolic phytonutrient has become a focus of intense research owing to its role in prevention and treatment of cancer. In the present study, we proposed to screen the dose response effect of free ellagic acid (EA and ellagic acid encapsulated nanoparticles (EANP against DMBA induced oxidative stress on hamster buccal pouch model. DMBA (0.5% in mineral oil was topically applied to the left buccal pouch of male Syrian hamsters 3 times a week for 14 weeks. Treatment groups received EA (20, 40, 80 mg/kg bw and EANP (10, 20, 40 mg/kg bw via oral gavage 3 times a week from 10 to 21 weeks. Animals were sacrificed at the end of the experimental period and free radical mediated oxidative damage was estimated using various biochemical markers such as lipid peroxidation and antioxidants (GSH, SOD, CAT & GPx which are the key indicators for cancer risk at the precancerous stage. DMBA induced positive controls showed altered levels of lipid peroxidation which is associated with diminished cellular antioxidant status. Treatment with EA and EANP significantly augmented the activities of cellular antitoxidants and ultimately diminished the levels of lipid peroxidation which point towards suppression of preneoplastic lesions thereby reduces the cancerous risk.  Thus from the aforementioned results it is showed that treatment with EA at the dose of 40 mg/kg bw and EANP at the dose of 20 mg/kg bw was found to be the optimal dose which proved antioxidant activity against DMBA induced oxidative stress on hamster buccal pouch carcinogenesis. Normal 0 false false false EN-US X-NONE X-NONE

  3. Steep Dose-Response Relationship for Stage I Non-Small-Cell Lung Cancer Using Hypofractionated High-Dose Irradiation by Real-Time Tumor-Tracking Radiotherapy

    Purpose: To investigate the clinical outcomes of patients with pathologically proven, peripherally located, Stage I non-small-cell lung cancer who had undergone stereotactic body radiotherapy using real-time tumor tracking radiotherapy during the developmental period. Methods and Materials: A total of 41 patients (25 with Stage T1 and 16 with Stage T2) were admitted to the study between February 2000 and June 2005. A 5-mm planning target volume margin was added to the clinical target volume determined with computed tomography at the end of the expiratory phase. The gating window ranged from 2 to 3 mm. The dose fractionation schedule was 40 or 48 Gy in four fractions within 1 week. The dose was prescribed at the center of the planning target volume, giving more than an 80% dose at the planning target volume periphery. Results: For 28 patients treated with 48 Gy in four fractions, the overall actuarial survival rate at 3 years was 82% for those with Stage IA and 32% for those with Stage IB. For patients treated with 40 Gy in four fractions within 1 week, the overall actuarial survival rate at 3 years was 50% for those with Stage IA and 0% for those with Stage IB. A significant difference was found in local control between those with Stage IB who received 40 Gy vs. 48 Gy (p = 0.0015) but not in those with Stage IA (p = 0.5811). No serious radiation morbidity was observed with either dose schedule. Conclusion: The results of our study have shown that 48 Gy in four fractions within 1 week is a safe and effective treatment for peripherally located, Stage IA non-small-cell lung cancer. A steep dose-response curve between 40 and 48 Gy using a daily dose of 12 Gy delivered within 1 week was identified for Stage IB non-small-cell lung cancer in stereotactic body radiotherapy using real-time tumor tracking radiotherapy

  4. Dose-response relationship in cyclophosphamide-treated B-cell lymphoma xenografts monitored with [{sup 18}F]FDG PET

    Brepoels, Lieselot; Saint-Hubert, Marijke de; Mortelmans, Luc [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Stroobants, Sigrid [University Hospital Antwerpen, Department of Nuclear Medicine, Edegem (Belgium); Verhoef, Gregor [University Hospital Gasthuisberg Leuven, Department of Hematology, Leuven (Belgium); Balzarini, Jan [KU Leuven, Department of Microbiology and Immunology, Leuven (Belgium); Mottaghy, Felix M. [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Universitaetsklinikum der RWTH Aachen, Klinik fuer Nuklearmedizin, Aachen (Germany)

    2010-09-15

    Although [{sup 18}F]FDG PET can measure therapy response sooner and more accurately than morphological imaging techniques, there is still some debate as to whether [{sup 18}F]FDG uptake really reflects changes in the viable cell fraction. In this study changes in [{sup 18}F]FDG uptake were investigated in a lymphoma model at several time-points after treatment and with different doses of chemotherapy. Data were analysed in terms of several parameters. SCID mice were subcutaneously inoculated with 5 x 10{sup 6} Daudi cells in the right thigh. One group was not treated (control group). The other groups received cyclophosphamide 75 mg/kg (low-dose group), 125 mg/kg (medium-dose group) and 175 mg/kg (high-dose group) on day 0. Sequential [{sup 18}F]FDG small-animal PET ({mu}PET) scans were performed on days 0, 2, 6, 9, 13 and 16 after treatment. The mean and maximum standardized uptake value (SUV{sub mean} and SUV{sub max}), metabolic tumour volume (Vol{sub metab}) and total lesion glycolysis (TLG) were calculated. A significant decrease in [{sup 18}F]FDG uptake was observed on day 2 in the medium-dose and high-dose groups and on day 6 in the low-dose group, all preceding morphological changes. SUV{sub mean} and SUV{sub max} formed a plateau from day 6 to day 9, corresponding to the known influx of inflammatory cells. No obvious plateau was observed with TLG which was found to be the most sensitive parameter clearly differentiating the low-dose group from the medium- and high-dose groups early after therapy. [{sup 18}F]FDG uptake was able to reflect the dose-response relationship for cyclophosphamide. TLG was the best parameter for dose-related response assessment in this tumour model. (orig.)

  5. Algebraic Statistics

    Norén, Patrik

    2013-01-01

    Algebraic statistics brings together ideas from algebraic geometry, commutative algebra, and combinatorics to address problems in statistics and its applications. Computer algebra provides powerful tools for the study of algorithms and software. However, these tools are rarely prepared to address statistical challenges and therefore new algebraic results need often be developed. This way of interplay between algebra and statistics fertilizes both disciplines. Algebraic statistics is a relativ...

  6. Tissue differences, dose-response relationship and persistence of DNA adducts in blue mussels (Mytilus edulis L.) exposed to benzo[a]pyrene

    Skarphethinsdottir, H.; Ericson, G.; Dalla Zuanna, L.; Gilek, M

    2003-01-24

    Baltic Sea blue mussels (Mytilus edulis) were experimentally exposed to the genotoxic model substance benzo[a]pyrene (B[a]P) to study DNA adduct formation. The specific aims were (a) to examine where in the mussels the DNA adducts were formed, in gills or digestive gland; (b) to study the dose-response relationship between B[a]P exposure and DNA adduct formation; and (c) to examine the persistence of the formed adducts. A Scope for growth (SFG) study was also run to compare physiological responses of the mussels with the degree of DNA adduct formation. In an initial dose-response experiment, the mussels were exposed to 0, 5, 50, and 100 {mu}g/l of tritium labelled B[a]P under semi-static conditions for 4 days, and thereafter the bioaccumulation of B[a]P and DNA adduct formation in different tissues was determined using liquid scintillation counting and {sup 32}P-postlabelling analysis, respectively. In a following exposure-depuration experiment, mussels were exposed to 17 {mu}g/l of radiolabelled B[a]P under semi-static conditions for 6 days. B[a]P accumulation and DNA adduct formation were determined during the exposure, and B[a]P elimination and persistence of DNA adducts were studied during 28 days of depuration in uncontaminated water. The results revealed large tissue differences in DNA adduct formation. DNA adduct levels were not elevated in the digestive gland of the mussels at any exposure concentration (0-100 {mu}g/l), even though the highest B[a]P tissue concentrations were found in the digestive gland (1.0{+-}0.1 mg B[a]P/g tissue dry wt at 100 {mu}g/l, mean{+-}SE, n=12). DNA adducts were on the other hand formed in the gills, with the highest levels found in mussels exposed to 50 and 100 {mu}g B[a]P/l, and a dose dependent increase in adduct levels (from 1.6 to 5.9 nmol adducts/mol nucleotides) from 0 to 50 {mu}g B[a]P/l. In gills, DNA adduct levels increased with time during the 6-day exposure period in the exposure-depuration experiment, and then persisted for at least 2 weeks after exposure cessation while B[a]P tissue levels exhibited a rapid decrease (half-life of 8 days). No significant differences were observed in SFG between the control and exposed groups. Since DNA adducts exhibited a relatively high persistence in gills compared to B[a]P tissue concentrations, they seem to be a more integrated measure of genotoxic exposure than only chemical analysis of the contaminant bioaccumulation. The results also suggest that if using analysis of DNA adducts in M. edulis for monitoring purposes, analysis of gills in addition to the more commonly used digestive gland should be taken into consideration.

  7. Tissue differences, dose-response relationship and persistence of DNA adducts in blue mussels (Mytilus edulis L.) exposed to benzo[a]pyrene

    Baltic Sea blue mussels (Mytilus edulis) were experimentally exposed to the genotoxic model substance benzo[a]pyrene (B[a]P) to study DNA adduct formation. The specific aims were (a) to examine where in the mussels the DNA adducts were formed, in gills or digestive gland; (b) to study the dose-response relationship between B[a]P exposure and DNA adduct formation; and (c) to examine the persistence of the formed adducts. A Scope for growth (SFG) study was also run to compare physiological responses of the mussels with the degree of DNA adduct formation. In an initial dose-response experiment, the mussels were exposed to 0, 5, 50, and 100 μg/l of tritium labelled B[a]P under semi-static conditions for 4 days, and thereafter the bioaccumulation of B[a]P and DNA adduct formation in different tissues was determined using liquid scintillation counting and 32P-postlabelling analysis, respectively. In a following exposure-depuration experiment, mussels were exposed to 17 μg/l of radiolabelled B[a]P under semi-static conditions for 6 days. B[a]P accumulation and DNA adduct formation were determined during the exposure, and B[a]P elimination and persistence of DNA adducts were studied during 28 days of depuration in uncontaminated water. The results revealed large tissue differences in DNA adduct formation. DNA adduct levels were not elevated in the digestive gland of the mussels at any exposure concentration (0-100 μg/l), even though the highest B[a]P tissue concentrations were found in the digestive gland (1.0±0.1 mg B[a]P/g tissue dry wt at 100 μg/l, mean±SE, n=12). DNA adducts were on the other hand formed in the gills, with the highest levels found in mussels exposed to 50 and 100 μg B[a]P/l, and a dose dependent increase in adduct levels (from 1.6 to 5.9 nmol adducts/mol nucleotides) from 0 to 50 μg B[a]P/l. In gills, DNA adduct levels increased with time during the 6-day exposure period in the exposure-depuration experiment, and then persisted for at least 2 weeks after exposure cessation while B[a]P tissue levels exhibited a rapid decrease (half-life of 8 days). No significant differences were observed in SFG between the control and exposed groups. Since DNA adducts exhibited a relatively high persistence in gills compared to B[a]P tissue concentrations, they seem to be a more integrated measure of genotoxic exposure than only chemical analysis of the contaminant bioaccumulation. The results also suggest that if using analysis of DNA adducts in M. edulis for monitoring purposes, analysis of gills in addition to the more commonly used digestive gland should be taken into consideration

  8. Are atomic-bomb dose-response data from ABCC/RERF reasonable for assessment of radiation risk?

    Ever since ABCC was established in 1948, the Unified Program, conceived in 1955 and a fixed population sample (Life Span Study extended) was selected from the A-Bomb survivors Supplementary Schedules of 1950 National Census, originally consisted of approximately 110,000 persons in Hiroshima and Nagasaki. Since 1958, the AHS, a fixed sub-sample of LSS-extend sample, originally consisting of nearly 20,000 persons, has been followed for long-term clinical examinations for any late ionizing radiation effects of the A-bombs. AHS participants are thus provided complete physical examinations and laboratory tests during their biennial ''cycle'' visits to the ABCC/RERF clinics. The AHS sample includes persons NIC as the control groups. On the basis of the survey of the fixed population sample, ABCC/RERF have published many papers upto the present. Those data became the basis for reports of ICRP (1979, 1990), UNSCEAR (1977, 1933), and BEIR (1990). The author would like to raise a question whether the use of ABCC/RERF data was reasonable or not. Based on the cancer incidence in Hiroshima and Nagasaki A-bomb survivors, LNT model that radiation risk is always proportional to dose, no matter how small, was adopted by ICRP, UNSCEAR, and BEIR for the assessment of risk at low doses and for recommendation of dose limits. RERF reported the cancer incidence in A-bomb survivors, 1958-1987 (1994). A linear dose-response relationship was expressed for all solid cancers. In the ABCC/RERF study, however, abscissa of dose-response curves is done from A-bomb with no consideration of dose-rate in spite that the dose-rate is a great factor for the incidence. Incidence is affected not only with radiation dose but also with radiation dose-rate both of which are in inverse proportion to distance from the A-bomb explosion center. The patients were exposed to the radiation at the different dose-rate depending on the distance. Real animal experimental data from HTO administration by Yamamoto et al. (1998, 2000) showed different incidence of tumors at different dose-rates. Dose on abscissa of data from ABCC/RERF has to be corrected to (Dose)dose-ratefactor. The contaminated medical radiation dose is not included in ''dose'' in ABCC/RERF reports. Our medical X-ray dosimetry program was begum in 1962. A report has been published by Yamamoto et al. (1988) as the initial analysis for potential contamination of A-bomb doses by medical X-ray doses received by the members in the AHS sample through the end of 1982. For the lowest A-bomb exposed group, the contamination rate is 25% in average. Sixteen percent of subjects has more than 100% contamination and a few percent has 250-500% contamination. Such contamination rate for the lowest A-bomb exposed group is very serious for assessment of radiation risk. For the middle A-bomb exposed group, the contamination rate is still effective, though it is very low for the high