Institute of Scientific and Technical Information of China (English)
GAO ChangAn; ZHANG AiQian; LIN Yuan; YIN DaQiang; WANG LianSheng
2009-01-01
Particular non-monotonic dose-response curves of many endocrine disrupting chemicals (EDCs) suggest the existence of diverse toxicity mechanisms at different dose levels. As a result, the biologi-cal activities of EDCs cannot be simply exhibited by unique EC/LD<,50. values, and the quantitative structure-activity relationship (QSAR) analysis for non-monotonic dose-response relationship be-comes an unknown field in the environmental science. In this paper, nine phenols with inverted U-shaped dose-response curves in lymphocyte proliferation test of Carassius auratus were selected. The binding interactions between the phenols and several typical EDCs-related receptors were then explored in a molecular simulation study. The estrogen receptor (ER), androgen receptor (AR), thyroid hormone receptor (TR), bacterial O2 sensing FixL protein (FixL), aryl hydrocarbon receptor (AhR), and the peroxisome proliferator-activated receptor (PPAR) were the target receptors in the study. Linear regression QSAR models for the low and high exposure levels of the compounds were developed separately. The results indicated that the lymphocyte proliferation in the low-dose range might involve ER-mediated process, while the proliferation inhibition in the high dose range was dominated by the acute toxicity of phenols due to receptor occupancy and cell damage.
QSAR study on the non-monotonic dose-response curve of PCBs in chicken embryo hepatocyte bioassay
Institute of Scientific and Technical Information of China (English)
MU YunSong; ZHANG AiQian; GAO ChangAn; PENG SuFen; WANG LianSheng
2009-01-01
Endocrine disrupting chemicals (EDCs) in the natural environment exhibit a unique non-monotonic dose-response curve and it is impossible to select one simple index to characterize the bilogogical activity of these compounds. Quantitative structure-activity relationship (QSAR) study on non-monotonic dose-response curve has become a real challenge presently. In order to explore the possible mechanism for the non-monotonic dose-response curve of polychlorinated biphenyls con-geners (PCBs) in chicken embryo hepatocyte bioassay, AM1 method of ChemOffice was adopted to calculate necessary structure descriptors for PCBs, while the interactions between PCBs and simulated AhR ligand binding domain (LBD) were analyzed by using FlexX in SYBYL7.0. Different binding modes for PCBs have been distinguished not only from aligned conformation but also from free binding energy. Some QSAR models were established separately for both low and high doses ranges, revealing that receptor binding may predominate in the interference of the physiological function of cytochrome P4501A-P4501A in the low doses range. But with the higher doses range, the EROD suppression might he related to acute toxicity owing to molecular polarity or distribution of charges and consequently damage structure and function of chicken embryo hepatocyte.
QSAR study on the non-monotonic dose-response curve of PCBs in chicken embryo hepatocyte bioassay
Institute of Scientific and Technical Information of China (English)
无
2009-01-01
Endocrine disrupting chemicals (EDCs) in the natural environment exhibit a unique non-monotonic dose-response curve and it is impossible to select one simple index to characterize the bilogogical activity of these compounds. Quantitative structure-activity relationship (QSAR) study on non-monotonic dose-response curve has become a real challenge presently. In order to explore the possible mechanism for the non-monotonic dose-response curve of polychlorinated biphenyls congeners (PCBs) in chicken embryo hepatocyte bioassay, AM1 method of ChemOffice was adopted to calculate necessary structure descriptors for PCBs, while the interactions between PCBs and simulated AhR ligand binding domain (LBD) were analyzed by using FlexX in SYBYL7.0. Different binding modes for PCBs have been distinguished not only from aligned conformation but also from free binding energy. Some QSAR models were established separately for both low and high doses ranges, revealing that receptor binding may predominate in the interference of the physiological function of cytochrome P4501A-P4501A in the low doses range. But with the higher doses range, the EROD suppression might be related to acute toxicity owing to molecular polarity or distribution of charges and consequently damage structure and function of chicken embryo hepatocyte.
Description of dose response curve
Al-Samarai, Firas
2011-01-01
The book included several methods to estimate LD50, in addition to explain how to use several programs to estimate LD50. Moreover the book illustrate the description of the dose response curves. Firas Al-Samarai
Inferring mechanisms from dose-response curves
Chow, Carson C.; Ong, Karen M.; Dougherty, Edward J.; Simons, S. Stoney
2011-01-01
The steady state dose-response curve of ligand-mediated gene induction usually appears to precisely follow a first-order Hill equation (Hill coefficient equal to 1). Additionally, various cofactors/reagents can affect both the potency and the maximum activity of gene induction in a gene-specific manner. Recently, we have developed a general theory for which an unspecified sequence of steps or reactions yields a first-order Hill dose-response curve (FHDC) for plots of the final product vs. ini...
A Strategy to Model Nonmonotonic Dose-Response Curve and Estimate IC50
Hui Zhang; Jeanne Holden-Wiltse; Jiong Wang; Hua Liang
2013-01-01
The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and igno...
A strategy to model nonmonotonic dose-response curve and estimate IC50.
Zhang, Hui; Holden-Wiltse, Jeanne; Wang, Jiong; Liang, Hua
2013-01-01
The half-maximal inhibitory concentration IC[Formula: see text] is an important pharmacodynamic index of drug effectiveness. To estimate this value, the dose response relationship needs to be established, which is generally achieved by fitting monotonic sigmoidal models. However, recent studies on Human Immunodeficiency Virus (HIV) mutants developing resistance to antiviral drugs show that the dose response curve may not be monotonic. Traditional models can fail for nonmonotonic data and ignore observations that may be of biologic significance. Therefore, we propose a nonparametric model to describe the dose response relationship and fit the curve using local polynomial regression. The nonparametric approach is shown to be promising especially for estimating the IC[Formula: see text] of some HIV inhibitory drugs, in which there is a dose-dependent stimulation of response for mutant strains. This model strategy may be applicable to general pharmacologic, toxicologic, or other biomedical data that exhibits a nonmonotonic dose response relationship for which traditional parametric models fail.
Review of dose-response curves for acute antimigraine drugs
DEFF Research Database (Denmark)
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......, whereas AEs often increase with increasing doses. The two other groups of drugs also have flat dose-response curves for efficacy. Overall, the triptans still have the most favorable efficacy-tolerability profile. Current acute antimigraine drugs do not fulfill the expectations of the patients, and thus...
Nonparallel nephrotoxicity dose-response curves of aminoglycosides.
1981-01-01
Nephrotoxicity comparisons of aminoglycosides in rats, utilizing large multiples of human doses, have indicated an advantage for netilmicin. However, no nephrotoxicity advantage of netilmicin has been demonstrated at the lower doses used in clinics. Some high-dose studies in rats have also suggested that the slope of the nephrotoxicity dose-response curve of netilmicin was less steep than the slopes of other aminoglycosides. Therefore, the slopes of the nephrotoxicity dose-response curves of ...
Optimal designs for dose response curves with common parameters
Feller, Chrystel; Schorning, Kirsten; Dette, Holger; Bermann, Georgina; Bornkamp, Björn
2016-01-01
A common problem in Phase II clinical trials is the comparison of dose response curves corresponding to different treatment groups. If the effect of the dose level is described by parametric regression models and the treatments differ in the administration frequency (but not in the sort of drug) a reasonable assumption is that the regression models for the different treatments share common parameters. This paper develops optimal design theory for the comparison of different regression models ...
Dose-response curve estimation: a semiparametric mixture approach.
Yuan, Ying; Yin, Guosheng
2011-12-01
In the estimation of a dose-response curve, parametric models are straightforward and efficient but subject to model misspecifications; nonparametric methods are robust but less efficient. As a compromise, we propose a semiparametric approach that combines the advantages of parametric and nonparametric curve estimates. In a mixture form, our estimator takes a weighted average of the parametric and nonparametric curve estimates, in which a higher weight is assigned to the estimate with a better model fit. When the parametric model assumption holds, the semiparametric curve estimate converges to the parametric estimate and thus achieves high efficiency; when the parametric model is misspecified, the semiparametric estimate converges to the nonparametric estimate and remains consistent. We also consider an adaptive weighting scheme to allow the weight to vary according to the local fit of the models. We conduct extensive simulation studies to investigate the performance of the proposed methods and illustrate them with two real examples.
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
DEFF Research Database (Denmark)
Beausoleil, Claire; Ormsby, Jean-Nicolas; Gies, Andreas
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...
Maximum likelihood estimation for cytogenetic dose-response curves
Energy Technology Data Exchange (ETDEWEB)
Frome, E.L; DuFrain, R.J.
1983-10-01
In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.
Topological recursion and a quantum curve for monotone Hurwitz numbers
Do, Norman; Dyer, Alastair; Mathews, Daniel V.
2017-10-01
Classical Hurwitz numbers count branched covers of the Riemann sphere with prescribed ramification data, or equivalently, factorisations in the symmetric group with prescribed cycle structure data. Monotone Hurwitz numbers restrict the enumeration by imposing a further monotonicity condition on such factorisations. In this paper, we prove that monotone Hurwitz numbers arise from the topological recursion of Eynard and Orantin applied to a particular spectral curve. We furthermore derive a quantum curve for monotone Hurwitz numbers. These results extend the collection of enumerative problems known to be governed by the paradigm of topological recursion and quantum curves, as well as the list of analogues between monotone Hurwitz numbers and their classical counterparts.
CALUX measurements: statistical inferences for the dose-response curve.
Elskens, M; Baston, D S; Stumpf, C; Haedrich, J; Keupers, I; Croes, K; Denison, M S; Baeyens, W; Goeyens, L
2011-09-30
Chemical Activated LUciferase gene eXpression [CALUX] is a reporter gene mammalian cell bioassay used for detection and semi-quantitative analyses of dioxin-like compounds. CALUX dose-response curves for 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] are typically smooth and sigmoidal when the dose is portrayed on a logarithmic scale. Non-linear regression models are used to calibrate the CALUX response versus TCDD standards and to convert the sample response into Bioanalytical EQuivalents (BEQs). Several complications may arise in terms of statistical inference, specifically and most important is the uncertainty assessment of the predicted BEQ. This paper presents the use of linear calibration functions based on Box-Cox transformations to overcome the issue of uncertainty assessment. Main issues being addressed are (i) confidence and prediction intervals for the CALUX response, (ii) confidence and prediction intervals for the predicted BEQ-value, and (iii) detection/estimation capabilities for the sigmoid and linearized models. Statistical comparisons between different calculation methods involving inverse prediction, effective concentration ratios (ECR(20-50-80)) and slope ratio were achieved with example datasets in order to provide guidance for optimizing BEQ determinations and expand assay performance with the recombinant mouse hepatoma CALUX cell line H1L6.1c3.
A Grid Algorithm for High Throughput Fitting of Dose-Response Curve Data
Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung
2010-01-01
We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program’s performance in reproducing the actual values that were used ...
Slope of the dose-response curve: usefulness in assessing bronchial responses to inhaled histamine.
Cockcroft, D. W.; Berscheid, B A
1983-01-01
The value of determining the slope of the histamine dose-response curve, in addition to the histamine provocation concentration producing a 20% reduction in FEV1 (PC20-FEV1), was assessed by analysis of histamine dose-response curves in 40 patients selected as having a wide range of increased non-specific bronchial responsiveness to inhaled histamine. The histamine dose-response curves were found to be fit the linear curve (dose v response, mean r2 = 0.97) better than the logarithmic curve (l...
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.
A grid algorithm for high throughput fitting of dose-response curve data.
Wang, Yuhong; Jadhav, Ajit; Southal, Noel; Huang, Ruili; Nguyen, Dac-Trung
2010-10-21
We describe a novel algorithm, Grid algorithm, and the corresponding computer program for high throughput fitting of dose-response curves that are described by the four-parameter symmetric logistic dose-response model. The Grid algorithm searches through all points in a grid of four dimensions (parameters) and finds the optimum one that corresponds to the best fit. Using simulated dose-response curves, we examined the Grid program's performance in reproducing the actual values that were used to generate the simulated data and compared it with the DRC package for the language and environment R and the XLfit add-in for Microsoft Excel. The Grid program was robust and consistently recovered the actual values for both complete and partial curves with or without noise. Both DRC and XLfit performed well on data without noise, but they were sensitive to and their performance degraded rapidly with increasing noise. The Grid program is automated and scalable to millions of dose-response curves, and it is able to process 100,000 dose-response curves from high throughput screening experiment per CPU hour. The Grid program has the potential of greatly increasing the productivity of large-scale dose-response data analysis and early drug discovery processes, and it is also applicable to many other curve fitting problems in chemical, biological, and medical sciences.
Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...
[Dose response curve of paclitaxel measured by histoculture drug response assay].
Yoshimasu, Tatsuya; Oura, Shoji; Hirai, Issei; Kokawa, Yozo; Okamura, Yoshitaka; Furukawa, Tomoko
2005-04-01
Dose response curves of paclitaxel were measured by histoculture drug response assay (HDRA) in 11 lung cancer patients. Inhibition rates of paclitaxel at several concentrations were measured and fitted to the sigmoid dose response curve, using non-linear least square analysis, with fitting equation y=A (1-1/(1+exp (b (x-log (ED50)). Parameters A, b, and ED50 were 88.3+/-6.0 (80.0-100.0) %, 9.57+/-4.32 (2.25-15.0), and 26.8+/-8.1 (15.0-41.0) microg/ml, respectively. The parameter b was lower in well-differentiated tumors compared with moderately and poorly-differentiated tumors. Dose response curves of paclitaxel could be measured by HDRA in lung cancer. This method provides us more information for drug sensitivity than the usual HDRA method. This may lead to the improved accuracy of HDRA.
Dose-Response Curve of Chromosome Aberrations in Human Lymphocytes Induced by Gamma-Rays
Directory of Open Access Journals (Sweden)
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 + αD + βD2. The result showed that α and β 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.
G.M. Moller (Trude); S.E. Overbeek (Shelley); C.G. van Helden-Meeuwsen; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)
1999-01-01
textabstractAsthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose a
Stebbing, A R D
2009-04-15
A re-interpretation of the 'dose-response' curve is given that accommodates homeostasis. The outcome, or overall effect, of toxicity is the consequence of toxicity that is moderated by homeodynamic responses. Equilibrium is achieved by a balance of opposing forces of toxic inhibition countered by a stimulatory response. A graphical model is given consisting of two linked curves (response vs concentration and effect vs concentration), which provide the basis for a re-interpretation of the 'dose-response' curve. The model indicates that such relationships are non-linear with a threshold, which is due to homeodynamic responses. Subthreshold concentrations in 'dose-response' curves provide the sum of toxic inhibition minus the homeodynamic response; the response itself is unseen in serving its purpose of neutralizing perturbation. This interpretation suggests why the alpha- and beta-curves are non-linear. The beta-curve indicates adaptive overcorrection to toxicity that confers greater resistance to subsequent toxic exposure, with hormesis as an epiphenomenon.
Dose-response curve to salbutamol during acute and chronic treatment with formoterol in COPD
Directory of Open Access Journals (Sweden)
La Piana GE
2011-07-01
Full Text Available Giuseppe Emanuele La Piana¹, Luciano Corda², Enrica Bertella¹, Luigi Taranto Montemurro¹, Laura Pini¹, Claudio Tantucci¹¹Cattedra di Malattie dell'Apparato Respiratorio, Università di Brescia, ²Prima Divisione di Medicina Interna, Spedali Civili, Brescia, ItalyBackground: Use of short-acting ß2-agonists in chronic obstructive pulmonary disease (COPD during treatment with long-acting ß2-agonists is recommended as needed, but its effectiveness is unclear. The purpose of this study was to assess the additional bronchodilating effect of increasing doses of salbutamol during acute and chronic treatment with formoterol in patients with COPD.Methods: Ten patients with COPD underwent a dose-response curve to salbutamol (until 800 µg of cumulative dose after a 1-week washout (baseline, 8 hours after the first administration of formoterol 12 µg (day 1, and after a 12-week and 24-week period of treatment with formoterol (12 µg twice daily by dry powder inhaler. Peak expiratory flow, forced expiratory volume in one second (FEV1, forced vital capacity, and inspiratory capacity were measured at the different periods of treatment and at different steps of the dose-response curve.Results: Despite acute or chronic administration of formoterol, maximal values of peak expiratory flow, FEV1, and forced vital capacity after 800 µg of salbutamol were unchanged compared with baseline. The baseline FEV1 dose-response curve was steeper than that at day 1, week 12, or week 24 (P < 0.0001. Within each dose-response curve, FEV1 was different only at baseline and at day 1 (P < 0.001, when FEV1 was still greater at 800 µg than at 0 µg (P < 0.02. In contrast, the forced vital capacity dose-response curves were similar at the different periods, while within each dose-response curve, forced vital capacity was different in all instances (P < 0.001, always being higher at 800 µg than at 0 µg (P < 0.05.Conclusion: In patients with stable COPD, the maximal effect
Shi, J Q; Wang, B; Will, E J; West, R M
2012-11-20
We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime.
DOSE RESPONSE CURVE OF 60Co FOR PREMATURE CONDENSED CHROMOSOME FRAGMENTS OF HUMAN LYMPHOCYTES
Institute of Scientific and Technical Information of China (English)
高锦声; 郑斯英; 等
1995-01-01
The dose-response curves obtained by premature condensed chromosome(PCC) and conventional cellular genetic methods can be represented by two linear equations.The ratio of the slopes,KPCC/KM1,is about 28,In compartison to the conventional method.The PCC method has many advantages;e.g.it is faster,simopler,more sensitive and accurate.Its significance in the study of radiation damage is also discussed.
Bayesian fitting of a logistic dose-response curve with numerically derived priors.
Huson, L W; Kinnersley, N
2009-01-01
In this report we describe the Bayesian analysis of a logistic dose-response curve in a Phase I study, and we present two simple and intuitive numerical approaches to construction of prior probability distributions for the model parameters. We combine these priors with the expert prior opinion and compare the results of the analyses with those obtained from the use of alternative prior formulations.
A Theoretical Model for the Hormetic Dose-response Curve for Anticancer Agents.
Yoshimasu, Tatsuya; Ohashi, Takuya; Oura, Shoji; Kokawa, Yozo; Kawago, Mitsumasa; Hirai, Yoshimitsu; Miyasaka, Miwako; Nishiguchi, Haruka; Kawashima, Sayoko; Yata, Yumi; Honda, Mariko; Fujimoto, Takahiro; Okamura, Yoshitaka
2015-11-01
In the present article, we quantitatively evaluated the dose-response relationship of hormetic reactions of anticancer agents in vitro. Serial dilutions of gemcitabine, cisplatin, 5-fluorouracil, vinorelbine, and paclitaxel were administered to the A549 non-small-cell lung cancer cell line. The bi-phasic sigmoidal curve with hormetic and cytotoxic effects is given by the formula y=(a-b/(1+exp(c(*)log(x)-d)))/(1+exp(e(*)log(x)-f)), that was used to perform a non-linear least square regression. The dose-responses of the five anticancer agents were fitted to this equation. Gemcitabine and 5-fluorouracil, which had the lowest ED50 for their hormetic reaction, had the most pronounced promotive effects out of the five anticancer agents tested. The hormetic reaction progressed exponentially with culturing time. Our theoretical model will be useful in predicting how hormetic reactions affect patients with malignant tumors.
Byers, John A
2013-08-01
Dose-response curves of the effects of semiochemicals on neurophysiology and behavior are reported in many articles in insect chemical ecology. Most curves are shown in figures representing points connected by straight lines, in which the x-axis has order of magnitude increases in dosage vs. responses on the y-axis. The lack of regression curves indicates that the nature of the dose-response relationship is not well understood. Thus, a computer model was developed to simulate a flux of various numbers of pheromone molecules (10(3) to 5 × 10(6)) passing by 10(4) receptors distributed among 10(6) positions along an insect antenna. Each receptor was depolarized by at least one strike by a molecule, and subsequent strikes had no additional effect. The simulations showed that with an increase in pheromone release rate, the antennal response would increase in a convex fashion and not in a logarithmic relation as suggested previously. Non-linear regression showed that a family of kinetic formation functions fit the simulated data nearly perfectly (R(2) >0.999). This is reasonable because olfactory receptors have proteins that bind to the pheromone molecule and are expected to exhibit enzyme kinetics. Over 90 dose-response relationships reported in the literature of electroantennographic and behavioral bioassays in the laboratory and field were analyzed by the logarithmic and kinetic formation functions. This analysis showed that in 95% of the cases, the kinetic functions explained the relationships better than the logarithmic (mean of about 20% better). The kinetic curves become sigmoid when graphed on a log scale on the x-axis. Dose-catch relationships in the field are similar to dose-EAR (effective attraction radius, in which a spherical radius indicates the trapping effect of a lure) and the circular EARc in two dimensions used in mass trapping models. The use of kinetic formation functions for dose-response curves of attractants, and kinetic decay curves for
Environmental standards for ionizing radiation: theoretical basis for dose-response curves.
Upton, A C
1983-10-01
The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell.
Quality control procedures for dose-response curve generation using nanoliter dispense technologies.
Quintero, Catherine; Rosenstein, Craig; Hughes, Bethany; Middleton, Richard; Kariv, Ilona
2007-09-01
With the advancement of high-throughput biomolecular screening techniques to the lead optimization stage, there is a critical need to quality control (QC) dose-response curves generated by robotic liquid handlers to ensure accurate affinity determinations. One challenge in evaluating the performance of liquid handlers is identifying and validating a robust method for testing dispense volumes across different instruments. Although traditional automated liquid handlers are still considered the standard platform in many laboratories, nanoliter dispensers are becoming more common and pose new challenges for routine quality control procedures. For example, standard gravimetric measurements are unreliable for testing the accuracy of nanoliter liquid dispenses. However, nanoliter dispensing technology allows for the conservation of compound, reduces compound carryover from well to well through discrete dispenses, and eliminates the need for intermediate compound dilution steps to achieve a low final DMSO assay concentration. Moreover, an intermediate dilution step in aqueous solution might result in compound precipitation at high concentrations. This study compared representative automation procedures done on a variety of liquid dispensers, including manual, traditional, and nanodispense volumes. The data confirmed the importance of establishing robust QC procedures for dose-response generation in addition to accuracy and precision determinations for each instrument, and they validated the use of nanoliter pipettors for dose-response testing. The results of this study also support the requirement for thorough mixing during serial compound dilutions prepared for high-throughput lead optimization strategies using traditional liquid handlers.
Dose-response curve of a microfluidic magnetic bead-based surface coverage sandwich assay.
Cornaglia, Matteo; Trouillon, Raphaël; Tekin, H Cumhur; Lehnert, Thomas; Gijs, Martin A M
2015-09-25
Magnetic micro- and nanoparticles ('magnetic beads') have been used to advantage in many microfluidic devices for sensitive antigen (Ag) detection. Today, assays that use as read-out of the signal the number count of immobilized beads on a surface for quantification of a sample's analyte concentration have been among the most sensitive and have allowed protein detection lower than the fgmL(-1) concentration range. Recently, we have proposed in this category a magnetic bead surface coverage assay (Tekin et al., 2013 [1]), in which 'large' (2.8μm) antibody (Ab)-functionalized magnetic beads captured their Ag from a serum and these Ag-carrying beads were subsequently exposed to a surface pattern of fixed 'small' (1.0μm) Ab-coated magnetic beads. When the system was exposed to a magnetic induction field, the magnet dipole attractive interactions between the two bead types were used as a handle to approach both bead surfaces and assist with Ag-Ab immunocomplex formation, while unspecific binding (in absence of an Ag) of a large bead was reduced by exploiting viscous drag flow. The dose-response curve of this type of assay had two remarkable features: (i) its ability to detect an output signal (i.e. bead number count) for very low Ag concentrations, and (ii) an output signal of the assay that was non-linear with respect to Ag concentration. We explain here the observed dose-response curves and show that the type of interactions and the concept of our assay are in favour of detecting the lowest analyte concentrations (where typically either zero or one Ag is carried per large bead), while higher concentrations are less efficiently detected. We propose a random walk process for the Ag-carrying bead over the magnetic landscape of small beads and this model description explains the enhanced overall capture probability of this assay and its particular non-linear dose response curves.
G.T. Verhoeven; A.F.M. Verbraak (Anton); S. Boere-van der Straat; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)
2000-01-01
textabstractSTUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the
Lynöe, N; Hoeyer, K
2005-12-01
Information is usually supposed to be a prerequisite for people making decisions on whether or not to participate in a clinical trial. Previously conducted studies and research ethics scandals indicate that participants have sometimes lacked important pieces of information. Over the past few decades the quantity of information believed to be adequate has increased significantly, and in some instances a new maxim seems to be in place: the more information, the better the ethics in terms of respecting a participant's autonomy. The authors hypothesise that the dose-response curve from pharmacology or toxicology serves as a model to illustrate that a large amount of written information does not equal optimality. Using the curve as a pedagogical analogy when teaching ethics to students in clinical sciences, and also in engaging in dialogue with research institutions, may promote reflection on how to adjust information in relation to the preferences of individual participants, thereby transgressing the maxim that more information means better ethics.
Investigating quartz optically stimulated luminescence dose-response curves at high doses
Energy Technology Data Exchange (ETDEWEB)
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
Patients who do not respond to the "usual" dose: why Terry fell off the dose-response curve.
Preskorn, Sheldon H
2009-11-01
Clinical trials are aimed at determining what happens in the "usual" patient; however, clinicians are interested in what happens in their patients even if they are not usual. The usual dose-response relationship is determined as part of the drug development process required for approval of a new drug. However, clinicians are likely to encounter patients who "fall off" the usual dose-response curve because they are either sensitive or resistant to the beneficial (efficacy) or adverse effects of a drug. This column is the first in a series that will examine why specific patients fall off the usual dose-response curve and how clinicians can manage such patients when they encounter them. This column discusses what a dose-response curve is, how it is determined, and why it is clinically important.
Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.
2004-01-01
Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity.
Rabin, B. M.; Joseph, J. A.; Shukitt-Hale, B.
2004-01-01
Exposure to heavy particles can affect the functioning of the central nervous system (CNS), particularly the dopaminergic system. In turn, the radiation-induced disruption of dopaminergic function affects a variety of behaviors that are dependent upon the integrity of this system, including motor behavior (upper body strength), amphetamine (dopamine)-mediated taste aversion learning, and operant conditioning (fixed-ratio bar pressing). Although the relationships between heavy particle irradiation and the effects of exposure depend, to some extent, upon the specific behavioral or neurochemical endpoint under consideration, a review of the available research leads to the hypothesis that the endpoints mediated by the CNS have certain characteristics in common. These include: (1) a threshold, below which there is no apparent effect; (2) the lack of a dose-response relationship, or an extremely steep dose-response curve, depending on the particular endpoint; and (3) the absence of recovery of function, such that the heavy particle-induced behavioral and neural changes are present when tested up to one year following exposure. The current report reviews the data relevant to the degree to which these characteristics are common to neurochemical and behavioral endpoints that are mediated by the effects of exposure to heavy particles on CNS activity. c2004 COSPAR. Published by Elsevier Ltd. All rights reserved.
Clinical application of Chamomilla recutita in phlebitis: dose response curve study.
Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp
2011-01-01
This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.
Therapeutic efficacy of endostatin exhibits a biphasic dose-response curve.
Celik, Ilhan; Sürücü, Oguzkan; Dietz, Carsten; Heymach, John V; Force, Jeremy; Höschele, Iris; Becker, Christian M; Folkman, Judah; Kisker, Oliver
2005-12-01
We show here that recombinant endostatin protein has a biphasic effect on the inhibition of endothelial cell migration in vitro. In tumor-bearing animals, there is a similar biphasic effect on the inhibition of tumor growth and on circulating endothelial cells after once-daily s.c. injections. This biphasic effect is revealed as a U-shaped curve in which efficacy is optimal between very low and very high doses depending on the tumor type. This result may be applicable to other inhibitors of endothelial growth and to angiogenesis. Furthermore, these results have important implications for clinicians who administer angiogenesis inhibitors for cancer or other angiogenesis-dependent diseases. When these results are taken together with two previous reports of angiogenesis inhibitors with a U-shaped dose-response, they suggest that other regulators of endothelial growth may display a similar pattern.
Otero-Muras, Irene; Yordanov, Pencho; Stelling, Joerg
2014-11-20
Within cells, stimuli are transduced into cell responses by complex networks of biochemical reactions. In many cell decision processes the underlying networks behave as bistable switches, converting graded stimuli or inputs into all or none cell responses. Observing how systems respond to different perturbations, insight can be gained into the underlying molecular mechanisms by developing mathematical models. Emergent properties of systems, like bistability, can be exploited to this purpose. One of the main challenges in modeling intracellular processes, from signaling pathways to gene regulatory networks, is to deal with high structural and parametric uncertainty, due to the complexity of the systems and the difficulty to obtain experimental measurements. Formal methods that exploit structural properties of networks for parameter estimation can help to overcome these problems. We here propose a novel method to infer the kinetic parameters of bistable biochemical network models. Bistable systems typically show hysteretic dose response curves, in which the so called bifurcation points can be located experimentally. We exploit the fact that, at the bifurcation points, a condition for multistationarity derived in the context of the Chemical Reaction Network Theory must be fulfilled. Chemical Reaction Network Theory has attracted attention from the (systems) biology community since it connects the structure of biochemical reaction networks to qualitative properties of the corresponding model of ordinary differential equations. The inverse bifurcation method developed here allows determining the parameters that produce the expected behavior of the dose response curves and, in particular, the observed location of the bifurcation points given by experimental data. Our inverse bifurcation method exploits inherent structural properties of bistable switches in order to estimate kinetic parameters of bistable biochemical networks, opening a promising route for developments in
Mathematical modeling improves EC50 estimations from classical dose-response curves.
Nyman, Elin; Lindgren, Isa; Lövfors, William; Lundengård, Karin; Cervin, Ida; Sjöström, Theresia Arbring; Altimiras, Jordi; Cedersund, Gunnar
2015-03-01
The β-adrenergic response is impaired in failing hearts. When studying β-adrenergic function in vitro, the half-maximal effective concentration (EC50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50 . Instead, we have applied a mathematical modeling approach to interpret the full dose-response curve in a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose-response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time-resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180-525 nm) is higher than the classically interpreted EC50 (46-191 nm). Mathematical modeling thus makes it possible to re-interpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible. The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database, and may be accessed at http://jjj.bio.vu.nl/database/nyman. © 2015 FEBS.
Bentzen, Søren M
2005-01-01
Clinically, there is growing interest in strategies for intensifying radiation therapy by escalating the dose per fraction. This paper considers the steepness of the dose-response curve in this case. The steepness of a radiation dose-response curve is most conveniently quantified by the normalized dose-response gradient, gamma. Under the assumption of a linear-quadratic dose-effect model, a simple analytical relationship is derived between the gamma-value for a dose-response curve generated by varying the total dose while keeping the number of fractions constant, i.e. escalating the dose per fraction, and the gamma-value for a dose-response curve generated by varying the total dose while keeping the dose per fraction constant. This formulation is compared with clinical dose-response data from the literature and shown to be in good agreement with the observations. Some implications of this formulation for non-uniform dose distributions delivered using 3D conformal radiotherapy or intensity modulated radiotherapy (IMRT) are briefly discussed.
Linearization of dose-response curve of the radiochromic film dosimetry system
Energy Technology Data Exchange (ETDEWEB)
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
Melatonin entrains free-running blind people according to a physiological dose-response curve.
Lewy, Alfred J; Emens, Jonathan S; Lefler, Bryan J; Yuhas, Krista; Jackman, Angela R
2005-01-01
The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 microg) of this chemical signal for the "biological night": the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase-response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 microg can entrain (synchronize) free-running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log-linear dose-response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free-running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.
Güerci, A; Zúñiga, L; Marcos, R
2011-01-01
Individual radiosensitivity is an individual characteristic associated with an increased reaction to ionizing radiation. The purpose of our work is to establish a dose-response curve useful to classify individuals as radiosensitive or radioresistant. Thus, a dose-response curve was constructed by measuring in vitro responses to increasing doses (0 to 8 Gy) of gamma radiation in the comet assay. The obtained curve fit well with a linear equation in the range of 0 to 8 Gy. The overall dose-response curve was constructed for percent DNA in tail, as a measure of the genetic damage induced by irradiation. To probe the goodness of the constructed curve, a validation study was carried out with whole blood from two donors in a blind study. Results show that, for the two applied doses (2 and 6 Gy), the obtained values fit well inside the interval of confidence of the curve. In conclusion, our results demonstrate the usefulness of the comet assay in determining individual responses to defined doses of gamma radiation. The standard dose-response curve constructed may be used to detect individuals departing from reference values.
Webb, Nicholas E; Montefiori, David C; Lee, Benhur
2015-09-29
A new generation of HIV broadly neutralizing antibodies (bnAbs) with remarkable potency, breadth and epitope diversity has rejuvenated interest in immunotherapeutic strategies. Potencies defined by in vitro IC50 and IC80 values (50 and 80% inhibitory concentrations) figure prominently into the selection of clinical candidates; however, much higher therapeutic levels will be required to reduce multiple logs of virus and impede escape. Here we predict bnAb potency at therapeutic levels by analysing dose-response curve slopes, and show that slope is independent of IC50/IC80 and specifically relates to bnAb epitope class. With few exceptions, CD4-binding site and V3-glycan bnAbs exhibit slopes >1, indicative of higher expected therapeutic effectiveness, whereas V2-glycan, gp41 membrane-proximal external region (MPER) and gp120-gp41 bnAbs exhibit less favourable slopes <1. Our results indicate that slope is one major predictor of both potency and breadth for bnAbs at clinically relevant concentrations, and may better coordinate the relationship between bnAb epitope structure and therapeutic expectations.
G.T. Verhoeven; A.F.M. Verbraak (Anton); S. Boere-van der Straat; H.C. Hoogsteden (Henk); J.M. Bogaard (Jan)
2000-01-01
textabstractSTUDY OBJECTIVES: The interpretation of nonspecific bronchial provocation dose-response curves in COPD is still a matter of debate. Bronchial hyperresponsiveness (BHR) in patients with COPD could be influenced by the destruction of the parenchyma and the aug
Luszczki, Jarogniew J
2007-04-01
The objective of this study was to characterize the anticonvulsant and acute adverse-effect potentials of topiramate (TPM) and gabapentin (GBP)-two second-generation antiepileptic drugs administered alone and in combination in the maximal electroshock (MES)-induced seizures and chimney test in mice. The anticonvulsant and acute adverse effects of the combination of TPM with GBP at the fixed ratio of 1:1 were determined using the type I isobolographic analysis for nonparallel dose-response relationship curves (DRRCs). To ascertain any pharmacokinetic contribution to the observed interaction between TPM and GBP, total brain concentrations of both drugs were determined. The isobolographic analysis of interaction for TPM and GBP, whose DRRCs were not parallel in both MES and chimney tests, was accompanied with a presentation of all required calculations allowing the determination of lower and upper lines of additivity. The isobolographic analysis revealed that TPM combined with GBP at the fixed-ratio combination of 1:1 interacted supraadditively (synergistically) in terms of suppression of MES-induced seizures, and simultaneously, the combination produced additive interaction with respect to motor coordination impairment (adverse effects) in the chimney test. The evaluation of pharmacokinetic characteristics of interaction for the combination of TPM with GBP revealed that neither TPM nor GBP affected their total brain concentrations in experimental animals, and thus, the observed interaction in the MES test was pharmacodynamic in nature. In conclusion, the combination of TPM with GBP, because of supraadditivity in the MES test and additivity in terms of motor coordination impairment in the chimney test as well as lack of pharmacokinetic interactions between drugs, fulfilled the criterion of a favorable combination, worthy of recommendation in further clinical practice.
Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses
Liu, Li; An, Min; Johnson, Ian R.; Lovett, John V.
2003-01-01
Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the alleloc...
Banner, W; Kahn, C M
2014-02-01
CONTEXT. Recent publications have graphically demonstrated a curvilinear relationship between measures of intelligence and blood lead levels at low concentrations (dose-response curves. METHODS. Random data based on varied distributions were constructed to simulate a previous study using a single, randomly generated covariate income (Inc) to demonstrate the impact of normally versus exponentially distributed data on the shape of the graph of intelligence quotient (IQ) versus blood lead. We also used an existing database of US blood lead levels and constructed a similar model of income and IQ using both assumptions of distribution for the intermediate variable income. RESULTS. When both lead and income are exponentially distributed, the graph of lead and IQ will be a curve. CONCLUSION. The apparent shape of a dose-response relationship from simulated epidemiological data is nonlinear when one variable and a covariate are exponentially distributed. A non-linear biological relationship should not be assumed and in fact may be the least likely explanation. The use of observational epidemiological data to discern a dose-response relationship between two variables may be misleading.
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
2011-05-03
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.
Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses
Liu, De Li; An, Min; Johnson, Ian R.; Lovett, John V.
2003-01-01
Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to α-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf. PMID:19330111
Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses.
Liu, De Li; An, Min; Johnson, Ian R; Lovett, John V
2003-01-01
Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to alpha-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf.
Rastkhah, E; Zakeri, F; Ghoranneviss, M; Rajabpour, M R; Farshidpour, M R; Mianji, F; Bayat, M
2016-03-01
An in vitro study of the dose responses of human peripheral blood lymphocytes was conducted with the aim of creating calibrated dose-response curves for biodosimetry measuring up to 4 Gy (0.25-4 Gy) of gamma radiation. The cytokinesis-blocked micronucleus (CBMN) assay was employed to obtain the frequencies of micronuclei (MN) per binucleated cell in blood samples from 16 healthy donors (eight males and eight females) in two age ranges of 20-34 and 35-50 years. The data were used to construct the calibration curves for men and women in two age groups, separately. An increase in micronuclei yield with the dose in a linear-quadratic way was observed in all groups. To verify the applicability of the constructed calibration curve, MN yields were measured in peripheral blood lymphocytes of two real overexposed subjects and three irradiated samples with unknown dose, and the results were compared with dose values obtained from measuring dicentric chromosomes. The comparison of the results obtained by the two techniques indicated a good agreement between dose estimates. The average baseline frequency of MN for the 130 healthy non-exposed donors (77 men and 55 women, 20-60 years old divided into four age groups) ranged from 6 to 21 micronuclei per 1000 binucleated cells. Baseline MN frequencies were higher for women and for the older age group. The results presented in this study point out that the CBMN assay is a reliable, easier and valuable alternative method for biological dosimetry.
A dose-response curve for biodosimetry from a 6 MV electron linear accelerator
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Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A., E-mail: marcelazoo@yahoo.com.br [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Departamento de Energia Nuclear
2015-10-15
Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. (author)
A dose-response curve for biodosimetry from a 6 MV electron linear accelerator
Lemos-Pinto, M.M.P.; Cadena, M.; Santos, N.; Fernandes, T.S.; Borges, E.; Amaral, A.
2015-01-01
Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334
A dose-response curve for biodosimetry from a 6 MV electron linear accelerator.
Lemos-Pinto, M M P; Cadena, M; Santos, N; Fernandes, T S; Borges, E; Amaral, A
2015-10-01
Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.
A dose-response curve for biodosimetry from a 6 MV electron linear accelerator
Directory of Open Access Journals (Sweden)
M.M.P. Lemos-Pinto
2015-01-01
Full Text Available Biological dosimetry (biodosimetry is based on the investigation of radiation-induced biological effects (biomarkers, mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA. Two software programs, CABAS (Chromosomal Aberration Calculation Software and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates.
DEFF Research Database (Denmark)
Timar-Gabor, Alida; Constantin, Daniela; Buylaert, Jan-Pieter
2015-01-01
SAR-OSL investigations on quartz from Romanian loess resulted in non concordant fine and coarse-grain ages for equivalent doses higher than ~100 Gy. The laboratory dose response for both grain sizes is well represented by a sum of two saturating exponential functions, fine and coarse grains chara...... equivalent dose of 2000e2500 Gy were found to be below the saturation level of the laboratory dose response curve for both grain sizes; this also applied to the luminescence signals measured after >5000 Gy given on top of natural doses. © 2015 Elsevier Ltd. All rights reserved....... characterised by D01 and D02 values of ~140 and ~1400 Gy and ~65 and ~650 Gy respectively. Pulsed OSL experiments confirmed that this behaviour is almost certainly inherent to quartz and not caused by contamination with another mineral. Natural doseeresponse curves do not follow the same pattern and enter...... saturation much earlier. Analysis of time resolved spectra indicated similar luminescence lifetimes for both fine and coarse quartz grains, and natural and laboratory generated OSL signals seem to use the same non-dosedependent recombination pathways. The natural signals of a sample with an expected...
Coloring intersection graphs of x-monotone curves in the plane
Suk, Andrew
2012-01-01
A class of graphs G is \\chi-bounded if the chromatic number of the graphs in G is bounded by some function of their clique number. We show that the class of intersection graphs of simple x-monotone curves in the plane intersecting a vertical line is \\chi-bounded. As a corollary, the class of intersection graphs of rays in the plane is \\chi-bounded.
Isochronous relaxation curves for type 304 stainless steel after monotonic and cyclic strain
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Swindeman, R.W.
1978-01-01
Relaxation tests to 100 hr were performed on type 304 stainless steel in the temperature range 480 to 650/sup 0/C and were used to develop isochronous relaxation curves. Behavior after monotonic and cyclic strain was compared. Relaxation differed only slightly as a consequence of the type of previous strain, provided that plastic flow preceded the relaxation period. We observed that the short-time relaxation behavior did not manifest strong heat-to-heat variation in creep strength.
Establishment of a Dose-response Curve for X-ray-Induced Micronuclei in Human Lymphocytes.
Lusiyanti, Yanti; Alatas, Zubaidah; Syaifudin, Mukh; Purnami, Sofiati
2016-01-01
The cytokinesis-block micronucleus assay in peripheral blood lymphocytes is an established technique for biodosimetry. The aim of this project was to generate a X-ray induced micronuclei (MN) curve for peripheral blood lymphocytes taken from five healthy donors. The blood samples were irradiated with X-rays of 122 KeV at a dose rate of 0.652 Gy/min to doses of 0.5, 1, 2, 3, and 4 Gy. The blood samples were then cultured for 72 h at 37°C and processed following the International Atomic Energy Agency standard procedure with slight modifications. The result showed that the yields of MN frequencies were increased with the increase of radiation dose. Reconstruction of the relationship of MN with dose was fitted to a linear-quadratic model using Chromosome Aberration Calculation Software version 2.0. Due to their advantages, mainly, the dependence on radiation dose and dose rate, despite their limitation, these curves will be useful as alternative method for in vitro dose reconstruction and can support the preparedness for public or occupational radiation overexposure and protection. The results reported here also give us confidence to apply the obtained calibration curve of MN for future biological dosimetry requirements in Indonesia.
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Brandao, Jose Odinilson de C.; Souza, Priscilla L.G.; Santos, Joelan A.L.; Vilela, Eudice C.; Lima, Fabiana F., E-mail: jodinilson@cnen.gov.b, E-mail: fflima@cnen.gov.b, E-mail: jasantos@cnen.gov.b [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Calixto, Merilane S.; Santos, Neide, E-mail: santos_neide@yahoo.com.b [Universidade Federal de Pernambuco (UFPE), Recife, PE (Brazil). Dept. de Genetica
2009-07-01
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 {sup 241}AmBe (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)
Krapf, Jill M; Simon, James A
2017-04-01
Testosterone treatment increases sexual desire and well-being in women with hypoactive sexual desire disorder; however, many studies have shown only modest benefits limited to moderate doses. Unlike men, available data indicate women show a bell-shaped dose-response curve for testosterone, wherein a threshold dosage of testosterone leads to desirable sexual function effects, but exceeding this threshold results in a lack of further positive sexual effects or may have a negative impact. Emotional and physical side-effects of excess testosterone, including aggression and virilization, may counteract the modest benefits on sexual interaction, providing a possible explanation for a threshold dose of testosterone in women. In this commentary, we will review and critically analyze data supporting a curvilinear dose-response relationship between testosterone treatment and sexual activity in women with low libido, and also explore possible explanations for this observed relationship. Understanding optimal dosing of testosterone unique to women may bring us one step closer to overcoming regulatory barriers in treating female sexual dysfunction.
Sparrow, A. H.; Underbrink, A. G.; Rossi, H. H.
1972-01-01
Dose-response curves for pink somatic mutations in Tradescantia stamen hairs were analyzed after neutron and X-ray irradiation with doses ranging from a fraction of a rad to the region of saturation. The dose-effect relation for neutrons indicates a linear dependence from 0.01 to 8 rads; between 0.25 and 5 rads, a linear dependence is indicated for X-rays also. As a consequence the relative biological effectiveness reaches a constant value (about 50) at low doses. The observations are in good agreement with the predictions of the theory of dual radiation action and support its interpretation of the effects of radiation on higher organisms. The doubling dose of X-rays was found to be nearly 1 rad.
Martins, V; Antunes, A C; Monteiro Gil, O
2013-01-20
An in vitro dose-response curve following exposure to γ-radiation was determined at the IST/ITN, by use of the chromosomal aberration assay. This is the first study of this kind carried out among the Portuguese population. Un-irradiated and γ-irradiated peripheral blood lymphocytes from 16 healthy donors were cultured. A total of 22,395 metaphases were analyzed for frequency and distribution of dicentrics and centric rings, as a function of the radiation dose. The dose-response data for dicentrics and dicentrics plus centric rings were fitted by use of a linear-quadratic model: Y(dic)=(0.0011±0.0006)+(0.0105±0.0035)D+(0.0480±0.0019)D(2) and Y(dic+rings)=(0.0011±0.0006)+(0.0095±0.0036)D+(0.0536±0.0020)D(2). Also, calibration curves related to age and gender were determined, but no significant differences were found. Following the establishment of the dose-response curves, a validation experiment was carried out with three individuals. Real and estimated doses, obtained with the dose-response curves, were in agreement. These results give us confidence to apply both dose-response calibration curves in future biological dosimetry requirements.
Classification, Dose-response Modelling and the Evaluation of Biomarkers in a Micro-array Setting
Lin, Dan
2008-01-01
Dose-response microarray experiments consist of monitoring expression levels of thousands of genes with respect to increasing dose of the treatment under investigation. The primary goal of such an experiment is to establish a dose-response relationship, while the secondary goals are to determine the minimum effective dose level and to identify the shape of the dose-response curve. Recently, Lin et al.[1] discussed several testing procedures to test for monotone trend based on isotonic regress...
Simons, S Stoney
2006-01-01
The position of the dose-response curve for steroid-regulated gene expression determines how much variation in response will accompany the normal physiological changes in circulating steroid. Over the last several years, it has become clear that the concentration of steroid hormone required for half-maximal induction or repression by a given receptor-steroid complex, which is normally called the EC50, is not constant for all responsive genes. Thus, the position of the dose-response curve can change so that a single concentration of steroid produces very different percentages of maximal activity. This, in turn, allows for the differential expression of genes by a common steroid hormone concentration during development, differentiation, and homeostasis. Here we review the variety of factors that influence the EC50 and position of the dose-response curve for steroid hormone receptors, discuss what is known about the mechanisms, and highlight promising areas for future research.
Verification of mesoscopic models of viscoelastic fluids with a non-monotonic flow curve
Kuznetsova, Julia L.; Skul'skiy, Oleg I.
2016-02-01
The non-monotonic flow curve of a 1 wt.% polyacrylonitrile solution in dimethyl sulfoxide is described by two mesoscopic models: the modified Vinogradov-Pokrovsky model and the model proposed by Remmelgas, Harrison and Leal. To obtain an adequate description of the experimental curve, we have selected suitable internal parameters for these models. Analytical solutions for the Couette-Poiseuille flow problems are determined in parametric form, which allows us to plot the distribution of stress components and anisotropy tensor as well as the velocity profiles containing closed loops and weak tangential discontinuities. It is shown that both models predict a similar qualitative picture of structure evolution, but exhibit a significant discrepancy in the quantitative description of the magnitude of molecular chain stretching.
Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi
2013-07-01
The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship.
Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs.
Shen, Lin; Peterson, Susan; Sedaghat, Ahmad R; McMahon, Moira A; Callender, Marc; Zhang, Haili; Zhou, Yan; Pitt, Eleanor; Anderson, Karen S; Acosta, Edward P; Siliciano, Robert F
2008-07-01
Highly active antiretroviral therapy (HAART) can control HIV-1 replication, but suboptimal treatment allows for the evolution of resistance and rebound viremia. A comparative measure of antiviral activity under clinically relevant conditions would guide drug development and the selection of regimens that maximally suppress replication. Here we show that current measures of antiviral activity, including IC(50) and inhibitory quotient, neglect a key dimension, the dose-response curve slope. Using infectivity assays with wide dynamic range, we show that this slope has noteworthy effects on antiviral activity. Slope values are class specific for antiviral drugs and define intrinsic limitations on antiviral activity for some classes. Nucleoside reverse transcriptase inhibitors and integrase inhibitors have slopes of approximately 1, characteristic of noncooperative reactions, whereas non-nucleoside reverse transcriptase inhibitors, protease inhibitors and fusion inhibitors unexpectedly show slopes >1. Instantaneous inhibitory potential (IIP), the log reduction in single-round infectivity at clinical drug concentrations, is strongly influenced by slope and varies by >8 logs for anti-HIV drugs. IIP provides a more accurate measure of antiviral activity and in general correlates with clinical outcomes. Only agents with slopes >1 achieve high-level inhibition of single-round infectivity, a finding with profound implications for drug and vaccine development.
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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.
Strikwold, M.; Spenkelink, B.; Woutersen, R.A.; Rietjens, I.M.C.M.; Punt, A.
2013-01-01
In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can
On the formation of localized peaks and non-monotonic tailing of breakthrough curves
Siirila, Erica R.; Sanchez-Vila, Xavier; Fernàndez-Garcia, Daniel
2014-05-01
While breakthrough curve (BTC) analysis is a traditional tool in hydrogeology to obtain hydraulic parameters, in recent years emphasis has been placed on analyzing the shape of the receding portion of the curve. A number of field and laboratory observations have found a constant BTC slope in log-log space, and thus it has been hypothesized that a power law behavior is representative of real aquifers. Usually, monotonicity of the late-time BTC slope is just assumed, meaning that local peaks in the BTC are not considered, and that a local (in time) increase or decrease of BTC slope is also not considered. We contend that local peaks may exist but are sometimes not reported for a number of reasons. For example, when BTCs are obtained from actual measurements, sub-sampling may mask non-monotonicity, or small peaks may be reported as measurement errors and thus smoothed out or removed. When numerical analyses of synthetic aquifers are performed, the simulation method may yield artificially monotonous curves as a consequence of the methods used. For example, Eulerian methods may suffer from numerical dispersion, where curves tend to become over-smoothed while Lagrangian methods may suffer from artificial BTC oscillations stemming from the reconstruction of concentrations from a limited number of particles. A paradigm shift in terms of the BTC shape must also accompany two major advancements within the hydrogeology field: 1) the increase of high frequency data and progression of data collection techniques that diminish the problems of under-sampling BTCs and 2) advancements in supercomputing and numerical simulation allowing for higher resolution of flow and transport problems. As more information is incorporated into BTCs and/or they are obtained in more spatial locations, it is likely that classical definitions of BTC shapes will no longer be adequate descriptors for future treatment of contaminant transport problems. For example, the presence of localized peaks in BTCs
Wang, Shuxing; Lim, Grewo; Yang, Liling; Zeng, Qing; Sung, Backil; Jeevendra Martyn, J A; Mao, Jianren
2005-07-01
Management of pain after burn injury is an unresolved clinical issue. In a rat model of hindpaw burn injury, we examined the effects of systemic morphine on nociceptive behaviors following injury. Injury was induced by immersing the dorsal part of one hindpaw into a hot water bath (85 degrees C) for 4, 7, or 12 s under pentobarbital anesthesia. Mechanical allodynia to von Frey filament stimulation and thermal hyperalgesia to radiant heat were assessed. Burn injury induced by the 12-s (but not 4-, or 7-s) hot water immersion resulted in reliable and lasting mechanical allodynia and thermal hyperalgesia evident by day 1. In addition, there was an upregulation of protein kinase Cgamma and a progressive downregulation of mu-opioid receptors within the spinal cord dorsal horn ipsilateral to injury as revealed by immunohistochemistry and Western blot. In both injured and sham rats, the anti-nociceptive effects of subcutaneous morphine were examined on post-injury days 7 and 14. While the morphine AD50 dose was comparable on day 7 between burn (1.61 mg/kg) and control (1.7 mg/kg) rats, the morphine dose-response curve was shifted to the right in burn-injured rats (4.6 mg/kg) on post-injury day 14 as compared with both the injured rats on post-injury day 7 and sham rats on day 14 (1.72 mg/kg). These data indicate that hindpaw burn injury reliably produces persistent mechanical allodynia and thermal hyperalgesia and that the reduced efficacy of morphine anti-nociception in chronic burn injury may be in part due to a downregulation of spinal mu-opioid receptors.
Ivanova, Anastasia; Xiao, Changfu
2013-01-01
Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology Phase II dose-finding studies the dose-response curve often plateaus in the range of interest and there are several doses with the mean response equal to the target. In this case it is usually of interest to find the lowest of these doses since hi...
DEFF Research Database (Denmark)
Timar-Gabor, Alida; Constantin, Daniela; Buylaert, Jan-Pieter;
2015-01-01
SAR-OSL investigations on quartz from Romanian loess resulted in non concordant fine and coarse-grain ages for equivalent doses higher than ~100 Gy. The laboratory dose response for both grain sizes is well represented by a sum of two saturating exponential functions, fine and coarse grains chara...
Suto, Yumiko; Akiyama, Miho; Noda, Takashi; Hirai, Momoki
2015-12-01
In order to estimate biological doses after low-dose ionizing radiation exposure, fluorescence in situ hybridization (FISH) using three differentially colored chromosome painting probes was employed to detect exchange-type chromosome aberrations. A reference dose response curve was constructed using blood samples from a female donor whose lymphocytes consistently exhibited a low frequency of cells at the second mitosis under routine culture conditions. Aberration yields were studied for a total of about 155 thousand metaphases obtained from seven dose-points of gamma irradiations (0, 50, 100, 150, 200, 250 and 300mGy). In situ hybridization was performed using commercially available painting probes for chromosomes 1, 2 and 4. With the aid of an automated image-capturing method, exchange-type aberrations involving painted chromosomes were detected with considerable accuracy and speed. The results on the exchange-type aberrations (dicentrics plus translocations) at the seven dose-points showed a good fit to the linear-quadratic model (y=0.0023+0.0015x+0.0819x(2), P=0.83). A blind test proved the reproducibility of the reference dose-response relationship. In the control experiments using blood samples from another donor, the estimated doses calculated on the basis of the present reference curve were proved to be in good agreement with the actual physical doses applied. The present dose-response curve may serve as a means to assess the individual differences in cytogenetical radio-sensitivities.
Ivanova, Anastasia; Xiao, Changfu
2013-01-01
Consider the problem of estimating a dose with a certain response rate. Many multistage dose-finding designs for this problem were originally developed for oncology studies where the mean dose-response is strictly increasing in dose. In non-oncology phase II dose-finding studies, the dose-response curve often plateaus in the range of interest, and there are several doses with the mean response equal to the target. In this case, it is usually of interest to find the lowest of these doses because higher doses might have higher adverse event rates. It is often desirable to compare the response rate at the estimated target dose with a placebo and/or active control. We investigate which of the several known dose-finding methods developed for oncology phase I trials is the most suitable when the dose-response curve plateaus. Some of the designs tend to spread the allocation among the doses on the plateau. Others, such as the continual reassessment method and the t-statistic design, concentrate allocation at one of the doses with the t-statistic design selecting the lowest dose on the plateau more frequently.
Goswami, C Pankaj; Cheng, L; Alexander, P S; Singal, A; Li, L
2015-02-01
Gene expression data before and after treatment with an individual drug and the IC20 of dose-response data were utilized to predict two drugs' interaction effects on a diffuse large B-cell lymphoma (DLBCL) cancer cell. A novel drug interaction scoring algorithm was developed to account for either synergistic or antagonistic effects between drug combinations. Different core gene selection schemes were investigated, which included the whole gene set, the drug-sensitive gene set, the drug-sensitive minus drug-resistant gene set, and the known drug target gene set. The prediction scores were compared with the observed drug interaction data at 6, 12, and 24 hours with a probability concordance (PC) index. The test result shows the concordance between observed and predicted drug interaction ranking reaches a PC index of 0.605. The scoring reliability and efficiency was further confirmed in five drug interaction studies published in the GEO database.
Preskorn, Sheldon H
2010-05-01
This column continues the discussion of outliers on the dose-response curve begun in earlier columns. It focuses on therapeutic drug monitoring (TDM) as an underutilized tool in psychiatry to minimize this problem. The scientific rationale for dose adjustment based on TDM is presented and its efficiency is contrasted with dose adjustment based on clinical assessment of response. In current practice, the use of TDM with psychiatric drugs is generally restricted to drugs with narrow therapeutic windows or drugs imported into psychiatry from neurology where TDM is more commonly used. Examples of each of these types of drugs are cited.
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Jo, Wol Soon; Oh, Su Jung; Jeong, Soo Kyun; Yang, Kwang Mo [Dept. of Research center, Dong Nam Institute of Radiological and Medical Sciences, Busan (Korea, Republic of); Jeong, Min Ho [Dept. of Microbiology, Dong A University College of Medicine, Busan (Korea, Republic of)
2012-11-15
Recently, the increased threat of radiologically industrial accident such as radiation nondestructive inspection or destruction of nuclear accident by natural disaster such as Fukushima accident requires a greater capacity for cytogenetic biodosimetry, which is critical for clinical triage of potentially thousands of radiation-exposed individuals. Dicentric chromosome aberration analysis is the conventional means of assessing radiation exposure. Dose–response calibration curves for {sup 13}'7Cs gamma rays have been established for unstable chromosome aberrations in human peripheral blood lymphocytes in many laboratories of international biodosimetry network. In this study, therefore, we established dose– response calibration curves of our laboratory for {sup 137}Cs gamma raysaccording to the IAEA protocols for conducting the dicentric chromosome assay We established in vitro dose–response calibration curves for dicentric chromosome aberrations in human lymphocytes for{sup 13}'7Cs gamma rays in the 0 to 5 Gy range, using the maximum likelihood linear-quadratic model, Y = c+αD+βD2. The estimated coefficients of the fitted curves were within the 95% confidence intervals (CIs) and the curve fitting of dose–effect relationship data indicated a good fit to the linear-quadratic model. Hence, meaningful dose estimation from unknown sample can be determined accurately by using our laboratory’s calibration curve according to standard protocol.
Brown, Thomas A D; Alvarez, Diane; Matthews, Kenneth L; Ham, Kyungmin; Dugas, Joseph P; 10.1118/1.4767770
2012-01-01
This work investigates the dose-response curves of GAFCHROMIC EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University CAMD synchrotron facility. Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10x10x10-cm3 PMMA phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Cent...
Salama, Raghda A M; El Gayar, Nesreen H; Georgy, Sonia S; Hamza, May
2016-01-01
Background. Ibuprofen is used chronically in different animal models of inflammation by administration in drinking water or in diet due to its short half-life. Though this practice has been used for years, ibuprofen doses were never assayed against parenteral dose-response curves. This study aims at identifying the equivalent intraperitoneal (i.p.) doses of ibuprofen, when it is administered in drinking water or in diet. Methods. Bioassays were performed using formalin test and incisional pain model for antinociceptive efficacy and serum TXB2 for eicosanoid inhibitory activity. The dose-response curve of i.p. administered ibuprofen was constructed for each test using 50, 75, 100 and 200 mg/kg body weight (b.w.). The dose-response curves were constructed of phase 2a of the formalin test (the most sensitive phase to COX inhibitory agents), the area under the 'change in mechanical threshold'-time curve in the incisional pain model and serum TXB2 levels. The assayed ibuprofen concentrations administered in drinking water were 0.2, 0.35, 0.6 mg/ml and those administered in diet were 82, 263, 375 mg/kg diet. Results. The 3 concentrations applied in drinking water lay between 73.6 and 85.5 mg/kg b.w., i.p., in case of the formalin test; between 58.9 and 77.8 mg/kg b.w., i.p., in case of the incisional pain model; and between 71.8 and 125.8 mg/kg b.w., i.p., in case of serum TXB2 levels. The 3 concentrations administered in diet lay between 67.6 and 83.8 mg/kg b.w., i.p., in case of the formalin test; between 52.7 and 68.6 mg/kg b.w., i.p., in case of the incisional pain model; and between 63.6 and 92.5 mg/kg b.w., i.p., in case of serum TXB2 levels. Discussion. The increment in pharmacological effects of different doses of continuously administered ibuprofen in drinking water or diet do not parallel those of i.p. administered ibuprofen. It is therefore difficult to assume the equivalent parenteral daily doses based on mathematical calculations.
Universal, non-monotonic structure in the saturation curves of a linear Paul trap
Wells, James; Kwolek, Jonathan; Goodman, Douglas; Blümel, Reinhold; Smith, Winthrop
2016-05-01
A common technique to measure ion-atom collision rates in a hybrid trap if the ions have no optical transitions (e.g. alkalis) is to monitor the fluorescence of the neutrals in the presence of a saturated linear Paul trap (LPT). We present numerical simulations, analytical calculations, and experimental results that show that the steady-state ion capacity of an LPT, Ns, exhibits nonlinear, nonmonotonic behavior as a function of ion loading rate, Λ. The steady state as a function of loading rate, Ns(Λ) , shows four distinct regions. In Region I, at the lowest Λ, Ns(Λ) increases monotonically. Then, Ns(Λ) reaches a plateau in Region II, before decreasing to a local minimum in Region III. Finally, in Region IV, Ns(Λ) once again increases monotonically. This behavior appears universal to any Paul trap, regardless of geometry or species trapped. We examine this behavior experimentally as a function of the q stability parameter of the Paul trap and simulate numerically the effect of the particular trap geometry on the onset of each of the four regions. Funding from NSF Grant PHY-1307874.
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Serna Berna, A.; Alcaraz, M.; Acevedo, C.; Vicente, V.; Fuente, I. de la; Canteras, M.
2006-07-01
The determination of the dose-response curve is a crucial step to use the Micronucleus assay in Lymphocytes as a biological dosimeters. The most widely used fitting function is the linear-quadratic function. The coefficients are fitted by calibration data provided by irradiations of blood from healthy donors. In our case we performed the calibration curve corresponding to gamma radiation from Cesium-137 (660 keV). Doses ranged from 0 to 16 Gy. The fitting procedure used was the iteratively re weighted least square algorithm implemented in a Matlab routine. The results of the analysis of our data show that the dose-effect curve does not follow a linear-quadratic curve at high radiation doses, diminishing the quadratic parameters as dose increases. This can be interpreted as a micronucleus saturation effect beyond a certain dose level. We conclude that the MN assay with lymphocytes can be well characterized as a biological dosimeters up to a maximum dose of 4.5 Gy. (Author)
Yamada, Tomohide; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi
2016-12-02
Adequate sleep is important for good health, but it is not always easy to achieve because of social factors. Daytime napping is widely prevalent around the world. We performed a meta-analysis to investigate the association between napping (or excessive daytime sleepiness: EDS) and the risk of type 2 diabetes or metabolic syndrome, and to quantify the potential dose-response relation using cubic spline models. Electronic databases were searched for articles published up to 2016, with 288,883 Asian and Western subjects. Pooled analysis revealed that a long nap (≥60 min/day) and EDS were each significantly associated with an increased risk of type 2 diabetes versus no nap or no EDS (odds ratio 1.46 (95% CI 1.23-1.74, p Dose-response meta-analysis showed a J-curve relation between nap time and the risk of diabetes or metabolic syndrome, with no effect of napping up to about 40 minutes/day, followed by a sharp increase in risk at longer nap times. In summary, longer napping is associated with an increased risk of metabolic disease. Further studies are needed to confirm the benefit of a short nap.
Rungsimaphorn, Benchawan; Rerkamnuaychoke, Budsaba; Sudprasert, Wanwisa
2016-01-01
The in vitro dose calibration curves using conventional biological dosimetry – dicentric chromosome assay (DCA) and premature chromosome condensation (PCC) assay – were performed for the first time in Thailand for reconstruction of radiation dose in the exposed individuals. The peripheral blood lymphocyte samples from healthy donors were irradiated with 137Cs source 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 as prescribed in the International Atomic Energy Agency report with slight modifications. The yield of dicentrics with dose from at least 1000 metaphases or 100 dicentrics was fitted to a linear quadratic model using Chromosome Aberration Calculation Software (CABAS, version 2.0) whereas those of PCC rings with dose from 100 rings was fitted to a linear quadratic equation at doses from 0 to 15 Gy. These curves will be useful for in vitro dose reconstruction and can support the preparedness for overexposure to radiation among public or occupational workers and eventual radiological accident in Thailand. PMID:28217284
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Antonio W. Zuardi
2017-05-01
Full Text Available The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg, and CBD (100, 300, and 900 mg. The subjects were underwent a test of public speaking in a real situation (TPSRS where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes after administration of the drug/placebo, as time 0: -5 (baseline, 80 (pre-test, 153 (speech, and 216 (post-speech. Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase.
Zuardi, Antonio W; Rodrigues, Natália P; Silva, Angélica L; Bernardo, Sandra A; Hallak, Jaime E C; Guimarães, Francisco S; Crippa, José A S
2017-01-01
The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase.
Strikwold, Marije; Spenkelink, Bert; Woutersen, Ruud A; Rietjens, Ivonne M C M; Punt, Ans
2013-09-01
In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (ECx) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose-response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling.
Louisse, Jochem; de Jong, Esther; van de Sandt, Johannes J M; Blaauboer, Bas J; Woutersen, Ruud A; Piersma, Aldert H; Rietjens, Ivonne M C M; Verwei, Miriam
2010-12-01
At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.
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Brown, Thomas A. D.; Hogstrom, Kenneth R.; Alvarez, Diane; Matthews, Kenneth L. II; Ham, Kyungmin; Dugas, Joseph P. [Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, Louisiana 70809 and Department of Physics and Astronomy, Louisiana State University and A and M College, 202 Nicholson Hall, Baton Rouge, Louisiana 70803 (United States); Department of Physics and Astronomy, Louisiana State University and A and M College, 202 Nicholson Hall, Baton Rouge, Louisiana 70803 (United States); Center for Advanced Microstructures and Devices, Louisiana State University and A and M College, 6980 Jefferson Highway, Baton Rouge, Louisiana 70806 (United States); Mary Bird Perkins Cancer Center, 4950 Essen Lane, Baton Rouge, Louisiana 70809 and Department of Physics and Astronomy, Louisiana State University and A and M College, 202 Nicholson Hall, Baton Rouge, Louisiana 70803 (United States)
2012-12-15
Purpose: This work investigates the dose-response curves of GAFCHROMIC{sup Registered-Sign} EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. Methods: Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10 Multiplication-Sign 10 Multiplication-Sign 10-cm{sup 3} polymethylmethacrylate phantom. AAPM TG-61 protocol was applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Center. Results: The sensitivity (NOD per unit dose) of EBT film at 35 keV relative to that for 4-MV x-rays was 0.73 and 0.76 for doses 50 and 100 cGy, respectively. The sensitivity of EBT2 film at 25, 30, and 35 keV relative to that for 4-MV x-rays varied from 1.09-1.07, 1.23-1.17, and 1.27-1.19 for doses 50-200 cGy, respectively. For EBT3 film the relative sensitivity was within 3% of unity for all three monochromatic x-ray beams. Conclusions: EBT and EBT2 film sensitivity showed strong energy dependence over an energy range of 25 keV-4 MV, although this dependence becomes weaker for larger doses. EBT3 film shows weak energy dependence, indicating that it would be a better dosimeter for kV x-ray beams where beam hardening effects can result in large changes in the effective energy.
Luszczki, Jarogniew J
2008-11-01
The aim of this study was to characterize the interaction between tiagabine (TGB) and ethosuximide (ETS), two antiepileptic drugs, in pentylenetetrazole (PTZ)-induced clonic seizures in mice using isobolographic analysis. The nature of the interaction between the drugs administered in combination was ascertained by estimating plasma and brain concentrations of ETS and TGB using fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). The results indicated that both drugs produced clear anticonvulsant effects against PTZ-induced clonic seizures in mice, but that their dose-response relationship curves (DRRCs) were not parallel, consequently necessitating the isobolographic analysis for non-parallel DRRCs. The isobolographic analysis revealed that the combination of TGB with ETS at the fixed-ratio of 1:1 exerted an additive interaction against PTZ-induced clonic seizures in mice. FPIA documented that TGB significantly elevated brain ETS concentrations (by 64%), while having no effect on plasma ETS concentrations in experimental animals. In contrast, ETS had no significant impact on plasma and brain concentrations of TGB in mice, as measured by HPLC. It can be concluded that the additive interaction between TGB and ETS at the fixed-ratio of 1:1 in the PTZ test was complicated by a significant pharmacokinetic increase in total brain ETS concentrations. At present, there are no recommendations to use this drug combination in epileptic patients.
Duval, M; Guilarte Moreno, V; Grün, R
2013-12-01
This work deals with the specific studies of three main sources of uncertainty in electron spin resonance (ESR) dosimetry/dating of fossil tooth enamel: (1) the precision of the ESR measurements, (2) the long-term signal fading the selection of the fitting function. They show a different influence on the equivalent dose (D(E)) estimates. Repeated ESR measurements were performed on 17 different samples: results show a mean coefficient of variation of the ESR intensities of 1.20 ± 0.23 %, inducing a mean relative variability of 3.05 ± 2.29 % in the D(E) values. ESR signal fading over 5 y was also observed: its magnitude seems to be quite sample dependant but is nevertheless especially important for the most irradiated aliquots. This fading has an apparent random effect on the D(E) estimates. Finally, the authors provide new insights and recommendations about the fitting of ESR dose-response curves of fossil enamel with a double saturating exponential (DSE) function. The potential of a new variation of the DSE was also explored. Results of this study also show that the choice of the fitting function is of major importance, maybe more than the other sources previously mentioned, in order to get accurate final D(E) values.
Schilling, Thomas M; Kölsch, Monika; Larra, Mauro F; Zech, Carina M; Blumenthal, Terry D; Frings, Christian; Schächinger, Hartmut
2013-09-01
Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.
Aurioles-López, Verónica; Polo-López, M. Inmaculada; Fernández-Ibáñez, Pilar; López-Malo, Aurelio; Bandala, Erick R.
2016-02-01
The inactivation of Fusarium solani in water was assessed by solar driven Fenton-like processes using three different iron salts: ferric acetylacetonate (Fe(acac)3), ferric chloride (FeCl3) and ferrous sulfate (FeSO4). The experimental conditions tested were [Fe] ≈ 5 mg L-1, [H2O2] ≈ 10 mg L-1 and [Fe] ≈ 10 mg L-1; [H2O2] ≈ 20 mg L-1 mild and high, respectively, and pH 3.0 and 5.0, under solar radiation. The highest inactivation rates were observed at high reaction conditions for the three iron salts tested at pH 5.0 with less than 3.0 kJ L-1 of accumulate energy (QUV) to achieve over 99.9% of F. solani inactivation. Fe(acac)3 was the best iron salt to accomplishing F. solani inactivation. The modified Fermi equation was used to fix the experimental inactivation, data showed it was helpful for modeling the process, adequately describing dose-response curves. Inactivation process using FeSO4 at pH 3.0 was modeled fairly with r2 = 0.98 and 0.99 (mild and high concentration, respectively). Fe(acac)3, FeCl3 and FeSO4 at high concentration (i.e. [Fe] ≈ 10 mg L-1; [H2O2] ≈ 20 mg L-1) and pH 5.0 showed the highest fitting values (r2 = 0.99). Iron salt type showed a remarkable influence on the Fenton-like inactivation process.
Dose-response meta-analysis of differences in means
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Alessio Crippa
2016-08-01
Full Text Available Abstract Background Meta-analytical methods are frequently used to combine dose-response findings expressed in terms of relative risks. However, no methodology has been established when results are summarized in terms of differences in means of quantitative outcomes. Methods We proposed a two-stage approach. A flexible dose-response model is estimated within each study (first stage taking into account the covariance of the data points (mean differences, standardized mean differences. Parameters describing the study-specific curves are then combined using a multivariate random-effects model (second stage to address heterogeneity across studies. Results The method is fairly general and can accommodate a variety of parametric functions. Compared to traditional non-linear models (e.g. E max, logistic, spline models do not assume any pre-specified dose-response curve. Spline models allow inclusion of studies with a small number of dose levels, and almost any shape, even non monotonic ones, can be estimated using only two parameters. We illustrated the method using dose-response data arising from five clinical trials on an antipsychotic drug, aripiprazole, and improvement in symptoms in shizoaffective patients. Using the Positive and Negative Syndrome Scale (PANSS, pooled results indicated a non-linear association with the maximum change in mean PANSS score equal to 10.40 (95 % confidence interval 7.48, 13.30 observed for 19.32 mg/day of aripiprazole. No substantial change in PANSS score was observed above this value. An estimated dose of 10.43 mg/day was found to produce 80 % of the maximum predicted response. Conclusion The described approach should be adopted to combine correlated differences in means of quantitative outcomes arising from multiple studies. Sensitivity analysis can be a useful tool to assess the robustness of the overall dose-response curve to different modelling strategies. A user-friendly R package has been developed to facilitate
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Mendonca, Julyanne C.G.; Mendes, Mariana E.; Hwang, Suy F.; Lima, Fabiana F. [Centro Regional de Ciencias Nucleares do Nordeste (CRCN-NE/CNEN-PE), Recife, PE (Brazil); Santos, Neide, E-mail: july_cgm@yahoo.com.br [Universidade Federal de Pernambuco (CCB/UFPE), Recife, PE (Brazil). Departamento de Genetica
2014-07-01
The cytogenetic study has the chromosomal alterations as biomarkers in absorbed dose estimation by the body of individuals involved in exposure to ionizing radiation by interpreting a dose response calibration curve. Since the development of the technique to the analysis of data, you can see protocol characteristics, leading the International Atomic Energy Agency indicate that any laboratory with intention to carry out biological dosimetry establish their own calibration curves. The Biological Dosimetry Laboratory of the Centro Regional de Ciencias Nucleares (CRCN-NE/CNEN), Brazil, recently established the calibration curve related to gamma radiation ({sup 60}Co). Thus, this work aimed to start the validation of this calibration curve from samples of three different blood donors which were irradiated with an absorbed known single dose of 1 Gy. Samples were exposed to {sup 60}Co source (Glaucoma 220) located in the Department of Nuclear Energy (DEN/UFPE). After fixation with methanol and acetic acid and 5% Giemsa staining, the frequency of chromosomal alterations (dicentric chromosomes, acentric rings and fragments) were established from reading of 500 metaphases per sample and doses were estimated using Dose Estimate program. The results showed that, using the dose-response curve calibration for dicentrics, the dose absorbed estimated for the three individuals ranged from 0.891 - 1,089Gy, taking into account the range of confidence of 95%. By using the dose-response curve for dicentrics added to rings and for the same interval of confidence the doses ranged from 0,849 - 1,081Gy. Thus, the estimative encompassed known absorbed dose the three individuals in confidence interval of 95%. These preliminary results seems to demonstrate that dicentric dose-response curves and dicentrics plus rings established by CRCN-NE / CNEN are valid for dose estimation in exposed individuals. This validation will continue with samples from different individuals at different doses.
Spassova, Maria A; Miller, David J; Nikolov, Alexander S
2015-01-01
We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS) can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical KBrO3 which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG). The single strand breaks (SSB) that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits KBrO3-caused oxidative damage. Our modeling revealed that sustained exposure to KBrO3 can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical's toxicity dose dependence based on the dose-response of early genotoxic events.
Horowitz, Y; Fuks, E; Datz, H; Oster, L; Livingstone, J; Rosenfeld, A
2011-06-01
Three outstanding effects of ionisation density on the thermoluminescence (TL) mechanisms giving rise to the glow peaks of LiF:Mg,Ti (TLD-100) are currently under investigation: (1) the dependence of the heavy charged particle (HCP) relative efficiency with increasing ionisation density and the effectiveness of its modelling by track structure theory (TST), (2) the behaviour of the TL efficiency, f(D), as a function of photon energy and dose. These studies are intended to promote the development of a firm theoretical basis for the evaluation of relative TL efficiencies to assist in their application in mixed radiation fields. And (3) the shape of composite peak 5 in the glow curve for various HCP types and energies and following high-dose electron irradiation, i.e. the ratio of the intensity of peak 5a to peak 5. Peak 5a is a low-temperature satellite of peak 5 arising from electron-hole capture in a spatially correlated trapping centre/luminescent centre (TC/LC) complex that has been suggested to possess a potential as a solid-state nanodosemeter due to the preferential electron/hole population of the TC/LC at high ionisation density. It is concluded that (1) the predictions of TST are very strongly dependent on the choice of photon energy used in the determination of f(D); (2) modified TST employing calculated values of f(D) at 2 keV is in agreement with 5-MeV alpha particle experimental results for composite peak 5 but underestimates the 1.5-MeV proton relative efficiencies. Both the proton and alpha particle relative TL efficiencies of the high-temperature TL (HTTL) peaks 7 and 8 are underestimated by an order of magnitude suggesting that the HTTL efficiencies are affected by other factors in addition to radial electron dose; (3) the dose-response supralinearity of peaks 7 and 8 change rapidly with photon energy: this behaviour is explained in the framework of the unified interaction model as due to a very strong dependence on photon energy of the relative
Confidence bounds for nonlinear dose-response relationships.
Baayen, C; Hougaard, P
2015-11-30
An important aim of drug trials is to characterize the dose-response relationship of a new compound. Such a relationship can often be described by a parametric (nonlinear) function that is monotone in dose. If such a model is fitted, it is useful to know the uncertainty of the fitted curve. It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated using a public dataset and simulations based on the Emax and sigmoid Emax models. Copyright © 2015 John Wiley & Sons, Ltd.
Dose response problems in carcinogenesis.
Crump, K S
1979-03-01
The estimation of risks from exposure to carcinogens is an important problem from the viewpoint of protection of human health. It also poses some very difficult dose-response problems. Two dose-response models may fit experimental data about equally well and yet predict responses that differ by many orders of magnitude at low doses. Mechanisms of carcinogenesis are not sufficiently understood so that the shape of the dose-response curve at low doses can be satisfactorily predicted. Mathematical theories of carcinogenesis and statistical procedures can be of use with dose-reponse problems such as this and, in addition, can lead to a better understanding of the mechanisms of carcinogenesis. In this paper, mathematical dose-response models of carcinogenesis are considered as well as various proposed dose-response procedures for estimating carcinogenic risks at low doses. Areas are suggested in which further work may be useful. These areas include experimental design problems, statistical procedures for use with time-to-occurrence data, and mathematical models that incorporate such biological features as pharmacokinetics of carcinogens, synergistic effects, DNA repair, susceptible subpopulations, and immune reactions.
Institute of Scientific and Technical Information of China (English)
李广伟; 李峰生
2012-01-01
目的 建立准确估算受辐射照射者辐射剂量的方法.方法 采用X射线照射离体人外周血,一步法培养外周血淋巴细胞56 h后收获制片,检测染色体"双着丝粒(dic)+环(r)"畸变率,拟合剂量效应曲线.结果 畸变率随照射剂量增加而增加,存在明显的剂量效应,剂量效应曲线回归方程为y=0.020 8x2+0.102 8x-0.024 8,r2=0.995 3(P<0.05).结论 通过建立X射线照射离体人外周血后的剂量效应曲线,能准确估算受照辐射剂量.%Objective To establish the method of estimating accurately radiation dose of the individuals exposed to ionizing-radi-ation. Methods The blood samples in vitro were irradiated by X-ray,then cultured using one-step method for 56 hours. According to the chromosomal aberration rate(including dicentric chromosome and ring) , radiation dose-response curve was fitted. Results The chromosomal aberration rate induced by the different radiation doses increased along with the increase of radiation dose, and there was an apparent dose-response relationship,the radiation dose-response curve regression equation:y=0. 020 8x2+0. 102 8x-0. 024 8. Conclusion The dose of the individual exposed to ionizing-radiation could be estimated accurately according to the radiation dose-response curve that might be fitted by the blood samples in vitro irradiated by X-ray.
Deng, Kai; Zink, M Christine; Clements, Janice E; Siliciano, Robert F
2012-10-01
Simian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.
Confidence bounds for nonlinear dose-response relationships
DEFF Research Database (Denmark)
Baayen, C; Hougaard, P
2015-01-01
. It is well known that Wald confidence intervals are based on linear approximations and are often unsatisfactory in nonlinear models. Apart from incorrect coverage rates, they can be unreasonable in the sense that the lower confidence limit of the difference to placebo can be negative, even when an overall...... test shows a significant positive effect. Bootstrap confidence intervals solve many of the problems of the Wald confidence intervals but are computationally intensive and prone to undercoverage for small sample sizes. In this work, we propose a profile likelihood approach to compute confidence...... intervals for the dose-response curve. These confidence bounds have better coverage than Wald intervals and are more precise and generally faster than bootstrap methods. Moreover, if monotonicity is assumed, the profile likelihood approach takes this automatically into account. The approach is illustrated...
Directory of Open Access Journals (Sweden)
S. E. Overbeek
1996-01-01
Full Text Available Hyperresponsiveness of the airways to nonspecific stimuli is a characteristic feature of asthma. Airway responsiveness is usually characterized in terms of the position and shape of the dose–response curve to methacholine (MDR. In the study we have investigated the influence of fluticasone propionate (FP, a topically active glucocorticoid, on arachidonic acid (AA metabolites in broncho-alveolar lavage (BAL fluid (i.e. TxB2, PGE2, PGD2, 6kPGF1α and LTC4 on the one hand and MDR curves on the other hand. The effect of FP was studied in a randomized, double-blind, placebo-controlled design in 33 stable nonsmoking asthmatics; 16 patients received FP (500 μg b.i.d. whereas 17 patients were treated with placebo. We found that the forced expiratory volume in 1s (FEV1 % predicted increased, the log2PC20 methacholine increased and the plateau value (% fall in FEV1 decreased after a 12 week treatment period. No changes in AA-metabolites could be determined after treatment except for PGD2 which decreased nearly significantly (p = 0.058 within the FP treated group, whereas the change of PGD2 differed significantly (p = 0.05 in the FP treated group from placebo. The levels of the other AA metabolites (i.e. TxB2, PGE2, 6kPGF1α and LTC4 remained unchanged after treatment and were not significantly different from the placebo group. Our results support the hypothesis that although FP strongly influences the position, the shape and also the maximum response plateau of the MDR curve, this effect is not mainly achieved by influence on the level of AA metabolites. Other pro-inflammatory factors may be of more importance for the shape of the MDR curve. It is suggested that these pro-inflammatory factors are downregulated by FP.
Vaidya, A H; Rosenthal, D I; Lang, W; Crooke, J J; Benjamin, D; Ilyin, S E; Reitz, A B
2005-05-01
Most studies concerning the effects of oral buspirone in the rat elevated plus-maze (EPM) test, spontaneous motor activity (SMA) test, and Vogel conflict (VC) test have used Sprague-Dawley or Wistar rats. Although it has been documented that the behavior of Long-Evans rats is more sensitive to detection of anxiolytics when compared to the aforementioned strains, the effects of oral buspirone have not been fully characterized in the Long-Evans strain in the EPM and VC tests. Thus, we studied the effects of orally administered buspirone (0.03-10.0 mg/kg) in the EPM, SMA, and VC (0.3-60.0 mg/kg) tests in Long-Evans rats. In a separate experiment, brain and plasma concentrations of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) were determined after oral administration of buspirone (0.3 and 10 mg/kg) to relate the behavioral effects of buspirone with brain and plasma concentrations of buspirone and 1-PP. Our results showed that buspirone exhibited an inverted-U-shaped dose-response curve in both the EPM and the VC tests. In the EPM, buspirone produced anxiolytic activity in a low, narrow dose-range (0.03, 0.1, 0.3 mg/kg, p.o.) with maximum efficacy at 0.3 mg/kg, whereas in the VC test, significant anxiolytic activity was observed in a high, narrow dose-range (10, 30 mg/kg, p.o.) with maximum efficacy occurring at 10 mg/kg. In the SMA test, buspirone (10 mg/kg, p.o.) significantly decreased horizontal activity and vertical movements suggestive of sedation. Also, one hour following oral doses of buspirone (0.3 and 10 mg/kg), both buspirone and 1-PP concentrations were higher in brain when compared with those in plasma. Additionally, the concentrations of 1-PP were always higher in brain and in plasma compared with the concentrations of buspirone. Of particular interest is our finding of the shift in the dose-response curve between the EPM and VC tests. This shift in the dose-response curve is discussed in relation to brain levels of buspirone and 1-PP levels and their
Jamal, Syed M; Bouma, Annemarie; van den Broek, Jan; Stegeman, Arjan; Chénard, Gilles; Dekker, Aldo
2008-11-25
The aim of this study was to determine a relationship between vaccine potency (amount of PD50 per dose) and fraction of clinically protected cattle following homologous challenge with infectious foot-and-mouth disease (FMD) virus, and to determine the effect of method of fractionation, serotype, type of adjuvant, valency and type of virus culture on the dose-response curve. Data from 297 potency tests of FMD vaccines, comprising 4004 vaccinated cattle, performed at the FMD vaccine production facility in the Netherlands, were used for the present study. A generalised linear mixed effect model was used to analyse the results. Our study showed that the relation between FMD vaccine potency and fraction protected was also affected by the serotype and type of adjuvant. No common level of protection could be assigned to all FMD vaccines with the same amount of PD50 per dose, this information is essential when designing a new standard FMD vaccines control.
Directory of Open Access Journals (Sweden)
Shuai Chang
Full Text Available This study was designed to identify common HIV-1 mutation complexes affecting the slope of inhibition curve, and to propose a new parameter incorporating both the IC50 and the slope to evaluate phenotypic resistance.Utilizing site-directed mutagenesis, we constructed 22 HIV-1 common mutation complexes. IC50 and slope of 10 representative approved drugs and a novel agent against these mutations were measured to determine the resistance phenotypes. The values of new parameter incorporating both the IC50 and the slope of the inhibition curve were calculated, and the correlations between parameters were assessed.Depending on the class of drug, there were intrinsic differences in how the resistance mutations affected the drug parameters. All of the mutations resulted in large increases in the IC50s of nucleoside reverse transcriptase inhibitors. The effects of the mutations on the slope were the most apparent when examining their effects on the inhibition of non-nucleoside reverse transcriptase inhibitors and protease inhibitors. For example, some mutations, such as V82A, had no effect on IC50, but reduced the slope. We proposed a new concept, termed IIPatoxic, on the basis of IC50, slope and the maximum limiting concentrations of the drug. The IIPatoxic values of 10 approved drugs and 1 novel agent were calculated, and were closely related to the IIPmax values (r > 0.95, p < 0.001.This study confirms that resistance mutations cannot be accurately assessed by IC50 alone, because it tends to underestimate the degree of resistance. The slope parameter is of very importance in the measurement of drug resistance and the effect can be applied to more complex patterns of resistance. This is the most apparent when testing the effects of the mutations on protease inhibitors activity. We also propose a new index, IIPatoxic, which incorporates both the IC50 and the slope. This new index could complement current IIP indices, thereby enabling predict the
Gordon, J. J.; Snyder, K.; Zhong, H.; Barton, K.; Sun, Z.; Chetty, I. J.; Matuszak, M.; Ten Haken, R. K.
2015-09-01
In conventionally fractionated radiation therapy for lung cancer, radiation pneumonitis’ (RP) dependence on the normal lung dose-volume histogram (DVH) is not well understood. Complication models alternatively make RP a function of a summary statistic, such as mean lung dose (MLD). This work searches over damage profiles, which quantify sub-volume damage as a function of dose. Profiles that achieve best RP predictive accuracy on a clinical dataset are hypothesized to approximate DVH dependence. Step function damage rate profiles R(D) are generated, having discrete steps at several dose points. A range of profiles is sampled by varying the step heights and dose point locations. Normal lung damage is the integral of R(D) with the cumulative DVH. Each profile is used in conjunction with a damage cutoff to predict grade 2 plus (G2+) RP for DVHs from a University of Michigan clinical trial dataset consisting of 89 CFRT patients, of which 17 were diagnosed with G2+ RP. Optimal profiles achieve a modest increase in predictive accuracy—erroneous RP predictions are reduced from 11 (using MLD) to 8. A novel result is that optimal profiles have a similar distinctive shape: enhanced damage contribution from low doses (curves, which can be modeled using Joiner’s induced repair model. A novel search strategy is employed, which has the potential to estimate RP dependence on the normal lung DVH. When applied to a clinical dataset, identified profiles share a characteristic shape, which resembles HRS/IRR. This suggests that normal lung may have enhanced sensitivity to low doses, and that this sensitivity can affect RP risk.
Energy Technology Data Exchange (ETDEWEB)
Oliveira, Romero Marcilio Barros Matias de
2002-08-01
Biological dosimetry estimates the absorbed dose taking into account changes in biological parameters. The most used biological indicator of an exposition to ionizing radiation is the quantification of chromosomal aberrations of lymphocytes from irradiated individuals. The curves of dose versus induced biological effects, obtained through bionalyses, are used in used in retrospective evaluations of the dose, mainly in the case of accidents. In this research, a simple model for electrons and photons transports was idealized to simulate the irradiation of lymphocytes with {sup 99m} Tc, representing a system used for irradiation of blood cells. The objective of the work was to establish a curve of dose versus frequencies of chromosomal aberrations in lymphocytes of human blood. For the irradiation of blood samples micro spheres of human serum of albumin (HSAM) market with {sup 99m} Tc were used, allowing the irradiation of blood with different administered activities of {sup 99m} Tc, making possible the study the cytogenetical effects as a function of such activities. The conditions of irradiation in vivo using HSAM spheres marked with {sup 99m} Tc were simulated with MCNP 4C (Monte Carlo N-Particle) code to obtain the dose-response curve. Soft tissue composition was employed to simulate blood tissue and the analyses of the curve of dose versus biological effect showed a linear quadratic response of the unstable chromosomal aberrations. As a result, the response of dose versus chromosomal aberrations of blood irradiation with {sup 99m} Tc was best fitted by the curve Y=(8,99 {+-}2,06) x 1-{sup -4} + (1,24 {+-}0,62) x 10{sup -2} D + (5,67 {+-} 0,64) x 10{sup -2} D{sup 2}. (author)
癫痫患者顺式阿曲库铵的剂量反应曲线测定%The measurement of dose-response curve of cisatracurium in epilepsy patients
Institute of Scientific and Technical Information of China (English)
刘中杰; 徐世元; 张庆国; 梁启波; 曾繁荣
2011-01-01
Objective To determine the dose-response curve and the ED95 of cisatracurium in epilepsy patients. Methods Forty ASA grade Ⅰ or Ⅱ epilepsy patients were randomly divided into four groups. The dose-response curve was determined by single bolus injection of cisatracurium under midazolam-fentanyl intravenous anesthesia. For each group, the dose of cisatracurium were 20,30, 40 and 50 μg/kg respectively. The neuromuscular block was measured by Neuromuscular Transmission Monitor, and the responses were defined in terms of the percentages of maximum suppression in T1 of TOF of the adductor pollicis muscle. After logprobit transformation of the data of dose and response, the dose-response curve of cisatracurium was then established by linear regression. The onset time of cisatracurium was also recorded. Results The ED50, ED75, ED90 and ED95 of cisatracurium in epilepsy patients were 36.3, 46.1, 57.4 and 65.4 μg/kg. There was no significant change in onset time among 4 groups. Conclusion The ED95 of cisatracurium in epilepsy patients is 65.4 μg/kg, which is about 30.8% higher than that in normal human.%目的 采用单次剂量注射法建立癫痫患者顺式阿曲库铵的剂量反应曲线,确定其量效关系及ED95,为癫痫患者合理应用顺式阿曲库铵提供依据.方法 选取择期癫痫手术患者40例,ASA Ⅰ～Ⅱ级,年龄16岁～42岁,病史3年～26年,均具有服用抗癫痫药物史,术前无酸碱平衡及水电解质紊乱,心肺、肝肾功能正常.患者按随机数字法分为20μg/kg组、30μg/kg组、40 μg/kg组、50μg/kg组共4个剂量组,每组10例.记录拇内收肌四个成串刺激反应中第1次反应最大抑制的百分率,并进行概率单位转换,将顺式阿曲库铵的首次剂量进行对数转换,用直线回归方法建立顺式阿曲库铵的剂量-反应曲线,并记录起效时间.结果 癫痫患者顺式阿曲库铵ED50、ED75、ED90、ED95值分别为36.3、46.1、57.4、65.4μg/kg,起效时间在4个剂
Dose-response relationships for carcinogens: a review.
Zeise, L; Wilson, R.; Crouch, E A
1987-01-01
We review the experimental evidence for various shapes of dose-response relationships for carcinogens and summarize those experiments that give the most information on relatively low doses. A brief review of some models is given to illustrate the shapes of dose-response curve expected from them. Our major interest is in the use of dose-response relationships to estimate risks to humans at low doses, and so we pay special attention to experimentally observed and theoretically expected nonlinea...
Luszczki, Jarogniew J; Filip, Damian; Czuczwar, Stanislaw J
2010-10-01
The aim of this study was to characterize the anticonvulsant effects of pregabalin (PGB-a third-generation antiepileptic drug) in combination with three second-generation antiepileptic drugs (i.e., lamotrigine [LTG], oxcarbazepine [OXC] and topiramate [TPM]) in the mouse maximal electroshock (MES)-induced seizure model by using the type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs). Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25mA, 500V, 50Hz, 0.2s stimulus duration) delivered via auricular electrodes. Potential adverse-effect profiles of interactions of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 in the MES test with respect to motor performance, long-term memory and skeletal muscular strength were measured. In the mouse MES model, PGB administered singly had its DRRC non-parallel to that for LTG, OXC and TPM. With type I isobolography for non-parallel DRRCs, the combinations of PGB with LTG, OXC and TPM at the fixed-ratio of 1:1 exerted additive interaction. In all combinations, neither motor coordination, long-term memory nor muscular strength were affected. In conclusion, the additive interactions between PGB and LTG, OXC and TPM are worthy of consideration while extrapolating the results from this study to clinical settings.
Preskorn, Sheldon H
2010-01-01
Venlafaxine is a model substrate for the drug metabolizing cytochrome P450 (CYP) enzyme 2D6. The desvenlafaxine/venlafaxine ratio, either after a single dose or at steady state, can be used to determine whether a patient is functionally (i.e., phenotypically) a CYP 2D6 extensive or poor metabolizer (EM or PM). In turn, CYP 2D6 EM and PM status is important in determining the efficacy of venlafaxine as an antidepressant. Based on a secondary analysis of four of the venlafaxine registration trials, venlafaxine was effective in patients who were CYP 2D6 EMs versus a parallel placebo-treated control group, whereas it was not effective in patients who were CYP 2D6 PMs. Thus, venlafaxine is a useful example of how drugs can be used to quantify differences in drug metabolizing capacity among patients and how such differences can in turn affect the efficacy of a drug (i.e., make a patient an outlier on the usual dose-response curve).
Directory of Open Access Journals (Sweden)
André Luiz de Souza Lacerda
2004-01-01
. The herbicide glyphosate, inhibitor of the enzyme EPSPs, was used at rate 0.0; 11.3; 22.5; 45; 90; 180; 360; 720 and 1440 g.ha-1 a.i. Curves of dose-response were made by the adjustment of the equation of the collected data of green biomass using the log-logistic model: Y = C+D-C / 1 + Exp{b[log(x-log(RC50]}, calculated by the no linear statistical model through the SAS statistical program. After the determination of the dose-response curves for the species mentioned above the Bidens pilosa was considered the most susceptible weed to glyphosate, showing the houvest RC50 (31.86 g.ha-1 a.i.. The species Tridax procumbens, Digitaria insularis, Spermacoce latifolia, Ipomoea grandifolia and Commelina benghalensis obtained RC50 equal to 58.40; 128.50; 250.44; 615.49 and > 1440.00 g.ha-1 a.i., respectively, what means that the necessary amount of herbicide to reduce in 50% the green biomass was 1.83; 4.03; 7.86; 19.31 and >359.56 times higher in relation the Bidens pilosa.
Institute of Scientific and Technical Information of China (English)
葛彦虎; 王宏月; 刘秀珍; 王恒林; 张斌; 王卓强
2013-01-01
目的 采用单次剂量注射法测定终末期肾病患者顺式阿曲库铵量效关系. 方法 选取接受肾移植的终末期肾病患者40例,按完全随机方法分为4组,每组10例,对4个剂量组患者按体重注射20、30、40、50 μg/kg的顺式阿曲库铵.选取无神经肌肉病变的患者20例作为对照组,给予相同剂量的苯磺酸顺式阿曲库铵.记录每个患者最大抑制效应,并对最大抑制效应进行概率转换,对应的肌松药剂量进行对数转换,用直线回归方法建立顺式阿曲库铵的剂量-反应曲线. 结果 终末期肾病患者顺式阿曲库铵50％有效剂量(ED50) 、75％有效剂量(ED75)、90％有效剂量(ED90)、95％有效剂量ED95分别为30.88、35.65、40.62、43.85 μg/kg,无神经肌肉病变患者顺式阿曲库铵ED50、ED75、ED90、ED95分别为35.37、42.22、49.60、54.55 μg/kg,终末期肾病患者顺式阿曲库铵ED95明显低于无神经肌肉病变患者ED95 (P＜0.01). 结论 终末期肾病患者因周围神经病变累及神经肌肉接头可导致对肌松药的敏感性增加.%Objective To determine the dose-response curve of cisatracurium in patients with end-stage renal disease.Methods Forty patients with end stage renal disease were randomly divided into four groups(n=10),the dose of cisatracurium were 20,30,40 or 50 μg/kg respectively.Twenty patients with normal neural and muscular function were randomly divided into four groups and received the same doses pattern.The dose-response curve was determined by single bolus of cisatracurium under midazolam-fentanyl intravenous anesthesia.Neuromuscular transmission monitoring was used to measure the block effect after injection of cisatracurium,and the responses were defined by terms of the percentages of maximum suppression in twitch response 1 of train of four of the adductor policies muscle.After logarithmic transformation,the dose-response curve of cisatracurium was then established by linear analysis
Institute of Scientific and Technical Information of China (English)
刘中杰; 张庆国; 卢爱珠; 赖露颖; 李乐; 徐世元
2015-01-01
Objective To evaluate the gender differences in dose-response curve of vecuronium in epilepsy patients and provide a reference for its individualized application.Methods Hundred ASA grade Ⅰ-Ⅱ epilepsy patients were enrolled in this study.All patients were divided into male group (group M) and female group (group F)(n=50),they recieved the method of single dose injection under midazolam-fentanyl intravenous anesthesia.Every patient received intravenous single bolus of 20,30,40,50,60 μg/kg of vecuronium respectively(n=l0).The neuromuscular block was measured by neuromuscular transmission monitor and the responses were defined in terms of the percentages of maximum suppression in T1 of train of four stimulation (TOF) of the adductor pollicis muscle.According to log-probit transformation of the data of dose and response,the dose-response curve of vecuronium was established through linear regression.The onset time of vecuronium was also observed.Results The 50％ effective dose (ED50),75％ effective dose (ED75),90％ effective dose (ED90),95％ effective dose (ED95) values of vecuronium in male epilepsy patients were (31±6),(40±8),(50±9),(57±7) μg/kg.The ED50,ED75,ED90,ED95 values of vecuronium in female epilepsy patients were(31±6),(40±7),(50±9),(58±9) μg/kg.No significant difference in onset time was observed among 5 dose groups (P＞0.05).Conclusions There was no gender difference in dose-response curve of vecuronium in epilepsy patients.%目的 研究性别对癫痫患者维库溴铵量效关系的影响,为维库溴铵个体化应用提供参考. 方法 选取择期癫痫手术患者100例,美国麻醉医师协会(ASA)分级Ⅰ～Ⅱ级,年龄19岁～4l岁,病史2年～23年,分为男性组(M组)与女性组(F组),每组各50例,均有服用抗癫痫药物史,术前无酸碱平衡及水电解质紊乱,心、肺、肝、肾功能正常.每组患者按随机数字表法分为20、30、40、50、60 μg/kg 5个剂量组,每组10例.记录拇
Institute of Scientific and Technical Information of China (English)
刘中杰; 张庆国; 李乐; 卢爱珠; 赖露颖; 徐世元
2014-01-01
Objective To evaluate the gender differences in dose-response curve with cisatra-curium in epileptics.Methods Eighty ASA grade Ⅰ or Ⅱ epileptics were enrolled in this study.All patients were divided into male and the female groups and received the method of single dose injection under midazolam-fentanyl intravenous anesthesia.Each patient received intravenous bolus of 20,30, 40,50μg/kg of cisatracurium respectively.The neuromuscular block was measured by Neuromuscular Transmission Monitor and the responses were defined in terms of the percentages of maximum sup-pression in T1 of TOF of the adductor pollicis muscle.According to log-probit transformation of the data of dose and response,the dose-response curve of cisatracurium was established through linear re-gression.The onset time of cisatracurium was also observed.Results The ED50 ,ED75 ,ED90 ,ED95 values of cisatracurium in male epilepsy patients were 37.2±9.7,48.1±11.3,60.4±12.8,69.3± 14.0 μg/kg and that of female epilepsy patients were 36.6±4.3,47.5±7.7,60.5±14.0,70.1± 19.4 μg/kg.There was no significant difference between the two gender groups.No significant change in onset time was observed among 4 dose groups.Conclusion No gender differences are ob-served in dose-response curve of cisatracurium in epileptics.%目的：研究性别对癫痫手术患者顺式阿曲库铵剂量-反应曲线的影响。方法选取择期癫痫手术患者80例，年龄17～42岁，病史3～26年，分为男性组（M 组）和女性组（F 组），每组按20、30、40、50μg／kg 再分为四个亚组（M1～M4组和 F1～F4组），每组10例。记录拇内收肌四个成串刺激（TOF）第一次反应最大抑制的百分率，并进行概率单位转换，将顺式阿曲库铵的首次剂量进行对数转换，用直线回归方法分别建立男、女患者顺式阿曲库铵剂量-反应曲线，并记录起效时间。结果M组顺式阿曲库铵单次剂量静注 ED50、ED75、ED90、ED95
Cardiac dose-response relationships of oral and intravenous pindolol
Carruthers, S. George
1982-01-01
1 The dose-response curve of pindolol on exercise heart rate has been constructed from observations in healthy male subjects studied 2 h after oral doses of pindolol 0.25 mg, 0.5 mg, 1 mg, 2.5 mg, 5 mg, 10 mg and 20 mg. This dose-response curve has been compared with historical controls who received atenolol, oxprenolol, practolol, propranolol and sotalol.
Directory of Open Access Journals (Sweden)
Maria A. Spassova
2015-01-01
Full Text Available We have developed a kinetic model to investigate how DNA repair processes and scavengers of reactive oxygen species (ROS can affect the dose-response shape of prooxidant induced DNA damage. We used as an example chemical KBrO3 which is activated by glutathione and forms reactive intermediates that directly interact with DNA to form 8-hydroxy-2-deoxyguanosine DNA adducts (8-OH-dG. The single strand breaks (SSB that can result from failed base excision repair of these adducts were considered as an effect downstream from 8-OH-dG. We previously demonstrated that, in the presence of effective base excision repair, 8-OH-dG can exhibit threshold-like dose-response dependence, while the downstream SSB can still exhibit a linear dose-response. Here we demonstrate that this result holds for a variety of conditions, including low levels of GSH, the presence of additional SSB repair mechanisms, or a scavenger. It has been shown that melatonin, a terminal scavenger, inhibits KBrO3-caused oxidative damage. Our modeling revealed that sustained exposure to KBrO3 can lead to fast scavenger exhaustion, in which case the dose-response shapes for both endpoints are not substantially affected. The results are important to consider when forming conclusions on a chemical’s toxicity dose dependence based on the dose-response of early genotoxic events.
MONOTONIZATION IN GLOBAL OPTIMIZATION
Institute of Scientific and Technical Information of China (English)
WU ZHIYOU; BAI FUSHENG; ZHANG LIANSHENG
2005-01-01
A general monotonization method is proposed for converting a constrained programming problem with non-monotone objective function and monotone constraint functions into a monotone programming problem. An equivalent monotone programming problem with only inequality constraints is obtained via this monotonization method. Then the existingconvexification and concavefication methods can be used to convert the monotone programming problem into an equivalent better-structured optimization problem.
Blümel, R; Goodman, D S; Kwolek, J M; Smith, W W
2015-01-01
We predict that the steady-state ion number $N_s$ for radio-frequency (rf) traps, loaded at a rate of $\\lambda$ particles per unit time, shows universal non-monotonic behavior as a function of loading rate $\\lambda$. The shape of $N_s(\\lambda)$, characterized by four dynamical regions, is universal in the sense that it is predicted to manifest itself in all rf traps independently of the details of their construction. For $\\lambda\\ll$ 1 particles / rf cycle (Region I), as expected, $N_s(\\lambda)$ increases monotonically with $\\lambda$. However, contrary to intuition, at intermediate $\\lambda \\sim 1$ particles / rf cycle (Region II), $N_s(\\lambda)$ reaches a maximum, followed by a minimum of $N_s(\\lambda)$ (Region III). For $\\lambda\\gg 1$ particles / rf cycle (Region IV), $N_s(\\lambda)$ again rises monotonically. In Region IV numerical simulations, analytical calculations, and experiments show $N_s(\\lambda)\\sim \\lambda^{2/3}$. We confirm this prediction experimentally with MOT-loaded Na$^+$ ions stored in a hyb...
Dose-response relationship in multistage carcinogenesis: promoters.
Kitchin, K T; Brown, J. L.; Setzer, R.W.
1994-01-01
Published dose-response curves of promoters of multistage carcinogenesis were selected that met the combined criteria of long study times, multiple doses, and low doses. In rat liver, 12 dose-response studies of 7 different promoters (phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], clophen A-50 (a polychlorinated biphenyl), alpha-, beta-, and gamma-hexachlorocyclohexane [HCH], and chloroform) were selected. These promoters were studied for 7-86 weeks and either altered hepatic foci...
Nonlinearity of dose-response functions for carcinogenicity.
Hoel, D G; Portier, C J
1994-01-01
Carcinogenesis data for 315 chemicals were obtained from the National Cancer Institute-National Toxicology Program (NCI-NTP) bioassay programs and were analyzed to examine the shape of carcinogenesis dose-response curves. Tumor site data were more often consistent with a quadratic response than with a linear response, suggesting that the routine use of linear dose-response models will often overestimate risk. Information from in vivo short-term mutagenicity and genotoxicity assays was also ob...
Directory of Open Access Journals (Sweden)
S.J.P. Carvalho
2005-09-01
Full Text Available O objetivo deste trabalho foi avaliar o controle de dois fluxos de emergência das plantas daninhas capim-marmelada (Brachiaria plantaginea e capim-colchão (Digitaria horizontalis pelo herbicida imazapic, aplicado em condição de pré-emergência, por meio de curvas de dose-resposta. O delineamento experimental foi o de blocos ao acaso, com quatro repetições; cada parcela constou de um vaso de 3 L de capacidade, preenchido com solo argiloso, acrescido de sementes de capim-marmelada e capim-colchão. Sendo D a dose recomendada do imazapic (140 g ha-1, os tratamentos foram: 4D, 2D, D, 1/2D, 1/4D, 1/8D, 1/16D e ausência do herbicida. Foram realizadas avaliações visuais de controle aos 30 e 60 dias após a infestação (DAI e de massa seca aos 60 DAI. Após a colheita da biomassa resultante do primeiro fluxo de emergência presente nas parcelas, os vasos foram novamente semeados com as plantas daninhas e foram realizadas novas avaliações de controle aos 30 e 60 dias após reinfestação (DAR e de massa seca aos 60 DAR. A partir dos resultados obtidos, pode-se afirmar que: o imazapic inibiu o desenvolvimento de ambas as plantas daninhas, alcançando resultados superiores a 80% de controle em todas as avaliações, para a dose recomendada, nos dois fluxos de emergência; a eficácia no controle de capim-colchão foi ligeiramente superior à do controle do capim-marmelada; e o herbicida imazapic apresentou-se como uma opção interessante para manejo dessas plantas daninhas.The objective of this work was to evaluate the control of two emergence fluxes of the weeds Brachiaria plantaginea and Digitaria horizontalis by the herbicide imazapic applied under pre-emergence conditions, by analyzing the dose-response curves. The experimental design adopted was randomized blocks, with four replicates, with each plot being a 3L capacity pot, filled with clay soil plus Brachiaria plantaginea and Digitaria horizontalis seeds. Considering D as the
Dose-Response Calculator for ArcGIS
Hanser, Steven E.; Aldridge, Cameron L.; Leu, Matthias; Nielsen, Scott E.
2011-01-01
The Dose-Response Calculator for ArcGIS is a tool that extends the Environmental Systems Research Institute (ESRI) ArcGIS 10 Desktop application to aid with the visualization of relationships between two raster GIS datasets. A dose-response curve is a line graph commonly used in medical research to examine the effects of different dosage rates of a drug or chemical (for example, carcinogen) on an outcome of interest (for example, cell mutations) (Russell and others, 1982). Dose-response curves have recently been used in ecological studies to examine the influence of an explanatory dose variable (for example, percentage of habitat cover, distance to disturbance) on a predicted response (for example, survival, probability of occurrence, abundance) (Aldridge and others, 2008). These dose curves have been created by calculating the predicted response value from a statistical model at different levels of the explanatory dose variable while holding values of other explanatory variables constant. Curves (plots) developed using the Dose-Response Calculator overcome the need to hold variables constant by using values extracted from the predicted response surface of a spatially explicit statistical model fit in a GIS, which include the variation of all explanatory variables, to visualize the univariate response to the dose variable. Application of the Dose-Response Calculator can be extended beyond the assessment of statistical model predictions and may be used to visualize the relationship between any two raster GIS datasets (see example in tool instructions). This tool generates tabular data for use in further exploration of dose-response relationships and a graph of the dose-response curve.
Single toxin dose-response models revisited
Glaholt, SP; Kyker-Snowman, E; Shaw, JR; Chen, CY
2016-01-01
The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of four models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 hours) toxicity tests with mortality as a function of NiCl or CuSO4 toxin. PMID:27847315
Monotone Boolean approximation
Energy Technology Data Exchange (ETDEWEB)
Hulme, B.L.
1982-12-01
This report presents a theory of approximation of arbitrary Boolean functions by simpler, monotone functions. Monotone increasing functions can be expressed without the use of complements. Nonconstant monotone increasing functions are important in their own right since they model a special class of systems known as coherent systems. It is shown here that when Boolean expressions for noncoherent systems become too large to treat exactly, then monotone approximations are easily defined. The algorithms proposed here not only provide simpler formulas but also produce best possible upper and lower monotone bounds for any Boolean function. This theory has practical application for the analysis of noncoherent fault trees and event tree sequences.
Dornbos, Peter; Crawford, Robert B; Kaminski, Norbert E; Hession, Sarah L; LaPres, John J
2016-10-01
The influence of interindividual variability is not typically assessed in traditional toxicological studies. Given that chemical exposures occur in heterogeneous populations, this knowledge gap has the potential to cause undue harm within the realms of public health and industrial and municipal finances. A recent report from the National Research Council (NRC) suggests that when accounting for interindividual variation in responses, traditionally assumed nonlinear dose-response relationships (DRRs) for noncancer-causing endpoints would better be explained with a linear relationship within the low-dose region. To address this knowledge gap and directly test the NRC's assumption, this study focused on assessing the DRR between 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) exposure and immune suppression in a cohort of unique human donors. Human B cells were isolated from 51 individual donors and treated with logarithmically increasing concentrations of TCDD (0-30 nM TCDD). Two endpoints sensitive to TCDD were assessed: (1) number of IgM-secreting B cells and (2) quantity of IgM secreted. The results show that TCDD significantly suppressed both the number of IgM-secreting B cells and the quantity of IgM secreted (P < .05). Statistical model comparisons indicate that the low-dose region of the two DRRs is best explained with a nonlinear relationship. Rather than assuming low-dose linearity for all noncancer-causing DRRs, our study suggests the need to consider the specific mode of action of toxicants and pharmaceuticals during risk-management decision making. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Louisse, J.; de Jong, E.; van de Sandt, J.J.M.; Blaauboer, B.J.; Woutersen, R.A.; Piersma, A.H.; Rietjens, I.M.C.M.; Verwei, M.
2010-01-01
At present, regulatory assessment of systemic toxicity is almost solely performed using animal models. The EU REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for
Energy Technology Data Exchange (ETDEWEB)
Korshunov, A D [S.L. Sobolev Institute for Mathematics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk (Russian Federation)
2003-10-31
Monotone Boolean functions are an important object in discrete mathematics and mathematical cybernetics. Topics related to these functions have been actively studied for several decades. Many results have been obtained, and many papers published. However, until now there has been no sufficiently complete monograph or survey of results of investigations concerning monotone Boolean functions. The object of this survey is to present the main results on monotone Boolean functions obtained during the last 50 years.
Curious cases: Altered dose-response relationships in addiction genetics.
Uhl, George R; Drgonova, Jana; Hall, F Scott
2014-03-01
Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics.
A method to adjust radiation dose-response relationships for clinical risk factors
DEFF Research Database (Denmark)
Appelt, Ane Lindegaard; Vogelius, Ivan R
2012-01-01
Several clinical risk factors for radiation induced toxicity have been identified in the literature. Here, we present a method to quantify the effect of clinical risk factors on radiation dose-response curves and apply the method to adjust the dose-response for radiation pneumonitis for patients...
Bayesian Dose-Response Modeling in Sparse Data
Kim, Steven B.
This book discusses Bayesian dose-response modeling in small samples applied to two different settings. The first setting is early phase clinical trials, and the second setting is toxicology studies in cancer risk assessment. In early phase clinical trials, experimental units are humans who are actual patients. Prior to a clinical trial, opinions from multiple subject area experts are generally more informative than the opinion of a single expert, but we may face a dilemma when they have disagreeing prior opinions. In this regard, we consider compromising the disagreement and compare two different approaches for making a decision. In addition to combining multiple opinions, we also address balancing two levels of ethics in early phase clinical trials. The first level is individual-level ethics which reflects the perspective of trial participants. The second level is population-level ethics which reflects the perspective of future patients. We extensively compare two existing statistical methods which focus on each perspective and propose a new method which balances the two conflicting perspectives. In toxicology studies, experimental units are living animals. Here we focus on a potential non-monotonic dose-response relationship which is known as hormesis. Briefly, hormesis is a phenomenon which can be characterized by a beneficial effect at low doses and a harmful effect at high doses. In cancer risk assessments, the estimation of a parameter, which is known as a benchmark dose, can be highly sensitive to a class of assumptions, monotonicity or hormesis. In this regard, we propose a robust approach which considers both monotonicity and hormesis as a possibility. In addition, We discuss statistical hypothesis testing for hormesis and consider various experimental designs for detecting hormesis based on Bayesian decision theory. Past experiments have not been optimally designed for testing for hormesis, and some Bayesian optimal designs may not be optimal under a
Dose-response aligned circuits in signaling systems.
Yan, Long; Ouyang, Qi; Wang, Hongli
2012-01-01
Cells use biological signal transduction pathways to respond to environmental stimuli and the behavior of many cell types depends on precise sensing and transmission of external information. A notable property of signal transduction that was characterized in the Saccharomyces cerevisiae yeast cell and many mammalian cells is the alignment of dose-response curves. It was found that the dose response of the receptor matches closely the dose responses of the downstream. This dose-response alignment (DoRA) renders equal sensitivities and concordant responses in different parts of signaling system and guarantees a faithful information transmission. The experimental observations raise interesting questions about the nature of the information transmission through DoRA signaling networks and design principles of signaling systems with this function. Here, we performed an exhaustive computational analysis on network architectures that underlie the DoRA function in simple regulatory networks composed of two and three enzymes. The minimal circuits capable of DoRA were examined with Michaelis-Menten kinetics. Several motifs that are essential for the dynamical function of DoRA were identified. Systematic analysis of the topology space of robust DoRA circuits revealed that, rather than fine-tuning the network's parameters, the function is primarily realized by enzymatic regulations on the controlled node that are constrained in limiting regions of saturation or linearity.
Simplified Warfarin Dose-response Pharmacodynamic Models
Kim, Seongho; Gaweda, Adam E.; Wu, Dongfeng; Li, Lang; Shesh N Rai; Brier, Michael E.
2015-01-01
Warfarin is a frequently used oral anticoagulant for long-term prevention and treatment of thromboembolic events. Due to its narrow therapeutic range and large inter-individual dose-response variability, it is highly desirable to personalize warfarin dosing. However, the complexity of the conventional kinetic-pharmacodynamic (K-PD) models hampers the development of the personalized dose management. To avert this challenge, we propose simplified PD models for warfarin dose-response relationshi...
Analytical modelling of regional radiotherapy dose response of lung
Lee, Sangkyu; Stroian, Gabriela; Kopek, Neil; AlBahhar, Mahmood; Seuntjens, Jan; El Naqa, Issam
2012-06-01
Knowledge of the dose-response of radiation-induced lung disease (RILD) is necessary for optimization of radiotherapy (RT) treatment plans involving thoracic cavity irradiation. This study models the time-dependent relationship between local radiation dose and post-treatment lung tissue damage measured by computed tomography (CT) imaging. Fifty-eight follow-up diagnostic CT scans from 21 non-small-cell lung cancer patients were examined. The extent of RILD was segmented on the follow-up CT images based on the increase of physical density relative to the pre-treatment CT image. The segmented RILD was locally correlated with dose distribution calculated by analytical anisotropic algorithm and the Monte Carlo method to generate the corresponding dose-response curves. The Lyman-Kutcher-Burman (LKB) model was fit to the dose-response curves at six post-RT time periods, and temporal change in the LKB parameters was recorded. In this study, we observed significant correlation between the probability of lung tissue damage and the local dose for 96% of the follow-up studies. Dose-injury correlation at the first three months after RT was significantly different from later follow-up periods in terms of steepness and threshold dose as estimated from the LKB model. Dependence of dose response on superior-inferior tumour position was also observed. The time-dependent analytical modelling of RILD might provide better understanding of the long-term behaviour of the disease and could potentially be applied to improve inverse treatment planning optimization.
Non-monotonic dynamics and crosstalk in signaling pathways and their implications for pharmacology
van Wijk, Roeland; Tans, Sander J.; Wolde, Pieter Rein Ten; Mashaghi, Alireza
2015-06-01
Currently, drug discovery approaches commonly assume a monotonic dose-response relationship. However, the assumption of monotonicity is increasingly being challenged. Here we show that for two simple interacting linear signaling pathways that carry two different signals with different physiological responses, a non-monotonic input-output relation can arise with simple network topologies including coherent and incoherent feed-forward loops. We show that non-monotonicity of the response functions has severe implications for pharmacological treatment. Fundamental constraints are imposed on the effectiveness and toxicity of any drug independent of its chemical nature and selectivity due to the specific network structure.
Lou, In Chio; Zhao, Yuchao; Wu, YingJie; Ricci, Paolo F
2012-01-01
The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transforma...
Lou, In Chio; Zhao, Yuchao; Wu, Yingjie; Ricci, Paolo F
2012-01-01
The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency. J-shaped dose response curves have been captured with consideration of cell cycle checkpoint control mechanisms. The simulation results indicate the shape of the dose response curve relates to the behavior of the saddle-node points of the model in the bifurcation diagram. A simplified version of the model in previous work of the authors was used mathematically to analyze behaviors relating to the saddle-node points for the J-shaped dose response curve. It indicates that low-linear energy transfer (LET) is more likely to have a J-shaped dose response curve. This result emphasizes the significance of systems biology approach, which encourages collaboration of multidiscipline of biologists, toxicologists and mathematicians, to illustrate complex cancer-related events, and confirm the biphasic dose-response at low doses.
Biphasic dose response in low level light therapy - an update.
Huang, Ying-Ying; Sharma, Sulbha K; Carroll, James; Hamblin, Michael R
2011-01-01
Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments.
Model identification for dose response signal detection
Bretz, Frank; Dette, Holger; Titoff, Stefanie; Volgushev, Stanislav
2012-01-01
We consider the problem of detecting a dose response signal if several competing regression models are available to describe the dose response relationship. In particular, we re-analyze the MCP-Mod approach from Bretz et al. (2005), which has become a very popular tool for this problem in recent years. We propose an improvement based on likelihood ratio tests and prove that in linear models this approach is always at least as powerful as the MCP-Mod method. This result remains ...
Dose-response analysis using R
DEFF Research Database (Denmark)
Ritz, Christian; Baty, Florent; Streibig, Jens Carl
2015-01-01
Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides...
Dose-response-a challenge for allelopathy?
Belz, Regina G; Hurle, Karl; Duke, Stephen O
2005-04-01
The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.
Guionnet, A
2012-01-01
By solving a free analog of the Monge-Amp\\`ere equation, we prove a non-commutative analog of Brenier's monotone transport theorem: if an $n$-tuple of self-adjoint non-commutative random variables $Z_{1},...,Z_{n}$ satisfies a regularity condition (its conjugate variables $\\xi_{1},...,\\xi_{n}$ should be analytic in $Z_{1},...,Z_{n}$ and $\\xi_{j}$ should be close to $Z_{j}$ in a certain analytic norm), then there exist invertible non-commutative functions $F_{j}$ of an $n$-tuple of semicircular variables $S_{1},...,S_{n}$, so that $Z_{j}=F_{j}(S_{1},...,S_{n})$. Moreover, $F_{j}$ can be chosen to be monotone, in the sense that $F_{j}=\\mathscr{D}_{j}g$ and $g$ is a non-commutative function with a positive definite Hessian. In particular, we can deduce that $C^{*}(Z_{1},...,Z_{n})\\cong C^{*}(S_{1},...,S_{n})$ and $W^{*}(Z_{1},...,Z_{n})\\cong L(\\mathbb{F}(n))$. Thus our condition is a useful way to recognize when an $n$-tuple of operators generate a free group factor. We obtain as a consequence that the q-deforme...
Dose Response of Alanine Detectors Irradiated with Carbon Ion Beams
DEFF Research Database (Denmark)
Herrmann, Rochus; Jäkel, Oliver; Palmans, Hugo
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......-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasi mono energetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties...
Dose response biology: the case of resveratrol.
Calabrese, Edward J; Mattson, Mark P; Calabrese, Vittorio
2010-12-01
Resveratrol often displays hormesis-like biphasic dose responses. This occurs in a broad range of biological models and for numerous endpoints of biomedical interest and public health concern. Recognition of the widespread occurrence of the hormetic nature of many of the responses of resveratrol is important on multiple levels. It can help optimize study design protocols by investigators, create a dose-response framework for better addressing dose-related biological complexities and assist in the development of public health and medical guidance with respect to considerations for what is an optimal dose not just for an agent such as resveratrol, but also for the plethora of agents that also act via hormetic mechanisms.
Modeling Dose-response at Low Dose: A Systems Biology Approach for Ionization Radiation.
Zhao, Yuchao; Ricci, Paolo F
2010-03-18
For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health.
Directory of Open Access Journals (Sweden)
N.D. Kruse
2006-09-01
Full Text Available A metodologia de curvas de resposta e isobologramas, feitos a partir dos I50 gerados pelas curvas, tem sido bastante apregoada na comprovação de sinergismo. O experimento foi conduzido em casa de vegetação, com girassol cultivado em solução nutritiva (Hoagland, aplicando-se na solução 27 tratamentos, com os herbicidas metribuzin nas doses de 0, 70, 140, 280, 560 e 1.130 nM e clomazone nas doses de 0, 40, 80, 160, 320 e 640 mM. Combinaram-se as doses dos herbicidas de maneira a produzir os I50 das seis curvas resultantes das associações. Nas plantas coletadas, cinco dias após a aplicação, determinou-se o percentual de dano, a massa fresca e a massa seca das plantas de girassol. Os seis pontos de I50 de cada variável foram utilizados para formar isobologramas, onde os I50 dos herbicidas aplicados isolados, unidos por uma reta, formaram a isobole de aditividade. Em torno desta, foram traçadas faixas de confiança, a partir do produto dos intervalos de confiança dos I50 dos herbicidas isolados, dentro das quais se posicionaram os I50 resultantes das associações. Todas as associações situaram-se na região de sinergismo, abaixo da isobole de aditividade, embora com diferentes probabilidades. Na variável massa seca, a associação das doses de clomazone com 140 nM de metribuzin demonstrou probabilidade de, em torno de 90%, ser uma interação sinérgica.The Dose-Response Curve and Isobolograms methodology, based on the I50 generated by curves has been largely recommended to demonstrate synergism. The experiment was conducted in a greenhouse, with sunflower cultivated in nutrient solution (Hoagland, applying in solution 27 treatments, with the herbicides metribuzin, at the rates of 0, 70, 140, 280, 560 and 1,130 nM and clomazone, at the rates of 0, 40, 80, 160, 320 and 640 mM. The herbicide doses were combined so as to produce the I50 of six resulting curves from the matches. Injury percentage, and fresh and dry weight of sunflower
Patient factors that influence warfarin dose response.
White, Pamela J
2010-06-01
Warfarin has long been the mainstay of oral anticoagulation therapy for the treatment and prevention of venous and arterial thrombosis. The narrow therapeutic index of warfarin, and the complex number of factors that influence international normalized ratio (INR) response, makes optimization of warfarin therapy challenging. Determination of the appropriate warfarin dose during initiation and maintenance therapy requires an understanding of patient factors that influence dose response: age, body weight, nutritional status, acute and chronic disease states, and changes in concomitant drug therapy and diet. This review will examine specific clinical factors that can affect the pharmacokinetics and pharmacodynamics of warfarin, as well as the role of pharmacogenetics in optimizing warfarin therapy.
Monotone data visualization using rational trigonometric spline interpolation.
Ibraheem, Farheen; Hussain, Maria; Hussain, Malik Zawwar
2014-01-01
Rational cubic and bicubic trigonometric schemes are developed to conserve monotonicity of curve and surface data, respectively. The rational cubic function has four parameters in each subinterval, while the rational bicubic partially blended function has eight parameters in each rectangular patch. The monotonicity of curve and surface data is retained by developing constraints on some of these parameters in description of rational cubic and bicubic trigonometric functions. The remaining parameters are kept free to modify the shape of curve and surface if required. The developed algorithm is verified mathematically and demonstrated graphically.
Monotone Data Visualization Using Rational Trigonometric Spline Interpolation
Directory of Open Access Journals (Sweden)
Farheen Ibraheem
2014-01-01
Full Text Available Rational cubic and bicubic trigonometric schemes are developed to conserve monotonicity of curve and surface data, respectively. The rational cubic function has four parameters in each subinterval, while the rational bicubic partially blended function has eight parameters in each rectangular patch. The monotonicity of curve and surface data is retained by developing constraints on some of these parameters in description of rational cubic and bicubic trigonometric functions. The remaining parameters are kept free to modify the shape of curve and surface if required. The developed algorithm is verified mathematically and demonstrated graphically.
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 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.
Directory of Open Access Journals (Sweden)
Paula Elaine Diniz dos Reis
2011-02-01
Full Text Available This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98 and 5% concentration (mean = 38.8h, standard deviation = 17.47. Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.En este estudio, se buscó realizar el control de calidad de la muestra de Chamomilla recutita, así como estimar la dosis ideal, para efecto antiinflamatorio, de la infusión de sus inflorescencias, en pacientes con flebitis proveniente de introducción intravenosa periférica de quimioterapia antineoplásica y evaluar la toxicidad de esta infusión en los seres humanos. Se trata de estudio experimental, del tipo curva dosis-respuesta, en el cual fue analizada y comparada la eficacia terapéutica, en cuanto al potencial antiinflamatorio, de diferentes dosis de la infusión de la Chamomilla recutita en 25 pacientes. El tiempo de regresión de la flebitis fue menor para los grupos con concentración 2,5% (promedio = 29,2h, desviación estándar = 8,98 y 5% (promedio = 38,8h, desviación estándar = 17,47 y prácticamente no se observó toxicidad local. Esta investigación contribuye para la innovación de la práctica clínica en enfermería, una vez que sugiere una alternativa para el tratamiento de
Monotone partitions and almost partitions
Bonanzinga, M.; Cammaroto, F.; van Mill, J.; Pansera, B.A.
2014-01-01
In this paper we are interested in monotone versions of partitionability of topological spaces and weak versions thereof. We identify several classes of spaces with these properties by constructing trees of open sets with various properties.
Why Monotonous Repetition is Unsatisfying
Salingaros, Nikos A
2011-01-01
Human beings prefer ordered complexity and not randomness in their environment, a result of our perceptual system evolving to interpret natural forms. We also recognize monotonously repeating forms as unnatural. Although widespread in today's built environment, such forms generate reactions ranging from boredom to unease. Christopher Alexander has introduced rules for generating forms adapted to natural geometries, which show structured variation with multiple symmetries in a hierarchy of scales. It turns out to be impossible to generate monotonously repeating forms by following those rules. As it is highly probable that traditional artifacts, buildings, and cities were created instinctively using a version of the same rules, this is the reason we never find monotonously repeating forms in traditional cultures.
Monotonicity of social welfare optima
DEFF Research Database (Denmark)
Hougaard, Jens Leth; Østerdal, Lars Peter Raahave
2010-01-01
This paper considers the problem of maximizing social welfare subject to participation constraints. It is shown that for an income allocation method that maximizes a social welfare function there is a monotonic relationship between the incomes allocated to individual agents in a given coalition...... (with at least three members) and its participation constraint if and only if the aggregate income to that coalition is always maximized. An impossibility result demonstrates that there is no welfare maximizing allocation method in which agents' individual incomes monotonically increase in society......'s income. Thus, for any such allocation method, there are situations where some agents have incentives to prevent society in becoming richer....
Dose Effects of Ion Beam Exposure on Deinococcus Radiodurans: Survival and Dose Response
Institute of Scientific and Technical Information of China (English)
无
2001-01-01
To explore the survival and dose response of organism for different radiation sources is of great importance in the research of radiobiology. In this study, the survival-dose response of Deinococcus radiodurans (E.coli, as the control) for ultra-violet (UV), γ-rays radiation and ion beam exposure was investigated. The shoulder type of survival curves were found for both UV and γ-ray ionizing radiation, but the saddle type of survival curves were shown for H+ 、 N+( 20keV and 30keV) and Ar+ beam exposure. This dose effect of the survival initially decreased withthe increase in dose and then increased in the high dose range and finally decreased again in thehigher dose range. Our experimental results suggest that D. radiodurans, which is considerablyradio-resistant to UV and x-ray and γ-ray ionizing radiation, do not resist ion beam exposure.
Sünram-Lea, Sandra I; Owen, Lauren; Finnegan, Yvonne; Hu, Henglong
2011-08-01
It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.
Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model.
Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie
2016-10-05
For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 (22α̂)0.50 for 0.020.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 dose-response curve.
A Characterization of Generalized Monotone Normed Cones
Institute of Scientific and Technical Information of China (English)
S.ROMAGUERA; E.A.S(A)NCHEZ-P(E)REZ; O.VALERO
2007-01-01
Let C be a cone and consider a quasi-norm p defined on it. We study the structure of the couple (C, p) as a topological space in the case where the function p is also monotone. We characterize when the topology of a quasi-normed cone can be defined by means of a monotone norm. We also define and study the dual cone of a monotone normed cone and the monotone quotient of a general cone.We provide a decomposition theorem which allows us to write a cone as a direct sum of a monotone subcone that is isomorphic to the monotone quotient and other particular subcone.
Testing Monotonicity of Pricing Kernels
Timofeev, Roman
2007-01-01
In this master thesis a mechanism to test mononicity of empirical pricing kernels (EPK) is presented. By testing monotonicity of pricing kernel we can determine whether utility function is concave or not. Strictly decreasing pricing kernel corresponds to concave utility function while non-decreasing EPK means that utility function contains some non-concave regions. Risk averse behavior is usually described by concave utility function and considered to be a cornerstone of classical behavioral ...
Monotonicity of chi-square test statistics
Ryu, Keunkwan
2003-01-01
This paper establishes monotonicity of the chi-square test statistic. As the more efficient parameter estimator is plugged into the test statistic, the degrees of freedom of the resulting chi-square test statistic monotonically increase.
Dixon, R A; Dey, P M; Murphy, D L; Whitehead, I M
1981-03-01
The induction of L-phenylalanine ammonialyase (PAL, EC 4.3.1.5) and flavanone synthase in French bean cell suspension cultures in response to heat-released elicitor from cell walls of the phytopathogenic fungus Colletotrichum lindemuthianum is highly dependent upon elicitor concentration. The elicitor dose-response curve for PAL induction shows two maxima at around 17.5 and 50 μg elicitor carbohydrate per ml culture, whereas the flavanone synthase response shows one maximum at around 100 μg ml(-1). The PAL response is independent of the elicitor concentration present during the lag phase of enzyme induction; if the initial elicitor concentration is increased after 2 h by addition of extra elicitor, or decreased by dilution of the cultures, the dose response curves obtained reflect the concentration of elicitor present at the time of harvest. PAL induction is not prevented by addition of methyl sugar derivatives to the cultures; α-methyl-D-glucoside, itself a weak elicitor of PAL activity, elicits a multiphasic PAL response when increasing concentrations are added in the presence of Colletotrichum elicitor. Eight fractions with different monosaccharide compositions, obtained from the crude elicitor by gel-filtration, each elicit different dose-responses for PAL induction; the response to unfractionated elicitor is not the sum of the response to the isolated fractions. There is no correlation between the ability of the fractions to induce PAL in the cultures and their ability to act as elicitors of isoflavonoid phytoalexin accumulation in bean hypocotyls.
Dose-response features of neuroprotective agents: an integrative summary.
Calabrese, Edward J
2008-01-01
This article provides an integrative summary of the effects of neuroprotective agents on neuronal survival and neurite outgrowth using primary cell cultures, multiple neuronal cell lines, and astroglial cells. These findings are dealt with in considerable detail in the following three articles (Calabrese, 2008a, 2008b, 2008c) of this series of issues of Critical Reviews in Toxicology. The principal finding is that the overwhelming majority of neuroprotective agents display biphasic dose responses, characterized by modest low-dose enhancement/stimulation and high-dose inhibitory responses. The quantitative features of these dose responses are consistent with the hormetic dose-response model. Mechanisms that account for numerous hormetic dose responses of neuroprotective agents are summarized, as well as the clinical implications of specific experimental findings.
Assembled cross-species perchlorate dose-response data
U.S. Environmental Protection Agency — This data set contains dose-response data for perchlorate exposure in multiple species. These data were assembled from peer-reviewed studies. Species included in...
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...
Directory of Open Access Journals (Sweden)
Paulo Ricardo Nazário Viecili
2009-05-01
diferencias en la PA, el índice de variación (D% y el efecto hipotensor máximo (EHM% entre las sesiones. Los datos estaban expresados por promedio ± desviación estándar, y se utilizó la prueba t y correlación, tomando p BACKGROUND: The effect of exercise on blood pressure (BP is already known; however, the dose-response curve of the hypotensive effect of exercise in hypertensive individuals is yet to be clarified. OBJECTIVE: To evaluate the dose-response curve of the number of sessions that are necessary to cause a hypotensive effect in hypertensive individuals. METHODS: 88 individuals, aged 58 ± 11 years, divided in Experimental group (EG, with 48 that participated in a physical exercise program (PEP, which consisted of 40 minutes of aerobic exercises performed 3x/week, for 3 months, at 70% of the VO2max, and muscular exercises at 40% of the maximal voluntary contraction (MVC and Control Group (CG with 40 individuals that did not participate in the PEP. The systolic (SAP and diastolic (DAP arterial pressures were measured before each of the 36 sessions in the EG and assessed by ambulatory blood pressure monitoring (ABPM in the CG. Differences in BP, the variation rate (D% and the maximum hypotensive effect (MHE% were observed between sessions. The data were expressed as means ± SD; the t test and correlation were used, with p<0.05 being considered significant. RESULTS: There was no difference regarding BP values in the CG. The EG showed an important decrease of 15 mmHg in SAP and 7 mmHg in DAP, with a large part of this effect occurring as early as the first session and the majority up to the 5th session. There was a strong inverse correlation (R:-0.66 with the number of sessions. CONCLUSION: An important hypotensive effect was observed from the 1st session on and it was observed that the dose-response curve can be abrupt and decrescent, instead of flat.
Some Generalizations of Monotonicity Condition and Applications
Institute of Scientific and Technical Information of China (English)
虞旦盛; 周颂平
2006-01-01
@@ O Introduction It is well known that there are a great number of interesting results in Fourier analysis established by assuming monotonicity of coefficients, and many of them have been generalized by loosing the condition to quasi-monotonicity, O-regularly varying quasi-monotonicity, etc..
DEFF Research Database (Denmark)
Nielson, Hanne Riis; Nielson, Flemming
2009-01-01
The calculus of communicating systems, CCS, was introduced by Robin Milner as a calculus for modelling concurrent systems. Subsequently several techniques have been developed for analysing such models in order to get further insight into their dynamic behaviour. In this paper we present a static...... analysis for approximating the control structure embedded within the models. We formulate the analysis as an instance of a monotone framework and thus draw on techniques that often are associated with the efficient implementation of classical imperative programming languages. We show how to construct...
Dose response on the 110 °C thermoluminescence peak of un-heated, synthetic Merck quartz
Energy Technology Data Exchange (ETDEWEB)
Kaya Keleş, Şule, E-mail: sule.kaya@ankara.edu.tr; Meriç, Niyazi; Polymeris, George S.
2016-07-15
Studies on 110 °C TL peak have been carried out using natural quartz from different origins and synthetic quartz produced by different suppliers. The interest in quartz is due to its usage in dating and retrospective dosimetry as a main material; both synthetic and natural types of quartz yield the 110 °C TL peak in their glow curve. In most studies to understand the physical mechanism behind the TL system, synthetic quartz samples are used and there are many investigations about dose response, in both low and high radiation dose region. In these studies generally synthetic quartz samples produced by Sawyer Research Products are used and the studies showed that both heated and un-heated synthetic quartz samples have intense supra-linear responses. Supra-linearity was enhanced by applying a pre-irradiation while several models have been developed towards an explanation to these supra-linearity effects. In this study commercially available synthetic Merck quartz was used. Different combinations of optical filters were used to obtain dose response curves upto 266 Gy and the effect of pre-dose to these dose response curves was studied. Un-pre-dosed Merck quartz samples dose supra-linearity index is below 1 independently on the optical filters; so Merck quartz showed linear or sub-linear dose response.
Pseudomonas aeruginosa dose response and bathing water infection.
Roser, D J; van den Akker, B; Boase, S; Haas, C N; Ashbolt, N J; Rice, S A
2014-03-01
Pseudomonas aeruginosa is the opportunistic pathogen mostly implicated in folliculitis and acute otitis externa in pools and hot tubs. Nevertheless, infection risks remain poorly quantified. This paper reviews disease aetiologies and bacterial skin colonization science to advance dose-response theory development. Three model forms are identified for predicting disease likelihood from pathogen density. Two are based on Furumoto & Mickey's exponential 'single-hit' model and predict infection likelihood and severity (lesions/m2), respectively. 'Third-generation', mechanistic, dose-response algorithm development is additionally scoped. The proposed formulation integrates dispersion, epidermal interaction, and follicle invasion. The review also details uncertainties needing consideration which pertain to water quality, outbreaks, exposure time, infection sites, biofilms, cerumen, environmental factors (e.g. skin saturation, hydrodynamics), and whether P. aeruginosa is endogenous or exogenous. The review's findings are used to propose a conceptual infection model and identify research priorities including pool dose-response modelling, epidermis ecology and infection likelihood-based hygiene management.
On the sample monotonization problem
Takhanov, R. S.
2010-07-01
The problem of finding a maximal subsample in a training sample consisting of the pairs “object-answer” that does not violate monotonicity constraints is considered. It is proved that this problem is NP-hard and that it is equivalent to the problem of finding a maximum independent set in special directed graphs. Practically important cases in which a partial order specified on the set of answers is a complete order or has dimension two are considered in detail. It is shown that the second case is reduced to the maximization of a quadratic convex function on a convex set. For this case, an approximate polynomial algorithm based on linear programming theory is proposed.
Wilson, Ander; Reif, David M; Reich, Brian J
2014-03-01
High-throughput screening (HTS) of environmental chemicals is used to identify chemicals with high potential for adverse human health and environmental effects from among the thousands of untested chemicals. Predicting physiologically relevant activity with HTS data requires estimating the response of a large number of chemicals across a battery of screening assays based on sparse dose-response data for each chemical-assay combination. Many standard dose-response methods are inadequate because they treat each curve separately and under-perform when there are as few as 6-10 observations per curve. We propose a semiparametric Bayesian model that borrows strength across chemicals and assays. Our method directly parametrizes the efficacy and potency of the chemicals as well as the probability of response. We use the ToxCast data from the U.S. Environmental Protection Agency (EPA) as motivation. We demonstrate that our hierarchical method provides more accurate estimates of the probability of response, efficacy, and potency than separate curve estimation in a simulation study. We use our semiparametric method to compare the efficacy of chemicals in the ToxCast data to well-characterized reference chemicals on estrogen receptor α (ERα) and peroxisome proliferator-activated receptor γ (PPARγ) assays, then estimate the probability that other chemicals are active at lower concentrations than the reference chemicals.
IncucyteDRC: An R package for the dose response analysis of live cell imaging data
Philip J. Chapman; Dominic I. James; Amanda J. Watson; Hopkins, Gemma V.; Waddell, Ian D.; Ogilvie, Donald J.
2016-01-01
We present IncucyteDRC, an R package for the analysis of data from live cell imaging cell proliferation experiments carried out on the Essen Biosciences IncuCyte ZOOM instrument. The package provides a simple workflow for summarising data into a form that can be used to calculate dose response curves and EC50 values for small molecule inhibitors. Data from different cell lines, or cell lines grown under different conditions, can be normalised as to their doubling time. A simple graphical web ...
Institute of Scientific and Technical Information of China (English)
陈锡明; 闻大翔; 杭燕南; 孙大金
2005-01-01
Objective To investigate the effect of succinylcholine on the dose-response relationship of subsequently administered rocuronium in healthy patients. Methods Forty-eight ASA physical status Ⅰ-Ⅱ patients,aged 17 -65 years, scheduled for elective general surgery, were randomly assigned to either the rocuronium treatment group (R) or succinylcholine-rocuronium treatment group (SR). General anesthesia was induced with thiopental 4 to 6mg/kg and fentanyl 2 to 5μg/kg intravenously and maintained with 60% nitrous oxide in oxygen. Additional doses of thiopental or fentanyl were administered as required. The dose-response relationship of rocuronium was determined by the single dose-response technique. In R group ( n =24) , rocuronium was given after induction of anesthesia. In SR group (n =24 ) , patients were intubated after 1.5mg/kg of succinylcholine and rocuronium was given after the complete recovery of neuromuscular blockade from succinylcholine. Patients were further randomly divided into 4 subgroups receiving 150, 200, 250 or 300μg/kg of rocuronium respectively in both groups. Neuromuscular function was assessed accelographically with train-of-four (TOF) stimulation at the wrist every 12s (using the TOF Guard(R) accelerometer). The relationship between probit-tranformed percentage depression of first twitch height (Th) of train-of-four stimulation and logarithm dose of rocuronium was analyzed using linear regression.Results The dose-response curve of rocuronium after succinylcholine was shifted to the left in a parallel fashion compared with that of rocuronium given alone. ED50 and ED95 of rocuronium were 193 ±69 and 367 ± 73μg/kg respectively in R group, and 158 ± 35 and 317 ± 80μg/kg respectively in SR group ( P ＜ 0. 05 ). Conclusion Succinylcholine shifts the dose-response curve of rocuronium to the left and potentiates the effects of the neuromuscular blockade by about 15% of subsequently administered rocuronium. Lower doses of rocuronium are
Design methods for some dose-response models
Albers, Willem/Wim; Strijbosch, Leo W.G.; Does, Ronald J.M.M.
1990-01-01
A recently described design method for one-parameter biomedical models such as limiting or serial dilution assays is generalized to two-parameter models for which the dose-response relationship can be expressed as a linear regression model with parameters α (intercept) and β (slope). Design formulae
Radiation Dose-Response Relationships and Risk Assessment
Energy Technology Data Exchange (ETDEWEB)
Strom, Daniel J.
2005-07-05
The notion of a dose-response relationship was probably invented shortly after the discovery of poisons, the invention of alcoholic beverages, and the bringing of fire into a confined space in the forgotten depths of ancient prehistory. The amount of poison or medicine ingested can easily be observed to affect the behavior, health, or sickness outcome. Threshold effects, such as death, could be easily understood for intoxicants, medicine, and poisons. As Paracelsus (1493-1541), the 'father' of modern toxicology said, 'It is the dose that makes the poison.' Perhaps less obvious is the fact that implicit in such dose-response relationships is also the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of
Monotonic Allocation Schemes in Clan Games
Voorneveld, M.; Tijs, S.H.; Grahn, S.
2000-01-01
Total clan games are characterized using monotonicity, veto power of the clan members, and a concavity condition reflecting the decreasing marginal contribution of non-clan members to growing coalitions.This decreasing marginal contribution is incorporated in the notion of a bi-monotonic allocation
Monotone models for prediction in data mining
Velikova, M.V.
2006-01-01
This dissertation studies the incorporation of monotonicity constraints as a type of domain knowledge into a data mining process. Monotonicity constraints are enforced at two stages¿data preparation and data modeling. The main contributions of the research are a novel procedure to test the degree of
Monotonic Stable Solutions for Minimum Coloring Games
Hamers, H.J.M.; Miquel, S.; Norde, H.W.
2011-01-01
For the class of minimum coloring games (introduced by Deng et al. (1999)) we investigate the existence of population monotonic allocation schemes (introduced by Sprumont (1990)). We show that a minimum coloring game on a graph G has a population monotonic allocation scheme if and only if G is (P4,
Monotonicity-preserving linear multistep methods
Hundsdorfer, W.; Ruuth, S.J.; Spiteri, R.J.
2002-01-01
In this paper we provide an analysis of monotonicity properties for linear multistep methods. These monotonicity properties include positivity and the diminishing of total variation. We also pay particular attention to related boundedness properties such as the total-variation-bounded (TVB) property
Version Spaces and Generalized Monotone Boolean Functions
J.C. Bioch (Cor); T. Ibaraki
2002-01-01
textabstractWe consider generalized monotone functions f: X --> {0,1} defined for an arbitrary binary relation <= on X by the property x <= y implies f(x) <= f(y). These include the standard monotone (or positive) Boolean functions, regular Boolean functions and other interesting functions as speci
Version Spaces and Generalized Monotone Boolean Functions
J.C. Bioch (Cor); T. Ibaraki
2002-01-01
textabstractWe consider generalized monotone functions f: X --> {0,1} defined for an arbitrary binary relation <= on X by the property x <= y implies f(x) <= f(y). These include the standard monotone (or positive) Boolean functions, regular Boolean functions and other interesting functions as
Monotone Hurwitz numbers in genus zero
Goulden, I P; Novak, Jonathan
2012-01-01
Hurwitz numbers count branched covers of the Riemann sphere with specified ramification data, or equivalently, transitive permutation factorizations in the symmetric group with specified cycle types. Monotone Hurwitz numbers count a restricted subset of the branched covers counted by the Hurwitz numbers, and have arisen in recent work on the the asymptotic expansion of the Harish-Chandra-Itzykson-Zuber integral. In this paper we begin a detailed study of monotone Hurwitz numbers. We prove two results that are reminiscent of those for classical Hurwitz numbers. The first is the monotone join-cut equation, a partial differential equation with initial conditions that characterizes the generating function for monotone Hurwitz numbers in arbitrary genus. The second is our main result, in which we give an explicit formula for monotone Hurwitz numbers in genus zero.
Bayesian multimodel inference for dose-response studies
Link, W.A.; Albers, P.H.
2007-01-01
Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.
Model Averaging Software for Dichotomous Dose Response Risk Estimation
Directory of Open Access Journals (Sweden)
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.
Using machine learning to model dose-response relationships.
Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K
2016-12-01
Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.
Characterization of a developmental toxicity dose-response model.
Faustman, E M; Wellington, D G; Smith, W P; Kimmel, C A
1989-01-01
The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included ...
Linearity of dose-response relationships for human carcinogenic exposures
Energy Technology Data Exchange (ETDEWEB)
Smith, A.H. (Univ. of California, Berkeley (USA))
The shape of dose-response relationships is a critical factor in considering cancer risks for the work place and environmental exposure to carcinogens. Markedly different risk estimates result from assumptions of linearity versus sublinear and threshold assumptions. This paper presents evidence that the relationship between the relative risk of development of cancer and the dose rate to carcinogenic exposures is frequently linear with no evidence for thresholds. Dose-response relationships from four studies of asbestos and lung cancer were examined, all of which were consistent with a linear relationship. Analysis of the relationship between the relative risk of lung cancer and exposure to nickel in a smelter study, selected because of relatively good exposure data, demonstrated a close agreement with a linear relationship. The relationship between the level of arsenic in drinking wter and the prevalence of skin cancer also was linear for males in the highest prevalence age group in Taiwan, although there was some evidence of sublinearity for females and younger persons. Also, the relationships between the number of cigarettes smoked per day and the relative risk of lung cancer was very close to linear in many studies. The analysis of these and other studies involving human exposure to carcinogens provides empirical evidence for linearity when the response variable is a rate ratio measure, rather than a risk difference measure. Linearity in dose-response is biologically plausible, without invoking a one-hit model. Except in special circumstances. the epidemiological evidence supports linear extrapolation of cancer relative risks.
The dose-response relationship for cardiovascular disease is not necessarily linear.
Schneider, Uwe; Ernst, Marina; Hartmann, Matthias
2017-04-27
The probability for a complication after radiotherapy is usually a function of dose and volume in the organ or tissue of interest. In most epidemiological studies the risk for a complication is stratified in terms of dose, but not irradiated volume. We show that the obtained risk cannot generally be applied to radiotherapy patients.The epidemiological data of Darby et al. (N Engl J Med 368:2527, 2013) who found a linear relationship between the excess relative risk of major coronary events as function of mean heart dose in patients treated with tangential breast irradiation are analyzed. We have used the relative seriality model for a partly irradiated heart ("a lot to a little") which models radiation therapy using two tangential fields. The relative seriality model was then used to predict NTCP of cardiovascular disease for a homogenously irradiated heart ("a little to a lot"). The relative seriality model was fitted to the data of Darby et al. (N Engl J Med 368:2527, 2013) for tangential breast irradiation. For the situation "a little to a lot" it was found that the dose-response relationship is sigmoidal and contradicts the findings of Darby et al. (N Engl J Med 368:2527, 2013). It was shown in this work that epidemiological studies which predict a linear dose-response relationship for cardiovascular disease can be reproduced by bio-physical models for normal tissue complication. For irradiation situations which were not included in the epidemiological studies, e.g. a homogenous irradiation of the heart ("a little to a lot") the dose-response curve can be different. This could have consequences whether or not IMRT should be used for treating breast cancer. We believe that the results of epidemiological studies should not be generally used to predict normal tissue complications. It is better to use such data to optimize bio-physical models which can then be applied (with caution) to general treatment situations.
Breastfeeding Mode and Risk of Breast Cancer: A Dose-Response Meta-Analysis.
Unar-Munguía, Mishel; Torres-Mejía, Gabriela; Colchero, M Arantxa; González de Cosío, Teresita
2017-05-01
Breastfeeding reduces women's risk of breast cancer. Since exclusive breastfeeding has a stronger hormonal effect, it could theoretically result in a greater reduction in breast cancer risk than any breastfeeding mode. No meta-analysis has examined breast cancer risk by breastfeeding mode. Research aim: The authors conducted a meta-analysis for breast cancer risk in parous women who breastfed exclusively or in any mode versus parous women who formula fed their infants, and they estimated the summary dose-response association by the accumulated duration of any breastfeeding mode. A systematic review of studies published between 2005 and 2015 analyzing breastfeeding and breast cancer risk in women was conducted in PubMed and EBSCOhost. A meta-analysis ( n = 65 studies) with fixed effects (or random effects, if heterogeneity existed) was carried out stratified by breastfeeding mode and menopausal and parity status. A summary dose-response association was estimated using the generalized least-squares method. The summary relative risk (SRR) for breast cancer in parous women who breastfed exclusively was 0.72, 95% confidence interval (CI) [0.58, 0.90], versus parous women who had never breastfed. For parous women who breastfed in any mode, the SRR was lower in both premenopausal women (0.86, 95% CI [0.80, 0.93]) and postmenopausal women (0.89, 95% CI [0.83, 0.95]). There was no heterogeneity or publication bias. There is weak evidence of a difference between exclusive and any breastfeeding mode ( p = .08). The summary dose-response curve was nonlinear ( p < .001). Exclusive breastfeeding among parous women reduces the risk of breast cancer compared with parous women who do not breastfeed exclusively.
Viable harvest of monotone bioeconomic models
De Lara, Michel; Cabrera, Hector Ramirez
2009-01-01
Some monospecies age class models, as well as specific multi-species models (with so-called technical interactions), exhibit useful monotonicity properties. This paper deals with discrete time monotone bioeconomics dynamics in the presence of state and control constraints. In practice, these latter ``acceptable configurations'' represent production and preservation requirements to be satisfied for all time, and they also possess monotonicity properties. A state $\\state$ is said to belong to the viability kernel if there exists a trajectory, of states and controls, starting from $\\state$ and satisfying the constraints. Under monotonicity assumptions, we present upper and lower estimates of the viability kernel. This helps delineating domains where a viable management is possible. Numerical examples, in the context of fisheries management, for the Chilean sea bass (\\emph{Dissostichus eleginoides}) and Alfonsino (\\emph{Beryx splendens}) are given.
Hyperbolic monotonicity in the Hilbert ball
Directory of Open Access Journals (Sweden)
Reich Simeon
2006-01-01
Full Text Available We first characterize -monotone mappings on the Hilbert ball by using their resolvents and then study the asymptotic behavior of compositions and convex combinations of these resolvents.
Dual effects of phytoestrogens result in u-shaped dose-response curves.
Almstrup, Kristian; Fern??ndez, Mariana F.; Petersen, J??rgen; Olea, Nicol??s; Skakkeb??k, Niels; Leffers, Henrik
2002-01-01
Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay that simultaneously detects aromatase inhibition and estrogenicity. The principle is similar to that of other MCF-7 estrogenicity assays, but with a fixed amount of testosterone added. The endogenous...
Dual effects of phytoestrogens result in u-shaped dose-response curves
DEFF Research Database (Denmark)
Almstrup, Kristian; Fernández, Mariana F; Petersen, Jørgen H
2002-01-01
Endocrine disruptors can affect the endocrine system without directly interacting with receptors, for example, by interfering with the synthesis or metabolism of steroid hormones. The aromatase that converts testosterone to 17beta-estradiol is a possible target. In this paper we describe an assay...
Outliers on the dose-response curve: if the problem is not concentration, then what?
Preskorn, Sheldon H
2013-11-01
This column addresses the two primary reasons some patients do not respond as usual to a medication. Such patients may not benefit either because they are uniquely sensitive to the adverse effects of the drug and/or because the drug does not work on the correct mechanism of action to treat the illness. This column explains and reviews these concepts and provides a rationale for using such information prospectively to increase the likelihood of an optimal outcome with the prescribed treatment.
Elahi, Behzad; Hutchison, William D; Daskalakis, Z Jeff; Gunraj, Carolyn; Chen, Robert
2014-02-01
Associative plasticity is hypothesized to be an important neurophysiological correlate of memory formation and learning with potentials for applications in neurorehabilitation and for the development of new electrophysiological measures to study disorders of cortical plasticity. We hypothesized that the magnitude of the paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like effect depends on the number of pairs in the PAS protocol. We also hypothesized that homeostatic interaction of PAS with subsequent motor learning is related to the magnitude of the PAS-induced LTP-like effect. We studied 10 healthy subjects. In experiment 1a, subjects received 90 (PAS90), 180 (PAS180), or 270 (PAS270) pairs of stimuli, followed by a dynamic motor practice (DMP) 1 h after the end of the PAS protocols. In experiment 1b, the DMP preceded the PAS protocol. In experiment 2, the time course of PAS270 was studied. We found that PAS270 resulted in greater increase in motor evoked potential (MEP) amplitude compared with protocols with fewer pairs of stimuli. Moreover, the interaction between PAS protocols with motor learning differed depending on the number of stimulus pairs used to induce PAS. While DMP alone increased MEP amplitudes, DMP during the LTP-like effects induced by PAS270 led to a long-term depression (LTD)-like effect (homeostatic interaction). This homeostatic interaction did not occur after PAS90 and PAS180. In conclusion, we found a dose-dependent effect of the number of stimulus pairs used in the PAS protocol on cortical plasticity. Homeostatic interaction between PAS and DMP was observed only after PAS270.
Martini and Habeck (2014) correctly describe the conceptual simulation model of Byers (2013) where molecules in an odor filament pass by an antenna causing an electrophysiological antennographic (EAG) response that is proportional to how many of the receptors are hit at least once by a molecule. Inc...
The U-shaped dose-response curve of alpha-ergocryptine. Risk assessment ergot alkaloids
Janssen GB; Boink ABTJ; Niesink RJM; Beekhof PK; Beems RB; te Biesebeek JD; van Egmond HP; Elvers LH; Jansen van ' t Land C; van Loenen HA; Schot C; Sizoo EA; Timmerman A; CSR; LEO; Open Universiteit; LPI; ARO; LIS; CDL
1998-01-01
In een voorgaand subacuut toxiciteits experiment met alpha- ergocryptine werd een U-vormige dosis respons relatie waargenomen voor voedselinname en enkele andere parameters. Weer andere parameters waren beinvloed op een dosis afhankelijke wijze. Een kwalitatieve risico beoordeling voor ergot alkal
The U-shaped dose-response curve of alpha-ergocryptine. Risk assessment ergot alkaloids
Janssen GB; Boink ABTJ; Niesink RJM; Beekhof PK; Beems RB; te Biesebeek JD; van Egmond HP; Elvers LH; Jansen van ' t Land C; van Loenen HA; Schot C; Sizoo EA; Timmerman A; CSR; LEO; Open Universiteit; LPI; ARO; LIS; CDL
1998-01-01
In een voorgaand subacuut toxiciteits experiment met alpha- ergocryptine werd een U-vormige dosis respons relatie waargenomen voor voedselinname en enkele andere parameters. Weer andere parameters waren beinvloed op een dosis afhankelijke wijze. Een kwalitatieve risico beoordeling voor ergot
Sütçü, Kerem; Osmanoǧlu, Yunus Emre
2017-02-01
In this study, Electron Paramagnetic Resonance (EPR) spectra of unirradiated and γ-irradiated at doses of 1, 5, 10, 12 and 15 kGy norfloxacin (NOF) were investigated. Before irradiation no EPR signal were observed. After irradiation a weak singlet signal at g = 2.0039 were obtained at room temperature. In order to describe the variation of EPR signal intensity with absorbed radiation dose, several mathematical equations were tried. Increasing irradiation dose up to 15 kGy has increased the signal intensity of the central signal however, no significant changes were observed in g spectroscopic splitting factor. The stability of signal intensity of irradiated NOF was studied over a storage period of 200 days. According to analyses conducted, EPR spectroscopy can be used to distinguish irradiated and unirradiated samples from each other.
Directory of Open Access Journals (Sweden)
Rui-Ru Ji
2009-09-01
Full Text Available The dose response curve is the gold standard for measuring the effect of a drug treatment, but is rarely used in genomic scale transcriptional profiling due to perceived obstacles of cost and analysis. One barrier to examining transcriptional dose responses is that existing methods for microarray data analysis can identify patterns, but provide no quantitative pharmacological information. We developed analytical methods that identify transcripts responsive to dose, calculate classical pharmacological parameters such as the EC50, and enable an in-depth analysis of coordinated dose-dependent treatment effects. The approach was applied to a transcriptional profiling study that evaluated four kinase inhibitors (imatinib, nilotinib, dasatinib and PD0325901 across a six-logarithm dose range, using 12 arrays per compound. The transcript responses proved a powerful means to characterize and compare the compounds: the distribution of EC50 values for the transcriptome was linked to specific targets, dose-dependent effects on cellular processes were identified using automated pathway analysis, and a connection was seen between EC50s in standard cellular assays and transcriptional EC50s. Our approach greatly enriches the information that can be obtained from standard transcriptional profiling technology. Moreover, these methods are automated, robust to non-optimized assays, and could be applied to other sources of quantitative data.
Dose-response plasma appearance of coffee chlorogenic and phenolic acids in adults.
Renouf, Mathieu; Marmet, Cynthia; Giuffrida, Francesca; Lepage, Mélissa; Barron, Denis; Beaumont, Maurice; Williamson, Gary; Dionisi, Fabiola
2014-02-01
Coffee contains phenolic compounds, mainly chlorogenic acids (CGAs). Even though coffee intake has been associated with some health benefits in epidemiological studies, the bioavailability of coffee phenolics is not fully understood. We performed a dose-response study measuring plasma bioavailability of phenolics after drinking three increasing, but still nutritionally relevant doses of instant pure soluble coffee. The study design was a one treatment (coffee) three-dose randomized cross-over design, with a washout period of 2 wks between visits. CGAs, phenolic acids, and late-appearing metabolites all increased with increasing ingested dose. Hence, the sum of area under the curve was significantly higher for the medium to low dose, and high to medium dose, by 2.23- and 2.38-fold, respectively. CGAs were not well absorbed in their intact form, regardless of the dose. CGA and phenolic acids appeared rapidly in plasma, indicating an early absorption in the gastrointestinal tract. Late-appearing metabolites were the most abundant, regardless of the dose. This study confirmed previous findings about coffee bioavailability but also showed that coffee phenolics appear in a positive dose-response manner in plasma when drank at nutritionally relevant doses. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Dose response relationship in local radiotherapy for hepatocellular carcinoma
Energy Technology Data Exchange (ETDEWEB)
Park, Hee Chul; Seong, Jin Sil; Han, Kwang Hyub; Chon, Chae Yoon; Moon, Young Myoung; Song, Jae Seok; Suh, Chang Ok [College of Medicine, Yonsei Univ., Seoul (Korea, Republic of)
2001-06-01
In this study, it was investigated whether dose response relation existed or not in local radiotherapy for primary hepatocellular carcinoma. From January 1992 to March 2000, 158 patients were included in present study. Exclusion criteria included the presence of extrahepatic metastasis, liver cirrhosis of Child's class C, tumors occupying more than two thirds of the entire liver, and performance status on the ECOG scale of more than 3. Radiotherapy was given to the field including tumor with generous margin using 6, 10-MV X-ray. Mean tumor dose was 48.2{+-}7.9 Gy in daily 1.8 Gy fractions. Tumor response was based on diagnostic radiologic examinations such as CT scan, MR imaging, hepatic artery angiography at 4-8 weeks following completion of treatment. Statistical analysis was done to investigate the existence of dose response relationship of local radiotherapy when it was applied to the treatment of primary hepatocellular carcinoma. An objective response was observed in 106 of 158 patients, giving a response rate of 67. 1%. Statistical analysis revealed that total dose was the most significant factor in relation to tumor response when local radiotherapy was applied to the treatment of primary hepatocellular carcinoma. Only 29.2% showed objective response in patients treated with dose less than 40 Gy, while 68.6% and 77.1 % showed major response in patients with 40-50 Gy and more than 50 Gy, respectively. Child-Pugh classification was significant factor in the development of ascites, overt radiation induced liver disease and gastroenteritis. Radiation dose was an important factor for development of radiation induced gastroduodenal ulcer. Present study showed the existence of dose response relationship in local radiotherapy for primary hepatocellular carcinoma. Only radiotherapy dose was a significant factor to predict the objective response. Further study is required to predict the maximal tolerance dose in consideration of liver function and non
Development of a dose-response model for SARS coronavirus.
Watanabe, Toru; Bartrand, Timothy A; Weir, Mark H; Omura, Tatsuo; Haas, Charles N
2010-07-01
In order to develop a dose-response model for SARS coronavirus (SARS-CoV), the pooled data sets for infection of transgenic mice susceptible to SARS-CoV and infection of mice with murine hepatitis virus strain 1, which may be a clinically relevant model of SARS, were fit to beta-Poisson and exponential models with the maximum likelihood method. The exponential model (k= 4.1 x l0(2)) could describe the dose-response relationship of the pooled data sets. The beta-Poisson model did not provide a statistically significant improvement in fit. With the exponential model, the infectivity of SARS-CoV was calculated and compared with those of other coronaviruses. The does of SARS-CoV corresponding to 10% and 50% responses (illness) were estimated at 43 and 280 PFU, respectively. Its estimated infectivity was comparable to that of HCoV-229E, known as an agent of human common cold, and also similar to those of some animal coronaviruses belonging to the same genetic group. Moreover, the exponential model was applied to the analysis of the epidemiological data of SARS outbreak that occurred at an apartment complex in Hong Kong in 2003. The estimated dose of SARS-CoV for apartment residents during the outbreak, which was back-calculated from the reported number of cases, ranged from 16 to 160 PFU/person, depending on the floor. The exponential model developed here is the sole dose-response model for SARS-CoV at the present and would enable us to understand the possibility for reemergence of SARS.
DEFF Research Database (Denmark)
Appelt, A. L.; Ploen, J.; Vogelius, I. R.
2013-01-01
of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect......Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we...... estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination...
Monotone Rank and Separations in Computational Complexity
Li, Yang D
2011-01-01
In the paper, we introduce the concept of monotone rank, and using it as a powerful tool, we obtain several important and strong separation results in computational complexity. We show a super-exponential separation between monotone and non-monotone computation in the non-commutative model, and thus give the answer to a longstanding open problem posed by Nisan \\cite{Nis1991} in algebraic complexity. More specifically, we exhibit a homogeneous algebraic function $f$ of degree $d$ ($d$ even) on $n$ variables with the monotone algebraic branching program (ABP) complexity $\\Omega(n^{d/2})$ and the non-monotone ABP complexity $O(d^2)$. We propose a relaxed version of the famous Bell's theorem\\cite{Bel1964}\\cite{CHSH1969}. Bell's theorem basically states that local hidden variable theory cannot predict the correlations produced by quantum mechanics, and therefore is an impossibility result. Bell's theorem heavily relies on the diversity of the measurements. We prove that even if we fix the measurement, infinite amo...
Linearization of EBT3 film dose response and virtual film dosimetry for SBRT quality assurance
Cai, M.; Archibald-Heeren, B.; Wang, Y.; Metcalfe, P.
2017-01-01
EBT3 film offers high spatial resolution and low energy dependence, making it a suitable choice for quality assurance where high dose gradients are present, such as the case for SBRT. This work presents a simple method to adjust scanner settings so that dose response becomes linear. This linearity eliminates the need to obtain a calibration curve and associated uncertainties in curve fitting. Relative dosimetry can be performed after dose normalization to a reference point. Linearity is also a more robust condition than calibration curve with respect to scanner warm-up conditions, resulting in reduced uncertainty in dose measurement. An in-house developed program reads the film scan and a 2D dose map then constructs both to virtual films using grayscale values. Film intensity value was normalized to dose at reference point. Relative dosimetry was performed by comparing the two resulting images. Patient specific quality assurance was conducted for two SBRT cases. In both plans more than 95% gamma function points passed the gamma criteria of 2%/3mm.
The monotonic and fatigue behavior of CFCCs
Energy Technology Data Exchange (ETDEWEB)
Miriyala, N.; Liaw, P.K.; McHargue, C.J. [Univ. of Tennessee, Knoxville, TN (United States); Snead, L.L. [Oak Ridge National Laboratory, TN (United States)
1996-04-01
Flexure tests were performed to study the fabric orientation effects on the monotonic and fatigue behavior of two commercially available continuous fiber reinforced ceramic composites (CFCCs), namely (i) Nicalon fiber fabric reinforced alumina (Al{sub 2}O{sub 3}) matrix composite fabricated by a direct molten metal oxidation (DIMOX) process and, (ii) Nicalon fiber fabric reinforced silicon carbide (SiC) matrix composite fabricated by an isothermal chemical vapor infiltration (ICVI) process. The fabric orientation effects on the monotonic and fatigue behavior were strong in the Nicalon/Al{sub 2}O{sub 3} composite, while they were relatively weak in the Nicalon/SiC composite.
Weighted monotonicity inequalities for unbounded operators
Hoa, Dinh Trung
2011-01-01
Let $\\tau$ be a faithful normal semifinite trace on a von Neumann algebra $\\mathcal{M}$. For a continuous nonnegative convex monotone nondecreasing function $f$ on convex subset $\\Omega$ of $\\mathbb{R}$ and weight nonnegative Borel function $w$ we consider weighted monotonicity inequalities of the form {equation*} \\tau(w(A)^{1/2}f(A)w(A)^{1/2}) \\le \\tau (w(A)^{1/2}f(B)w(A)^{1/2}), {equation*} where $A$ and $B$ are unbounded operators affiliated with respect to algebra $\\mathcal{M}$.
Alcohol and cirrhosis: dose--response or threshold effect?
DEFF Research Database (Denmark)
Kamper-Jørgensen, Mads; Grønbaek, Morten; Tolstrup, Janne;
2004-01-01
BACKGROUND/AIMS: General population studies have shown a strong association between alcohol intake and death from alcoholic cirrhosis, but whether this is a dose-response or a threshold effect remains unknown, and the relation among alcohol misusers has not been studied. METHODS: A cohort of 6152...... alcohol misusing men and women aged 15-83 were interviewed about drinking pattern and social issues and followed for 84,257 person-years. Outcome was alcoholic cirrhosis mortality. Data was analyzed by means of Cox-regression models. RESULTS: In this large prospective cohort study of alcohol misusers...... there was a 27 fold increased mortality from alcoholic cirrhosis in men and a 35 fold increased mortality from alcoholic cirrhosis in women compared to the Danish population. Number of drinks per day was not significantly associated with death from alcoholic cirrhosis, since there was no additional risk of death...
Dose-response of EBT3 radiochromic films to proton and carbon ion clinical beams
Castriconi, Roberta; Ciocca, Mario; Mirandola, Alfredo; Sini, Carla; Broggi, Sara; Schwarz, Marco; Fracchiolla, Francesco; Martišíková, Mária; Aricò, Giulia; Mettivier, Giovanni; Russo, Paolo
2017-01-01
We investigated the dose-response of the external beam therapy 3 (EBT3) films for proton and carbon ion clinical beams, in comparison with conventional radiotherapy beams; we also measured the film response along the energy deposition-curve in water. We performed measurements at three hadrontherapy centres by delivering monoenergetic pencil beams (protons: 63-230 MeV; carbon ions: 115-400 MeV/u), at 0.4-20 Gy dose to water, in the plateau of the depth-dose curve. We also irradiated the films to clinical MV-photon and electron beams. We placed the EBT3 films in water along the whole depth-dose curve for 148.8 MeV protons and 398.9 MeV/u carbon ions, in comparison with measurements provided by a plane-parallel ionization chamber. For protons, the response of EBT3 in the plateau of the depth-dose curve is not different from that of photons, within experimental uncertainties. For carbon ions, we observed an energy dependent under-response of EBT3 film, from 16% to 29% with respect to photon beams. Moreover, we observed an under-response in the Bragg peak region of about 10% for 148.8 MeV protons and of about 42% for 398.9 MeV/u carbon ions. For proton and carbon ion clinical beams, an under-response occurs at the Bragg peak. For carbon ions, we also observed an under-response of the EBT3 in the plateau of the depth-dose curve. This effect is the highest at the lowest initial energy of the clinical beams, a phenomenon related to the corresponding higher LET in the film sensitive layer. This behavior should be properly modeled when using EBT3 films for accurate 3D dosimetry.
Insulin dose response analysis of free fatty acid kinetics.
Jensen, Michael D; Nielsen, Søren
2007-01-01
Insulin regulation of free fatty acid (FFA) release is an important aspect of metabolic function; however, FFA release is exquisitely sensitive to insulin, which complicates the design and analysis of dose response experiments. We measured FFA ([(3)H]palmitate) and glucose ([(3)H]glucose) kinetics in 7 nonobese men, 7 nonobese women, 7 obese men, and 7 obese women by using a two-step insulin clamp (0.25 and 2.5 mU/kg fat-free mass per minute). Obese men and women were characterized as having a BMI of 28 or greater and body fat of 28% and 40% or greater for men and for women, respectively. Nonobese men and women had 22% and 35% or less body fat, respectively. All volunteers were Caucasian. Glucose disposal increased in a linear fashion with plasma insulin concentrations. The nonlinear suppression of plasma palmitate flux and concentrations could be linearized by logarithmically transforming both the insulin concentration and palmitate axes, except in nonobese men. We repeated the studies in 7 nonobese and 7 obese men, using 1.0 mU/kg fat-free mass per minute as the second insulin dose, which linearized the log-transformed lipolysis measures. The indices of insulin regulation of lipolysis predicted using 2 points (basal and second insulin dose) vs 3 points (basal, low, and high dose) were not different provided the proper second dose was selected. The EC(50) for insulin suppression of lipolysis correlated linearly with plasma triglycerides (r = 0.52, P < .001) and exponentially with insulin sensitivity(glucose) (r = 0.70, P < .001). We conclude that log transformation of insulin dose response data for FFA permits straightforward data analysis and simplifies the estimation of metabolically relevant parameters.
Gentry, P R; Yager, J W; Clewell, R A; Clewell, H J
2014-10-01
In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.
Monotone Comparative Statics for the Industry Composition
DEFF Research Database (Denmark)
Laugesen, Anders Rosenstand
2015-01-01
We let heterogeneous firms face decisions on a number of complementary activities in a monopolistically-competitive industry. The endogenous level of competition and selection regarding entry and exit of firms introduces a wedge between monotone comparative statics (MCS) at the firm level and MCS...
On a Monotone Ill-posed Problem
Institute of Scientific and Technical Information of China (English)
Nguyen BUONG
2005-01-01
A class of a posteriori parameter choice strategies for the operator version of Tikhonovregularization (including variants of Morozov's and Arcangeli's methods) is proposed and used in investigating the rate of convergence of the regularized solution for ill-posed nonlinear equation involving a monotone operator in Banach space.
Population Monotonic Path Schemes for Simple Games
Ciftci, B.B.; Borm, P.E.M.; Hamers, H.J.M.
2006-01-01
A path scheme for a simple game is composed of a path, i.e., a sequence of coalitions that is formed during the coalition formation process and a scheme, i.e., a payoff vector for each coalition in the path.A path scheme is called population monotonic if a player's payoff does not decrease as the pa
Monotone method for nonlinear nonlocal hyperbolic problems
Directory of Open Access Journals (Sweden)
Azmy S. Ackleh
2003-02-01
Full Text Available We present recent results concerning the application of the monotone method for studying existence and uniqueness of solutions to general first-order nonlinear nonlocal hyperbolic problems. The limitations of comparison principles for such nonlocal problems are discussed. To overcome these limitations, we introduce new definitions for upper and lower solutions.
Limit points of the monotonic schemes
Salomon, J
2005-01-01
Many numerical simulations in quantum (bilinear) control use the monotonically convergent algorithms of Krotov (introduced by Tannor), Zhu & Rabitz or the general form of Maday & Turinici. This paper presents an analysis of the limit set of controls provided by these algorithms and a proof of convergence in a particular case.
REGULAR RELATIONS AND MONOTONE NORMAL ORDERED SPACES
Institute of Scientific and Technical Information of China (English)
XU XIAOQUAN; LIU YINGMING
2004-01-01
In this paper the classical theorem of Zareckii about regular relations is generalized and an intrinsic characterization of regularity is obtained. Based on the generalized Zareckii theorem and the intrinsic characterization of regularity, the authors give a characterization of monotone normality of ordered spaces. A new proof of the UrysohnNachbin lemma is presented which is quite different from the classical one.
Monotonicity and bounds on Bessel functions
Directory of Open Access Journals (Sweden)
Larry Landau
2000-07-01
Full Text Available survey my recent results on monotonicity with respect to order of general Bessel functions, which follow from a new identity and lead to best possible uniform bounds. Application may be made to the "spreading of the wave packet" for a free quantum particle on a lattice and to estimates for perturbative expansions.
Strong monotonicity for analytic ordinary differential equations
Directory of Open Access Journals (Sweden)
Sebastian Walcher
2009-09-01
Full Text Available We present a necessary and sufficient criterion for the flow of an analytic ordinary differential equation to be strongly monotone; equivalently, strongly order-preserving. The criterion is given in terms of the reducibility set of the derivative of the right-hand side. Some applications to systems relevant in biology and ecology, including nonlinear compartmental systems, are discussed.
A monotonic archive for pareto-coevolution.
de Jong, Edwin D
2007-01-01
Coevolution has already produced promising results, but its dynamic evaluation can lead to a variety of problems that prevent most algorithms from progressing monotonically. An important open question therefore is how progress towards a chosen solution concept can be achieved. A general solution concept for coevolution is obtained by viewing opponents or tests as objectives. In this setup known as Pareto-coevolution, the desired solution is the Pareto-optimal set. We present an archive that guarantees monotonicity for this solution concept. The algorithm is called the Incremental Pareto-Coevolution Archive (IPCA), and is based on Evolutionary Multi-Objective Optimization (EMOO). By virtue of its monotonicity, IPCA avoids regress even when combined with a highly explorative generator. This capacity is demonstrated on a challenging test problem requiring both exploration and reliability. IPCA maintains a highly specific selection of tests, but the size of the test archive nonetheless grows unboundedly. We therefore furthermore investigate how archive sizes may be limited while still providing approximate reliability. The LAyered Pareto-Coevolution Archive (LAPCA) maintains a limited number of layers of candidate solutions and tests, and thereby permits a trade-off between archive size and reliability. The algorithm is compared in experiments, and found to be more efficient than IPCA. The work demonstrates how the approximation of a monotonic algorithm can lead to algorithms that are sufficiently reliable in practice while offering better efficiency.
Limit properties of monotone matrix functions
Behrndt, Jussi; Hassi, Seppo; de Snoo, Henk; Wietsma, Rudi
2012-01-01
The basic objects in this paper are monotonically nondecreasing n x n matrix functions D(center dot) defined on some open interval l = (a, b) of R and their limit values D(a) and D(b) at the endpoints a and b which are, in general, selfadjoint relations in C-n. Certain space decompositions induced b
Concerns on Monotonic Imbalance Bounding Matching Methods
Yatracos, Yannis G.
2013-01-01
Concerns are expressed for the Monotonic Imbalance Bounding (MIB) property (Iacus et al. 2011) and for MIB matching because i) the definition of the MIB property leads to inconsistencies and the nature of the imbalance measure is not clearly defined, ii) MIB property does not generalize Equal Percent Bias Reducing (EPBR) property, iii) MIB matching does not provide statistical information available with EPBR matching.
Nonparametric confidence intervals for monotone functions
Groeneboom, P.; Jongbloed, G.
2015-01-01
We study nonparametric isotonic confidence intervals for monotone functions. In [Ann. Statist. 29 (2001) 1699–1731], pointwise confidence intervals, based on likelihood ratio tests using the restricted and unrestricted MLE in the current status model, are introduced. We extend the method to the trea
Competitive learning of monotone Boolean functions
2014-01-01
We apply competitive analysis onto the problem of minimizing the number of queries to an oracle to completely reconstruct a given monotone Boolean function. Besides lower and upper bounds on the competitivity we determine optimal deterministic online algorithms for the smallest problem instances.
Nonparametric confidence intervals for monotone functions
Groeneboom, P.; Jongbloed, G.
2015-01-01
We study nonparametric isotonic confidence intervals for monotone functions. In [Ann. Statist. 29 (2001) 1699–1731], pointwise confidence intervals, based on likelihood ratio tests using the restricted and unrestricted MLE in the current status model, are introduced. We extend the method to the
Edit Distance to Monotonicity in Sliding Windows
DEFF Research Database (Denmark)
Chan, Ho-Leung; Lam, Tak-Wah; Lee, Lap Kei
2011-01-01
of a data stream is becoming well-understood over the past few years. Motivated by applications on network quality monitoring, we extend the study to estimating the edit distance to monotonicity of a sliding window covering the w most recent items in the stream for any w ≥ 1. We give a deterministic...
New concurrent iterative methods with monotonic convergence
Energy Technology Data Exchange (ETDEWEB)
Yao, Qingchuan [Michigan State Univ., East Lansing, MI (United States)
1996-12-31
This paper proposes the new concurrent iterative methods without using any derivatives for finding all zeros of polynomials simultaneously. The new methods are of monotonic convergence for both simple and multiple real-zeros of polynomials and are quadratically convergent. The corresponding accelerated concurrent iterative methods are obtained too. The new methods are good candidates for the application in solving symmetric eigenproblems.
Classification Trees for Problems with Monotonicity Constraints
R. Potharst (Rob); A.J. Feelders
2002-01-01
textabstractFor classification problems with ordinal attributes very often the class attribute should increase with each or some of the explaining attributes. These are called classification problems with monotonicity constraints. Classical decision tree algorithms such as CART or C4.5 generally do
Directory of Open Access Journals (Sweden)
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.
Şahiner, Eren
2017-10-01
This paper reports Thermoluminescence (TL) and Optically Stimulated Luminescence (OSL) dose response characteristics of ten different commercial glass samples collected from Turkey. Nowadays, glass samples are widely used mostly in objects of everyday life. The study focuses to both TL and OSL dose responses, through a dose region within 1 and 512Gy. Lowest detectable dose limit (LDDL) as well as the respective linearity features of the corresponding dose response curves were studied for both TL and OSL. Moreover, signal reproducibility and fading behaviors have also been studied in detail. For specific samples, the lowest detectable dose was yielded at 2Gy, making thus these samples appropriate for retrospective dosimetry applications. Nevertheless, based on the features reported in the present study, the majority of the samples could be possibly used effectively for dosimetric applications of higher doses in the UV region emission. Copyright © 2017 Elsevier Ltd. All rights reserved.
Energy Technology Data Exchange (ETDEWEB)
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.
Institute of Scientific and Technical Information of China (English)
王晓琳; 李进; 王知权
2001-01-01
Objective To study dose-response relationship for chromosome translocation and its persistence measured in human lymphocytes exposed to 60Co γ-rays.Methods The chromosome translocations in human peripheral lymphocytes were detected by fluorescence in situ hybridization using 4# and 7# combination of composite whole chromosome-specific DNA probes and Giemsa stain.Results The dose-response relationship for chromosome translocation induced by 60Co γ-rays in vitro could be described by the function:Y=0.0030+0.0134D+0.0165D2.The frequencies of chromosome translocations induced by 0.5 and 2 Gy γ-irradiation did not diminish over time,so it exhibited excellent persistence.Conclusions The results indicate that retrospective dose-reconstruction can be accomplished using chromosome translocation frequency.%目的研究不同剂量60Coγ射线诱发人外周血淋巴细胞染色体易位率和辐射剂量间的剂量效应关系以及观察易位率在同一剂量、不同时相点的变化。方法采用荧光原位杂交技术和连续Giemsa法，用4号和7号全染色体探针分析0、0.25、0.5、0.75、1和2 Gy 60Coγ射线离体照射诱发人外周血淋巴细胞染色体易位率，同时对两个剂量点进行52和72 h培养，比较其易位率。结果易位率和辐射剂量间的量效关系可以用一个二次多项式方程Y＝0.0030+0.0134D+0.0165D2来描述；易位率在52和72 h培养时差异无显著性。结论易位率和辐射剂量间存在良好的量效关系，可作为进行早先照射剂量重建的理论依据。
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.
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.
Monotone operators and "bigger conjugate" functions
Bauschke, Heinz H; Wang, Xianfu; Yao, Liangjin
2011-01-01
We study a question posed by Stephen Simons in his 2008 monograph involving "bigger conjugate" (BC) functions and the partial infimal convolution. As Simons demonstrated in his monograph, these function have been crucial to the understanding and advancement of the state-of-the-art of harder problems in monotone operator theory, especially the sum problem. In this paper, we provide some tools for further analysis of BC--functions which allow us to answer Simons' problem in the negative. We are also able to refute a similar but much harder conjecture which would have generalized a classical result of Br\\'ezis, Crandall and Pazy. Our work also reinforces the importance of understanding unbounded skew linear relations to construct monotone operators with unexpected properties.
Convex functions, monotone operators and differentiability
Phelps, Robert R
1993-01-01
The improved and expanded second edition contains expositions of some major results which have been obtained in the years since the 1st edition. Theaffirmative answer by Preiss of the decades old question of whether a Banachspace with an equivalent Gateaux differentiable norm is a weak Asplund space. The startlingly simple proof by Simons of Rockafellar's fundamental maximal monotonicity theorem for subdifferentials of convex functions. The exciting new version of the useful Borwein-Preiss smooth variational principle due to Godefroy, Deville and Zizler. The material is accessible to students who have had a course in Functional Analysis; indeed, the first edition has been used in numerous graduate seminars. Starting with convex functions on the line, it leads to interconnected topics in convexity, differentiability and subdifferentiability of convex functions in Banach spaces, generic continuity of monotone operators, geometry of Banach spaces and the Radon-Nikodym property, convex analysis, variational princ...
Complexity of Non-Monotonic Logics
Thomas, Michael
2010-01-01
Over the past few decades, non-monotonic reasoning has developed to be one of the most important topics in computational logic and artificial intelligence. Different ways to introduce non-monotonic aspects to classical logic have been considered, e.g., extension with default rules, extension with modal belief operators, or modification of the semantics. In this survey we consider a logical formalism from each of the above possibilities, namely Reiter's default logic, Moore's autoepistemic logic and McCarthy's circumscription. Additionally, we consider abduction, where one is not interested in inferences from a given knowledge base but in computing possible explanations for an observation with respect to a given knowledge base. Complexity results for different reasoning tasks for propositional variants of these logics have been studied already in the nineties. In recent years, however, a renewed interest in complexity issues can be observed. One current focal approach is to consider parameterized problems and ...
Linear Inviscid Damping for Monotone Shear Flows
Zillinger, Christian
2014-01-01
In this article we prove linear stability, inviscid damping and scattering of the 2D Euler equations around regular, strictly monotone shear flows $(U(y),0)$ in a periodic channel under Sobolev perturbations. We treat the settings of an infinite channel, $\\mathbb{T} \\times \\mathbb{R}$, as well as a finite channel, $\\mathbb{T} \\times [0,1]$, with impermeable boundary. We first prove inviscid damping with optimal algebraic rates for strictly monotone shear flows under the assumption of controlling the regularity of the scattered vorticity. Subsequently, we establish linear stability of the scattering equation in Sobolev spaces under perturbations which are of not too large wave-length with respect to $x$, depending on $U''$.
Improved selection in totally monotone arrays
Energy Technology Data Exchange (ETDEWEB)
Mansour, Y. (Harvard Univ., Cambridge, MA (United States). Aiken Computation Lab.); Park, J.K. (Sandia National Labs., Albuquerque, NM (United States)); Schieber, B. (International Business Machines Corp., Yorktown Heights, NY (United States). Thomas J. Watson Research Center); Sen, S. (AT and T Bell Labs., Murray Hill, NJ (United States))
1991-01-01
This paper's main result is an O(({radical}{bar m}lgm)(n lg n) + mlg n)-time algorithm for computing the kth smallest entry in each row of an m {times} n totally monotone array. (A two-dimensional A = a(i,j) is totally monotone if for all i{sub 1} < i{sub 2} and j{sub 1} < j{sup 2}, < a(i{sub 1},j{sub 2}) implies a(i{sub 2},j{sub 1})). For large values of k (in particular, for k=(n/2)), this algorithm is significantly faster than the O(k(m+n))-time algorithm for the same problem due to Kravets and Park. An immediate consequence of this result is an O(n{sup 3/2} lg{sup 2}n)-time algorithm for computing the kth nearest neighbor of each vertex of a convex n-gon. In addition to the main result, we also give an O(n lg m)-time algorithm for computing an approximate median in each row of an m {times} n totally monotone array; this approximate median is an entry whose rank in its row lies between (n/4) and (3n/4) {minus} 1. 20 refs., 3 figs.
Edit Distance to Monotonicity in Sliding Windows
Chan, Ho-Leung; Lee, Lap-Kei; Pan, Jiangwei; Ting, Hing-Fung; Zhang, Qin
2011-01-01
Given a stream of items each associated with a numerical value, its edit distance to monotonicity is the minimum number of items to remove so that the remaining items are non-decreasing with respect to the numerical value. The space complexity of estimating the edit distance to monotonicity of a data stream is becoming well-understood over the past few years. Motivated by applications on network quality monitoring, we extend the study to estimating the edit distance to monotonicity of a sliding window covering the $w$ most recent items in the stream for any $w \\ge 1$. We give a deterministic algorithm which can return an estimate within a factor of $(4+\\eps)$ using $O(\\frac{1}{\\eps^2} \\log^2(\\eps w))$ space. We also extend the study in two directions. First, we consider a stream where each item is associated with a value from a partial ordered set. We give a randomized $(4+\\epsilon)$-approximate algorithm using $O(\\frac{1}{\\epsilon^2} \\log \\epsilon^2 w \\log w)$ space. Second, we consider an out-of-order strea...
Chronic periodontitis and smoking Prevalence and dose-response relationship
Khan, Shahrukh; Khalid, Taimur; Awan, Kamran H.
2016-01-01
Objectives: To determine the prevalence and dose-response relationship of chronic periodontitis among smokers in Pakistan. Methods: This is a cross-sectional study among participants seeking dental care in Karachi Medical and Dental College, Karachi, Pakistan. A total of 443 participants with a mean age of 44.3 (±6.5) participated in the study from April 2011 to December 2011. Males comprised 64.7%, and females comprised 35.2%. Participants were interviewed on social demographics and oral habits. Participants with shallow pockets (3.5-5.5 mm) and deep pockets (>5.5 mm) were considered suffering from chronic periodontitis. The characteristics of participants were assessed using frequency distribution for categorical variables and mean (standard deviation) for continuous variables. Results: Among 443 participants, smokers were distributed as 55.1% and non-smokers as 44.9%. Smoking was found to be significantly related to young adults (p<0.007), male gender (p<0.001), and lower education level (p<0.01). Overall prevalence of chronic periodontitis among smokers was estimated at 81.6%. Heavy smoking was found to have significantly high prevalence (p<0.001) and severity (p<0.001) of periodontitis as compared with moderate and light smokers. The multivariate unadjusted model depicted 3.5 times higher risk of chronic periodontitis among smokers (p<0.001). Conclusion: Chronic periodontitis had a high prevalence among smokers. Heavy smoking was found to have a higher risk for having periodontitis. PMID:27464867
Weak monotonicity inequality and partial regularity for harmonic maps
Institute of Scientific and Technical Information of China (English)
沈尧天; 严树森
1999-01-01
The notion of locally weak monotonicity inequality for weakly harmonic maps is introduced and various results on this class of maps are obtained. For example, the locally weak monotonicity inequality is nearly equivalent to the ε-regularity.
Monotonic Loading of Circular Surface Footings on Clay
DEFF Research Database (Denmark)
Ibsen, Lars Bo; Barari, Amin
2011-01-01
Appropriate modeling of offshore foundations under monotonic loading is a significant challenge in geotechnical engineering. This paper reports experimental and numerical analyses, specifically investigating the response of circular surface footings during monotonic loading and elastoplastic beha...
Ma Shao Gang; Song Yi Xin
2002-01-01
Objective: To study the dose response characteristics and the influence factors such as gantry angle, field size and acquisition mode on the dosimetric response curves, when using a scanning liquid ion-chamber electronic portal imaging device (EPID) for dose verification. Methods: All experiments were carried out on a Varian 600 C/D accelerator (6 MV X-ray) equipped with a Varian PortalVision sup T sup M MK2 type EPID. To obtain the dose response curve, the relationship between the incident radiation intensity to the detector and the pixel value output from the EPID were established. Firstly, the different dose rates of 6 MV X-rays were obtained by varying SSD. Secondly, three digital portal images were acquired for each dose rate using the EPID and averaged to avoid the influence of the dose rate fluctuations of the accelerator. The pixel values of all images were read using self-designed image analysis software, and and average for a region consisting of 11 x 11 pixels around the center was taken as the res...
Carlsen, B C; Fischer, L A; Sosted, H; Vølund, A; Menné, T; Johansen, J D
2009-01-01
It is not known if reduced elicitation thresholds are evident among polysensitized individuals when using allergens to which the patients are already sensitized. Reduced elicitation thresholds may be an expression of increased reactivity in this patient group. To examine and 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. 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. The dose-response curves of the polysensitized group for MDBGN and PPD were shifted to the right, and for nickel sulphate shifted to the left, compared with the single/double-sensitized group. The relative sensitivity for each of the three allergens and a combined relative sensitivity for all three allergens were not significantly different when comparing the polysensitized and single/double-sensitized groups. No increased sensitivity, in the form of distinct elicitation thresholds, could be demonstrated in polysensitized individuals compared with individuals with one or two contact allergies.
A-monotonicity and applications to nonlinear variational inclusion problems
Directory of Open Access Journals (Sweden)
Ram U. Verma
2004-01-01
Full Text Available A new notion of the A-monotonicity is introduced, which generalizes the H-monotonicity. Since the A-monotonicity originates from hemivariational inequalities, and hemivariational inequalities are connected with nonconvex energy functions, it turns out to be a useful tool proving the existence of solutions of nonconvex constrained problems as well.
On the strong monotonicity of the CABARET scheme
Ostapenko, V. V.
2012-03-01
The strong monotonicity of the CABARET scheme with single flux correction is analyzed as applied to the linear advection equation. It is shown that the scheme is strongly monotone (has the NED property) at Courant numbers r ∈ (0,0,5), for which it is monotone. Test computations illustrating this property of the CABARET scheme are presented.
Testing Manifest Monotonicity Using Order-Constrained Statistical Inference
Tijmstra, Jesper; Hessen, David J.; van der Heijden, Peter G. M.; Sijtsma, Klaas
2013-01-01
Most dichotomous item response models share the assumption of latent monotonicity, which states that the probability of a positive response to an item is a nondecreasing function of a latent variable intended to be measured. Latent monotonicity cannot be evaluated directly, but it implies manifest monotonicity across a variety of observed scores,…
Wehrl entropy, Lieb conjecture and entanglement monotones
Mintert, F; Mintert, Florian; Zyczkowski, Karol
2004-01-01
We propose to quantify the entanglement of pure states of $N \\times N$ bipartite quantum system by defining its Husimi distribution with respect to $SU(N)\\times SU(N)$ coherent states. The Wehrl entropy is minimal if and only if the pure state analyzed is separable. The excess of the Wehrl entropy is shown to be equal to the subentropy of the mixed state obtained by partial trace of the bipartite pure state. This quantity, as well as the generalized (R{\\'e}nyi) subentropies, are proved to be Schur--convex, so they are entanglement monotones and may be used as alternative measures of entanglement.
Dose-response relationships and threshold levels in skin and respiratory allergy
Arts, J.H.E.; Mommers, C.; Heer, C.de
2006-01-01
A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well
Buchanan, R.L.; Havelaar, A.H.; Smith, M.A.; Whiting, R.C.; Julien, E.
2009-01-01
The Key Events Dose-Response Framework (KEDRF) is an analytical approach that facilitates the use of currently available data to gain insight regarding dose-response relationships. The use of the KEDRF also helps identify critical knowledge gaps that once filled, will reduce reliance on assumptions.
Health damage of air pollution : an estimate of a dose-response relationship for The Netherlands
Nentjes, A; Schneider, T
1998-01-01
This paper estimates the dose-response relationship between air pollution and the number of work loss days for The Netherlands. The study is based on illness data (work loss days) for the Dutch labor population and average year concentrations of air pollution in 29 districts. The dose-response
Statistical strategies for averaging EC50 from multiple dose-response experiments.
Jiang, Xiaoqi; Kopp-Schneider, Annette
2015-11-01
In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.
The Monotonicity Puzzle: An Experimental Investigation of Incentive Structures
Directory of Open Access Journals (Sweden)
Jeannette Brosig
2010-05-01
Full Text Available Non-monotone incentive structures, which - according to theory - are able to induce optimal behavior, are often regarded as empirically less relevant for labor relationships. We compare the performance of a theoretically optimal non-monotone contract with a monotone one under controlled laboratory conditions. Implementing some features relevant to real-world employment relationships, our paper demonstrates that, in fact, the frequency of income-maximizing decisions made by agents is higher under the monotone contract. Although this observed behavior does not change the superiority of the non-monotone contract for principals, they do not choose this contract type in a significant way. This is what we call the monotonicity puzzle. Detailed investigations of decisions provide a clue for solving the puzzle and a possible explanation for the popularity of monotone contracts.
The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields
Energy Technology Data Exchange (ETDEWEB)
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
Energy Technology Data Exchange (ETDEWEB)
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.
Dose-response relationship of {gamma}-H2AX foci induction in human lymphocytes after X-rays exposure
Energy Technology Data Exchange (ETDEWEB)
Mandina, Tania [Centro de Proteccion e Higiene de las Radiaciones, Calle 20 No. 4113 e/41y 47 Miramar, AP 6195 C. Habana (Cuba); Roch-Lefevre, Sandrine H.; Voisin, Pascale [Institut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, SRBE, LDB, BP17, 92262 Fontenay-aux-Roses (France); Gonzalez, Jorge E.; Lamadrid, Ana I.; Romero, Ivonne [Centro de Proteccion e Higiene de las Radiaciones, Calle 20 No. 4113 e/41y 47 Miramar, AP 6195 C. Habana (Cuba); Garcia, Omar, E-mail: omar@cphr.edu.cu [Centro de Proteccion e Higiene de las Radiaciones, Calle 20 No. 4113 e/41y 47 Miramar, AP 6195 C. Habana (Cuba); Voisin, Philippe; Roy, Laurence [Institut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, SRBE, LDB, BP17, 92262 Fontenay-aux-Roses (France)
2011-09-15
Biological dosimeters are recommended for dose estimation in case of human overexposure to ionising radiation. Rapid measurement of {gamma}-H2AX foci as a marker of DNA double-strand breaks (DSB) induction has been recently tested with this purpose. Here we reported a dose-response relationship after X-ray irradiation at different times post-exposure. Blood samples were obtained from several healthy donors and exposed to doses between 0 and 2 Gy. After irradiation, blood samples were incubated at 37 deg. C during 0.5 h, 5 h, and 8 h. Scoring of cells and {gamma}-H2AX foci was performed by software. The dose-response curves for different incubation times were as follows: Y{sub (0.5h)} = 11.66D + 0.15 (R{sup 2} = 0.99), Y{sub (5h)} = 2.44D + 0.15 (R{sup 2} = 0.99), Y{sub (8h)} = 1.57D + 0.22 (R{sup 2} = 0.99). At 0.5 h post-exposure, the dose-response relationship for X-irradiated lymphocytes was similar to the one obtained after gamma-irradiation using the same protocol. On the other hand, the results were not similar after 8 h due to different kinetics after gamma- and X-irradiation. Our results confirm the possibilities of using {gamma}-H2AX foci method for dose estimation in a period from 0.5 h up to 8 h post X-irradiation and support the hypothesis of differences in {gamma}-H2AX foci kinetics after gamma- and X-irradiation in vitro.
Directory of Open Access Journals (Sweden)
Magdalena Adamus-Górka
2011-05-01
Full Text Available 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 χ2-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.
Convex functions, monotone operators and differentiability
Phelps, Robert R
1989-01-01
These notes start with an introduction to the differentiability of convex functions on Banach spaces, leading to the study of Asplund spaces and their intriguing relationship to monotone operators (and more general set-values maps) and Banach spaces with the Radon-Nikodym property. While much of this is classical, some of it is presented using streamlined proofs which were not available until recently. Considerable attention is paid to contemporary results on variational principles and perturbed optimization in Banach spaces, exhibiting their close connections with Asplund spaces. An introductory course in functional analysis is adequate background for reading these notes which can serve as the basis for a seminar of a one-term graduate course. There are numerous excercises, many of which form an integral part of the exposition.
Generalized convexity, generalized monotonicity recent results
Martinez-Legaz, Juan-Enrique; Volle, Michel
1998-01-01
A function is convex if its epigraph is convex. This geometrical structure has very strong implications in terms of continuity and differentiability. Separation theorems lead to optimality conditions and duality for convex problems. A function is quasiconvex if its lower level sets are convex. Here again, the geo metrical structure of the level sets implies some continuity and differentiability properties for quasiconvex functions. Optimality conditions and duality can be derived for optimization problems involving such functions as well. Over a period of about fifty years, quasiconvex and other generalized convex functions have been considered in a variety of fields including economies, man agement science, engineering, probability and applied sciences in accordance with the need of particular applications. During the last twenty-five years, an increase of research activities in this field has been witnessed. More recently generalized monotonicity of maps has been studied. It relates to generalized conve...
Fischer, Louise Arup; Voelund, Aage; Andersen, Klaus Ejner; Menné, Torkil; Johansen, Jeanne Duus
2009-10-01
Allergic contact dermatitis is common and can be prevented. The relationship between thresholds for patch tests and the repeated open application test (ROAT) is unclear. It would be desirable if patch test and ROAT data from already sensitized individuals could be used in prevention. The aim was to develop an equation that could predict the response to an allergen in a ROAT based on the dose-response curve derived by patch testing. Results from two human experimental elicitation studies with non-volatile allergens, nickel and the preservative methyldibromo glutaronitrile (MDBGN), were analysed by logistic dose-response statistics. The relation for volatile compounds was investigated using the results from experiments with the fragrance chemicals hydroxyisohexyl 3-cyclohexene carboxaldehyde and isoeugenol. For non-volatile compounds, the outcome of a ROAT can be estimated from the patch test by: ED(xx)(ROAT) = 0.0296 ED(xx)(patch test). For volatile compounds, the equation predicts that the response in the ROAT is more severe than the patch test response, but it overestimates the response. This equation may be used for non-volatile compounds other than nickel and MDBGN, after further validation. The relationship between the patch test and the ROAT can be used for prevention, to set safe levels of allergen exposure based on patch test data.
Dose-response of thermoluminescence in natural kaolinite
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Correcher, V., E-mail: v.correcher@ciemat.es [CIEMAT, Av. Complutense, 22, Madrid 28040 (Spain); Garcia-Guinea, J.; Crespo-Feo, E. [Museo Nacional de Ciencias Naturales, CSIC, C. Jose Gutierrez Abascal 2, Madrid 28006 (Spain); Rodriguez-Lazcano, Y. [UCM, Dpto. Fisica de Materiales. Fac. CC. Fisicas. Av. Complutense, Madrid 28040 (Spain); Prado-Herrero, P. [MICINN, Albacete 5, Madrid 28027 (Spain)
2010-05-20
The thermal effect on the luminescence emission of a well-characterized natural kaolinite has been investigated by means of differential thermal analysis (DTA) and thermoluminescence (TL) to determine, respectively, the modifications of the material due to the thermal treatments up to 1000 {sup o}C and its potential use in the field of dating and retrospective dosimetry. The DTA detects water loss starting at 100-120 {sup o}C, a dehydroxylation process in the range of 400-500 {sup o}C and the transformation of kaolinite into metakaolinite at 570 {sup o}C. The dose dependence of the 400 nm TL intensity of kaolinite exhibits an excellent linearity in the range of 50 mGy to 8 Gy. In addition, the stability of the induced TL signal after six months of storage shows an initial rapid decay (ca. 60%) followed by a mild slope reaching the stability longer than six months. The tests of thermal stability at different temperatures allow us to speculate in a continuum of trap distribution with progressive changes in the glow curve shape, intensity and temperature position of the maximum peak. According to this thermal behavior, some physical parameters have been estimated using the initial rise method.
Stability of dynamical systems on the role of monotonic and non-monotonic Lyapunov functions
Michel, Anthony N; Liu, Derong
2015-01-01
The second edition of this textbook provides a single source for the analysis of system models represented by continuous-time and discrete-time, finite-dimensional and infinite-dimensional, and continuous and discontinuous dynamical systems. For these system models, it presents results which comprise the classical Lyapunov stability theory involving monotonic Lyapunov functions, as well as corresponding contemporary stability results involving non-monotonicLyapunov functions.Specific examples from several diverse areas are given to demonstrate the applicability of the developed theory to many important classes of systems, including digital control systems, nonlinear regulator systems, pulse-width-modulated feedback control systems, and artificial neural networks. The authors cover the following four general topics: - Representation and modeling of dynamical systems of the types described above - Presentation of Lyapunov and Lagrange stability theory for dynamical sy...
Stepsize Restrictions for Boundedness and Monotonicity of Multistep Methods
Hundsdorfer, W.
2011-04-29
In this paper nonlinear monotonicity and boundedness properties are analyzed for linear multistep methods. We focus on methods which satisfy a weaker boundedness condition than strict monotonicity for arbitrary starting values. In this way, many linear multistep methods of practical interest are included in the theory. Moreover, it will be shown that for such methods monotonicity can still be valid with suitable Runge-Kutta starting procedures. Restrictions on the stepsizes are derived that are not only sufficient but also necessary for these boundedness and monotonicity properties. © 2011 Springer Science+Business Media, LLC.
On the monotonicity of multidimensional finite difference schemes
Kovyrkina, O.; Ostapenko, V.
2016-10-01
The classical concept of monotonicity, introduced by Godunov for linear one-dimensional difference schemes, is extended to multidimensional case. Necessary and sufficient conditions of monotonicity are obtained for linear multidimensional difference schemes of first order. The constraints on the numerical viscosity are given that ensure the monotonicity of a difference scheme in the multidimensional case. It is proposed a modification of the second order multidimensional CABARET scheme that preserves the monotonicity of one-dimensional discrete solutions and, as a result, ensures higher smoothness in the computation of multidimensional discontinuous solutions. The results of two-dimensional test computations illustrating the advantages of the modified CABARET scheme are presented.
Toward a unified approach to dose-response modeling in ecotoxicology.
Ritz, Christian
2010-01-01
This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.
DEFF Research Database (Denmark)
Christensen, Erik R.; Kusk, Kresten Ole; Nyholm, Niels
2009-01-01
% inhibition). For illustration, data from closed, freshwater algal assays are analyzed using the green alga Pseudokirchneriella subcapitata with growth rate as the response parameter. Dose-response regressions for four test chemicals (tetraethylammonium bromide, musculamine, benzonitrile, and 4...
Dose-response effects of atropine and HI-6 treatment of organophosphorus poisoning in guinea pigs
Energy Technology Data Exchange (ETDEWEB)
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.
DEFF Research Database (Denmark)
Bosch, Ernesto; Nyboe Andersen, Anders; Barri, Pedro
2015-01-01
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 hormones, and no clear dose-related increase was observed for the number of follicles in these patients. CONCLUSIONS: Dose-response relationships between rhFSH and follicular development and endocrine parameters are significantly different for IVF/ICSI patients with lower and higher serum AMH levels......: 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 dose...
Monotone measures of ergodicity for Markov chains
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J. Keilson
1998-01-01
Full Text Available The following paper, first written in 1974, was never published other than as part of an internal research series. Its lack of publication is unrelated to the merits of the paper and the paper is of current importance by virtue of its relation to the relaxation time. A systematic discussion is provided of the approach of a finite Markov chain to ergodicity by proving the monotonicity of an important set of norms, each measures of egodicity, whether or not time reversibility is present. The paper is of particular interest because the discussion of the relaxation time of a finite Markov chain [2] has only been clean for time reversible chains, a small subset of the chains of interest. This restriction is not present here. Indeed, a new relaxation time quoted quantifies the relaxation time for all finite ergodic chains (cf. the discussion of Q1(t below Equation (1.7]. This relaxation time was developed by Keilson with A. Roy in his thesis [6], yet to be published.
Remarks on a monotone Markov chain
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P. Todorovic
1987-01-01
Full Text Available In applications, considerations on stochastic models often involve a Markov chain {ζn}0∞ with state space in R+, and a transition probability Q. For each x R+ the support of Q(x,. is [0,x]. This implies that ζ0≥ζ1≥…. Under certain regularity assumptions on Q we show that Qn(x,Bu→1 as n→∞ for all u>0 and that 1−Qn(x,Bu≤[1−Q(x,Bu]n where Bu=[0,u. Set τ0=max{k;ζk=ζ0}, τn=max{k;ζk=ζτn−1+1} and write Xn=ζτn−1+1, Tn=τn−τn−1. We investigate some properties of the imbedded Markov chain {Xn}0∞ and of {Tn}0∞. We determine all the marginal distributions of {Tn}0∞ and show that it is asymptotically stationary and that it possesses a monotonicity property. We also prove that under some mild regularity assumptions on β(x=1−Q(x,Bx, ∑1n(Ti−a/bn→dZ∼N(0,1.
Robust Monotone Iterates for Nonlinear Singularly Perturbed Boundary Value Problems
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Boglaev Igor
2009-01-01
Full Text Available This paper is concerned with solving nonlinear singularly perturbed boundary value problems. Robust monotone iterates for solving nonlinear difference scheme are constructed. Uniform convergence of the monotone methods is investigated, and convergence rates are estimated. Numerical experiments complement the theoretical results.
Regularization and Iterative Methods for Monotone Variational Inequalities
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Xiubin Xu
2010-01-01
Full Text Available We provide a general regularization method for monotone variational inequalities, where the regularizer is a Lipschitz continuous and strongly monotone operator. We also introduce an iterative method as discretization of the regularization method. We prove that both regularization and iterative methods converge in norm.
LIMITED MEMORY BFGS METHOD FOR NONLINEAR MONOTONE EQUATIONS
Institute of Scientific and Technical Information of China (English)
Weijun Zhou; Donghui Li
2007-01-01
In this paper, we propose an algorithm for solving nonlinear monotone equations by combining the limited memory BFGS method (L-BFGS) with a projection method. We show that the method is globally convergent if the equation involves a Lipschitz continuous monotone function. We also present some preliminary numerical results.
Positivity and Monotonicity Preserving Biquartic Rational Interpolation Spline Surface
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Xinru Liu
2014-01-01
Full Text Available A biquartic rational interpolation spline surface over rectangular domain is constructed in this paper, which includes the classical bicubic Coons surface as a special case. Sufficient conditions for generating shape preserving interpolation splines for positive or monotonic surface data are deduced. The given numeric experiments show our method can deal with surface construction from positive or monotonic data effectively.
Garland, Cedric F; Gorham, Edward D
2017-04-01
Fifteen nested case-control or cohort studies in 14 countries have examined the association between serum 25-hydroxyvitamin D [25(OH)D] and risk of colorectal cancer. A meta-analysis of these studies would provide a useful dose-response gradient curve based on pooling of the results of known studies to date. An up-to-date dose-response curve that combines the findings of these studies has not been reported, to our knowledge. This curve would help in designing interventions for future studies. A new meta-analysis would be more precise than any previous analysis due to its larger sample size. Therefore a search of PubMed and other resources was performed in May 2016 for all cohort or nested case-control observational studies that reported risk of colon or colorectal cancer by quantiles of 25(OH)D. All but two of the 15 studies found a trend toward lower risk of colorectal cancer associated with higher serum 25(OH)D. There was a linear reduction in the odds ratio (OR) with each 10ng/ml-increment in 25(OH)D concentration. The lowest quantile of the serum 25(OH)D concentration was generallyD concentrations was statistically significant in 3 studies. The pooled OR from all studies comparing highest with lowest quantile of 25(OH)D was 0.67 (95% confidence interval [CI], 0.59-0.76), meaning there was a 33% lower risk associated with the highest compared with the lowest quantile of serum 25(OH)D. A dose-response analysis revealed that a serum 25(OH)D of 50ng/ml was associated with an OR of 0.4 (95% CI, 0.2-1.0) compared with a concentration of 5ng/ml. The formula for the linear relationship was OR=0.008x. For example, individuals with a 25(OH)D concentration of 50ng/ml had an approximately 60% lower risk of colorectal cancer than those with a concentration of 5ng/ml. Those with a 25(OH)D concentration of 30ng/ml had a 33% lower risk than those with a concentration of 5ng/ml. The inverse association between serum 25(OH)D and risk of colorectal cancer overall was strong and
Monotone complete C*-algebras and generic dynamics
Saitô, Kazuyuki
2015-01-01
This monograph is about monotone complete C*-algebras, their properties and the new classification theory. A self-contained introduction to generic dynamics is also included because of its important connections to these algebras. Our knowledge and understanding of monotone complete C*-algebras has been transformed in recent years. This is a very exciting stage in their development, with much discovered but with many mysteries to unravel. This book is intended to encourage graduate students and working mathematicians to attack some of these difficult questions. Each bounded, upward directed net of real numbers has a limit. Monotone complete algebras of operators have a similar property. In particular, every von Neumann algebra is monotone complete but the converse is false. Written by major contributors to this field, Monotone Complete C*-algebras and Generic Dynamics takes readers from the basics to recent advances. The prerequisites are a grounding in functional analysis, some point set topology and an eleme...
Schmid, E; Wagner, F M; Romm, H; Walsh, L; Roos, H
2009-02-01
The biological effectiveness of neutrons from the neutron therapy facility MEDAPP (mean neutron energy 1.9 MeV) at the new research reactor FRM II at Garching, Germany, has been analyzed, at different depths in a polyethylene phantom. Whole blood samples were exposed to the MEDAPP beam in special irradiation chambers to total doses of 0.14-3.52 Gy at 2-cm depth, and 0.18-3.04 Gy at 6-cm depth of the phantom. The neutron and gamma-ray absorbed dose rates were measured to be 0.55 Gy min(-1) and 0.27 Gy min(-1) at 2-cm depth, while they were 0.28 and 0.25 Gy min(-1) at 6-cm depth. Although the irradiation conditions at the MEDAPP beam and the RENT beam of the former FRM I research reactor were not identical, neutrons from both facilities gave a similar linear-quadratic dose-response relationship for dicentric chromosomes at a depth of 2 cm. Different dose-response curves for dicentrics were obtained for the MEDAPP beam at 2 and 6 cm depth, suggesting a significantly lower biological effectiveness of the radiation with increasing depth. No obvious differences in the dose-response curves for dicentric chromosomes estimated under interactive or additive prediction between neutrons or gamma-rays and the experimentally obtained dose-response curves could be determined. Relative to (60)Co gamma-rays, the values for the relative biological effectiveness at the MEDAPP beam decrease from 5.9 at 0.14 Gy to 1.6 at 3.52 Gy at 2-cm depth, and from 4.1 at 0.18 Gy to 1.5 at 3.04 Gy at 6-cm depth. Using the best possible conditions of consistency, i.e., using blood samples from the same donor and the same measurement techniques for about two decades, avoiding the inter-individual variations in sensitivity or the differences in methodology usually associated with inter-laboratory comparisons, a linear-quadratic dose-response relationship for the mixed neutron and gamma-ray MEDAPP field as well as for its fission neutron part was obtained. Therefore, the debate on whether the fission
Lack-of-fit tests for assessing mean structures for continuous dose-response data
DEFF Research Database (Denmark)
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 classical methods are inadequate in certain situations, where the new tests may be applied. Power comparisons are carried out by means of extensive simulation studies, covering both designs with and without replicates at small and large sample sizes. Three datasets from dose-response applications illustrate...... differences and similarities between the tests. The results suggest that the new tests perform better and exhibit a wider applicability....
Leenen, F H; Smith, D L; Farkas, R M; Boer, W H; Reeves, R A; Marquez-Julio, A
1988-01-29
Fifteen patients with mild-to-moderate hypertension (10 with normal and five with decreased renal function) were studied after treatment with placebo and low (1 mg), intermediate (2.5 mg), and high (5.0 mg per day) doses of indapamide, each for four weeks. Six patients--five with normal renal function--were classified as nonresponders (decrease in diastolic blood pressure less than 5 mm Hg). The remaining nine patients had dose-related decreases in blood pressure. Patients with or without renal failure showed similar decreases in blood pressure. Blood pressure reduction was associated with a significant decrease in cardiac index in the responders at the highest dose, related to a decrease in left ventricular end-diastolic dimension and stroke volume, whereas heart rate did not increase. This apparent decrease in venous return was associated with a significant decrease in body weight but not plasma volume in the responders. Indapamide did not change plasma norepinephrine levels, but decreased pressor responsiveness to exogenous norepinephrine. Responders had lower initial plasma renin activity and a smaller absolute increase in plasma renin activity while receiving indapamide, whereas angiotensin II pressor responsiveness was decreased more. The results presented indicate that the blood pressure lowering effect of indapamide in the present patient population is observed with or without renal failure and is associated with a decrease in pressor reactivity. In nonresponders, compensatory mechanisms (e.g., renin) may negate the antihypertensive effect of indapamide.
Eits, R.M.; Kwakkel, R.P.; Verstegen, M.W.A.; Hartog, den L.A.
2005-01-01
1. An empirical model of exponential form was developed, different versions of which can be used to predict growth rate, feed conversion and carcase and breast meat yield of broiler chickens as a function of dietary balanced protein ( DBP) content. The model was developed to support decision- making
2002-01-01
The Atlas of Stress-Strain Curves, Second Edition is substantially bigger in page dimensions, number of pages, and total number of curves than the previous edition. It contains over 1,400 curves, almost three times as many as in the 1987 edition. The curves are normalized in appearance to aid making comparisons among materials. All diagrams include metric (SI) units, and many also include U.S. customary units. All curves are captioned in a consistent format with valuable information including (as available) standard designation, the primary source of the curve, mechanical properties (including hardening exponent and strength coefficient), condition of sample, strain rate, test temperature, and alloy composition. Curve types include monotonic and cyclic stress-strain, isochronous stress-strain, and tangent modulus. Curves are logically arranged and indexed for fast retrieval of information. The book also includes an introduction that provides background information on methods of stress-strain determination, on...
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.
The Number of Monotone and Self-Dual Boolean Functions
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Haviarova L.
2014-12-01
Full Text Available In the present paper we study properties of pre-complete class of Boolean functions - monotone Boolean functions. We discuss interval graph, the abbreviated d.n.f., a minimal d.n.f. and a shortest d.n.f. of this function. Then we present a d.n.f. with the highest number of conjunctionsand we determinate the exact number of them. We count the number of monotone Boolean functions with some special properties. In the end we estimate the number of Boolean functionthat are monotone and self-dual at the same time.
Ratio Monotonicity of Polynomials Derived from Nondecreasing Sequences
Chen, William Y C; Zhou, Elaine L F
2010-01-01
The ratio monotonicity of a polynomial is a stronger property than log-concavity. Let P(x) be a polynomial with nonnegative and nondecreasing coefficients. We prove the ratio monotone property of P(x+1), which leads to the log-concavity of P(x+c) for any $c\\geq 1$ due to Llamas and Mart\\'{\\i}nez-Bernal. As a consequence, we obtain the ratio monotonicity of the Boros-Moll polynomials obtained by Chen and Xia without resorting to the recurrence relations of the coefficients.
An overall and dose-response meta-analysis of red blood cell distribution width and CVD outcomes
Hou, Haifeng; Sun, Tao; Li, Cheng; Li, Yuanmin; Guo, Zheng; Wang, Wei; Li, Dong
2017-01-01
Red blood cell distribution width (RDW) is the coefficient of variation of red blood cell size, considered to be associated with cardiovascular disease (CVD). This study aimed to comprehensively synthesize previous studies on RDW and CVD outcomes through an overall and dose-response meta-analysis. PubMed, Embase and Web of Science were searched systematically for English and Chinese language publications up to November 30, 2015. We extracted data from publications matching our inclusion criteria for calculating pooled hazard ratio (HR), which was used to assess prognostic impact of RDW on CVD. Twenty-seven articles, consisting of 28 studies and 102,689 participants (mean age 63.9 years, 63,703 males/36,846 females, 2,140 gender-unmentioned subjects) were included in the present meta-analysis. The pooled HRs are 1.12 (95% CI = 1.09–1.15) for the association of all-cause mortality (ACM) per 1% increase of RDW, 1.12(95% CI = 1.08–1.17) for major adverse cardiac events (MACEs) per 1% increase of RDW. A dose-response curve relating RDW increase to its effect on CVD outcomes was established (pcurve ACM (pooled HR = 1.03, 95% CI = 1.02–1.04) and MACEs (pooled HR = 1.04, 95% CI = 1.01–1.06). This study indicates RDW may be a prognostic indicator for CVD outcomes. PMID:28233844
An overall and dose-response meta-analysis of red blood cell distribution width and CVD outcomes.
Hou, Haifeng; Sun, Tao; Li, Cheng; Li, Yuanmin; Guo, Zheng; Wang, Wei; Li, Dong
2017-02-24
Red blood cell distribution width (RDW) is the coefficient of variation of red blood cell size, considered to be associated with cardiovascular disease (CVD). This study aimed to comprehensively synthesize previous studies on RDW and CVD outcomes through an overall and dose-response meta-analysis. PubMed, Embase and Web of Science were searched systematically for English and Chinese language publications up to November 30, 2015. We extracted data from publications matching our inclusion criteria for calculating pooled hazard ratio (HR), which was used to assess prognostic impact of RDW on CVD. Twenty-seven articles, consisting of 28 studies and 102,689 participants (mean age 63.9 years, 63,703 males/36,846 females, 2,140 gender-unmentioned subjects) were included in the present meta-analysis. The pooled HRs are 1.12 (95% CI = 1.09-1.15) for the association of all-cause mortality (ACM) per 1% increase of RDW, 1.12(95% CI = 1.08-1.17) for major adverse cardiac events (MACEs) per 1% increase of RDW. A dose-response curve relating RDW increase to its effect on CVD outcomes was established (pcurve < 0.001). For every 1-unit increase of RDW, there is an increased risk of occurrence of ACM (pooled HR = 1.03, 95% CI = 1.02-1.04) and MACEs (pooled HR = 1.04, 95% CI = 1.01-1.06). This study indicates RDW may be a prognostic indicator for CVD outcomes.
Energy Technology Data Exchange (ETDEWEB)
Fattore, E.; Fanelli, R. [' ' Mario Negri' ' Institute for Pharmacological Research, Milan (Italy); Chu, I. [Safe Environments Programme, Healthy Environments and Consumer Safety Branch, Tunney' s Pasture, Ottawa, ON (Canada); Sand, S.; Haakansson, H. [Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Falk-Filippson, A. [Swedish Chemicals Inspectorate, Sundbyberg (Sweden)
2004-09-15
The benchmark dose (BMD) approach was proposed as an alternative to the no-observedadverse- effect-level (NOAEL) or the lowest-observed-adverse-effect-level (LOAEL) as point of departure (POD) for extrapolation of data from animal studies to the low dose human exposure situation. In the risk assessment process using the NOAEL/LOAEL parameter, the reference dose (RfD) or the admissible daily intake (ADI) is obtained by dividing the NOAEL/LOAEL value by uncertainty factors. The uncertainty factors are incorporated in order to take into account variability in the sensitivity of different species, inter-individual differences in sensitivity within the human population, and variability in experimental data. In the BMD approach a dose-response curve is fitted to experimental data (Figure 1) and the BMD is calculated from the equation of the curve as the dose corresponding to a predetermined change in the response defined as the benchmark response (BMR). The 95% lower confidence bound of the BMD, usually referred to as BMDL, can be used as the POD in the extrapolation process to get a RfD or an ADI. The advantages of using the BMD approach are many. First, all the experimental data are utilized to construct the doseresponse curve; second, the variability and uncertainty are taken into account by incorporating standard deviations of means; and third, it represents a single methodology for cancer and noncancer endpoints. In this study the BMD methodology was applied to evaluate dose-response data of seven chlorinated biphenyl (CB) congeners (Table 1), some of which are dioxin-like while others are not. The data were obtained from subchronic dietary exposure studies in male and female Sprague Dawley rats. Elevation in ethoxyresorufin-O-deethylase (EROD) activity was selected as biological response because it is known to be an endpoint sensitive to the exposure of dioxin-like PCBs. Since this response is not an adverse effect per se, in this paper we will refer to the no
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; Kelly, S
1995-01-01
HI-6 (1-2-hydroxyiminomethyl-1-pyridino-3-(4-carbamoyl-1-pyridino -2- oxapropane dichloride) 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 HI6 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. It is concluded that 1) ATR has a large effect on the efficacy of HI-6 against OP poisoning, 2) the dose of ATR must be carefully selected in studies investigating the efficacy of HI-6 against OP poisoning, 3) the effective dose of ATR in the guinea pig is approximately 16 mg/kg, and 4) diazepam is a useful
Directory of Open Access Journals (Sweden)
Plubtieng Somyot
2009-01-01
Full Text Available Abstract We introduce an iterative scheme for finding a common element of the solution set of a maximal monotone operator and the solution set of the variational inequality problem for an inverse strongly-monotone operator in a uniformly smooth and uniformly convex Banach space, and then we prove weak and strong convergence theorems by using the notion of generalized projection. The result presented in this paper extend and improve the corresponding results of Kamimura et al. (2004, and Iiduka and Takahashi (2008. Finally, we apply our convergence theorem to the convex minimization problem, the problem of finding a zero point of a maximal monotone operator and the complementary problem.
Directory of Open Access Journals (Sweden)
Somyot Plubtieng
2009-01-01
Full Text Available We introduce an iterative scheme for finding a common element of the solution set of a maximal monotone operator and the solution set of the variational inequality problem for an inverse strongly-monotone operator in a uniformly smooth and uniformly convex Banach space, and then we prove weak and strong convergence theorems by using the notion of generalized projection. The result presented in this paper extend and improve the corresponding results of Kamimura et al. (2004, and Iiduka and Takahashi (2008. Finally, we apply our convergence theorem to the convex minimization problem, the problem of finding a zero point of a maximal monotone operator and the complementary problem.
On the Monotone Iterative Method for Set Valued Equation
Institute of Scientific and Technical Information of China (English)
无
2000-01-01
This paper deals with the monotone iterative method for set- valued operator equation in ordered normed space. Some results for the case of single valued operator are generalized here, as an application, a discontinuous nonlinear differential equation problem is discussed.
Monotone method for initial value problem for fractional diffusion equation
Institute of Scientific and Technical Information of China (English)
ZHANG Shuqin
2006-01-01
Using the method of upper and lower solutions and its associated monotone iterative, consider the existence and uniqueness of solution of an initial value problem for the nonlinear fractional diffusion equation.
Approximations for Monotone and Non-monotone Submodular Maximization with Knapsack Constraints
Kulik, Ariel; Tamir, Tami
2011-01-01
Submodular maximization generalizes many fundamental problems in discrete optimization, including Max-Cut in directed/undirected graphs, maximum coverage, maximum facility location and marketing over social networks. In this paper we consider the problem of maximizing any submodular function subject to $d$ knapsack constraints, where $d$ is a fixed constant. We establish a strong relation between the discrete problem and its continuous relaxation, obtained through {\\em extension by expectation} of the submodular function. Formally, we show that, for any non-negative submodular function, an $\\alpha$-approximation algorithm for the continuous relaxation implies a randomized $(\\alpha - \\eps)$-approximation algorithm for the discrete problem. We use this relation to improve the best known approximation ratio for the problem to $1/4- \\eps$, for any $\\eps > 0$, and to obtain a nearly optimal $(1-e^{-1}-\\eps)-$approximation ratio for the monotone case, for any $\\eps>0$. We further show that the probabilistic domain ...
Action-Maslov Homomorphism for Monotone Symplectic Manifolds
Branson, Mark
2009-01-01
We explore conditions under which the action-Maslov homomorphism vanishes on monotone symplectic manifolds. Our strategy involves showing that the units in the quantum homology, and thus the Seidel element, have a very specific form. Then we use induction to show that other relevant Gromov-Witten invariants vanish. We prove that these conditions hold for monotone products of projective spaces and for the Grassmannian of 2-planes in $\\C^4$.
Completely monotonic functions related to logarithmic derivatives of entire functions
DEFF Research Database (Denmark)
Pedersen, Henrik Laurberg
2011-01-01
The logarithmic derivative l(x) of an entire function of genus p and having only non-positive zeros is represented in terms of a Stieltjes function. As a consequence, (-1)p(xml(x))(m+p) is a completely monotonic function for all m ≥ 0. This generalizes earlier results on complete monotonicity...... of functions related to Euler's psi-function. Applications to Barnes' multiple gamma functions are given....
Isotonicity of the projection onto the monotone cone
Németh, A B
2012-01-01
A wedge (i.e., a closed nonempty set in the Euclidean space stable under addition and multiplication with non-negative scalars) induces by a standard way a semi-order (a reflexive and transitive binary relation) in the space. The wedges admitting isotone metric projection with respect to the semi-order induced by them are characterized. The obtained result is used to show that the monotone wedge (called monotone cone in regression theory) admits isotone projection.
Monotonic loading of circular surface footings on clay
Energy Technology Data Exchange (ETDEWEB)
Ibsen, Lars Bo; Barari, Amin [Aalborg University, Aalborg (Denmark)
2011-12-15
Appropriate modeling of offshore foundations under monotonic loading is a significant challenge in geotechnical engineering. This paper reports experimental and numerical analyses, specifically investigating the response of circular surface footings during monotonic loading and elastoplastic behavior during reloading. By using the findings presented in this paper, it is possible to extend the model to simulate the vertical-load displacement response of offshore bucket foundations.
Convergence for pseudo monotone semiflows on product ordered topological spaces
Yi, Taishan; Huang, Lihong
In this paper, we consider a class of pseudo monotone semiflows, which only enjoy some weak monotonicity properties and are defined on product-ordered topological spaces. Under certain conditions, several convergence principles are established for each precompact orbit of such a class of semiflows to tend to an equilibrium, which improve and extend some corresponding results already known. Some applications to delay differential equations are presented.
Layered neural networks with non-monotonic transfer functions
Katayama, Katsuki; Sakata, Yasuo; Horiguchi, Tsuyoshi
2003-01-01
We investigate storage capacity and generalization ability for two types of fully connected layered neural networks with non-monotonic transfer functions; random patterns are embedded into the networks by a Hebbian learning rule. One of them is a layered network in which a non-monotonic transfer function of even layers is different from that of odd layers. The other is a layered network with intra-layer connections, in which the non-monotonic transfer function of inter-layer is different from that of intra-layer, and inter-layered neurons and intra-layered neurons are updated alternately. We derive recursion relations for order parameters for those layered networks by the signal-to-noise ratio method. We clarify that the storage capacity and the generalization ability for those layered networks are enhanced in comparison with those with a conventional monotonic transfer function when non-monotonicity of the transfer functions is selected optimally. We also point out that some chaotic behavior appears in the order parameters for the layered networks when non-monotonicity of the transfer functions increases.
Dose response of subcutaneous GLP-1 infusion in patients with type 2 diabetes
DEFF Research Database (Denmark)
Torekov, Signe Sørensen; Kipnes, M S; Harley, R E;
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....
Concord grape juice polyphenols and cardiovascular risk factors: dose-response relationships
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 ...
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.)…
Empirical Evaluation of Meta-Analytic Approaches for Nutrient and Health Outcome Dose-Response Data
Yu, Winifred W.; Schmid, Christopher H.; Lichtenstein, Alice H.; Lau, Joseph; Trikalinos, Thomas A.
2013-01-01
The objective of this study is to empirically compare alternative meta-analytic methods for combining dose-response data from epidemiological studies. We identified meta-analyses of epidemiological studies that analyzed the association between a single nutrient and a dichotomous outcome. For each topic, we performed meta-analyses of odds ratios…
G. Koshy; A. Delpisheh; B.J. Brabin
2011-01-01
The combined dose response effects of pregnancy cigarette smoke exposure on childhood overweight, obesity and short stature have not been reported. A community based cross-sectional survey of 3038 children aged 5-11 years from 15 primary schools in Merseyside, UK. Self-completed parental questionnai
Imre, G; Fokkema, DS; Den Boer, JA; Ter Horst, GJ
2006-01-01
The present dose-response study sought to determine the effects of subanesthetic dosages (4-16 mg/kg) of ketamine on locomotion, sensorimotor gating (PP1), working memory, as well as c-fos expression in various limbic regions implicated in the pathogenesis of schizophrenia. In addition, we examined
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:…
Dose response of a new phytse on dry matter, calcium, and phosphorus digestibility in weaned piglets
Bento, M.H.L.; Pedersen, C.; Plumstead, P.W.; Salmon, L.; Nyachoti, C.M.; Bikker, P.
2012-01-01
The present study evaluated the dose response of Buttiauxella phytase on apparent total tract digestibility (ATTD) of DM, Ca, and P in weaned pigs at 2 locations. Experimental diets fed to weaned pigs were a positive control (PC), a negative control (NC), and NC supplemented with increasing levels o
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:…
Estimating the predictive quality of dose-response after model selection.
Hu, Chuanpu; Dong, Yingwen
2007-07-20
Prediction of dose-response is important in dose selection in drug development. As the true dose-response shape is generally unknown, model selection is frequently used, and predictions based on the final selected model. Correctly assessing the quality of the predictions requires accounting for the uncertainties caused by the model selection process, which has been difficult. Recently, a new approach called data perturbation has emerged. It allows important predictive characteristics be computed while taking model selection into consideration. We study, through simulation, the performance of data perturbation in estimating standard error of parameter estimates and prediction errors. Data perturbation was found to give excellent prediction error estimates, although at times large Monte Carlo sizes were needed to obtain good standard error estimates. Overall, it is a useful tool to characterize uncertainties in dose-response predictions, with the potential of allowing more accurate dose selection in drug development. We also look at the influence of model selection on estimation bias. This leads to insights into candidate model choices that enable good dose-response prediction.
Physical activity and cancer risk: dose-response and cancer, all sites and site-specific.
Thune, I; Furberg, A S
2001-06-01
The association between physical activity and overall and site-specific cancer risk is elaborated in relation to whether any observed dose-response association between physical activity and cancer can be interpreted in terms of how much physical activity (type, intensity, duration, frequency) is needed to influence site- and gender-specific cancer risk. Observational studies were reviewed that have examined the independent effect of the volume of occupational physical activity (OPA) and/or leisure time physical activity (LPA) on overall and site-specific cancer risk. The evidence of cohort and case-control studies suggests that both leisure time and occupational physical activity protect against overall cancer risk, with a graded dose-response association suggested in both sexes. Confounding effects such as diet, body weight, and parity are often included as a covariate in the analyses, with little influence on the observed associations. A crude graded inverse dose-response association was observed between physical activity and colon cancer in 48 studies including 40,674 colon/colorectal cancer cases for both sexes. A dose-response effect of physical activity on colon cancer risk was especially observed, when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed as MET-hours per week. An observed inverse association with a dose-response relationship between physical activity and breast cancer was also identified in the majority of the 41 studies including 108,031 breast cancer cases. The dose-response relationship was in particular observed in case-control studies and supported by observations in cohort studies when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed by MET-hours per week. This association between physical activity and breast cancer risk is possibly dependent on age at exposure, age at diagnosis, menopausal status and other effect
Jansen, Justin; Burdorf, Alex
2003-01-01
textabstractBACKGROUND: In epidemiological studies on physical workloads and back complaints, among the important features in modelling dose-response relations are the measurement strategy of the exposure and the nature of the dose-response relation that is assumed. AIM: To evaluate the effect of these two features on the strength of the dose-response relation between physical load and severe low back pain. METHODS: The study population consisted of 769 workers in nursing homes and homes for ...
Energy Technology Data Exchange (ETDEWEB)
Gordon, J; Snyder, K; Zhong, H; Chetty, I [Henry Ford Health System, Dept. Radiation Oncology, Detroit, MI (United States)
2014-06-01
Purpose: Dose-response models that can reliably predict radiation pneumonitis (RP) to guide radiation therapy (RT) for lung cancer presently do not exist. A model is proposed that incorporates non-local radiationinduced bystander effect (RIBE). Methods: A single sigmoid response function, derived from published data for whole lung irradiation, relates RP probability to cumulative lung damage, regardless of fractionation scheme. Lung damage is assumed to be caused by direct local radiation damage, quantified via the linear-quadratic (LQ) model, and RIBE. Based on published data, RIBE is assumed to be activated when per-fraction dose rises above ∼0.6 Gy, but is constant with dose above that threshold. Integral RIBE damage is assumed proportional to lung volume irradiated above ∼0.6 Gy per fraction. Key model parameters include LQ α and β, and two RIBE parameters: the single-fraction probability δ of damage, and a proportionality parameter κ that relates the potential for RIBE damage to irradiated lung volume. All parameters are tentatively fitted from published data, the RIBE parameters from published RP rates for conventionally fractionated RT (CFRT) and stereotactic body RT (SBRT). Results: The model predicts dose-response curves that are consistent with clinical experience. It provides a tentative explanation for why V20 (33 fractions), V13 (20 fractions) and V5 (<10 fractions) are observed to be correlated with RP. It also provides a plausible explanation for the success of SBRT — RIBE damage increases with the number of fractions, so penalizes CFRT relative to SBRT. Conclusion: The proposed model is relatively simple, extrapolates from published data, plausibly explains several clinical observations, and produces dose-response curves that are consistent with clinical experience. While capable of elaboration, its ability to explain doseresponse experience with different fractionation schemes using a small number of assumptions and parameters is an
Driving performance impairments due to hypovigilance on monotonous roads.
Larue, Grégoire S; Rakotonirainy, Andry; Pettitt, Anthony N
2011-11-01
Drivers' ability to react to unpredictable events deteriorates when exposed to highly predictable and uneventful driving tasks. Highway design reduces the driving task mainly to a lane-keeping manoeuvre. Such a task is monotonous, providing little stimulation and this contributes to crashes due to inattention. Research has shown that driver's hypovigilance can be assessed with EEG measurements and that driving performance is impaired during prolonged monotonous driving tasks. This paper aims to show that two dimensions of monotony - namely road design and road side variability - decrease vigilance and impair driving performance. This is the first study correlating hypovigilance and driver performance in varied monotonous conditions, particularly on a short time scale (a few seconds). We induced vigilance decrement as assessed with an EEG during a monotonous driving simulator experiment. Road monotony was varied through both road design and road side variability. The driver's decrease in vigilance occurred due to both road design and road scenery monotony and almost independently of the driver's sensation seeking level. Such impairment was also correlated to observable measurements from the driver, the car and the environment. During periods of hypovigilance, the driving performance impairment affected lane positioning, time to lane crossing, blink frequency, heart rate variability and non-specific electrodermal response rates. This work lays the foundation for the development of an in-vehicle device preventing hypovigilance crashes on monotonous roads.
Energy Technology Data Exchange (ETDEWEB)
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%.
Chang, Yu-Kai; Etnier, Jennifer L
2009-10-01
The purpose of this study was to explore the dose-response relationship between resistance exercise intensity and cognitive performance. Sixty-eight participants were randomly assigned into control, 40%, 70%, or 100% of 10-repetition maximal resistance exercise groups. Participants were tested on Day 1 (baseline) and on Day 2 (measures were taken relative to performance of the treatment). Heart rate, ratings of perceived exertion, self-reported arousal, and affect were assessed on both days. Cognitive performance was assessed on Day 1 and before and following treatment on Day 2. Results from regression analyses indicated that there is a significant linear effect of exercise intensity on information processing speed, and a significant quadratic trend for exercise intensity on executive function. Thus, there is a dose-response relationship between the intensity of resistance exercise and cognitive performance such that high-intensity exercise benefits speed of processing, but moderate intensity exercise is most beneficial for executive function.
Epidemiological methods for assessing dose-response and dose-effect relationships
DEFF Research Database (Denmark)
Kjellström, Tord; Grandjean, Philippe
2007-01-01
of the Toxic Effects of Metals Aluminum Antimony Arsenic Barium Beryllium Bismuth Cadmium Chromium Cobalt Copper Gallium and Semiconductor Compounds Germanium Indium Iron Lead Manganese Mercury Molybdenum Nickel Palladium Platinum Selenium Silver Tellurium Thallium Tin Titanium Tungsten Uranium Vanadium Zinc...... and their compounds. An entirely new structure and illustrations represent the vast array of advancements made since the last edition. Special emphasis has been placed on the toxic effects in humans with chapters on the diagnosis, treatment and prevention of metal poisoning. This up-to-date reference provides easy...... Selected Molecular Mechanisms of Metal Toxicity and Carcinogenicity General Considerations of Dose-Effect and Dose-Response Relationships Interactions in Metal Toxicology Epidemiological Methods for Assessing Dose-Response and Dose-Effect Relationships Essential Metals: Assessing Risks from Deficiency...
Directory of Open Access Journals (Sweden)
Cheng-Ting Shih
Full Text Available Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM images. The modified N-isopropyl-acrylamide (NIPAM gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM. The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R (2 value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were -7.60%, 5.80%, 2.53%, and -0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection.
Shih, Cheng-Ting; Hsu, Jui-Ting; Han, Rou-Ping; Hsieh, Bor-Tsung; Chang, Shu-Jun; Wu, Jay
2013-01-01
Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM) images. The modified N-isopropyl-acrylamide (NIPAM) gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM). The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R (2) value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were -7.60%, 5.80%, 2.53%, and -0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection.
Fischer, Louise Arup; Menné, Torkil; Voelund, Aage; Johansen, Jeanne Duus
2011-06-01
Allergic contact dermatitis is triggered by chemicals in the environment. Primary prevention is aimed at minimizing the risk of induction, whereas secondary and tertiary prevention are aimed at reducing elicitation. To identify the elicitation doses that will elicit an allergic reaction in 10% of allergic individuals under patch test conditions (ED(10) patch test) for different allergens, and to compare the results with those for different allergens and with animal data indicating sensitizing potency from the literature. The literature was searched for patch test elicitation studies that fulfilled six selected criteria. The elicitation doses were calculated, and fitted dose-response curves were drawn. Sixteen studies with eight different allergens-methylchloroisothiazolinone/ methylisothiazolinone, formaldehyde, nickel, cobalt, chromium, isoeugenol, hydroxyiso hexyl 3-cyclohexene carboxaldehyde, and methyldibromo glutaronitrile-were selected. The median ED(10) value was 0.835 µg/cm(2). The ED(10) patch test values were all within a factor of 7 from the lowest to the highest value, leaving out three outliers. No obvious patterns between the sensitization and elicitation doses for the allergens were found. We found a rather small variation in the ED(10) patch test between the allergens, and no clear relationship between induction potency and elicitation threshold of a range of allergens. This knowledge may stimulate thoughts on introducing a generic approach for limitations in exposure to well-known allergens. © 2011 John Wiley & Sons A/S.
Thiele-Bruhn, Sören
2005-04-01
Soil contamination from pharmaceuticals is an emerging problem, though quantitative data on their microbial effects are lacking. Thus, nine pharmaceutical antibiotics were tested for their effects on the microbial iron(III) reduction in six different topsoils. Complete dose-response curves were obtained and best-fit by sigmoidal Logit, Weibull, Box-Cox Logit, and Box-Cox Weibull equations (r2 0.73-1.00). The derived effective doses (ED [micromol/kg soil]) for the different antibiotics increased in the order (average ED50 in parentheses) chlortetracycline (53) fenbendazole at doses up to 5,800 and 3,300 micromol/kg, respectively. Due to a strong soil adsorption, especially of the tetracyclines, the corresponding effective concentrations in the soil solution (EC50), derived from sorption experiments, were considerably smaller and ranged from 0.004 micromol/L (chlortetracycline) to 120 micromol/L (sulfapyridine). The effects of the antibiotics were governed by soil sorptive properties, especially the concentration of soil organic matter. The microbial inhibition was influenced indirectly by the soil pH, which affects the ionization status of the amphoteric antibiotics.
Hada, M.; George, Kerry; Cucinotta, Francis A.
2011-01-01
The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivors with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (1-20 cGy) of 170 MeV/u Si-28- ions or 600 MeV/u Fe-56-ions. Chromosomes were analyzed using the whole chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving greater than 2 breaks in 2 or more chromosomes). The curves for doses above 10 cGy were fitted with linear or linear-quadratic functions. For Si-28- ions no dose response was observed in the 2-10 cGy dose range, suggesting a non-target effect in this range.
Vinnikov, Volodymyr A; Maznyk, Nataliya A
2013-04-01
The dose response for dicentrics plus centric rings and total unstable chromosome-type aberrations was studied in the first mitoses of cultured human peripheral blood lymphocytes irradiated in vitro to doses of ∼2, 4, 6, 8, 10, 16 and 20 Gy of acute (60)Со gamma-rays. A dose-dependent increase of aberration yield was accompanied by a tendency to the underdispersion of dicentrics and centric rings among cells distributions compared with Poisson statistics at doses ≥6 Gy. The formal fitting of the data to a linear-quadratic model resulted in an equation with the linear and quadratic coefficients ranged 0.098-0.129×cell(-1)×Gy(-1) and 0.039-0.034×cell(-1)×Gy(-2), respectively, depending on the fitting method. The actual radiation-induced aberration yield was markedly lower than expected from a calibration curve, generated earlier within a lower dose range. Interlaboratory variations in reported dicentric yields induced by medium-to-high radiation doses in vitro are discussed.
Energy Technology Data Exchange (ETDEWEB)
Naqa, I El [Washington University, Saint Louis, MO (United States); Suneja, G [Brown Medical School, Providence, RI (United States); Lindsay, P E [Washington University, St. Louis, MO (United States); Hope, A J [Washington University, Saint Louis, MO (United States); Alaly, J R [Washington University, Saint Louis, MO (United States); Vicic, M [Washington University, Saint Louis, MO (United States); Bradley, J D [Washington University, Saint Louis, MO (United States); Apte, A [Washington University, Saint Louis, MO (United States); Deasy, J O [Washington University, Saint Louis, MO (United States)
2006-11-21
Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.
El Naqa, I.; Suneja, G.; Lindsay, P. E.; Hope, A. J.; Alaly, J. R.; Vicic, M.; Bradley, J. D.; Apte, A.; Deasy, J. O.
2006-11-01
Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.
Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics
Nesse, Willem; Linde, Annemiek; Abbas, Frank; Spijkervet, Frederik Karst Lucien; Dijkstra, Pieter Ubele; de Brabander, Eric Carl; Gerstenbluth, Izzy; Vissink, Arjan
2009-01-01
Nesse W, Linde A, Abbas F, Spijkervet FKL, Dijkstra PU, de Brabander EC, Gerstenbluth I, Vissink A. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 diabetics. J Clin Periodontol 2009; 36: 295-300. doi: 10.1111/j.1600-051X.2009.01377.x. A dose-response relatio
J.J.P. Jansen (Justin); A. Burdorf (Alex)
2003-01-01
textabstractBACKGROUND: In epidemiological studies on physical workloads and back complaints, among the important features in modelling dose-response relations are the measurement strategy of the exposure and the nature of the dose-response relation that is assumed. AIM: To evaluat
Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics
Nesse, Willem; Linde, Annemiek; Abbas, Frank; Spijkervet, Frederik Karst Lucien; Dijkstra, Pieter Ubele; de Brabander, Eric Carl; Gerstenbluth, Izzy; Vissink, Arjan
Nesse W, Linde A, Abbas F, Spijkervet FKL, Dijkstra PU, de Brabander EC, Gerstenbluth I, Vissink A. Dose-response relationship between periodontal inflamed surface area and HbA1c in type 2 diabetics. J Clin Periodontol 2009; 36: 295-300. doi: 10.1111/j.1600-051X.2009.01377.x. A dose-response
DEFF Research Database (Denmark)
Diez, Patricia; Vogelius, Ivan S; Bentzen, Søren M
2010-01-01
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).......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)....
Estimating monotonic rates from biological data using local linear regression.
Olito, Colin; White, Craig R; Marshall, Dustin J; Barneche, Diego R
2017-03-01
Accessing many fundamental questions in biology begins with empirical estimation of simple monotonic rates of underlying biological processes. Across a variety of disciplines, ranging from physiology to biogeochemistry, these rates are routinely estimated from non-linear and noisy time series data using linear regression and ad hoc manual truncation of non-linearities. Here, we introduce the R package LoLinR, a flexible toolkit to implement local linear regression techniques to objectively and reproducibly estimate monotonic biological rates from non-linear time series data, and demonstrate possible applications using metabolic rate data. LoLinR provides methods to easily and reliably estimate monotonic rates from time series data in a way that is statistically robust, facilitates reproducible research and is applicable to a wide variety of research disciplines in the biological sciences. © 2017. Published by The Company of Biologists Ltd.
Monotone traveling wavefronts of the KPP-Fisher delayed equation
Gomez, Adrian
2010-01-01
In the early 2000's, Gourley (2000), Wu et al. (2001), Ashwin et al. (2002) initiated the study of the positive wavefronts in the delayed Kolmogorov-Petrovskii-Piskunov-Fisher equation. Since then, this model has become one of the most popular objects in the studies of traveling waves for the monostable delayed reaction-diffusion equations. In this paper, we give a complete solution to the problem of existence and uniqueness of monotone waves in the KPP-Fisher equation. We show that each monotone traveling wave can be found via an iteration procedure. The proposed approach is based on the use of special monotone integral operators (which are different from the usual Wu-Zou operator) and appropriate upper and lower solutions associated to them. The analysis of the asymptotic expansions of the eventual traveling fronts at infinity is another key ingredient of our approach.
Drawable Region of the Generalized Log Aesthetic Curves
Directory of Open Access Journals (Sweden)
R. U. Gobithaasan
2013-01-01
Full Text Available The main characteristic of visually pleasing curves used for product design is a monotonic curvature profile. Recently, a planar curve called Generalized Log Aesthetic Curve (GLAC has been extended from the Log Aesthetic Curve (LAC, and it has an additional shape parameter, ν. This curve preserves the monotonicity of curvature and is said to produce visually pleasing curves. This paper delves on the drawable region of the GLAC segment which indicates the probable solutions of shape parameters from given interpolating points and the direction of travel at those points. The first section reviews the formulation of GLAC and its related bounds. The section describes the algorithm for identifying the drawable region. It is followed by the section describing how small changes of ν widen the drawable boundaries. The final section discusses the superiority of GLAC compared to LAC for use in industrial product design.
Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease
Energy Technology Data Exchange (ETDEWEB)
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.
Diethylene glycol-induced toxicities show marked threshold dose response in rats
Energy Technology Data Exchange (ETDEWEB)
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.
Directory of Open Access Journals (Sweden)
Cardozo Linda
2010-08-01
Full Text Available Abstract Background Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI, usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine. Methods Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models. Results The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively. Conclusions A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials. Trial Registration The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723.
Cardozo, Linda; Khullar, Vik; El-Tahtawy, Ahmed; Guan, Zhonghong; Malhotra, Bimal; Staskin, David
2010-08-19
Fesoterodine is an antimuscarinic for the treatment of overactive bladder, a syndrome of urgency, with or without urgency urinary incontinence (UUI), usually with increased daytime frequency and nocturia. Our objective was to develop predictive models to describe the dose response of fesoterodine. Data from subjects enrolled in double-blind, placebo-controlled phase II and III trials were used for developing longitudinal dose-response models. The models predicted that clinically significant and near-maximum treatment effects would be seen within 3 to 4 weeks after treatment initiation. For a typical patient with 11 micturitions per 24 hours at baseline, predicted change was -1.2, -1.7, and -2.2 micturitions for placebo and fesoterodine 4 mg and 8 mg, respectively. For a typical patient with 2 UUI episodes per 24 hours at baseline, predicted change was -1.05, -1.26, and -1.43 UUI episodes for placebo and fesoterodine 4 mg and 8 mg, respectively. Increase in mean voided volume was estimated at 9.7 mL for placebo, with an additional 14.2 mL and 28.4 mL for fesoterodine 4 mg and 8 mg, respectively. A consistent dose response for fesoterodine was demonstrated for bladder diary endpoints in subjects with overactive bladder, a result that supports the greater efficacy seen with fesoterodine 8 mg in post hoc analyses of clinical trial data. The dose-response models can be used to predict outcomes for doses not studied or for patient subgroups underrepresented in clinical trials. The phase III trials used in this analysis have been registered at ClinicalTrials.gov (NCT00220363 and NCT00138723).
Dose response of hydrazine - Deproteinated tooth enamel under blue light stimulation
Energy Technology Data Exchange (ETDEWEB)
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.
Testing the Capacity of the National Biological Dose Response Plan (NBDRP) EX40801
2009-11-01
providing radiation biological dose estimates using the dicentric chromosome assay (DCA). As indicated in the CRTI-06-0146RD charter, the existing...laboratories of the National Biological Dose Response Plan plus two US laboratories. Samples were scored for the dicentric chromosome assay and the CBMN...Wilkins, R.C. QuickScan dicentric chromosome analysis for radiation biodosimetry , Health Physics Journal, In Press (2009). 2. McNamee, J.P., Flegal
Childhood adversity specificity and dose-response effect in non-affective first-episode psychosis
DEFF Research Database (Denmark)
Trauelsen, Anne Marie; Bendall, Sarah; Jansen, Jens Einar
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 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
Concord Grape Juice Polyphenols and Cardiovascular Risk Factors: Dose-Response Relationships
Directory of Open Access Journals (Sweden)
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.
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.
Directory of Open Access Journals (Sweden)
Hemantkumar Chavan
2017-01-01
Full Text Available Arsenite is a known carcinogen and its exposure has been implicated in a variety of noncarcinogenic health concerns. Increased oxidative stress is thought to be the primary cause of arsenite toxicity and the toxic effect is thought to be linear with detrimental effects reported at all concentrations of arsenite. But the paradigm of linear dose response in arsenite toxicity is shifting. In the present study we demonstrate that arsenite effects on mitochondrial respiration in primary hepatocytes follow a nonlinear dose response. In vitro exposure of primary hepatocytes to an environmentally relevant, moderate level of arsenite results in increased oxidant production that appears to arise from changes in the expression and activity of respiratory Complex I of the mitochondrial proton circuit. In primary hepatocytes the excess oxidant production appears to elicit adaptive responses that promote resistance to oxidative stress and a propensity to increased proliferation. Taken together, these results suggest a nonlinear dose-response characteristic of arsenite with low-dose arsenite promoting adaptive responses in a process known as mitohormesis, with transient increase in ROS levels acting as transducers of arsenite-induced mitohormesis.
Ultimate generalization to monotonicity for uniform convergence of trigonometric series
Institute of Scientific and Technical Information of China (English)
无
2010-01-01
Chaundy and Jolliffe proved that if {a n } is a non-increasing (monotonic) real sequence with lim n →∞ a n = 0, then a necessary and sufficient condition for the uniform convergence of the series ∑∞ n=1 a n sin nx is lim n →∞ na n = 0. We generalize (or weaken) the monotonic condition on the coefficient sequence {a n } in this classical result to the so-called mean value bounded variation condition and prove that the generalized condition cannot be weakened further. We also establish an analogue to the generalized Chaundy-Jolliffe theorem in the complex space.
Vector optimization and monotone operators via convex duality recent advances
Grad, Sorin-Mihai
2014-01-01
This book investigates several duality approaches for vector optimization problems, while also comparing them. Special attention is paid to duality for linear vector optimization problems, for which a vector dual that avoids the shortcomings of the classical ones is proposed. Moreover, the book addresses different efficiency concepts for vector optimization problems. Among the problems that appear when the framework is generalized by considering set-valued functions, an increasing interest is generated by those involving monotone operators, especially now that new methods for approaching them by means of convex analysis have been developed. Following this path, the book provides several results on different properties of sums of monotone operators.
Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Brahme, Anders; Lind, Bengt K.
2008-11-01
Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the
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.
Rosier, Bob T; Lazova, Milena D
2016-01-01
The chemotaxis system enables motile bacteria to search for an optimum level of environmental factors. Salmonella typhimurium senses the amino acid cysteine as an attractant and its oxidized dimeric form, cystine, as a repellent. We investigated the dose-response dependence of changes in chemotactic signaling activity upon exposure to cysteine and cystine of S. typhimurium LT2 using in vivo fluorescence resonance energy transfer (FRET) measurements. The dose-response curve of the attractant response to cysteine had a sigmoidal shape, typical for receptor-ligand interactions. However, in a knockout strain of the chemoreceptor genes tsr and tar, we detected a repellent response to cysteine solutions, scaling linearly with the logarithm of the cysteine concentration. Interestingly, the magnitude of the repellent response to cystine also showed linear dependence to the logarithm of the cystine concentration. This linear dependence was observed over more than four orders of magnitude, where detection started at nanomolar concentrations. Notably, low concentrations of another oxidized compound, benzoquinone, triggered similar responses. In contrast to S. typhimurium 14028, where no response to cystine was observed in a knockout strain of chemoreceptor genes mcpB and mcpC, here we showed that McpB/McpC-independent responses to cystine existed in the strain S. typhimurium LT2 even at nanomolar concentrations. Additionally, knocking out mcpB and mcpC did not affect the linear dose-response dependence, whereas enhanced responses were only observed to solutions that where not pH neutral (>100 μM cystine) in the case of McpC overexpression. We discuss that the linear dependence of the response on the logarithm of cystine concentrations could be a result of a McpB/C-independent redox-sensing pathway that exists in S. typhimurium LT2. We supported this hypothesis with experiments with defined cysteine/cystine mixed solutions, where a transition from repellent to attractant
Dealing with non-unique and non-monotonic response in particle sizing instruments
Rosenberg, Phil
2017-04-01
A number of instruments used as de-facto standards for measuring particle size distributions are actually incapable of uniquely determining the size of an individual particle. This is due to non-unique or non-monotonic response functions. Optical particle counters have non monotonic response due to oscillations in the Mie response curves, especially for large aerosol and small cloud droplets. Scanning mobility particle sizers respond identically to two particles where the ratio of particle size to particle charge is approximately the same. Images of two differently sized cloud or precipitation particles taken by an optical array probe can have similar dimensions or shadowed area depending upon where they are in the imaging plane. A number of methods exist to deal with these issues, including assuming that positive and negative errors cancel, smoothing response curves, integrating regions in measurement space before conversion to size space and matrix inversion. Matrix inversion (also called kernel inversion) has the advantage that it determines the size distribution which best matches the observations, given specific information about the instrument (a matrix which specifies the probability that a particle of a given size will be measured in a given instrument size bin). In this way it maximises use of the information in the measurements. However this technique can be confused by poor counting statistics which can cause erroneous results and negative concentrations. Also an effective method for propagating uncertainties is yet to be published or routinely implemented. Her we present a new alternative which overcomes these issues. We use Bayesian methods to determine the probability that a given size distribution is correct given a set of instrument data and then we use Markov Chain Monte Carlo methods to sample this many dimensional probability distribution function to determine the expectation and (co)variances - hence providing a best guess and an uncertainty for
MONOTONE ITERATION FOR ELLIPTIC PDEs WITH DISCONTINUOUS NONLINEAR TERMS
Institute of Scientific and Technical Information of China (English)
Zou Qingsong
2005-01-01
In this paper, we use monotone iterative techniques to show the existence of maximal or minimal solutions of some elliptic PDEs with nonlinear discontinuous terms. As the numerical analysis of this PDEs is concerned, we prove the convergence of discrete extremal solutions.
Modeling non-monotone risk aversion using SAHARA utility functions
A. Chen; A. Pelsser; M. Vellekoop
2011-01-01
We develop a new class of utility functions, SAHARA utility, with the distinguishing feature that it allows absolute risk aversion to be non-monotone and implements the assumption that agents may become less risk averse for very low values of wealth. The class contains the well-known exponential and
On Uniqueness of Conjugacy of Continuous and Piecewise Monotone Functions
Directory of Open Access Journals (Sweden)
Ciepliński Krzysztof
2009-01-01
Full Text Available We investigate the existence and uniqueness of solutions of the functional equation , , where are closed intervals, and , are some continuous piecewise monotone functions. A fixed point principle plays a crucial role in the proof of our main result.
L^p solutions of reflected BSDEs under monotonicity condition
Rozkosz, Andrzej
2012-01-01
We prove existence and uniqueness of L^p solutions of reflected backward stochastic differential equations with p-integrable data and generators satisfying the monotonicity condition. We also show that the solution may be approximated by the penalization method. Our results are new even in the classical case p=2.
A monotonic method for solving nonlinear optimal control problems
Salomon, Julien
2009-01-01
Initially introduced in the framework of quantum control, the so-called monotonic algorithms have shown excellent numerical results when dealing with various bilinear optimal control problems. This paper aims at presenting a unified formulation of such procedures and the intrinsic assumptions they require. In this framework, we prove the feasibility of the general algorithm. Finally, we explain how these assumptions can be relaxed.
On Some Conjectures on the Monotonicity of Some Arithmetical Sequences
2012-01-01
THE MONOTONICITY OF SOME ARITHMETICAL SEQUENCES ∗ Florian Luca † Centro de Ciencias Matemáticas, Universidad Nacional Autonoma de México, C.P. 58089...visit of P. S. to the Centro de Ciencias Matemáticas de la UNAM in Morelia in August 2012. During the preparation of this paper, F. L. was supported in
Interval Routing and Minor-Monotone Graph Parameters
Bakker, E.M.; Bodlaender, H.L.; Tan, R.B.; Leeuwen, J. van
2006-01-01
We survey a number of minor-monotone graph parameters and their relationship to the complexity of routing on graphs. In particular we compare the interval routing parameters κslir(G) and κsir(G) with Colin de Verdi`ere’s graph invariant μ(G) and its variants λ(G) and κ(G). We show that for all the k
Multivariate Regression with Monotone Missing Observation of the Dependent Variables
Raats, V.M.; van der Genugten, B.B.; Moors, J.J.A.
2002-01-01
Multivariate regression is discussed, where the observations of the dependent variables are (monotone) missing completely at random; the explanatory variables are assumed to be completely observed.We discuss OLS-, GLS- and a certain form of E(stimated) GLS-estimation.It turns out that
Minimum Cost Spanning Tree Games and Population Monotonic Allocation Schemes
Norde, H.W.; Moretti, S.; Tijs, S.H.
2001-01-01
In this paper we present the Subtraction Algorithm that computes for every classical minimum cost spanning tree game a population monotonic allocation scheme.As a basis for this algorithm serves a decomposition theorem that shows that every minimum cost spanning tree game can be written as nonnegati
Size monotonicity and stability of the core in hedonic games
Dimitrov, Dinko; Sung, Shao Chin
2011-01-01
We show that the core of each strongly size monotonic hedonic game is not empty and is externally stable. This is in sharp contrast to other sufficient conditions for core non-emptiness which do not even guarantee the existence of a stable set in such games.
Monotone missing data and repeated controls of fallible authors
Raats, V.M.
2004-01-01
Chapters 2 and 3 focus on repeated audit controls with categorical variables. Chapter 4 and 5 introduce and analyse a very general multivariate regression model for (monotone) missing data. In the final Chapter 6 the previous chapters are combined into a more realistic model for repeated audit contr
A POTENTIAL REDUCTION ALGORITHM FOR MONOTONE VARIATIONAL INEQUALITY PROBLEMS
Institute of Scientific and Technical Information of China (English)
无
2000-01-01
A potential reduction algorithm is proposed for the solution of monotone variational inequality problems. At each step of the algorithm, a system of linear equations is solved to get the search direction and the Armijo's rule is used to determine the stepsize.It is proved that the algorithm is globally convergent. Computational results are reported.
Relaxing monotonicity in the identification of local average treatment effects
DEFF Research Database (Denmark)
Huber, Martin; Mellace, Giovanni
In heterogeneous treatment effect models with endogeneity, the identification of the local average treatment effect (LATE) typically relies on an instrument that satisfies two conditions: (i) joint independence of the potential post-instrument variables and the instrument and (ii) monotonicity...
Incorporating "Unconscious Reanalysis" into an Incremental, Monotonic Parser
Sturt, P
1995-01-01
This paper describes an implementation based on a recent model in the psycholinguistic literature. We define a parsing operation which allows the reanalysis of dependencies within an incremental and monotonic processing architecture, and discuss search strategies for its application in a head-initial language (English) and a head-final language (Japanese).
Interval Routing and Minor-Monotone Graph Parameters
Bakker, E.M.; Bodlaender, H.L.; Tan, R.B.; Leeuwen, J. van
2006-01-01
We survey a number of minor-monotone graph parameters and their relationship to the complexity of routing on graphs. In particular we compare the interval routing parameters κslir(G) and κsir(G) with Colin de Verdi`ere’s graph invariant μ(G) and its variants λ(G) and κ(G). We show that for all the
Reasoning Biases, Non-Monotonic Logics, and Belief Revision
Dutilh Novaes, Catarina; Veluwenkamp, Herman
2017-01-01
A range of formal models of human reasoning have been proposed in a number of fields such as philosophy, logic, artificial intelligence, computer science, psychology, cognitive science etc.: various logics (epistemic logics; non-monotonic logics), probabilistic systems (most notably, but not exclusi
Variability among polysulphone calibration curves
Energy Technology Data Exchange (ETDEWEB)
Casale, G R [University of Rome ' La Sapienza' , Physics Department, P.le A. Moro 2, I-00185, Rome (Italy); Borra, M [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy); Colosimo, A [University of Rome ' La Sapienza' , Department of Human Physiology and Pharmacology, P.le A. Moro 2, I-00185, Rome (Italy); Colucci, M [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy); Militello, A [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy); Siani, A M [University of Rome ' La Sapienza' , Physics Department, P.le A. Moro 2, I-00185, Rome (Italy); Sisto, R [ISPESL - Istituto Superiore per la Prevenzione E la Sicurezza del Lavoro, Occupational Hygiene Department, Via Fontana Candida 1, I-0040 Monteporzio Catone (RM) (Italy)
2006-09-07
Within an epidemiological study regarding the correlation between skin pathologies and personal ultraviolet (UV) exposure due to solar radiation, 14 field campaigns using polysulphone (PS) dosemeters were carried out at three different Italian sites (urban, semi-rural and rural) in every season of the year. A polysulphone calibration curve for each field experiment was obtained by measuring the ambient UV dose under almost clear sky conditions and the corresponding change in the PS film absorbance, prior and post exposure. Ambient UV doses were measured by well-calibrated broad-band radiometers and by electronic dosemeters. The dose-response relation was represented by the typical best fit to a third-degree polynomial and it was parameterized by a coefficient multiplying a cubic polynomial function. It was observed that the fit curves differed from each other in the coefficient only. It was assessed that the multiplying coefficient was affected by the solar UV spectrum at the Earth's surface whilst the polynomial factor depended on the photoinduced reaction of the polysulphone film. The mismatch between the polysulphone spectral curve and the CIE erythemal action spectrum was responsible for the variability among polysulphone calibration curves. The variability of the coefficient was related to the total ozone amount and the solar zenith angle. A mathematical explanation of such a parameterization was also discussed.
Estimates for J-curves as submanifolds
Fish, Joel W
2009-01-01
Here we develop some basic analytic tools to study compactness properties of $J$-curves (i.e. pseudo-holomorphic curves) when regarded as submanifolds. Incorporating techniques from the theory of minimal surfaces, we derive an inhomogeneous mean curvature equation for such curves, we establish an extrinsic monotonicity principle for non-negative functions $f$ satisfying $\\Delta f\\geq -c^2 f$, we show that curves locally parameterized as a graph over a coordinate tangent plane have all derivatives a priori bounded in terms of curvature and ambient geometry, and we establish $\\epsilon$-regularity for the square length of their second fundamental forms. These results are all provided for $J$-curves either with or without Lagrangian boundary and hold in almost Hermitian manifolds of arbitrary even dimension (i.e. Riemannian manifolds for which the almost complex structure is an isometry).
Schmid, E; Selbach, H-J; Voth, M; Pinkert, J; Gildehaus, F J; Klett, R; Haney, M
2006-07-01
The production of dicentric chromosomes in human lymphocytes by beta-particles of yttrium-90 (Y-90) was studied in vitro to provide a basis of biological dosimetry after radiosynoviorthesis (RSO) of persistent synovitis by intra-articular administration of yttrium-90 citrate colloid. Since the injected colloid may leak into the lymphatic drainage exposing other parts of the body to radiation, the measurement of biological damage induced by beta-particles of Y-90 is important for the assessment of radiation risk to the patients. A linear dose-response relationship (alpha = 0.0229 +/- 0.0028 dicentric chromosomes per cell per gray) was found over the dose range of 0.2176-2.176 Gy. The absorbed doses were calculated for exposure of blood samples to Y-90 activities from 40 to 400 kBq using both Monte Carlo simulation and an analytical model. The maximum low-dose RBE, the RBE(M) which is equivalent to the ratio of the alpha coefficients of the dose-response curves, is well in line with published results obtained earlier for irradiation of blood of the same donor with heavily filtered 220 kV X-rays (3.35 mm copper), but half of the RBE(M) relative to weakly filtered 220 kV X-rays. Therefore, it can be concluded that for estimating an absorbed dose during RSO by the technique of biological dosimetry, in vitro and in vivo data for the same radiation quality are necessary.
Effect of Enamel Caries Lesion Baseline Severity on Fluoride Dose-Response
Directory of Open Access Journals (Sweden)
Frank Lippert
2017-01-01
Full Text Available This study aimed to investigate the effect of enamel caries lesion baseline severity on fluoride dose-response under pH cycling conditions. Early caries lesions were created in human enamel specimens at four different severities (8, 16, 24, and 36 h. Lesions were allocated to treatment groups (0, 83, and 367 ppm fluoride as sodium fluoride based on Vickers surface microhardness (VHN and pH cycled for 5 d. The cycling model comprised 3 × 1 min fluoride treatments sandwiched between 2 × 60 min demineralization challenges with specimens stored in artificial saliva in between. VHN was measured again and changes versus lesion baseline were calculated (ΔVHN. Data were analyzed using two-way ANOVA (p<0.05. Increased demineralization times led to increased surface softening. The lesion severity×fluoride concentration interaction was significant (p<0.001. Fluoride dose-response was observed in all groups. Lesions initially demineralized for 16 and 8 h showed similar overall rehardening (ΔVHN and more than 24 and 36 h lesions, which were similar. The 8 h lesions showed the greatest fluoride response differential (367 versus 0 ppm F which diminished with increasing lesion baseline severity. The extent of rehardening as a result of the 0 ppm F treatment increased with increasing lesion baseline severity, whereas it decreased for the fluoride treatments. In conclusion, lesion baseline severity impacts the extent of the fluoride dose-response.
Alanine aminotransferase and risk of the metabolic syndrome: a linear dose-response relationship.
Directory of Open Access Journals (Sweden)
Setor K Kunutsor
Full Text Available BACKGROUND: Elevated baseline circulating alanine aminotransferase (ALT level has been demonstrated to be associated with an increased risk of the metabolic syndrome (MetS, but the nature of the dose-response relationship is uncertain. METHODS: We performed a systematic review and meta-analysis of published prospective cohort studies to characterize in detail the nature of the dose-response relationship between baseline ALT level and risk of incident MetS in the general population. Relevant studies were identified in a literature search of MEDLINE, EMBASE, and Web of Science up to December 2013. Prospective studies in which investigators reported relative risks (RRs of MetS for 3 or more categories of ALT levels were eligible. A potential nonlinear relationship between ALT levels and MetS was examined using restricted cubic splines. RESULTS: Of the 489 studies reviewed, relevant data were available on 29,815 non-overlapping participants comprising 2,125 incident MetS events from five prospective cohort studies. There was evidence of a linear association (P for nonlinearity=0.38 between ALT level and risk of MetS, characterised by a graded increase in MetS risk at ALT levels 6-40 U/L. The risk of MetS increased by 14% for every 5 U/L increment in circulating ALT level (95% CI: 12-17%. Evidence was lacking of heterogeneity and publication bias among the contributing studies. CONCLUSIONS: Baseline ALT level is associated with risk of the MetS in a linear dose-response manner. Studies are needed to determine whether the association represents a causal relationship.
Dose-response relationship between physical activity and dyslipidemia in youth.
LeBlanc, Allana G; Janssen, Ian
2010-01-01
The minimal and optimal amount of physical activity associated with cardiovascular health benefits in young people is unknown. To determine the dose-response relationship between moderate-to-vigorous physical activity (MVPA) with high-risk low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride values in youth. The study sample consisted of 1235 adolescents (12 to 19 years of age) from the 20032004 and 20052006 cycles of the United States National Health and Nutrition Examination Survey. Objective measures of MVPA were obtained over seven days with accelerometers. LDL cholesterol, HDL cholesterol and triglycerides were measured from a fasting blood sample. High-risk values for these lipidslipoproteins were determined using age- and sex-specific thresholds. Logistic regression models were used to determine the dose-response relationships between MVPA and high-risk lipid levels. ORs for high-risk HDL cholesterol and triglyceride values decreased in a curvilinear manner with increasing minutes of MVPA. Compared with no MVPA (0 min), the ORs for high-risk HDL cholesterol values at 15 min, 30 min and 60 min per day of MVPA were 0.29 (95% CI 0.13 to 0.67), 0.24 (95% CI 0.10 to 0.64) and 0.21 (95% CI 0.07 to 0.61), respectively. The corresponding ORs for high-risk triglyceride values were 0.40 (95% CI 0.18 to 0.76), 0.22 (95% CI 0.06 to 0.66) and 0.10 (95% CI 0.01 to 0.51). There was no discernible dose-response relationship between MVPA and LDL cholesterol. Small amounts of MVPA were associated with a large reduction in the likelihood of having high-risk HDL cholesterol and triglyceride values in this representative sample of adolescents.
Directory of Open Access Journals (Sweden)
Hugo A. Rondón-Quintana
2012-12-01
Full Text Available The influence of compaction temperature on resistance under monotonic loading (Marshall of Crumb-Rubber Modified (CRM Hot-Mix Asphalt (HMA was evaluated. The emphasis of this study was the application in Bogotá D.C. (Colombia. In this city the compaction temperature of HMA mixtures decreases, compared to the optimum, in about 30°C. Two asphalt cements (AC 60-70 and AC 80-100 were modified. Two particle sizes distribution curve were used. The compaction temperatures used were 120, 130, 140 and 150°C. The decrease of the compaction temperature produces a small decrease in resistance under monotonic loading of the modified mixtures tested. Mixtures without CRM undergo a lineal decrease in its resistance of up to 34%.
Time course and dose response of alpha tocopherol on oxidative stress in haemodialysis patients
Directory of Open Access Journals (Sweden)
Coombes Jeff S
2009-10-01
Full Text Available Abstract Background Oxidative stress is associated with increased cardiovascular morbidity and mortality particularly in patients with end stage kidney disease. Although observational data from the general population has shown dietary antioxidant intake is associated with reduced cardiovascular morbidity and mortality, most clinical intervention trials have failed to support this relationship. This may be a consequence of not using an effective antioxidant dose and/or not investigating patients with elevated oxidative stress. The SPACE study, conducted in haemodialysis patients, reported that 800 IU/day of alpha tocopherol significantly reduced cardiovascular disease endpoints. A recent time course and dose response study conducted in hypercholesterolaemic patients that found 1600 IU/day of alpha tocopherol was an optimal dose. There is no such dose response data available for haemodialysis patients. Therefore the aim of this study is to investigate the effect of different doses of oral alpha tocopherol on oxidative stress in haemodialysis patients with elevated oxidative stress and the time taken to achieve this effect. Methods The study will consist of a time-course followed by a dose response study. In the time course study 20 haemodialysis patients with elevated oxidative stress will take either 1600 IU/day natural (RRR alpha tocopherol for 20 weeks or placebo. Blood will be collected every two weeks and analysed for a marker of oxidative stress (plasma F2-isoprostanes and alpha tocopherol. The optimum time period to significantly decrease plasma F2-isoprostanes will be determined from this study. In the dose response study 60 patients will be randomised to receive either placebo, 100, 200, 400, 800 or 1600 IU/day of natural (RRR alpha tocopherol for a time period determined from the time course study. Blood will be collected at baseline and every two weeks and analysed for plasma F2-isoprostanes and alpha tocopherol. It is hypothesised that
Dose-response of strengthening exercise for treatment of severe neck pain in women
DEFF Research Database (Denmark)
Andersen, Christoffer H; Andersen, Lars Louis; Pedersen, Mogens T
2013-01-01
Specific strength training is shown relieves neck pain in office workers. The purpose of this study is to evaluate the effectiveness of specific strength training in women with severe neck pain and to analyze the dose-response relationship between training adherence and pain reduction. 118...... untrained women with severe neck pain (>30 mm VAS pain) were included from a larger study, in which the subjects were randomized to 20-weeks specific strength training for the neck/shoulders or to a control group. In the intention-to-treat analysis, the training group experienced greater pain relief than...
Stereo Matching of Planar Curves Composed of Time Stamped Points
Institute of Scientific and Technical Information of China (English)
Wang Shuwen; Zhang Tianxu
2006-01-01
Matching features such as curve segments in stereo images play a very important role in scene reconstruction. In this paper, a stereo matching algorithm for the trajectories composed of time stamped points is proposed. Based on time stamped points, planar curve match measurements are given first, such as time constraint, cross-ratio invariant constraint and epipolar geometry constraint;then, a trajectory matching method is proposed based on epipolar geometry constraint and cross-ratio invariant constraint. In order to match the planar curve segments projected by perspective projection system, the curve start time and end time are selected first to prepare match candidates. Then, the epipolar equation is used to discard the unmatched curve segment candidates. At last, a cross ratio invariant constraint is used to find the most matched curve segments. If their match measurement is higher than the specialized threshold, a candidate with the least cross ratio difference is then selected as the match result; otherwise, no match is found. Unlike the conventional planar curve segments matching algorithm, this paper presents a weakly calibrated binocular stereo vision system which is based on wide baseline. The stamped points are obtained by targets detecting method of flying objects from image sequences.Due to wide baseline, there must exist the projection not in epipolar monotonic order or the curve segments located in very short distance and keeping the epipolar monotonic order. By using the method mentioned above, experiments are made to match planar curve segments not only in epipolar monotonic order but also not in epipolar monotonic order. The results show that the performance of our curve matching algorithm is effective for matching the arc-like planar trajectories composed of time stamped points.
Non-monotonic effect of confinement on the glass transition
Varnik, Fathollah; Franosch, Thomas
2016-04-01
The relaxation dynamics of glass forming liquids and their structure are influenced in the vicinity of confining walls. This effect has mostly been observed to be a monotonic function of the slit width. Recently, a qualitatively new behaviour has been uncovered by Mittal and coworkers, who reported that the single particle dynamics in a hard-sphere fluid confined in a planar slit varies in a non-monotonic way as the slit width is decreased from five to roughly two particle diametres (Mittal et al 2008 Phys. Rev. Lett. 100 145901). In view of the great potential of this effect for applications in those fields of science and industry, where liquids occur under strong confinement (e.g. nano-technology), the number of researchers studying various aspects and consequences of this non-monotonic behaviour has been rapidly growing. This review aims at providing an overview of the research activity in this newly emerging field. We first briefly discuss how competing mechanisms such as packing effects and short-range attraction may lead to a non-monotonic glass transition scenario in the bulk. We then analyse confinement effects on the dynamics of fluids using a thermodynamic route which relates the single particle dynamics to the excess entropy. Moreover, relating the diffusive dynamics to the Widom’s insertion probability, the oscillations of the local dynamics with density at moderate densities are fairly well described. At high densities belonging to the supercooled regime, however, this approach breaks down signaling the onset of strongly collective effects. Indeed, confinement introduces a new length scale which in the limit of high densities and small pore sizes competes with the short-range local order of the fluid. This gives rise to a non-monotonic dependence of the packing structure on confinement, with a corresponding effect on the dynamics of structural relaxation. This non-monotonic effect occurs also in the case of a cone-plate type channel, where the degree
DEFF Research Database (Denmark)
Christiansen, E; Goldney, R D; Beautrai, A L;
2011-01-01
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......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...... to each case and a link to the offspring's biological parents was established. RESULTS: There was a dose-response relationship between the number of exposures and the risk of suicide attempts, with the increased risk seeming to be a multiplicative effect. Parental suicide, suicide attempt, psychiatric...
Leusden FM van; MGB
2001-01-01
A hazard identification and characterisation, including a preliminary dose response assessment, of sporeforming pathogens in cooked chilled food containing vegetables was performed according to the structure and principles for a quantitative microbiological risk assessment as described by the Codex
Mureşan, Ioana Cristina; Bâlc, Roxana
2017-07-01
This paper presents an experimental investigation of a statically monotonic loaded extended end-plate connection, with preloaded high strength bolts, that was carried out at Laboratory of Faculty of Civil Engineering from Cluj-Napoca. A finite element model using the software package Abaqus [1] was developed in parallel. In order to calibrate the numerical model, the results were analyzed on the basis of moment-rotation curves, stress distribution state and the failure mode of connection. Then, a study was conducted on the numerical model by using a high strength steel (HSS) and changing the stiffness and strength characteristics of some elements. Validation of the numerical modeling was performed against the experimental results and it can be seen that good agreements exist in general.
DEFF Research Database (Denmark)
Matthews, Charles E; Keadle, S. K.; Troiano, Richard P
2016-01-01
Background: Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. Objectives: Using accelerometer-based measures, we 1) described the mortality dose-response for se......Background: Moderate-to-vigorous-intensity physical activity is recommended to maintain and improve health, but the mortality benefits of light activity and risk for sedentary time remain uncertain. Objectives: Using accelerometer-based measures, we 1) described the mortality dose......-response for sedentary time and light-and moderateto-vigorous-intensity activity using restricted cubic splines, and 2) estimated the mortality benefits associated with replacing sedentary time with physical activity, accounting for total activity. Design: US adults (n = 4840) from NHANES (2003-2006) wore...... an accelerometer for #7 d and were followed prospectively for mortality. Proportional hazards models were used to estimate adjusted HRs and 95% CIs for mortality associations with time spent sedentary and in light-and moderate-to-vigorous-intensity physical activity. Splines were used to graphically present...
Cancer risk assessment: Optimizing human health through linear dose-response models.
Calabrese, Edward J; Shamoun, Dima Yazji; Hanekamp, Jaap C
2015-07-01
This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot". Copyright © 2015 Elsevier Ltd. All rights reserved.
Bayesian penalized log-likelihood ratio approach for dose response clinical trial studies.
Tang, Yuanyuan; Cai, Chunyan; Sun, Liangrui; He, Jianghua
2017-02-13
In literature, there are a few unified approaches to test proof of concept and estimate a target dose, including the multiple comparison procedure using modeling approach, and the permutation approach proposed by Klingenberg. We discuss and compare the operating characteristics of these unified approaches and further develop an alternative approach in a Bayesian framework based on the posterior distribution of a penalized log-likelihood ratio test statistic. Our Bayesian approach is much more flexible to handle linear or nonlinear dose-response relationships and is more efficient than the permutation approach. The operating characteristics of our Bayesian approach are comparable to and sometimes better than both approaches in a wide range of dose-response relationships. It yields credible intervals as well as predictive distribution for the response rate at a specific dose level for the target dose estimation. Our Bayesian approach can be easily extended to continuous, categorical, and time-to-event responses. We illustrate the performance of our proposed method with extensive simulations and Phase II clinical trial data examples.
Directory of Open Access Journals (Sweden)
Paul D. Loprinzi
2013-08-01
Full Text Available Background: Few population-based studies have examined the association between physical activity (PA and cardiovascular disease risk factors, demographic variables, and perceptions of health status, and we do not have a clear understanding of the dose-response relationship among these variables. Methods: Data from the 2003-2006 National Health and Nutrition Examination Survey was used to examine the dose-response relationship between objectively measured PA and metabolic syndrome (and its individual cardiovascular disease risk factors, demographic variables, and perceptions of health. After exclusions, 5,538 participants 18 years or older were included in the present study, with 2,538 participants providing fasting glucose and 2,527 providing fasting triglyceride data. PA was categorized into deciles. Results: Overall, the health benefits showed a general pattern of increase with each increasing levels of PA. Of the ten PA classifications examined, participants in the highest moderate-to-vigorous physical activity (MVPA category (at least 71 min/day had the lowest odds of developing metabolic syndrome. Conclusion: At a minimum, sedentary adults should strive to meet current PA guidelines (i.e., 150 min/week of MVPA, with additional positive benefits associated with engaging in three times this level of PA.
Greenwood, Darren C; Thatcher, Natalie J; Ye, Jin; Garrard, Lucy; Keogh, Georgina; King, Laura G; Cade, Janet E
2014-10-01
Caffeine is commonly consumed during pregnancy, crosses the placenta, with fetal serum concentrations similar to the mother's, but studies of birth outcome show conflicting findings. We systematically searched Medline and Embase for relevant publications. We conducted meta-analysis of dose-response curves for associations between caffeine intake and spontaneous abortion, stillbirth, preterm delivery, low birth weight and small for gestational age (SGA) infants. Meta-analyses included 60 unique publications from 53 cohort and case-control studies. An increment of 100 g caffeine was associated with a 14 % (95 % CI 10-19 %) increase in risk of spontaneous abortion, 19 % (5-35 %) stillbirth, 2 % (-2 to 6 %) preterm delivery, 7 % (1-12 %) low birth weight, and 10 % (95 % CI 6-14 %) SGA. There was substantial heterogeneity in all models, partly explained by adjustment for smoking and previous obstetric history, but not by prospective assessment of caffeine intake. There was evidence of small-study effects such as publication bias. Greater caffeine intake is associated with an increase in spontaneous abortion, stillbirth, low birth weight, and SGA, but not preterm delivery. There is no identifiable threshold below which the associations are not apparent, but the size of the associations are generally modest within the range of usual intake and are potentially explained by bias in study design or publication. There is therefore insufficient evidence to support further reductions in the maximum recommended intake of caffeine, but maintenance of current recommendations is a wise precaution.
Hsieh, Yu-wei; Wu, Ching-yi; Lin, Keh-chung; Yao, Grace; Wu, Kuen-yuh; Chang, Ya-ju
2012-10-01
The increasing availability of robot-assisted therapy (RT), which provides quantifiable, reproducible, interactive, and intensive practice, holds promise for stroke rehabilitation, but data on its dose-response relation are scanty. This study used 2 different intensities of RT to examine the treatment effects of RT and the effect on outcomes of the severity of initial motor deficits. Fifty-four patients with stroke were randomized to a 4-week intervention of higher-intensity RT, lower-intensity RT, or control treatment. The primary outcome, the Fugl-Meyer Assessment, was administered at baseline, midterm, and posttreatment. Secondary outcomes included the Medical Research Council scale, the Motor Activity Log, and the physical domains of the Stroke Impact Scale. The higher-intensity RT group showed significantly greater improvements on the Fugl-Meyer Assessment than the lower-intensity RT and control treatment groups at midterm (P=0.003 and P=0.02) and at posttreatment (P=0.04 and P=0.02). Within-group gains on the secondary outcomes were significant, but the differences among the 3 groups did not reach significance. Recovery rates of the higher-intensity RT group were higher than those of the lower-intensity RT group, particularly on the Fugl-Meyer Assessment. Scatterplots with curve fitting showed that patients with moderate motor deficits gained more improvements than those with severe or mild deficits after the higher-intensity RT. This study demonstrated the higher treatment intensity provided by RT was associated with better motor outcome for patients with stroke, which may shape further stroke rehabilitation. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00917605.
A Hybrid Approach to Proving Memory Reference Monotonicity
Oancea, Cosmin E.
2013-01-01
Array references indexed by non-linear expressions or subscript arrays represent a major obstacle to compiler analysis and to automatic parallelization. Most previous proposed solutions either enhance the static analysis repertoire to recognize more patterns, to infer array-value properties, and to refine the mathematical support, or apply expensive run time analysis of memory reference traces to disambiguate these accesses. This paper presents an automated solution based on static construction of access summaries, in which the reference non-linearity problem can be solved for a large number of reference patterns by extracting arbitrarily-shaped predicates that can (in)validate the reference monotonicity property and thus (dis)prove loop independence. Experiments on six benchmarks show that our general technique for dynamic validation of the monotonicity property can cover a large class of codes, incurs minimal run-time overhead and obtains good speedups. © 2013 Springer-Verlag.
Measurement of non-monotonic Casimir forces between silicon nanostructures
Tang, L.; Wang, M.; Ng, C. Y.; Nikolic, M.; Chan, C. T.; Rodriguez, A. W.; Chan, H. B.
2017-01-01
Casimir forces are of fundamental interest because they originate from quantum fluctuations of the electromagnetic field. Apart from controlling this force via the optical properties of materials, a number of novel geometries have been proposed to generate repulsive and/or non-monotonic Casimir forces between bodies separated by vacuum gaps. Experimental realization of these geometries, however, is hindered by the difficulties in alignment when the bodies are brought into close proximity. Here, using an on-chip platform with integrated force sensors and actuators, we circumvent the alignment problem and measure the Casimir force between two surfaces with nanoscale protrusions. We demonstrate that the force depends non-monotonically on the displacement. At some displacements, the Casimir force leads to an effective stiffening of the nanomechanical spring. Our findings pave the way for exploiting the Casimir force in nanomechanical systems using structures of complex and non-conventional shapes.
A Monotonic Precise Current DAC for Sensor Applications
Directory of Open Access Journals (Sweden)
P. Horsky
2008-12-01
Full Text Available In this paper a 17 bit monotonic precise current DAC for sensor applications is described. It is working in a harsh automotive environment in a wide temperature range with high output voltage swing and low current consumption. To guarantee monotonicity current division and segmentation techniques are used. To improve the output impedance, the accuracy and the voltage compliance of the DAC, two active cascoding loops and one follower loop are used. The resolution of the DAC is further increased by applying pulse width modulation to one fine LSB current. To achieve low power consumption unused coarse current sources are switched off. Several second order technological effects influencing final performance and circuits dealing with them are discussed.
Computation of Optimal Monotonicity Preserving General Linear Methods
Ketcheson, David I.
2009-07-01
Monotonicity preserving numerical methods for ordinary differential equations prevent the growth of propagated errors and preserve convex boundedness properties of the solution. We formulate the problem of finding optimal monotonicity preserving general linear methods for linear autonomous equations, and propose an efficient algorithm for its solution. This algorithm reliably finds optimal methods even among classes involving very high order accuracy and that use many steps and/or stages. The optimality of some recently proposed methods is verified, and many more efficient methods are found. We use similar algorithms to find optimal strong stability preserving linear multistep methods of both explicit and implicit type, including methods for hyperbolic PDEs that use downwind-biased operators.
Rational functions with maximal radius of absolute monotonicity
Loczi, Lajos
2014-05-19
We study the radius of absolute monotonicity R of rational functions with numerator and denominator of degree s that approximate the exponential function to order p. Such functions arise in the application of implicit s-stage, order p Runge-Kutta methods for initial value problems and the radius of absolute monotonicity governs the numerical preservation of properties like positivity and maximum-norm contractivity. We construct a function with p=2 and R>2s, disproving a conjecture of van de Griend and Kraaijevanger. We determine the maximum attainable radius for functions in several one-parameter families of rational functions. Moreover, we prove earlier conjectured optimal radii in some families with 2 or 3 parameters via uniqueness arguments for systems of polynomial inequalities. Our results also prove the optimality of some strong stability preserving implicit and singly diagonally implicit Runge-Kutta methods. Whereas previous results in this area were primarily numerical, we give all constants as exact algebraic numbers.
DEFF Research Database (Denmark)
Christiansen, E; Vestergaard, H; Tibell, A
1996-01-01
Insulin resistance is a characteristic feature in recipients of a pancreas transplant, but the relative contribution of the liver and peripheral tissues to this abnormality within a spanning range of insulin concentrations is unknown. To assess the impact of insulin action on glucose metabolism....... The overall effects of insulin on whole-body glucose metabolism, determined as the glucose infusion rates versus the corresponding steady-state serum insulin concentrations, demonstrated a rightward shift in the dose-response curves of the transplanted groups compared with those of normal subjects. The dose...... subjects (19.1 +/- 2.2 mg.kg-1 fat-free mass.min-1) (P insulin concentrations. Glucose oxidation rates were similar in all groups, whereas nonoxidative glucose rates were reduced...
On Uniqueness of Conjugacy of Continuous and Piecewise Monotone Functions
Directory of Open Access Journals (Sweden)
Krzysztof Ciepliński
2009-01-01
Full Text Available We investigate the existence and uniqueness of solutions φ:I→J of the functional equation φ(f(x=F(φ(x, x∈I, where I,J are closed intervals, and f:I→I, F:J→J are some continuous piecewise monotone functions. A fixed point principle plays a crucial role in the proof of our main result.
Block Monotone Iterative Algorithms for Variational Inequalities with Nonlinear Operators
Institute of Scientific and Technical Information of China (English)
Ming-hui Ren; Jin-ping Zeng
2008-01-01
Some block iterative methods for solving variational inequalities with nonlinear operators are proposed. Monotone convergence of the algorithms is obtained. Some comparison theorems are also established.Compared with the research work in given by Pao in 1995 for nonlinear equations and research work in given by Zeng and Zhou in 2002 for elliptic variational inequalities, the algorithms proposed in this paper are independent of the boundedness of the derivatives of the nonlinear operator.
Monotonic Property in Field Algebra of G-Spin Model
Institute of Scientific and Technical Information of China (English)
蒋立宁
2003-01-01
Let F be the field algebra of G-spin model, D(G) the double algebra of a finite group G and D(H) the sub-Hopf algerba of D(G) determined by the subgroup H of G. The paper builds a correspondence between D(H) and the D(H)-invariant sub-C*-algebra AH in F, and proves that the correspondence is strictly monotonic.
Modeling argumentation based semantics using non-monotonic reasoning
2005-01-01
Argumentation theory is an alternative style of formalizing non-monotonic reasoning. It seems, argumentation theory is a suitable framework for practical and uncertain reasoning, where arguments support conclusions. Dung's approach is an unifying framework which has played an influential role on argumentation research and Artificial Intelligence. Even though the success of the argumentation theory, it seems that argumentation theory is so far from being efficiently implemented like the logic ...
Nonparametric estimation for hazard rate monotonously decreasing system
Institute of Scientific and Technical Information of China (English)
Han Fengyan; Li Weisong
2005-01-01
Estimation of density and hazard rate is very important to the reliability analysis of a system. In order to estimate the density and hazard rate of a hazard rate monotonously decreasing system, a new nonparametric estimator is put forward. The estimator is based on the kernel function method and optimum algorithm. Numerical experiment shows that the method is accurate enough and can be used in many cases.
Stability and monotonicity of Lotka-Volterra type operators
Mukhamedov, Farrukh
2009-01-01
In the present paper, we study Lotka-Volterra (LV) type operators defined in finite dimensional simplex. We prove that any LV type operator is a surjection of the simplex. After, we introduce a new class of LV-type operators, called $M$LV type. We prove convergence of their trajectories and study certain its properties. Moreover, we show that such kind of operators have totaly different behavior than ${\\mathbf{f}}$-monotone LV type operators.
Monotone traveling wavefronts of the KPP-Fisher delayed equation
Gomez, Adrian; Trofimchuk, Sergei
In the early 2000's, Gourley (2000), Wu et al. (2001), Ashwin et al. (2002) initiated the study of the positive wavefronts in the delayed Kolmogorov-Petrovskii-Piskunov-Fisher equation u(t,x)=Δu(t,x)+u(t,x)(1-u(t-h,x)), u⩾0, x∈R. Since then, this model has become one of the most popular objects in the studies of traveling waves for the monostable delayed reaction-diffusion equations. In this paper, we give a complete solution to the problem of existence and uniqueness of monotone waves in Eq. (*). We show that each monotone traveling wave can be found via an iteration procedure. The proposed approach is based on the use of special monotone integral operators (which are different from the usual Wu-Zou operator) and appropriate upper and lower solutions associated to them. The analysis of the asymptotic expansions of the eventual traveling fronts at infinity is another key ingredient of our approach.
Solving the power flow equations: a monotone operator approach
Energy Technology Data Exchange (ETDEWEB)
Dvijotham, Krishnamurthy [California Inst. of Technology (CalTech), Pasadena, CA (United States); Low, Steven [California Inst. of Technology (CalTech), Pasadena, CA (United States); Chertkov, Michael [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
2015-07-21
The AC power flow equations underlie all operational aspects of power systems. They are solved routinely in operational practice using the Newton-Raphson method and its variants. These methods work well given a good initial “guess” for the solution, which is always available in normal system operations. However, with the increase in levels of intermittent generation, the assumption of a good initial guess always being available is no longer valid. In this paper, we solve this problem using the theory of monotone operators. We show that it is possible to compute (using an offline optimization) a “monotonicity domain” in the space of voltage phasors. Given this domain, there is a simple efficient algorithm that will either find a solution in the domain, or provably certify that no solutions exist in it. We validate the approach on several IEEE test cases and demonstrate that the offline optimization can be performed tractably and the computed “monotonicity domain” includes all practically relevant power flow solutions.
Zhao, Qi; Yi, Ming; Liu, Yan
2011-10-01
The mitogen-activated protein kinase (MAPK) cascade plays a critical role in the control of cell growth. Deregulation of this pathway contributes to the development of many cancers. To better understand its signal transduction, we constructed a reaction-diffusion model for the MAPK pathway. We modeled the three layers of phosphorylation-dephosphorylation reactions and diffusion processes from the cell membrane to the nucleus. Based on different types of feedback in the MAPK cascade, four operation modes are introduced. For each of the four modes, spatial distributions and dose-response curves of active kinases (i.e. ppMAPK) are explored by numerical simulation. The effects of propagation length, diffusion coefficient and feedback strength on the pathway dynamics are investigated. We found that intrinsic bistability in the MAPK cascade can generate a traveling wave of ppMAPK with constant amplitude when the propagation length is short. ppMAPK in this mode of intrinsic bistability decays more slowly than it does in all other modes as the propagation length increases. Moreover, we examined the global and local responses to Ras-GTP of these four modes, and demonstrated how the shapes of these dose-response curves change as the propagation length increases. Also, we found that larger diffusion constant gives a higher response level on the zero-order regime and makes the ppMAPK profiles flatter under strong Ras-GTP stimulus. Furthermore, we observed that spatial responses of ppMAPK are more sensitive to negative feedback than to positive feedback in the broader signal range. Finally, we showed how oscillatory signals pass through the kinase cascade, and found that high frequency signals are damped faster than low frequency ones.
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
Directory of Open Access Journals (Sweden)
Feng Qi
2014-10-01
Full Text Available The authors find the absolute monotonicity and complete monotonicity of some functions involving trigonometric functions and related to estimates the lower bounds of the first eigenvalue of Laplace operator on Riemannian manifolds.
Non-monotonic reasoning in conceptual modeling and ontology design: A proposal
CSIR Research Space (South Africa)
Casini, G
2013-06-01
Full Text Available and modeling of defeasible information and non-monotonic reasoning services. Here we formalize a possible way of introducing non-monotonic reasoning into ORM2 schemas, enriching the language with special set of new constraints....
Dose-response effect of the lercanidipine/enalapril combination: a pooled analysis.
Rizzoni, Damiano
2016-10-01
The dose-effect relationship of fixed-dose combinations of anti-hypertensive drugs has been only poorly explored. This pooled analysis investigates the dose-response relationship of fixed-dose lercanidipine + enalapril in patients with mild-to-moderate hypertension. This was an individual patient data analysis of four randomized studies (n = 2340). The primary efficacy variable was the change from baseline in sitting diastolic blood pressure (SDBP). Secondary variables were change from baseline in sitting systolic BP (SSBP), proportion of responder patients, and safety. All fixed-dose combinations were superior to placebo in the reduction of SDBP. The greatest effect was observed with the market-available combination lercanidipine 20 mg/enalapril 20 mg (-15.3 mmHg vs. baseline; p < 0.05). The reduction in SDBP associated with the other two marketed fixed combinations of lercanidipine/enalapril were -10.7 mmHg for the 10 mg/20 mg combination and -9.8 mmHg for the 10 mg/10 mg combination (p < .05 for both comparisons). Similar findings were reported for SSBP reduction: the greatest effect was observed with lercanidipine 20 mg/enalapril 20 mg (-19.2 mmHg). The reduction in SSBP was -12.5 mmHg for the 10 mg/20 mg combination and -11.1 mmHg for the 10 mg/10 mg combination (p < .05 for all comparisons). The highest responder rate was reported with lercanidipine 20 mg/enalapril 20 mg (75.0%); this figure was 56.1% with the 10 mg/20 mg and 53.0% with the 10/10 mg combination. No safety concerns were reported. This pooled analysis of four randomized studies shows evidence of a dose-response effect in BP reduction with different fixed combinations of lercanidipine + enalapril. To our knowledge, this is the first analysis investigating the dose-response effect of a specific fixed-dose combination of anti-hypertensive agents. Further studies on this intriguing topic are however necessary.
Mixed Monotonicity of Partial First-In-First-Out Traffic Flow Models
Coogan, Samuel; Arcak, Murat; Kurzhanskiy, Alexander A.
2015-01-01
In vehicle traffic networks, congestion on one outgoing link of a diverging junction often impedes flow to other outgoing links, a phenomenon known as the first-in-first-out (FIFO) property. Simplified traffic models that do not account for the FIFO property result in monotone dynamics for which powerful analysis techniques exist. FIFO models are in general not monotone, but have been shown to be mixed monotone - a generalization of monotonicity that enables similarly powerful analysis techni...
SO/sub 2/ dose-response sensitivity classification data for crops and natural vegetation species
Energy Technology Data Exchange (ETDEWEB)
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.
Israelsson, A; Gustafsson, H; Lund, E
2013-04-01
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).
Mass shootings: a meta-analysis of the dose-response relationship.
Wilson, Laura C
2014-12-01
A meta-analysis was conducted to examine the dose-response theory as it relates to posttraumatic stress symptoms (PTSSs) following mass shootings. It was hypothesized that greater exposure to a mass shooting would be associated with greater PTSSs. Trauma exposure in the current study was broadly defined as the extent to which a person experienced or learned about a mass shooting. The meta-analysis identified 11 qualifying studies that included 13 independent effect sizes from a total of 8,047 participants. The overall weighted mean effect size, based on a random effects model, was r = .19, p < .001, 95% CI [.13, .25]. Maximum likelihood meta-regressions revealed no significant linear effects of participant gender, participant age, or time elapsed since the shooting on the relationship between exposure and PTSSs. Because so few studies satisfied the inclusion criteria, the present study also documents that this area of the literature is underresearched.
SynergyFinder: a web application for analyzing drug combination dose-response matrix data.
Ianevski, Aleksandr; He, Liye; Aittokallio, Tero; Tang, Jing
2017-08-01
Rational design of drug combinations has become a promising strategy to tackle the drug sensitivity and resistance problem in cancer treatment. To systematically evaluate the pre-clinical significance of pairwise drug combinations, functional screening assays that probe combination effects in a dose-response matrix assay are commonly used. To facilitate the analysis of such drug combination experiments, we implemented a web application that uses key functions of R-package SynergyFinder, and provides not only the flexibility of using multiple synergy scoring models, but also a user-friendly interface for visualizing the drug combination landscapes in an interactive manner. The SynergyFinder web application is freely accessible at https://synergyfinder.fimm.fi ; The R-package and its source-code are freely available at http://bioconductor.org/packages/release/bioc/html/synergyfinder.html . jing.tang@helsinki.fi.
Extended application of dose-response models of infection on injectable insulin products in vials
Directory of Open Access Journals (Sweden)
Mostafa Essam Eissa
2016-09-01
Full Text Available Microbial contamination from in-use application of multidose pharmaceutical products constitutes health hazard to the consumer especially when considering injectable medicines. In the present study, an attempt has been made to integrate dose-response models of infections with pharmacopeial preservative efficacy test (PET in a single simulation study that supposed accidental reuse of hypodermic syringe. Probability risk ratio of infection from assumed equal doses of two types of microbes by two routes of infection was greater than 1300 at most equivalent administration doses when considering the same reduction factor for both bacteria in the antimicrobial efficacy test (AET. The probability of infection would diminish much more rapidly for Staphylococcus aureus rather than Pseudomonas aeruginosa. The short interval of product administration increased the risk of infection with regular-type of Insulin vials. The current quantitative study provided extension and made the best use of the standard AET but also highlighted its limitations.
Muller's Nobel lecture on dose-response for ionizing radiation: ideology or science?
Calabrese, Edward J
2011-12-01
In his Nobel Prize Lecture of December 12, 1946, Hermann J. Muller argued that the dose-response for radiation-induced germ cell mutations was linear and that there was "no escape from the conclusion that there is no threshold". However, assessment of correspondence between Muller and Curt Stern 1 month prior to his Nobel Prize Lecture reveals that Muller knew the results and implications of a recently completed study at the University of Rochester under the direction of Stern, which directly contradicted his Nobel Prize Lecture. This finding is of historical importance since Muller's Nobel Lecture gained considerable international attention and is a turning point in the acceptance of the linearity model in risk assessment for germ cell mutations and carcinogens.
Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure.
Directory of Open Access Journals (Sweden)
Sara C Johnston
Full Text Available Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies.
Directory of Open Access Journals (Sweden)
Shitikov Vladimir Kirilloviсh
2015-09-01
Full Text Available The review of regression models for the approximation of dependences "dose- response" was performed based on ecotoxicological results. The advantages and deficiencies of different models as well as the problems arising both in modeling and subsequent interpreting results are discussed for the purpose of ecological rationing and estimation of negative influence risk. Search procedures of best dependences based on statistical criteria and the methods of uncertainty estimation of calculated parameters are shown. Construction of models is illustrated in detail using the analysis of toxicity results of soil samples received from uranium mines tailings in Kadzhi-Say province (Kyrgyzstan. Threshold values of activity for U-238 and Ra-226 radionuclides providing the minimum probability of ecological risk were determined.
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.
The dose-response relationship between in-ear occupational noise exposure and hearing loss.
Rabinowitz, Peter M; Galusha, Deron; Dixon-Ernst, Christine; Clougherty, Jane E; Neitzel, Richard L
2013-10-01
Current understanding of the dose-response relationship between occupational noise and hearing loss is based on cross-sectional studies prior to the widespread use of hearing protection, and with limited data regarding noise exposures below 85 dBA. We report on the hearing loss experience of a unique cohort of industrial workers, with daily monitoring of noise inside of hearing protection devices. At an industrial facility, workers exhibiting accelerated hearing loss were enrolled in a mandatory programme to monitor daily noise exposures inside of hearing protection. We compared these noise measurements (as time-weighted LAVG) to interval rates of high-frequency hearing loss over a 6-year period using a mixed-effects model, adjusting for potential confounders. Workers' high-frequency hearing levels at study inception averaged more than 40 dB Hearing threshold level (HTL). Most noise exposures were less than 85 dBA (mean LAVG 76 dBA, IQR 74-80 dBA). We found no statistical relationship between LAvg and high-frequency hearing loss (p=0.53). Using a metric for monthly maximum noise exposure did not improve model fit. At-ear noise exposures below 85 dBA did not show an association with risk of high-frequency hearing loss among workers with substantial past noise exposure and hearing loss at baseline. Therefore, effective noise control to below 85 dBA may lead to significant reduction in occupational hearing loss risk in such individuals. Further research is needed on the dose-response relationship of noise and hearing loss in individuals with normal hearing and little prior noise exposure.
Parity and risk of colorectal cancer: a dose-response meta-analysis of prospective studies.
Directory of Open Access Journals (Sweden)
Hong-Bo Guan
Full Text Available BACKGROUND: Association between parity and colorectal cancer (CRC risk has been investigated by several epidemiological studies but results are controversial, yet a comprehensive and quantitative assessment of this association has not been reported so far. METHODS: Relevant published studies of parity and CRC were identified using MEDLINE, EMBASE and Web of Science databases through end of April 2013. Two authors independently assessed eligibility and extracted data. Eleven prospective studies reported relative risk (RR estimates and 95% confidence intervals (CIs of CRC risk associated with parity. We pooled the RR from individual studies using fixed- or random-effects models and carried out heterogeneity and publication bias analyses. RESULTS: The summary RR for the ever parity vs. nulliparous was 0.95 (95% CI: 0.88-1.02, with no heterogeneity (Q = 9.04, P = 0.443, I (2 = 0.5%. Likewise, no significant association was yielded for the highest vs. lowest parity number (RR = 1.02, 95% CI: 0.89-1.17, with moderate heterogeneity (Q = 17.48, P = 0.094, I (2 = 37.1%. Dose-response analysis still indicated no effect of parity on CRC risk and the summary RR of per one livebirth was 0.99 (95% CI: 0.96-1.02, with moderate of heterogeneity (Q = 16.50, P<0.021, I (2 = 57.6%. Similar results were observed among all the subgroup analyses. No evidence of publication bias and significant heterogeneity between subgroups were detected by meta-regression analyses. CONCLUSION: Results of this dose-response meta-analysis of prospective studies found that there was little evidence of an association between parity and CRC risk.
[Occlusion treatment for amblyopia. Age dependence and dose-response relationship].
Fronius, M
2016-04-01
Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.
Horowitz, Y S; Eliyahu, I; Oster, L
2016-12-01
The reader will time-travel through almost seven decades of kinetic models and mathematical simulations of thermoluminescence (TL) characteristics based on the band-gap theory of the solid state. From post-World-War II, ideas concerning electron trapping mechanisms to the highly idealised one trap-one recombination (OTOR) model first elaborated in 1956 but still in 'high gear' today. The review caresses but purposely avoids in-depth discussion of the endless stream of papers discussing the intricacies of glow peak shapes arising from first-order, second-order, mixed-order and general-order kinetics predominantly based on non-interacting systems, and then on to the more physically realistic scenarios that have attempted to analyse complex systems involving ever greater numbers of interacting trapping centres, luminescent centres and non-luminescent centres. The review emphasises the difficulty the band-gap models have in the simulation of dose response linear/supralinear behaviour and especially the dependence of the supralinearity on ionisation density. The significance of the non-observation of filling-rate supralinearity in the absorption stage is emphasised since it removes from consideration the possibility of TL supralinearity arising from irradiation stage supralinearity. The importance of the simultaneous action of both localised and delocalised transitions has gradually penetrated the mindset of the community of kinetic researchers, but most simulations have concentrated on the shape of glow peaks and the extraction of the glow peak parameters, E (the thermal activation energy) and s (the attempt-to-escape frequency). The simulation of linear/supralinear dose response and its dependence on ionisation density have been largely avoided until recently due to the fundamental schism between the effects of ionisation density and some basic assumptions of the band-gap model. The review finishes with an in-depth presentation and discussion of the most recent
Coffee consumption and risk of fractures: a systematic review and dose-response meta-analysis.
Lee, Dong Ryul; Lee, Jungun; Rota, Matteo; Lee, Juneyoung; Ahn, Hyeong Sik; Park, Sang Min; Shin, Doosup
2014-06-01
The data on the association between coffee consumption and the risk of fractures are inconclusive. We performed a comprehensive literature review and meta-analysis to better quantify this association. We identified all potentially relevant articles by searching MEDLINE, EMBASE, Cochrane Library, Web of Science, SCOPUS, and CINAHL (until February 2013). The keywords "coffee," "caffeine," "drink," and "beverage" were used as the exposure factors, and the keyword "fracture" was used as the outcome factor. We determined the overall relative risk (RR) and confidence interval (CI) for the highest and lowest levels of coffee consumption. A dose-response analysis was performed to assess the risk of fractures based on the level of coffee consumption. We included 253,514 participants with 12,939 fracture cases from 9 cohort and 6 case-control studies. The estimated RR of fractures at the highest level of coffee consumption was 1.14 (95% CI: 1.05-1.24; I(2)=0.0%) in women and 0.76 (95% CI: 0.62-0.94; I(2)=7.3%) in men. In the dose-response analysis, the pooled RRs of fractures in women who consumed 2 and 8 cups of coffee per day were 1.02 (95% CI: 1.01-1.04) and 1.54 (95% CI: 1.19-1.99), respectively. Our meta-analysis suggests that daily consumption of coffee is associated with an increased risk of fractures in women and a contrasting decreased risk in men. However, future well-designed studies should be performed to confirm these findings. Copyright © 2014 Elsevier Inc. All rights reserved.
The Shape of the Dose-Response Relationship between Sugars and Caries in Adults.
Bernabé, 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.
An alternate method for estimating the dose-response relationships of neuromuscular blocking drugs.
Kopman, A F; Klewicka, M M; Neuman, G G
2000-05-01
Slopes of the dose-response relationships for all available neuromuscular blocking drugs appear to be essentially parallel and to approximate a log-dose/logit value of 4.75. We tested the possibility of estimating both 50% effective dose (ED(50)) and 95% effective dose (ED(95)) values from a single dose-response data point when that slope is postulated. We compared the ED(50) and ED(95) values of rocuronium and succinylcholine calculated by using traditional log-dose/logit regression analysis with the same values obtained by averaging individual estimates of potency as determined by using the Hill equation. After the induction of anesthesia (propofol/alfentanil), tracheal intubation was accomplished without the administration of neuromuscular blocking drugs. Anesthesia was maintained with nitrous oxide and propofol. The evoked electromyographic response to 0.10-Hz single stimuli was continuously recorded. After baseline stabilization, a single IV bolus of succinylcholine (0.08-0.26 mg/kg, n = 50) or rocuronium (0. 13-0.30 mg/kg, n = 40) was administered and the peak effect noted. By using log-dose/logit regression analysis, we calculated ED(50) and ED(95) values for rocuronium of 0.17 and 0.33 mg/kg and 0.14 and 0.27 mg/kg for succinylcholine. When potency was calculated from the Hill equation, the resultant ED(50) and ED(95) values did not differ by more than +/-4% from those obtained by using regression analysis. Averaging of single-dose estimates of neuromuscular potency provides a useful adjunct and reasonable alternative to conventional regression analysis.
Dose-response relationship for breast cancer induction at radiotherapy dose
Directory of Open Access Journals (Sweden)
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.
Dose-response study of spinal hyperbaric ropivacaine for cesarean section
Institute of Scientific and Technical Information of China (English)
CHEN Xin-zhong; CHEN Hong; LOU Ai-fei; L(U) Chang-cheng
2006-01-01
Background: Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind,randomized, dose-response study determined the ED50 (50% effective dose) and ED95 (95% effective dose) of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods: Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1～L2 vertebral interspace,then lumbar puncture was performed at the L3～L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels (pinprick) were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective ifan upper sensory level to pin prick ofT7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results: ED50 (95% confidence interval)of spinal hyperbaric ropivacaine was determined to be 10.37 (5.23～11.59) mg and ED95 (95% confidence interval) to be 15.39(13.81～23.59) mg. The maximum sensory block levels and the duration of motor block and the rate ofhypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion: The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery.
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.
Directory of Open Access Journals (Sweden)
Jan B W J Cornelissen
Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.
Ouwehand, Arthur C; DongLian, Cai; Weijian, Xu; Stewart, Morgan; Ni, Jiayi; Stewart, Tad; Miller, Larry E
2014-01-16
Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients.
Cornelissen, Jan B. W. J.; van der Giessen, Joke W. B.; Takumi, Katsuhisa; Teunis, Peter F. M.; Wisselink, Henk J.
2014-01-01
High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application. PMID:25184619
Aged garlic extract reduces blood pressure in hypertensives: a dose-response trial.
Ried, K; Frank, O R; Stocks, N P
2013-01-01
Hypertension affects about 30% of adults worldwide. Garlic has blood pressure-lowering properties and the mechanism of action is biologically plausible. Our trial assessed the effect, dose-response, tolerability and acceptability of different doses of aged garlic extract as an adjunct treatment to existing antihypertensive medication in patients with uncontrolled hypertension. A total of 79 general practice patients with uncontrolled systolic hypertension participated in a double-blind randomised placebo-controlled dose-response trial of 12 weeks. Participants were allocated to one of three garlic groups with either of one, two or four capsules daily of aged garlic extract (240/480/960 mg containing 0.6/1.2/2.4 mg of S-allylcysteine) or placebo. Blood pressure was assessed at 4, 8 and 12 weeks and compared with baseline using a mixed-model approach. Tolerability was monitored throughout the trial and acceptability was assessed at 12 weeks by questionnaire. Mean systolic blood pressure was significantly reduced by 11.8±5.4 mm Hg in the garlic-2-capsule group over 12 weeks compared with placebo (P=0.006), and reached borderline significant reduction in the garlic-4-capsule group at 8 weeks (-7.4±4.1 mm Hg, P=0.07). Changes in systolic blood pressure in the garlic-1-capsule group and diastolic blood pressure were not significantly different to placebo. Tolerability, compliance and acceptability were high in all garlic groups (93%) and highest in the groups taking one or two capsules daily. Our trial suggests aged garlic extract to be an effective and tolerable treatment in uncontrolled hypertension, and may be considered as a safe adjunct treatment to conventional antihypertensive therapy.
Khee Looe, Hui; Harder, Dietrich; Poppe, Björn
2017-02-01
The lateral dose response function is a general characteristic of the volume effect of a detector used for photon dosimetry in a water phantom. It serves as the convolution kernel transforming the true absorbed dose to water profile, which would be produced within the undisturbed water phantom, into the detector-measured signal profile. The shape of the lateral dose response function characterizes (i) the volume averaging attributable to the detector’s size and (ii) the disturbance of the secondary electron field associated with the deviation of the electron density of the detector material from the surrounding water. In previous work, the characteristic dependence of the shape of the lateral dose response function upon the electron density of the detector material was studied for 6 MV photons by Monte Carlo simulation of a wall-less voxel-sized detector (Looe et al 2015 Phys. Med. Biol. 60 6585-07). This study is here continued for 60Co gamma rays and 15 MV photons in comparison with 6 MV photons. It is found (1) that throughout these photon spectra the shapes of the lateral dose response functions are retaining their characteristic dependence on the detector’s electron density, and (2) that their energy-dependent changes are only moderate. This appears as a practical advantage because the lateral dose response function can then be treated as practically invariant across a clinical photon beam in spite of the known changes of the photon spectrum with increasing distance from the beam axis.
Energy Technology Data Exchange (ETDEWEB)
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.
Monotonicity Formula and Regularity for General Free Discontinuity Problems
Bucur, Dorin; Luckhaus, Stephan
2014-02-01
We give a general monotonicity formula for local minimizers of free discontinuity problems which have a critical deviation from minimality, of order d - 1. This result allows us to prove partial regularity results (that is closure and density estimates for the jump set) for a large class of free discontinuity problems involving general energies associated to the jump set, as for example free boundary problems with Robin conditions. In particular, we give a short proof to the De Giorgi-Carriero-Leaci result for the Mumford-Shah functional.
The Non-Monotonic Effect of Financing Constraints on Investment
DEFF Research Database (Denmark)
Hirth, Stefan; Viswanatha, Marc
We analyze investment timing in a discrete-time framework with two possible investment dates, which is an extension of the model by Lyandres (2007). While Lyandres could only show non-monotonicity of investment in market frictions, we derive an investment threshold that is U-shaped in the firm's ......'s liquid funds, a result similar to the infinite-horizon model by Boyle and Guthrie (2003). However, due to the tractability of our model, we can more clearly explain the relevant trade-offs leading to the U-shape....
Contribution to the ergodic theory of piecewise monotone continuous maps
Faller, Bastien
2008-01-01
This thesis is devoted to the ergodic theory of the piecewise monotone continuous maps of the interval. The coding is a classical approach for these maps. Thanks to the coding, we get a symbolic dynamical system which is almost isomorphic to the initial dynamical system. The principle of the coding is very similar to the one of expansion of real numbers. We first define the coding in a perspective similar to the one of the expansions of real numbers; this perspective was already adopted by Ré...
Stability of generalized monotonicity with respect to their characterizations
An, P T
2002-01-01
We show that known types of generalized monotone maps are not stable with respect to their characterizations (i.e., the characterizations are not maintained during an arbitrary map of this type is disturbed by an element with sufficiently small norm) then introduce s-quasimonotone maps, which are stable with respect to their characterization. For gradient maps, s-quasimonotonicity is related to s-quasiconvexity of the underlying function. A necessary and sufficient condition for a univariate polynomial to be s-quasimonotone is given. Furthermore, some stability properties of a-quasiconvex functions are presented.
Deterministic homogenization of parabolic monotone operators with time dependent coefficients
Directory of Open Access Journals (Sweden)
Gabriel Nguetseng
2004-06-01
Full Text Available We study, beyond the classical periodic setting, the homogenization of linear and nonlinear parabolic differential equations associated with monotone operators. The usual periodicity hypothesis is here substituted by an abstract deterministic assumption characterized by a great relaxation of the time behaviour. Our main tool is the recent theory of homogenization structures by the first author, and our homogenization approach falls under the two-scale convergence method. Various concrete examples are worked out with a view to pointing out the wide scope of our approach and bringing the role of homogenization structures to light.
A Neurodynamic Model to Solve Nonlinear Pseudo-Monotone Projection Equation and Its Applications.
Eshaghnezhad, Mohammad; Effati, Sohrab; Mansoori, Amin
2016-09-29
In this paper, a neurodynamic model is given to solve nonlinear pseudo-monotone projection equation. Under pseudo-monotonicity condition and Lipschitz continuous condition, the projection neurodynamic model is proved to be stable in the sense of Lyapunov, globally convergent, globally asymptotically stable, and globally exponentially stable. Also, we show that, our new neurodynamic model is effective to solve the nonconvex optimization problems. Moreover, since monotonicity is a special case of pseudo-monotonicity and also since a co-coercive mapping is Lipschitz continuous and monotone, and a strongly pseudo-monotone mapping is pseudo-monotone, the neurodynamic model can be applied to solve a broader classes of constrained optimization problems related to variational inequalities, pseudo-convex optimization problem, linear and nonlinear complementarity problems, and linear and convex quadratic programming problems. Finally, several illustrative examples are stated to demonstrate the effectiveness and efficiency of our new neurodynamic model.
Calabrese, Edward J; Bachmann, Kenneth A; Bailer, A John; Bolger, P Michael; Borak, Jonathan; Cai, Lu; Cedergreen, Nina; Cherian, M George; Chiueh, Chuang C; Clarkson, Thomas W; Cook, Ralph R; Diamond, David M; Doolittle, David J; Dorato, Michael A; Duke, Stephen O; Feinendegen, Ludwig; Gardner, Donald E; Hart, Ronald W; Hastings, Kenneth L; Hayes, A Wallace; Hoffmann, George R; Ives, John A; Jaworowski, Zbigniew; Johnson, Thomas E; Jonas, Wayne B; Kaminski, Norbert E; Keller, John G; Klaunig, James E; Knudsen, Thomas B; Kozumbo, Walter J; Lettieri, Teresa; Liu, Shu-Zheng; Maisseu, Andre; Maynard, Kenneth I; Masoro, Edward J; McClellan, Roger O; Mehendale, Harihara M; Mothersill, Carmel; Newlin, David B; Nigg, Herbert N; Oehme, Frederick W; Phalen, Robert F; Philbert, Martin A; Rattan, Suresh I S; Riviere, Jim E; Rodricks, Joseph; Sapolsky, Robert M; Scott, Bobby R; Seymour, Colin; Sinclair, David A; Smith-Sonneborn, Joan; Snow, Elizabeth T; Spear, Linda; Stevenson, Donald E; Thomas, Yolene; Tubiana, Maurice; Williams, Gary M; Mattson, Mark P
2007-07-01
Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.
Conway, Sadie H; Pompeii, Lisa A; Roberts, Robert E; Follis, Jack L; Gimeno, David
2016-03-01
The aim of this study was to examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. A retrospective cohort study of 1926 individuals from the Panel Study of Income Dynamics (1986 to 2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with an increased risk of CVD. Compared with working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD.
Wang, Yaopeng; Yu, Xuyi; Wu, Yili; Zhang, Dongfeng
2012-11-01
Results from the recent meta-analysis suggested a favorable effect of green tea consumption and risk of lung cancer, while no significant association was found between black tea consumption and risk of lung cancer. Besides, a significantly positive association was found between coffee consumption and risk of lung cancer. However, the relationship of green tea and coffee consumption is unclear. Thus the dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. Results suggested that a linear dose-response relationship exists between coffee consumption and risk of lung cancer, while the dose-response relationship is nonlinear between green tea consumption and risk of lung cancer.
Testing monotonicity of a hazard: asymptotic distribution theory
Groeneboom, Piet
2011-01-01
Two new test statistics are introduced to test the null hypotheses that the sampling distribution has an increasing hazard rate on a specified interval [0,a]. These statistics are empirical L_1-type distances between the isotonic estimates, which use the monotonicity constraint, and either the empirical distribution function or the empirical cumulative hazard. They measure the excursions of the empirical estimates with respect to the isotonic estimates, due to local non-monotonicity. Asymptotic normality of the test statistics, if the hazard is strictly increasing on [0,a], is established under mild conditions. This is done by first approximating the global empirical distance by an distance with respect to the underlying distribution function. The resulting integral is treated as sum of increasingly many local integrals to which a CLT can be applied. The behavior of the local integrals is determined by a canonical process: the difference between the stochastic process x -> W(x)+x^2 where W is standard two-sid...
DATA PREORDERING IN GENERALIZED PAV ALGORITHM FOR MONOTONIC REGRESSION
Institute of Scientific and Technical Information of China (English)
Oleg Burdakov; Anders Grimvall; Oleg Sysoev
2006-01-01
Monotonic regression (MR) is a least distance problem with monotonicity constraints induced by a partially ordered data set of observations. In our recent publication [In Ser.Nonconvex Optimization and Its Applications, Springer-Verlag, (2006) 83, pp. 25-33],the Pool-Adjacent-Violators algorithm (PAV) was generalized from completely to partially ordered data sets (posets). The new algorithm, called GPAV, is characterized by the very low computational complexity, which is of second order in the number of observations.It treats the observations in a consecutive order, and it can follow any arbitrarily chosen topological order of the poset of observations. The GPAV algorithm produces a sufficiently accurate solution to the MR problem, but the accuracy depends on the chosen topological order. Here we prove that there exists a topological order for which the resulted GPAV solution is optimal. Furthermore, we present results of extensive numerical experiments,from which we draw conclusions about the most and the least preferable topological orders.
Energy Technology Data Exchange (ETDEWEB)
Reynolds, M; Fallone, B; Rathee, S [Cross Cancer Institute, Edmonton, AB (Canada)
2014-06-01
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 0.5–1% 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.
Energy Technology Data Exchange (ETDEWEB)
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.
Schöllnberger, H; Kaiser, J C; Jacob, P; Walsh, L
2012-05-01
The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates.
Energy Technology Data Exchange (ETDEWEB)
Schoellnberger, H.; Kaiser, J.C.; Jacob, P. [Institute of Radiation Protection, Helmholtz Zentrum Muenchen, Department of Radiation Sciences, Neuherberg (Germany); Walsh, L. [BfS-Federal Office for Radiation Protection, Neuherberg (Germany)
2012-05-15
The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates. (orig.)
Habitual Chocolate Consumption May Increase Body Weight in a Dose-Response Manner
Greenberg, James A.; Buijsse, Brian
2013-01-01
Objective Habitual chocolate intake was recently found to be associated with lower body weight in three cross-sectional epidemiological studies. Our objective was to assess whether these cross-sectional results hold up in a more rigorous prospective analysis. Methods We used data from the Atherosclerosis Risk in Communities cohort. Usual dietary intake was assessed by questionnaire at baseline (1987–98), and after six years. Participants reported usual chocolate intake as the frequency of eating a 1-oz (∼28 g) serving. Body weight and height were measured at the two visits. Missing data were replaced by multiple imputation. Linear mixed-effects models were used to evaluate cross-sectional and prospective associations between chocolate intake and adiposity. Results Data were from 15,732 and 12,830 participants at the first and second visit, respectively. More frequent chocolate consumption was associated with a significantly greater prospective weight gain over time, in a dose-response manner. For instance, compared to participants who ate a chocolate serving less often than monthly, those who ate it 1–4 times a month and at least weekly experienced an increase in Body Mass Index (kg/m2) of 0.26 (95% CI 0.08, 0.44) and 0.39 (0.23, 0.55), respectively, during the six-year study period. In cross-sectional analyses the frequency of chocolate consumption was inversely associated with body weight. This inverse association was attenuated after excluding participants with preexisting obesity-related illness. Compared to participants without such illness, those with it had higher BMI and reported less frequent chocolate intake, lower caloric intake, and diets richer in fruits and vegetables. They tended to make these dietary changes after becoming ill. Conclusions Our prospective analysis found that a chocolate habit was associated with long-term weight gain, in a dose-response manner. Our cross-sectional finding that chocolate intake was associated with lower body
Quantitative Models of the Dose-Response and Time Course of Inhalational Anthrax in Humans
Schell, Wiley A.; Bulmahn, Kenneth; Walton, Thomas E.; Woods, Christopher W.; Coghill, Catherine; Gallegos, Frank; Samore, Matthew H.; Adler, Frederick R.
2013-01-01
Anthrax poses a community health risk due to accidental or intentional aerosol release. Reliable quantitative dose-response analyses are required to estimate the magnitude and timeline of potential consequences and the effect of public health intervention strategies under specific scenarios. Analyses of available data from exposures and infections of humans and non-human primates are often contradictory. We review existing quantitative inhalational anthrax dose-response models in light of criteria we propose for a model to be useful and defensible. To satisfy these criteria, we extend an existing mechanistic competing-risks model to create a novel Exposure–Infection–Symptomatic illness–Death (EISD) model and use experimental non-human primate data and human epidemiological data to optimize parameter values. The best fit to these data leads to estimates of a dose leading to infection in 50% of susceptible humans (ID50) of 11,000 spores (95% confidence interval 7,200–17,000), ID10 of 1,700 (1,100–2,600), and ID1 of 160 (100–250). These estimates suggest that use of a threshold to human infection of 600 spores (as suggested in the literature) underestimates the infectivity of low doses, while an existing estimate of a 1% infection rate for a single spore overestimates low dose infectivity. We estimate the median time from exposure to onset of symptoms (incubation period) among untreated cases to be 9.9 days (7.7–13.1) for exposure to ID50, 11.8 days (9.5–15.0) for ID10, and 12.1 days (9.9–15.3) for ID1. Our model is the first to provide incubation period estimates that are independently consistent with data from the largest known human outbreak. This model refines previous estimates of the distribution of early onset cases after a release and provides support for the recommended 60-day course of prophylactic antibiotic treatment for individuals exposed to low doses. PMID:24058320
Olsson, C.; Thor, M.; Liu, M.; Moissenko, V.; Petersen, S. E.; Høyer, M.; Apte, A.; Deasy, J. O.
2014-07-01
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 three-dimensional conformal radiotherapy to either 74 Gy (N = 159) or 78 Gy (N = 159) at 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 generalized equivalent uniform dose (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 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
When Is a Bernstein-bezier Curve the Graph of a Function?
Mclaughlin, H. W.
1985-01-01
The question of determining when a Bernstein-Bezier cubic curve in the plane can be represented as the graph of function in some fixed orthogonal coordinate system is considered. The notion of a curve being monotone in a given direction is introduced to aid in the analysis.
The Environmental Kuznets Curve. An empirical analysis for OECD countries
Energy Technology Data Exchange (ETDEWEB)
Georgiev, E.
2008-09-15
This paper tests the Environmental Kuznets Curve hypothesis for four local (SOx, NOx, CO, VOC) and two global (CO2, GHG) air pollutants. Using a new panel data set of thirty OECD countries, the paper finds that the postulated inverted U-shaped relationship between income and pollution does not hold for all gases. A meaningful Environmental Kuznets Curve exists only for CO, VOC and NOx, where for CO2 the curve is monotonically increasing. For GHG there is indication of an inverted U-shaped relationship between income and pollution, but still most countries are on the increasing path of the curve and hence the future development of the curve is uncertain. For SOx it was found that emissions follow an U-shaped curve. Based on the empirical results, the paper concludes that the Environmental Kuznets Curve does not hold for all gases, it is rather an empirical artefact than a regularity.
Plasticity and rectangularity in survival curves
Weon, Byung Mook; Je, Jung Ho
2011-09-01
Living systems inevitably undergo a progressive deterioration of physiological function with age and an increase of vulnerability to disease and death. To maintain health and survival, living systems should optimize survival strategies with adaptive interactions among molecules, cells, organs, individuals, and environments, which arises plasticity in survival curves of living systems. In general, survival dynamics in a population is mathematically depicted by a survival rate, which monotonically changes from 1 to 0 with age. It would be then useful to find an adequate function to describe complicated survival dynamics. Here we describe a flexible survival function, derived from the stretched exponential function by adopting an age-dependent shaping exponent. We note that the exponent is associated with the fractal-like scaling in cumulative mortality rate. The survival function well depicts general features in survival curves; healthy populations exhibit plasticity and evolve towards rectangular-like survival curves, as examples in humans or laboratory animals.
Nano-silver induces dose-response effects on the nematode Caenorhabditis elegans
DEFF Research Database (Denmark)
Ellegaard-Jensen, Lea; Alstrup Jensen, Keld; Johansen, Anders
2012-01-01
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......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 28 nm (AgNP28, PVP coated), respectively. Tests were performed with and without...... 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....
Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms
DEFF Research Database (Denmark)
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 sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered...... a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P vitamin D2 per 100 g of fresh mushrooms and comparable to levels found...
The notion of hormesis and the dose-response theory: a unified approach.
Murado, M A; Vázquez, J A
2007-02-07
According to an opinion which is vigorous and insistently defended for approximately one decade, hormesis (the response of a biological entity to an effector, with stimulatory results at low doses and inhibitory results at high doses) radically puts into question the classic theory of dose-response (DR) relationships and demands a profound revision of environmental protection policies. Herein we show that DR theory, with the modifications which we propose, allows the modelling of various kinds of biphasic responses which are phenomenologically similar to hormetic ones and of well-defined origin, as well as responses which have been treated as genuinely hormetic. Our descriptive approach may also represent a useful resource for experimental design, directed towards identifying some of the potentially heterogeneous mechanisms which underlie the hormetic phenomenon. Finally, it also allows to discuss some factors which prevent the use of the notion of hormesis-perhaps useful in a clinical context, under strictly controlled conditions-to make decisions on environmental protection measures.
Dose - response relationship between noise exposure and the risk of occupational injury
Directory of Open Access Journals (Sweden)
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.
DOSE RESPONSE EFFECT OF Paracoccidioides brasiliensis IN AN EXPERIMENTAL MODEL OF ARTHRITIS
Directory of Open Access Journals (Sweden)
Eduardo Alexandre Loth
2014-06-01
Full Text Available Paracoccidioidomycosis (PCM is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb and corresponds to prevalent systemic mycosis in Latin America. The aim of the present work was to evaluate the dose response effect of the fungal yeast phase for the standardization of an experimental model of septic arthritis. The experiments were performed with groups of 14 rats that received doses of 103, 104 or 105 P. brasiliensis (Pb18 cells. The fungi were injected in 50 µL of phosphate-buffered saline (PBS directly into the knee joints of the animals. The following parameters were analyzed in this work: the formation of swelling in knees infused with yeast cells and the radiological and anatomopathological alterations, besides antibody titer by ELISA. After 15 days of infection, signs of inflammation were evident. At 45 days, some features of damage and necrosis were observed in the articular cartilage. The systemic dissemination of the fungus was observed in 11% of the inoculated animals, and it was concluded that the experimental model is able to mimic articular PCM in humans and that the dose of 105 yeast cells can be used as standard in this model.
Dose response effect of Paracoccidioides brasiliensis in an experimental model of arthritis.
Loth, Eduardo Alexandre; Biazim, Samia Khalil; Dos Santos, José Henrique Fermino Ferreira; Puccia, Rosana; Brancalhão, Rosimeire Costa; Chasco, Lucinéia de Fátima; Gandra, Rinaldo Ferreira; Simão, Rita de Cássia Garcia; de Franco, Marcello Fabiano
2014-01-01
Paracoccidioidomycosis (PCM) is caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb) and corresponds to prevalent systemic mycosis in Latin America. The aim of the present work was to evaluate the dose response effect of the fungal yeast phase for the standardization of an experimental model of septic arthritis. The experiments were performed with groups of 14 rats that received doses of 103, 104 or 105 P. brasiliensis (Pb18) cells. The fungi were injected in 50 µL of phosphate-buffered saline (PBS) directly into the knee joints of the animals. The following parameters were analyzed in this work: the formation of swelling in knees infused with yeast cells and the radiological and anatomopathological alterations, besides antibody titer by ELISA. After 15 days of infection, signs of inflammation were evident. At 45 days, some features of damage and necrosis were observed in the articular cartilage. The systemic dissemination of the fungus was observed in 11% of the inoculated animals, and it was concluded that the experimental model is able to mimic articular PCM in humans and that the dose of 105 yeast cells can be used as standard in this model.
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.
Ordered multiple comparisons with the best and their applications to dose-response studies.
Strassburger, K; Bretz, F; Finner, H
2007-12-01
This article considers the problem of comparing several treatments (dose levels, interventions, etc.) with the best, where the best treatment is unknown and the treatments are ordered in some sense. Order relations among treatments often occur quite naturally in practice. They may be ordered according to increasing risks, such as tolerability or safety problems with increasing dose levels in a dose-response study, for example. We tackle the problem of constructing a lower confidence bound for the smallest index of all treatments being at most marginally less effective than the (best) treatment having the largest effect. Such a bound ensures at confidence level 1 -alpha that all treatments with lower indices are relevantly less effective than the best competitor. We derive a multiple testing strategy that results in sharp confidence bounds. The proposed lower confidence bound is compared with those derived from other testing strategies. We further derive closed-form expressions for power and sample size calculations. Finally, we investigate several real data sets to illustrate various applications of our methods.
Dose-response relationships using brain-computer interface technology impact stroke rehabilitation.
Young, Brittany M; Nigogosyan, Zack; Walton, Léo M; Remsik, Alexander; Song, Jie; Nair, Veena A; Tyler, Mitchell E; Edwards, Dorothy F; Caldera, Kristin; Sattin, Justin A; Williams, Justin C; Prabhakaran, Vivek
2015-01-01
Brain-computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 stroke rehabilitation, therapy frequency may be less important than dose and intensity.
Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms.
Urbain, Paul; Jakobsen, Jette
2015-09-23
The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P < 0.0001), which is equivalent to 17.6 μg (704 IU) vitamin D2 per 100 g of fresh mushrooms and comparable to levels found in fatty fish like the Atlantic salmon.
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...
Bonfils, S; Chen, W W; Vatier, J
1988-01-01
In 10 healthy male volunteers a dose-response study was carried out with roxatidine acetate, 75, 150, 300, and 600 mg, and placebo on food-stimulated gastric acid secretion (intragastric titration (IGT]. The design of the study, with drug intake 150 min before starting IGT, enabled stable inhibition over the 90-min observation period of the test. Cumulative secretory results showed a dose-related acid secretion inhibition (67% for 75 mg; 87.6% for 150 mg; 98.8% for 300 mg; 99.6% for 600 mg). The results were statistically significantly different from placebo and from each other, except for 300 mg versus 600 mg. With a Lineweaver-Burk plot, the ED50 was 41 mg and r = 0.98. Peak concentrations of roxatidine were observed either at T 150 or T 180. Significant correlation (r = 0.7; p less than 0.001) was obtained for the percentage inhibition with 75 mg and 150 mg together versus peak concentrations. Antisecretory potency with the IGT model applied to normal subjects appears to be of the same order for roxatidine acetate and for ranitidine.
Increasing food deprivation relative to baseline influences D-amphetamine dose-response gradients.
Lotfizadeh, Amin D; Zimmermann, Zachary J; Watkins, Erin E; Edwards, Timothy L; Poling, Alan
2014-10-01
Several studies using non-pharmacological discriminative stimuli have found that stimulus control, as evident in generalization gradients, changes when motivation for (i.e., deprivation of) the relevant reinforcer is altered. Drug-discrimination studies, however, have not consistently revealed such an effect. A procedural detail that may account for the lack of a reliable effect in drug-discrimination studies is that motivation was characteristically reduced relative to the training condition in these studies. The present experiment examined how substantially increasing motivation affects D-amphetamine discrimination. Rats initially were trained to discriminate D-amphetamine (1.0 mg/kg) from vehicle (0 mg/kg) injections under 22-h food deprivation conditions. Dose-response gradients were then obtained under 22-h and 46-h deprivation levels. The ED50 was significantly higher with greater deprivation. This finding suggests that increasing motivation relative to the training condition may reduce stimulus control by drugs, while decreasing it may sharpen stimulus control. Copyright © 2014. Published by Elsevier Inc.
Dose response studies and longterm evaluation of auranofin in rheumatoid arthritis.
Champion, G D; Cairns, D R; Bieri, D; Adena, M A; Browne, C D; Cohen, M L; Day, R O; Edmonds, J P; Graham, G G; de Jager, J
1988-01-01
Fifty-eight patients with rheumatoid arthritis (RA) entered a double blind trial of auranofin (AF) designed to assess dose response relationships and longterm outcome. Multivariate analysis of repeated measures with trend analysis and discriminant function analysis of standard measures of RA activity were applied to a randomized double blind trial of AF at daily doses of 4, 6 and 8 mg over 6 months. Improvement occurred in each group. There was a highly significant (p less than 0.001) linear trend in the 6 mg group, 73% of whom showed linear improvement. A significant correlation (p less than 0.05) was found between response of individual patients and AF dose (mg/kg/day), but there was no significant correlation between dosage and mean steady state serum gold concentration. No significant correlation was seen between outcome and pretreatment demographic and disease variables. In a subsequent 6 month phase of dosage adjustment, aiming for optimal dosage, no advantage resulted from increasing the dose above 6 mg/day. Patients apparently benefiting from treatment continued an open long-term trial of AF. By 45 months, 33.5% had stopped treatment due to lack of efficacy and 14.5% due to toxicity, mainly rash and diarrhea.
Dose-response modeling in mental health using stein-like estimators with instrumental variables.
Ginestet, Cedric E; Emsley, Richard; Landau, Sabine
2017-02-21
A mental health trial is analyzed using a dose-response model, in which the number of sessions attended by the patients is deemed indicative of the dose of psychotherapeutic treatment. Here, the parameter of interest is the difference in causal treatment effects between the subpopulations that take part in different numbers of therapy sessions. For this data set, interactions between random treatment allocation and prognostic baseline variables provide the requisite instrumental variables. While the corresponding two-stage least squares (TSLS) estimator tends to have smaller bias than the ordinary least squares (OLS) estimator; the TSLS suffers from larger variance. It is therefore appealing to combine the desirable properties of the OLS and TSLS estimators. Such a trade-off is achieved through an affine combination of these two estimators, using mean squared error as a criterion. This produces the semi-parametric Stein-like (SPSL) estimator as introduced by Judge and Mittelhammer (2004). The SPSL estimator is used in conjunction with multiple imputation with chained equations, to provide an estimator that can exploit all available information. Simulated data are also generated to illustrate the superiority of the SPSL estimator over its OLS and TSLS counterparts. A package entitled SteinIV implementing these methods has been made available through the R platform. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.
Calabrese, Edward J
2016-08-01
This article provides the first extensive documentation of the dose response features of pre- and postconditioning. Pre- and postconditioning studies with rigorous study designs, using multiple doses/concentrations along with refined dose/concentration spacing strategies, often display hormetic dose/concentration response relationships with considerable generality across biological model, inducing (i.e., conditioning) agent, challenging dose treatment, endpoint, and mechanism. Pre- and postconditioning hormesis dose/concentration-response relationships are reported for 154 diverse conditioning agents, affecting more than 550 dose/concentration responses, across a broad range of biological models and endpoints. The quantitative features of the pre- and postconditioning-induced protective responses are modest, typically being 30-60% greater than control values at maximum, findings that are consistent with a large body (>10,000) of hormetic dose/concentration responses not related to pre- and postconditioning. Regardless of the biological model, inducing agent, endpoint or mechanism, the quantitative features of hormetic dose/concentration responses are similar, suggesting that the magnitude of response is a measure of biological plasticity. This paper also provides the first documentation that hormetic effects account for preconditioning induced early (1-3h) and delayed (12-72h) windows of protection. These findings indicate that pre- and postconditioning are specific types of hormesis.
Western red cedar dust exposure and lung function: a dose-response relationship.
Noertjojo, H K; Dimich-Ward, H; Peelen, S; Dittrick, M; Kennedy, S M; Chan-Yeung, M
1996-10-01
The relationship between levels of cumulative red cedar dust exposure and decline in lung function was explored in an 11-yr follow-up study of 243 sawmill workers who participated in at least two occasions. We also studied 140 office workers in a similar manner as control subjects. Workers with asthma were excluded from the analysis. During the period of the study, 916 personal and 216 area samples of dust were collected from the sawmill. Cumulative wood dust exposure was calculated for each sawmill worker according to the duration and exposure in each job, based on the geometric mean of all dust measurements for that job. Average daily dust exposure was calculated by dividing the total cumulative exposure by the number of days of work. Workers were divided into low-, medium-, and high-exposure groups with mean daily level of exposure of 0.4 mg/m3, respectively. Sawmill workers had significantly greater declines in FEV1 and FVC compared with office workers adjusted for age, smoking, and initial lung function. A dose-response relationship was observed between the level of exposure and the annual decline in FVC. We conclude that exposure to Western red cedar dust is associated with a greater decline in lung function which may lead to development of chronic airflow limitation.
Pulmonary inflammation and crystalline silica in respirable coal mine dust: dose-response
Indian Academy of Sciences (India)
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.
Aldrin and dieldrin: a reevaluation of the cancer and noncancer dose-response assessments.
Hooker, Eric P; Fulcher, Keri G; Gibb, Herman J
2014-05-01
The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA. © 2013 Society for Risk Analysis.
The approximation of generalized Log-aesthetic curves using Quintic Bezier curves
Albayari, Diya’ J.; Gobithaasan, R. U.; Miura, Kenjiro T.
2017-09-01
Generalized Log Aesthetic Curve segments (GLAC) are aesthetic curves that have monotonic curvature profile and hence they are considered fair. In the field of Computer-Aided Design (CAD), there exists a demand to construct fair curves for various design intent. However, we cannot implement GLAC in CAD system partly due to its transcendental form. A viable solution is to approximate GLACs using a quintic polynomial curve in the form of Bezier using curvature error measure. The problem of this approach is that it requires a formidable size of computations due to arc length reparametrization. In this paper, we introduce a new method of calculating curvature error measure using natural spline interpolation function to minimize computation effort while preserving the accuracy. The final section shows numerical examples depicting the proposed approximation of two types of the GLAC, which clearly indicate the efficiency of proposed method.
The regularized monotonicity method: detecting irregular indefinite inclusions
DEFF Research Database (Denmark)
Garde, Henrik; Staboulis, Stratos
2017-01-01
In inclusion detection in electrical impedance tomography, the support of perturbations (inclusion) from a known background conductivity is typically reconstructed from idealized continuum data modelled by a Neumann-to-Dirichlet map. Only few reconstruction methods apply when detecting indefinite...... of approximative measurement models, including the Complete Electrode Model, hence making the method robust against modelling error and noise. In particular, we demonstrate that for a convergent family of approximative models there exists a sequence of regularization parameters such that the outer shape...... of the inclusions is asymptotically exactly characterized. Finally, a peeling-type reconstruction algorithm is presented and, for the first time in literature, numerical examples of monotonicity reconstructions for indefinite inclusions are presented....
Convex analysis and monotone operator theory in Hilbert spaces
Bauschke, Heinz H
2017-01-01
This reference text, now in its second edition, offers a modern unifying presentation of three basic areas of nonlinear analysis: convex analysis, monotone operator theory, and the fixed point theory of nonexpansive operators. Taking a unique comprehensive approach, the theory is developed from the ground up, with the rich connections and interactions between the areas as the central focus, and it is illustrated by a large number of examples. The Hilbert space setting of the material offers a wide range of applications while avoiding the technical difficulties of general Banach spaces. The authors have also drawn upon recent advances and modern tools to simplify the proofs of key results making the book more accessible to a broader range of scholars and users. Combining a strong emphasis on applications with exceptionally lucid writing and an abundance of exercises, this text is of great value to a large audience including pure and applied mathematicians as well as researchers in engineering, data science, ma...
Monotonic childhoods: representations of otherness in research writing
Directory of Open Access Journals (Sweden)
Denise Marcos Bussoletti
2011-12-01
Full Text Available This paper is part of a doctoral thesis entitled “Monotonic childhoods – a rhapsody of hope”. It follows the perspective of a critical psychosocial and cultural study, and aims at discussing the other’s representation in research writing, electing childhood as an allegorical and refl ective place. It takes into consideration, by means of analysis, the drawings and poems of children from the Terezin ghetto during the Second World War. The work is mostly based on Serge Moscovici’s Social Representation Theory, but it is also in constant dialogue with other theories and knowledge fi elds, especially Walter Benjamin’s and Mikhail Bakhtin’s contributions. At the end, the paper supports the thesis that conceives poetics as one of the translation axes of childhood cultures.
PPA BASED PREDICTION-CORRECTION METHODS FOR MONOTONE VARIATIONAL INEQUALITIES
Institute of Scientific and Technical Information of China (English)
He Bingsheng; Jiang Jianlin; Qian Maijian; Xu Ya
2005-01-01
In this paper we study the proximal point algorithm (PPA) based predictioncorrection (PC) methods for monotone variational inequalities. Each iteration of these methods consists of a prediction and a correction. The predictors are produced by inexact PPA steps. The new iterates are then updated by a correction using the PPA formula. We present two profit functions which serve two purposes: First we show that the profit functions are tight lower bounds of the improvements obtained in each iteration. Based on this conclusion we obtain the convergence inexactness restrictions for the prediction step. Second we show that the profit functions are quadratically dependent upon the step lengths, thus the optimal step lengths are obtained in the correction step. In the last part of the paper we compare the strengths of different methods based on their inexactness restrictions.
Strong convergence theorems for maximal monotone mappings in Banach spaces
Zegeye, Habtu
2008-07-01
Let E be a uniformly convex and 2-uniformly smooth real Banach space with dual E*. Let be a Lipschitz continuous monotone mapping with A-1(0)[not equal to][empty set]. For given u,x1[set membership, variant]E, let {xn} be generated by the algorithm xn+1:=[beta]nu+(1-[beta]n)(xn-[alpha]nAJxn), n[greater-or-equal, slanted]1, where J is the normalized duality mapping from E into E* and {[lambda]n} and {[theta]n} are real sequences in (0,1) satisfying certain conditions. Then it is proved that, under some mild conditions, {xn} converges strongly to x*[set membership, variant]E where Jx*[set membership, variant]A-1(0). Finally, we apply our convergence theorems to the convex minimization problems.
Convergence of the natural approximations of piecewise monotone interval maps.
Haydn, Nicolai
2004-06-01
We consider piecewise monotone interval mappings which are topologically mixing and satisfy the Markov property. It has previously been shown that the invariant densities of the natural approximations converge exponentially fast in uniform pointwise topology to the invariant density of the given map provided its derivative is piecewise Lipshitz continuous. We provide an example of a map which is Lipshitz continuous and for which the densities converge in the bounded variation norm at a logarithmic rate. This shows that in general one cannot expect exponential convergence in the bounded variation norm. Here we prove that if the derivative of the interval map is Holder continuous and its variation is well approximable (gamma-uniform variation for gamma>0), then the densities converge exponentially fast in the norm.
A COMPARISON OF DIFFERENT CONTRACTION METHODS FOR MONOTONE VARIATIONAL INEQUALITIES
Institute of Scientific and Technical Information of China (English)
Bingsheng He; Xiang Wang; Junfeng Yang
2009-01-01
It is interesting to compare the efficiency of two methods when their computational loads in each iteration are equal. In this paper, two classes of contraction methods for monotone variational inequalities are studied in a unified framework. The methods of both classes can be viewed as prediction-correction methods, which generate the same test vector in the prediction step and adopt the same step-size rule in the correction step. The only difference is that they use different search directions. The computational loads of each iteration of the different classes are equal. Our analysis explains theoretically why one class of the contraction methods usually outperforms the other class. It is demonstrated that many known methods belong to these two classes of methods. Finally, the presented numerical results demonstrate the validity of our analysis.
A new non-monotone fitness scaling for genetic algorithm
Institute of Scientific and Technical Information of China (English)
无
2001-01-01
The properties of selection operators in the genetic algorithm (GA) are studied in detail. It is indicated that the selection of operations is significant for both improving the general fitness of a population and leading to the schema deceptiveness. The stochastic searching characteristics of GA are compared with those of heuristic methods. The influence of selection operators on the GA' s exploration and exploitation is discussed, and the performance of selection operators is evaluated with the premature convergence of the GA taken as an example based on One-Max function. In order to overcome the schema deceptiveness of the GA, a new type of fitness scaling, non monotone scaling, is advanced to enhance the evolutionary ability of a population. The effectiveness of the new scaling method is tested by a trap function and a needle-in-haystack (NiH) function.
MINLIP for the Identification of Monotone Wiener Systems
Pelckmans, Kristiaan
2010-01-01
This paper studies the MINLIP estimator for the identification of Wiener systems consisting of a sequence of a linear FIR dynamical model, and a monotonically increasing (or decreasing) static function. Given $T$ observations, this algorithm boils down to solving a convex quadratic program with $O(T)$ variables and inequality constraints, implementing an inference technique which is based entirely on model complexity control. The resulting estimates of the linear submodel are found to be almost consistent when no noise is present in the data, under a condition of smoothness of the true nonlinearity and local Persistency of Excitation (local PE) of the data. This result is novel as it does not rely on classical tools as a 'linearization' using a Taylor decomposition, nor exploits stochastic properties of the data. It is indicated how to extend the method to cope with noisy data, and empirical evidence contrasts performance of the estimator against other recently proposed techniques.
A new approximate proximal point algorithm for maximal monotone operator
Institute of Scientific and Technical Information of China (English)
HE; Bingsheng(何炳生); LIAO; Lizhi(廖立志); YANG; Zhenhua(杨振华)
2003-01-01
The problem concerned in this paper is the set-valued equation 0 ∈ T(z) where T is a maximal monotone operator. For given xk and βk ＞ 0, some existing approximate proximal point algorithms take xk+1 = xk such that xk +ek∈ xk + βkT(xk) and||ek|| ≤ηk||xk - xk||, where {ηk} is a non-negative summable sequence. Instead of xk+1 = xk, the new iterate of the proposing method is given by xk+1 = PΩ[xk - ek], where Ω is the domain of T and PΩ(@) denotes the projection on Ω. The convergence is proved under a significantly relaxed restriction supk＞0 ηk ＜ 1.
Borde, Ron; Hortobagyi, Tibor; Granacher, Urs
2015-01-01
Background Resistance training (RT) is an intervention frequently used to improve muscle strength and morphology in old age. However, evidence-based, dose-response relationships regarding specific RT variables (e.g., training period, frequency, intensity, volume) are unclear in healthy old adults. O
Soedamah-Muthu, S.S.; Verberne, L.D.M.; Ding, E.L.; Engberink, M.F.; Geleijnse, J.M.
2012-01-01
Dairy Consumption and Incidence of Hypertension : A Dose-Response Meta-Analysis Prospective Cohort Studies Sabita S. Soedamah-Muthu, Lisa D.M. Verberne, Eric L. Ding, Mariëlle F. Engberink and Johanna M. Geleijnse Hypertension. published online September 17, 2012; Hypertension is published by the Am
Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses us...
Formalin-fixed paraffin-embedded (FFPE) samples provide a vast untapped resource for chemical safety and translational science. To date, genomic profiling of FFPE samples has been limited by poor RNA quality and inconsistent results with limited utility in dose-response assessmen...
A state of the science document providing a judgment on the degree to which nonmonotonic dose-responses are evidenced in the scientific literature and to evaluate the extent to which they may impact U.S. EPA’s chemical testing and risk assessment.
Lesinski, Melanie; Hortobagyi, Tibor; Muehlbauer, Thomas; Gollhofer, Albert; Granacher, Urs
2015-01-01
Background Balance training (BT) has been used for the promotion of balance and sports-related skills as well as for prevention and rehabilitation of lower extremity sport injuries. However, evidence-based dose-response relationships in BT parameters have not yet been established. Objective The obje
DEFF Research Database (Denmark)
Calderón, M A; Larenas, D; Kleine-Tebbe, J
2011-01-01
For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen prod...
Gijsbers, L.; Geleijnse, J.M.; Soedamah-Muthu, S.S.
2011-01-01
Observational studies suggest an inverse association between dairy intake and incident type 2 diabetes, but the quantity of dairy is not known. Previous meta-analyses did not take into account the type of dairy product. Therefore, we examined dose-response associations between the intake of total
Langford, Oliver; Aronson, Jeffrey K; van Valkenhoef, Gert; Stevens, Richard J
2016-01-01
Standard methods for meta-analysis of dose-response data in epidemiology assume a model with a single scalar parameter, such as log-linear relationships between exposure and outcome; such models are implicitly unbounded. In contrast, in pharmacology, multi-parameter models, such as the widely used E
H. Morgenstern; A. Burdorf (Alex); J.P. Jansen (Jeroen)
2004-01-01
textabstractAIMS: To assess dose-response relations between occupational exposures to physical and psychosocial factors and the risk of low back pain. METHODS: A cohort of 523 subjects, working in nursing homes and homes for the elderly, was followed prospectively for one year. Phy
Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses us...