Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

PubMed

Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

2016-05-01

The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Caffeine Increases the Linearity of the Visual BOLD Response

PubMed Central

Liu, Thomas T.; Liau, Joy

2009-01-01

Although the blood oxygenation level dependent (BOLD) signal used in most functional magnetic resonance imaging (fMRI) studies has been shown to exhibit nonlinear characteristics, most analyses assume that the BOLD signal responds in a linear fashion to stimulus. This assumption of linearity can lead to errors in the estimation of the BOLD response, especially for rapid event-related fMRI studies. In this study, we used a rapid event-related design and Volterra kernel analysis to assess the effect of a 200 mg oral dose of caffeine on the linearity of the visual BOLD response. The caffeine dose significantly (p < 0.02) increased the linearity of the BOLD response in a sample of 11 healthy volunteers studied on a 3 Tesla MRI system. In addition, the agreement between nonlinear and linear estimates of the hemodynamic response function was significantly increased (p= 0.013) with the caffeine dose. These findings indicate that differences in caffeine usage should be considered as a potential source of bias in the analysis of rapid event-related fMRI studies. PMID:19854278

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

PubMed

Chen, D G; Pounds, J G

1998-12-01

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium.

A nonlinear isobologram model with Box-Cox transformation to both sides for chemical mixtures.

PubMed Central

Chen, D G; Pounds, J G

1998-01-01

The linear logistical isobologram is a commonly used and powerful graphical and statistical tool for analyzing the combined effects of simple chemical mixtures. In this paper a nonlinear isobologram model is proposed to analyze the joint action of chemical mixtures for quantitative dose-response relationships. This nonlinear isobologram model incorporates two additional new parameters, Ymin and Ymax, to facilitate analysis of response data that are not constrained between 0 and 1, where parameters Ymin and Ymax represent the minimal and the maximal observed toxic response. This nonlinear isobologram model for binary mixtures can be expressed as [formula: see text] In addition, a Box-Cox transformation to both sides is introduced to improve the goodness of fit and to provide a more robust model for achieving homogeneity and normality of the residuals. Finally, a confidence band is proposed for selected isobols, e.g., the median effective dose, to facilitate graphical and statistical analysis of the isobologram. The versatility of this approach is demonstrated using published data describing the toxicity of the binary mixtures of citrinin and ochratoxin as well as a new experimental data from our laboratory for mixtures of mercury and cadmium. PMID:9860894

SU-F-T-263: Dosimetric Characteristics of the Cine Acquisition Mode of An A-Si EPID

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bawazeer, O; Deb, P; Sarasanandarajah, S

2016-06-15

Purpose: To investigate the dosimetric characteristics of Varian a-Si-500 electronic portal imaging device (EPID) operated in cine mode particularly considering linearity with delivered dose, dose rate, field size, phantom thickness, MLC speed and common IMRT fields. Methods: The EPID that attached to a Varian Clinac 21iX linear accelerator, was irradiated with 6 and 18 MV using 600 MU/min. Image acquisition is controlled by the IAS3 software, Trigger delay was 6 ms, BeamOnDelay and FrameStartDelay were zero. Different frame rates were utilized. Cine mode response was calculated using MATLAB as summation of mean pixel values in a region of interest ofmore » the acquired images. The performance of cine mode was compared to integrated mode and dose measurements in water using CC13 ionization chamber. Results: Figure1 illustrates that cine mode has nonlinear response for small MU, when delivering 10 MU was about 0.5 and 0.64 for 6 and 18 MV respectively. This is because the missing acquired images that were calculated around four images missing in each delivery. With the increase MU the response became linear and comparable with integrated mode and ionization chamber within 2%. Figure 2 shows that cine mode has comparable response with integrated mode and ionization chamber within 2% with changing dose rate for 10 MU delivered. This indicates that the dose rate change has no effect on nonlinearity of cine mode response. Except nonlinearity, cine mode is well matched to integrated mode response within 2% for field size, phantom thickness, MLC speed dependences. Conclusion: Cine mode has similar dosimetric characteristics to integrated mode with open and IMRT fields, and the main limitation with cine mode is missing images. Therefore, the calibration of EPID images with this mode should be run with large MU, and when IMRT verification field has low MU, the correction for missing images are required.« less

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

Optimal clinical trial design based on a dichotomous Markov-chain mixed-effect sleep model.

PubMed

Steven Ernest, C; Nyberg, Joakim; Karlsson, Mats O; Hooker, Andrew C

2014-12-01

D-optimal designs for discrete-type responses have been derived using generalized linear mixed models, simulation based methods and analytical approximations for computing the fisher information matrix (FIM) of non-linear mixed effect models with homogeneous probabilities over time. In this work, D-optimal designs using an analytical approximation of the FIM for a dichotomous, non-homogeneous, Markov-chain phase advanced sleep non-linear mixed effect model was investigated. The non-linear mixed effect model consisted of transition probabilities of dichotomous sleep data estimated as logistic functions using piecewise linear functions. Theoretical linear and nonlinear dose effects were added to the transition probabilities to modify the probability of being in either sleep stage. D-optimal designs were computed by determining an analytical approximation the FIM for each Markov component (one where the previous state was awake and another where the previous state was asleep). Each Markov component FIM was weighted either equally or by the average probability of response being awake or asleep over the night and summed to derive the total FIM (FIM(total)). The reference designs were placebo, 0.1, 1-, 6-, 10- and 20-mg dosing for a 2- to 6-way crossover study in six dosing groups. Optimized design variables were dose and number of subjects in each dose group. The designs were validated using stochastic simulation/re-estimation (SSE). Contrary to expectations, the predicted parameter uncertainty obtained via FIM(total) was larger than the uncertainty in parameter estimates computed by SSE. Nevertheless, the D-optimal designs decreased the uncertainty of parameter estimates relative to the reference designs. Additionally, the improvement for the D-optimal designs were more pronounced using SSE than predicted via FIM(total). Through the use of an approximate analytic solution and weighting schemes, the FIM(total) for a non-homogeneous, dichotomous Markov-chain phase advanced sleep model was computed and provided more efficient trial designs and increased nonlinear mixed-effects modeling parameter precision.

Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies.

PubMed

Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

2016-11-19

The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%-13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Calabrese, Edward J.; Kostecki, Paul T.

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

Long-Term Coffee Consumption Is Associated with Decreased Incidence of New-Onset Hypertension: A Dose-Response Meta-Analysis.

PubMed

Grosso, Giuseppe; Micek, Agnieszka; Godos, Justyna; Pajak, Andrzej; Sciacca, Salvatore; Bes-Rastrollo, Maira; Galvano, Fabio; Martinez-Gonzalez, Miguel A

2017-08-17

To perform a dose-response meta-analysis of prospective cohort studies investigating the association between long-term coffee intake and risk of hypertension. An online systematic search of studies published up to November 2016 was performed. Linear and non-linear dose-response meta-analyses were conducted; potential evidence of heterogeneity, publication bias, and confounding effect of selected variables were investigated through sensitivity and meta-regression analyses. Seven cohorts including 205,349 individuals and 44,120 cases of hypertension were included. In the non-linear analysis, there was a 9% significant decreased risk of hypertension per seven cups of coffee a day, while, in the linear dose-response association, there was a 1% decreased risk of hypertension for each additional cup of coffee per day. Among subgroups, there were significant inverse associations for females, caffeinated coffee, and studies conducted in the US with longer follow-up. Analysis of potential confounders revealed that smoking-related variables weakened the strength of association between coffee consumption and risk of hypertension. Increased coffee consumption is associated with a modest decrease in risk of hypertension in prospective cohort studies. Smoking status is a potential effect modifier on the association between coffee consumption and risk of hypertension.

Nonlinear association between betel quid chewing and oral cancer: Implications for prevention.

PubMed

Madathil, Sreenath Arekunnath; Rousseau, Marie-Claude; Wynant, Willy; Schlecht, Nicolas F; Netuveli, Gopalakrishnan; Franco, Eduardo L; Nicolau, Belinda

2016-09-01

Betel quid chewing is a major oral cancer risk factor and the human papillomaviruses (HPV) may play an aetiological role in these cancers. However, little is known about the shape of the dose-response relationship between the betel quid chewing habit and oral cancer risk in populations without HPV. We estimate the shape of this dose-response relationship, and discuss implications for prevention. Cases with oral squamous cell carcinoma (350) and non-cancer controls (371) were recruited from two major teaching hospitals in South India. Information on socio-demographic and behavioral factors was collected using a questionnaire and the life grid technique. The effect of daily amount of use and duration of the habit were estimated jointly as risk associated with cumulative exposure (chew-years). The shape of the dose-response curve was estimated using restricted cubic spline transformation of chew-years in a conditional logistic regression model. Risk estimates for low dose combinations of daily amount and duration of the habit were computed from flexible regression. Most (72%) oral cancer cases were betel quid chewers in contrast to only 18% of controls. A nonlinear dose-response relationship was observed; the risk increased steeply at low doses and plateaued at high exposures to betel quid (>425 chew-years). A threefold increase in risk (OR=3.92, 95%CI: 1.87-8.21) was observed for the lowest dose; equivalent to the use of one quid per day for one year. Our findings may be used to counsel people to refrain from even low betel quid chewing. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dose-response relationships in a microneutralization test for foot-and-mouth disease viruses.

PubMed Central

Booth, J. C.; Rweyemamu, M. M.; Pay, T. W.

1978-01-01

Two-dimensional quantal microneutralization tests on foot-and-mouth disease viruses, in which neutralizing antibody activity was titrated against a serial range of virus doses, demonstrated a variety of dose-response curves some of which were rectilinear, others clearly curvilinear. Moreover, in the case of the non-linear responses obtained with some antisera, the shape of the curve was such that antibody titres recorded with doses of virus ranging from 10(3)-10(5) TCD50 were closely similar. Studies were carried out on the effect of varying the conditions of the test on the shape of the dose-response curve: significant differences were obtained after treatment of the antiserum-virus mixtures with anti-species globulin, and when the test was assayed in cells of differing susceptibility to infection. PMID:202650

BENCHMARK DOSE TECHNICAL GUIDANCE DOCUMENT ...

EPA Pesticide Factsheets

The purpose of this document is to provide guidance for the Agency on the application of the benchmark dose approach in determining the point of departure (POD) for health effects data, whether a linear or nonlinear low dose extrapolation is used. The guidance includes discussion on computation of benchmark doses and benchmark concentrations (BMDs and BMCs) and their lower confidence limits, data requirements, dose-response analysis, and reporting requirements. This guidance is based on today's knowledge and understanding, and on experience gained in using this approach.

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

PubMed

Dropkin, Greg

2016-11-24

Analyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour. GAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 - 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy. For all solid cancer incidence, RR estimated from 0 - 100 mGy and 0 - 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 - 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort. Non-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.

Dose-Response Association Between Physical Activity and Incident Hypertension: A Systematic Review and Meta-Analysis of Cohort Studies.

PubMed

Liu, Xuejiao; Zhang, Dongdong; Liu, Yu; Sun, Xizhuo; Han, Chengyi; Wang, Bingyuan; Ren, Yongcheng; Zhou, Junmei; Zhao, Yang; Shi, Yuanyuan; Hu, Dongsheng; Zhang, Ming

2017-05-01

Despite the inverse association between physical activity (PA) and incident hypertension, a comprehensive assessment of the quantitative dose-response association between PA and hypertension has not been reported. We performed a meta-analysis, including dose-response analysis, to quantitatively evaluate this association. We searched PubMed and Embase databases for articles published up to November 1, 2016. Random effects generalized least squares regression models were used to assess the quantitative association between PA and hypertension risk across studies. Restricted cubic splines were used to model the dose-response association. We identified 22 articles (29 studies) investigating the risk of hypertension with leisure-time PA or total PA, including 330 222 individuals and 67 698 incident cases of hypertension. The risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.96) with each 10 metabolic equivalent of task h/wk increment of leisure-time PA. We found no evidence of a nonlinear dose-response association of PA and hypertension ( P nonlinearity =0.094 for leisure-time PA and 0.771 for total PA). With the linear cubic spline model, when compared with inactive individuals, for those who met the guidelines recommended minimum level of moderate PA (10 metabolic equivalent of task h/wk), the risk of hypertension was reduced by 6% (relative risk, 0.94; 95% confidence interval, 0.92-0.97). This meta-analysis suggests that additional benefits for hypertension prevention occur as the amount of PA increases. © 2017 American Heart Association, Inc.

Continuous functional magnetic resonance imaging reveals dynamic nonlinearities of "dose-response" curves for finger opposition.

PubMed

Berns, G S; Song, A W; Mao, H

1999-07-15

Linear experimental designs have dominated the field of functional neuroimaging, but although successful at mapping regions of relative brain activation, the technique assumes that both cognition and brain activation are linear processes. To test these assumptions, we performed a continuous functional magnetic resonance imaging (MRI) experiment of finger opposition. Subjects performed a visually paced bimanual finger-tapping task. The frequency of finger tapping was continuously varied between 1 and 5 Hz, without any rest blocks. After continuous acquisition of fMRI images, the task-related brain regions were identified with independent components analysis (ICA). When the time courses of the task-related components were plotted against tapping frequency, nonlinear "dose- response" curves were obtained for most subjects. Nonlinearities appeared in both the static and dynamic sense, with hysteresis being prominent in several subjects. The ICA decomposition also demonstrated the spatial dynamics with different components active at different times. These results suggest that the brain response to tapping frequency does not scale linearly, and that it is history-dependent even after accounting for the hemodynamic response function. This implies that finger tapping, as measured with fMRI, is a nonstationary process. When analyzed with a conventional general linear model, a strong correlation to tapping frequency was identified, but the spatiotemporal dynamics were not apparent.

Biological mechanisms of non-linear dose-response for respirable mineral fibers.

PubMed

Cox, Louis Anthony Tony

2018-06-19

Sufficiently high and prolonged inhalation exposures to some respirable elongated mineral particles (REMPs), notably including amphibole asbestos fibers, can increase risk of inflammation-mediated diseases including malignant mesothelioma, pleural diseases, fibrosis, and lung cancer. Chronic inflammation involves ongoing activation of the NLRP3 inflammasome, which enables immune cells to produce potent proinflammatory cytokines IL-1β and IL-18. Reactive oxygen species (ROS) (in particular, mitochondrial ROS) contribute to NRLP3 activation via a well-elucidated mechanism involving oxidation of reduced thioredoxin and association of thioredoxin-interacting protein with NLRP3. Lysosomal destabilization, efflux of cytosolic potassium ions and influx of calcium ions, signals from damaged mitochondria, both translational and post-translational controls, and prion-like polymerization have increasingly clear roles in regulating NLRP3 activation. As the molecular biology of inflammation-mediated responses to REMP exposure becomes clearer, a practical question looms: What do these mechanisms imply for the shape of the dose-response function relating exposure concentrations and durations for EMPs to risk of pathological responses? Dose-response thresholds or threshold-like nonlinearities can arise from (a) Cooperativity in assembly of supramolecular signaling complexes; (b) Positive feedback loops and bistability in regulatory networks; (c) Overwhelming of defensive barriers maintaining homeostasis; and (d) Damage thresholds, as in lysosome destabilization-induced activation of NLRP3. Each of these mechanisms holds for NLRP3 activation in response to stimuli such as REMP exposures. It is therefore timely to consider the implications of these advances in biological understanding for human health risk assessment with dose-response thresholds. Copyright © 2018. Published by Elsevier Inc.

BENCHMARK DOSE TECHNICAL GUIDANCE DOCUMENT ...

EPA Pesticide Factsheets

The U.S. EPA conducts risk assessments for an array of health effects that may result from exposure to environmental agents, and that require an analysis of the relationship between exposure and health-related outcomes. The dose-response assessment is essentially a two-step process, the first being the definition of a point of departure (POD), and the second extrapolation from the POD to low environmentally-relevant exposure levels. The benchmark dose (BMD) approach provides a more quantitative alternative to the first step in the dose-response assessment than the current NOAEL/LOAEL process for noncancer health effects, and is similar to that for determining the POD proposed for cancer endpoints. As the Agency moves toward harmonization of approaches for human health risk assessment, the dichotomy between cancer and noncancer health effects is being replaced by consideration of mode of action and whether the effects of concern are likely to be linear or nonlinear at low doses. Thus, the purpose of this project is to provide guidance for the Agency and the outside community on the application of the BMD approach in determining the POD for all types of health effects data, whether a linear or nonlinear low dose extrapolation is used. A guidance document is being developed under the auspices of EPA's Risk Assessment Forum. The purpose of this project is to provide guidance for the Agency and the outside community on the application of the benchmark dose (BMD) appr

Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies

PubMed Central

Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

2016-01-01

The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%–13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups. PMID:27869762

Radiotherapy Dose Fractionation under Parameter Uncertainty

NASA Astrophysics Data System (ADS)

Davison, Matt; Kim, Daero; Keller, Harald

2011-11-01

In radiotherapy, radiation is directed to damage a tumor while avoiding surrounding healthy tissue. Tradeoffs ensue because dose cannot be exactly shaped to the tumor. It is particularly important to ensure that sensitive biological structures near the tumor are not damaged more than a certain amount. Biological tissue is known to have a nonlinear response to incident radiation. The linear quadratic dose response model, which requires the specification of two clinically and experimentally observed response coefficients, is commonly used to model this effect. This model yields an optimization problem giving two different types of optimal dose sequences (fractionation schedules). Which fractionation schedule is preferred depends on the response coefficients. These coefficients are uncertainly known and may differ from patient to patient. Because of this not only the expected outcomes but also the uncertainty around these outcomes are important, and it might not be prudent to select the strategy with the best expected outcome.

Maternal vitamin D status during pregnancy and risk of childhood asthma: A meta-analysis of prospective studies.

PubMed

Song, Huihui; Yang, Lei; Jia, Chongqi

2017-05-01

Mounting evidence suggests that maternal vitamin D status during pregnancy may be associated with development of childhood asthma, but the results are still inconsistent. A dose-response meta-analysis was performed to quantitatively summarize evidence on the association of maternal vitamin D status during pregnancy with the risk of childhood asthma. A systematic search was conducted to identify all studies assessing the association of maternal 25-hydroxyvitamin D (25(OH)D) during pregnancy with risk of childhood asthma. The fixed or random-effect model was selected based on the heterogeneity test among studies. Nonlinear dose-response relationship was assessed by restricted cubic spline model. Fifteen prospective studies with 12 758 participants and 1795 cases were included in the meta-analysis. The pooled relative risk of childhood asthma comparing the highest versus lowest category of maternal 25(OH)D levels was 0.87 (95% confidence interval, CI, 0.75-1.02). For dose-response analysis, evidence of a U-shaped relationship was found between maternal 25(OH)D levels and risk of childhood asthma (P nonlinearity = 0.02), with the lowest risk at approximately 70 nmol/L of 25(OH)D. This dose-response meta-analysis suggested a U-shaped relationship between maternal blood 25(OH)D levels and risk of childhood asthma. Further studies are needed to confirm the association. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Relationship between shift work and overweight/obesity in male steel workers].

PubMed

Xiao, M Y; Wang, Z Y; Fan, H M; Che, C L; Lu, Y; Cong, L X; Gao, X J; Liu, Y J; Yuan, J X; Li, X M; Hu, B; Chen, Y P

2016-11-10

Objective: To investigate the relationship between shift work and overweight/obesity in male steel workers. Methods: A questionnaire survey was conducted among the male steel workers selected during health examination in Tangshan Steel Company from March 2015 to March 2016. The relationship between shift work and overweight/obesity in the male steel workers were analyzed by using logistic regression model and restricted cubic splinemodel. Results: A total of 7 262 male steel workers were surveyed, the overall prevalence of overweight/obesitywas 64.5% (4 686/7 262), the overweight rate was 34.3% and the obesity rate was 30.2%, respectively. After adjusting for age, educational level and average family income level per month by multivariable logistic regression analysis, shift work was associated with overweight/obesity and obesity in the male steel workers. The OR was 1.19(95% CI : 1.05-1.35) and 1.15(95% CI : 1.00-1.32). Restricted cubic spline model analysis showed that the relationship between shift work years and overweight/obesity in the male steel workers was a nonlinear dose response one (nonlinear test χ 2 =7.43, P <0.05). Restricted cubic spline model analysis showed that the relationship between shift work years and obesity in the male steel workers was a nonlinear dose response one (nonlinear test χ 2 =10.48, P <0.05). Conclusion: Shift work was associated with overweight and obesity in the male steel workers, and shift work years and overweight/obesity had a nonlinear relationship.

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

NASA Technical Reports Server (NTRS)

Chappelli, Lori J.; Cucinotta, Francis A.

2010-01-01

BACKGROUND: There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies. DOSE RESPONSE MODELS: The Harderian Gland data of Alpen et al.[1-3] was re-analyzed [4] using non-linear least square regression. The data set measured the induction of Harderian gland tumors in mice by high-energy protons, helium, neon, iron, niobium and lanthanum with LET s ranging from 0.4 to 950 keV/micron. We were able to strengthen the individual ion models by combining data for all ions into a model that relates both radiation dose and LET for the ion to tumor prevalence. We compared models based on Targeted Effects (TE) to one motivated by Non-targeted Effects (NTE) that included a bystander term that increased tumor induction at low doses non-linearly. When comparing fitted models to the experimental data, we considered the adjusted R2, the Akaike Information Criteria (AIC), and the Bayesian Information Criteria (BIC) to test for Goodness of fit.In the adjusted R2test, the model with the highest R2values provides a better fit to the available data. In the AIC and BIC tests, the model with the smaller values of the summary value provides the better fit. The non-linear NTE models fit the combined data better than the TE models that are linear at low doses. We evaluated the differences in the relative biological effectiveness (RBE) and found the NTE model provides a higher RBE at low dose compared to the TE model. POWER ANALYSIS: The final NTE model estimates were used to simulate example data to consider the design of new experiments to detect NTE at low dose for validation. Power and sample sizes were calculated for a variety of radiation qualities including some not considered in the Harderian Gland data set and with different background tumor incidences. We considered different experimental designs with varying number of doses and varying low doses dependant on the LET of the radiation. The optimal design to detect a NTE for an individual ion had 4 doses equally spaced below a maximal dose where bending due to cell sterilization was < 2%. For example at 100 keV/micron we would irradiate at 0.03 Gy, 0.065 Gy, 0.13 Gy, and 0.26 Gy and require 850 mice including a control dose for a sensitivity to detect NTE with 80% power. Sample sizes could be improved by combining ions similar to the methods used with the Harderian Gland data.

Mixed-effects Gaussian process functional regression models with application to dose-response curve prediction.

PubMed

Shi, J Q; Wang, B; Will, E J; West, R M

2012-11-20

We propose a new semiparametric model for functional regression analysis, combining a parametric mixed-effects model with a nonparametric Gaussian process regression model, namely a mixed-effects Gaussian process functional regression model. The parametric component can provide explanatory information between the response and the covariates, whereas the nonparametric component can add nonlinearity. We can model the mean and covariance structures simultaneously, combining the information borrowed from other subjects with the information collected from each individual subject. We apply the model to dose-response curves that describe changes in the responses of subjects for differing levels of the dose of a drug or agent and have a wide application in many areas. We illustrate the method for the management of renal anaemia. An individual dose-response curve is improved when more information is included by this mechanism from the subject/patient over time, enabling a patient-specific treatment regime. Copyright © 2012 John Wiley & Sons, Ltd.

Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation.

PubMed

Allen, Christian Harry; Kumar, Achint; Qutob, Sami; Nyiri, Balazs; Chauhan, Vinita; Murugkar, Sangeeta

2018-01-09

Recent findings in populations exposed to ionizing radiation (IR) indicate dose-related lens opacification occurs at much lower doses (<2 Gy) than indicated in radiation protection guidelines. As a result, research efforts are now being directed towards identifying early predictors of lens degeneration resulting in cataractogenesis. In this study, Raman micro-spectroscopy was used to investigate the effects of varying doses of radiation, ranging from 0.01 Gy to 5 Gy, on human lens epithelial (HLE) cells which were chemically fixed 24 h post-irradiation. Raman spectra were acquired from the nucleus and cytoplasm of the HLE cells. Spectra were collected from points in a 3  ×  3 grid pattern and then averaged. The raw spectra were preprocessed and principal component analysis followed by linear discriminant analysis was used to discriminate between dose and control for 0.25, 0.5, 2, and 5 Gy. Using leave-one-out cross-validation accuracies of greater than 74% were attained for each dose/control combination. The ultra-low doses 0.01 and 0.05 Gy were included in an analysis of band intensities for Raman bands found to be significant in the linear discrimination, and an induced repair model survival curve was fit to a band-difference-ratio plot of this data, suggesting HLE cells undergo a nonlinear response to low-doses of IR. A survival curve was also fit to clonogenic assay data done on the irradiated HLE cells, showing a similar nonlinear response.

Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low-dose-range of ionizing radiation

NASA Astrophysics Data System (ADS)

Allen, Christian Harry; Kumar, Achint; Qutob, Sami; Nyiri, Balazs; Chauhan, Vinita; Murugkar, Sangeeta

2018-01-01

Recent findings in populations exposed to ionizing radiation (IR) indicate dose-related lens opacification occurs at much lower doses (<2 Gy) than indicated in radiation protection guidelines. As a result, research efforts are now being directed towards identifying early predictors of lens degeneration resulting in cataractogenesis. In this study, Raman micro-spectroscopy was used to investigate the effects of varying doses of radiation, ranging from 0.01 Gy to 5 Gy, on human lens epithelial (HLE) cells which were chemically fixed 24 h post-irradiation. Raman spectra were acquired from the nucleus and cytoplasm of the HLE cells. Spectra were collected from points in a 3  ×  3 grid pattern and then averaged. The raw spectra were preprocessed and principal component analysis followed by linear discriminant analysis was used to discriminate between dose and control for 0.25, 0.5, 2, and 5 Gy. Using leave-one-out cross-validation accuracies of greater than 74% were attained for each dose/control combination. The ultra-low doses 0.01 and 0.05 Gy were included in an analysis of band intensities for Raman bands found to be significant in the linear discrimination, and an induced repair model survival curve was fit to a band-difference-ratio plot of this data, suggesting HLE cells undergo a nonlinear response to low-doses of IR. A survival curve was also fit to clonogenic assay data done on the irradiated HLE cells, showing a similar nonlinear response.

A competitive binding model predicts the response of mammalian olfactory receptors to mixtures

NASA Astrophysics Data System (ADS)

Singh, Vijay; Murphy, Nicolle; Mainland, Joel; Balasubramanian, Vijay

Most natural odors are complex mixtures of many odorants, but due to the large number of possible mixtures only a small fraction can be studied experimentally. To get a realistic understanding of the olfactory system we need methods to predict responses to complex mixtures from single odorant responses. Focusing on mammalian olfactory receptors (ORs in mouse and human), we propose a simple biophysical model for odor-receptor interactions where only one odor molecule can bind to a receptor at a time. The resulting competition for occupancy of the receptor accounts for the experimentally observed nonlinear mixture responses. We first fit a dose-response relationship to individual odor responses and then use those parameters in a competitive binding model to predict mixture responses. With no additional parameters, the model predicts responses of 15 (of 18 tested) receptors to within 10 - 30 % of the observed values, for mixtures with 2, 3 and 12 odorants chosen from a panel of 30. Extensions of our basic model with odorant interactions lead to additional nonlinearities observed in mixture response like suppression, cooperativity, and overshadowing. Our model provides a systematic framework for characterizing and parameterizing such mixing nonlinearities from mixture response data.

Alcohol Consumption as a Risk Factor for Acute and Chronic Pancreatitis: A Systematic Review and a Series of Meta-analyses.

PubMed

Samokhvalov, Andriy V; Rehm, Jürgen; Roerecke, Michael

2015-12-01

Pancreatitis is a highly prevalent medical condition associated with a spectrum of endocrine and exocrine pancreatic insufficiencies. While high alcohol consumption is an established risk factor for pancreatitis, its relationship with specific types of pancreatitis and a potential threshold have not been systematically examined. We conducted a systematic literature search for studies on the association between alcohol consumption and pancreatitis based on PRISMA guidelines. Non-linear and linear random-effect dose-response meta-analyses using restricted cubic spline meta-regressions and categorical meta-analyses in relation to abstainers were conducted. Seven studies with 157,026 participants and 3618 cases of pancreatitis were included into analyses. The dose-response relationship between average volume of alcohol consumption and risk of pancreatitis was monotonic with no evidence of non-linearity for chronic pancreatitis (CP) for both sexes (p = 0.091) and acute pancreatitis (AP) in men (p = 0.396); it was non-linear for AP in women (p = 0.008). Compared to abstention, there was a significant decrease in risk (RR = 0.76, 95%CI: 0.60-0.97) of AP in women below the threshold of 40 g/day. No such association was found in men (RR = 1.1, 95%CI: 0.69-1.74). The RR for CP at 100 g/day was 6.29 (95%CI: 3.04-13.02). The dose-response relationships between alcohol consumption and risk of pancreatitis were monotonic for CP and AP in men, and non-linear for AP in women. Alcohol consumption below 40 g/day was associated with reduced risk of AP in women. Alcohol consumption beyond this level was increasingly detrimental for any type of pancreatitis. The work was financially supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (R21AA023521) to the last author.

Quantitative assessment of the dose-response of alkylating agents in DNA repair proficient and deficient ames tester strains.

PubMed

Tang, Leilei; Guérard, Melanie; Zeller, Andreas

2014-01-01

Mutagenic and clastogenic effects of some DNA damaging agents such as methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS) have been demonstrated to exhibit a nonlinear or even "thresholded" dose-response in vitro and in vivo. DNA repair seems to be mainly responsible for these thresholds. To this end, we assessed several mutagenic alkylators in the Ames test with four different strains of Salmonella typhimurium: the alkyl transferases proficient strain TA1535 (Ogt+/Ada+), as well as the alkyl transferases deficient strains YG7100 (Ogt+/Ada-), YG7104 (Ogt-/Ada+) and YG7108 (Ogt-/Ada-). The known genotoxins EMS, MMS, temozolomide (TMZ), ethylnitrosourea (ENU) and methylnitrosourea (MNU) were tested in as many as 22 concentration levels. Dose-response curves were statistically fitted by the PROAST benchmark dose model and the Lutz-Lutz "hockeystick" model. These dose-response curves suggest efficient DNA-repair for lesions inflicted by all agents in strain TA1535. In the absence of Ogt, Ada is predominantly repairing methylations but not ethylations. It is concluded that the capacity of alkyl-transferases to successfully repair DNA lesions up to certain dose levels contributes to genotoxicity thresholds. Copyright © 2013 Wiley Periodicals, Inc.

A novel approach to multihazard modeling and simulation.

PubMed

Smith, Silas W; Portelli, Ian; Narzisi, Giuseppe; Nelson, Lewis S; Menges, Fabian; Rekow, E Dianne; Mincer, Joshua S; Mishra, Bhubaneswar; Goldfrank, Lewis R

2009-06-01

To develop and apply a novel modeling approach to support medical and public health disaster planning and response using a sarin release scenario in a metropolitan environment. An agent-based disaster simulation model was developed incorporating the principles of dose response, surge response, and psychosocial characteristics superimposed on topographically accurate geographic information system architecture. The modeling scenarios involved passive and active releases of sarin in multiple transportation hubs in a metropolitan city. Parameters evaluated included emergency medical services, hospital surge capacity (including implementation of disaster plan), and behavioral and psychosocial characteristics of the victims. In passive sarin release scenarios of 5 to 15 L, mortality increased nonlinearly from 0.13% to 8.69%, reaching 55.4% with active dispersion, reflecting higher initial doses. Cumulative mortality rates from releases in 1 to 3 major transportation hubs similarly increased nonlinearly as a function of dose and systemic stress. The increase in mortality rate was most pronounced in the 80% to 100% emergency department occupancy range, analogous to the previously observed queuing phenomenon. Effective implementation of hospital disaster plans decreased mortality and injury severity. Decreasing ambulance response time and increasing available responding units reduced mortality among potentially salvageable patients. Adverse psychosocial characteristics (excess worry and low compliance) increased demands on health care resources. Transfer to alternative urban sites was possible. An agent-based modeling approach provides a mechanism to assess complex individual and systemwide effects in rare events.

Steroid therapy and the risk of osteonecrosis in SARS patients: a dose-response meta-analysis.

PubMed

Zhao, R; Wang, H; Wang, X; Feng, F

2017-03-01

This meta-analysis synthesized current evidence from 10 trials to evaluate the association between steroid therapy and osteonecrosis incidence in patients with severe acute respiratory syndrome (SARS). Our results suggest that higher cumulative doses and longer treatment durations of steroids are more likely to lead to the development of osteonecrosis in SARS patients. The link between steroid treatment and the risk of osteonecrosis in SARS patients remains unknown. The present meta-analysis aimed to examine the dose-response association between steroid therapy and osteonecrosis incidence in SARS patients. The sex differences in the development of steroid-induced osteonecrosis were also examined. We searched PubMed, Web of Science, CNKI, and WANFANG for studies that involved steroid therapy and reported osteonecrosis data in SARS patients. Two authors independently extracted the data from the individual studies, and the rate ratio (RR) of osteonecrosis was calculated using random-effect models. Ten studies with 1137 recovered SARS patients met the inclusion criteria. Close relationships between osteonecrosis incidence and both the cumulative dose and treatment duration of steroids were observed. The summary RR of osteonecrosis was 1.57 (95% confidence interval (CI) 1.30-1.89, p < 0.001) per 5.0 g increase in the cumulative dose of steroids and was 1.29 (95% CI 1.09-1.53, p = 0.003) for each 10-day increment of increase in treatment duration. The relationship was non-linear (p non-linear  < 0.001 and p non-linear  = 0.022). There were no significant differences in the risk of developing osteonecrosis between the male and female patients (RR 0.01, 95% CI -0.03 to 0.06, p = 0.582). SARS patients who received higher cumulative doses and longer treatment durations of steroids were more likely to develop osteonecrosis, and there were no sex differences in this dose-dependent side effect. Our findings suggest that it is important to reduce osteonecrosis risk by modifying the cumulative dose and the treatment duration of steroids in SARS patients.

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

PubMed Central

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

2012-01-01

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

Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.

PubMed

Ding, Ming; Bhupathiraju, Shilpa N; Satija, Ambika; van Dam, Rob M; Hu, Frank B

2014-02-11

Considerable controversy exists on the association between coffee consumption and cardiovascular disease (CVD) risk. A meta-analysis was performed to assess the dose-response relationship of long-term coffee consumption with CVD risk. PubMed and EMBASE were searched for prospective cohort studies of the relationship between coffee consumption and CVD risk, which included coronary heart disease, stroke, heart failure, and CVD mortality. Thirty-six studies were included with 1 279 804 participants and 36 352 CVD cases. A nonlinear relationship of coffee consumption with CVD risk was identified (P for heterogeneity=0.09, P for trend <0.001, P for nonlinearity <0.001). Compared with the lowest category of coffee consumption (median, 0 cups per day), the relative risk of CVD was 0.95 (95% confidence interval, 0.87-1.03) for the highest category (median, 5 cups per day) category, 0.85 (95% confidence interval, 0.80-0.90) for the second highest category (median, 3.5 cups per day), and 0.89 (95% confidence interval, 0.84-0.94) for the third highest category (median, 1.5 cups per day). Looking at separate outcomes, coffee consumption was nonlinearly associated with both coronary heart disease (P for heterogeneity=0.001, P for trend <0.001, P for nonlinearity <0.001) and stroke (P for heterogeneity=0.07, P for trend <0.001, P for nonlinearity <0.001; P for trend differences >0.05) risks. A nonlinear association between coffee consumption and CVD risk was observed in this meta-analysis. Moderate coffee consumption was inversely significantly associated with CVD risk, with the lowest CVD risk at 3 to 5 cups per day, and heavy coffee consumption was not associated with elevated CVD risk.

Long-Term Coffee Consumption and Risk of Cardiovascular Disease: A Systematic Review and a Dose-Response Meta-Analysis of Prospective Cohort Studies

PubMed Central

Ding, Ming; Bhupathiraju, Shilpa N; Satija, Ambika; van Dam, Rob M; Hu, Frank B

2013-01-01

Background Considerable controversy exists regarding the association between coffee consumption and cardiovascular disease (CVD) risk. A meta-analysis was performed to assess the dose-response relationship of long-term coffee consumption with CVD risk. Methods and Results Pubmed and EMBASE were searched for prospective cohort studies of the relationship between coffee consumption and CVD risk, which included coronary heart disease, stroke, heart failure, and CVD mortality. Thirty-six studies were included with 1,279,804 participants and 36,352 CVD cases. A non-linear relationship of coffee consumption with CVD risk was identified (P for heterogeneity = 0.09, P for trend < 0.001, P for non-linearity < 0.001). Compared with the lowest category of coffee consumption (median: 0 cups/d), the relative risk of CVD was 0.95 (95% CI, 0.87 to 1.03) for the highest (median: 5 cups/d) category, 0.85 (0.80 to 0.90) for the second highest (median: 3.5 cups/d), and 0.89 (0.84 to 0.94) for the third highest category (median: 1.5 cups/d). Looking at separate outcomes, coffee consumption was non-linearly associated with both CHD (P for heterogeneity = 0.001, P for trend < 0.001, P for non-linearity < 0.001) and stroke risks (P for heterogeneity = 0.07, P for trend < 0.001, P for non-linearity< 0.001) (P for trend differences > 0.05). Conclusions A non-linear association between coffee consumption with CVD risk was observed in this meta-analysis. Moderate coffee consumption was inversely significantly associated with CVD risk, with the lowest CVD risk at 3 to 5 cups/d, and heavy coffee consumption was not associated with elevated CVD risk. PMID:24201300

Epiphytic lichenosynusia under conditions of chemical pollution: Dose-effect dependencies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mikhailova, I.N.; Vorobeichik, E.L.

1995-11-01

The dose-effect dependencies, which characterize response of the epiphytic lichenosynusia of southern taiga in the Middle Urals to pollution by discharges of a copper-smelting plant, are substantially non-linear and, in most cases, have an S-shaped form. A transition from background to impact state is very sharp and begins when the background level of pollution is exceeded by 1.5 - 2.3 times.

Radiation Hormesis: Historical Perspective and Implications for Low-Dose Cancer Risk Assessment

PubMed Central

Vaiserman, Alexander M.

2010-01-01

Current guidelines for limiting exposure of humans to ionizing radiation are based on the linear-no-threshold (LNT) hypothesis for radiation carcinogenesis under which cancer risk increases linearly as the radiation dose increases. With the LNT model even a very small dose could cause cancer and the model is used in establishing guidelines for limiting radiation exposure of humans. A slope change at low doses and dose rates is implemented using an empirical dose and dose rate effectiveness factor (DDREF). This imposes usually unacknowledged nonlinearity but not a threshold in the dose-response curve for cancer induction. In contrast, with the hormetic model, low doses of radiation reduce the cancer incidence while it is elevated after high doses. Based on a review of epidemiological and other data for exposure to low radiation doses and dose rates, it was found that the LNT model fails badly. Cancer risk after ordinarily encountered radiation exposure (medical X-rays, natural background radiation, etc.) is much lower than projections based on the LNT model and is often less than the risk for spontaneous cancer (a hormetic response). Understanding the mechanistic basis for hormetic responses will provide new insights about both risks and benefits from low-dose radiation exposure. PMID:20585444

A Mode-of-Action Approach for the Identification of Genotoxic Carcinogens

PubMed Central

Hernández, Lya G.; van Benthem, Jan; Johnson, George E.

2013-01-01

Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-β-oestradiol (E2). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E2 and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. PMID:23675539

Genetic radiation risks: a neglected topic in the low dose debate

PubMed Central

2016-01-01

Objectives To investigate the accuracy and scientific validity of the current very low risk factor for hereditary diseases in humans following exposures to ionizing radiation adopted by the United Nations Scientific Committee on the Effects of Atomic Radiation and the International Commission on Radiological Protection. The value is based on experiments on mice due to reportedly absent effects in the Japanese atomic bomb (Abomb) survivors. Methods To review the published evidence for heritable effects after ionising radiation exposures particularly, but not restricted to, populations exposed to contamination from the Chernobyl accident and from atmospheric nuclear test fallout. To make a compilation of findings about early deaths, congenital malformations, Down’s syndrome, cancer and other genetic effects observed in humans after the exposure of the parents. To also examine more closely the evidence from the Japanese A-bomb epidemiology and discuss its scientific validity. Results Nearly all types of hereditary defects were found at doses as low as one to 10 mSv. We discuss the clash between the current risk model and these observations on the basis of biological mechanism and assumptions about linear relationships between dose and effect in neonatal and foetal epidemiology. The evidence supports a dose response relationship which is non-linear and is either biphasic or supralinear (hogs-back) and largely either saturates or falls above 10 mSv. Conclusions We conclude that the current risk model for heritable effects of radiation is unsafe. The dose response relationship is non-linear with the greatest effects at the lowest doses. Using Chernobyl data we derive an excess relative risk for all malformations of 1.0 per 10 mSv cumulative dose. The safety of the Japanese A-bomb epidemiology is argued to be both scientifically and philosophically questionable owing to errors in the choice of control groups, omission of internal exposure effects and assumptions about linear dose response. PMID:26791091

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devic, Slobodan; Tomic, Nada; Aldelaijan, Saad

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 testmore » the invariance of the proposed functional form with respect to the film model used we tested it with three different GAFCHROMIC Trade-Mark-Sign film models (EBT, EBT2, and EBT3) irradiated to various doses and scanned on a same scanner. For one of the film models (EBT2), we tested the invariance of the functional form to the scanner model used by scanning irradiated film pieces with three different flatbed scanner models (Epson V700, 1680, and 10000XL). To test our hypothesis that the proposed functional argument linearizes the response of the radiochromic film dosimetry system, verification tests have been performed in clinical applications: percent depth dose measurements, IMRT quality assurance (QA), and brachytherapy QA. Results: Obtained R{sup 2} values indicate that the choice of the functional form of the new argument appropriately linearizes the dose response of the radiochromic film dosimetry system we used. The linear behavior was insensitive to both film model and flatbed scanner model used. Measured PDD values using the green channel response of the GAFCHROMIC Trade-Mark-Sign EBT3 film model are well within {+-}2% window of the local relative dose value when compared to the tabulated Cobalt-60 data. It was also found that criteria of 3%/3 mm for an IMRT QA plan and 3%/2 mm for a brachytherapy QA plan are passing 95% gamma function points. Conclusions: In this paper, we demonstrate the use of functional argument to linearize the inherently nonlinear response of a radiochromic film based reference dosimetry system. In this way, relative dosimetry can be conveniently performed using radiochromic film dosimetry system without the need of establishing calibration curve.« less

Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950-2003.

PubMed

Schöllnberger, Helmut; Eidemüller, Markus; Cullings, Harry M; Simonetto, Cristoforo; Neff, Frauke; Kaiser, Jan Christian

2018-03-01

The scientific community faces important discussions on the validity of the linear no-threshold (LNT) model for radiation-associated cardiovascular diseases at low and moderate doses. In the present study, mortalities from cerebrovascular diseases (CeVD) and heart diseases from the latest data on atomic bomb survivors were analyzed. The analysis was performed with several radio-biologically motivated linear and nonlinear dose-response models. For each detrimental health outcome one set of models was identified that all fitted the data about equally well. This set was used for multi-model inference (MMI), a statistical method of superposing 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. MMI provides a more accurate determination of the dose response and a more comprehensive characterization of uncertainties. It was found that for CeVD, the dose-response curve from MMI is located below the linear no-threshold model at low and medium doses (0-1.4 Gy). At higher doses MMI predicts a higher risk compared to the LNT model. A sublinear dose-response was also found for heart diseases (0-3 Gy). The analyses provide no conclusive answer to the question whether there is a radiation risk below 0.75 Gy for CeVD and 2.6 Gy for heart diseases. MMI suggests that the dose-response curves for CeVD and heart diseases in the Lifespan Study are sublinear at low and moderate doses. This has relevance for radiotherapy treatment planning and for international radiation protection practices in general.

Kinetics of DSB rejoining and formation of simple chromosome exchange aberrations

NASA Technical Reports Server (NTRS)

Cucinotta, F. A.; Nikjoo, H.; O'Neill, P.; Goodhead, D. T.

2000-01-01

PURPOSE: To investigate the role of kinetics in the processing of DNA double strand breaks (DSB), and the formation of simple chromosome exchange aberrations following X-ray exposures to mammalian cells based on an enzymatic approach. METHODS: Using computer simulations based on a biochemical approach, rate-equations that describe the processing of DSB through the formation of a DNA-enzyme complex were formulated. A second model that allows for competition between two processing pathways was also formulated. The formation of simple exchange aberrations was modelled as misrepair during the recombination of single DSB with undamaged DNA. Non-linear coupled differential equations corresponding to biochemical pathways were solved numerically by fitting to experimental data. RESULTS: When mediated by a DSB repair enzyme complex, the processing of single DSB showed a complex behaviour that gives the appearance of fast and slow components of rejoining. This is due to the time-delay caused by the action time of enzymes in biomolecular reactions. It is shown that the kinetic- and dose-responses of simple chromosome exchange aberrations are well described by a recombination model of DSB interacting with undamaged DNA when aberration formation increases with linear dose-dependence. Competition between two or more recombination processes is shown to lead to the formation of simple exchange aberrations with a dose-dependence similar to that of a linear quadratic model. CONCLUSIONS: Using a minimal number of assumptions, the kinetics and dose response observed experimentally for DSB rejoining and the formation of simple chromosome exchange aberrations are shown to be consistent with kinetic models based on enzymatic reaction approaches. A non-linear dose response for simple exchange aberrations is possible in a model of recombination of DNA containing a DSB with undamaged DNA when two or more pathways compete for DSB repair.

Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.

PubMed

Ngan Kee, Warwick D; Khaw, Kim S; Ng, Floria F; Ng, Karman K L; So, Rita; Lee, Anna

2014-05-01

Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose-response curves for individual drugs were fitted to a hyperbolic dose-response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. The derived dose-response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1-14.1] and 6.4 [95% CI, 1.2-11.5] units of the normalized response, respectively), indicating a synergistic interaction. The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.

Aspirin and non-steroidal anti-inflammatory drugs use reduce gastric cancer risk: A dose-response meta-analysis.

PubMed

Huang, Xuan-Zhang; Chen, You; Wu, Jian; Zhang, Xi; Wu, Cong-Cong; Zhang, Chao-Ying; Sun, Shuang-Shuang; Chen, Wen-Jun

2017-01-17

The association between non-steroidal anti-inflammatory drugs (NSAIDs) and gastric cancer (GC) risk is controversial. The aim of this study is to evaluate the chemopreventive effect of NSAIDs for GC. A literature search was performed for relevant studies using the PubMed and Embase database (up to March 2016). Risk ratios (RRs) and 95% confidence intervals (CIs) were used as the effect measures. The dose-response analysis and subgroup analysis were also performed. Twenty-four studies were included. Our results indicated that NSAIDs could reduce GC risk (any NSAIDs: RR=0.78, 96%CI=0.72-0.85; aspirin: RR=0.70, 95%CI=0.62-0.80; non-aspirin NSAIDs: RR=0.86, 95%CI=0.80-0.94), especially for non-cardia GC risk. Moreover, the dose-response analysis indicated the risk of GC decreased by 11% and 5% for 2 years increment of any NSAIDs and aspirin use, respectively. There were nonlinear relationships between the frequency of any NSAIDs use and aspirin use and GC risk (P for non-linearity<0.01), with a threshold effect of 5 times/week. A monotonically decreasing trend was observed only for the frequency of less than 5 times/week. Our results indicate that NSAIDs is inversely associated with GC risk, especially for non-cardia GC risk. NSAIDs use may become a feasible approach to prevent GC.

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents

PubMed Central

Simon, Nicholas W.; Moghaddam, Bita

2016-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3 mg/kg) improving inhibition, and high dose (3 mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. PMID:27431940

Uncertainty analysis of absorbed dose calculations from thermoluminescence dosimeters.

PubMed

Kirby, T H; Hanson, W F; Johnston, D A

1992-01-01

Thermoluminescence dosimeters (TLD) are widely used to verify absorbed doses delivered from radiation therapy beams. Specifically, they are used by the Radiological Physics Center for mailed dosimetry for verification of therapy machine output. The effects of the random experimental uncertainties of various factors on dose calculations from TLD signals are examined, including: fading, dose response nonlinearity, and energy response corrections; reproducibility of TL signal measurements and TLD reader calibration. Individual uncertainties are combined to estimate the total uncertainty due to random fluctuations. The Radiological Physics Center's (RPC) mail out TLD system, utilizing throwaway LiF powder to monitor high-energy photon and electron beam outputs, is analyzed in detail. The technique may also be applicable to other TLD systems. It is shown that statements of +/- 2% dose uncertainty and +/- 5% action criterion for TLD dosimetry are reasonable when related to uncertainties in the dose calculations, provided the standard deviation (s.d.) of TL readings is 1.5% or better.

A critical point: the problems associated with the variety of criteria to quantify the antioxidant capacity.

PubMed

Prieto, M A; Vázquez, J A; Murado, M A

2014-06-18

The oxidant action implies interfering in an autocatalytic process, in which no less than five chemical species are present (oxygen, oxidizable substrate, radicals, antioxidants, and oxidation products); furthermore, reactions of first and second order can take place, and interactions can occur, at several levels of the process. The common and incorrect practice is to use the single-time dose-response of an established antioxidant as a calibration curve to compute the equivalent antioxidant capacity of a sample, which is only tested at one single time-dose, assuming too many false aspects as true. Its use is unreasonable, given the availability of computational applications and instrumental equipment that, combined, provide the adequate tools to work with different variables in nonlinear models. The evaluation of the dose-time dependency of the response of the β-carotene method as a case study, using the combination of strong quantification procedures and a high amount of results with lower experimental error (applying microplate readers), reveals the lack of meaning of single-time criteria. Also, it demonstrates that, in most of the reactions, the time-dependent response in the oxidation process is inherently nonlinear and should not be standardized at one single time, because it would lead to unreliable results, hiding the real aspects of the response. In food matrices, the application of single-time criteria causes deficiencies in the control of the antioxidant content. Therefore, it is logical that, in the past decade, researchers have claimed consensus to increase the determination and effectiveness of antioxidant responses.

The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS.

PubMed

Jenkins, G J S; Cronin, J; Alhamdani, A; Rawat, N; D'Souza, F; Thomas, T; Eltahir, Z; Griffiths, A P; Baxter, J N

2008-09-01

Deoxycholic acid (DCA) is a secondary bile acid implicated in various cancers of the gastrointestinal (GI) tract. In oesophageal adenocarcinoma, DCA is believed to contribute to carcinogenesis during reflux where stomach contents enter the lower oesophagus. It is imperative that we understand the mechanisms whereby oesophageal carcinogens function in order that therapeutic options may be developed. We have previously shown that DCA can damage chromosomes and does so through its generation of reactive oxygen species (ROS). We show here, after detailed experiments, that DCA appears to have a non-linear dose response for DNA damage. DCA induces DNA damage (as measured by the micronucleus assay) at doses of 100 microM and higher in oesophageal OE33 cells, but fails to induce such DNA damage below this cut-off dose. We also show that in terms of NF-kappaB activation (as measured by up-regulation of two NF-kappaB target genes) by DCA, a similar dose response is observed. This dose-response data may be important clinically as DCA exposure to the oesophagus may be used as a way to identify the 10% of Barrett's oesophagus patients currently progressing to cancer from the 90% of patients who do not progress. Only quantitative studies measuring DCA concentrations in refluxates correlated with histological progression will answer this question. We further show here that ROS are behind DCAs ability to activate NF-kappaB as antioxidants (epigallocatechin gallate, resveratrol and vitamin C) abrogate DCAs ability to up-regulate NF-kappaB-controlled genes. In conclusion, low doses of DCA appear to be less biologically significant in vitro. If this were to be confirmed in vivo, it might suggest that reflux patients with low DCA concentrations may be at a lower risk of cancer progression compared to patients with high levels of DCA in their refluxate. Either way, antioxidant supplementation may possibly help prevent the deleterious effects of DCA in the whole GI tract.

WE-H-BRA-01: BEST IN PHYSICS (THERAPY): Nano-Dosimetric Kinetic Model for Variable Relative Biological Effectiveness of Proton and Ion Beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abolfath, R; Bronk, L; Titt, U.

2016-06-15

Purpose: Recent clonogenic cell survival and γH2AX studies suggest proton relative biological effectiveness (RBE) may be a non-linear function of linear energy transfer (LET) in the distal edge of the Bragg peak and beyond. We sought to develop a multiscale model to account for non-linear response phenomena to aid in the optimization of intensity-modulated proton therapy. Methods: The model is based on first-principle simulations of proton track structures, including secondary ions, and an analytical derivation of the dependence on particle LET of the linear-quadratic (LQ) model parameters α and β. The derived formulas are an extension of the microdosimetric kineticmore » (MK) model that captures dissipative track structures and non-Poissonian distribution of DNA damage at the distal edge of the Bragg peak and beyond. Monte Carlo simulations were performed to confirm the non-linear dose-response characteristics arising from the non-Poisson distribution of initial DNA damage. Results: In contrast to low LET segments of the proton depth dose, from the beam entrance to the Bragg peak, strong deviations from non-dissipative track structures and Poisson distribution in the ionization events in the Bragg peak distal edge govern the non-linear cell response and result in the transformation α=(1+c-1 L) α-x+2(c-0 L+c-2 L^2 )(1+c-1 L) β-x and β=(1+c-1 L)^2 β-x. Here L is the charged particle LET, and c-0,c-1, and c-2 are functions of microscopic parameters and can be served as fitting parameters to the cell-survival data. In the low LET limit c-1, and c-2 are negligible hence the linear model proposed and used by Wilkins-Oelfke for the proton treatment planning system can be retrieved. The present model fits well the recent clonogenic survival data measured recently in our group in MDACC. Conclusion: The present hybrid method provides higher accuracy in calculating the RBE-weighted dose in the target and normal tissues.« less

Linear response theory for annealing of radiation damage in semiconductor devices

NASA Technical Reports Server (NTRS)

Litovchenko, Vitaly

1988-01-01

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

Hormetic concentrations of hydrogen peroxide but not ethanol induce cross-adaptation to different stresses in budding yeast.

PubMed

Semchyshyn, Halyna M

2014-01-01

The biphasic-dose response of microorganisms to hydrogen peroxide is a phenomenon of particular interest in hormesis research. In different animal models, the dose-response curve for ethanol is also nonlinear showing an inhibitory effect at high doses but a stimulatory effect at low doses. In this study, we observed the hormetic-dose response to ethanol in budding yeast S. cerevisiae. Cross-protection is a phenomenon in which exposure to mild stress results in the acquisition of cellular resistance to lethal stress induced by different factors. Since both hydrogen peroxide and ethanol at low concentrations were found to stimulate yeast colony growth, we evaluated the role of one substance in cell cross-adaptation to the other substance as well as some weak organic acid preservatives. This study demonstrates that, unlike ethanol, hydrogen peroxide at hormetic concentrations causes cross-resistance of S. cerevisiae to different stresses. The regulatory protein Yap1 plays an important role in the hormetic effects by low concentrations of either hydrogen peroxide or ethanol, and it is involved in the yeast cross-adaptation by low sublethal doses of hydrogen peroxide.

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

PubMed

Rothenberg, Stephen J; Rothenberg, Jesse C

2005-09-01

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

Methylphenidate has nonlinear dose effects on cued response inhibition in adults but not adolescents.

PubMed

Simon, Nicholas W; Moghaddam, Bita

2017-01-01

Ongoing development of the dopamine system during adolescence may provide a partial mechanism for behavioral and psychiatric vulnerabilities. Despite early evidence for a hyperactive adolescent dopaminergic system, recent data suggest that adolescent dopamine may be functionally hypoactive compared to in adults. While this distinction has been established in response to dopaminergic drugs and natural rewards, little is known about age-related differences in cognitive efficacy of dopaminergic drugs. Using a recently established Cued Response Inhibition Task, we tested the effects of acute systemic methylphenidate, commonly known as Ritalin, on response inhibition and response initiation in adolescent and adults rats. First, we replicated previous data that adolescents are able to inhibit a response to a cue on par with adults, but are slower to produce a rewarded response after a stop cue. Next, we observed that methylphenidate modulated response inhibition in adult rats, with low dose (0.3mg/kg) improving inhibition, and high dose (3mg/kg) impairing performance. This dose-response pattern is commonly observed with psychostimulant cognitive modulation. In adolescents, however, methylphenidate had no effect on response inhibition at any dose. Latency of response initiation after the stop cue was not affected by methylphenidate in either adult or adolescent rats. These data establish that dose-response of a commonly prescribed psychostimulant medication is different in adolescents and adults. They further demonstrate that healthy adolescent response inhibition is not as sensitive to psychostimulants as in adults, supporting the idea that the dopamine system is hypoactive in adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity. Copyright © 2016 Elsevier B.V. All rights reserved.

Toxicogenomics and cancer risk assessment: a framework for key event analysis and dose-response assessment for nongenotoxic carcinogens.

PubMed

Bercu, Joel P; Jolly, Robert A; Flagella, Kelly M; Baker, Thomas K; Romero, Pedro; Stevens, James L

2010-12-01

In order to determine a threshold for nongenotoxic carcinogens, the traditional risk assessment approach has been to identify a mode of action (MOA) with a nonlinear dose-response. The dose-response for one or more key event(s) linked to the MOA for carcinogenicity allows a point of departure (POD) to be selected from the most sensitive effect dose or no-effect dose. However, this can be challenging because multiple MOAs and key events may exist for carcinogenicity and oftentimes extensive research is required to elucidate the MOA. In the present study, a microarray analysis was conducted to determine if a POD could be identified following short-term oral rat exposure with two nongenotoxic rodent carcinogens, fenofibrate and methapyrilene, using a benchmark dose analysis of genes aggregated in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) biological processes, which likely encompass key event(s) for carcinogenicity. The gene expression response for fenofibrate given to rats for 2days was consistent with its MOA and known key events linked to PPARα activation. The temporal response from daily dosing with methapyrilene demonstrated biological complexity with waves of pathways/biological processes occurring over 1, 3, and 7days; nonetheless, the benchmark dose values were consistent over time. When comparing the dose-response of toxicogenomic data to tumorigenesis or precursor events, the toxicogenomics POD was slightly below any effect level. Our results suggest that toxicogenomic analysis using short-term studies can be used to identify a threshold for nongenotoxic carcinogens based on evaluation of potential key event(s) which then can be used within a risk assessment framework. Copyright © 2010 Elsevier Inc. All rights reserved.

Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis.

PubMed

Crippa, Alessio; Discacciati, Andrea; Larsson, Susanna C; Wolk, Alicja; Orsini, Nicola

2014-10-15

Several studies have analyzed the relationship between coffee consumption and mortality, but the shape of the association remains unclear. We conducted a dose-response meta-analysis of prospective studies to examine the dose-response associations between coffee consumption and mortality from all causes, cardiovascular disease (CVD), and all cancers. Pertinent studies, published between 1966 and 2013, were identified by searching PubMed and by reviewing the reference lists of the selected articles. Prospective studies in which investigators reported relative risks of mortality from all causes, CVD, and all cancers for 3 or more categories of coffee consumption were eligible. Results from individual studies were pooled using a random-effects model. Twenty-one prospective studies, with 121,915 deaths and 997,464 participants, met the inclusion criteria. There was strong evidence of nonlinear associations between coffee consumption and mortality for all causes and CVD (P for nonlinearity < 0.001). The largest risk reductions were observed for 4 cups/day for all-cause mortality (16%, 95% confidence interval: 13, 18) and 3 cups/day for CVD mortality (21%, 95% confidence interval: 16, 26). Coffee consumption was not associated with cancer mortality. Findings from this meta-analysis indicate that coffee consumption is inversely associated with all-cause and CVD mortality. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies.

PubMed

Keum, N; Lee, D H; Marchand, N; Oh, H; Liu, H; Aune, D; Greenwood, D C; Giovannucci, E L

2015-10-14

Evidence suggests that egg intake may be implicated in the aetiology of sex hormone-related cancers. However, dose-response relationships between egg intake and such cancers are unclear. Thus, we conducted a dose-response meta-analysis to summarise the dose-response relationships between egg consumption and the risk of breast, prostate and gynaecological cancers. A literature search was performed using PubMed and Embase up to April 2015 to identify relevant prospective observational studies. Summary relative risk (RR) and 95% CI were estimated using a random-effects model. For breast cancer, the linear dose-response meta-analysis found a non-significantly increased risk (RR for an increase of 5 eggs consumed/week: 1·05, 95% CI 0·99, 1·11, n 16,023 cases). Evidence for non-linearity was not statistically significant (P non-linearity= 0·50, n 15,415 cases) but consuming ≥ 5 eggs/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1·04 (95% CI 1·01, 1·07) for consuming 5 eggs/week and 1·09 (95% CI 1·03, 1·15) for consuming about 9 eggs/week. For other cancers investigated, the summary RR for an increase of 5 eggs consumed/week was 1·09 (95% CI 0·96, 1·24, n 2636 cases) for ovarian cancer; 1·47 (95% CI 1·01, 2·14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (P Egger= 0·04). No evidence was found for an association with the risk of total prostate cancer. While our conclusion was tempered by the potential for publication bias and confounding, high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out.

Dose-response characteristics of an amorphous silicon EPID.

PubMed

Winkler, Peter; Hefner, Alfred; Georg, Dietmar

2005-10-01

Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output characteristics of the accelerator. If ghosting is prevented from affecting the results and all dose-response effects are properly corrected for, the EPID signal becomes independent of dose rate, dose, and exposure time.

Physical activity and incident type 2 diabetes mellitus: a systematic review and dose-response meta-analysis of prospective cohort studies.

PubMed

Smith, Andrea D; Crippa, Alessio; Woodcock, James; Brage, Søren

2016-12-01

Inverse associations between physical activity (PA) and type 2 diabetes mellitus are well known. However, the shape of the dose-response relationship is still uncertain. This review synthesises results from longitudinal studies in general populations and uses non-linear models of the association between PA and incident type 2 diabetes. A systematic literature search identified 28 prospective studies on leisure-time PA (LTPA) or total PA and risk of type 2 diabetes. PA exposures were converted into metabolic equivalent of task (MET) h/week and marginal MET (MMET) h/week, a measure only considering energy expended above resting metabolic rate. Restricted cubic splines were used to model the exposure-disease relationship. Our results suggest an overall non-linear relationship; using the cubic spline model we found a risk reduction of 26% (95% CI 20%, 31%) for type 2 diabetes among those who achieved 11.25 MET h/week (equivalent to 150 min/week of moderate activity) relative to inactive individuals. Achieving twice this amount of PA was associated with a risk reduction of 36% (95% CI 27%, 46%), with further reductions at higher doses (60 MET h/week, risk reduction of 53%). Results for the MMET h/week dose-response curve were similar for moderate intensity PA, but benefits were greater for higher intensity PA and smaller for lower intensity activity. Higher levels of LTPA were associated with substantially lower incidence of type 2 diabetes in the general population. The relationship between LTPA and type 2 diabetes was curvilinear; the greatest relative benefits are achieved at low levels of activity, but additional benefits can be realised at exposures considerably higher than those prescribed by public health recommendations.

The New Radiobiology: Returning to Our Roots

PubMed Central

Ulsh, Brant A.

2012-01-01

In 2005, two expert advisory bodies examined the evidence on the effects of low doses of ionizing radiation. The U.S. National Research Council concluded that current scientific evidence is consistent with the linear no-threshold dose-response relationship (NRCNA 2005) while the French National Academies of Science and Medicine concluded the opposite (Aurengo et al. 2005). These contradictory conclusions may stem in part from an emphasis on epidemiological data (a “top down” approach) versus an emphasis on biological mechanisms (a “bottom up” approach). In this paper, the strengths and limitations of the top down and bottom up approaches are discussed, and proposals for strengthening and reconciling them are suggested. The past seven years since these two reports were published have yielded increasing evidence of nonlinear responses of biological systems to low radiation doses delivered at low dose-rates. This growing body of evidence is casting ever more doubt on the extrapolation of risks observed at high doses and dose-rates to estimate risks associated with typical environmental and occupational exposures. This paper compares current evidence on low dose, low dose-rate effects against objective criteria of causation. Finally, some questions for a post-LNT world are posed. PMID:23304107

SIMPLIFIED PRACTICAL TEST METHOD FOR PORTABLE DOSE METERS USING SEVERAL SEALED RADIOACTIVE SOURCES.

PubMed

Mikamoto, Takahiro; Yamada, Takahiro; Kurosawa, Tadahiro

2016-09-01

Sealed radioactive sources which have small activity were employed for the determination of response and tests for non-linearity and energy dependence of detector responses. Close source-to-detector geometry (at 0.3 m or less) was employed to practical tests for portable dose meters to accumulate statistically sufficient ionizing currents. Difference between response in the present experimentally studied field and in the reference field complied with ISO 4037 due to non-uniformity of radiation fluence at close geometry was corrected by use of Monte Carlo simulation. As a consequence, corrected results were consistent with the results obtained in the ISO 4037 reference field within their uncertainties. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Nonlinear Simulation of the Tooth Enamel Spectrum for EPR Dosimetry

NASA Astrophysics Data System (ADS)

Kirillov, V. A.; Dubovsky, S. V.

2016-07-01

Software was developed where initial EPR spectra of tooth enamel were deconvoluted based on nonlinear simulation, line shapes and signal amplitudes in the model initial spectrum were calculated, the regression coefficient was evaluated, and individual spectra were summed. Software validation demonstrated that doses calculated using it agreed excellently with the applied radiation doses and the doses reconstructed by the method of additive doses.

X-ray-induced bystander responses reduce spontaneous mutations in V79 cells

PubMed Central

Maeda, Munetoshi; Kobayashi, Katsumi; Matsumoto, Hideki; Usami, Noriko; Tomita, Masanori

2013-01-01

The potential for carcinogenic risks is increased by radiation-induced bystander responses; these responses are the biological effects in unirradiated cells that receive signals from the neighboring irradiated cells. Bystander responses have attracted attention in modern radiobiology because they are characterized by non-linear responses to low-dose radiation. We used a synchrotron X-ray microbeam irradiation system developed at the Photon Factory, High Energy Accelerator Research Organization, KEK, and showed that nitric oxide (NO)-mediated bystander cell death increased biphasically in a dose-dependent manner. Here, we irradiated five cell nuclei using 10 × 10 µm2 5.35 keV X-ray beams and then measured the mutation frequency at the hypoxanthine-guanosine phosphoribosyl transferase (HPRT) locus in bystander cells. The mutation frequency with the null radiation dose was 2.6 × 10–5 (background level), and the frequency decreased to 5.3 × 10–6 with a dose of approximately 1 Gy (absorbed dose in the nucleus of irradiated cells). At high doses, the mutation frequency returned to the background level. A similar biphasic dose-response effect was observed for bystander cell death. Furthermore, we found that incubation with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), a specific scavenger of NO, suppressed not only the biphasic increase in bystander cell death but also the biphasic reduction in mutation frequency of bystander cells. These results indicate that the increase in bystander cell death involves mechanisms that suppress mutagenesis. This study has thus shown that radiation-induced bystander responses could affect processes that protect the cell against naturally occurring alterations such as mutations. PMID:23660275

Temporal processes that contribute to nonlinearity in vegetation responses to ozone exposure and dose

Treesearch

Robert L. Heath; Allen S. Lefohn; Robert C. Musselman

2009-01-01

Ozone interacts with plant tissue through distinct temporal processes. Sequentially, plants are exposed to ambient O3 hat (1) moves through the leaf boundary layer, (2) is taken up into plant tissue primarily through stomata, and (3) undergoes chemical interaction within plant tissue, first by initiating alterations and then as part of plant...

How feasible is remote 3D dosimetry for MR guided Radiation Therapy (MRgRT)?

NASA Astrophysics Data System (ADS)

Mein, S.; Rankine, L.; Miles, D.; Juang, T.; Cai, B.; Curcuru, A.; Mutic, S.; Fenoli, J.; Adamovics, J.; Li, H.; Oldham, M.

2017-05-01

To develop and apply a remote dosimetry protocol with PRESAGE® radiochromic plastic and optical-CT readout in the validation of MRI guided radiation therapy (MRgRT) treatments (MRIdian® by ViewRay®). Through multi-institutional collaboration we performed PRESAGE® dosimetry studies in 4ml cuvettes to investigate dose-response linearity, MR-compatibility, and energy-independence. An open calibration field and symmetrical 3-field plans were delivered to 10cm diameter PRESAGE® to examine percent depth dose and response uniformity under a magnetic field. Evidence of non-linear dose response led to a large volume PRESAGE® study where small corrections were developed for temporally- and spatially-dependent behaviors observed between irradiation and delayed readout. TG-119 plans were created in the MRIdian® TPS and then delivered to 14.5cm 2kg PRESAGE® dosimeters. Through the domestic investigation of an off-site MRgRT system, a refined 3D remote dosimetry protocol is presented capable of validation of advanced MRgRT radiation treatments.

Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure–response relations from two phase II clinical trials

PubMed Central

Savic, RM; MacKenzie, WR; Engle, M; Whitworth, WC; Johnson, JL; Nsubuga, P; Nahid, P; Nguyen, NV; Peloquin, CA; Dooley, KE; Dorman, SE

2017-01-01

Rifapentine is a highly active antituberculosis antibiotic with treatment‐shortening potential; however, exposure–response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive‐phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed‐effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses. PMID:28124478

Nonlinear reduction in risk for colorectal cancer by fruit and vegetable intake based on meta-analysis of prospective studies.

PubMed

Aune, Dagfinn; Lau, Rosa; Chan, Doris S M; Vieira, Rui; Greenwood, Darren C; Kampman, Ellen; Norat, Teresa

2011-07-01

The association between fruit and vegetable intake and colorectal cancer risk has been investigated by many studies but is controversial because of inconsistent results and weak observed associations. We summarized the evidence from cohort studies in categorical, linear, and nonlinear, dose-response meta-analyses. We searched PubMed for studies of fruit and vegetable intake and colorectal cancer risk that were published until the end of May 2010. We included 19 prospective studies that reported relative risk estimates and 95% confidence intervals (CIs) of colorectal cancer-associated with fruit and vegetable intake. Random effects models were used to estimate summary relative risks. The summary relative risk for the highest vs the lowest intake was 0.92 (95% CI: 0.86-0.99) for fruit and vegetables combined, 0.90 (95% CI: 0.83-0.98) for fruit, and 0.91 (95% CI: 0.86-0.96) for vegetables (P for heterogeneity=.24, .05, and .54, respectively). The inverse associations appeared to be restricted to colon cancer. In linear dose-response analysis, only intake of vegetables was significantly associated with colorectal cancer risk (summary relative risk=0.98; 95% CI: 0.97-0.99), per 100 g/d. However, significant inverse associations emerged in nonlinear models for fruits (Pnonlinearity<.001) and vegetables (Pnonlinearity=.001). The greatest risk reduction was observed when intake increased from very low levels of intake. There was generally little evidence of heterogeneity in the analyses and there was no evidence of small-study bias. Based on meta-analysis of prospective studies, there is a weak but statistically significant nonlinear inverse association between fruit and vegetable intake and colorectal cancer risk. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates adverse effects in female mice

PubMed Central

Rubin, Beverly S.; Paranjpe, Maneesha; DaFonte, Tracey; Schaeberle, Cheryl; Soto, Ana M.; Obin, Martin; Greenberg, Andrew S.

2017-01-01

Body weight (BW) and body composition were examined in CD-1 mice exposed perinatally or perinatally and peripubertally to 0, 0.25, 2.5, 25, or 250 μg BPA/kg BW/day. Our goal was to identify the BPA dose (s) and the exposure window(s) that increased BW and adiposity, and to assess potential sex differences in this response. Both perinatal exposure alone and perinatal plus peripubertal exposure to environmentally relevant levels of BPA resulted in lasting effects on body weight and body composition. The effects were dose specific and sex specific and were influenced by the precise window of BPA exposure. The addition of peripubertal BPA exposure following the initial perinatal exposure exacerbated adverse effects in the females but appeared to reduce differences in body weight and body composition between control and BPA exposed males. Some effects of BPA on body weight and body composition showed a non-linear dose response. PMID:27496714

Intake of fruit and vegetables and risk of bladder cancer: a dose-response meta-analysis of observational studies.

PubMed

Yao, Baodong; Yan, Yujie; Ye, Xianwu; Fang, Hong; Xu, Huilin; Liu, Yinan; Li, Sheran; Zhao, Yanping

2014-12-01

Observational studies suggest an association between fruit and vegetables intake and risk of bladder cancer, but the results are controversial. We therefore summarized the evidence from observational studies in categorical, linear, and nonlinear, dose-response meta-analysis. Pertinent studies were identified by searching EMBASE and PubMed from their inception to August 2013. Thirty-one observational studies involving 12,610 cases and 1,121,649 participants were included. The combined rate ratio (RR, 95 % CI) of bladder cancer for the highest versus lowest intake was 0.83 (0.69-0.99) for total fruit and vegetables, 0.81 (0.70-0.93) for total vegetables, 0.77 (0.69-0.87) for total fruit, 0.84 (0.77-0.91) for cruciferous vegetables, 0.79 (0.68-0.91) for citrus fruits, and 0.74 (0.66-0.84) for yellow-orange vegetables. Subgroup analysis showed study design and gender as possible sources of heterogeneity. A nonlinear relationship was found of citrus fruits intake with risk of bladder cancer (P for nonlinearity = 0.018), and the RRs (95 % CI) of bladder cancer were 0.87 (0.78-0.96), 0.80 (0.67-0.94), 0.79 (0.66-0.94), 0.79 (0.65-0.96), and 0.79 (0.64-0.99) for 30, 60, 90, 120, and 150 g/day. A nonlinear relationship was also found of yellow-orange vegetable intake with risk of bladder cancer risk (P for nonlinearity = 0.033). Some evidence of publication bias was observed for fruit, citrus fruits, and yellow-orange vegetables. This meta-analysis supports the hypothesis that intakes of fruit and vegetables may reduce the risk of bladder cancer. Future well-designed studies are required to confirm this finding.

Effect of low-dose ionizing radiation on luminous marine bacteria: radiation hormesis and toxicity.

PubMed

Kudryasheva, N S; Rozhko, T V

2015-04-01

The paper summarizes studies of effects of alpha- and beta-emitting radionuclides (americium-241, uranium-235+238, and tritium) on marine microorganisms under conditions of chronic low-dose irradiation in aqueous media. Luminous marine bacteria were chosen as an example of these microorganisms; bioluminescent intensity was used as a tested physiological parameter. Non-linear dose-effect dependence was demonstrated. Three successive stages in the bioluminescent response to americium-241 and tritium were found: 1--absence of effects (stress recognition), 2--activation (adaptive response), and 3--inhibition (suppression of physiological function, i.e. radiation toxicity). The effects were attributed to radiation hormesis phenomenon. Biological role of reactive oxygen species, secondary products of the radioactive decay, is discussed. The study suggests an approach to evaluation of non-toxic and toxic stages under conditions of chronic radioactive exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.

MMB-4 Inhibition of Aceylcholinesterase Is Similar across Species

DTIC Science & Technology

2014-11-01

version 5.4). An IC50 value was determined for AChE from each animal species by fitting the percent of AChE activity with respect to MMB 4 concentration...in GraphPad Prism (version 5) using a nonlinear regression dose response model for inhibition (normalized response with variable slope). Assessing the...Therefore, AChE activity and inhibition studies were carried out at 435 nm to reduce interference from MMB 4. Comparison of IC50 Values for MMB 4 with AChE

Mechanism of cell destruction and cell protection during methylene-blue-induced PDT

NASA Astrophysics Data System (ADS)

Rueck, Angelika C.; Beck, G.; Heckelsmiller, K.; Knoedlsdorfer, U.; Genze, Felicitas; Orth, K.

1999-02-01

Methylene Blue (MB+) is a well-known dye in medicine and has been discussed as an easily applicable drug for the topical treatment in photodynamic therapy (PDT). MB+ can potentially be used as a redox indicator to detect the important redox reactions that are induced during PDT. MB+ induced PDT was successful in the intraluminal treatment of inoperable esophageal tumors and in the topical treatment of psoriasis. In order to improve the therapy, the reaction mechanism of MB+ was investigated in vivo by local injection of MB+ in a xenotransplanted subcutaneous tumor (adeno-carcinoma, G-3) in female nude mice. The MB+ preparation 'MB+1%' was applied both undiluted and diluted to 0.1% and 0.01% with isotonic sodium chloride. After an incubation period of 1 h, the tumors were irradiated at 662 nm. Treatment with 1% MB+ and subsequent irradiation with 100 J/cm2 led to complete tumor destruction in 79% of the treated animals. A decrease of the fluence rate from 100 mW/cm2 to 50 mW/cm2 significantly increased the phototoxic response, which was attributed to oxygen depletion but also to nonlinear redox reactions. In addition, fractionated light application with 15 s interruption intervals enhanced the effect. When 0.1% MB+ was used, complete tumor destruction was observed only in 10% of the treated animals. Below a relatively high threshold dose the therapeutic response was not significant. The efficiency of the therapy was correlated with nonlinear dynamics of MB+ on a subcellular level, using laser scanning microscopy. During MB+-PDT nonlinear redox- reactions were induced. This could be deduced from local fast changes of the MB+-fluorescence as well as the pH-value during irradiation of single cells. The light induced reaction of MB+ seems to be correlated with the nonlinear production of reactive oxygen species (ROS). As a consequence below a threshold dose the reducing ability of MB+ prevents tissue from oxidative damage. However, above this dose, as a point of no return, MB+ acts as an extremely potent oxidant.

Nonlinear mixed effects dose response modeling in high throughput drug screens: application to melanoma cell line analysis.

PubMed

Ding, Kuan-Fu; Petricoin, Emanuel F; Finlay, Darren; Yin, Hongwei; Hendricks, William P D; Sereduk, Chris; Kiefer, Jeffrey; Sekulic, Aleksandar; LoRusso, Patricia M; Vuori, Kristiina; Trent, Jeffrey M; Schork, Nicholas J

2018-01-12

Cancer cell lines are often used in high throughput drug screens (HTS) to explore the relationship between cell line characteristics and responsiveness to different therapies. Many current analysis methods infer relationships by focusing on one aspect of cell line drug-specific dose-response curves (DRCs), the concentration causing 50% inhibition of a phenotypic endpoint (IC 50 ). Such methods may overlook DRC features and do not simultaneously leverage information about drug response patterns across cell lines, potentially increasing false positive and negative rates in drug response associations. We consider the application of two methods, each rooted in nonlinear mixed effects (NLME) models, that test the relationship relationships between estimated cell line DRCs and factors that might mitigate response. Both methods leverage estimation and testing techniques that consider the simultaneous analysis of different cell lines to draw inferences about any one cell line. One of the methods is designed to provide an omnibus test of the differences between cell line DRCs that is not focused on any one aspect of the DRC (such as the IC 50 value). We simulated different settings and compared the different methods on the simulated data. We also compared the proposed methods against traditional IC 50 -based methods using 40 melanoma cell lines whose transcriptomes, proteomes, and, importantly, BRAF and related mutation profiles were available. Ultimately, we find that the NLME-based methods are more robust, powerful and, for the omnibus test, more flexible, than traditional methods. Their application to the melanoma cell lines reveals insights into factors that may be clinically useful.

Dose-response relationship between dietary magnesium intake and cardiovascular mortality: A systematic review and dose-based meta-regression analysis of prospective studies.

PubMed

Fang, Xin; Liang, Chun; Li, Mei; Montgomery, Scott; Fall, Katja; Aaseth, Jan; Cao, Yang

2016-12-01

Although epidemiology studies have reported the relationship, including a dose-response relationship, between dietary magnesium intake and risk of cardiovascular disease (CVD), the risk for CVD mortality is inconclusive and the evidence for a dose-response relationship has not been summarized. We conducted a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the association of dietary magnesium intake with risk of CVD mortality and describe their dose-response relationship. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to August 2015, and reviewed references lists of retrieved articles. We included population-based studies that reported mortality risks, i.e. relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) of CVD mortality or cause-specific CVD death. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. Out of 3002 articles, 9 articles from 8 independent studies met the eligibility criteria. These studies comprised 449,748 individuals and 10,313 CVD deaths. Compared with the lowest dietary magnesium consumption group in the population, the risk of CVD mortality was reduced by 16% in women and 8% in men. No significant linear dose-response relationship was found between increment in dietary magnesium intake and CVD mortality across all the studies. After adjusting for age and BMI, the risk of CVD mortality was reduced by 24-25% per 100mg/d increment in dietary magnesium intake in women of all the participants and in all the US participants. Although the combined data confirm the role of dietary magnesium intake in reducing CVD mortality, the dose-response relationship was only found among women and in US population. Copyright © 2016 Elsevier GmbH. All rights reserved.

Non linear processes modulated by low doses of radiation exposure

NASA Astrophysics Data System (ADS)

Mariotti, Luca; Ottolenghi, Andrea; Alloni, Daniele; Babini, Gabriele; Morini, Jacopo; Baiocco, Giorgio

The perturbation induced by radiation impinging on biological targets can stimulate the activation of several different pathways, spanning from the DNA damage processing to intra/extra -cellular signalling. In the mechanistic investigation of radiobiological damage this complex “system” response (e.g. omics, signalling networks, micro-environmental modifications, etc.) has to be taken into account, shifting from a focus on the DNA molecule solely to a systemic/collective view. An additional complication comes from the finding that the individual response of each of the involved processes is often not linear as a function of the dose. In this context, a systems biology approach to investigate the effects of low dose irradiations on intra/extra-cellular signalling will be presented, where low doses of radiation act as a mild perturbation of a robustly interconnected network. Results obtained through a multi-level investigation of both DNA damage repair processes (e.g. gamma-H2AX response) and of the activation kinetics for intra/extra cellular signalling pathways (e.g. NFkB activation) show that the overall cell response is dominated by non-linear processes - such as negative feedbacks - leading to possible non equilibrium steady states and to a poor signal-to-noise ratio. Together with experimental data of radiation perturbed pathways, different modelling approaches will be also discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Berrington de Gonzalez, Amy, E-mail: berringtona@mail.nih.gov; Gilbert, Ethel; Curtis, Rochelle

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 studiesmore » 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.« less

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition.

PubMed

Falgreen, Steffen; Laursen, Maria Bach; Bødker, Julie Støve; Kjeldsen, Malene Krag; Schmitz, Alexander; Nyegaard, Mette; Johnsen, Hans Erik; Dybkær, Karen; Bøgsted, Martin

2014-06-05

In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves' dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological interpretations. Time independent summary statistics may aid the understanding of drugs' action mechanism on tumour cells and potentially renew previous drug sensitivity evaluation studies.

Exposure time independent summary statistics for assessment of drug dependent cell line growth inhibition

PubMed Central

2014-01-01

Background In vitro generated dose-response curves of human cancer cell lines are widely used to develop new therapeutics. The curves are summarised by simplified statistics that ignore the conventionally used dose-response curves’ dependency on drug exposure time and growth kinetics. This may lead to suboptimal exploitation of data and biased conclusions on the potential of the drug in question. Therefore we set out to improve the dose-response assessments by eliminating the impact of time dependency. Results First, a mathematical model for drug induced cell growth inhibition was formulated and used to derive novel dose-response curves and improved summary statistics that are independent of time under the proposed model. Next, a statistical analysis workflow for estimating the improved statistics was suggested consisting of 1) nonlinear regression models for estimation of cell counts and doubling times, 2) isotonic regression for modelling the suggested dose-response curves, and 3) resampling based method for assessing variation of the novel summary statistics. We document that conventionally used summary statistics for dose-response experiments depend on time so that fast growing cell lines compared to slowly growing ones are considered overly sensitive. The adequacy of the mathematical model is tested for doxorubicin and found to fit real data to an acceptable degree. Dose-response data from the NCI60 drug screen were used to illustrate the time dependency and demonstrate an adjustment correcting for it. The applicability of the workflow was illustrated by simulation and application on a doxorubicin growth inhibition screen. The simulations show that under the proposed mathematical model the suggested statistical workflow results in unbiased estimates of the time independent summary statistics. Variance estimates of the novel summary statistics are used to conclude that the doxorubicin screen covers a significant diverse range of responses ensuring it is useful for biological interpretations. Conclusion Time independent summary statistics may aid the understanding of drugs’ action mechanism on tumour cells and potentially renew previous drug sensitivity evaluation studies. PMID:24902483

Sinogram noise reduction for low-dose CT by statistics-based nonlinear filters

NASA Astrophysics Data System (ADS)

Wang, Jing; Lu, Hongbing; Li, Tianfang; Liang, Zhengrong

2005-04-01

Low-dose CT (computed tomography) sinogram data have been shown to be signal-dependent with an analytical relationship between the sample mean and sample variance. Spatially-invariant low-pass linear filters, such as the Butterworth and Hanning filters, could not adequately handle the data noise and statistics-based nonlinear filters may be an alternative choice, in addition to other choices of minimizing cost functions on the noisy data. Anisotropic diffusion filter and nonlinear Gaussian filters chain (NLGC) are two well-known classes of nonlinear filters based on local statistics for the purpose of edge-preserving noise reduction. These two filters can utilize the noise properties of the low-dose CT sinogram for adaptive noise reduction, but can not incorporate signal correlative information for an optimal regularized solution. Our previously-developed Karhunen-Loeve (KL) domain PWLS (penalized weighted least square) minimization considers the signal correlation via the KL strategy and seeks the PWLS cost function minimization for an optimal regularized solution for each KL component, i.e., adaptive to the KL components. This work compared the nonlinear filters with the KL-PWLS framework for low-dose CT application. Furthermore, we investigated the nonlinear filters for post KL-PWLS noise treatment in the sinogram space, where the filters were applied after ramp operation on the KL-PWLS treated sinogram data prior to backprojection operation (for image reconstruction). By both computer simulation and experimental low-dose CT data, the nonlinear filters could not outperform the KL-PWLS framework. The gain of post KL-PWLS edge-preserving noise filtering in the sinogram space is not significant, even the noise has been modulated by the ramp operation.

Single toxin dose-response models revisited

DOE Office of Scientific and Technical Information (OSTI.GOV)

Demidenko, Eugene, E-mail: eugened@dartmouth.edu

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 the fourmore » 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 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.« less

Mode-of-action evaluation for the effect of trans fatty acids on low-density lipoprotein cholesterol.

PubMed

Reichard, John F; Haber, Lynne T

2016-12-01

The purpose of this work is to systematically consider the data relating to the mode of action (MOA) for the effects of industrially produced trans fatty acid (iTFA) on plasma low-density lipoprotein (LDL) levels. The hypothesized MOA is composed of two key events: increased LDL production and decreased LDL clearance. A substantial database supports this MOA, although the key events are likely to be interdependent, rather than sequential. Both key events are functions of nonlinear biological processes including rate-limited clearance, receptor-mediated transcription, and both positive and negative feedback regulation. Each key event was evaluated based on weight-of-evidence analysis and for human relevance. We conclude that the data are inadequate for a detailed dose-response analysis in the context of the evolved Bradford Hill considerations; however, the weight of evidence is strong and the overall shape of the dose-response curves for markers of the key events and the key determinants of those relationships is well understood in many cases and is nonlinear. Feedback controls are responsible for maintaining homeostasis of cholesterol and triglyceride levels and underlie both of the key events, resulting in a less-than-linear or thresholded relationship between TFA and LDL-C. The inconsistencies and gaps in the database are discussed. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Nonlinear dose response model with repair and repair suppression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leonard, B.E.

1996-12-31

In March 1996, the Health Physics Society issued a position statement supporting a nonlinear threshold (NLT) concept for radiation risk at low-dose/low-dose-rate (LD/LDR) levels. This action was after receipt of an overwhelming consensus from world-renown radiobiologists and is contrary to the opinions of the United Nations Scientific Committee on Effects of Atomic Radiation, the National Research Council Committee on the Biological Effects of Ionizing Radiations, and U.S. Environmental Protection Agency. Alvarez and others have called for a new NLT model for radiation risk. Two mathematical models have historically been used to describe cell survival experimental results. Each provides the abilitymore » to account for the shoulder observed in cell survival curves, predominantly for low-linear energy transfer (LET) radiation, and the wide variation in radio sensitivity of cell species and particular phase of the mitotic cycle. Only Kellerer and Rossi, Elkind and Whitmore, and Green and Burki have proposed modified models explicitly incorporating radiobiological repair and departing from LNT. None of these were subsequently used with any extent of success in cell survival analysis. The author reports initial work on a program to reexamine radiobiology research exhibiting repair processes at LD/LDR levels.« less

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

PubMed Central

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

2015-01-01

Controversial results of the association between household physical activity and cancer risk were reported among previous epidemiological studies. We conducted a meta-analysis to investigate the relationship of household physical activity and cancer risk quantitatively, especially in dose-response manner. PubMed, Embase, Web of science and the Cochrane Library were searched for cohort or case-control studies that examined the association between household physical activity and cancer risks. Random–effect models were conducted to estimate the summary relative risks (RRs), nonlinear or linear dose–response meta-analyses were performed to estimate the trend from the correlated log RR estimates across levels of household physical activity quantitatively. Totally, 30 studies including 41 comparisons met the inclusion criteria. Total cancer risks were reduced 16% among the people with highest household physical activity compared to those with lowest household physical activity (RR = 0.84, 95% CI = 0.76–0.93). The dose-response analyses indicated an inverse linear association between household physical activity and cancer risk. The relative risk was 0.98 (95% CI = 0.97–1.00) for per additional 10 MET-hours/week and it was 0.99 (95% CI = 0.98–0.99) for per 1 hour/week increase. These findings provide quantitative data supporting household physical activity is associated with decreased cancer risk in dose-response effect. PMID:26443426

Body mass index had different effects on premenopausal and postmenopausal breast cancer risks: a dose-response meta-analysis with 3,318,796 subjects from 31 cohort studies.

PubMed

Chen, Yanzi; Liu, Li; Zhou, Quan; Imam, Mustapha Umar; Cai, Jialin; Wang, Yaxuan; Qi, Minjie; Sun, Panpan; Ping, Zhiguang; Fu, Xiaoli

2017-12-08

There is sufficient evidence supporting a relationship between increased body mass index (BMI) and an increased risk for breast cancer among postmenopausal women. However, most studies have found a decreased risk for premenopausal breast cancer. This study was conducted to find out the different effects of BMI on the risk of breast cancer among premenopausal and postmenopausal women, and explore the potential factors that influence the associations. A dose-response meta-analysis with 3,318,796 participants from 31 articles was conducted. Cohort studies that included BMI and corresponding breast cancer risk were selected through various databases including PubMed, Medline, Web of Science, the China National Knowledge Infrastructure (CNKI) and Chinese Scientific Journals (VIP). Random effects models were used for analyzing the data. The summary relative risks (RRs) were 1.33 (95%CI: 1.20-1.48) and 0.94(95%CI: 0.80-1.11) among postmenopausal and premenopausal women, respectively. The dose-response meta-analysis indicated a positive non-linear association between BMI and breast cancer risk among postmenopausal women, and compared to the mean level of the normal BMI category (21.5 kg/m 2 ) the RR in total postmenopausal women were1.03 (95% CI: 1.02-1.05) per 1 kg/m 2 increment. However, no statistically significant association among total premenopausal women was detected. In subgroup analysis among European premenopausal women, the summary RR was 0.79(95%CI: 0.70-0.88). The non-linear relationship showed a negative non-linear association between BMI and breast cancer risk among European premenopausal women. When compared to the mean level of the normal BMI category, the RRs were 0.98 (95%CI: 0.96-1.00) per 1 kg/m 2 increment, respectively. In line with previous studies BMI had different effects on pre-menopausal and postmenopausal breast cancer risk. However, contrary to previous studies, a high BMI was not associated with decreased risk in total pre-menopausal women. More research is needed to better understand these differences.

Systematic review with meta-analysis: coffee consumption and the risk of gallstone disease.

PubMed

Zhang, Y-P; Li, W-Q; Sun, Y-L; Zhu, R-T; Wang, W-J

2015-09-01

Epidemiologic evidence on coffee consumption reducing the risk of gallstone disease has been contradictory. To perform a meta-analysis of observational studies, to investigate an association and dose-response of coffee consumption with gallstone disease. We used PubMed and EMBASE databases to identify all published studies before June 2015. A random-effects model was used to compute a pooled relative risk (RR) and corresponding 95% confidence intervals (CIs). One case-control study and five prospective cohort studies (with seven cohorts) involving 227,749 participants and 11,477 gallstone disease cases were included. Coffee consumption was significantly associated with a reduced risk of gallstone disease (RR, 0.83; 95% CI, 0.76 to 0.89; I(2) = 35.9%), based on prospective studies; specifically, we observed an inverse relation in females, but not in males. The case-control study did not reveal any association between coffee and gallstone disease (OR, 0.99; 95% CI, 0.64 to 1.53). In a dose-response analysis, the RR of gallstone disease was 0.95 (95% CI, 0.91 to 1.00; P = 0.049) per 1 cup/day of coffee consumption. A significant nonlinear dose-response association was also identified (P for nonlinearity = 0.0106). For people who drank 2, 4 and 6 cups of coffee per day, the estimated RRs of gallstone disease were 0.89 (95% CI, 0.79 to 0.99), 0.81 (95% CI, 0.72 to 0.92) and 0.75 (95% CI, 0.64 to 0.88), respectively, compared with the lowest level drinkers. This study suggests that coffee consumption is related to a significantly decreased risk of gallstone disease. © 2015 John Wiley & Sons Ltd.

Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates adverse effects in female mice.

PubMed

Rubin, Beverly S; Paranjpe, Maneesha; DaFonte, Tracey; Schaeberle, Cheryl; Soto, Ana M; Obin, Martin; Greenberg, Andrew S

2017-03-01

Body weight (BW) and body composition were examined in CD-1 mice exposed perinatally or perinatally and peripubertally to 0, 0.25, 2.5, 25, or 250μg BPA/kg BW/day. Our goal was to identify the BPA dose (s) and the exposure window(s) that increased BW and adiposity, and to assess potential sex differences in this response. Both perinatal exposure alone and perinatal plus peripubertal exposure to environmentally relevant levels of BPA resulted in lasting effects on body weight and body composition. The effects were dose specific and sex specific and were influenced by the precise window of BPA exposure. The addition of peripubertal BPA exposure following the initial perinatal exposure exacerbated adverse effects in the females but appeared to reduce differences in body weight and body composition between control and BPA exposed males. Some effects of BPA on body weight and body composition showed a non-linear dose response. Copyright © 2016. Published by Elsevier Inc.

Robust ridge regression estimators for nonlinear models with applications to high throughput screening assay data.

PubMed

Lim, Changwon

2015-03-30

Nonlinear regression is often used to evaluate the toxicity of a chemical or a drug by fitting data from a dose-response study. Toxicologists and pharmacologists may draw a conclusion about whether a chemical is toxic by testing the significance of the estimated parameters. However, sometimes the null hypothesis cannot be rejected even though the fit is quite good. One possible reason for such cases is that the estimated standard errors of the parameter estimates are extremely large. In this paper, we propose robust ridge regression estimation procedures for nonlinear models to solve this problem. The asymptotic properties of the proposed estimators are investigated; in particular, their mean squared errors are derived. The performances of the proposed estimators are compared with several standard estimators using simulation studies. The proposed methodology is also illustrated using high throughput screening assay data obtained from the National Toxicology Program. Copyright © 2014 John Wiley & Sons, Ltd.

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

NASA Technical Reports Server (NTRS)

Litovchenko, V.; Ivakhnenko, I.

1991-01-01

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

Daytime Napping and the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Study and Dose-Response Meta-Analysis

PubMed Central

Yamada, Tomohide; Hara, Kazuo; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

2015-01-01

Study Objectives: To summarize evidence about the association between daytime napping and the risk of cardiovascular disease and all-cause mortality, and to quantify the potential dose-response relation. Design: Meta-analysis of prospective cohort studies. Methods and Results: Electronic databases were searched for articles published up to December 2014 using the terms nap, cardiovascular disease, and all-cause mortality. We selected well-adjusted prospective cohort studies reporting risk estimates for cardiovascular disease and all-cause mortality related to napping. Eleven prospective cohort studies were identified with 151,588 participants (1,625,012 person-years) and a mean follow-up period of 11 years (60% women, 5,276 cardiovascular events, and 18,966 all-cause deaths). Pooled analysis showed that a long daytime nap (≥ 60 min/day) was associated with a higher risk of cardiovascular disease (rate ratio [RR]: 1.82 [1.22–2.71], P = 0.003, I2 = 37%) compared with not napping. All-cause mortality was associated with napping for ≥ 60 min/day (RR: 1.27 [1.11–1.45], P < 0.001, I2 = 0%) compared with not napping. In contrast, napping for < 60 min/day was not associated with cardiovascular disease (P = 0.98) or all-cause mortality (P = 0.08). Meta-analysis demonstrated a significant J-curve dose-response relation between nap time and cardiovascular disease (P for nonlinearity = 0.01). The RR initially decreased from 0 to 30 min/day. Then it increased slightly until about 45 min/day, followed by a sharp increase at longer nap times. There was also a positive linear relation between nap time and all-cause mortality (P for non-linearity = 0.97). Conclusions: Nap time and cardiovascular disease may be associated via a J-curve relation. Further studies are needed to confirm the efficacy of a short nap. Citation: Yamada T, Hara K, Shojima N, Yamauchi T, Kadowaki T. Daytime napping and the risk of cardiovascular disease and all-cause mortality: a prospective study and dose-response meta-analysis. SLEEP 2015;38(12):1945–1953. PMID:26158892

Food Groups and Risk of Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies.

PubMed

Schwingshackl, Lukas; Schwedhelm, Carolina; Hoffmann, Georg; Knüppel, Sven; Iqbal, Khalid; Andriolo, Violetta; Bechthold, Angela; Schlesinger, Sabrina; Boeing, Heiner

2017-11-01

The aim of this systematic review and meta-analysis was to summarize the evidence on the relation of the intakes of 12 major food groups, including whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSBs) with the risk of hypertension. PubMed, Scopus, and Web of Science were searched systematically until June 2017 for prospective studies having quantitatively investigated the above-mentioned foods. We conducted meta-analysis on the highest compared with the lowest intake categories and linear and nonlinear dose-response meta-analyses to analyze the association. Summary RRs and 95% CIs were estimated by using a random-effects model. Overall, 28 reports were included in the meta-analysis. An inverse association for the risk of hypertension was observed for 30 g whole grains/d (RR: 0.92; 95% CI: 0.87, 0.98), 100 g fruits/d (RR: 0.97; 95% CI: 0.96, 0.99), 28 g nuts/d (RR: 0.70; 95% CI: 0.45, 1.08), and 200 g dairy/d (RR: 0.95; 95% CI: 0.94, 0.97), whereas a positive association for 100 g red meat/d (RR: 1.14; 95% CI: 1.02, 1.28), 50 g processed meat/d (RR: 1.12; 95% CI: 1.00, 1.26), and 250 mL SSB/d (RR: 1.07; 95% CI: 1.04, 1.10) was seen in the linear dose-response meta-analysis. Indication for nonlinear relations of the intakes of whole grains, fruits, fish, and processed meats with the risk of hypertension was detected. In summary, this comprehensive dose-response meta-analysis of 28 reports identified optimal intakes of whole grains, fruits, nuts, legumes, dairy, red and processed meats, and SSBs related to the risk of hypertension. These findings need to be seen under the light of very-low to low quality of meta-evidence. However, the findings support the current dietary guidelines in the prevention of hypertension. © 2017 American Society for Nutrition.

Parity and osteoporotic fracture risk in postmenopausal women: a dose-response meta-analysis of prospective studies.

PubMed

Wang, Q; Huang, Q; Zeng, Y; Liang, J-J; Liu, S-Y; Gu, X; Liu, J-A

2016-01-01

The present dose-response meta-analysis shows linearly decreased hip fracture (HF) risk and nonlinearly decreased osteoporotic fracture (OF) risk associated with increasing number of parity of up to five live births among postmenopausal women. Epidemiological reports suggest that parity is associated with reduced OF risk among women. However, these findings are controversial. Here, we present a meta-analysis of prospective studies of parity in relation to OF risk. We performed systematic searches using Medline and Embase from January 1, 1966, to December 31, 2014, with limits of language in English and prospective study design. Relative risks (RRs) and confidence intervals (CIs) were derived mainly using random-effects models. Categorical, dose-response, heterogeneity, publication bias, and subgroup analyses were conducted. We analyzed 10 articles of 19 independent reports from 1966 to 2014, comprising a total of 217,295 participants and 26,525 cases of OF. Compared to nulliparous women, the OF and HF risks of parous women with at least one live birth were reduced by 11 % (95 % confidence interval (CI) 3-19 %; I (2) = 77.1 %, p < 0.001) and 26 % (95 % CI 17-35 %; I (2) = 19.5 %, p = 0.287), respectively. Representative nonlinearly and linearly inverse dose-response associations were found between parity (range of 0-6) and OF risk (p nonlinearity = 0.0163; I (2) = 79.7 %, p < 0.001), and between parity (range of 0-5) and HF risk (p nonlinearity = 0.054; I (2) = 76.5 %, p < 0.001), respectively. The lowest risk reduction for OF of 25 % (95 % CI 16-33 %) was observed for five live births. And, the summary risk reduction for HF was 12 % (95 % CI 9-15 %) for each one increased live birth. We found that increasing number of parity is associated with linearly reduced HF risks among women. The association between parity of six or more live births and HF risks should be studied further in future.

Exposures involving perturbations of the EM field have non-linear effects on radiation response and can alter the expression of radiation induced bystander effects

NASA Astrophysics Data System (ADS)

Mothersill, Carmel; Seymour, Colin

2012-07-01

Our recent data suggest there is a physical component to the bystander signal induced by radiation exposure and that alternative medicine techniques such as Reiki and acupuncture or exposures to weak EM fields alter the response of cells to direct irradiation and either altered bystander signal production or altered the response of cells receiving bystander signals. Our proposed mechanism to explain these findings is that perturbation of electromagnetic (EM) fields is central to the induction of low radiation dose responses especially non-targeted bystander effects. In this presentation we review the alternative medicine data and other data sets from our laboratory which test our hypothesis that perturbation of bio-fields will modulate radiation response in the low dose region. The other data sets include exposure to MRI, shielding using lead and or Faraday cages, the use of physical barriers to bystander signal transmission and the use of membrane channel blockers. The data taken together strongly suggest that EM field perturbation can modulate low dose response and that in fact the EM field rather than the targeted deposition of ionizing energy in the DNA may be the key determinant of dose response in a cell or organism The results also lead us to suspect that at least when chemical transmission is blocked, bystander signals can be transmitted by other means. Our recent experiments suggest light signals and volatiles are not likely. We conclude that alternative medicine and other techniques involving electromagnetic perturbations can modify the response of cells to low doses of ionizing radiation and can induce bystander effects similar to those seen in medium transfer experiments. In addition to the obvious implications for mechanistic studies of low dose effects, this could perhaps provide a novel target to exploit in space radiation protection and in optimizing therapeutic gain during radiotherapy.

Chromosome damage in human cells by γ rays, α particles and heavy ions: track interactions in basic dose-response relationships.

PubMed

Loucas, Bradford D; Durante, Marco; Bailey, Susan M; Cornforth, Michael N

2013-01-01

We irradiated normal human lymphocytes and fibroblasts with (137)Cs γ rays, 3.5 MeV α particles and 1 GeV/amu (56)Fe ions and measured the subsequent formation of chromosome-type aberrations by mFISH at the first mitosis following irradiation. This was done for the purposes of characterizing the shape of dose-response relationships and determining the frequency distribution of various aberration types with respect to the parameters of dose, radiation quality and cell type. Salient results and conclusions include the following. For low-LET γ rays, lymphocytes showed a more robust dose response for overall damage and a higher degree of upward curvature compared to fibroblasts. For both sources of high-LET radiation, and for both cell types, the response for simple and complex exchanges was linear with dose. Independent of all three parameters considered, the most likely damage outcome was the formation of a simple exchange event involving two breaks. However, in terms of the breakpoints making up exchange events, the majority of damage registered following HZE particle irradiation was due to complex aberrations involving multiple chromosomes. This adds a decidedly nonlinear component to the overall breakpoint response, giving it a significant degree of positive curvature, which we interpret as being due to interaction between ionizations of the primary HZE particle track and long-range δ rays produced by other nearby tracks. While such track interaction had been previously theorized, to the best of our knowledge, it has never been demonstrated experimentally.

Chromosome Damage in Human Cells by γ Rays, α Particles and Heavy Ions: Track Interactions in Basic Dose-Response Relationships

PubMed Central

Loucas, Bradford D.; Durante, Marco; Bailey, Susan M.; Cornforth, Michael N.

2013-01-01

We irradiated normal human lymphocytes and fibroblasts with 137Cs γ rays, 3.5 MeV α particles and 1 GeV/amu 56Fe ions and measured the subsequent formation of chromosome-type aberrations by mFISH at the first mitosis following irradiation. This was done for the purposes of characterizing the shape of dose-response relationships and determining the frequency distribution of various aberration types with respect to the parameters of dose, radiation quality and cell type. Salient results and conclusions include the following. For low-LET γ rays, lymphocytes showed a more robust dose response for overall damage and a higher degree of upward curvature compared to fibroblasts. For both sources of high-LET radiation, and for both cell types, the response for simple and complex exchanges was linear with dose. Independent of all three parameters considered, the most likely damage outcome was the formation of a simple exchange event involving two breaks. However, in terms of the breakpoints making up exchange events, the majority of damage registered following HZE particle irradiation was due to complex aberrations involving multiple chromosomes. This adds a decidedly nonlinear component to the overall breakpoint response, giving it a significant degree of positive curvature, which we interpret as being due to interaction between ionizations of the primary HZE particle track and long-range δ rays produced by other nearby tracks. While such track interaction had been previously theorized, to the best of our knowledge, it has never been demonstrated experimentally. PMID:23198992

Tuning the third-order nonlinear optical properties of In:ZnO thin films by 8 MeV electron beam irradiation

NASA Astrophysics Data System (ADS)

Shettigar, Nayana; Pramodini, S.; Kityk, I. V.; Abd-Lefdil, M.; Eljald, E. M.; Regragui, M.; Antony, Albin; Rao, Ashok; Sanjeev, Ganesh; Ajeyakashi, K. C.; Poornesh, P.

2017-11-01

We report the third-order nonlinear optical properties of electron beam treated Indium doped ZnO (Zn1-xInxO (x = 0.03) thin films at different dose rate. Zn1-xInxO (x = 0.03) thin films prepared by spray pyrolysis deposition technique were irradiated using 8 MeV electron beam at dose rates ranging from 1 kGy to 4 kGy. X-ray diffraction patterns were obtained to examine the structural changes, The transformation from sphalerite to wurtzite structure of ZnO was observed which indicates occurrence of structural changes due to irradiation. Morphology of irradiated thin films examined using atomic force microscopy (AFM) technique indicates the surface roughness varying with irradiation dose rate. The switching over from Saturable Absorption (SA) to Reverse Saturable Absorption (RSA) behaviour was noted when the irradiation dose rate was increased from 1 kGy to 4 kGy. The significant changes observed in the third-order nonlinear optical susceptibility χ(3) of the Zn1-xInxO (x = 0.03) thin films is attributed mainly due to electron beam irradiation. The study indicates that nonlinear optical parameters can be controlled by electron beam irradiation by choosing appropriate dose rate which is very much essential for device applications. Hence Zn1-xInxO (x = 0.03) materialize as a promising material for use in nonlinear optical device applications.

Selenium Exposure and Cancer Risk: an Updated Meta-analysis and Meta-regression

PubMed Central

Cai, Xianlei; Wang, Chen; Yu, Wanqi; Fan, Wenjie; Wang, Shan; Shen, Ning; Wu, Pengcheng; Li, Xiuyang; Wang, Fudi

2016-01-01

The objective of this study was to investigate the associations between selenium exposure and cancer risk. We identified 69 studies and applied meta-analysis, meta-regression and dose-response analysis to obtain available evidence. The results indicated that high selenium exposure had a protective effect on cancer risk (pooled OR = 0.78; 95%CI: 0.73–0.83). The results of linear and nonlinear dose-response analysis indicated that high serum/plasma selenium and toenail selenium had the efficacy on cancer prevention. However, we did not find a protective efficacy of selenium supplement. High selenium exposure may have different effects on specific types of cancer. It decreased the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, and prostate cancer, but it was not associated with colorectal cancer, bladder cancer, and skin cancer. PMID:26786590

Human responses to bright light of different durations.

PubMed

Chang, Anne-Marie; Santhi, Nayantara; St Hilaire, Melissa; Gronfier, Claude; Bradstreet, Dayna S; Duffy, Jeanne F; Lockley, Steven W; Kronauer, Richard E; Czeisler, Charles A

2012-07-01

Light exposure in the early night induces phase delays of the circadian rhythm in melatonin in humans. Previous studies have investigated the effect of timing, intensity, wavelength, history and pattern of light stimuli on the human circadian timing system. We present results from a study of the duration–response relationship to phase-delaying bright light. Thirty-nine young healthy participants (16 female; 22.18±3.62 years) completed a 9-day inpatient study. Following three baseline days, participants underwent an initial circadian phase assessment procedure in dim light (<3 lux), and were then randomized for exposure to a bright light pulse (∼10,000 lux) of 0.2 h, 1.0 h, 2.5 h or 4.0 h duration during a 4.5 h controlled-posture episode centred in a 16 h wake episode. After another 8 h sleep episode, participants completed a second circadian phase assessment. Phase shifts were calculated from the difference in the clock time of the dim light melatonin onset (DLMO) between the initial and final phase assessments. Exposure to varying durations of bright light reset the circadian pacemaker in a dose-dependent, non-linear manner. Per minute of exposure, the 0.2 h duration was over 5 times more effective at phase delaying the circadian pacemaker (1.07±0.36 h) as compared with the 4.0 h duration (2.65±0.24 h). Acute melatonin suppression and subjective sleepiness also had a dose-dependent response to light exposure duration. These results provide strong evidence for a non-linear resetting response of the human circadian pacemaker to light duration.

Biological Effects of High-Energy Neutrons Measured In Vivo Using a Vertebrate Model

PubMed Central

Kuhne, Wendy W.; Gersey, Brad B.; Wilkins, Richard; Wu, Honglu; Wender, Stephen A.; George, Varghese; Dynan, William S.

2009-01-01

Interaction of solar protons and galactic cosmic radiation with the atmosphere and other materials produces high-energy secondary neutrons from below 1 to 1000 MeV and higher. Although secondary neutrons may provide an appreciable component of the radiation dose equivalent received by space and high-altitude air travelers, the biological effects remain poorly defined, particularly in vivo in intact organisms. Here we describe the acute response of Japanese medaka (Oryzias latipes) embryos to a beam of high-energy spallation neutrons that mimics the energy spectrum of secondary neutrons encountered aboard spacecraft and high-altitude aircraft. To determine RBE, embryos were exposed to 0–0.5 Gy of high-energy neutron radiation or 0–15 Gy of reference γ radiation. The radiation response was measured by imaging apoptotic cells in situ in defined volumes of the embryo, an assay that provides a quantifiable, linear dose response. The slope of the dose response in the developing head, relative to reference γ radiation, indicates an RBE of 24.9 (95% CI 13.6–40.7). A higher RBE of 48.1 (95% CI 30.0–66.4) was obtained based on overall survival. A separate analysis of apoptosis in muscle showed an overall nonlinear response, with the greatest effects at doses of less than 0.3 Gy. Results of this experiment indicate that medaka are a useful model for investigating biological damage associated with high-energy neutron exposure. PMID:19772468

Dosimetric characteristics of a PIN diode for radiotherapy application.

PubMed

Kumar, R; Sharma, S D; Philomina, A; Topkar, A

2014-08-01

The PIN diode developed by Bhabha Atomic Research Centre (BARC) was modified for its use as a dosimeter in radiation therapy. For this purpose the diode was mounted on a printed circuit board (PCB) and provided with necessary connections so that its response against irradiation can be recorded by a standard radiotherapy electrometer. The dosimetric characteristics of the diode were studied in Co-60 gamma rays as well as high energy X-rays. The measured sensitivity of this PIN diode is 4 nC/cGy which is about ten times higher than some commercial diode dosimeters. The leakage current from the diode is 0.04 nA. The response of the PIN diode is linear in the range of 20-1000 cGy which covers the full range of radiation dose encountered in radiotherapy treatments. The non-linearity of the diode response is 3.5% at 20 cGy and it is less than 1.5% at higher dose values. Its repeatability is within 0.5%. The angular response variation is about 5.6% within 6608 with respect to normal beam incidence. The response of the PIN diode at 6 and 18 MV X-rays varies within 2% with respect to its response at Co-60 gamma rays. The source to surface distance (SSD) dependence of the PIN diode was studied for Co-60 beam. It was found that the response of the diode decreases almost linearly relative to given dose for beams with constant collimator setting but increasing SSD (decreasing dose-rate). Within this study the diode response varied by about 2.5% between the maximum and minimum SSD. The dose-rate dependence of the PIN diode for 6 and 15 MV-rays was studied. The variation in response of diode for both energies in the studied dose range is less than 1%. The field size dependence of the PIN diode response is within 1% with respect to the response of ionisation chamber. These studies indicate that the characteristics of the PIN diode are suitable for use in radiotherapy dosimetry.

Lead-induced anemia: Dose-response relationships and evidence for a threshold

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwartz, J.; Landrigan, P.J.; Baker, E.L. Jr.

1990-02-01

We conducted a cross-sectional epidemiologic study to assess the association between blood lead level and hematocrit in 579 one to five year-old children living near a primary lead smelter in 1974. Blood lead levels ranged from 0.53 to 7.91 mumol/L (11 to 164 micrograms/dl). To predict hematocrit as a function of blood lead level and age, we derived non-linear regression models and fit percentile curves. We used logistic regression to predict the probability of hematocrit values less than 35 per cent. We found a strong non-linear, dose-response relationship between blood lead level and hematocrit. This relationship was influenced by age,more » but (in this age group) not by sex; the effect was strongest in youngest children. In one year-olds, the age group most severely affected, the risk of an hematocrit value below 35 percent was 2 percent above background at blood lead levels between 0.97 and 1.88 mumol/L (20 and 39 micrograms/dl), 18 percent above background at lead levels of 1.93 to 2.85 mumol/L (40 to 59 micrograms/dl), and 40 percent above background at lead levels of 2.9 mumol/L (60 micrograms/dl) and greater; background was defined as a blood lead level below 1.88 mumol/L (20 micrograms/dl). This effect appeared independent of iron deficiency. These findings suggest that blood lead levels close to the currently recommended limit value of 1.21 mumol/L (25 micrograms/dl) are associated with dose-related depression of hematocrit in young children.« less

Does cocoa/dark chocolate supplementation have favorable effect on body weight, body mass index and waist circumference? A systematic review, meta-analysis and dose-response of randomized clinical trials.

PubMed

Kord-Varkaneh, Hamed; Ghaedi, Ehsan; Nazary-Vanani, Ali; Mohammadi, Hamed; Shab-Bidar, Sakineh

2018-03-19

Cocoa and dark chocolate (DC) have been reported to be effective for health promotion; however the exact effect of cocoa/DC on anthropometric measures have not been yet defined. A comprehensive search to identify randomized clinical trials investigating the impact of cocoa/DC on body weight, body mass index (BMI) and waist circumference (WC) was performed up to December 2017. A meta-analysis of eligible studies was performed using random effects model to estimate pooled effect size. Fractional polynominal modeling was used to explore dose-response relationships. A total of 35 RCTs investigated the effects of cocoa/DC on weight, BMI and WC were included. Meta-analysis did not suggest any significant effect of cocoa/DC supplementation on body weight (-0.108 kg, 95% CI -0.262, 0.046 P = 0.168), BMI (-0.014 kg/m 2 95% CI -0.105, 0.077, P: 0.759,) and WC (0.025 cm 95% CI -0.083, 0.129, P = 0.640). Subgroup analysis revealed that that weight and BMI were reduced with cocoa/DC supplementation ≥ 30 g chocolate per day in trials between 4-8 weeks. Cocoa/DC consumption resulted in WC reduction in non-linear fashion (r = 0.042, P-nonlinearity = 0.008). Cocoa/DC supplementation does not reduce anthropometric measures significantly. However subgroup analysis regarding dose (≥ 30 g/day) and duration (between 4 to 8 weeks) revealed significant reduction of body weight and BMI.

SU-F-BRE-03: Consideration of a Track-Interaction Model for Radiochromic Film Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosen, B; DeWerd, L

2014-06-15

Purpose: Conventional methods for characterizing the energy response of radiochromic film (RCF) typically involve assessing changes in response when exposed to various beam qualities and use Monte Carlo to determine absorbed dose. These methods represent RCF as a dose integrator of a homogeneous energy deposition volume. Apparent film saturation, nonlinearity, and intrinsic energy dependence are unpredicted with conventional methods. Recent work has shown significant RCF intrinsic energy dependence, which limits its use in absolute dosimetry. This work introduces a track-interaction model (TIM) for RCF and assesses its ability to predict total energy response. Methods: A TIM based on Katz single-hitmore » theory was developed to accumulate energy flux along particle tracks within active crystals, represented as (1×1×20)um{sup 3} prisms about the Gafchromic™ EBT3 active volume using MCNP5 and Matlab. Energy flux contributed to film response only if near the threshold energy for polymerization in polydiacetylenes (2.5eV/monomer). Energy deposition in excess of maximum efficiency represented crystal saturation and did not contribute to film response. The TIM was applied to RCF exposed in air to various monoenergetic photon beams and Co-60. Geometric distribution of energy flux was found for each beam quality in a (1×1)mm{sup 2} RCF area. RCF response relative to Co-60 absorbed dose-to-water (S-TIM) was determined and compared to published values (S-PUB). Results: TIM successfully predicted that lower energy radiation is less effective at inducing polymerization, though the magnitude of the phenomenon was overpredicted. S-TIM was −29% and +20% for 20 and 40 keV, respectively. This agreed qualitatively with S-PUB of −27% and +16%. TIM-generated sensitometric curves contained the non-linearity and saturation apparent in RCF. Conclusion: This work indicates the possibility for TIMs to predict changes in RCF response to various energies. Future work will refine TIM by considering size distributions of active elements, other RCF formulations, and response in complex treatment fields. Acknowledgements: The authors wish to thank Dr. Christopher Soares at NIST (Gaithersburg, MD) for performing film measurements and Dr. David Lewis of Ashland, Inc. (Wayne, NJ) for making the EBT3 film available to us.« less

Dose-Response Curves for Intrathecal Bupivacaine, Levobupivacaine, and Ropivacaine Given for Labor Analgesia in Nulliparous Women.

PubMed

Ngan Kee, Warwick D; Ng, Floria F; Khaw, Kim S; Tang, Shannon P Y; Koo, Alison G P

Bupivacaine, levobupivacaine, and ropivacaine are often given intrathecally for labor analgesia, but limited data are available for their dose-response properties in this context. The objective of this study was to describe the dose-response curves of these local anesthetics when given intrathecally for labor analgesia, to determine values for D50 (dose producing a 50% response) and to compare the calculated values of D50 for levobupivacaine and ropivacaine with those for bupivacaine. With ethics approval and written consent, we randomized 270 nulliparous laboring patients requesting neuraxial analgesia at 5-cm cervical dilation or less to receive a single dose of intrathecal local anesthetic without opioid as part of a combined spinal-epidural technique. Patients received either bupivacaine, levobupivacaine, or ropivacaine at a dose of 0.625, 1.0, 1.5, 2.5, 4.0, or 6.25 mg (n = 15 per group). Visual analog scale pain scores were measured for 15 minutes, after which further analgesia and management were at the clinician's discretion. The primary end point was percentage reduction of pain score at 15 minutes. Logistic sigmoidal dose-response curves were fitted to the data using nonlinear regression, and D50 values were calculated for each drug. Data were analyzed from 270 patients. Patient characteristics were similar between groups. The calculated D50 and 95% confidence interval values were as follows: bupivacaine, 1.56 mg (1.25-1.94 mg); ropivacaine, 1.95 mg (1.57-2.43 mg); and levobupivacaine, 2.20 mg (1.76-2.73 mg). The results of this study support previous work showing that intrathecal levobupivacaine and ropivacaine are less potent than bupivacaine. Chinese Clinical Trial Registry (identifier: ChiCTR-TRC-09000773) and Centre of Clinical Trials Clinical Registry of the Chinese University of Hong Kong (identifier: CUHK_CCT00245).

Magnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies

PubMed Central

Hao, Yongqiang; Li, Huiwu; Tang, Tingting; Wang, Hao; Yan, Weili; Dai, Kerong

2013-01-01

Background Prospective studies that have examined the association between dietary magnesium intake and serum magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported conflicting findings. We undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events. Methodology/Principal Findings We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1, 2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and meta-regression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (Pnonlinearity = 0.465). However, significant inverse associations emerged in nonlinear models for dietary magnesium intake (Pnonlinearity = 0.024). The greatest risk reduction occurred when intake increased from 150 to 400 mg/d. There was no evidence of publication bias. Conclusions/Significance There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events. PMID:23520480

Whole grain and refined grain consumption and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies.

PubMed

Aune, Dagfinn; Norat, Teresa; Romundstad, Pål; Vatten, Lars J

2013-11-01

Several studies have suggested a protective effect of intake of whole grains, but not refined grains on type 2 diabetes risk, but the dose-response relationship between different types of grains and type 2 diabetes has not been established. We conducted a systematic review and meta-analysis of prospective studies of grain intake and type 2 diabetes. We searched the PubMed database for studies of grain intake and risk of type 2 diabetes, up to June 5th, 2013. Summary relative risks were calculated using a random effects model. Sixteen cohort studies were included in the analyses. The summary relative risk per 3 servings per day was 0.68 (95% CI 0.58-0.81, I(2) = 82%, n = 10) for whole grains and 0.95 (95% CI 0.88-1.04, I(2) = 53%, n = 6) for refined grains. A nonlinear association was observed for whole grains, p nonlinearity < 0.0001, but not for refined grains, p nonlinearity = 0.10. Inverse associations were observed for subtypes of whole grains including whole grain bread, whole grain cereals, wheat bran and brown rice, but these results were based on few studies, while white rice was associated with increased risk. Our meta-analysis suggests that a high whole grain intake, but not refined grains, is associated with reduced type 2 diabetes risk. However, a positive association with intake of white rice and inverse associations between several specific types of whole grains and type 2 diabetes warrant further investigations. Our results support public health recommendations to replace refined grains with whole grains and suggest that at least two servings of whole grains per day should be consumed to reduce type 2 diabetes risk.

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials.

PubMed

Del Gobbo, Liana C; Falk, Michael C; Feldman, Robin; Lewis, Kara; Mozaffarian, Dariush

2015-12-01

The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger's and Begg's tests. Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (-4.7 mg/dL; 95% CI: -5.3, -4.0 mg/dL), LDL cholesterol (-4.8 mg/dL; 95% CI: -5.5, -4.2 mg/dL), ApoB (-3.7 mg/dL; 95% CI: -5.2, -2.3 mg/dL), and triglycerides (-2.2 mg/dL; 95% CI: -3.8, -0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (-11.5 mg/dL; 95% CI: -16.2, -6.8 mg/dL) than in healthy populations (-2.5 mg/dL; 95% CI: -4.7, -0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. © 2015 American Society for Nutrition.

Higher parity is associated with increased risk of Type 2 diabetes mellitus in women: A linear dose-response meta-analysis of cohort studies.

PubMed

Guo, Peng; Zhou, Quan; Ren, Lei; Chen, Yu; Hui, Yue

2017-01-01

The goal of this study is to investigate the association between higher parity and the risk of occurrence of type 2 diabetes mellitus (T2DM) in women and to quantify the potential dose-response relation. We searched MEDLINE, and EMBASE electronic databases for related cohort studies up to March 10th, 2016. Summary rate ratios (RRs) and 95% confidence intervals (CIs) for T2DM with at least 3 categories of exposure were eligible. A random-effects dose-response analysis procedure was used to study the relations between them. After screening a total of 13,647 published studies, only 7 cohort studies (9,394 incident cases and 286,840 female participants) were found to be eligible for this meta-analysis. In the category analysis, the pooled RR for the highest number of parity vs. the lowest one was 1.42 (95% CI: 1.17-1.72, I 2 =71.5%, P heterogeneity =0.002, Power=0.99). In the dose-response analysis, a noticeable linear dose-risk relation was found between parity and T2DM (P for nonlinearity test =0.942). For every live birth increase in parity, the combined RR was 1.06 (95% CI: 1.02-1.09, I 2 =84.3%, P heterogeneity =0.003, Power=0.99). Subgroup and sensitivity analyses yielded similar results. No publication bias was found in the results. This meta-analysis suggests that higher parity and the risk of T2DM show a linear relationship in women. Copyright © 2017 Elsevier Inc. All rights reserved.

Six months exposure to a real life mixture of 13 chemicals' below individual NOAELs induced non monotonic sex-dependent biochemical and redox status changes in rats.

PubMed

Docea, Anca Oana; Gofita, Eliza; Goumenou, Marina; Calina, Daniela; Rogoveanu, Otilia; Varut, Marius; Olaru, Cristian; Kerasioti, Efthalia; Fountoucidou, Polyxeni; Taitzoglou, Ioannis; Zlatian, Ovidiu; Rakitskii, Valerii N; Hernandez, Antonio F; Kouretas, Dimitrios; Tsatsakis, Aristidis

2018-05-01

This study assessed the potential adverse health effects of long-term low-dose exposure to chemical mixtures simulating complex real-life human exposures. Four groups of Sprague Dawley rats were administered mixtures containing carbaryl, dimethoate, glyphosate, methomyl, methyl parathion, triadimefon, aspartame, sodium benzoate, calcium disodium ethylene diamine tetra-acetate, ethylparaben, butylparaben, bisphenol A, and acacia gum at doses of 0, 0.25, 1 or 5 times the respective Toxicological Reference Values (TRV): acceptable daily intake (ADI) or tolerable daily intake (TDI) in a 24 weeks toxicity study. Body weight gain, feed and water consumption were evaluated weekly. At 24 weeks blood was collected and biochemistry parameters and redox status markers were assessed. Adverse effects were observed on body weight gain and in hepatotoxic parameters such as the total bilirubin, alanine aminotransferase (ALT) and alkaline phosphatase (ALP), especially in low dose and affecting mainly male rats. The low dose group showed increased catalase activity both in females and males, whereas the high dose group exhibited decreased protein carbonyl and total antioxidant capacity (TAC) levels in both sex groups. Non-monotonic effects and adaptive responses on liver function tests and redox status, leading to non-linear dose-responses curves, are probably produced by modulation of different mechanisms. Copyright © 2018. Published by Elsevier Ltd.

Sol-gel derived copper-doped silica glass as a sensitive material for X-ray beam dosimetry

NASA Astrophysics Data System (ADS)

Capoen, Bruno; Hamzaoui, Hicham El; Bouazaoui, Mohamed; Ouerdane, Youcef; Boukenter, Aziz; Girard, Sylvain; Marcandella, Claude; Duhamel, Olivier

2016-01-01

The light emission from a sol-gel-derived Cu-doped silica glass was studied under 10 keV X-ray irradiation using a fibered setup. Both radioluminescence (RL) and optically stimulated luminescence (OSL) were analyzed at different high dose rates up to 50 Gy/s and for different exposure times, yielding accumulated doses up to 50 kGy (in SiO2). Even if a darkening effect appears at this dose level, the material remains X-sensitive after exposure to several kGy. At low dose rate, the scintillation mechanisms are similar to photoluminescence, involving the Cu+ ions electronic levels, contrary to the nonlinear domain (for dose rates higher than 30 Gy/s). This RL, as well as the OSL, could be exploited in their linear domain to measure doses as high as 3 kGy. A thorough study of the OSL signal has shown that it must be employed with caution in order to take the fading phenomenon and the response dependency on stimulation source intensity into consideration.

Manganese Exposure and Cognition Across the Lifespan: Contemporary Review and Argument for Biphasic Dose-Response Health Effects

PubMed Central

Vollet, Kaitlin; Dietrich, Kim N.

2016-01-01

Manganese (Mn) is both an essential micronutrient and potential neurotoxicant. This dual role underlies a growing body of literature demonstrating that Mn exhibits a biphasic dose-response relationship with neurocognitive outcomes. We reviewed recent epidemiologic studies from 2007–2016 that investigated the relationship between Mn exposure and cognitive outcomes across the lifespan: early life, school-aged children, and adulthood. In total, 27 research articles were included in this review: 12 pediatric and 15 adult studies (10 occupational and five environmental exposures). The majority of these studies provided evidence of the negative effects of Mn exposure on cognition. The pediatric literature provides evidence that both high and low levels of Mn are negatively associated with intellectual development. Future Mn research should include examination of non-linear relationships and multiple neurotoxicants across the lifespan, and particularly during critical developmental windows. PMID:27722879

Joint feedback analysis modeling of nonesterified fatty acids in obese Zucker rats and normal Sprague-Dawley rats after different routes of administration of nicotinic acid.

PubMed

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-08-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

A phenomenological biological dose model for proton therapy based on linear energy transfer spectra.

PubMed

Rørvik, Eivind; Thörnqvist, Sara; Stokkevåg, Camilla H; Dahle, Tordis J; Fjaera, Lars Fredrik; Ytre-Hauge, Kristian S

2017-06-01

The relative biological effectiveness (RBE) of protons varies with the radiation quality, quantified by the linear energy transfer (LET). Most phenomenological models employ a linear dependency of the dose-averaged LET (LET d ) to calculate the biological dose. However, several experiments have indicated a possible non-linear trend. Our aim was to investigate if biological dose models including non-linear LET dependencies should be considered, by introducing a LET spectrum based dose model. The RBE-LET relationship was investigated by fitting of polynomials from 1st to 5th degree to a database of 85 data points from aerobic in vitro experiments. We included both unweighted and weighted regression, the latter taking into account experimental uncertainties. Statistical testing was performed to decide whether higher degree polynomials provided better fits to the data as compared to lower degrees. The newly developed models were compared to three published LET d based models for a simulated spread out Bragg peak (SOBP) scenario. The statistical analysis of the weighted regression analysis favored a non-linear RBE-LET relationship, with the quartic polynomial found to best represent the experimental data (P = 0.010). The results of the unweighted regression analysis were on the borderline of statistical significance for non-linear functions (P = 0.053), and with the current database a linear dependency could not be rejected. For the SOBP scenario, the weighted non-linear model estimated a similar mean RBE value (1.14) compared to the three established models (1.13-1.17). The unweighted model calculated a considerably higher RBE value (1.22). The analysis indicated that non-linear models could give a better representation of the RBE-LET relationship. However, this is not decisive, as inclusion of the experimental uncertainties in the regression analysis had a significant impact on the determination and ranking of the models. As differences between the models were observed for the SOBP scenario, both non-linear LET spectrum- and linear LET d based models should be further evaluated in clinically realistic scenarios. © 2017 American Association of Physicists in Medicine.

Calcium intake and colorectal adenoma risk: dose-response meta-analysis of prospective observational studies.

PubMed

Keum, NaNa; Lee, Dong Hoon; Greenwood, Darren C; Zhang, Xuehong; Giovannucci, Edward L

2015-04-01

Evidence from randomized controlled trials suggests that calcium may protect against recurrence of colorectal adenomas, which could lead to the subsequent prevention of cancer. Yet the trials used only a large single dose and were of small sizes, and thus, knowledge of the dose-response relationship and influence on high-risk adenomas is limited. To address these issues, we conducted linear and nonlinear dose-response meta-analyses primarily based on prospective observational studies published up to July 2014 identified from PubMed and Embase. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated for total and supplemental calcium intake, respectively, using a random-effects model. For total calcium intake, summary RR for each 300 mg/day increase was 0.95 (95% CI = 0.92-0.98; I(2)  = 45%; eight studies with 11,005 cases; range of intake = 333-2,229 mg/day). Evidence of nonlinearity was indicated: approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.92 (95% CI = 0.89-0.94) at 1,000 mg/day and 0.87 (95% CI = 0.84-0.90) at 1,450 mg/day (pnonlinearity  < 0.01). Associations were stronger for high-risk adenomas (≥1 cm in diameter, (tubulo)villous histology, dysplasia, or multiplicity): approximately, compared to 550 mg/day of total calcium intake, the summary RR was 0.77 (95% CI = 0.74-0.81) at 1,000 mg/day and reduced to 0.69 (95% CI = 0.66-0.73) at 1,450 mg/da (pnonlinearity  < 0.01). For supplemental calcium intake, summary RR of total adenoma risk for each 300 mg/day increase was 0.96 (95% CI = 0.93-0.99; I(2)  = 0%; three studies with 4,548 cases; range of supplementation = 0-1,366 mg/day). In conclusion, calcium intake may continue to decrease the risk of adenomas, particularly high-risk adenomas, over a wide range of calcium intake. © 2014 UICC.

Cytogenetic effect of low dose gamma-radiation in Hordeum vulgare seedlings: non-linear dose-effect relationship.

PubMed

Geras'kin, Stanislav A; Oudalova, Alla A; Kim, Jin Kyu; Dikarev, Vladimir G; Dikareva, Nina S

2007-03-01

The induction of chromosome aberrations in Hordeum vulgare germinated seeds was studied after ionizing irradiation with doses in the range of 10-1,000 mGy. The relationship between the frequency of aberrant cells and the absorbed dose was found to be nonlinear. A dose-independent plateau in the dose range from about 50 to 500 mGy was observed, where the level of cytogenetic damage was significantly different from the spontaneous level. The comparison of the goodness of the experimental data fitting with mathematical models of different complexity, using the most common quantitative criteria, demonstrated the advantage of a piecewise linear model over linear and polynomial models in approximating the frequency of cytogenetical disturbances. The results of the study support the hypothesis of indirect mechanisms of mutagenesis induced by low doses. Fundamental and applied implications of these findings are discussed.

Carcinogenicity and mode of action evaluation for alpha-hexachlorocyclohexane: Implications for human health risk assessment.

PubMed

Bradley, Ann E; Shoenfelt, Joanna L; Durda, Judi L

2016-04-01

Alpha-hexachlorocyclohexane (alpha-HCH) is one of eight structural isomers that have been used worldwide as insecticides. Although no longer produced or used agriculturally in the United States, exposure to HCH isomers is of continuing concern due to legacy usage and persistence in the environment. The U.S. Environmental Protection Agency (EPA) classifies alpha-HCH as a probable human carcinogen and provides a slope factor of 6.3 (mg/kg-day)(-1) for the compound, based on hepatic nodules and hepatocellular carcinomas observed in male mice and derived using a default linear approach for modeling carcinogens. EPA's evaluation, last updated in 1993, does not consider more recently available guidance that allows for the incorporation of mode of action (MOA) for determining a compound's dose-response. Contrary to the linear approach assumed by EPA, the available data indicate that alpha-HCH exhibits carcinogenicity via an MOA that yields a nonlinear, threshold dose-response. In our analysis, we conducted an MOA evaluation and dose-response analysis for alpha-HCH-induced liver carcinogenesis. We concluded that alpha-HCH causes liver tumors in rats and mice through an MOA involving increased promotion of cell growth, or mitogenesis. Based on these findings, we developed a threshold, cancer-based, reference dose (RfD) for alpha-HCH. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Daytime napping and risk of type 2 diabetes: a meta-analysis of prospective studies.

PubMed

Chen, Guo-Chong; Liu, Meng-Meng; Chen, Li-Hua; Xu, Jia-Ying; Hidayat, Khemayanto; Li, Fu-Rong; Qin, Li-Qiang

2017-06-13

Prospective studies reported inconsistent findings on the relationship between daytime napping and risk of type 2 diabetes (T2D). Categorized and dose-response meta-analyses were performed to quantify this relation. Potentially eligible studies were identified by searching PubMed and Embase databases. Dose-response effects were assessed by the generalized least squares trend estimation and study-specific summary relative risks (RRs) with 95% confidence intervals (CIs) were computed with a random-effects model. Seven prospective studies including one US, four European, and two Chinese cohorts involving 249,077 participants and 13,237 cases of T2D were included. The overall analyses showed a 17% increased risk of T2D when comparing habitual nappers with non-nappers (RR = 1.17, 95% CI 1.08-1.27). By region, the summary RR was 1.21 (95% CI 1.17-1.26), 1.15 (95% CI 1.03-1.30) and 1.23 (95% CI 0.87-1.73) for the US, European, and Chinese studies, respectively. Limiting to five studies that excluded subjects with known major chronic disorders yielded a summary RR of 1.16 (95% CI 1.03-1.30). A dose-response analysis suggested an 11% (95% CI 7-16%) increased T2D risk for each increment in daytime napping of 30 min/day and, despite no evidence for nonlinearity (P nonlinearity  = 0.65), the increased risk of T2D for short nap (<50 min/day) was dominated by the US study. This meta-analysis suggests that daytime napping is associated with an increased risk of T2D. Given the limited number of cohorts and inconsistency in terms of methodological and population characteristics across these cohorts, residual confounders and/or reverse causality cannot be fully addressed, and our findings should be interpreted with great caution. Future well-designed prospective studies are still warranted.

Daytime Napping and the Risk of Cardiovascular Disease and All-Cause Mortality: A Prospective Study and Dose-Response Meta-Analysis.

PubMed

Yamada, Tomohide; Hara, Kazuo; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi

2015-12-01

To summarize evidence about the association between daytime napping and the risk of cardiovascular disease and all-cause mortality, and to quantify the potential dose-response relation. Meta-analysis of prospective cohort studies. Electronic databases were searched for articles published up to December 2014 using the terms nap, cardiovascular disease, and all-cause mortality. We selected well-adjusted prospective cohort studies reporting risk estimates for cardiovascular disease and all-cause mortality related to napping. Eleven prospective cohort studies were identified with 151,588 participants (1,625,012 person-years) and a mean follow-up period of 11 years (60% women, 5,276 cardiovascular events, and 18,966 all-cause deaths). Pooled analysis showed that a long daytime nap (≥ 60 min/day) was associated with a higher risk of cardiovascular disease (rate ratio [RR]: 1.82 [1.22-2.71], P = 0.003, I(2) = 37%) compared with not napping. All-cause mortality was associated with napping for ≥ 60 min/day (RR: 1.27 [1.11-1.45], P < 0.001, I(2) = 0%) compared with not napping. In contrast, napping for < 60 min/day was not associated with cardiovascular disease (P = 0.98) or all-cause mortality (P = 0.08). Meta-analysis demonstrated a significant J-curve dose-response relation between nap time and cardiovascular disease (P for nonlinearity = 0.01). The RR initially decreased from 0 to 30 min/day. Then it increased slightly until about 45 min/day, followed by a sharp increase at longer nap times. There was also a positive linear relation between nap time and all-cause mortality (P for non-linearity = 0.97). Nap time and cardiovascular disease may be associated via a J-curve relation. Further studies are needed to confirm the efficacy of a short nap. © 2015 Associated Professional Sleep Societies, LLC.

Relationship of tree nut, peanut and peanut butter intake with total and cause-specific mortality: a cohort study and meta-analysis.

PubMed

van den Brandt, Piet A; Schouten, Leo J

2015-06-01

Nut intake has been associated with lower mortality, but few studies have investigated causes of death other than cardiovascular disease, and dose-response relationships remain unclear. We investigated the relationship of nut (tree nut, peanut) and peanut butter intake with overall and cause-specific mortality. In the Netherlands Cohort Study, 120,852 men and women aged 55-69 years provided information on dietary and lifestyle habits in 1986. Mortality follow-up until 1996 consisted of linkage to Statistics Netherlands. Multivariate case-cohort analyses were based on 8823 deaths and 3202 subcohort members with complete data on nuts and potential confounders. We also conducted meta-analyses of our results with those published from other cohort studies. Total nut intake was related to lower overall and cause-specific mortality (cancer, diabetes, cardiovascular, respiratory, neurodegenerative diseases, other causes) in men and women. When comparing those consuming 0.1-<5, 5-<10 and 10+ g nuts/day with non-consumers, multivariable hazard ratios for total mortality were 0.88, 0.74 and 0.77 [95% confidence interval (CI), 0.66-0.89], respectively (Ptrend = 0.003). Cause-specific hazard ratios comparing 10+ vs 0 g/day varied from 0.56 for neurodegenerative to 0.83 for cardiovascular disease mortality. Restricted cubic splines showed nonlinear dose-response relationships with mortality. Peanuts and tree nuts were inversely related to mortality, whereas peanut butter was not. In meta-analyses, summary hazard ratios for highest vs lowest nut consumption were 0.85 for cancer, and 0.71 for respiratory mortality. Nut intake was related to lower overall and cause-specific mortality, with evidence for nonlinear dose-response relationships. Peanut butter was not related to mortality. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

Association of fish and n-3 fatty acid intake with the risk of type 2 diabetes: a meta-analysis of prospective studies.

PubMed

Zhou, Yunping; Tian, Changwei; Jia, Chongqi

2012-08-01

Results from observational studies on the association of fish and n-3 fatty acid consumption with type 2 diabetes mellitus (T2DM) risk are conflicting. Hence, a meta-analysis was performed to investigate this association from cohort studies. A comprehensive search was then conducted to identify cohort studies on the association of fish and/or n-3 fatty acid intake with T2DM risk. In the highest v. lowest categorical analyses, the fixed or random-effect model was selected based on the homogeneity test among studies. Linear and non-linear dose-response relationships were also assessed by univariate and bivariate random-effect meta-regression with restricted maximum likelihood estimation. In the highest v. lowest categorical analyses, the pooled relative risk (RR) of T2DM for intake of fish and n-3 fatty acid was 1·146 (95 % CI 0·975, 1·346) and 1·076 (95 % CI 0·955, 1·213), respectively. In the linear dose-response relationship, the pooled RR for an increment of one time (about 105 g)/week of fish intake (four times/month) and of 0·1 g/d of n-3 fatty acid intake was 1·042 (95 % CI 1·026, 1·058) and 1·057 (95 % CI 1·042, 1·073), respectively. The significant non-linear dose-response associations of fish and n-3 fatty acid intake with T2DM risk were not observed. The present evidence from observational studies suggests that the intake of both fish and n-3 fatty acids might be weakly positively associated with the T2DM risk. Further studies are needed to confirm these results.

Probability Distribution of Dose and Dose-Rate Effectiveness Factor for use in Estimating Risks of Solid Cancers From Exposure to Low-Let Radiation.

PubMed

Kocher, David C; Apostoaei, A Iulian; Hoffman, F Owen; Trabalka, John R

2018-06-01

This paper presents an analysis to develop a subjective state-of-knowledge probability distribution of a dose and dose-rate effectiveness factor for use in estimating risks of solid cancers from exposure to low linear energy transfer radiation (photons or electrons) whenever linear dose responses from acute and chronic exposure are assumed. A dose and dose-rate effectiveness factor represents an assumption that the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation, RL, differs from the risk per Gy at higher acute doses, RH; RL is estimated as RH divided by a dose and dose-rate effectiveness factor, where RH is estimated from analyses of dose responses in Japanese atomic-bomb survivors. A probability distribution to represent uncertainty in a dose and dose-rate effectiveness factor for solid cancers was developed from analyses of epidemiologic data on risks of incidence or mortality from all solid cancers as a group or all cancers excluding leukemias, including (1) analyses of possible nonlinearities in dose responses in atomic-bomb survivors, which give estimates of a low-dose effectiveness factor, and (2) comparisons of risks in radiation workers or members of the public from chronic exposure to low linear energy transfer radiation at low dose rates with risks in atomic-bomb survivors, which give estimates of a dose-rate effectiveness factor. Probability distributions of uncertain low-dose effectiveness factors and dose-rate effectiveness factors for solid cancer incidence and mortality were combined using assumptions about the relative weight that should be assigned to each estimate to represent its relevance to estimation of a dose and dose-rate effectiveness factor. The probability distribution of a dose and dose-rate effectiveness factor for solid cancers developed in this study has a median (50th percentile) and 90% subjective confidence interval of 1.3 (0.47, 3.6). The harmonic mean is 1.1, which implies that the arithmetic mean of an uncertain estimate of the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation is only about 10% less than the mean risk per Gy at higher acute doses. Data were also evaluated to define a low acute dose or low dose rate of low linear energy transfer radiation, i.e., a dose or dose rate below which a dose and dose-rate effectiveness factor should be applied in estimating risks of solid cancers.

Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.

PubMed

Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J; Saran, Anna

2015-10-13

There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response.

Molecular Mechanisms of Nonlinearity in Response to Low Dose Ionizing Radiation

DTIC Science & Technology

2007-10-12

nucleotide-binding protein 1 HSP27 heat shock protein 27 IR ionizing radiation LDH-A lactate dehydrogenase A PDI protein disulfide isomerase precursor 2...sc-9322, SCB, CA), E-FABP (sc-16060, SCB, CA), and LDH-A (sc-27230, SCB, CA), cytokeratin I (sc- 17091, SCB, CA), CaM (sc-1989, SCB, CA), HSP27 (sc...the 24 hour time point included: calmodulin (CaM), heat shock protein 27 ( HSP27 ), lactate dehydrogenase A (LDH-A) and protein disulfide isomerase

Association between alcohol consumption and the risk of incident type 2 diabetes: a systematic review and dose-response meta-analysis.

PubMed

Li, Xiao-Hua; Yu, Fei-Fei; Zhou, Yu-Hao; He, Jia

2016-03-01

Previous cohort studies have shown that moderate alcohol consumption was associated with a lower risk of type 2 diabetes (T2D). However, whether these associations differ according to the characteristics of patients with T2D remains controversial. The purpose of this study was to explore and summarize the evidence on the strength of the association between alcohol consumption and the subsequent risk of T2D by using a dose-response meta-analytic approach. We identified potential studies by searching the PubMed, Embase, and Cochrane Library databases up to 24 March 2015. Prospective observational studies that evaluated the relation between alcohol consumption and the risk of T2D and reported its effect estimates with 95% CIs were included. Analyses were based on 706,716 individuals (275,711 men and 431,005 women) from 26 studies with 31,621 T2D cases. We detected a nonlinear relation between alcohol consumption and the risk of T2D, which was identified in all cohorts (P-trend < 0.001, P-nonlinearity < 0.001), in men (P-trend < 0.001, P-nonlinearity < 0.001), and in women (P-trend < 0.001, P-nonlinearity < 0.001). Compared with the minimal category of alcohol consumption, light (RR: 0.83; 95% CI: 0.73, 0.95; P = 0.005) and moderate (RR: 0.74; 95% CI: 0.67, 0.82; P < 0.001) alcohol consumption was associated with a lower risk of T2D. However, heavy alcohol consumption had little or no effect on subsequent T2D risk. Furthermore, the summary RR ratio (RRR; male to female) of the comparison between moderate alcohol consumption and the minimal alcohol categories for T2D was significantly higher, and the pooled RRR (current smoker to never smoker) of light alcohol consumption was significantly reduced. Light and moderate alcohol consumption was associated with a lower risk of T2D, whereas heavy alcohol consumption was not related to the risk of T2D. © 2016 American Society for Nutrition.

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials123

PubMed Central

Del Gobbo, Liana C; Falk, Michael C; Feldman, Robin; Lewis, Kara; Mozaffarian, Dariush

2015-01-01

Background: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. Objectives: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. Design: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger’s and Begg’s tests. Results: Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (−4.7 mg/dL; 95% CI: −5.3, −4.0 mg/dL), LDL cholesterol (−4.8 mg/dL; 95% CI: −5.5, −4.2 mg/dL), ApoB (−3.7 mg/dL; 95% CI: −5.2, −2.3 mg/dL), and triglycerides (−2.2 mg/dL; 95% CI: −3.8, −0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (−11.5 mg/dL; 95% CI: −16.2, −6.8 mg/dL) than in healthy populations (−2.5 mg/dL; 95% CI: −4.7, −0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. Conclusions: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. PMID:26561616

Extension of a nonlinear systems theory to general-frequency unsteady transonic aerodynamic responses

NASA Technical Reports Server (NTRS)

Silva, Walter A.

1993-01-01

A methodology for modeling nonlinear unsteady aerodynamic responses, for subsequent use in aeroservoelastic analysis and design, using the Volterra-Wiener theory of nonlinear systems is presented. The methodology is extended to predict nonlinear unsteady aerodynamic responses of arbitrary frequency. The Volterra-Wiener theory uses multidimensional convolution integrals to predict the response of nonlinear systems to arbitrary inputs. The CAP-TSD (Computational Aeroelasticity Program - Transonic Small Disturbance) code is used to generate linear and nonlinear unit impulse responses that correspond to each of the integrals for a rectangular wing with a NACA 0012 section with pitch and plunge degrees of freedom. The computed kernels then are used to predict linear and nonlinear unsteady aerodynamic responses via convolution and compared to responses obtained using the CAP-TSD code directly. The results indicate that the approach can be used to predict linear unsteady aerodynamic responses exactly for any input amplitude or frequency at a significant cost savings. Convolution of the nonlinear terms results in nonlinear unsteady aerodynamic responses that compare reasonably well with those computed using the CAP-TSD code directly but at significant computational cost savings.

Theoretical models and simulation codes to investigate bystander effects and cellular communication at low doses

NASA Astrophysics Data System (ADS)

Ballarini, F.; Alloni, D.; Facoetti, A.; Mairani, A.; Nano, R.; Ottolenghi, A.

Astronauts in space are continuously exposed to low doses of ionizing radiation from Galactic Cosmic Rays During the last ten years the effects of low radiation doses have been widely re-discussed following a large number of observations on the so-called non targeted effects in particular bystander effects The latter consist of induction of cytogenetic damage in cells not directly traversed by radiation most likely as a response to molecular messengers released by directly irradiated cells Bystander effects which are observed both for lethal endpoints e g clonogenic inactivation and apoptosis and for non-lethal ones e g mutations and neoplastic transformation tend to show non-linear dose responses This might have significant consequences in terms of low-dose risk which is generally calculated on the basis of the Linear No Threshold hypothesis Although the mechanisms underlying bystander effects are still largely unknown it is now clear that two types of cellular communication i e via gap junctions and or release of molecular messengers into the extracellular environment play a fundamental role Theoretical models and simulation codes can be of help in elucidating such mechanisms In the present paper we will review different available modelling approaches including one that is being developed at the University of Pavia The focus will be on the different assumptions adopted by the various authors and on the implications of such assumptions in terms of non-targeted radiobiological damage and more generally low-dose

Nonlinear cancer response at ultralow dose: a 40800-animal ED(001) tumor and biomarker study.

PubMed

Bailey, George S; Reddy, Ashok P; Pereira, Clifford B; Harttig, Ulrich; Baird, William; Spitsbergen, Jan M; Hendricks, Jerry D; Orner, Gayle A; Williams, David E; Swenberg, James A

2009-07-01

Assessment of human cancer risk from animal carcinogen studies is severely limited by inadequate experimental data at environmentally relevant exposures and by procedures requiring modeled extrapolations many orders of magnitude below observable data. We used rainbow trout, an animal model well-suited to ultralow-dose carcinogenesis research, to explore dose-response down to a targeted 10 excess liver tumors per 10000 animals (ED(001)). A total of 40800 trout were fed 0-225 ppm dibenzo[a,l]pyrene (DBP) for 4 weeks, sampled for biomarker analyses, and returned to control diet for 9 months prior to gross and histologic examination. Suspect tumors were confirmed by pathology, and resulting incidences were modeled and compared to the default EPA LED(10) linear extrapolation method. The study provided observed incidence data down to two above-background liver tumors per 10000 animals at the lowest dose (that is, an unmodeled ED(0002) measurement). Among nine statistical models explored, three were determined to fit the liver data well-linear probit, quadratic logit, and Ryzin-Rai. None of these fitted models is compatible with the LED(10) default assumption, and all fell increasingly below the default extrapolation with decreasing DBP dose. Low-dose tumor response was also not predictable from hepatic DBP-DNA adduct biomarkers, which accumulated as a power function of dose (adducts = 100 x DBP(1.31)). Two-order extrapolations below the modeled tumor data predicted DBP doses producing one excess cancer per million individuals (ED(10)(-6)) that were 500-1500-fold higher than that predicted by the five-order LED(10) extrapolation. These results are considered specific to the animal model, carcinogen, and protocol used. They provide the first experimental estimation in any model of the degree of conservatism that may exist for the EPA default linear assumption for a genotoxic carcinogen.

Approaches for characterizing threshold dose-response relationships for DNA-damage pathways involved in carcinogenicity in vivo and micronuclei formation in vitro.

PubMed

Clewell, Rebecca A; Andersen, Melvin E

2016-05-01

Assessing the shape of dose-response curves for DNA-damage in cellular systems and for the consequences of DNA damage in intact animals remains a controversial topic. This overview looks at aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of cellular DNA-damage/repair and their role in defining the shape of dose-response curves using an in vivo example with formaldehyde and in vitro examples for micronuclei (MN) formation with several test compounds. Formaldehyde is both strongly mutagenic and an endogenous metabolite in cells. With increasing inhaled concentrations, there were transitions in gene changes, from activation of selective stress pathway genes at low concentrations, to activation of pathways for cell-cycle control, p53-DNA damage, and stem cell niche pathways at higher exposures. These gene expression changes were more consistent with dose-dependent transitions in the PD responses to formaldehyde in epithelial cells in the intact rat rather than the low-dose linear extrapolation methods currently used for carcinogens. However, more complete PD explanations of non-linear dose response for creation of fixed damage in cells require detailed examination of cellular responses in vitro using measures of DNA damage and repair that are not easily accessible in the intact animal. In the second section of the article, we illustrate an approach from our laboratory that develops fit-for-purpose, in vitro assays and evaluates the PD of DNA damage and repair through studies using prototypical DNA-damaging agents. Examination of a broad range of responses in these cells showed that transcriptional upregulation of cell cycle control and DNA repair pathways only occurred at doses higher than those causing overt damage fixed damage-measured as MN formation. Lower levels of damage appear to be handled by post-translational repair process using pre-existing proteins. In depth evaluation of the PD properties of one such post-translational process (formation of DNA repair centers; DRCs) has indicated that the formation of DRCs and their ability to complete repair before replication are consistent with threshold behaviours for mutagenesis and, by extension, with chemical carcinogenesis. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

TLD efficiency calculations for heavy ions: an analytical approach

DOE PAGES

Boscolo, Daria; Scifoni, Emanuele; Carlino, Antonio; ...

2015-12-18

The use of thermoluminescent dosimeters (TLDs) in heavy charged particles’ dosimetry is limited by their non-linear dose response curve and by their response dependence on the radiation quality. Thus, in order to use TLDs with particle beams, a model that can reproduce the behavior of these detectors under different conditions is needed. Here a new, simple and completely analytical algorithm for the calculation of the relative TL-efficiency depending on the ion charge Z and energy E is presented. In addition, the detector response is evaluated starting from the single ion case, where the computed effectiveness values have been compared withmore » experimental data as well as with predictions from a different method. The main advantage of this approach is that, being fully analytical, it is computationally fast and can be efficiently integrated into treatment planning verification tools. In conclusion, the calculated efficiency values have been then implemented in the treatment planning code TRiP98 and dose calculations on a macroscopic target irradiated with an extended carbon ion field have been performed and verified against experimental data.« less

Dose response relationship in anti-stress gene regulatory networks.

PubMed

Zhang, Qiang; Andersen, Melvin E

2007-03-02

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

Joint Feedback Analysis Modeling of Nonesterified Fatty Acids in Obese Zucker Rats and Normal Sprague–Dawley Rats after Different Routes of Administration of Nicotinic Acid

PubMed Central

Tapani, Sofia; Almquist, Joachim; Leander, Jacob; Ahlström, Christine; Peletier, Lambertus A; Jirstrand, Mats; Gabrielsson, Johan

2014-01-01

Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague–Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague–Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration–response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the “degree of disease” can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2571–2584, 2014 PMID:24986056

Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model.

PubMed

Chuang, Shu-Chun; Rota, Matteo; Gunter, Marc J; Zeleniuch-Jacquotte, Anne; Eussen, Simone J P M; Vollset, Stein Emil; Ueland, Per Magne; Norat, Teresa; Ziegler, Regina G; Vineis, Paolo

2013-10-01

Most epidemiologic studies on folate intake suggest that folate may be protective against colorectal cancer, but the results on circulating (plasma or serum) folate are mostly inconclusive. We conducted a meta-analysis of case-control studies nested within prospective studies on circulating folate and colorectal cancer risk by using flexible meta-regression models to test the linear and nonlinear dose-response relationships. A total of 8 publications (10 cohorts, representing 3,477 cases and 7,039 controls) were included in the meta-analysis. The linear and nonlinear models corresponded to relative risks of 0.96 (95% confidence interval (CI): 0.91, 1.02) and 0.99 (95% CI: 0.96, 1.02), respectively, per 10 nmol/L of circulating folate in contrast to the reference value. The pooled relative risks when comparing the highest with the lowest category were 0.80 (95% CI: 0.61, 0.99) for radioimmunoassay and 1.03 (95% CI: 0.83, 1.22) for microbiological assay. Overall, our analyses suggest a null association between circulating folate and colorectal cancer risk. The stronger association for the radioimmunoassay-based studies could reflect differences in cohorts and study designs rather than assay performance. Further investigations need to integrate more accurate measurements and flexible modeling to explore the effects of folate in the presence of genetic, lifestyle, dietary, and hormone-related factors.

Fruits and vegetables consumption and risk of stroke: a meta-analysis of prospective cohort studies.

PubMed

Hu, Dan; Huang, Junqian; Wang, Yuchun; Zhang, Dongfeng; Qu, Yan

2014-06-01

We conducted a meta-analysis to summarize evidence from prospective cohort studies about the association of fruits and vegetables consumption with the risk of stroke. Pertinent studies were identified by a search of Embase and PubMed databases to January 2014. Study-specific relative risks with 95% confidence intervals were pooled using a random-effects model. Dose-response relationship was assessed by restricted cubic spline. Twenty prospective cohort studies were included, involving 16 981 stroke events among 760 629 participants. The multivariable relative risk (95% confidence intervals) of stroke for the highest versus lowest category of total fruits and vegetables consumption was 0.79 (0.75-0.84), and the effect was 0.77 (0.71-0.84) for fruits consumption and 0.86 (0.79-0.93) for vegetables consumption. Subgroup and meta-regression showed that the inverse association of total fruits and vegetables consumption with the risk of stroke was consistent in subgroup analysis. Citrus fruits, apples/pears, and leafy vegetables might contribute to the protection. The linear dose-response relationship showed that the risk of stroke decreased by 32% (0.68 [0.56-0.82]) and 11% (0.89 [0.81-0.98]) for every 200 g per day increment in fruits consumption (P for nonlinearity=0.77) and vegetables consumption (P for nonlinearity=0.62), respectively. Fruits and vegetables consumption are inversely associated with the risk of stroke. © 2014 American Heart Association, Inc.

Modeling marrow damage from response data: Evolution from radiation biology to benzene toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jones, T.D.; Morris, M.D.; Hasan, J.S.

1996-12-01

Consensus principles from radiation biology were used to describe a generic set of nonlinear, first-order differential equations for modeling toxicity-induced compensatory cell kinetics in terms of sublethal injury, repair, direct killing, killing of cells with unrepaired sublethal injury, and repopulation. This cellular model was linked to a probit model of hematopoietic mortality that describes death from infection and/or hemorrhage between 5 and 30 days. Mortality data from 27 experiments with 851 dose-response groups, in which doses were protracted by rate and/or fractionation, were used to simultaneously estimate all rate constants by maximum-likelihood methods. Data used represented 18,940 test animals: 12,827more » mice, 2925 rats, 1676 sheep, 829 swine, 479 dogs, and 204 burros. Although a long-term, repopulating hematopoietic stem cell is ancestral to all lineages needed to restore normal homeostasis, the dose-response data from the protracted irradiations indicate clearly that the particular lineage that is critical to hematopoietic recovery does not resemble stemlike cells with regard to radiosensitivity and repopulation rates. Instead, the weakest link in the chain of hematopoiesis was found to have an intrinsic radioresistance equal to or greater than stromal cells and to repopulate at the same rates. Model validation has been achieved by predicting the LD50 and/or fractional group mortality in 38 protracted-dose experiments (rats and mice) that were not used in the fitting of model coefficients. 29 refs., 5 figs., 5 tabs.« less

Deviation from additivity in mixture toxicity: relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and gamma-radiation.

PubMed

Lutz, Werner K; Vamvakas, Spyros; Kopp-Schneider, Annette; Schlatter, Josef; Stopper, Helga

2002-12-01

Sublinear dose-response relationships are often seen in toxicity testing, particularly with bioassays for carcinogenicity. This is the result of a superimposition of various effects that modulate and contribute to the process of cancer formation. Examples are saturation of detoxification pathways or DNA repair with increasing dose, or regenerative hyperplasia and indirect DNA damage as a consequence of high-dose cytotoxicity and cell death. The response to a combination treatment can appear to be supra-additive, although it is in fact dose-additive along a sublinear dose-response curve for the single agents. Because environmental exposure of humans is usually in a low-dose range and deviation from linearity is less likely at the low-dose end, combination effects should be tested at the lowest observable effect levels (LOEL) of the components. This principle has been applied to combinations of genotoxic agents in various cellular models. For statistical analysis, all experiments were analyzed for deviation from additivity with an n-factor analysis of variance with an interaction term, n being the number of components tested in combination. Benzo[a]pyrene, benz[a]anthracene, and dibenz[a,c]anthracene were tested at the LOEL, separately and in combination, for the induction of revertants in the Ames test, using Salmonella typhimurium TA100 and rat liver S9 fraction. Combined treatment produced no deviation from additivity. The induction of micronuclei in vitro was investigated with ionizing radiation from a 137Cs source and ethyl methanesulfonate. Mouse lymphoma L5178Y cells revealed a significant 40% supra-additive combination effect in an experiment based on three independent replicates for controls and single and combination treatments. On the other hand, two human lymphoblastoid cell lines (TK6 and WTK1) as well as a pilot study with human primary fibroblasts from fetal lung did not show deviation from additivity. Data derived from one cell line should therefore not be generalized. Regarding the testing of mixtures for deviation from additive toxicity, the suggested experimental protocol is easily followed by toxicologists.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza

NASA Astrophysics Data System (ADS)

Smith, Amber M.; Smith, Amanda P.

2016-12-01

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

A Critical, Nonlinear Threshold Dictates Bacterial Invasion and Initial Kinetics During Influenza.

PubMed

Smith, Amber M; Smith, Amanda P

2016-12-15

Secondary bacterial infections increase morbidity and mortality of influenza A virus (IAV) infections. Bacteria are able to invade due to virus-induced depletion of alveolar macrophages (AMs), but this is not the only contributing factor. By analyzing a kinetic model, we uncovered a nonlinear initial dose threshold that is dependent on the amount of virus-induced AM depletion. The threshold separates the growth and clearance phenotypes such that bacteria decline for dose-AM depletion combinations below the threshold, stay constant near the threshold, and increase above the threshold. In addition, the distance from the threshold correlates to the growth rate. Because AM depletion changes throughout an IAV infection, the dose requirement for bacterial invasion also changes accordingly. Using the threshold, we found that the dose requirement drops dramatically during the first 7d of IAV infection. We then validated these analytical predictions by infecting mice with doses below or above the predicted threshold over the course of IAV infection. These results identify the nonlinear way in which two independent factors work together to support successful post-influenza bacterial invasion. They provide insight into coinfection timing, the heterogeneity in outcome, the probability of acquiring a coinfection, and the use of new therapeutic strategies to combat viral-bacterial coinfections.

Pharmacokinetics and concentration-effect relationships of therapeutic monoclonal antibodies and fusion proteins.

PubMed

Ternant, David; Paintaud, Gilles

2005-09-01

Although monoclonal antibodies (mAbs) constitute a major advance in therapeutics, their pharmacokinetic (PK) and pharmacodynamic (PD) properties are not fully understood. Saturable mechanisms are thought to occur in distribution and elimination of mAbs, which are protected from degradation by the Brambell's receptor (FcRn). The binding of mAbs to their target antigen explains part of their nonlinear PK and PD properties. The interindividual variability in mAb PK can be explained by several factors, including immune response against the biodrug and differences in the number of antigenic sites. The concentration-effect relationships of mAbs are complex and dependent on their mechanism of action. Interindividual differences in mAb PD can be explained by factors such as genetics and clinical status. PK and concentration-effect studies are necessary to design optimal dosing regimens. Because of their above-mentioned characteristics, the interindividual variability in their dose-response relationships must be studied by PK-PD modelling.

Radiation resistance of a gamma-ray irradiated nonlinear optic chromophore

NASA Astrophysics Data System (ADS)

Zhang, Cheng; Taylor, Edward W.

2009-11-01

The radiation resistance of organic electro-optic and optoelectronic materials for space applications is receiving increased attention. An earlier investigation reported that guest-host poled polymer EO modulator devices composed of a phenyltetraene bridge-type chromophore in amorphous polycarbonate (CLD/APC) did not exhibit a decrease in EO response (i.e., an increase in modulation-switching voltage- Vπ) following irradiation by low dose [10-160 krad(Si)] 60Co gamma-rays. To provide further evidences to the observed radiation stability, the post-irradiation responses of 60Co gamma-rays on CLD1/APC thin films are examined by various chemical and spectroscopic methods including: a solubility test, thin-layer chromatography, proton nuclear magnetic resonance spectroscopy, UV-vis absorption, and infra-red absorption. The results indicate that CLD1 and APC did not decompose under gamma-ray irradiation at dose levels ranging from 66-274 krad(Si) and from 61-154 krad(Si), respectively which support the previously reported data.

[Passive smoking--health consequences and effects of exposure prevention].

PubMed

Raupach, T; Radon, K; Nowak, D; Andreas, S

2008-01-01

Passive smoking is the third leading but preventable cause of death worldwide. It is associated with an elevated risk of developing acute respiratory diseases, obstructive lung disorders, lung cancer, and cardiovascular disease. Whereas the dose-response relationship between second-hand smoke exposure and respiratory diseases is likely to be linear, a non-linear dose-response curve has been observed with respect to acute cardiovascular events. This explains the disproportionately high risk of myocardial infarction among passive smokers as compared to unexposed individuals. Over the last ten years, exposure to second-hand smoke has declined in Germany, but it is still substantial. With passive smoking in the home being a difficult target for preventive measures, public smoking bans have recently been shown to greatly reduce second-hand smoke-related morbidity and mortality. In addition, such measures are usually well tolerated and highly relevant regarding legal aspects related to workplace issues. This article summarises the current evidence on the health consequences of passive smoking and on the favourable effects of public smoking bans.

Influence of very low doses of mediators on fungal laccase activity - nonlinearity beyond imagination

PubMed Central

Malarczyk, Elzbieta; Kochmanska-Rdest, Janina; Jarosz-Wilkolazka, Anna

2009-01-01

Laccase, an enzyme responsible for aerobic transformations of natural phenolics, in industrial applications requires the presence of low-molecular substances known as mediators, which accelerate oxidation processes. However, the use of mediators is limited by their toxicity and the high costs of exploitation. The activation of extracellular laccase in growing fungal culture with highly diluted mediators, ABTS and HBT is described. Two high laccase-producing fungal strains, Trametes versicolor and Cerrena unicolor, were used in this study as a source of enzyme. Selected dilutions of the mediators significantly increased the activity of extracellular laccase during 14 days of cultivation what was distinctly visible in PAGE technique and in colorimetric tests. The same mediator dilutions increased demethylation properties of laccase, which was demonstrated during incubation of enzyme with veratric acid. It was established that the activation effect was assigned to specific dilutions of mediators. Our dose-response dilution process smoothly passes into the range of action of homeopathic dilutions and is of interest for homeopaths. PMID:19732425

X-ray irradiation of yeast cells

NASA Astrophysics Data System (ADS)

Masini, Alessandra; Batani, Dimitri; Previdi, Fabio; Conti, Aldo; Pisani, Francesca; Botto, Cesare; Bortolotto, Fulvia; Torsiello, Flavia; Turcu, I. C. Edmond; Allott, Ric M.; Lisi, Nicola; Milani, Marziale; Costato, Michele; Pozzi, Achille; Koenig, Michel

1997-10-01

Saccharomyces Cerevisiae yeast cells were irradiated using the soft X-ray laser-plasma source at Rutherford Laboratory. The aim was to produce a selective damage of enzyme metabolic activity at the wall and membrane level (responsible for fermentation) without interfering with respiration (taking place in mitochondria) and with nuclear and DNA activity. The source was calibrated by PIN diodes and X-ray spectrometers. Teflon stripes were chosen as targets for the UV laser, emitting X-rays at about 0.9 keV, characterized by a very large decay exponent in biological matter. X-ray doses to the different cell compartments were calculated following a Lambert-Bouguet-Beer law. After irradiation, the selective damage to metabolic activity at the membrane level was measured by monitoring CO2 production with pressure silicon detectors. Preliminary results gave evidence of pressure reduction for irradiated samples and non-linear response to doses. Also metabolic oscillations were evidenced in cell suspensions and it was shown that X-ray irradiation changed the oscillation frequency.

A theoretical investigation of soliton induced supercontinuum generation in liquid core photonic crystal fiber and dual core optical fiber

NASA Astrophysics Data System (ADS)

Porsezian, K.; Nithyanandan, K.; Vasantha Jayakantha Raja, R.; Ganapathy, R.

2013-07-01

The supercontinuum generation (SCG) in liquid core photonic crystal fiber (LCPCF) with versatile nonlinear response and the spectral broadening in dual core optical fiber is presented. The analysis is presented in two phase, phase I deals with the SCG in LCPCF with the effect of saturable nonlinearity and re-orientational nonlinearity. We identify and discuss the generic nature of the saturable nonlinearity and reorientational nonlinearity in the SCG, using suitable model. For the physical explanation, modulational instability and soliton fission techniques is implemented to investigate the impact of saturable nonlinear response and slow nonlinear response, respectively. It is observed that the saturable nonlinearity inevitably suppresses the MI and the subsequent SCG. On the other hand, the re-orientational nonlinearity contributes to the slow nonlinear response in addition to the conventional fast response due to the electronic contribution. The phase II features the exclusive investigation of the spectral broadening in the dual core optical fiber.

Molecular, cellular, and genetic basis of radiosensitivity at low doses: a case of inducible repair?

PubMed

Skov, K A

1994-04-01

Many proteins are induced by ionizing radiation, and genes are activated. We still do not know which, if any, are responsible for IRR, or what leads to the adaptive response seen at still lower doses. Are these the same responses? Are they related to apoptosis, repair of potentially lethal damage and other responses? Does the cell have a whole battery of responses, depending on the dose? I suspect this is the case. Can the responses be explained more simply, as effects on regulators of cell cycle or induction of fidelity, or is there induction of repair? Are there still other explanations for the apparent protection? The initial slope of the survival curve which was addressed earlier (1) must take on new meaning given the hyperradiosensitive portion. Similarly, we may have to change our thinking with respect to the LQ description of survival data. It is not surprising that this workshop, held at such an early stage primarily to address the phenomenon of increased radioresistance, produced more questions than answers. Single-strand breaks may trigger resistance, but additional lesions or classes of damage may be relevant. Some physicists expect the damage caused to be linear with dose; the biologists suggest that the response is nonlinear (e.g. saturation of an enzyme, induction of repair, cell cycle effects) and there is room for biochemistry which could also vary with dose (e.g. consumption of a protector or a sensitizer). Some biophysicists would argue that the observed structures in survival curves might be explained by change in the target cross section such as a large change in DNA conformation caused by a very low dose. There is some reluctance in the radiobiology community to accept that cells may respond to ionizing radiation by inducing or activating protective mechanisms, although the cell exhibits defensive responses to many other detrimental stimuli. If "the heart of the matter is in the shape of the survival curve" as suggested by Dr. Elkind in his summary of the 1974 "low doses" conference (p. 385 in ref. 1), then we are fortunate indeed that there are now additional methods to attack the question directly of what is turned on or activated. It is anticipated that there will be many further developments within the year, to be presented at related sessions at larger meetings, and at a closely related meeting to be held in June 1994 in Montreal, entitled "Gene Induction and Adaptive Responses in Irradiated Cells: Mechanisms and Clinical Implications."

Life-stage-, sex-, and dose-dependent dietary toxicokinetics and relationship to toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) in rats: implications for toxicity test dose selection, design, and interpretation.

PubMed

Saghir, Shakil A; Marty, Mary S; Zablotny, Carol L; Passage, Julie K; Perala, Adam W; Neal, Barbara H; Hammond, Larry; Bus, James S

2013-12-01

Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥ 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.

Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

PubMed Central

Marty, Mary S.

2013-01-01

Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥1200 ppm (63mg/kg/day) for P1 males and between 200 and 400 ppm (14–27mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21–35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies. PMID:24105888

Meta-regression analysis of the effect of trans fatty acids on low-density lipoprotein cholesterol.

PubMed

Allen, Bruce C; Vincent, Melissa J; Liska, DeAnn; Haber, Lynne T

2016-12-01

We conducted a meta-regression of controlled clinical trial data to investigate quantitatively the relationship between dietary intake of industrial trans fatty acids (iTFA) and increased low-density lipoprotein cholesterol (LDL-C). Previous regression analyses included insufficient data to determine the nature of the dose response in the low-dose region and have nonetheless assumed a linear relationship between iTFA intake and LDL-C levels. This work contributes to the previous work by 1) including additional studies examining low-dose intake (identified using an evidence mapping procedure); 2) investigating a range of curve shapes, including both linear and nonlinear models; and 3) using Bayesian meta-regression to combine results across trials. We found that, contrary to previous assumptions, the linear model does not acceptably fit the data, while the nonlinear, S-shaped Hill model fits the data well. Based on a conservative estimate of the degree of intra-individual variability in LDL-C (0.1 mmoL/L), as an estimate of a change in LDL-C that is not adverse, a change in iTFA intake of 2.2% of energy intake (%en) (corresponding to a total iTFA intake of 2.2-2.9%en) does not cause adverse effects on LDL-C. The iTFA intake associated with this change in LDL-C is substantially higher than the average iTFA intake (0.5%en). Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A polymer, random walk model for the size-distribution of large DNA fragments after high linear energy transfer radiation

NASA Technical Reports Server (NTRS)

Ponomarev, A. L.; Brenner, D.; Hlatky, L. R.; Sachs, R. K.

2000-01-01

DNA double-strand breaks (DSBs) produced by densely ionizing radiation are not located randomly in the genome: recent data indicate DSB clustering along chromosomes. Stochastic DSB clustering at large scales, from > 100 Mbp down to < 0.01 Mbp, is modeled using computer simulations and analytic equations. A random-walk, coarse-grained polymer model for chromatin is combined with a simple track structure model in Monte Carlo software called DNAbreak and is applied to data on alpha-particle irradiation of V-79 cells. The chromatin model neglects molecular details but systematically incorporates an increase in average spatial separation between two DNA loci as the number of base-pairs between the loci increases. Fragment-size distributions obtained using DNAbreak match data on large fragments about as well as distributions previously obtained with a less mechanistic approach. Dose-response relations, linear at small doses of high linear energy transfer (LET) radiation, are obtained. They are found to be non-linear when the dose becomes so large that there is a significant probability of overlapping or close juxtaposition, along one chromosome, for different DSB clusters from different tracks. The non-linearity is more evident for large fragments than for small. The DNAbreak results furnish an example of the RLC (randomly located clusters) analytic formalism, which generalizes the broken-stick fragment-size distribution of the random-breakage model that is often applied to low-LET data.

Effects of a novel sodium channel blocker, GSK2339345, in patients with refractory chronic cough
.

PubMed

Smith, Jaclyn A; McGarvey, Lorcan P A; Badri, Huda; Satia, Imran; Warren, Francis; Siederer, Sarah; Liefaard, Lia; Murdoch, Robert D; Povey, Kathryn; Marks-Konczalik, Joanna

2017-09-01

Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods. Patients were monitored for cough for 8 hours post-first dose using the VitaloJAK, ambulatory cough monitor. In parts B and C, patients underwent full dose-response cough challenges with capsaicin and citric acid respectively following single doses of randomly assigned GSK2339345 or placebo (4 study days). Part A was analyzed using a mixed effects model and parts B and C using population non-linear mixed effects models. Of 16 enrolled patients, 11 completed the study. 8-hour cough counts increased following GSK2339345 treatment compared with placebo (GSK2339345/placebo ratio of adjusted geometric means: 1.26 (90% credible interval 1.10, 1.44), associated with GSK2339345-evoked coughing, recorded during the 2 minutes post-dose. This was not observed with placebo. The effect of GSK2339345 on cough responses during cough challenges was inconclusive. GSK2339345 was well tolerated. While these data could not determine if GSK2339345 reached the target VGSC, they strongly suggest that GSK2339345 has no anti-tussive effect despite reaching airway sensory nerves as evidenced by the evoked transient cough.
.

Effectiveness of urban shelter-in-place—II: Residential districts

NASA Astrophysics Data System (ADS)

Chan, Wanyu R.; Nazaroff, William W.; Price, Phillip N.; Gadgil, Ashok J.

In the event of a short-term, large-scale toxic chemical release to the atmosphere, shelter-in-place (SIP) may be used as an emergency response to protect public health. We modeled hypothetical releases using realistic, empirical parameters to explore how key factors influence SIP effectiveness for single-family dwellings in a residential district. Four classes of factors were evaluated in this case study: (a) time scales associated with release duration, SIP implementation delay, and SIP termination; (b) building air-exchange rates, including air infiltration and ventilation; (c) the degree of sorption of toxic chemicals to indoor surfaces; and (d) the shape of the dose-response relationship for acute adverse health effects. Houses with lower air leakage are more effective shelters, and thus variability in the air leakage of dwellings is associated with varying degrees of SIP protection in a community. Sorption on indoor surfaces improves SIP effectiveness by lowering the peak indoor concentrations and reducing the amount of contamination in the indoor air. Nonlinear dose-response relationships imply substantial reduction in adverse health effects from lowering the peak exposure concentration. However, if the scenario is unfavorable for indefinite sheltering (e.g. sheltering in leaky houses for protection against a nonsorbing chemical with a linear dose-response), the community must implement SIP without delay and exit from shelter when it first becomes safe to do so. Otherwise, the community can be subjected to even greater risk than if they did not take shelter indoors.

Potassium and Obesity/Metabolic Syndrome: A Systematic Review and Meta-Analysis of the Epidemiological Evidence.

PubMed

Cai, Xianlei; Li, Xueying; Fan, Wenjie; Yu, Wanqi; Wang, Shan; Li, Zhenhong; Scott, Ethel Marian; Li, Xiuyang

2016-03-25

The objective of this study was to investigate the associations between potassium and obesity/metabolic syndrome. We identified eight relevant studies and applied meta-analysis, and nonlinear dose-response analysis to obtain the available evidence. The results of the pooled analysis and systematic review indicated that high potassium intake could not reduce the risk of obesity (pooled OR = 0.78; 95% CI: 0.61-1.01), while serum potassium and urinary sodium-to-potassium ratio was associated with obesity. Potassium intake was associated with metabolic syndrome (pooled OR = 0.75; 95% CI: 0.50-0.97). Nonlinear analysis also demonstrated a protective effect of adequate potassium intake on obesity and metabolic syndrome. Adequate intake of fruits and vegetables, which were the major sources of potassium, was highly recommended. However, additional pertinent studies are needed to examine the underlying mechanism.

Potassium and Obesity/Metabolic Syndrome: A Systematic Review and Meta-Analysis of the Epidemiological Evidence

PubMed Central

Cai, Xianlei; Li, Xueying; Fan, Wenjie; Yu, Wanqi; Wang, Shan; Li, Zhenhong; Scott, Ethel Marian; Li, Xiuyang

2016-01-01

The objective of this study was to investigate the associations between potassium and obesity/metabolic syndrome. We identified eight relevant studies and applied meta-analysis, and nonlinear dose-response analysis to obtain the available evidence. The results of the pooled analysis and systematic review indicated that high potassium intake could not reduce the risk of obesity (pooled OR = 0.78; 95% CI: 0.61–1.01), while serum potassium and urinary sodium-to-potassium ratio was associated with obesity. Potassium intake was associated with metabolic syndrome (pooled OR = 0.75; 95% CI: 0.50–0.97). Nonlinear analysis also demonstrated a protective effect of adequate potassium intake on obesity and metabolic syndrome. Adequate intake of fruits and vegetables, which were the major sources of potassium, was highly recommended. However, additional pertinent studies are needed to examine the underlying mechanism. PMID:27023597

Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies.

PubMed

Shrime, Mark G; Bauer, Scott R; McDonald, Anna C; Chowdhury, Nubaha H; Coltart, Cordelia E M; Ding, Eric L

2011-11-01

A growing body of evidence suggests that the consumption of foods rich in polyphenolic compounds, particularly cocoa, may have cardioprotective effects. No review, however, has yet examined the effect of flavonoid-rich cocoa (FRC) on all major cardiovascular risk factors or has examined potential dose-response relationships for these effects. A systematic review and meta-analysis of randomized, controlled trials was performed to evaluate the effect of FRC on cardiovascular risk factors and to assess a dose-response relationship. Inclusion and exclusion criteria as well as dependent and independent variables were determined a priori. Data were collected for: blood pressure, pulse, total cholesterol, HDL cholesterol, LDL cholesterol, TG, BMI, C-reactive protein, flow-mediated vascular dilation (FMD), fasting glucose, fasting insulin, serum isoprostane, and insulin sensitivity/resistance indices. Twenty-four papers, with 1106 participants, met the criteria for final analysis. In response to FRC consumption, systolic blood pressure decreased by 1.63 mm Hg (P = 0.033), LDL cholesterol decreased by 0.077 mmol/L (P = 0.038), and HDL cholesterol increased by 0.046 mmol/L (P = 0.037), whereas total cholesterol, TG, and C-reactive protein remained the same. Moreover, insulin resistance decreased (HOMA-IR: -0.94 points; P < 0.001), whereas FMD increased (1.53%; P < 0.001). A nonlinear dose-response relationship was found between FRC and FMD (P = 0.004), with maximum effect observed at a flavonoid dose of 500 mg/d; a similar relationship may exist with HDL cholesterol levels (P = 0.06). FRC consumption significantly improves blood pressure, insulin resistance, lipid profiles, and FMD. These short-term benefits warrant larger long-term investigations into the cardioprotective role of FRC.

A non-linear pharmacokinetic-pharmacodynamic relationship of metformin in healthy volunteers: An open-label, parallel group, randomized clinical study.

PubMed

Chung, Hyewon; Oh, Jaeseong; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Chung, Jae-Yong

2018-01-01

The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers. A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated. The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms. This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin. ClinicalTrials.gov NCT02712619.

Determining the mechanical properties of a radiochromic silicone-based 3D dosimeter

NASA Astrophysics Data System (ADS)

Kaplan, L. P.; Høye, E. M.; Balling, P.; Muren, L. P.; Petersen, J. B. B.; Poulsen, P. R.; Yates, E. S.; Skyt, P. S.

2017-07-01

New treatment modalities in radiotherapy (RT) enable delivery of highly conformal dose distributions in patients. This creates a need for precise dose verification in three dimensions (3D). A radiochromic silicone-based 3D dosimetry system has recently been developed. Such a dosimeter can be used for dose verification in deformed geometries, which requires knowledge of the dosimeter’s mechanical properties. In this study we have characterized the dosimeter’s elastic behaviour under tensile and compressive stress. In addition, the dose response under strain was determined. It was found that the dosimeter behaved as an incompressible hyperelastic material with a non-linear stress/strain curve and with no observable hysteresis or plastic deformation even at high strains. The volume was found to be constant within a 2% margin at deformations up to 60%. Furthermore, it was observed that the dosimeter returned to its original geometry within a 2% margin when irradiated under stress, and that the change in optical density per centimeter was constant regardless of the strain during irradiation. In conclusion, we have shown that this radiochromic silicone-based dosimeter’s mechanical properties make it a viable candidate for dose verification in deformable 3D geometries.

The dose-response analysis between BMI and common chronic diseases in northeast China.

PubMed

Yu, Jianxing; Tao, Yuchun; Dou, Jing; Ye, Junsen; Yu, Yaqin; Jin, Lina

2018-03-09

High body mass index (BMI) predisposes to several chronic diseases, but a large-scale systematic and detailed study of dose-response relationship between BMI and chronic diseases has not been reported previously. In this study, we aimed to investigate the relationship between BMI and 3 chronic diseases (hypertension, dyslipidemia and MetS) in northeast China. A sample of 16412 participants aged 18~79 years old were included in Jilin province in 2012. The lambda-mu-sigma (LMS) method was applied to examine the trend of BMI by age, and the restricted cubic splines were used to investigate the non-linear associations (dose-response curve) between BMI and chronic diseases. It was pointed out that BMI increased rapidly when young, then kept steady in middle age, and finally declined slowly in old age, and accordingly age was divided into 3 segments, which were different by gender. The odds ratios (ORs) of BMI for the chronic diseases increased relatively slowly when young, then increased dramatically in middle-age and old population, especially for men. Further, the ORs of BMI among non-smokers were lower than those among smokers, and the same trend was shown to be more apparent among drinkers and non-drinkers. The risk of BMI for common chronic diseases increased dramatically in middle-aged, especially for men with drinking and smoking habits.

Coffee, tea, caffeine and risk of depression: A systematic review and dose-response meta-analysis of observational studies.

PubMed

Grosso, Giuseppe; Micek, Agnieszka; Castellano, Sabrina; Pajak, Andzrej; Galvano, Fabio

2016-01-01

The aim of the study was to systematically review and analyze results from observational studies on coffee, caffeine, and tea consumption and association or risk of depression. Embase and PubMed databases were searched from inception to June 2015 for observational studies reporting the odds ratios or relative risks (RRs) and 95% confidence intervals (CI) of depression by coffee/tea/caffeine consumption. Random effects models, subgroup analyses, and dose-response analyses were performed. Twelve studies with 23 datasets were included in the meta-analysis, accounting for a total of 346 913 individuals and 8146 cases of depression. Compared to individuals with lower coffee consumption, those with higher intakes had pooled RR of depression of 0.76 (95% CI: 0.64, 0.91). Dose-response effect suggests a nonlinear J-shaped relation between coffee consumption and risk of depression with a peak of protective effect for 400 mL/day. A borderline nonsignificant association between tea consumption and risk of depression was found (RR 0.70, 95% CI: 0.48, 1.01), while significant results were found only for analysis of prospective studies regarding caffeine consumption (RR = 0.84, 95% CI: 0.75, 0.93). This study suggests a protective effect of coffee and, partially, of tea and caffeine on risk of depression. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells

PubMed Central

Neumaier, Teresa; Swenson, Joel; Pham, Christopher; Polyzos, Aris; Lo, Alvin T.; Yang, PoAn; Dyball, Jane; Asaithamby, Aroumougame; Chen, David J.; Bissell, Mina J.; Thalhammer, Stefan; Costes, Sylvain V.

2012-01-01

The concept of DNA “repair centers” and the meaning of radiation-induced foci (RIF) in human cells have remained controversial. RIFs are characterized by the local recruitment of DNA damage sensing proteins such as p53 binding protein (53BP1). Here, we provide strong evidence for the existence of repair centers. We used live imaging and mathematical fitting of RIF kinetics to show that RIF induction rate increases with increasing radiation dose, whereas the rate at which RIFs disappear decreases. We show that multiple DNA double-strand breaks (DSBs) 1 to 2 μm apart can rapidly cluster into repair centers. Correcting mathematically for the dose dependence of induction/resolution rates, we observe an absolute RIF yield that is surprisingly much smaller at higher doses: 15 RIF/Gy after 2 Gy exposure compared to approximately 64 RIF/Gy after 0.1 Gy. Cumulative RIF counts from time lapse of 53BP1-GFP in human breast cells confirmed these results. The standard model currently in use applies a linear scale, extrapolating cancer risk from high doses to low doses of ionizing radiation. However, our discovery of DSB clustering over such large distances casts considerable doubts on the general assumption that risk to ionizing radiation is proportional to dose, and instead provides a mechanism that could more accurately address risk dose dependency of ionizing radiation. PMID:22184222

Source position verification and dosimetry in HDR brachytherapy using an EPID.

PubMed

Smith, R L; Taylor, M L; McDermott, L N; Haworth, A; Millar, J L; Franich, R D

2013-11-01

Accurate treatment delivery in high dose rate (HDR) brachytherapy requires correct source dwell positions and dwell times to be administered relative to each other and to the surrounding anatomy. Treatment delivery inaccuracies predominantly occur for two reasons: (i) anatomical movement or (ii) as a result of human errors that are usually related to incorrect implementation of the planned treatment. Electronic portal imaging devices (EPIDs) were originally developed for patient position verification in external beam radiotherapy and their application has been extended to provide dosimetric information. The authors have characterized the response of an EPID for use with an (192)Ir brachytherapy source to demonstrate its use as a verification device, providing both source position and dosimetric information. Characterization of the EPID response using an (192)Ir brachytherapy source included investigations of reproducibility, linearity with dose rate, photon energy dependence, and charge build-up effects associated with exposure time and image acquisition time. Source position resolution in three dimensions was determined. To illustrate treatment verification, a simple treatment plan was delivered to a phantom and the measured EPID dose distribution compared with the planned dose. The mean absolute source position error in the plane parallel to the EPID, for dwells measured at 50, 100, and 150 mm source to detector distances (SDD), was determined to be 0.26 mm. The resolution of the z coordinate (perpendicular distance from detector plane) is SDD dependent with 95% confidence intervals of ± 0.1, ± 0.5, and ± 2.0 mm at SDDs of 50, 100, and 150 mm, respectively. The response of the EPID is highly linear to dose rate. The EPID exhibits an over-response to low energy incident photons and this nonlinearity is incorporated into the dose calibration procedure. A distance (spectral) dependent dose rate calibration procedure has been developed. The difference between measured and planned dose is less than 2% for 98.0% of pixels in a two-dimensional plane at an SDD of 100 mm. Our application of EPID dosimetry to HDR brachytherapy provides a quality assurance measure of the geometrical distribution of the delivered dose as well as the source positions, which is not possible with any current HDR brachytherapy verification system.

Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice.

PubMed

Shen, Hong-Wu; Jiang, Xi-Ling; Yu, Ai-Ming

2011-07-01

5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses.

Nonlinear Pharmacokinetics of 5-Methoxy-N,N-dimethyltryptamine in MiceS⃞

PubMed Central

Shen, Hong-Wu; Jiang, Xi-Ling

2011-01-01

5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses. PMID:21464174

Carbohydrate and protein intake and risk of ulcerative colitis: Systematic review and dose-response meta-analysis of epidemiological studies.

PubMed

Wang, Fan; Feng, Juerong; Gao, Qian; Ma, Minxing; Lin, Xue; Liu, Jing; Li, Jin; Zhao, Qiu

2017-10-01

Dietary carbohydrate and protein intake is generally thought as risk factors for onset of ulcerative colitis (UC), while epidemiological data had been controversial. This study aimed to evaluate the role of carbohydrate and protein intake in the development of UC. Comprehensive search in PubMed and Embase was conducted to identify all relevant studies, and the role of carbohydrate and protein intake in the development of UC was quantitatively assessed by dose-response meta-analysis. Nine studies (5 case-control and 4 prospective cohort) were identified with a total of 975 UC cases and 239352 controls. The summary relative risks (RR) for per 10 g increment/day were 1.005 (95%CI: 0.991-1.019, I 2  = 31.5%, n = 5) for total carbohydrate intake, 1.001 (95%CI: 0.971-1.032, I 2  = 0.0%, n = 7) for the subtype of fiber intake, 1.029 (95%CI: 0.962-1.101, I 2  = 68.9%, n = 2) for the subtype of sugar intake, and 1.010 (95%CI: 0.975-1.047, I 2  = 12.4%, n = 7) for total protein intake. Among sugar subtypes, only sucrose intake was found positively related with UC risk (RR for per 10 g increment/day: 1.098, 95%CI: 1.024-1.177, I 2  = 0.0%, n = 3). No evidence of a non-linear dose-response association was found between the nutrient intake and UC risk, except for the subtype of sucrose (P for non-linear trend = 0.032). Subgroup analyses showed consistent results. This meta-analysis suggested a lack of association between dietary carbohydrate or protein intake and the risk of UC, except for the subtype of sucrose which played a significant role in the development of UC. Large-scale prospective designed studies are needed to confirm our findings. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Risk analysis: divergent models and convergent interpretations

NASA Technical Reports Server (NTRS)

Carnes, B. A.; Gavrilova, N.

2001-01-01

Material presented at a NASA-sponsored workshop on risk models for exposure conditions relevant to prolonged space flight are described in this paper. Analyses used mortality data from experiments conducted at Argonne National Laboratory on the long-term effects of external whole-body irradiation on B6CF1 mice by 60Co gamma rays and fission neutrons delivered as a single exposure or protracted over either 24 or 60 once-weekly exposures. The maximum dose considered was restricted to 1 Gy for neutrons and 10 Gy for gamma rays. Proportional hazard models were used to investigate the shape of the dose response at these lower doses for deaths caused by solid-tissue tumors and tumors of either connective or epithelial tissue origin. For protracted exposures, a significant mortality effect was detected at a neutron dose of 14 cGy and a gamma-ray dose of 3 Gy. For single exposures, radiation-induced mortality for neutrons also occurred within the range of 10-20 cGy, but dropped to 86 cGy for gamma rays. Plots of risk relative to control estimated for each observed dose gave a visual impression of nonlinearity for both neutrons and gamma rays. At least for solid-tissue tumors, male and female mortality was nearly identical for gamma-ray exposures, but mortality risks for females were higher than for males for neutron exposures. As expected, protracting the gamma-ray dose reduced mortality risks. Although curvature consistent with that observed visually could be detected by a model parameterized to detect curvature, a relative risk term containing only a simple term for total dose was usually sufficient to describe the dose response. Although detectable mortality for the three pathology end points considered typically occurred at the same level of dose, the highest risks were almost always associated with deaths caused by tumors of epithelial tissue origin.

Influence of laminate sequence and fabric type on the inherent acoustic nonlinearity in carbon fiber reinforced composites.

PubMed

Chakrapani, Sunil Kishore; Barnard, Daniel J; Dayal, Vinay

2016-05-01

This paper presents the study of influence of laminate sequence and fabric type on the baseline acoustic nonlinearity of fiber-reinforced composites. Nonlinear elastic wave techniques are increasingly becoming popular in detecting damage in composite materials. It was earlier observed by the authors that the non-classical nonlinear response of fiber-reinforced composite is influenced by the fiber orientation [Chakrapani, Barnard, and Dayal, J. Acoust. Soc. Am. 137(2), 617-624 (2015)]. The current study expands this effort to investigate the effect of laminate sequence and fabric type on the non-classical nonlinear response. Two hypotheses were developed using the previous results, and the theory of interlaminar stresses to investigate the influence of laminate sequence and fabric type. Each hypothesis was tested by capturing the nonlinear response by performing nonlinear resonance spectroscopy and measuring frequency shifts, loss factors, and higher harmonics. It was observed that the laminate sequence can either increase or decrease the nonlinear response based on the stacking sequence. Similarly, tests were performed to compare unidirectional fabric and woven fabric and it was observed that woven fabric exhibited a lower nonlinear response compared to the unidirectional fabric. Conjectures based on the matrix properties and interlaminar stresses were used in an attempt to explain the observed nonlinear responses for different configurations.

Modeling late rectal toxicities based on a parameterized representation of the 3D dose distribution

NASA Astrophysics Data System (ADS)

Buettner, Florian; Gulliford, Sarah L.; Webb, Steve; Partridge, Mike

2011-04-01

Many models exist for predicting toxicities based on dose-volume histograms (DVHs) or dose-surface histograms (DSHs). This approach has several drawbacks as firstly the reduction of the dose distribution to a histogram results in the loss of spatial information and secondly the bins of the histograms are highly correlated with each other. Furthermore, some of the complex nonlinear models proposed in the past lack a direct physical interpretation and the ability to predict probabilities rather than binary outcomes. We propose a parameterized representation of the 3D distribution of the dose to the rectal wall which explicitly includes geometrical information in the form of the eccentricity of the dose distribution as well as its lateral and longitudinal extent. We use a nonlinear kernel-based probabilistic model to predict late rectal toxicity based on the parameterized dose distribution and assessed its predictive power using data from the MRC RT01 trial (ISCTRN 47772397). The endpoints under consideration were rectal bleeding, loose stools, and a global toxicity score. We extract simple rules identifying 3D dose patterns related to a specifically low risk of complication. Normal tissue complication probability (NTCP) models based on parameterized representations of geometrical and volumetric measures resulted in areas under the curve (AUCs) of 0.66, 0.63 and 0.67 for predicting rectal bleeding, loose stools and global toxicity, respectively. In comparison, NTCP models based on standard DVHs performed worse and resulted in AUCs of 0.59 for all three endpoints. In conclusion, we have presented low-dimensional, interpretable and nonlinear NTCP models based on the parameterized representation of the dose to the rectal wall. These models had a higher predictive power than models based on standard DVHs and their low dimensionality allowed for the identification of 3D dose patterns related to a low risk of complication.

Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease.

PubMed

Qi, Hui; Li, Shixue

2014-04-01

A dose-response meta-analysis was carried out between Parkinson's disease (PD) risk, and coffee, tea and caffeine consumption. A comprehensive search was carried out to identify eligible studies. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline. A total of 13 articles involving 901 764 participants for coffee, eight articles involving 344 895 participants for tea and seven articles involving 492 724 participants for caffeine were included. A non-linear relationship was found between coffee consumption and PD risk overall, and the strength of protection reached the maximum at approximately 3 cups/day (smoking-adjusted relative risk: 0.72, 95% confidence interval 0.65-0.81). A linear relationship was found between tea and caffeine consumption, and PD risk overall, and the smoking-adjusted risk of PD decreased by 26% and 17% for every two cups/day and 200 mg/day increments, respectively. The association of coffee and tea consumption with PD risk was stronger for men than that for women, and the association of caffeine consumption with PD risk was stronger for ever users of hormones than that for never users of hormones among postmenopausal women. The aforementioned associations were weaker for USA relative to Europe or Asia. A linear dose-relationship for decreased PD risk with tea and caffeine consumption was found, whereas the strength of protection reached a maximum at approximately 3 cups/day for coffee consumption overall. Further studies are required to confirm the findings. © 2013 Japan Geriatrics Society.

Quantitative disease progression model of α‐1 proteinase inhibitor therapy on computed tomography lung density in patients with α‐1 antitrypsin deficiency

PubMed Central

Rogers, James A.; Vit, Oliver; Bexon, Martin; Sandhaus, Robert A.; Burdon, Jonathan; Chorostowska‐Wynimko, Joanna; Thompson, Philip; Stocks, James; McElvaney, Noel G.; Chapman, Kenneth R.; Edelman, Jonathan M.

2017-01-01

Aims Early‐onset emphysema attributed to α‐1 antitrypsin deficiency (AATD) is frequently overlooked and undertreated. RAPID‐RCT/RAPID‐OLE, the largest clinical trials of purified human α‐1 proteinase inhibitor (A1‐PI; 60 mg kg–1 week–1) therapy completed to date, demonstrated for the first time that A1‐PI is clinically effective in slowing lung tissue loss in AATD. A posthoc pharmacometric analysis was undertaken to further explore dose, exposure and response. Methods A disease progression model was constructed, utilizing observed A1‐PI exposure and lung density decline rates (measured by computed tomography) from RAPID‐RCT/RAPID‐OLE, to predict effects of population variability and higher doses on A1‐PI exposure and clinical response. Dose–exposure and exposure–response relationships were characterized using nonlinear and linear mixed effects models, respectively. The dose–exposure model predicts summary exposures and not individual concentration kinetics; covariates included baseline serum A1‐PI, forced expiratory volume in 1 s and body weight. The exposure–response model relates A1‐PI exposure to lung density decline rate at varying exposure levels. Results A dose of 60 mg kg–1 week–1 achieved trough serum levels >11 μmol l–1 (putative ‘protective threshold’) in ≥98% patients. Dose–exposure–response simulations revealed increasing separation between A1‐PI and placebo in the proportions of patients achieving higher reductions in lung density decline rate; improvements in decline rates ≥0.5 g l–1 year–1 occurred more often in patients receiving A1‐PI: 63 vs. 12%. Conclusion Weight‐based A1‐PI dosing reliably raises serum levels above the 11 μmol l–1 threshold. However, our exposure–response simulations question whether this is the maximal, clinically effective threshold for A1‐PI therapy in AATD. The model suggested higher doses of A1‐PI would yield greater clinical effects. PMID:28662542

Association between pulmonary function and renal function: findings from China and Australia.

PubMed

Yu, Dahai; Chen, Tao; Cai, Yamei; Zhao, Zhanzheng; Simmons, David

2017-05-01

The relationship between obstructive lung function and impaired renal function is unclear. This study investigated the dose-response relationship between obstructive lung function and impaired renal function. Two independent cross-sectional studies with representative sampling were applied. 1454 adults from rural Victoria, Australia (1298 with normal renal function, 156 with impaired renal function) and 5824 adults from Nanjing, China (4313 with normal renal function, 1511 with impaired renal function). Pulmonary function measurements included forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). Estimated glomerular filtration rate (eGFR), and impaired renal function marked by eGFR <60 mL/min/1.73m 2 were used as outcome. eGFR increased linearly with FEV1 in Chinese participants and with FVC in Australians. A non-linear relationship with peaked eGFR was found for FEV1 at 2.65 L among Australians and for FVC at 2.78 L among Chinese participants, respectively. A non-linear relationship with peaked eGFR was found for the predicted percentage value of forced expiratory volume in 1 s (PFEV1) at 81-82% and for the predicted percentage value of forced vital capacity (PFVC) at 83-84% among both Chinese and Australian participants, respectively. The non-linear dose-response relationships between lung capacity measurements (both for FEV1 and FVC) and risk of impaired renal function were consistently identified in both Chinese and Australian participants. An increased risk of impaired renal function was found below 3.05 L both for FEV1 and FVC, respectively. The non-linear relationship between PFEV and PVC and the risk of impaired renal function were consistently identified in both Chinese and Australian participants. An increased risk of impaired renal function was found below 76-77% for PFEV1 and 79-80% for PFVC, respectively. In both Australian and Chinese populations, the risk of impaired renal function increased both with FEV1 and FVC below 3.05 L, with PFEV1 below 76-77% or with PFVC below 79-80%, respectively. Obstructive lung function was associated with increased risk of reduced renal function. The screen for impaired renal function in patients with obstructive lung disease might be useful to ensure there was no impaired renal function before the commencement of potentially nephrotoxic medication where indicated (eg diuretics).

A novel method to produce nonlinear empirical physical formulas for experimental nonlinear electro-optical responses of doped nematic liquid crystals: Feedforward neural network approach

NASA Astrophysics Data System (ADS)

Yildiz, Nihat; San, Sait Eren; Okutan, Mustafa; Kaya, Hüseyin

2010-04-01

Among other significant obstacles, inherent nonlinearity in experimental physical response data poses severe difficulty in empirical physical formula (EPF) construction. In this paper, we applied a novel method (namely layered feedforward neural network (LFNN) approach) to produce explicit nonlinear EPFs for experimental nonlinear electro-optical responses of doped nematic liquid crystals (NLCs). Our motivation was that, as we showed in a previous theoretical work, an appropriate LFNN, due to its exceptional nonlinear function approximation capabilities, is highly relevant to EPF construction. Therefore, in this paper, we obtained excellently produced LFNN approximation functions as our desired EPFs for above-mentioned highly nonlinear response data of NLCs. In other words, by using suitable LFNNs, we successfully fitted the experimentally measured response and predicted the new (yet-to-be measured) response data. The experimental data (response versus input) were diffraction and dielectric properties versus bias voltage; and they were all taken from our previous experimental work. We conclude that in general, LFNN can be applied to construct various types of EPFs for the corresponding various nonlinear physical perturbation (thermal, electronic, molecular, electric, optical, etc.) data of doped NLCs.

An extended harmonic balance method based on incremental nonlinear control parameters

NASA Astrophysics Data System (ADS)

Khodaparast, Hamed Haddad; Madinei, Hadi; Friswell, Michael I.; Adhikari, Sondipon; Coggon, Simon; Cooper, Jonathan E.

2017-02-01

A new formulation for calculating the steady-state responses of multiple-degree-of-freedom (MDOF) non-linear dynamic systems due to harmonic excitation is developed. This is aimed at solving multi-dimensional nonlinear systems using linear equations. Nonlinearity is parameterised by a set of 'non-linear control parameters' such that the dynamic system is effectively linear for zero values of these parameters and nonlinearity increases with increasing values of these parameters. Two sets of linear equations which are formed from a first-order truncated Taylor series expansion are developed. The first set of linear equations provides the summation of sensitivities of linear system responses with respect to non-linear control parameters and the second set are recursive equations that use the previous responses to update the sensitivities. The obtained sensitivities of steady-state responses are then used to calculate the steady state responses of non-linear dynamic systems in an iterative process. The application and verification of the method are illustrated using a non-linear Micro-Electro-Mechanical System (MEMS) subject to a base harmonic excitation. The non-linear control parameters in these examples are the DC voltages that are applied to the electrodes of the MEMS devices.

Effect of the dose of exogenous fibrolytic enzyme preparations on preingestive fiber hydrolysis, ruminal fermentation, and in vitro digestibility of bermudagrass haylage.

PubMed

Romero, J J; Zarate, M A; Adesogan, A T

2015-01-01

Our objectives were to evaluate the effects of the dose rates of 5 Trichoderma reesei and Aspergillus oryzae exogenous fibrolytic enzymes (EFE; 1A, 2A, 11C, 13D, and 15D) on in vitro digestibility, fermentation characteristics, and preingestive hydrolysis of bermudagrass haylage and to identify the optimal dose of each EFE for subsequent in vitro and in vivo studies. In experiment 1, EFE were diluted in citrate-phosphate buffer (pH 6) and applied in quadruplicate in each of 2 runs at 0× (control), 0.5×, 1×, 2×, and 3×; where 1× was the respective manufacturer-recommended dose (2.25, 2.25, 10, 15, and 15g of EFE/kg of dry matter). The suspension was incubated for 24h at 25°C and for a further 24h at 39°C after the addition of ruminal fluid. In experiment 2, a similar approach to that in experiment 1 was used to evaluate simulated preingestive effects, except that sodium azide (0.02% wt/vol) was added to the EFE solution. The suspension was incubated for 24h at 25°C and then 15mL of water was added before filtration to extract water-soluble compounds. For both experiments, data for each enzyme were analyzed separately as a completely randomized block design with a model that included effects of EFE dose, run, and their interaction. In experiment 1, increasing the EFE dose rate nonlinearly increased the DM digestibility of 1A, 2A, 11C, and 13D and the neutral detergent fiber digestibility (NDFD) of 1A, 2A, 11C, and 13D. Optimal doses of 1A, 2A, 11C, 13D, and 15D, as indicated by the greatest increases in NDFD at the lowest dose tested, were 2×, 2×, 1×, 0.5×, and 0.5×, respectively. Increasing the dose rate of 2A, 11C, and 13D nonlinearly increased concentrations of total volatile fatty acids and propionate (mM), decreased their acetate-to-propionate ratios and linearly decreased those of samples treated with 1A and 15D. In experiment 2, increasing the dose rate of each EFE nonlinearly decreased concentrations of netural detergent fiber; also, increasing the dose rate of 1A, 2A, 11C, and 1D nonlinearly increased concentrations of water-soluble carbohydrates and free ferulic acid (μg/g). Application of increasing doses of the EFE increased NDF hydrolysis, NDFD, and ruminal fluid fermentation of bermudagrass haylage, but the optimal dose varied with the EFE. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

An alternative approach to characterize nonlinear site effects

USGS Publications Warehouse

Zhang, R.R.; Hartzell, S.; Liang, J.; Hu, Y.

2005-01-01

This paper examines the rationale of a method of nonstationary processing and analysis, referred to as the Hilbert-Huang transform (HHT), for its application to a recording-based approach in quantifying influences of soil nonlinearity in site response. In particular, this paper first summarizes symptoms of soil nonlinearity shown in earthquake recordings, reviews the Fourier-based approach to characterizing nonlinearity, and offers justifications for the HHT in addressing nonlinearity issues. This study then uses the HHT method to analyze synthetic data and recordings from the 1964 Niigata and 2001 Nisqually earthquakes. In doing so, the HHT-based site response is defined as the ratio of marginal Hilbert amplitude spectra, alternative to the Fourier-based response that is the ratio of Fourier amplitude spectra. With the Fourier-based approach in studies of site response as a reference, this study shows that the alternative HHT-based approach is effective in characterizing soil nonlinearity and nonlinear site response.

Optical nonlinearities in plasmonic metamaterials (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zayats, Anatoly V.

2016-04-01

Metals exhibit strong and fast nonlinearities making metallic, plasmonic, structures very promising for ultrafast all-optical applications at low light intensities. Combining metallic nanostructures in metamaterials provides additional functionalities via prospect of precise engineering of spectral response and dispersion. From this point of view, hyperbolic metamaterials, in particular those based on plasmonic nanorod arrays, provide wealth of exciting possibilities in nonlinear optics offering designed linear and nonlinear properties, polarization control, spontaneous emission control and many others. Experiments and modeling have already demonstrated very strong Kerr-nonlinear response and its ultrafast recovery due to the nonlocal nature of the plasmonic mode of the metamaterial, so that small changes in the permittivity of the metallic component under the excitation modify the nonlocal response that in turn leads to strong changes of the metamaterial transmission. In this talk, we will discuss experimental studies and numerical modeling of second- and third-order nonlinear optical processes in hyperbolic metamaterials based on metallic nanorods and other plasmonic systems where coupling between the resonances plays important role in defining nonlinear response. Second-harmonic generation and ultrafast Kerr-type nonlinearity originating from metallic component of the metamaterial will be considered, including nonlinear magneto-optical effects. Nonlinear optical response of stand-alone as well as integrated metamaterial components will be presented. Some of the examples to be discussed include nonlinear polarization control, nonlinear metamaterial integrated in silicon photonic circuitry and second-harmonic generation, including magneto-optical effects.

Spatial nonlinearities: Cascading effects in the earth system

USGS Publications Warehouse

Peters, Debra P.C.; Pielke, R.A.; Bestelmeyer, B.T.; Allen, Craig D.; Munson-McGee, Stuart; Havstad, K. M.; Canadell, Josep G.; Pataki, Diane E.; Pitelka, Louis F.

2006-01-01

Nonlinear behavior is prevalent in all aspects of the Earth System, including ecological responses to global change (Gallagher and Appenzeller 1999; Steffen et al. 2004). Nonlinear behavior refers to a large, discontinuous change in response to a small change in a driving variable (Rial et al. 2004). In contrast to linear systems where responses are smooth, well-behaved, continuous functions, nonlinear systems often undergo sharp or discontinuous transitions resulting from the crossing of thresholds. These nonlinear responses can result in surprising behavior that makes forecasting difficult (Kaplan and Glass 1995). Given that many system dynamics are nonlinear, it is imperative that conceptual and quantitative tools be developed to increase our understanding of the processes leading to nonlinear behavior in order to determine if forecasting can be improved under future environmental changes (Clark et al. 2001).

Plasmon-induced nonlinear response of silver atomic chains.

PubMed

Yan, Lei; Guan, Mengxue; Meng, Sheng

2018-05-10

Nonlinear response of a linear silver atomic chain upon ultrafast laser excitation has been studied in real time using the time-dependent density functional theory. We observe the presence of nonlinear responses up to the fifth order in tunneling current, which is ascribed to the excitation of high-energy electrons generated by Landau damping of plasmons. The nonlinear effect is enhanced after adsorption of polar molecules such as water due to the enhanced damping rates during plasmon decay. Increasing the length of atomic chains also increases the nonlinear response, favoring higher-order plasmon excitation. These findings offer new insights towards a complete understanding and ultimate control of plasmon-induced nonlinear phenomena to atomic precision.

A Matter of Timing: Identifying Significant Multi-Dose Radiotherapy Improvements by Numerical Simulation and Genetic Algorithm Search

PubMed Central

Angus, Simon D.; Piotrowska, Monika Joanna

2014-01-01

Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17–18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy. PMID:25460164

A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search.

PubMed

Angus, Simon D; Piotrowska, Monika Joanna

2014-01-01

Multi-dose radiotherapy protocols (fraction dose and timing) currently used in the clinic are the product of human selection based on habit, received wisdom, physician experience and intra-day patient timetabling. However, due to combinatorial considerations, the potential treatment protocol space for a given total dose or treatment length is enormous, even for relatively coarse search; well beyond the capacity of traditional in-vitro methods. In constrast, high fidelity numerical simulation of tumor development is well suited to the challenge. Building on our previous single-dose numerical simulation model of EMT6/Ro spheroids, a multi-dose irradiation response module is added and calibrated to the effective dose arising from 18 independent multi-dose treatment programs available in the experimental literature. With the developed model a constrained, non-linear, search for better performing cadidate protocols is conducted within the vicinity of two benchmarks by genetic algorithm (GA) techniques. After evaluating less than 0.01% of the potential benchmark protocol space, candidate protocols were identified by the GA which conferred an average of 9.4% (max benefit 16.5%) and 7.1% (13.3%) improvement (reduction) on tumour cell count compared to the two benchmarks, respectively. Noticing that a convergent phenomenon of the top performing protocols was their temporal synchronicity, a further series of numerical experiments was conducted with periodic time-gap protocols (10 h to 23 h), leading to the discovery that the performance of the GA search candidates could be replicated by 17-18 h periodic candidates. Further dynamic irradiation-response cell-phase analysis revealed that such periodicity cohered with latent EMT6/Ro cell-phase temporal patterning. Taken together, this study provides powerful evidence towards the hypothesis that even simple inter-fraction timing variations for a given fractional dose program may present a facile, and highly cost-effecitive means of significantly improving clinical efficacy.

Linear and nonlinear winter atmospheric responses to extreme phases of low frequency Pacific sea surface temperature variability

NASA Astrophysics Data System (ADS)

Cao, Dandan; Wu, Qigang; Hu, Aixue; Yao, Yonghong; Liu, Shizuo; Schroeder, Steven R.; Yang, Fucheng

2018-02-01

This study examines Northern Hemisphere winter (DJFM) atmospheric responses to opposite strong phases of interdecadal (low frequency, LF) Pacific sea surface temperature (SST) forcing, which resembles El Niño-Southern Oscillation (ENSO) on a longer time scale, in observations and GFDL and CAM4 model simulations. Over the Pacific-North America (PNA) sector, linear observed responses of 500-hPa height (Z500) anomalies resemble the PNA teleconnection pattern, but show a PNA-like nonlinear response because of a westward Z500 shift in the negative (LF-) relative to the positive LF (LF+) phase. Significant extratropical linear responses include a North Atlantic Oscillation (NAO)-like Z500 anomaly, a dipole-like Z500 anomaly over northern Eurasia associated with warming over mid-high latitude Eurasia, and a Southern Annular anomaly pattern associated with warming in southern land areas. Significant nonlinear Z500 responses also include a NAO-like anomaly pattern. Models forced by LF+ and LF- SST anomalies reproduce many aspects of observed linear and nonlinear responses over the Pacific-North America sector, and linear responses over southern land, but not in the North Atlantic-European sector and Eurasia. Both models simulate PNA-like linear responses in the North Pacific-North America region similar to observed, but show larger PNA-like LF+ responses, resulting in a PNA nonlinear response. The nonlinear PNA responses result from both nonlinear western tropical Pacific rainfall changes and extratropical transient eddy feedbacks. With LF tropical Pacific forcing only (LFTP+ and LFTP-, climatological SST elsewhere), CAM4 simulates a significant NAO response to LFTP-, including a linear negative and nonlinear positive NAO response.

Predicting the nonlinear optical response in the resonant region from the linear characterization: a self-consistent theory for the first-, second-, and third-order (non)linear optical response

NASA Astrophysics Data System (ADS)

Pérez-Moreno, Javier; Clays, Koen; Kuzyk, Mark G.

2010-08-01

We introduce a self-consistent theory for the description of the optical linear and nonlinear response of molecules that is based strictly on the results of the experimental characterization. We show how the Thomas-Kuhn sum-rules can be used to eliminate the dependence of the nonlinear response on parameters that are not directly measurable. Our approach leads to the successful modeling of the dispersion of the nonlinear response of complex molecular structures with different geometries (dipolar and octupolar), and can be used as a guide towards the modeling in terms of fundamental physical parameters.

SU-F-T-550: Radiochromic Plastic Thin Sheet Dosimeter: Initial Performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jordan, K; Adamovics, J

Purpose: Thin sheets, of a high sensitivity formulation of radiochromic dosimeter, Presage were prepared and evaluated for optical readout. Methods: Sheets of radiochromic polyurethane, 12 cm long, 10 cm wide and 0.2 cm thick were prepared with leuco crystal violet as the reporter molecule. Sample transmission was evaluated at a wavelength of 590 nm with in-house constructed instruments: optical cone beam laser CT scanner, fixed and scanning spot densitometers. Sample sequential irradiations to a total dose of 40 Gy were conducted with a modified, Theratron 60, cobalt radiotherapy machine at dose rates of 1 or 0.25 Gy per minute. Exposuremore » to ambient and readout light was minimized to limit background photochromic signals. Samples were stored at 4°C. Optical activity was assessed from linearly polarized transmission images. Comparison sensitivity measurements with EBT3 film were conducted. Results: Samples were transparent, smooth and pale purple before irradiation. Radiochromic reaction was completed in less than 5 minutes. A linear dose response with a sensitivity of 0.5 cm-1Gy-1 was observed. Micrometer measurements found sheet thickness variations up to 20%. Uniform dose, 2 Gy attenuation images, correlated with local sheet thicknesses. Comparable measurements with EBT3 film were 3 times more sensitive at 1 Gy but above 15 Gy, EBT3 film had lower sensitivity than 0.2 cm thick Presage sheet dosimeter due to its non-linear response. Conclusion: Dose sensitivity provided a 10% decrease in transmission for a 1 Gy dose. Improvements in mold design are expected to allow production of sheets with less than 5% variation in thickness. Above, 10 Gy, Presage sheet dosimeter performance expected to exceed EBT3 film based on linearity, sensitivity, transparency and smoothness of samples. J Adamovics is owner of Heuris Inc.« less

Assessing human health response in life cycle assessment using ED10s and DALYs: part 2--Noncancer effects.

PubMed

Pennington, David; Crettaz, Pierre; Tauxe, Annick; Rhomberg, Lorenz; Brand, Kevin; Jolliet, Olivier

2002-10-01

In Part 1 of this article we developed an approach for the calculation of cancer effect measures for life cycle assessment (LCA). In this article, we propose and evaluate the method for the screening of noncancer toxicological health effects. This approach draws on the noncancer health risk assessment concept of benchmark dose, while noting important differences with regulatory applications in the objectives of an LCA study. We adopt the centraltendency estimate of the toxicological effect dose inducing a 10% response over background, ED10, to provide a consistent point of departure for default linear low-dose response estimates (betaED10). This explicit estimation of low-dose risks, while necessary in LCA, is in marked contrast to many traditional procedures for noncancer assessments. For pragmatic reasons, mechanistic thresholds and nonlinear low-dose response curves were not implemented in the presented framework. In essence, for the comparative needs of LCA, we propose that one initially screens alternative activities or products on the degree to which the associated chemical emissions erode their margins of exposure, which may or may not be manifested as increases in disease incidence. We illustrate the method here by deriving the betaED10 slope factors from bioassay data for 12 chemicals and outline some of the possibilities for extrapolation from other more readily available measures, such as the no observable adverse effect levels (NOAEL), avoiding uncertainty factors that lead to inconsistent degrees of conservatism from chemical to chemical. These extrapolations facilitated the initial calculation of slope factors for an additional 403 compounds; ranging from 10(-6) to 10(3) (risk per mg/kg-day dose). The potential consequences of the effects are taken into account in a preliminary approach by combining the betaED10 with the severity measure disability adjusted life years (DALY), providing a screening-level estimate of the potential consequences associated with exposures, integrated over time and space, to a given mass of chemical released into the environment for use in LCA.

Numerical study of surface plasmon enhanced nonlinear absorption and refraction.

PubMed

Kohlgraf-Owens, Dana C; Kik, Pieter G

2008-07-07

Maxwell Garnett effective medium theory is used to study the influence of silver nanoparticle induced field enhancement on the nonlinear response of a Kerr-type nonlinear host. We show that the composite nonlinear absorption coefficient, beta(c), can be enhanced relative to the host nonlinear absorption coefficient near the surface plasmon resonance of silver nanoparticles. This enhancement is not due to a resonant enhancement of the host nonlinear absorption, but rather due to a phase shifted enhancement of the host nonlinear refractive response. The enhancement occurs at the expense of introducing linear absorption, alpha(c), which leads to an overall reduced figure of merit beta(c)/alpha(c) for nonlinear absorption. For thin (< 1 microm) composites, the use of surface plasmons is found to result in an increased nonlinear absorption response compared to that of the host material.

Wide-range radiation dose monitor

DOEpatents

Kopp, Manfred K.

1986-01-01

A radiation dose-rate monitor is provided which operates in a conventional linear mode for radiation in the 0 to 0.5 R/h range and utilizes a nonlinear mode of operation for sensing radiation from 0.5 R/h to over 500 R/h. The nonlinear mode is achieved by a feedback circuit which adjusts the high voltage bias of the proportional counter, and hence its gas gain, in accordance with the amount of radiation being monitored. This allows compression of readout onto a single scale over the range of 0 to greater than 500 R/h without scale switching operations.

Wide-range radiation dose monitor

DOEpatents

Kopp, M.K.

1984-09-20

A radiation dose-rate monitor is provided which operates in a conventional linear mode for radiation in the 0 to 0.5 R/h range and utilizes a nonlinear mode of operation for sensing radiation from 0.5 R/h to over 500 R/h. The nonlinear mode is achieved by a feedback circuit which adjusts the high voltage bias of the proportional counter, and hence its gas gain, in accordance with the amount of radiation being monitored. This allows compression of readout onto a single scale over the range of 0 to greater than 500 R/h without scale switching operations.

Lung development and the host response to influenza A virus are altered by different doses of neonatal oxygen in mice

PubMed Central

Buczynski, Bradley W.; Yee, Min; Paige Lawrence, B.

2012-01-01

Oxygen exposure in preterm infants has been associated with altered lung development and increased risk for respiratory viral infections later in life. Although the dose of oxygen sufficient to exert these changes in humans remains unknown, adult mice exposed to 100% oxygen between postnatal days 1–4 exhibit alveolar simplification and increased sensitivity to influenza virus infection. Additionally, two nonlinear thresholds of neonatal oxygen exposures were previously identified that promote modest (between 40% and 60% oxygen) and severe (between 80% and 100% oxygen) changes in lung development. Here, we investigate whether these two thresholds correlate with the severity of lung disease following respiratory viral infection. Adult mice exposed to 100% oxygen at birth, and to a lesser extent 80% oxygen, demonstrated enhanced body weight loss, persistent inflammation, and fibrosis following infection compared with infected siblings exposed to room air at birth. In contrast, the host response to infection was indistinguishable between mice exposed to room air and 40% or 60% oxygen. Interestingly, levels of monocyte chemoattractant protein (MCP)-1 were equivalently elevated in infected mice that had been exposed to 80% or 100% oxygen as neonates. However, reducing levels of MCP-1 using heterozygous Mcp-1 mice did not affect oxygen-dependent changes in the response to infection. Thus lung development and the host response to respiratory viral infection are disrupted by different doses of oxygen. Our findings suggest that measuring lung function alone may not be sufficient to identify individuals born prematurely who have increased risk for respiratory viral infection. PMID:22408042

Yeast cell metabolism investigated by CO{_2} production and soft X-ray irradiation

NASA Astrophysics Data System (ADS)

Masini, A.; Batani, D.; Previdi, F.; Milani, M.; Pozzi, A.; Turcu, E.; Huntington, S.; Takeyasu, H.

1999-01-01

Results obtained using a new technique for studying cell metabolism are presented. The technique, consisting in CO2 production monitoring, has been applied to Saccharomyces cerevisiae yeast cells. Also the cells were irradiated using the soft X-ray laser-plasma source at Rutherford Appleton Laboratory with the aim of producing a damage of metabolic processes at the wall level, responsible for fermentation, without great interference with respiration, taking place in mitochondria, and DNA activity. The source was calibrated with PIN diodes and X-ray spectrometers and used Teflon stripes as target, emitting X-rays at about 0.9 keV, with a very low penetration in biological material. X-ray doses delivered to the different cell compartments were calculated following a Lambert-Bouguet-Beer law. Immediately after irradiation, the damage to metabolic activity was measured again by monitoring CO2 production. Results showed a general reduction in gas production by irradiated samples, together with non-linear and non-monotone response to dose. There was also evidence of oscillations in cell metabolic activity and of X-ray induced changes in oscillation frequency.

Dose-response relationship between cigarette smoking and site-specific cancer risk: protocol for a systematic review with an original design combining umbrella and traditional reviews.

PubMed

Lugo, Alessandra; Bosetti, Cristina; Peveri, Giulia; Rota, Matteo; Bagnardi, Vincenzo; Gallus, Silvano

2017-11-01

Only a limited number of meta-analyses providing risk curve functions of dose-response relationships between various smoking-related variables and cancer-specific risk are available. To identify all relevant original publications on the issue, we will conduct a series of comprehensive systematic reviews based on three subsequent literature searches: (1) an umbrella review, to identify meta-analyses, pooled analyses and systematic reviews published before 28 April 2017 on the association between cigarette smoking and the risk of 28 (namely all) malignant neoplasms; (2) for each cancer site, an updated review of original publications on the association between cigarette smoking and cancer risk, starting from the last available comprehensive review identified through the umbrella review; and (3) a review of all original articles on the association between cigarette smoking and site-specific cancer risk included in the publications identified through the umbrella review and the updated reviews. The primary outcomes of interest will be (1) the excess incidence/mortality of various cancers for smokers compared with never smokers; and (2) the dose-response curves describing the association between smoking intensity, duration and time since stopping and incidence/mortality for various cancers. For each cancer site, we will perform a meta-analysis by pooling study-specific estimates for smoking status. We will also estimate the dose-response curves for other smoking-related variables through random-effects meta-regression models based on a non-linear dose-response relationship framework. Ethics approval is not required for this study. Main results will be published in peer-reviewed journals and will also be included in a publicly available website. We will provide therefore the most complete and updated estimates on the association between various measures of cigarette smoking and site-specific cancer risk. This will allow us to obtain precise estimates on the cancer burden attributable to cigarette smoking. This protocol was registered in the International Prospective Register of Systematic Reviews (CRD42017063991). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

PubMed Central

Hawke, Roy L.; Schrieber, Sarah J.; Soule, Tedi A.; Wen, Zhiming; Smith, Philip C.; Reddy, K. Rajender; Wahed, Abdus S.; Belle, Steven H.; Afdhal, Nezam H.; Navarro, Victor J.; Berman, Josh; Liu, Qi-Ying; Doo, Edward; Fried, Michael W.

2011-01-01

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg. PMID:19841158

Species difference in the mechanism of nonlinear pharmacokinetics of E2074, a novel sodium channel inhibitor, in rats, dogs, and monkeys.

PubMed

Nagaya, Yoko; Takenaka, Osamu; Kusano, Kazutomi; Yoshimura, Tsutomu

2013-05-01

New chemical entities often exhibit nonlinear pharmacokinetics (PK) profiles in experimental animals. However, the number of studies that have focused on species differences in nonlinear PK is very limited; thus, the aim of this study was to clarify the mechanism of the nonlinear PK of E2074 (2-[(2R)-2-fluoro-3-{(3r)-[(3-fluorobenzyl)oxy]-8-azabicyclo[3.2.1]oct-8-yl}propyl]-4,5-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one), a novel sodium channel inhibitor, in rats, dogs, and monkeys. Nonlinear PK profiles with more than dose-proportional increases of Cmax and area under the plasma concentration curve were observed in all species after oral administration. The Michaelis-Menten constant (Km) values of hepatic microsomal metabolism were 7.23 and 0.41 μM in rats and dogs in vitro, respectively, which were lower than the unbound maximum plasma concentrations after oral administration in vivo, indicating that the nonlinear PK in rats and dogs was attributable to the saturation of hepatic metabolism. However, we do not believe that the saturation of hepatic metabolism was the mechanism of nonlinearity in monkeys because of the high Km value (42.44 μM) observed in liver microsomes. Intestinal metabolism was observed in monkey intestinal microsomes but not in rats and dogs, and the nonlinear PK in monkeys was diminished by inhibition of intestinal metabolism with a concomitant oral dose of ketoconazole. These results suggest that saturation of the intestinal metabolism is the potential mechanism of nonlinearity in monkeys. P-glycoprotein was not involved in the nonlinear PK profiles in any species. In conclusion, the mechanism of the nonlinear PK of E2074 is species dependent, with the saturation of hepatic metabolism in rats and dogs and that of intestinal metabolism in monkeys being the primary cause.

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

PubMed Central

Klapacz, Joanna; Pottenger, Lynn H.; Engelward, Bevin P.; Heinen, Christopher D.; Johnson, George E.; Clewell, Rebecca A.; Carmichael, Paul L.; Adeleye, Yeyejide; Andersen, Melvin E.

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. PMID:27036068

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents.

PubMed

Klapacz, Joanna; Pottenger, Lynn H; Engelward, Bevin P; Heinen, Christopher D; Johnson, George E; Clewell, Rebecca A; Carmichael, Paul L; Adeleye, Yeyejide; Andersen, Melvin E

2016-01-01

From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance of a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations. Copyright © 2015 Elsevier B.V. All rights reserved.

Neural activation in the "reward circuit" shows a nonlinear response to facial attractiveness.

PubMed

Liang, Xiaoyun; Zebrowitz, Leslie A; Zhang, Yi

2010-01-01

Positive behavioral responses to attractive faces have led neuroscientists to investigate underlying neural mechanisms in a "reward circuit" that includes brain regions innervated by dopamine pathways. Using male faces ranging from attractive to extremely unattractive, disfigured ones, this study is the first to demonstrate heightened responses to both rewarding and aversive faces in numerous areas of this putative reward circuit. Parametric analyses employing orthogonal linear and nonlinear regressors revealed positive nonlinear effects in anterior cingulate cortex, lateral orbital frontal cortex (LOFC), striatum (nucleus accumbens, caudate, putamen), and ventral tegmental area, in addition to replicating previously documented linear effects in medial orbital frontal cortex (MOFC) and LOFC and nonlinear effects in amygdala and MOFC. The widespread nonlinear responses are consistent with single cell recordings in animals showing responses to both rewarding and aversive stimuli, and with some human fMRI investigations of non-face stimuli. They indicate that the reward circuit does not process face valence with any simple dissociation of function across structures. Perceiver gender modulated some responses to our male faces: Women showed stronger linear effects, and men showed stronger nonlinear effects, which may have functional implications. Our discovery of nonlinear responses to attractiveness throughout the reward circuit echoes the history of amygdala research: Early work indicated a linear response to threatening stimuli, including faces; later work also revealed a nonlinear response with heightened activation to affectively salient stimuli regardless of valence. The challenge remains to determine how such dual coding influences feelings, such as pleasure and pain, and guides goal-related behavioral responses, such as approach and avoidance.

Nonlinear Reduced-Order Simulation Using An Experimentally Guided Modal Basis

NASA Technical Reports Server (NTRS)

Rizzi, Stephen A.; Przekop, Adam

2012-01-01

A procedure is developed for using nonlinear experimental response data to guide the modal basis selection in a nonlinear reduced-order simulation. The procedure entails using nonlinear acceleration response data to first identify proper orthogonal modes. Special consideration is given to cases in which some of the desired response data is unavailable. Bases consisting of linear normal modes are then selected to best represent the experimentally determined transverse proper orthogonal modes and either experimentally determined inplane proper orthogonal modes or the special case of numerically computed in-plane companions. The bases are subsequently used in nonlinear modal reduction and dynamic response simulations. The experimental data used in this work is simulated to allow some practical considerations, such as the availability of in-plane response data and non-idealized test conditions, to be explored. Comparisons of the nonlinear reduced-order simulations are made with the surrogate experimental data to demonstrate the effectiveness of the approach.

Third order nonlinear optical response exhibited by mono- and few-layers of WS 2

DOE PAGES

Torres-Torres, Carlos; Perea-López, Néstor; Elías, Ana Laura; ...

2016-04-13

In this work, strong third order nonlinear optical properties exhibited by WS 2 layers are presented. Optical Kerr effect was identified as the dominant physical mechanism responsible for these third order optical nonlinearities. An extraordinary nonlinear refractive index together with an important contribution of a saturated absorptive response was observed to depend on the atomic layer stacking. Comparative experiments performed in mono- and few-layer samples of WS 2 revealed that this material is potentially capable of modulating nonlinear optical processes by selective near resonant induced birefringence. In conclusion, we envision applications for developing all-optical bidimensional nonlinear optical devices.

Association between physical activity and risk of nonalcoholic fatty liver disease: a meta-analysis.

PubMed

Qiu, Shanhu; Cai, Xue; Sun, Zilin; Li, Ling; Zügel, Martina; Steinacker, Jürgen Michael; Schumann, Uwe

2017-09-01

Increased physical activity (PA) is a key element in the management of patients with nonalcoholic fatty liver disease (NAFLD); however, its association with NAFLD risk has not been systematically assessed. This meta-analysis of observational studies was to quantify this association with dose-response analysis. Electronic databases were searched to January 2017 for studies of adults reporting the risk of NAFLD in relation to PA with cohort or case-control designs. Studies that reported sex-specific data were included as separate studies. The overall risk estimates were pooled using a random-effects model, and the dose-response analysis was conducted to shape the quantitative relationship. A total of 6 cohort studies from 5 articles with 32,657 incident NAFLD cases from 142,781 participants, and 4 case-control studies from 3 articles with 382 NAFLD cases and 302 controls were included. Compared with the lowest PA level, the highest PA level was associated with a risk reduction of NAFLD in cohort [RR (risk ratio) 0.79, 95% CI (confidence interval) 0.71-0.89] and case-control studies [OR (odds ratio) 0.43, 95% CI 0.27-0.68]. For cohort studies, both highest and moderate PA levels were superior to the light one in lowering NAFLD risk ( p for interaction = 0.006 and 0.02, respectively), and there was a log-linear dose-response association ( p for nonlinearity = 0.10) between PA and NAFLD risk [RR 0.82 (95% CI 0.73-0.91) for every 500 metabolic equivalent (MET)-minutes/week increment in PA]. Increased PA may lead to a reduced risk of NAFLD in a dose-dependent manner, and the current guideline-recommended minimum PA level that approximates to 500 MET-minutes/week is able to moderately reduce the NAFLD risk.

Population pharmacodynamic model of bicarbonate response to acetazolamide in mechanically ventilated chronic obstructive pulmonary disease patients

PubMed Central

2011-01-01

Introduction Acetazolamide is commonly given to chronic obstructive pulmonary disease (COPD) patients with metabolic alkalosis. Little is known of the pharmacodynamics of acetazolamide in the critically ill. We undertook the pharmacodynamic modeling of bicarbonate response to acetazolamide in COPD patients under mechanical ventilation. Methods This observational, retrospective study included 68 invasively ventilated COPD patients who received one or multiple doses of 250 or 500 mg of acetazolamide during the weaning period. Among the 68 investigated patients, 207 time-serum bicarbonate observations were available for analysis. Population pharmacodynamics was modeled using a nonlinear mixedeffect model. The main covariates of interest were baseline demographic data, Simplified Acute Physiology Score II (SAPS II) at ICU admission, cause of respiratory failure, co-prescription of drugs interfering with the acid-base equilibrium, and serum concentrations of protein, creatinin, potassium and chloride. The effect of acetazolamide on serum bicarbonate levels at different doses and in different clinical conditions was subsequently simulated in silico. Results The main covariates interacting with acetazolamide pharmacodynamics were SAPS II at ICU admission (P = 0.01), serum chloride (P < 0.001) and concomitant administration of corticosteroids (P = 0.02). Co-administration of furosemide significantly decreased bicarbonate elimination. Acetazolamide induced a decrease in serum bicarbonate with a dose-response relationship. The amount of acetazolamide inducing 50% of the putative maximum effect was 117 ± 21 mg. According to our model, an acetazolamide dosage > 500 mg twice daily is required to reduce serum bicarbonate concentrations > 5 mmol/L in the presence of high serum chloride levels or coadministration of systemic corticosteroids or furosemide. Conclusions This study identified several covariates that influenced acetazolamide pharmacodynamics and could allow a better individualization of acetazolamide dosing when treating COPD patients with metabolic alkalosis. PMID:21917139

Development of an in vitro bioassay for measuring susceptibility to macrocyclic lactone anthelmintics in Dirofilaria immitis.

PubMed

Evans, Christopher C; Moorhead, Andrew R; Storey, Bobby E; Wolstenholme, Adrian J; Kaplan, Ray M

2013-12-01

For more than 20 years, anthelmintics of the macrocyclic lactone (ML) drug class have been widely and effectively used as preventives against the canine heartworm, Dirofilaria immitis. However, in recent years an increased number of lack of efficacy (LOE) cases are being reported, in which dogs develop mature heartworm infections despite receiving monthly prophylactic doses of ML drugs. While this situation is raising concerns that heartworms may be developing resistance to MLs, compelling evidence for this is still lacking. Resolution of this dilemma requires validated biological or molecular diagnostic assays, but, unfortunately, no such tests currently exist. To address this need, we developed and optimized a larval migration inhibition assay (LMIA) for use with D. immitis third-stage larvae. The LMIA was used to measure the in vitro dose-response of two ML drugs (ivermectin and eprinomectin) on a known ML-susceptible laboratory strain of D. immitis. A nonlinear regression model was fit to the dose-response data, from which IC50 values were calculated; the mean IC50 and 95% confidence interval for IVM was 4.56 μM (1.26-16.4 μM), greater than that for EPR at 2.02 μM (1.68-2.42 μM), and this difference was significant (p = 0.0428). The R (2) value for EPR assays (0.90) was also greater than that for IVM treatment (0.71). The consistency and reproducibility of the dose-response data obtained with this assay suggests that it may be a useful technique for investigating the relative susceptibilities to ML drugs in other D. immitis populations.

The reliability of nonlinear least-squares algorithm for data analysis of neural response activity during sinusoidal rotational stimulation in semicircular canal neurons.

PubMed

Ren, Pengyu; Li, Bowen; Dong, Shiyao; Chen, Lin; Zhang, Yuelin

2018-01-01

Although many mathematical methods were used to analyze the neural activity under sinusoidal stimulation within linear response range in vestibular system, the reliabilities of these methods are still not reported, especially in nonlinear response range. Here we chose nonlinear least-squares algorithm (NLSA) with sinusoidal model to analyze the neural response of semicircular canal neurons (SCNs) during sinusoidal rotational stimulation (SRS) over a nonlinear response range. Our aim was to acquire a reliable mathematical method for data analysis under SRS in vestibular system. Our data indicated that the reliability of this method in an entire SCNs population was quite satisfactory. However, the reliability was strongly negatively depended on the neural discharge regularity. In addition, stimulation parameters were the vital impact factors influencing the reliability. The frequency had a significant negative effect but the amplitude had a conspicuous positive effect on the reliability. Thus, NLSA with sinusoidal model resulted a reliable mathematical tool for data analysis of neural response activity under SRS in vestibular system and more suitable for those under the stimulation with low frequency but high amplitude, suggesting that this method can be used in nonlinear response range. This method broke out of the restriction of neural activity analysis under nonlinear response range and provided a solid foundation for future study in nonlinear response range in vestibular system.

The reliability of nonlinear least-squares algorithm for data analysis of neural response activity during sinusoidal rotational stimulation in semicircular canal neurons

PubMed Central

Li, Bowen; Dong, Shiyao; Chen, Lin; Zhang, Yuelin

2018-01-01

Although many mathematical methods were used to analyze the neural activity under sinusoidal stimulation within linear response range in vestibular system, the reliabilities of these methods are still not reported, especially in nonlinear response range. Here we chose nonlinear least-squares algorithm (NLSA) with sinusoidal model to analyze the neural response of semicircular canal neurons (SCNs) during sinusoidal rotational stimulation (SRS) over a nonlinear response range. Our aim was to acquire a reliable mathematical method for data analysis under SRS in vestibular system. Our data indicated that the reliability of this method in an entire SCNs population was quite satisfactory. However, the reliability was strongly negatively depended on the neural discharge regularity. In addition, stimulation parameters were the vital impact factors influencing the reliability. The frequency had a significant negative effect but the amplitude had a conspicuous positive effect on the reliability. Thus, NLSA with sinusoidal model resulted a reliable mathematical tool for data analysis of neural response activity under SRS in vestibular system and more suitable for those under the stimulation with low frequency but high amplitude, suggesting that this method can be used in nonlinear response range. This method broke out of the restriction of neural activity analysis under nonlinear response range and provided a solid foundation for future study in nonlinear response range in vestibular system. PMID:29304173

Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC.

PubMed

Figueroa, Isabel; Leipold, Doug; Leong, Steve; Zheng, Bing; Triguero-Carrasco, Montserrat; Fourie-O'Donohue, Aimee; Kozak, Katherine R; Xu, Keyang; Schutten, Melissa; Wang, Hong; Polson, Andrew G; Kamath, Amrita V

2018-05-14

For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions.

Beam tests of proton-irradiated PbWO4 crystals and evaluation of double-ended read-out technique for mitigation of radiation damage effects

NASA Astrophysics Data System (ADS)

Lucchini, Marco; CMS Collaboration

2017-11-01

The harsh radiation environment in which detectors will have to operate during the High Luminosity phase of LHC (HL-LHC) represents a crucial challenge for many calorimeter technologies. In the CMS forward calorimeters, ionizing doses and hadron fluences will reach up to 300 kGy (at a dose rate of 30 Gy/h) and 2 × 1014 cm-2, respectively, at the pseudo-rapidity region of |η| = 2.6. To evaluate the evolution of the CMS ECAL performance in such conditions, a set of PbWO4 crystals, exposed to 24 GeV protons up to integrated fluences between 2.1 × 1013 cm-2 and 1:3 × 1014 cm2, has been studied in beam tests. A degradation of the energy resolution and a non-linear response to electron showers are observed in damaged crystals. Direct measurements of the light output from the crystals show the amplitude decreasing and pulse becoming faster as the fluence increases. The evolution of the PbWO4 crystals calorimetric performance has been well understood and parameterized in terms of increasing light absorption inside the crystal volume. A double-ended read-out configuration, in which two identical photodetectors are coupled to the opposite ends of each crystal, has also been tested. The separate and simultaneous read out of the light from the two ends of the crystal allows to correct for longitudinal shower fluctuations and to mitigate the degradation of energy resolution in highly damaged crystals. The non-linear response to electromagnetic showers, arising from high non-uniformity of light collection efficiency along the longitudinal axis of irradiated crystals, can also be corrected by means of the double-ended read-out technique.

Food groups and risk of type 2 diabetes mellitus: a systematic review and meta-analysis of prospective studies.

PubMed

Schwingshackl, Lukas; Hoffmann, Georg; Lampousi, Anna-Maria; Knüppel, Sven; Iqbal, Khalid; Schwedhelm, Carolina; Bechthold, Angela; Schlesinger, Sabrina; Boeing, Heiner

2017-05-01

The aim of this systematic review and meta-analysis was to synthesize the knowledge about the relation between intake of 12 major food groups and risk of type 2 diabetes (T2D). We conducted a systematic search in PubMed, Embase, Medline (Ovid), Cochrane Central, and Google Scholar for prospective studies investigating the association between whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy, fish, red meat, processed meat, and sugar-sweetened beverages (SSB) on risk of T2D. Summary relative risks were estimated using a random effects model by contrasting categories, and for linear and non-linear dose-response relationships. Six out of the 12 food-groups showed a significant relation with risk of T2D, three of them a decrease of risk with increasing consumption (whole grains, fruits, and dairy), and three an increase of risk with increasing consumption (red meat, processed meat, and SSB) in the linear dose-response meta-analysis. There was evidence of a non-linear relationship between fruits, vegetables, processed meat, whole grains, and SSB and T2D risk. Optimal consumption of risk-decreasing foods resulted in a 42% reduction, and consumption of risk-increasing foods was associated with a threefold T2D risk, compared to non-consumption. The meta-evidence was graded "low" for legumes and nuts; "moderate" for refined grains, vegetables, fruit, eggs, dairy, and fish; and "high" for processed meat, red meat, whole grains, and SSB. Among the investigated food groups, selecting specific optimal intakes can lead to a considerable change in risk of T2D.

Fruits, vegetables, and bladder cancer risk: a systematic review and meta-analysis.

PubMed

Vieira, Ana R; Vingeliene, Snieguole; Chan, Doris S M; Aune, Dagfinn; Abar, Leila; Navarro Rosenblatt, Deborah; Greenwood, Darren C; Norat, Teresa

2015-01-01

Smoking is estimated to cause about half of all bladder cancer cases. Case-control studies have provided evidence of an inverse association between fruit and vegetable intake and bladder cancer risk. As part of the World Cancer Research/American Institute for Cancer Research Continuous Update Project, we conducted a systematic review and meta-analysis of prospective studies to assess the dose-response relationship between fruit and vegetables and incidence and mortality of bladder cancer. We searched PubMed up to December 2013 for relevant prospective studies. We conducted highest compared with lowest meta-analyses and dose-response meta-analyses using random effects models to estimate summary relative risks (RRs) and 95% confidence intervals (CIs), and used restricted cubic splines to examine possible nonlinear associations. Fifteen prospective studies were included in the review. The summary RR for an increase of 1 serving/day (80 g) were 0.97 (95% CI: 0.95-0.99) I(2)  = 0%, eight studies for fruits and vegetables, 0.97 (95% CI: 0.94-1.00, I(2)  = 10%, 10 studies) for vegetables and 0.98 (95% CI: 0.96-1.00, I(2)  = 0%, 12 studies) for fruits. Results were similar in men and women and in current, former and nonsmokers. Amongst fruits and vegetables subgroups, for citrus fruits the summary RR for the highest compared with the lowest intake was 0.87 (95% CI: 0.76-0.99, I(2)  = 0%, eight studies) and for cruciferous vegetables there was evidence of a nonlinear relationship (P = 0.001). The current evidence from cohort studies is not consistent with a role for fruits and vegetables in preventing bladder cancer. © 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

[A dose-response analysis on the association of gestational weight gain rate and the normal term neonate birth weight].

PubMed

Mao, Yuanyuan; Hu, Wenbin; Liu, Qin; Liu, Li; Li, Yuanming; Shen, Yueping

2015-08-01

To examine the dose-response relationship between gestational weight gain rate and the neonate birth weight. A total of 18 868 women with singleton gestations who delivered between January 2006 and December 2013 were included in this study. Maternal and neonate details of these women were drawn from the Perinatal Monitoring System database. Gestational weight gain rate was defined as the total weight gain during the last and first prenatal care visits divided by the interval weeks. Both Multiple logistic regression analysis and restricted cubic spline methods were performed. Confounding factors included maternal age, education, pre-pregnancy body mass index (BMI), state of residence, parity, gestational weeks of prenatal care entry, and sex of the neonate. The adjusted odds ratio for macrosomia was associated with gestational weight gain rate in lower pre-pregnancy BMI (OR = 3.15, 95% CI: 1.40-7.07), normal (OR = 3.64, 95% CI: 2.84-4.66) or overweight (OR = 2.37, 95% CI: 1.71-3.27). The odds ratios of low birth weight appeared a decrease in those women with lower pre-pregnancy BMI (OR = 0.28, 95% CI: 0.13-0.61) while the normal weight (OR = 0.37, 95% CI: 0.22-0.64) group with gestational weight gain, the rate showed an increase. Association of gestational weight gain rate for macrosomia was found a S-curve in those term delivery women (non-linearity test P < 0.000 1). However, L-curve was observed for low birth weight and gestational weight gain rate in term births (non-linearity test P < 0.000 1). A S-curve was seen between gestational weight gain rate and term delivered macrosomia while L-curve was observed among term delivered low birth weight neonates.

Efficient techniques for forced response involving linear modal components interconnected by discrete nonlinear connection elements

NASA Astrophysics Data System (ADS)

Avitabile, Peter; O'Callahan, John

2009-01-01

Generally, response analysis of systems containing discrete nonlinear connection elements such as typical mounting connections require the physical finite element system matrices to be used in a direct integration algorithm to compute the nonlinear response analysis solution. Due to the large size of these physical matrices, forced nonlinear response analysis requires significant computational resources. Usually, the individual components of the system are analyzed and tested as separate components and their individual behavior may essentially be linear when compared to the total assembled system. However, the joining of these linear subsystems using highly nonlinear connection elements causes the entire system to become nonlinear. It would be advantageous if these linear modal subsystems could be utilized in the forced nonlinear response analysis since much effort has usually been expended in fine tuning and adjusting the analytical models to reflect the tested subsystem configuration. Several more efficient techniques have been developed to address this class of problem. Three of these techniques given as: equivalent reduced model technique (ERMT);modal modification response technique (MMRT); andcomponent element method (CEM); are presented in this paper and are compared to traditional methods.

Effect of initial strain and material nonlinearity on the nonlinear static and dynamic response of graphene sheets

NASA Astrophysics Data System (ADS)

Singh, Sandeep; Patel, B. P.

2018-06-01

Computationally efficient multiscale modelling based on Cauchy-Born rule in conjunction with finite element method is employed to study static and dynamic characteristics of graphene sheets, with/without considering initial strain, involving Green-Lagrange geometric and material nonlinearities. The strain energy density function at continuum level is established by coupling the deformation at continuum level to that at atomic level through Cauchy-Born rule. The atomic interactions between carbon atoms are modelled through Tersoff-Brenner potential. The governing equation of motion obtained using Hamilton's principle is solved through standard Newton-Raphson method for nonlinear static response and Newmark's time integration technique to obtain nonlinear transient response characteristics. Effect of initial strain on the linear free vibration frequencies, nonlinear static and dynamic response characteristics is investigated in detail. The present multiscale modelling based results are found to be in good agreement with those obtained through molecular mechanics simulation. Two different types of boundary constraints generally used in MM simulation are explored in detail and few interesting findings are brought out. The effect of initial strain is found to be greater in linear response when compared to that in nonlinear response.

Experimental study of isolas in nonlinear systems featuring modal interactions

PubMed Central

Noël, Jean-Philippe; Virgin, Lawrence N.; Kerschen, Gaëtan

2018-01-01

The objective of the present paper is to provide experimental evidence of isolated resonances in the frequency response of nonlinear mechanical systems. More specifically, this work explores the presence of isolas, which are periodic solutions detached from the main frequency response, in the case of a nonlinear set-up consisting of two masses sliding on a horizontal guide. A careful experimental investigation of isolas is carried out using responses to swept-sine and stepped-sine excitations. The experimental findings are validated with advanced numerical simulations combining nonlinear modal analysis and bifurcation monitoring. In particular, the interactions between two nonlinear normal modes are shown to be responsible for the creation of the isolas. PMID:29584758

Effects of Initial Geometric Imperfections On the Non-Linear Response of the Space Shuttle Superlightweight Liquid-Oxygen Tank

NASA Technical Reports Server (NTRS)

Nemeth, Michael P.; Young, Richard D.; Collins, Timothy J.; Starnes, James H., Jr.

2002-01-01

The results of an analytical study of the elastic buckling and nonlinear behavior of the liquid-oxygen tank for the new Space Shuttle superlightweight external fuel tank are presented. Selected results that illustrate three distinctly different types of non-linear response phenomena for thin-walled shells which are subjected to combined mechanical and thermal loads are presented. These response phenomena consist of a bifurcation-type buckling response, a short-wavelength non-linear bending response and a non-linear collapse or "snap-through" response associated with a limit point. The effects of initial geometric imperfections on the response characteristics are emphasized. The results illustrate that the buckling and non-linear response of a geometrically imperfect shell structure subjected to complex loading conditions may not be adequately characterized by an elastic linear bifurcation buckling analysis, and that the traditional industry practice of applying a buckling-load knock-down factor can result in an ultraconservative design. Results are also presented that show that a fluid-filled shell can be highly sensitive to initial geometric imperfections, and that the use a buckling-load knock-down factor is needed for this case.

Transcriptomic changes in wind-exposed poplar leaves are dependent on developmental stage.

PubMed

Fluch, Silvia; Olmo, Christian Carlo; Tauber, Stefanie; Stierschneider, Michael; Kopecky, Dieter; Reichenauer, Thomas G; Matusíková, Ildikó

2008-10-01

Responses of plant tissue to environmental challenges can vary among different plant parts and among plants of different ages. Investment into defense has been proposed to be influenced by fitness value and/or allocation of available resources. Here we show at first time at transcriptome level that plant defense is non-linear. On very young, expanding, adult and old leaves of Populus nigra plants exposed to air perturbation, we studied the ontogenic trajectory of gene expression changes to such a low-dose factor similar to wind. Although plant responses to mechanical sensation (wind, touch) are described and summarized as thigmomorphogenesis, the knowledge on the molecular background of plant responses to wind is largely incomplete. Our data describe which genes are activated during a ubiquitous and continuous environmental factor such as wind, and based on existing knowledge complement the picture on ongoing processes.

A therapy inactivating the tumor angiogenic factors.

PubMed

Morales-Rodrigo, Cristian

2013-02-01

This paper is devoted to a nonlinear system of partial differential equations modeling the effect of an anti-angiogenic therapy based on an agent that binds to the tumor angiogenic factors. The main feature of the model under consideration is a nonlinear flux production of tumor angiogenic factors at the boundary of the tumor. It is proved the global existence for the nonlinear system and the effect in the large time behavior of the system for high doses of the therapeutic agent.

Nonlinear frequency response based adaptive vibration controller design for a class of nonlinear systems

NASA Astrophysics Data System (ADS)

Thenozhi, Suresh; Tang, Yu

2018-01-01

Frequency response functions (FRF) are often used in the vibration controller design problems of mechanical systems. Unlike linear systems, the FRF derivation for nonlinear systems is not trivial due to their complex behaviors. To address this issue, the convergence property of nonlinear systems can be studied using convergence analysis. For a class of time-invariant nonlinear systems termed as convergent systems, the nonlinear FRF can be obtained. The present paper proposes a nonlinear FRF based adaptive vibration controller design for a mechanical system with cubic damping nonlinearity and a satellite system. Here the controller gains are tuned such that a desired closed-loop frequency response for a band of harmonic excitations is achieved. Unlike the system with cubic damping, the satellite system is not convergent, therefore an additional controller is utilized to achieve the convergence property. Finally, numerical examples are provided to illustrate the effectiveness of the proposed controller.

Frequency Response of Synthetic Vocal Fold Models with Linear and Nonlinear Material Properties

PubMed Central

Shaw, Stephanie M.; Thomson, Scott L.; Dromey, Christopher; Smith, Simeon

2014-01-01

Purpose The purpose of this study was to create synthetic vocal fold models with nonlinear stress-strain properties and to investigate the effect of linear versus nonlinear material properties on fundamental frequency during anterior-posterior stretching. Method Three materially linear and three materially nonlinear models were created and stretched up to 10 mm in 1 mm increments. Phonation onset pressure (Pon) and fundamental frequency (F0) at Pon were recorded for each length. Measurements were repeated as the models were relaxed in 1 mm increments back to their resting lengths, and tensile tests were conducted to determine the stress-strain responses of linear versus nonlinear models. Results Nonlinear models demonstrated a more substantial frequency response than did linear models and a more predictable pattern of F0 increase with respect to increasing length (although range was inconsistent across models). Pon generally increased with increasing vocal fold length for nonlinear models, whereas for linear models, Pon decreased with increasing length. Conclusions Nonlinear synthetic models appear to more accurately represent the human vocal folds than linear models, especially with respect to F0 response. PMID:22271874

Frequency response of synthetic vocal fold models with linear and nonlinear material properties.

PubMed

Shaw, Stephanie M; Thomson, Scott L; Dromey, Christopher; Smith, Simeon

2012-10-01

The purpose of this study was to create synthetic vocal fold models with nonlinear stress-strain properties and to investigate the effect of linear versus nonlinear material properties on fundamental frequency (F0) during anterior-posterior stretching. Three materially linear and 3 materially nonlinear models were created and stretched up to 10 mm in 1-mm increments. Phonation onset pressure (Pon) and F0 at Pon were recorded for each length. Measurements were repeated as the models were relaxed in 1-mm increments back to their resting lengths, and tensile tests were conducted to determine the stress-strain responses of linear versus nonlinear models. Nonlinear models demonstrated a more substantial frequency response than did linear models and a more predictable pattern of F0 increase with respect to increasing length (although range was inconsistent across models). Pon generally increased with increasing vocal fold length for nonlinear models, whereas for linear models, Pon decreased with increasing length. Nonlinear synthetic models appear to more accurately represent the human vocal folds than do linear models, especially with respect to F0 response.

Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression

NASA Technical Reports Server (NTRS)

Zeitzer, J. M.; Dijk, D. J.; Kronauer, R.; Brown, E.; Czeisler, C.

2000-01-01

Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

Mapping the central effects of (±)-ketamine and traxoprodil using pharmacological magnetic resonance imaging in awake rats.

PubMed

Tang, Haiying; Kukral, Daniel; Li, Yu-Wen; Fronheiser, Matthew; Malone, Harold; Pena, Adrienne; Pieschl, Rick; Sidik, Kurex; Tobon, Gabriel; Chow, Patrick L; Bristow, Linda J; Hayes, Wendy; Luo, Feng

2018-02-01

Major depressive disorder is a leading cause of disability globally. Improvements in the efficacy of antidepressant therapy are needed as a high proportion (>40%) of individuals with major depressive disorder fail to respond adequately to current treatments. The non-selective N-methyl-D-aspartate receptor channel blocker, (±)-ketamine, has been reported to produce a rapid and long-lasting antidepressant response in treatment-resistant major depressive disorder patients, which provides a unique opportunity for investigation of mechanisms that mediate its therapeutic effect. Efforts have also focused on the development of selective N-methyl-D-aspartate receptor subtype 2B antagonists which may retain antidepressant activity but have lower potential for dissociative/psychotomimetic effects. In the present study, we examined the central nervous system effects of acute, intravenous administration of (±)-ketamine or the N-methyl-D-aspartate receptor subtype 2B antagonist, traxoprodil, in awake rats using pharmacological magnetic resonance imaging. The study contained five treatment groups: vehicle, 3 mg/kg (±)-ketamine, and three doses of traxoprodil (0.3 mg/kg, 5 mg/kg, and 15 mg/kg). Non-linear model fitting was performed on the temporal hemodynamic pharmacological magnetic resonance imaging data to generate brain activation maps as well as regional responses based on blood oxygen level dependent signal changes for group analysis. Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [ 3 H]Ro 25-6981 binding. The middle dose of traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous).

Health-based ingestion exposure guidelines for Vibrio cholerae: Technical basis for water reuse applications.

PubMed

Watson, Annetta P; Armstrong, Anthony Q; White, George H; Thran, Brandolyn H

2018-02-01

U.S. military and allied contingency operations are increasingly occurring in locations with limited, unstable or compromised fresh water supplies. Non-potable graywater reuse is currently under assessment as a viable means to increase mission sustainability while significantly reducing the resources, logistics and attack vulnerabilities posed by transport of fresh water. Development of health-based (non-potable) exposure guidelines for the potential microbial components of graywater would provide a logical and consistent human-health basis for water reuse strategies. Such health-based strategies will support not only improved water security for contingency operations, but also sustainable military operations. Dose-response assessment of Vibrio cholerae based on adult human oral exposure data were coupled with operational water exposure scenario parameters common to numerous military activities, and then used to derive health risk-based water concentrations. The microbial risk assessment approach utilized oral human exposure V. cholerae dose studies in open literature. Selected studies focused on gastrointestinal illness associated with experimental infection by specific V. cholerae serogroups most often associated with epidemics and pandemics (O1 and O139). Nonlinear dose-response model analyses estimated V. cholerae effective doses (EDs) aligned with gastrointestinal illness severity categories characterized by diarrheal purge volume. The EDs and water exposure assumptions were used to derive Risk-Based Water Concentrations (CFU/100mL) for mission-critical illness severity levels over a range of water use activities common to military operations. Human dose-response studies, data and analyses indicate that ingestion exposures at the estimated ED 1 (50CFU) are unlikely to be associated with diarrheal illness while ingestion exposures at the lower limit (200CFU) of the estimated ED 10 are not expected to result in a level of diarrheal illness associated with degraded individual capability. The current analysis indicates that the estimated ED 20 (approximately 1000CFU) represents initiation of a more advanced stage of diarrheal illness associated with clinical care. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

A Modal Model to Simulate Typical Structural Dynamic Nonlinearity [PowerPoint

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mayes, Randall L.; Pacini, Benjamin Robert; Roettgen, Dan

2016-01-01

Some initial investigations have been published which simulate nonlinear response with almost traditional modal models: instead of connecting the modal mass to ground through the traditional spring and damper, a nonlinear Iwan element was added. This assumes that the mode shapes do not change with amplitude and there are no interactions between modal degrees of freedom. This work expands on these previous studies. An impact experiment is performed on a structure which exhibits typical structural dynamic nonlinear response, i.e. weak frequency dependence and strong damping dependence on the amplitude of vibration. Use of low level modal test results in combinationmore » with high level impacts are processed using various combinations of modal filtering, the Hilbert Transform and band-pass filtering to develop response data that are then fit with various nonlinear elements to create a nonlinear pseudo-modal model. Simulations of forced response are compared with high level experimental data for various nonlinear element assumptions.« less

A Modal Model to Simulate Typical Structural Dynamic Nonlinearity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pacini, Benjamin Robert; Mayes, Randall L.; Roettgen, Daniel R

2015-10-01

Some initial investigations have been published which simulate nonlinear response with almost traditional modal models: instead of connecting the modal mass to ground through the traditional spring and damper, a nonlinear Iwan element was added. This assumes that the mode shapes do not change with amplitude and there are no interactions between modal degrees of freedom. This work expands on these previous studies. An impact experiment is performed on a structure which exhibits typical structural dynamic nonlinear response, i.e. weak frequency dependence and strong damping dependence on the amplitude of vibration. Use of low level modal test results in combinationmore » with high level impacts are processed using various combinations of modal filtering, the Hilbert Transform and band-pass filtering to develop response data that are then fit with various nonlinear elements to create a nonlinear pseudo-modal model. Simulations of forced response are compared with high level experimental data for various nonlinear element assumptions.« less

Buckling Behavior of Compression-Loaded Composite Cylindrical Shells with Reinforced Cutouts

NASA Technical Reports Server (NTRS)

Hilburger, Mark W.; Starnes, James H., Jr.

2002-01-01

Results from a numerical study of the response of thin-wall compression-loaded quasi-isotropic laminated composite cylindrical shells with reinforced and unreinforced square cutouts are presented. The effects of cutout reinforcement orthotropy, size, and thickness on the nonlinear response of the shells are described. A high-fidelity nonlinear analysis procedure has been used to predict the nonlinear response of the shells. The analysis procedure includes a nonlinear static analysis that predicts stable response characteristics of the shells and a nonlinear transient analysis that predicts unstable dynamic buckling response characteristics. The results illustrate how a compression-loaded shell with an unreinforced cutout can exhibit a complex nonlinear response. In particular, a local buckling response occurs in the shell near the cutout and is caused by a complex nonlinear coupling between local shell-wall deformations and in-plane destabilizing compression stresses near the cutout. In general, the addition of reinforcement around a cutout in a compression-loaded shell can retard or eliminate the local buckling response near the cutout and increase the buckling load of the shell, as expected. However, results are presented that show how certain reinforcement configurations can actually cause an unexpected increase in the magnitude of local deformations and stresses in the shell and cause a reduction in the buckling load. Specific cases are presented that suggest that the orthotropy, thickness, and size of a cutout reinforcement in a shell can be tailored to achieve improved response characteristics.

Experimental and theoretical studies of spectral alteration in ultrasonic waves resulting from nonlinear elastic response in rock

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, P.A.; McCall, K.R.; Meegan, G.D. Jr.

1993-11-01

Experiments in rock show a large nonlinear elastic wave response, far greater than that of gases, liquids and most other solids. The large response is attributed to structural defects in rock including microcracks and grain boundaries. In the earth, a large nonlinear response may be responsible for significant spectral alteration at amplitudes and distances currently considered to be well within the linear elastic regime.

Superradiance Effects in the Linear and Nonlinear Optical Response of Quantum Dot Molecules

NASA Astrophysics Data System (ADS)

Sitek, A.; Machnikowski, P.

2008-11-01

We calculate the linear optical response from a single quantum dot molecule and the nonlinear, four-wave-mixing response from an inhomogeneously broadened ensemble of such molecules. We show that both optical signals are affected by the coupling-dependent superradiance effect and by optical interference between the two polarizations. As a result, the linear and nonlinear responses are not identical.

Mathematical models of cytotoxic effects in endpoint tumor cell line assays: critical assessment of the application of a single parametric value as a standard criterion to quantify the dose-response effects and new unexplored proposal formats.

PubMed

Calhelha, Ricardo C; Martínez, Mireia A; Prieto, M A; Ferreira, Isabel C F R

2017-10-23

The development of convenient tools for describing and quantifying the effects of standard and novel therapeutic agents is essential for the research community, to perform more precise evaluations. Although mathematical models and quantification criteria have been exchanged in the last decade between different fields of study, there are relevant methodologies that lack proper mathematical descriptions and standard criteria to quantify their responses. Therefore, part of the relevant information that can be drawn from the experimental results obtained and the quantification of its statistical reliability are lost. Despite its relevance, there is not a standard form for the in vitro endpoint tumor cell lines' assays (TCLA) that enables the evaluation of the cytotoxic dose-response effects of anti-tumor drugs. The analysis of all the specific problems associated with the diverse nature of the available TCLA used is unfeasible. However, since most TCLA share the main objectives and similar operative requirements, we have chosen the sulforhodamine B (SRB) colorimetric assay for cytotoxicity screening of tumor cell lines as an experimental case study. In this work, the common biological and practical non-linear dose-response mathematical models are tested against experimental data and, following several statistical analyses, the model based on the Weibull distribution was confirmed as the convenient approximation to test the cytotoxic effectiveness of anti-tumor compounds. Then, the advantages and disadvantages of all the different parametric criteria derived from the model, which enable the quantification of the dose-response drug-effects, are extensively discussed. Therefore, model and standard criteria for easily performing the comparisons between different compounds are established. The advantages include a simple application, provision of parametric estimations that characterize the response as standard criteria, economization of experimental effort and enabling rigorous comparisons among the effects of different compounds and experimental approaches. In all experimental data fitted, the calculated parameters were always statistically significant, the equations proved to be consistent and the correlation coefficient of determination was, in most of the cases, higher than 0.98.

A Randomized Trial of Vitamin D3 Supplementation in Children: Dose-Response Effects on Vitamin D Metabolites and Calcium Absorption

PubMed Central

Laing, E. M.; Hill Gallant, K. M.; Hall, D. B.; McCabe, G. P.; Hausman, D. B.; Martin, B. R.; Warden, S. J.; Peacock, M.; Weaver, C. M.

2013-01-01

Context: Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D3 in healthy children are unknown. Objective: Our objective was to examine the dose-response effects of supplemental vitamin D3 on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes. Design: Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D3 (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope 44Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption. Results: The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from −10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)2D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D. Conclusion: Large increases in serum 25(OH)D with vitamin D3 supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children. PMID:24092833

A randomized trial of vitamin D₃ supplementation in children: dose-response effects on vitamin D metabolites and calcium absorption.

PubMed

Lewis, R D; Laing, E M; Hill Gallant, K M; Hall, D B; McCabe, G P; Hausman, D B; Martin, B R; Warden, S J; Peacock, M; Weaver, C M

2013-12-01

Changes in serum vitamin D metabolites and calcium absorption with varying doses of oral vitamin D₃ in healthy children are unknown. Our objective was to examine the dose-response effects of supplemental vitamin D₃ on serum vitamin D metabolites and calcium absorption in children living at two U.S. latitudes. Black and white children (n = 323) participated in a multisite (U.S. latitudes 34° N and 40° N), triple-masked trial. Children were randomized to receive oral vitamin D₃ (0, 400, 1000, 2000, and 4000 IU/d) and were sampled over 12 weeks in winter. Serum 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)₂D) were measured using RIA and intact PTH (iPTH) by immunoradiometric assay. Fractional calcium absorption was determined from an oral stable isotope ⁴⁴Ca (5 mg) in a 150-mg calcium meal. Nonlinear and linear regression models were fit for vitamin D metabolites, iPTH, and calcium absorption. The mean baseline 25(OH)D value for the entire sample was 70.0 nmol/L. Increases in 25(OH)D depended on dose with 12-week changes ranging from -10 nmol/L for placebo to 76 nmol/L for 4000 IU. Larger 25(OH)D gains were observed for whites vs blacks at the highest dose (P < .01). Gains for 1,25(OH)₂D were not significant (P = .07), and decreases in iPTH were not dose-dependent. There was no dose effect of vitamin D on fractional calcium absorption when adjusted for pill compliance, race, sex, or baseline 25(OH)D. Large increases in serum 25(OH)D with vitamin D₃ supplementation did not increase calcium absorption in healthy children living at 2 different latitudes. Supplementation with 400 IU/d was sufficient to maintain wintertime 25(OH)D concentrations in healthy black, but not white, children.

Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model.

PubMed

Larsen, Malte Selch; Keizer, Ron; Munro, Gordon; Mørk, Arne; Holm, René; Savic, Rada; Kreilgaard, Mads

2016-05-01

Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m  = 44.1 mg/kg, V max  = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma  = 16.7 μg/mL, EC 50, brain  = 3.3 μg/mL). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

Nonlinear response of unidirectional boron/aluminum

NASA Technical Reports Server (NTRS)

Pindera, M.-J.; Herakovich, C. T.; Becker, W.; Aboudi, J.

1990-01-01

Experimental results obtained for unidirectional boron/aluminum subjected to combined loading using off-axis tension, compression and Iosipescu shear specimens are correlated with a nonlinear micromechanics model. It is illustrated that the nonlinear response in the principal material directions is markedly influenced by the different loading modes and different ratios of the applied stress components. The observed nonlinear response under pure and combined loading is discussed in terms of initial yielding, subsequent hardening, stress-interaction effects and unloading-reloading characteristics. The micromechanics model is based on the concept of a repeating unit cell representative of the composite-at-large and employs the unified theory of Bodner and Partom to model the inelastic response of the matrix. It is shown that the employed micromechanics model is sufficiently general to predict the observed nonlinear response of unidirectional boron/aluminum with good accuracy.

Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

PubMed Central

Lu, Yanhui; Bliven-Sizemore, Erin; Weiner, Marc; Nuermberger, Eric; Burman, William; Dorman, Susan E.; Dooley, Kelly E.

2014-01-01

Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h−1, respectively, after a single dose to 2.2 and 5.0 liters · h−1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) PMID:24614383

Nonlinear Response of the Stratosphere and the North Atlantic-European Climate to Global Warming

NASA Astrophysics Data System (ADS)

Manzini, E.; Karpechko, A. Yu.; Kornblueh, L.

2018-05-01

The response of the northern winter atmospheric circulation for two consecutive global warming periods of 2 K is examined in a grand ensemble (68 members) of idealized CO2 increase experiments performed with the same climate model. The comparison of the atmospheric responses for the two periods shows remarkable differences, indicating the nonlinearity of the response. The nonlinear signature of the atmospheric and surface responses is reminiscent of the positive phase of the annular mode of variability. The stratospheric vortex response shifts from an easterly wind change for the first 2 K to a westerly wind change for the second 2 K. The North Atlantic storm track shifts poleward only in the second period. A weaker November Arctic amplification during the second period suggests that differences in Arctic sea ice changes can act to trigger the atmospheric nonlinear response. Stratosphere-troposphere coupling thereafter can provide for the persistence of this nonlinearity throughout the winter.

A physiologically based pharmacokinetic model for ethylene oxide in mouse, rat, and human.

PubMed

Fennell, T R; Brown, C D

2001-06-15

Ethylene oxide (EO) is widely used as a gaseous sterilant and industrial intermediate and is a direct-acting mutagen and carcinogen. The objective of these studies was to develop physiologically based pharmacokinetic (PB-PK) models for EO to describe the exposure-tissue dose relationship in rodents and humans. We previously reported results describing in vitro and in vivo kinetics of EO metabolism in male and female F344 rats and B6C3F1 mice. These studies were extended by determining the kinetics of EO metabolism in human liver cytosol and microsomes. The results indicate enzymatically catalyzed GSH conjugation via cytosolic glutathione S-transferase (cGST) and hydrolysis via microsomal epoxide hydrolase (mEH) occur in both rodents and humans. The in vitro kinetic constants were scaled to account for cytosolic (cGST) and microsomal (mEH) protein content and incorporated into PB-PK descriptions for mouse, rat, and human. Flow-limited models adequately predicted blood and tissue EO levels, disposition, and elimination kinetics determined experimentally in rats and mice, with the exception of testis concentrations, which were overestimated. Incorporation of a diffusion-limited description for testis improved the ability of the model to describe testis concentrations. The model accounted for nonlinear increases in blood and tissue concentrations that occur in mice on exposure to EO concentrations greater than 200 ppm. Species differences are predicted in the metabolism and exposure-dose relationship, with a nonlinear relationship observed in the mouse as a result of GSH depletion. These models represent an essential step in developing a mechanistically based EO exposure-dose-response description for estimating human risk from exposure to EO. Copyright 2001 Academic Press.

The Effect of Basis Selection on Static and Random Acoustic Response Prediction Using a Nonlinear Modal Simulation

NASA Technical Reports Server (NTRS)

Rizzi, Stephen A.; Przekop, Adam

2005-01-01

An investigation of the effect of basis selection on geometric nonlinear response prediction using a reduced-order nonlinear modal simulation is presented. The accuracy is dictated by the selection of the basis used to determine the nonlinear modal stiffness. This study considers a suite of available bases including bending modes only, bending and membrane modes, coupled bending and companion modes, and uncoupled bending and companion modes. The nonlinear modal simulation presented is broadly applicable and is demonstrated for nonlinear quasi-static and random acoustic response of flat beam and plate structures with isotropic material properties. Reduced-order analysis predictions are compared with those made using a numerical simulation in physical degrees-of-freedom to quantify the error associated with the selected modal bases. Bending and membrane responses are separately presented to help differentiate the bases.

Off-resonant third-order optical nonlinearities of squarylium and croconium dyes

NASA Astrophysics Data System (ADS)

Li, Zhongyu; Xu, Song; Niu, Lihong; Zhang, Zhi; Chen, Zihui; Zhang, Fushi

2008-01-01

The magnitude and dynamic response of the third-order optical nonlinearities of squarylium and croconium dyes in methanol solution were measured by femtosecond degenerate four-wave mixing (DFWM) technique at 800 nm. Ultrafast nonlinear optical responses have been observed, and the magnitude of the second-order hyperpolarizabilities was evaluated to be 5.80 × 10 -31 esu for the squarylium dye and 8.69 × 10 -31 esu for the croconium dye, respectively. The large optical nonlinearities of the dyes can be attributed to their rigid and intramolecular charge transfer structure, and the instantaneous NLO responses of dyes are shorter than the experimental time resolution (50 fs), which is mainly contributed from the electron delocalization. The fast nonlinear response and large third-order optical nonlinearities show that the studied squarylium and croconium dyes might a kind of promising materials for the applications in all-optical switching and modulator.

The incidence of leukemia, lymphoma, and multiple myeloma among atomic bomb survivors: 1950 – 2001

PubMed Central

Hsu, Wan-Ling; Preston, Dale L.; Soda, Midori; Sugiyama, Hiromi; Funamoto, Sachiyo; Kodama, Kazunori; Kimura, Akiro; Kamada, Nanao; Dohy, Hiroo; Tomonaga, Masao; Iwanaga, Masako; Miyazaki, Yasushi; Cullings, Harry M.; Suyama, Akihiko; Ozasa, Kotaro; Shore, Roy E.; Mabuchi, Kiyohiko

2013-01-01

A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This paper presents analyses of radiation effects on leukemia, lymphoma, and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry-based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma, and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose response relationship and, to the extent the data allowed, to investigate variation in the excess risks with sex, attained age, exposure age, and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a non-linear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this non-linearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence that the radiation-associated excess leukemia risks, especially for acute myeloid leukemia, had persisted throughout the follow-up period out to – 55 years after the bombings. As in earlier analyses, there was a weak suggestion of a radiation dose response for non-Hodgkin lymphoma among men with no indication of such an effect among women. There was no evidence of radiation-associated excess risks for either Hodgkin lymphoma or multiple myeloma. PMID:23398354

Nonlinear Response of Thin Cylindrical Shells with Longitudinal Cracks and Subjected to Internal Pressure and Axial compression Loads

NASA Technical Reports Server (NTRS)

Starnes, James H.; Rose, Cheryl A.

1998-01-01

The results of an analytical study of the nonlinear response of a thin unstiffened aluminum cylindrical shell with a longitudinal crack are presented. The shell is analyzed with a nonlinear shell analysis code that maintains the shell in a nonlinear equilibrium state while the crack is grown. The analysis accurately accounts for global and local structural response phenomena. Results are presented for internal pressure, axial compression, and combined internal pressure and axial compression loads. The effects of varying crack length on the nonlinear response of the shell subjected to internal pressure are described. The effects of varying crack length on the prebuckling, buckling and postbuckling responses of the shell subjected to axial compression, and subjected to combined internal pressure and axial compression are also described. The results indicate that the nonlinear interaction between the in-plane stress resultants and the out-of-plane displacements near a crack can significantly affect the structural response of the shell. The results also indicate that crack growth instabilities and shell buckling instabilities can both affect the response of the shell as the crack length is increased.

On the nonlinear forced response of the North Atlantic atmosphere to meridional shifts of the Gulf Stream path

NASA Astrophysics Data System (ADS)

Seo, H.; Kwon, Y. O.; Joyce, T. M.; Ummenhofer, C.

2016-12-01

This study examines the North Atlantic atmospheric circulation response to the meridional shift of Gulf Stream path using a large-ensemble, high-resolution, and hemispheric-scale WRF simulations. The model is forced with wintertime SST anomalies derived from a wide range of Gulf Stream shift scenarios. The key result of the model experiments, supported in part by an independent analysis of a reanalysis data set, is that the large-scale, quasi-steady North Atlantic circulation response is unambiguously nonlinear about the sign and amplitude of chosen SST anomalies. This nonlinear response prevails over the weak linear response and resembles the negative North Atlantic Oscillation, the leading intrinsic mode of variability in the model and the observations. Further analysis of the associated dynamics reveals that the nonlinear responses are accompanied by the anomalous southward shift of the North Atlantic eddy-driven jet stream, which is reinforced nearly equally by the high-frequency transient eddy feedback and the low-frequency high-latitude wave breaking events. The result highlights the importance of the intrinsically nonlinear transient eddy dynamics and eddy-mean flow interactions in generating the nonlinear forced response to the meridional shift in the Gulf Stream.

Techniques for forced response involving discrete nonlinearities. I - Theory. II - Applications

NASA Astrophysics Data System (ADS)

Avitabile, Peter; Callahan, John O.

Several new techniques developed for the forced response analysis of systems containing discrete nonlinear connection elements are presented and compared to the traditional methods. In particular, the techniques examined are the Equivalent Reduced Model Technique (ERMT), Modal Modification Response Technique (MMRT), and Component Element Method (CEM). The general theory of the techniques is presented, and applications are discussed with particular reference to the beam nonlinear system model using ERMT, MMRT, and CEM; frame nonlinear response using the three techniques; and comparison of the results obtained by using the ERMT, MMRT, and CEM models.

Computational systems biology and dose-response modeling in relation to new directions in toxicity testing.

PubMed

Zhang, Qiang; Bhattacharya, Sudin; Andersen, Melvin E; Conolly, Rory B

2010-02-01

The new paradigm envisioned for toxicity testing in the 21st century advocates shifting from the current animal-based testing process to a combination of in vitro cell-based studies, high-throughput techniques, and in silico modeling. A strategic component of the vision is the adoption of the systems biology approach to acquire, analyze, and interpret toxicity pathway data. As key toxicity pathways are identified and their wiring details elucidated using traditional and high-throughput techniques, there is a pressing need to understand their qualitative and quantitative behaviors in response to perturbation by both physiological signals and exogenous stressors. The complexity of these molecular networks makes the task of understanding cellular responses merely by human intuition challenging, if not impossible. This process can be aided by mathematical modeling and computer simulation of the networks and their dynamic behaviors. A number of theoretical frameworks were developed in the last century for understanding dynamical systems in science and engineering disciplines. These frameworks, which include metabolic control analysis, biochemical systems theory, nonlinear dynamics, and control theory, can greatly facilitate the process of organizing, analyzing, and understanding toxicity pathways. Such analysis will require a comprehensive examination of the dynamic properties of "network motifs"--the basic building blocks of molecular circuits. Network motifs like feedback and feedforward loops appear repeatedly in various molecular circuits across cell types and enable vital cellular functions like homeostasis, all-or-none response, memory, and biological rhythm. These functional motifs and associated qualitative and quantitative properties are the predominant source of nonlinearities observed in cellular dose response data. Complex response behaviors can arise from toxicity pathways built upon combinations of network motifs. While the field of computational cell biology has advanced rapidly with increasing availability of new data and powerful simulation techniques, a quantitative orientation is still lacking in life sciences education to make efficient use of these new tools to implement the new toxicity testing paradigm. A revamped undergraduate curriculum in the biological sciences including compulsory courses in mathematics and analysis of dynamical systems is required to address this gap. In parallel, dissemination of computational systems biology techniques and other analytical tools among practicing toxicologists and risk assessment professionals will help accelerate implementation of the new toxicity testing vision.

Geometrically Nonlinear Static Analysis of 3D Trusses Using the Arc-Length Method

NASA Technical Reports Server (NTRS)

Hrinda, Glenn A.

2006-01-01

Rigorous analysis of geometrically nonlinear structures demands creating mathematical models that accurately include loading and support conditions and, more importantly, model the stiffness and response of the structure. Nonlinear geometric structures often contain critical points with snap-through behavior during the response to large loads. Studying the post buckling behavior during a portion of a structure's unstable load history may be necessary. Primary structures made from ductile materials will stretch enough prior to failure for loads to redistribute producing sudden and often catastrophic collapses that are difficult to predict. The responses and redistribution of the internal loads during collapses and possible sharp snap-back of structures have frequently caused numerical difficulties in analysis procedures. The presence of critical stability points and unstable equilibrium paths are major difficulties that numerical solutions must pass to fully capture the nonlinear response. Some hurdles still exist in finding nonlinear responses of structures under large geometric changes. Predicting snap-through and snap-back of certain structures has been difficult and time consuming. Also difficult is finding how much load a structure may still carry safely. Highly geometrically nonlinear responses of structures exhibiting complex snap-back behavior are presented and analyzed with a finite element approach. The arc-length method will be reviewed and shown to predict the proper response and follow the nonlinear equilibrium path through limit points.

Response of biological uv dosimeters to the simulated extraterrestrial uv radiation

NASA Astrophysics Data System (ADS)

Bérces, A.; Rontó, G.; Kerékgyártó, T.; Kovács, G.; Lammer, H.

In the Laboratory polycrystalline uracil thin layer and bacteriophage T7 detectors have been developed for UV dosimetry on the EarthSs surface. Exponential response of the uracil polycrystal has been detected both by absorption spectroscopy and measurements of the refractive index under the influence of terrestrial solar radiation or using UV-C sources. In UV biological dosimetry the UV dose scale is additive starting at a value of zero according to the definition of CIE (Technical Report TC-6-18). The biological dose can be defined by a measured end-effect. In our dosimeters (phage T7 and uracil dosimeter) exposed to natural (terrestrial) UV radiation the proportion of pyrimidin photoproducts among the total photoproducts is smaller than 0.1 and the linear correlation between the biological and physical dose is higher than 0.9. According to the experimental data this linear relationship is often not valid. We observed that UV radiation did not only induce dimerisation but shorter wavelengths caused monomerisation of pyrimidin dimers. Performing the irradiation in oxygen free environment and using a Deuterium lamp as UV source, we could increase monomerisation against dimerisation thus the DNA-based dosimetrySs additivity rule is not fulfilled in these conditions. In this study we will demonstrate those non-linear experiments which constitute the basis of our biological experiments on the International Space Station.

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

PubMed

Brown, Kathryn; Comisar, Craig; Witjes, Han; Maringwa, John; de Greef, Rik; Vishwanathan, Karthick; Cantarini, Mireille; Cox, Eugène

2017-06-01

To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed. © 2016 The British Pharmacological Society.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

PubMed

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van't Klooster, Gerben

2015-08-01

Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

Volterra Series Approach for Nonlinear Aeroelastic Response of 2-D Lifting Surfaces

NASA Technical Reports Server (NTRS)

Silva, Walter A.; Marzocca, Piergiovanni; Librescu, Liviu

2001-01-01

The problem of the determination of the subcritical aeroelastic response and flutter instability of nonlinear two-dimensional lifting surfaces in an incompressible flow-field via Volterra series approach is addressed. The related aeroelastic governing equations are based upon the inclusion of structural nonlinearities, of the linear unsteady aerodynamics and consideration of an arbitrary time-dependent external pressure pulse. Unsteady aeroelastic nonlinear kernels are determined, and based on these, frequency and time histories of the subcritical aeroelastic response are obtained, and in this context the influence of geometric nonlinearities is emphasized. Conclusions and results displaying the implications of the considered effects are supplied.

Association of coffee consumption with risk of colorectal cancer: a meta-analysis of prospective cohort studies.

PubMed

Gan, Yong; Wu, Jiang; Zhang, Shengchao; Li, Liqing; Cao, Shiyi; Mkandawire, Naomie; Ji, Kun; Herath, Chulani; Gao, Chao; Xu, Hong; Zhou, Yanfeng; Song, Xingyue; Chen, Shanquan; Chen, Yawen; Yang, Tingting; Li, Jing; Qiao, Yan; Hu, Sai; Yin, Xiaoxv; Lu, Zuxun

2017-03-21

A meta-analysis was performed to assess the association of coffee consumption with colorectal cancer and to investigate the shape of the association. Relevant prospective cohort studies were identified by a comprehensive search of the PubMed, Embase and Web of Science databases from their inception through August 2015. Either a random-effects model or fixed-effects model was used to compute the pooled risk estimates when appropriate. Linear and nonlinear dose-response meta-analyses were also performed. Nineteen prospective cohort studies involving 2,046,575 participants and 22,629 patients with colorectal cancer were included. The risk of colon cancer was decreased by 7% for every 4 cups per day of coffee (RR=0.93, 95%CI, 0.88-0.99; P=0.199). There was a threshold approximately five cups of coffee per day, and the inverse association for colorectal cancer appeared to be stronger at a higher range of intake. However, a nonlinear association of rectal cancer with coffee consumption was not observed (P for nonlinearity = 0.214). In conclusion, coffee consumption is significantly associated with a decreased risk of colorectal cancer at ≥ 5 cups per day of coffee consumption. The findings support the recommendations of including coffee as a healthy beverage for the prevention of colorectal cancer.

Association of coffee consumption with risk of colorectal cancer: a meta-analysis of prospective cohort studies

PubMed Central

Zhang, Shengchao; Li, Liqing; Cao, Shiyi; Mkandawire, Naomie; Ji, Kun; Herath, Chulani; Gao, Chao; Xu, Hong; Zhou, Yanfeng; Song, Xingyue; Chen, Shanquan; Chen, Yawen; Yang, Tingting; Li, Jing; Qiao, Yan; Hu, Sai; Yin, Xiaoxv; Lu, Zuxun

2017-01-01

A meta-analysis was performed to assess the association of coffee consumption with colorectal cancer and to investigate the shape of the association. Relevant prospective cohort studies were identified by a comprehensive search of the PubMed, Embase and Web of Science databases from their inception through August 2015. Either a random-effects model or fixed-effects model was used to compute the pooled risk estimates when appropriate. Linear and nonlinear dose-response meta-analyses were also performed. Nineteen prospective cohort studies involving 2,046,575 participants and 22,629 patients with colorectal cancer were included. The risk of colon cancer was decreased by 7% for every 4 cups per day of coffee (RR=0.93, 95%CI, 0.88-0.99; P=0.199). There was a threshold approximately five cups of coffee per day, and the inverse association for colorectal cancer appeared to be stronger at a higher range of intake. However, a nonlinear association of rectal cancer with coffee consumption was not observed (P for nonlinearity = 0.214). In conclusion, coffee consumption is significantly associated with a decreased risk of colorectal cancer at ≥ 5 cups per day of coffee consumption. The findings support the recommendations of including coffee as a healthy beverage for the prevention of colorectal cancer. PMID:27078843

Linearity and nonlinearity of basin response as a function of scale: Discussion of alternative definitions

NASA Astrophysics Data System (ADS)

Sivapalan, M.; Jothityangkoon, C.; Menabde, M.

2002-02-01

Two uses of the terms ``linearity'' and ``nonlinearity'' appear in recent literature. The first definition of nonlinearity is with respect to the dynamical property such as the rainfall-runoff response of a catchment, and nonlinearity in this sense refers to a nonlinear dependence of the storm response on the magnitude of the rainfall inputs [Minshall, 1960; Wang et al., 1981]. The second definition of nonlinearity [Huang and Willgoose, 1993; Goodrich et al., 1997] is with respect to the dependence of a catchment statistical property, such as the mean annual flood, on the area of the catchment. They are both linked to important and interconnected hydrologic concepts, and furthermore, the change of nonlinearity with area (scale) has been an important motivation for hydrologic research. While both definitions are correct mathematically, they refer to hydrologically different concepts. In this paper we show that nonlinearity in the dynamical sense and that in the statistical sense can exist independently of each other (i.e., can be unrelated). If not carefully distinguished, the existence of these two definitions can lead to a catchment's response being described as being both linear and nonlinear at the same time. We therefore recommend separating these definitions by reserving the term ``nonlinearity'' for the classical, dynamical definition with respect to rainfall inputs, while adopting the term ``scaling relationship'' for the dependence of a catchment hydrological property on catchment area.

Relationships between nonlinear normal modes and response to random inputs

NASA Astrophysics Data System (ADS)

Schoneman, Joseph D.; Allen, Matthew S.; Kuether, Robert J.

2017-02-01

The ability to model nonlinear structures subject to random excitation is of key importance in designing hypersonic aircraft and other advanced aerospace vehicles. When a structure is linear, superposition can be used to construct its response to a known spectrum in terms of its linear modes. Superposition does not hold for a nonlinear system, but several works have shown that a system's dynamics can still be understood qualitatively in terms of its nonlinear normal modes (NNMs). This work investigates the connection between a structure's undamped nonlinear normal modes and the spectrum of its response to high amplitude random forcing. Two examples are investigated: a spring-mass system and a clamped-clamped beam modeled within a geometrically nonlinear finite element package. In both cases, an intimate connection is observed between the smeared peaks in the response spectrum and the frequency-energy dependence of the nonlinear normal modes. In order to understand the role of coupling between the underlying linear modes, reduced order models with and without modal coupling terms are used to separate the effect of each NNM's backbone from the nonlinear couplings that give rise to internal resonances. In the cases shown here, uncoupled, single-degree-of-freedom nonlinear models are found to predict major features in the response with reasonable accuracy; a highly inexpensive approximation such as this could be useful in design and optimization studies. More importantly, the results show that a reduced order model can be expected to give accurate results only if it is also capable of accurately predicting the frequency-energy dependence of the nonlinear modes that are excited.

Analysis for delamination initiation in postbuckled dropped-ply laminates

NASA Technical Reports Server (NTRS)

Davila, Carlos G.; Johnson, Eric R.

1992-01-01

The compression strength of dropped-ply, graphite-epoxy laminated plates for the delamination mode of failure is studied by analysis and corroborated with experiments. The nonlinear response of the test specimens is modeled by a geometrically nonlinear finite element analysis. The methodology for predicting delamination is based on a quadratic interlaminar stress criterion evaluated at a characteristic distance from the ply drop-off. The compression strength of specimens exhibiting a linear response is greater than the compression strength of specimens with the same layup exhibiting a geometrically nonlinear response. The analyses for both linear and nonlinear response show that severe interlaminar stress gradients occur in the interfaces at the drop-off because of the thickness/stiffness discontinuity. However, these interlaminar stress distributions are altered in the geometrically nonlinear response such that, with increasing load, their growth at the center of the laminate is retarded while their growth near the unloaded supported edge is increased.

Response phase mapping of nonlinear joint dynamics using continuous scanning LDV measurement method

NASA Astrophysics Data System (ADS)

Di Maio, D.; Bozzo, A.; Peyret, Nicolas

2016-06-01

This study aims to present a novel work aimed at locating discrete nonlinearities in mechanical assemblies. The long term objective is to develop a new metric for detecting and locating nonlinearities using Scanning LDV systems (SLDV). This new metric will help to improve the modal updating, or validation, of mechanical assemblies presenting discrete and sparse nonlinearities. It is well established that SLDV systems can scan vibrating structures with high density of measurement points and produc e highly defined Operational Deflection Shapes (ODSs). This paper will present some insights on how to use response phase mapping for locating nonlinearities of a bolted flange. This type of structure presents two types of nonlinearities, which are geometr ical and frictional joints. The interest is focussed on the frictional joints and, therefore, the ability to locate which joint s are responsible for nonlinearity is seen highly valuable for the model validation activities.

Application of Adaptive DP-optimality to Design a Pilot Study for a Clotting Time Test for Enoxaparin.

PubMed

Gulati, Abhishek; Faed, James M; Isbister, Geoffrey K; Duffull, Stephen B

2015-10-01

Dosing of enoxaparin, like other anticoagulants, may result in bleeding following excessive doses and clot formation if the dose is too low. We recently showed that a factor Xa based clotting time test could potentially assess the effect of enoxaparin on the clotting system. However, the test did not perform well in subsequent individuals and effectiveness of an exogenous phospholipid, Actin FS, in reducing the variability in the clotting time was assessed. The aim of this work was to conduct an adaptive pilot study to determine the range of concentrations of Xa and Actin FS to take forward into a proof-of-concept study. A nonlinear parametric function was developed to describe the response surface over the factors of interest. An adaptive method was used to estimate the parameters using a D-optimal design criterion. In order to provide a reasonable probability of observing a success of the clotting time test, a P-optimal design criterion was incorporated using a loss function to describe the hybrid DP-optimality. The use of adaptive DP-optimality method resulted in an efficient estimation of model parameters using data from only 6 healthy volunteers. The use of response surface modelling identified a range of sets of Xa and Actin FS concentrations, any of which could be used for the proof-of-concept study. This study shows that parsimonious adaptive DP-optimal designs may provide both precise parameter estimates for response surface modelling as well as clinical confidence in the potential benefits of the study.

Equivalent reduced model technique development for nonlinear system dynamic response

NASA Astrophysics Data System (ADS)

Thibault, Louis; Avitabile, Peter; Foley, Jason; Wolfson, Janet

2013-04-01

The dynamic response of structural systems commonly involves nonlinear effects. Often times, structural systems are made up of several components, whose individual behavior is essentially linear compared to the total assembled system. However, the assembly of linear components using highly nonlinear connection elements or contact regions causes the entire system to become nonlinear. Conventional transient nonlinear integration of the equations of motion can be extremely computationally intensive, especially when the finite element models describing the components are very large and detailed. In this work, the equivalent reduced model technique (ERMT) is developed to address complicated nonlinear contact problems. ERMT utilizes a highly accurate model reduction scheme, the System equivalent reduction expansion process (SEREP). Extremely reduced order models that provide dynamic characteristics of linear components, which are interconnected with highly nonlinear connection elements, are formulated with SEREP for the dynamic response evaluation using direct integration techniques. The full-space solution will be compared to the response obtained using drastically reduced models to make evident the usefulness of the technique for a variety of analytical cases.

Insight into the effect of screw dislocations and oxygen vacancy defects on the optical nonlinear refraction response in chemically grown ZnO/Al2O3 films

NASA Astrophysics Data System (ADS)

Agrawal, Arpana; Saroj, Rajendra K.; Dar, Tanveer A.; Baraskar, Priyanka; Sen, Pratima; Dhar, Subhabrata

2017-11-01

We report the effect of screw dislocations and oxygen vacancy defects on the optical nonlinear refraction response of ZnO films grown on a sapphire substrate at various oxygen flow rates using the chemical vapor deposition technique. The nonlinear refraction response was investigated in the off-resonant regime using a CW He-Ne laser source to examine the role of the intermediate bandgap states. It has been observed that the structural defects strongly influence the optical nonlinearity in the off-resonant regime. Nonlinearity has been found to improve as the oxygen flow rate is lowered from 2 sccm to 0.3 sccm. From photoluminescence studies, we observe that the enhanced defect density of the electronic defect levels due to the increased concentration of structural defects (with the decrease in the oxygen flow rate) is responsible for this improved optical nonlinearity along with the thermal effect. This suggests that defect engineering is an effective way to tailor the nonlinearity of ZnO films and their utility for optoelectronic device applications.

Volterra-series-based nonlinear system modeling and its engineering applications: A state-of-the-art review

NASA Astrophysics Data System (ADS)

Cheng, C. M.; Peng, Z. K.; Zhang, W. M.; Meng, G.

2017-03-01

Nonlinear problems have drawn great interest and extensive attention from engineers, physicists and mathematicians and many other scientists because most real systems are inherently nonlinear in nature. To model and analyze nonlinear systems, many mathematical theories and methods have been developed, including Volterra series. In this paper, the basic definition of the Volterra series is recapitulated, together with some frequency domain concepts which are derived from the Volterra series, including the general frequency response function (GFRF), the nonlinear output frequency response function (NOFRF), output frequency response function (OFRF) and associated frequency response function (AFRF). The relationship between the Volterra series and other nonlinear system models and nonlinear problem solving methods are discussed, including the Taylor series, Wiener series, NARMAX model, Hammerstein model, Wiener model, Wiener-Hammerstein model, harmonic balance method, perturbation method and Adomian decomposition. The challenging problems and their state of arts in the series convergence study and the kernel identification study are comprehensively introduced. In addition, a detailed review is then given on the applications of Volterra series in mechanical engineering, aeroelasticity problem, control engineering, electronic and electrical engineering.

Non-linear relationship of cell hit and transformation probabilities in a low dose of inhaled radon progenies.

PubMed

Balásházy, Imre; Farkas, Arpád; Madas, Balázs Gergely; Hofmann, Werner

2009-06-01

Cellular hit probabilities of alpha particles emitted by inhaled radon progenies in sensitive bronchial epithelial cell nuclei were simulated at low exposure levels to obtain useful data for the rejection or support of the linear-non-threshold (LNT) hypothesis. In this study, local distributions of deposited inhaled radon progenies in airway bifurcation models were computed at exposure conditions characteristic of homes and uranium mines. Then, maximum local deposition enhancement factors at bronchial airway bifurcations, expressed as the ratio of local to average deposition densities, were determined to characterise the inhomogeneity of deposition and to elucidate their effect on resulting hit probabilities. The results obtained suggest that in the vicinity of the carinal regions of the central airways the probability of multiple hits can be quite high, even at low average doses. Assuming a uniform distribution of activity there are practically no multiple hits and the hit probability as a function of dose exhibits a linear shape in the low dose range. The results are quite the opposite in the case of hot spots revealed by realistic deposition calculations, where practically all cells receive multiple hits and the hit probability as a function of dose is non-linear in the average dose range of 10-100 mGy.

Research in nonlinear structural and solid mechanics

NASA Technical Reports Server (NTRS)

Mccomb, H. G., Jr. (Compiler); Noor, A. K. (Compiler)

1980-01-01

Nonlinear analysis of building structures and numerical solution of nonlinear algebraic equations and Newton's method are discussed. Other topics include: nonlinear interaction problems; solution procedures for nonlinear problems; crash dynamics and advanced nonlinear applications; material characterization, contact problems, and inelastic response; and formulation aspects and special software for nonlinear analysis.

Nonlinear mixed effects modelling approach in investigating phenobarbital pharmacokinetic interactions in epileptic patients.

PubMed

Vučićević, Katarina; Jovanović, Marija; Golubović, Bojana; Kovačević, Sandra Vezmar; Miljković, Branislava; Martinović, Žarko; Prostran, Milica

2015-02-01

The present study aimed to establish population pharmacokinetic model for phenobarbital (PB), examining and quantifying the magnitude of PB interactions with other antiepileptic drugs concomitantly used and to demonstrate its use for individualization of PB dosing regimen in adult epileptic patients. In total 205 PB concentrations were obtained during routine clinical monitoring of 136 adult epilepsy patients. PB steady state concentrations were measured by homogeneous enzyme immunoassay. Nonlinear mixed effects modelling (NONMEM) was applied for data analyses and evaluation of the final model. According to the final population model, significant determinant of apparent PB clearance (CL/F) was daily dose of concomitantly given valproic acid (VPA). Typical value of PB CL/F for final model was estimated at 0.314 l/h. Based on the final model, co-therapy with usual VPA dose of 1000 mg/day, resulted in PB CL/F average decrease of about 25 %, while 2000 mg/day leads to an average 50 % decrease in PB CL/F. Developed population PB model may be used in estimating individual CL/F for adult epileptic patients and could be applied for individualizing dosing regimen taking into account dose-dependent effect of concomitantly given VPA.

D-optimal experimental designs to test for departure from additivity in a fixed-ratio mixture ray.

PubMed

Coffey, Todd; Gennings, Chris; Simmons, Jane Ellen; Herr, David W

2005-12-01

Traditional factorial designs for evaluating interactions among chemicals in a mixture may be prohibitive when the number of chemicals is large. Using a mixture of chemicals with a fixed ratio (mixture ray) results in an economical design that allows estimation of additivity or nonadditive interaction for a mixture of interest. This methodology is extended easily to a mixture with a large number of chemicals. Optimal experimental conditions can be chosen that result in increased power to detect departures from additivity. Although these designs are used widely for linear models, optimal designs for nonlinear threshold models are less well known. In the present work, the use of D-optimal designs is demonstrated for nonlinear threshold models applied to a fixed-ratio mixture ray. For a fixed sample size, this design criterion selects the experimental doses and number of subjects per dose level that result in minimum variance of the model parameters and thus increased power to detect departures from additivity. An optimal design is illustrated for a 2:1 ratio (chlorpyrifos:carbaryl) mixture experiment. For this example, and in general, the optimal designs for the nonlinear threshold model depend on prior specification of the slope and dose threshold parameters. Use of a D-optimal criterion produces experimental designs with increased power, whereas standard nonoptimal designs with equally spaced dose groups may result in low power if the active range or threshold is missed.

Estimation of rhG-CSF absorption kinetics after subcutaneous administration using a modified Wagner-Nelson method with a nonlinear elimination model.

PubMed

Hayashi, N; Aso, H; Higashida, M; Kinoshita, H; Ohdo, S; Yukawa, E; Higuchi, S

2001-05-01

The clearance of recombinant human granulocyte-colony stimulating factor (rhG-CSF) is known to decrease with dose increase, and to be saturable. The average clearance after intravenous administration will be lower than that after subcutaneous administration. Therefore, the apparent absolute bioavailability with subcutaneous administration calculated from the AUC ratio is expected to be an underestimate. The absorption pharmacokinetics after subcutaneous administration was examined using the results of the bioequivalency study between two rhG-CSF formulations with a dose of 2 microg/kg. The analysis was performed using a modified Wagner-Nelson method with the nonlinear elimination model. The apparent absolute bioavailability for subcutaneous administration was 56.9 and 67.5% for each formulation, and the ratio between them was approximately 120%. The true absolute bioavailability was, however, estimated to be 89.8 and 96.9%, respectively, and the ratio was approximately 108%. The absorption pattern was applied to other doses, and the predicted clearance values for subcutaneous and intravenous administrations were then similar to the values for several doses reported in the literature. The underestimation of bioavailability was around 30%, and the amplification of difference was 2.5 times, from 8 to 20%, because of the nonlinear pharmacokinetics. The neutrophil increases for each formulation were identical, despite the different bioavailabilities. The reason for this is probably that the amount eliminated through the saturable process, which might indicate the amount consumed by the G-CSF receptor, was identical for each formulation.

Induction of sister chromatid exchanges and inhibition of cellular proliferation in vitro. I. Caffeine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guglielmi, G.E.; Vogt, T.F.; Tice, R.R.

1982-01-01

While many agents have been examined for their ability to induce SCE's, complete dose-response information has often been lacking. We have reexamined the ability of one such compound - caffeine - to induce SCEs and also to inhibit cellular proliferation in human peripheral lymphocytes in vitro. An acute exposure to caffeine prior to the DNA synthetic period did not affect either SCE frequency or the rate of cellular proliferation. Chronic exposure to caffeine throughout the culture period lead to both a dose-dependent increase in SCEs (SCE/sub d/ or doubling dose = 2.4 mM; SCE/sub 10/ or the dose capable ofmore » inducing 10 SCE = 1.4 mM) and a dose-dependent inhibition of cellular proliferation (IC/sub 50/ or the 50% inhibition concentration = 2.6 mM). The relative proportion of first generation metaphase cells, an assessment of proliferative inhibiton, increased linearly with increasing caffeine concentrations. However, SCE frequency increased nonlinearly over the same range of caffeine concentrations. Examination of the ratio of nonsymmetrical to symmetrical SCEs in third generation metaphase cells indicated that caffeine induced SCEs in equal frequency in each of three successive generations. The dependency of SCE induction and cellular proliferative inhibition on caffeine's presence during the DNA synthetic period suggests that caffeine may act as an antimetabolite in normal human cells.« less

Retrieval of all effective susceptibilities in nonlinear metamaterials

NASA Astrophysics Data System (ADS)

Larouche, Stéphane; Radisic, Vesna

2018-04-01

Electromagnetic metamaterials offer a great avenue to engineer and amplify the nonlinear response of materials. Their electric, magnetic, and magnetoelectric linear and nonlinear response are related to their structure, providing unprecedented liberty to control those properties. Both the linear and the nonlinear properties of metamaterials are typically anisotropic. While the methods to retrieve the effective linear properties are well established, existing nonlinear retrieval methods have serious limitations. In this work, we generalize a nonlinear transfer matrix approach to account for all nonlinear susceptibility terms and show how to use this approach to retrieve all effective nonlinear susceptibilities of metamaterial elements. The approach is demonstrated using sum frequency generation, but can be applied to other second-order or higher-order processes.

Association of coffee drinking with all-cause mortality: a systematic review and meta-analysis.

PubMed

Zhao, Yimin; Wu, Kejian; Zheng, Jusheng; Zuo, Ruiting; Li, Duo

2015-05-01

We aimed to use the meta-analysis method to assess the relationship between coffee drinking and all-cause mortality. Categorical and dose-response meta-analyses were conducted using random-effects models. We systematically searched and identified eligible literature in the PubMed and Scopus databases. Seventeen studies including 1 054 571 participants and 131 212 death events from all causes were included in the present study. Seventeen studies were included and evaluated in the meta-analysis. A U-shaped dose-response relationship was found between coffee consumption and all-cause mortality (P for non-linearity <0.001). Compared with non/occasional coffee drinkers, the relative risks for all-cause mortality were 0.89 (95 % CI 0.85, 0.93) for 1-<3 cups/d, 0.87 (95 % CI 0.83, 0.91) for 3-<5 cups/d and 0.90 (95 % CI 0.87, 0.94) for ≥5 cups/d, and the relationship was more marked in females than in males. The present meta-analysis of prospective cohort studies indicated that light to moderate coffee intake is associated with a reduced risk of death from all causes, particularly in women.

Evaluation of Effective Sources in Uncertainty Measurements of Personal Dosimetry by a Harshaw TLD System

PubMed Central

Hosseini Pooya, SM; Orouji, T

2014-01-01

Background: The accurate results of the individual doses in personal dosimety which are reported by the service providers in personal dosimetry are very important. There are national / international criteria for acceptable dosimetry system performance. Objective: In this research, the sources of uncertainties are identified, measured and calculated in a personal dosimetry system by TLD. Method: These sources are included; inhomogeneity of TLDs sensitivity, variability of TLD readings due to limited sensitivity and background, energy dependence, directional dependence, non-linearity of the response, fading, dependent on ambient temperature / humidity and calibration errors, which may affect on the dose responses. Some parameters which influence on the above sources of uncertainty are studied for Harshaw TLD-100 cards dosimeters as well as the hot gas Harshaw 6600 TLD reader system. Results: The individual uncertainties of each sources was measured less than 6.7% in 68% confidence level. The total uncertainty was calculated 17.5% with 95% confidence level. Conclusion: The TLD-100 personal dosimeters as well as the Harshaw TLD-100 reader 6600 system show the total uncertainty value which is less than that of admissible value of 42% for personal dosimetry services. PMID:25505769

Aeroelastic Response of Nonlinear Wing Section By Functional Series Technique

NASA Technical Reports Server (NTRS)

Marzocca, Piergiovanni; Librescu, Liviu; Silva, Walter A.

2000-01-01

This paper addresses the problem of the determination of the subcritical aeroelastic response and flutter instability of nonlinear two-dimensional lifting surfaces in an incompressible flow-field via indicial functions and Volterra series approach. The related aeroelastic governing equations are based upon the inclusion of structural and damping nonlinearities in plunging and pitching, of the linear unsteady aerodynamics and consideration of an arbitrary time-dependent external pressure pulse. Unsteady aeroelastic nonlinear kernels are determined, and based on these, frequency and time histories of the subcritical aeroelastic response are obtained, and in this context the influence of the considered nonlinearities is emphasized. Conclusions and results displaying the implications of the considered effects are supplied.

Aeroelastic Response of Nonlinear Wing Section by Functional Series Technique

NASA Technical Reports Server (NTRS)

Silva, Walter A.; Marzocca, Piergiovanni

2001-01-01

This paper addresses the problem of the determination of the subcritical aeroelastic response and flutter instability of nonlinear two-dimensional lifting surfaces in an incompressible flow-field via indicial functions and Volterra series approach. The related aeroelastic governing equations are based upon the inclusion of structural and damping nonlinearities in plunging and pitching, of the linear unsteady aerodynamics and consideration of an arbitrary time-dependent external pressure pulse. Unsteady aeroelastic nonlinear kernels are determined, and based on these, frequency and time histories of the subcritical aeroelastic response are obtained, and in this context the influence of the considered nonlinearities is emphasized. Conclusions and results displaying the implications of the considered effects are supplied.

Synthesis of nonlinear frequency responses with experimentally extracted nonlinear modes

NASA Astrophysics Data System (ADS)

Peter, Simon; Scheel, Maren; Krack, Malte; Leine, Remco I.

2018-02-01

Determining frequency response curves is a common task in the vibration analysis of nonlinear systems. Measuring nonlinear frequency responses is often challenging and time consuming due to, e.g., coexisting stable or unstable vibration responses and structure-exciter-interaction. The aim of the current paper is to develop a method for the synthesis of nonlinear frequency responses near an isolated resonance, based on data that can be easily and automatically obtained experimentally. The proposed purely experimental approach relies on (a) a standard linear modal analysis carried out at low vibration levels and (b) a phase-controlled tracking of the backbone curve of the considered forced resonance. From (b), the natural frequency and vibrational deflection shape are directly obtained as a function of the vibration level. Moreover, a damping measure can be extracted by power considerations or from the linear modal analysis. In accordance with the single nonlinear mode assumption, the near-resonant frequency response can then be synthesized using this data. The method is applied to a benchmark structure consisting of a cantilevered beam attached to a leaf spring undergoing large deflections. The results are compared with direct measurements of the frequency response. The proposed approach is fast, robust and provides a good estimate for the frequency response. It is also found that direct frequency response measurement is less robust due to bifurcations and using a sine sweep excitation with a conventional force controller leads to underestimation of maximum vibration response.

Ultrafast nonlinear dynamics of thin gold films due to an intrinsic delayed nonlinearity

NASA Astrophysics Data System (ADS)

Bache, Morten; Lavrinenko, Andrei V.

2017-09-01

Using long-range surface plasmon polaritons light can propagate in metal nano-scale waveguides for ultracompact opto-electronic devices. Gold is an important material for plasmonic waveguides, but although its linear optical properties are fairly well understood, the nonlinear response is still under investigation. We consider the propagation of pulses in ultrathin gold strip waveguides, modeled by the nonlinear Schrödinger equation. The nonlinear response of gold is accounted for by the two-temperature model, revealing it as a delayed nonlinearity intrinsic in gold. The consequence is that the measured nonlinearities are strongly dependent on pulse duration. This issue has so far only been addressed phenomenologically, but we provide an accurate estimate of the quantitative connection as well as a phenomenological theory to understand the enhanced nonlinear response as the gold thickness is reduced. In comparison with previous works, the analytical model for the power-loss equation has been improved, and can be applied now to cases with a high laser peak power. We show new fits to experimental data from the literature and provide updated values for the real and imaginary parts of the nonlinear susceptibility of gold for various pulse durations and gold layer thicknesses. Our simulations show that the nonlinear loss is inhibiting efficient nonlinear interaction with low-power laser pulses. We therefore propose to design waveguides suitable for the mid-IR, where the ponderomotive instantaneous nonlinearity can dominate over the delayed hot-electron nonlinearity and provide a suitable plasmonics platform for efficient ultrafast nonlinear optics.

Glucuronidation and Sulfation Kinetics of Diflunisal in Man.

NASA Astrophysics Data System (ADS)

Loewen, Gordon Rapheal

Diflunisal is a nonsteroidal anti-inflammatory drug used in the treatment of arthritis and musculoskeletal pain. Diflunisal exhibits concentration- and dose-dependent kinetics, the mechanism of which has not been determined. The purpose of this study was to determine the mechanism(s) responsible for non-linear disposition of diflunisal and to examine environmental factors which may affect the elimination of diflunisal. The metabolites of diflunisal, including a new metabolite, the sulphate conjugate, were purified by column and semi-preparative high pressure liquid chromatography. Assays for the quantitation of diflunisal and conjugates in urine and diflunisal in plasma were developed. Plasma protein binding of diflunisal in blank plasma and in plasma obtained following multiple doses of diflunisal was determined by equilibrium dialysis. Total body clearance of diflunisal decreased when dose increased from 100 to 750 mg. Total clearance increased when dose increased from 750 to 1000 mg. The percent of recovered dose eliminated as the acyl glucuronide decreased and the percent eliminated as the sulphate increased with increasing dose of diflunisal. Plasma protein binding of diflunisal was concentration dependent over a range of diflunisal plasma concentrations of 3 to 257 mug/ml. Total clearance, and to a lesser degree, unbound clearance of diflunisal were decreased following multiple dose administration of 250 and 500 mg diflunisal. Percent of recovered dose eliminated as the acyl glucuronide decreased and percent eliminated as the sulphate conjugate increased following multiple dosing. Plasma protein binding of diflunisal was similar in blank plasma and plasma obtained at steady state. Unbound clearance of diflunisal exceeded liver plasma flow. Frequency distributions of the elimination of the conjugates of diflunisal were normally distributed. Sex, smoking, and use of vitamins or oral contraceptives were identified as factors which may affect the elimination of diflunisal.

Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia.

PubMed

Dong, Min; McGann, Patrick T; Mizuno, Tomoyuki; Ware, Russell E; Vinks, Alexander A

2016-04-01

Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1)  h. We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly. © 2015 The British Pharmacological Society.

Dose-Dependent Associations between Wine Drinking and Breast Cancer Risk - Meta-Analysis Findings.

PubMed

Chen, Jia-Yan; Zhu, Hong-Cheng; Guo, Qing; Shu, Zheng; Bao, Xu-Hui; Sun, Feng; Qin, Qin; Yang, Xi; Zhang, Chi; Cheng, Hong-Yan; Sun, Xin-Chen

2016-01-01

To investigate any potential association between wine and breast cancer risk. We quantitatively assessed associations by conducting a meta-analysis based on evidence from observational studies. In May 2014, we performed electronic searches in PubMed, EmBase and the Cochrane Library to identify studies examining the effect of wine drinking on breast cancer incidence. The relative risk (RR) or odds ratio (OR) were used to measure any such association. The analysis was further stratified by confounding factors that could influence the results. A total of twenty-six studies (eight case-control and eighteen cohort studies) involving 21,149 cases were included in our meta-analysis. Our study demonstrated that wine drinking was associated with breast cancer risk. A 36% increase in breast cancer risk was observed across overall studies based on the highest versus lowest model, with a combined RR of 1.0059 (95%CI 0.97-1.05) in dose-response analysis. However, 5 g/d ethanol from wine seemed to have protective value from our non-linear model. Our findings indicate that wine drinking is associated with breast cancer risk in a dose-dependent manner. High consumption of wine contributes to breast cancer risk with protection exerted by low doses. Further investigations are needed for clarification.

A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system

PubMed Central

2012-01-01

Background This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution; (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism-dependent adaptive and endogenously amplified effects; (d) improve systemic resilience. Discussion The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk-form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create “top-down” nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism’s allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease. Summary Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine. PMID:23088629

A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system.

PubMed

Bell, Iris R; Koithan, Mary

2012-10-22

This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution; (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism-dependent adaptive and endogenously amplified effects; (d) improve systemic resilience. The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk-form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create "top-down" nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism's allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease. Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine.

Relationships between nonlinear normal modes and response to random inputs

DOE PAGES

Schoneman, Joseph D.; Allen, Matthew S.; Kuether, Robert J.

2016-07-25

The ability to model nonlinear structures subject to random excitation is of key importance in designing hypersonic aircraft and other advanced aerospace vehicles. When a structure is linear, superposition can be used to construct its response to a known spectrum in terms of its linear modes. Superposition does not hold for a nonlinear system, but several works have shown that a system's dynamics can still be understood qualitatively in terms of its nonlinear normal modes (NNMs). Here, this work investigates the connection between a structure's undamped nonlinear normal modes and the spectrum of its response to high amplitude random forcing.more » Two examples are investigated: a spring-mass system and a clamped-clamped beam modeled within a geometrically nonlinear finite element package. In both cases, an intimate connection is observed between the smeared peaks in the response spectrum and the frequency-energy dependence of the nonlinear normal modes. In order to understand the role of coupling between the underlying linear modes, reduced order models with and without modal coupling terms are used to separate the effect of each NNM's backbone from the nonlinear couplings that give rise to internal resonances. In the cases shown here, uncoupled, single-degree-of-freedom nonlinear models are found to predict major features in the response with reasonable accuracy; a highly inexpensive approximation such as this could be useful in design and optimization studies. More importantly, the results show that a reduced order model can be expected to give accurate results only if it is also capable of accurately predicting the frequency-energy dependence of the nonlinear modes that are excited.« less

Towards a unifying theory for the first-, second-, and third-order molecular (non)linear optical response

NASA Astrophysics Data System (ADS)

Pérez-Moreno, Javier; Clays, Koen; Kuzyk, Mark G.

2010-05-01

We present a procedure for the modeling of the dispersion of the nonlinear optical response of complex molecular structures that is based strictly on the results from experimental characterization. We show how under some general conditions, the use of the Thomas-Kuhn sum-rules leads to a successful modeling of the nonlinear response of complex molecular structures.

Inducing in situ, nonlinear soil response applying an active source

USGS Publications Warehouse

Johnson, P.A.; Bodin, P.; Gomberg, J.; Pearce, F.; Lawrence, Z.; Menq, F.-Y.

2009-01-01

[1] It is well known that soil sites have a profound effect on ground motion during large earthquakes. The complex structure of soil deposits and the highly nonlinear constitutive behavior of soils largely control nonlinear site response at soil sites. Measurements of nonlinear soil response under natural conditions are critical to advancing our understanding of soil behavior during earthquakes. Many factors limit the use of earthquake observations to estimate nonlinear site response such that quantitative characterization of nonlinear behavior relies almost exclusively on laboratory experiments and modeling of wave propagation. Here we introduce a new method for in situ characterization of the nonlinear behavior of a natural soil formation using measurements obtained immediately adjacent to a large vibrator source. To our knowledge, we are the first group to propose and test such an approach. Employing a large, surface vibrator as a source, we measure the nonlinear behavior of the soil by incrementally increasing the source amplitude over a range of frequencies and monitoring changes in the output spectra. We apply a homodyne algorithm for measuring spectral amplitudes, which provides robust signal-to-noise ratios at the frequencies of interest. Spectral ratios are computed between the receivers and the source as well as receiver pairs located in an array adjacent to the source, providing the means to separate source and near-source nonlinearity from pervasive nonlinearity in the soil column. We find clear evidence of nonlinearity in significant decreases in the frequency of peak spectral ratios, corresponding to material softening with amplitude, observed across the array as the source amplitude is increased. The observed peak shifts are consistent with laboratory measurements of soil nonlinearity. Our results provide constraints for future numerical modeling studies of strong ground motion during earthquakes.

Study of cumulative fatigue damage detection for used parts with nonlinear output frequency response functions based on NARMAX modelling

NASA Astrophysics Data System (ADS)

Huang, Honglan; Mao, Hanying; Mao, Hanling; Zheng, Weixue; Huang, Zhenfeng; Li, Xinxin; Wang, Xianghong

2017-12-01

Cumulative fatigue damage detection for used parts plays a key role in the process of remanufacturing engineering and is related to the service safety of the remanufactured parts. In light of the nonlinear properties of used parts caused by cumulative fatigue damage, the based nonlinear output frequency response functions detection approach offers a breakthrough to solve this key problem. First, a modified PSO-adaptive lasso algorithm is introduced to improve the accuracy of the NARMAX model under impulse hammer excitation, and then, an effective new algorithm is derived to estimate the nonlinear output frequency response functions under rectangular pulse excitation, and a based nonlinear output frequency response functions index is introduced to detect the cumulative fatigue damage in used parts. Then, a novel damage detection approach that integrates the NARMAX model and the rectangular pulse is proposed for nonlinear output frequency response functions identification and cumulative fatigue damage detection of used parts. Finally, experimental studies of fatigued plate specimens and used connecting rod parts are conducted to verify the validity of the novel approach. The obtained results reveal that the new approach can detect cumulative fatigue damages of used parts effectively and efficiently and that the various values of the based nonlinear output frequency response functions index can be used to detect the different fatigue damages or working time. Since the proposed new approach can extract nonlinear properties of systems by only a single excitation of the inspected system, it shows great promise for use in remanufacturing engineering applications.

Final Technical Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

W. C. Griffith

In this project we provide an example of how to develop multi-tiered models to go across levels of biological organization to provide a framework for relating results of studies of low doses of ionizing radiation. This framework allows us to better understand how to extrapolate laboratory results to policy decisions, and to identify future studies that will increase confidence in policy decisions. In our application of the conceptual Model we were able to move across multiple levels of biological assessment for rodents going from molecular to organism level for in vitro and in vivo endpoints and to relate these tomore » human in vivo organism level effects. We used the rich literature on the effects of ionizing radiation on the developing brain in our models. The focus of this report is on disrupted neuronal migration due to radiation exposure and the structural and functional implications of these early biological effects. The cellular mechanisms resulting in pathogenesis are most likely due to a combination of the three mechanisms mentioned. For the purposes of a computational model, quantitative studies of low dose radiation effects on migration of neuronal progenitor cells in the cerebral mantle of experimental animals were used. In this project we were able to show now results from studies of low doses of radiation can be used in a multidimensional framework to construct linked models of neurodevelopment using molecular, cellular, tissue, and organ level studies conducted both in vitro and in vivo in rodents. These models could also be linked to behavioral endpoints in rodents which can be compared to available results in humans. The available data supported modeling to 10 cGy with limited data available at 5 cGy. We observed gradual but non-linear changes as the doses decreased. For neurodevelopment it appears that the slope of the dose response decreases from 25 cGy to 10 cGy. Future studies of neurodevelopment should be able to better define the dose response in this range.« less

WE-E-18A-04: Precision In-Vivo Dosimetry Using Optically Stimulated Luminescence Dosimeters and a Pulsed-Stimulating Dose Reader

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Q; Herrick, A; Hoke, S

Purpose: A new readout technology based on pulsed optically stimulating luminescence is introduced (microSTARii, Landauer, Inc, Glenwood, IL60425). This investigation searches for approaches that maximizes the dosimetry accuracy in clinical applications. Methods: The sensitivity of each optically stimulated luminescence dosimeter (OSLD) was initially characterized by exposing it to a given radiation beam. After readout, the luminescence signal stored in the OSLD was erased by exposing its sensing area to a 21W white LED light for 24 hours. A set of OSLDs with consistent sensitivities was selected to calibrate the dose reader. Higher order nonlinear curves were also derived from themore » calibration readings. OSLDs with cumulative doses below 15 Gy were reused. Before an in-vivo dosimetry, the OSLD luminescence signal was erased with the white LED light. Results: For a set of 68 manufacturer-screened OSLDs, the measured sensitivities vary in a range of 17.3%. A sub-set of the OSLDs with sensitivities within ±1% was selected for the reader calibration. Three OSLDs in a group were exposed to a given radiation. Nine groups were exposed to radiation doses ranging from 0 to 13 Gy. Additional verifications demonstrated that the reader uncertainty is about 3%. With an external calibration function derived by fitting the OSLD readings to a 3rd-order polynomial, the dosimetry uncertainty dropped to 0.5%. The dose-luminescence response curves of individual OSLDs were characterized. All curves converge within 1% after the sensitivity correction. With all uncertainties considered, the systematic uncertainty is about 2%. Additional tests emulating in-vivo dosimetry by exposing the OSLDs under different radiation sources confirmed the claim. Conclusion: The sensitivity of individual OSLD should be characterized initially. A 3rd-order polynomial function is a more accurate representation of the dose-luminescence response curve. The dosimetry uncertainty specified by the manufacturer is 4%. Following the proposed approach, it can be controlled to 2%.« less

Effects of Combined Loads on the Nonlinear Response and Residual Strength of Damaged Stiffened Shells

NASA Technical Reports Server (NTRS)

Starnes, James H., Jr.; Rose, Cheryl A.; Rankin, Charles C.

1996-01-01

The results of an analytical study of the nonlinear response of stiffened fuselage shells with long cracks are presented. The shells are modeled with a hierarchical modeling strategy and analyzed with a nonlinear shell analysis code that maintains the shell in a nonlinear equilibrium state while the crack is grown. The analysis accurately accounts for global and local structural response phenomena. Results are presented for various combinations of internal pressure and mechanical loads, and the effects of crack orientation on the shell response are described. The effects of combined loading conditions and the effects of varying structural parameters on the stress-intensity factors associated with a crack are presented.

Nonlinear random response prediction using MSC/NASTRAN

NASA Technical Reports Server (NTRS)

Robinson, J. H.; Chiang, C. K.; Rizzi, S. A.

1993-01-01

An equivalent linearization technique was incorporated into MSC/NASTRAN to predict the nonlinear random response of structures by means of Direct Matrix Abstract Programming (DMAP) modifications and inclusion of the nonlinear differential stiffness module inside the iteration loop. An iterative process was used to determine the rms displacements. Numerical results obtained for validation on simple plates and beams are in good agreement with existing solutions in both the linear and linearized regions. The versatility of the implementation will enable the analyst to determine the nonlinear random responses for complex structures under combined loads. The thermo-acoustic response of a hexagonal thermal protection system panel is used to highlight some of the features of the program.

Exponential increase in postprandial blood-glucose exposure with increasing carbohydrate loads using a linear carbohydrate-to-insulin ratio.

PubMed

Marran, K J; Davey, B; Lang, A; Segal, D G

2013-04-10

Postprandial glucose excursions contribute significantly to average blood glucose, glycaemic variability and cardiovascular risk. Carbohydrate counting is a method of insulin dosing that balances carbohydrate load to insulin dose using a fixed ratio. Many patients and current insulin pumps calculate insulin delivery for meals based on a linear carbohydrate-to-insulin relationship. It is our hypothesis that a non-linear relationship exists between the amounts of carbohydrate consumed and the insulin required to cover it. To document blood glucose exposure in response to increasing carbohydrate loads on fixed carbohydrate-to-insulin ratios. Five type 1 diabetic subjects receiving insulin pump therapy with good control were recruited. Morning basal rates and carbohydrate- to-insulin ratios were optimised. A Medtronic glucose sensor was used for 5 days to collect data for area-under-the-curve (AUC) analysis, during which standardised meals of increasing carbohydrate loads were consumed. Increasing carbohydrate loads using a fixed carbohydrate-to-insulin ratio resulted in increasing glucose AUC. The relationship was found to be exponential rather than linear. Late postprandial hypoglycaemia followed carbohydrate loads of >60 g and this was often followed by rebound hyperglycaemia that lasted >6 hours. A non-linear relationship exists between carbohydrates consumed and the insulin required to cover them. This has implications for control of postprandial blood sugars, especially when consuming large carbohydrate loads. Further studies are required to look at the optimal ratios, duration and type of insulin boluses required to cover increasing carbohydrate loads.

Nonlinear Wavefront Control with All-Dielectric Metasurfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Lei; Kruk, Sergey; Koshelev, Kirill

Metasurfaces, two-dimensional lattices of nanoscale resonators, offer unique opportunities for functional flat optics and allow the control of the transmission, reflection, and polarization of a wavefront of light. Recently, all-dielectric metasurfaces reached remarkable efficiencies, often matching or out-performing conventional optical elements. The exploitation of the nonlinear optical response of metasurfaces offers a paradigm shift in nonlinear optics, and dielectric nonlinear metasurfaces are expected to enrich subwavelength photonics by enhancing substantially nonlinear response of natural materials combined with the efficient control of the phase of nonlinear waves. Here, we suggest a novel and rather general approach for engineering the wavefront ofmore » parametric waves of arbitrary complexity generated by a nonlinear metasurface. We design all-dielectric nonlinear metasurfaces, achieve a highly efficient wavefront control of a third-harmonic field, and demonstrate the generation of nonlinear beams at a designed angle and the generation of nonlinear focusing vortex beams. Lastly, our nonlinear metasurfaces produce phase gradients over a full 0–2π phase range with a 92% diffraction efficiency.« less

Nonlinear Wavefront Control with All-Dielectric Metasurfaces.

PubMed

Wang, Lei; Kruk, Sergey; Koshelev, Kirill; Kravchenko, Ivan; Luther-Davies, Barry; Kivshar, Yuri

2018-06-13

Metasurfaces, two-dimensional lattices of nanoscale resonators, offer unique opportunities for functional flat optics and allow the control of the transmission, reflection, and polarization of a wavefront of light. Recently, all-dielectric metasurfaces reached remarkable efficiencies, often matching or out-performing conventional optical elements. The exploitation of the nonlinear optical response of metasurfaces offers a paradigm shift in nonlinear optics, and dielectric nonlinear metasurfaces are expected to enrich subwavelength photonics by enhancing substantially nonlinear response of natural materials combined with the efficient control of the phase of nonlinear waves. Here, we suggest a novel and rather general approach for engineering the wavefront of parametric waves of arbitrary complexity generated by a nonlinear metasurface. We design all-dielectric nonlinear metasurfaces, achieve a highly efficient wavefront control of a third-harmonic field, and demonstrate the generation of nonlinear beams at a designed angle and the generation of nonlinear focusing vortex beams. Our nonlinear metasurfaces produce phase gradients over a full 0-2π phase range with a 92% diffraction efficiency.

Nonlinear Wavefront Control with All-Dielectric Metasurfaces

DOE PAGES

Wang, Lei; Kruk, Sergey; Koshelev, Kirill; ...

2018-05-11

Metasurfaces, two-dimensional lattices of nanoscale resonators, offer unique opportunities for functional flat optics and allow the control of the transmission, reflection, and polarization of a wavefront of light. Recently, all-dielectric metasurfaces reached remarkable efficiencies, often matching or out-performing conventional optical elements. The exploitation of the nonlinear optical response of metasurfaces offers a paradigm shift in nonlinear optics, and dielectric nonlinear metasurfaces are expected to enrich subwavelength photonics by enhancing substantially nonlinear response of natural materials combined with the efficient control of the phase of nonlinear waves. Here, we suggest a novel and rather general approach for engineering the wavefront ofmore » parametric waves of arbitrary complexity generated by a nonlinear metasurface. We design all-dielectric nonlinear metasurfaces, achieve a highly efficient wavefront control of a third-harmonic field, and demonstrate the generation of nonlinear beams at a designed angle and the generation of nonlinear focusing vortex beams. Lastly, our nonlinear metasurfaces produce phase gradients over a full 0–2π phase range with a 92% diffraction efficiency.« less

A Photonic Basis for Deriving Nonlinear Optical Response

ERIC Educational Resources Information Center

Andrews, David L.; Bradshaw, David S.

2009-01-01

Nonlinear optics is generally first presented as an extension of conventional optics. Typically the subject is introduced with reference to a classical oscillatory electric polarization, accommodating correction terms that become significant at high intensities. The material parameters that quantify the extent of the nonlinear response are cast as…

The influence of and the identification of nonlinearity in flexible structures

NASA Technical Reports Server (NTRS)

Zavodney, Lawrence D.

1988-01-01

Several models were built at NASA Langley and used to demonstrate the following nonlinear behavior: internal resonance in a free response, principal parametric resonance and subcritical instability in a cantilever beam-lumped mass structure, combination resonance in a parametrically excited flexible beam, autoparametric interaction in a two-degree-of-freedom system, instability of the linear solution, saturation of the excited mode, subharmonic bifurcation, and chaotic responses. A video tape documenting these phenomena was made. An attempt to identify a simple structure consisting of two light-weight beams and two lumped masses using the Eigensystem Realization Algorithm showed the inherent difficulty of using a linear based theory to identify a particular nonlinearity. Preliminary results show the technique requires novel interpretation, and hence may not be useful for structural modes that are coupled by a guadratic nonlinearity. A literature survey was also completed on recent work in parametrically excited nonlinear system. In summary, nonlinear systems may possess unique behaviors that require nonlinear identification techniques based on an understanding of how nonlinearity affects the dynamic response of structures. In this was, the unique behaviors of nonlinear systems may be properly identified. Moreover, more accutate quantifiable estimates can be made once the qualitative model has been determined.

Measurement of material nonlinearity using surface acoustic wave parametric interaction and laser ultrasonics.

PubMed

Stratoudaki, Theodosia; Ellwood, Robert; Sharples, Steve; Clark, Matthew; Somekh, Michael G; Collison, Ian J

2011-04-01

A dual frequency mixing technique has been developed for measuring velocity changes caused by material nonlinearity. The technique is based on the parametric interaction between two surface acoustic waves (SAWs): The low frequency pump SAW generated by a transducer and the high frequency probe SAW generated and detected using laser ultrasonics. The pump SAW stresses the material under the probe SAW. The stress (typically <5 MPa) is controlled by varying the timing between the pump and probe waves. The nonlinear interaction is measured as a phase modulation of the probe SAW and equated to a velocity change. The velocity-stress relationship is used as a measure of material nonlinearity. Experiments were conducted to observe the pump-probe interaction by changing the pump frequency and compare the nonlinear response of aluminum and fused silica. Experiments showed these two materials had opposite nonlinear responses, consistent with previously published data. The technique could be applied to life-time predictions of engineered components by measuring changes in nonlinear response caused by fatigue.

NONLINEAR OPTICAL EFFECTS AND FIBER OPTICS: Theory of four-wave mixing in photorefractive media when the response of a medium is nonlinear in respect of the modulation parameter

NASA Astrophysics Data System (ADS)

Zozulya, A. A.

1988-12-01

A theoretical model is constructed for four-wave mixing in a photorefractive crystal where a transmission grating is formed by the drift-diffusion nonlinearity mechanism in the absence of an external electrostatic field and the response of the medium is nonlinear in respect of the modulation parameter. A comparison is made with a model in which the response of the medium is linear in respect of the modulation parameter. Theoretical models of four-wave and two-wave mixing are also compared with experiments.

Nonlinear dynamics of the human lumbar intervertebral disc.

PubMed

Marini, Giacomo; Huber, Gerd; Püschel, Klaus; Ferguson, Stephen J

2015-02-05

Systems with a quasi-static response similar to the axial response of the intervertebral disc (i.e. progressive stiffening) often present complex dynamics, characterized by peculiar nonlinearities in the frequency response. However, such characteristics have not been reported for the dynamic response of the disc. The accurate understanding of disc dynamics is essential to investigate the unclear correlation between whole body vibration and low back pain. The present study investigated the dynamic response of the disc, including its potential nonlinear response, over a range of loading conditions. Human lumbar discs were tested by applying a static preload to the top and a sinusoidal displacement at the bottom of the disc. The frequency of the stimuli was set to increase linearly from a low frequency to a high frequency limit and back down. In general, the response showed nonlinear and asymmetric characteristics. For each test, the disc had different response in the frequency-increasing compared to the frequency-decreasing sweep. In particular, the system presented abrupt changes of the oscillation amplitude at specific frequencies, which differed between the two sweeps. This behaviour indicates that the system oscillation has a different equilibrium condition depending on the path followed by the stimuli. Preload and amplitude of the oscillation directly influenced the disc response by changing the nonlinear dynamics and frequency of the jump-phenomenon. These results show that the characterization of the dynamic response of physiological systems should be readdressed to determine potential nonlinearities. Their direct effect on the system function should be further investigated. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nonlinear dynamics of cortical responses to color in the human cVEP.

PubMed

Nunez, Valerie; Shapley, Robert M; Gordon, James

2017-09-01

The main finding of this paper is that the human visual cortex responds in a very nonlinear manner to the color contrast of pure color patterns. We examined human cortical responses to color checkerboard patterns at many color contrasts, measuring the chromatic visual evoked potential (cVEP) with a dense electrode array. Cortical topography of the cVEPs showed that they were localized near the posterior electrode at position Oz, indicating that the primary cortex (V1) was the major source of responses. The choice of fine spatial patterns as stimuli caused the cVEP response to be driven by double-opponent neurons in V1. The cVEP waveform revealed nonlinear color signal processing in the V1 cortex. The cVEP time-to-peak decreased and the waveform's shape was markedly narrower with increasing cone contrast. Comparison of the linear dynamics of retinal and lateral geniculate nucleus responses with the nonlinear dynamics of the cortical cVEP indicated that the nonlinear dynamics originated in the V1 cortex. The nature of the nonlinearity is a kind of automatic gain control that adjusts cortical dynamics to be faster when color contrast is greater.

Nonlinear Reduced Order Random Response Analysis of Structures with Shallow Curvature

NASA Technical Reports Server (NTRS)

Przekop, Adam; Rizzi, Stephen A.

2006-01-01

The goal of this investigation is to further develop nonlinear modal numerical simulation methods for application to geometrically nonlinear response of structures with shallow curvature under random loadings. For reduced order analysis, the modal basis selection must be capable of reflecting the coupling in both the linear and nonlinear stiffness. For the symmetric shallow arch under consideration, four categories of modal basis functions are defined. Those having symmetric transverse displacements (ST modes) can be designated as transverse dominated (ST-T) modes and in-plane dominated (ST-I) modes. Those having anti-symmetric transverse displacements (AT modes) can similarly be designated as transverse dominated (AT-T) modes and in-plane dominated (AT-I) modes. The response of an aluminum arch under a uniformly distributed transverse random loading is investigated. Results from nonlinear modal simulations made using various modal bases are compared with those obtained from a numerical simulation in physical degrees-of-freedom. While inclusion of ST-T modes is important for all response regimes, it is found that the ST-I modes become increasingly important in the nonlinear response regime, and that AT-T and AT-I modes are critical in the autoparametric regime.

Nonlinear Reduced Order Random Response Analysis of Structures With Shallow Curvature

NASA Technical Reports Server (NTRS)

Przekop, Adam; Rizzi, Stephen A.

2005-01-01

The goal of this investigation is to further develop nonlinear modal numerical simulation methods for application to geometrically nonlinear response of structures with shallow curvature under random loadings. For reduced order analysis, the modal basis selection must be capable of reflecting the coupling in both the linear and nonlinear stiffness. For the symmetric shallow arch under consideration, four categories of modal basis functions are defined. Those having symmetric transverse displacements (ST modes) can be designated as transverse dominated (ST-T) modes and in-plane dominated (ST-I) modes. Those having anti-symmetric transverse displacements (AT modes) can similarly be designated as transverse dominated (AT-T) modes and in-plane dominated (AT-I) modes. The response of an aluminum arch under a uniformly distributed transverse random loading is investigated. Results from nonlinear modal simulations made using various modal bases are compared with those obtained from a numerical simulation in physical degrees-of-freedom. While inclusion of ST-T modes is important for all response regimes, it is found that the ST-I modes become increasingly important in the nonlinear response regime, and that AT-T and AT-I modes are critical in the autoparametric regime.

Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility.

PubMed

Snijders, Antoine M; Marchetti, Francesco; Bhatnagar, Sandhya; Duru, Nadire; Han, Ju; Hu, Zhi; Mao, Jian-Hua; Gray, Joe W; Wyrobek, Andrew J

2012-01-01

High dose ionizing radiation (IR) is a well-known risk factor for breast cancer but the health effects after low-dose (LD, <10 cGy) exposures remain highly uncertain. We explored a systems approach that compared LD-induced chromosome damage and transcriptional responses in strains of mice with genetic differences in their sensitivity to radiation-induced mammary cancer (BALB/c and C57BL/6) for the purpose of identifying mechanisms of mammary cancer susceptibility. Unirradiated mammary and blood tissues of these strains differed significantly in baseline expressions of DNA repair, tumor suppressor, and stress response genes. LD exposures of 7.5 cGy (weekly for 4 weeks) did not induce detectable genomic instability in either strain. However, the mammary glands of the sensitive strain but not the resistant strain showed early transcriptional responses involving: (a) diminished immune response, (b) increased cellular stress, (c) altered TGFβ-signaling, and (d) inappropriate expression of developmental genes. One month after LD exposure, the two strains showed opposing responses in transcriptional signatures linked to proliferation, senescence, and microenvironment functions. We also discovered a pre-exposure expression signature in both blood and mammary tissues that is predictive for poor survival among human cancer patients (p = 0.0001), and a post-LD-exposure signature also predictive for poor patient survival (p<0.0001). There is concordant direction of expression in the LD-exposed sensitive mouse strain, in biomarkers of human DCIS and in biomarkers of human breast tumors. Our findings support the hypothesis that genetic mechanisms that determine susceptibility to LD radiation induced mammary cancer in mice are similar to the tissue mechanisms that determine poor-survival in breast cancer patients. We observed non-linearity of the LD responses providing molecular evidence against the LNT risk model and obtained new evidence that LD responses are strongly influenced by genotype. Our findings suggest that the biological assumptions concerning the mechanisms by which LD radiation is translated into breast cancer risk should be reexamined and suggest a new strategy to identify genetic features that predispose or protect individuals from LD-induced breast cancer.

Tuning the nonlinear response of (6,5)-enriched single-wall carbon nanotubes dispersions

NASA Astrophysics Data System (ADS)

Aréstegui, O. S.; Silva, E. C. O.; Baggio, A. L.; Gontijo, R. N.; Hickmann, J. M.; Fantini, C.; Alencar, M. A. R. C.; Fonseca, E. J. S.

2017-04-01

Ultrafast nonlinear optical properties of (6,5)-enriched single-wall carbon nanotubes (SWCNTs) dispersions are investigated using the thermally managed Z-scan technique. As the (6,5) SWCNTs presented a strong resonance in the range of 895-1048 nm, the nonlinear refractive index (n2) and the absorption coefficients (β) measurements were performed tuning the laser exactly around absorption peak of the (6,5) SWCNTs. It is observed that the nonlinear response is very sensitive to the wavelength and the spectral behavior of n2 is strongly correlated to the tubes one-photon absorption band, presenting also a peak when the laser photon energy is near the tube resonance energy. This result suggests that a suitable selection of nanotubes types may provide optimized nonlinear optical responses in distinct regions of the electromagnetic spectrum. Analysis of the figures of merit indicated that this material is promising for ultrafast nonlinear optical applications under near infrared excitation.

Ultra-fast dynamics in the nonlinear optical response of silver nanoprism ordered arrays.

PubMed

Sánchez-Esquivel, Héctor; Raygoza-Sanchez, Karen Y; Rangel-Rojo, Raúl; Kalinic, Boris; Michieli, Niccolò; Cesca, Tiziana; Mattei, Giovanni

2018-03-15

In this work we present the study of the ultra-fast dynamics of the nonlinear optical response of a honeycomb array of silver triangular nanoprisms, performed using a femtosecond pulsed laser tuned with the dipolar surface plasmon resonance of the nanoarray. Nonlinear absorption and refraction, and their time-dependence, were explored using the z-scan and time-resolved excite-probe techniques. Nonlinear absorption is shown to change sign with the input irradiance and the behavior was explained on the basis of a three-level model. The response time was determined to be in the picosecond regime. A technique based on a variable frequency chopper was also used in order to discriminate the thermal and electronic contributions to the nonlinearity, which were found to have opposite signs. All these findings propel the investigated nanoprism arrays as good candidates for applications in advanced ultra-fast nonlinear nanophotonic devices.

A mathematical model to describe the nonlinear elastic properties of the gastrocnemius tendon of chickens.

PubMed

Foutz, T L

1991-03-01

A phenomenological model was developed to describe the nonlinear elastic behavior of the avian gastrocnemius tendon. Quasistatic uniaxial tensile tests were used to apply a deformation and resulting load on the tendon at a deformation rate of 5 mm/min. Plots of deformation versus load indicated a nonlinear loading response. By calculating engineering stress and engineering strain, the experimental data were normalized for tendon shape. The elastic response was determined from stress-strain curves and was found to vary with engineering strain. The response to the applied engineering strain could best be described by a mathematical model that combined a linear function and a nonlinear function. Three parameters in the model were developed to represent the nonlinear elastic behavior of the tendon, thereby allowing analysis of elasticity without prior knowledge of engineering strain. This procedure reduced the amount of data needed for the statistical analysis of nonlinear elasticity.

Generating giant and tunable nonlinearity in a macroscopic mechanical resonator from a single chemical bond

NASA Astrophysics Data System (ADS)

Huang, Pu; Zhou, Jingwei; Zhang, Liang; Hou, Dong; Lin, Shaochun; Deng, Wen; Meng, Chao; Duan, Changkui; Ju, Chenyong; Zheng, Xiao; Xue, Fei; Du, Jiangfeng

2016-05-01

Nonlinearity in macroscopic mechanical systems may lead to abundant phenomena for fundamental studies and potential applications. However, it is difficult to generate nonlinearity due to the fact that macroscopic mechanical systems follow Hooke's law and respond linearly to external force, unless strong drive is used. Here we propose and experimentally realize high cubic nonlinear response in a macroscopic mechanical system by exploring the anharmonicity in chemical bonding interactions. We demonstrate the high tunability of nonlinear response by precisely controlling the chemical bonding interaction, and realize, at the single-bond limit, a cubic elastic constant of 1 × 1020 N m-3. This enables us to observe the resonator's vibrational bi-states transitions driven by the weak Brownian thermal noise at 6 K. This method can be flexibly applied to a variety of mechanical systems to improve nonlinear responses, and can be used, with further improvements, to explore macroscopic quantum mechanics.

Nonlinear terahertz devices utilizing semiconducting plasmonic metamaterials

DOE PAGES

Seren, Huseyin R.; Zhang, Jingdi; Keiser, George R.; ...

2016-01-26

The development of responsive metamaterials has enabled the realization of compact tunable photonic devices capable of manipulating the amplitude, polarization, wave vector and frequency of light. Integration of semiconductors into the active regions of metallic resonators is a proven approach for creating nonlinear metamaterials through optoelectronic control of the semiconductor carrier density. Metal-free subwavelength resonant semiconductor structures offer an alternative approach to create dynamic metamaterials. We present InAs plasmonic disk arrays as a viable resonant metamaterial at terahertz frequencies. Importantly, InAs plasmonic disks exhibit a strong nonlinear response arising from electric field-induced intervalley scattering, resulting in a reduced carrier mobilitymore » thereby damping the plasmonic response. here, we demonstrate nonlinear perfect absorbers configured as either optical limiters or saturable absorbers, including flexible nonlinear absorbers achieved by transferring the disks to polyimide films. Nonlinear plasmonic metamaterials show potential for use in ultrafast terahertz (THz) optics and for passive protection of sensitive electromagnetic devices.« less

Nonlinear terahertz devices utilizing semiconducting plasmonic metamaterials

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seren, Huseyin R.; Zhang, Jingdi; Keiser, George R.

The development of responsive metamaterials has enabled the realization of compact tunable photonic devices capable of manipulating the amplitude, polarization, wave vector and frequency of light. Integration of semiconductors into the active regions of metallic resonators is a proven approach for creating nonlinear metamaterials through optoelectronic control of the semiconductor carrier density. Metal-free subwavelength resonant semiconductor structures offer an alternative approach to create dynamic metamaterials. We present InAs plasmonic disk arrays as a viable resonant metamaterial at terahertz frequencies. Importantly, InAs plasmonic disks exhibit a strong nonlinear response arising from electric field-induced intervalley scattering, resulting in a reduced carrier mobilitymore » thereby damping the plasmonic response. here, we demonstrate nonlinear perfect absorbers configured as either optical limiters or saturable absorbers, including flexible nonlinear absorbers achieved by transferring the disks to polyimide films. Nonlinear plasmonic metamaterials show potential for use in ultrafast terahertz (THz) optics and for passive protection of sensitive electromagnetic devices.« less

Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT Pathways

NASA Technical Reports Server (NTRS)

Carra, Claudio; Wang, Minli; Huff, Janice L.; Hada, Megumi; ONeill, Peter; Cucinotta, Francis A.

2010-01-01

Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.

Role of space charges on light-induced effects in nematic liquid crystals doped by methyl red.

PubMed

Lucchetti, L; Simoni, F

2014-03-01

We show that both the extraordinarily large nonlinear response and the light-induced permanent reorientation in liquid crystals doped by the azo dye methyl red originates from the same phenomenon of modification of the charge density on the irradiated surface. The demonstration is done by applying ac voltage to the samples, showing that in this case no permanent anchoring is possible. The measurements confirm the role of photoisomerization that gives a transient contribution to the actual reorientation process only in the high dose regime. This result allows us to draw a picture for light-induced effects that might be applied to a large class of compounds.

Testing the Dose–Response Specification in Epidemiology: Public Health and Policy Consequences for Lead

PubMed Central

Rothenberg, Stephen J.; Rothenberg, Jesse C.

2005-01-01

Statistical evaluation of the dose–response function in lead epidemiology is rarely attempted. Economic evaluation of health benefits of lead reduction usually assumes a linear dose–response function, regardless of the outcome measure used. We reanalyzed a previously published study, an international pooled data set combining data from seven prospective lead studies examining contemporaneous blood lead effect on IQ (intelligence quotient) of 7-year-old children (n = 1,333). We constructed alternative linear multiple regression models with linear blood lead terms (linear–linear dose response) and natural-log–transformed blood lead terms (log-linear dose response). We tested the two lead specifications for nonlinearity in the models, compared the two lead specifications for significantly better fit to the data, and examined the effects of possible residual confounding on the functional form of the dose–response relationship. We found that a log-linear lead–IQ relationship was a significantly better fit than was a linear–linear relationship for IQ (p = 0.009), with little evidence of residual confounding of included model variables. We substituted the log-linear lead–IQ effect in a previously published health benefits model and found that the economic savings due to U.S. population lead decrease between 1976 and 1999 (from 17.1 μg/dL to 2.0 μg/dL) was 2.2 times ($319 billion) that calculated using a linear–linear dose–response function ($149 billion). The Centers for Disease Control and Prevention action limit of 10 μg/dL for children fails to protect against most damage and economic cost attributable to lead exposure. PMID:16140626

Extrinsic Contribution and Instability Properties in Lead-Based and Lead-Free Piezoceramics

PubMed Central

García, José Eduardo

2015-01-01

Piezoceramic materials generally exhibit a notable instability of their functional properties when they work under real external conditions. This undesirable effect, known as nonlinear behavior, is mostly associated with the extrinsic contribution to material response. In this article, the role of the ferroelectric domain walls’ motion in the nonlinear response in the most workable lead-based and lead-free piezoceramics is reviewed. Initially, the extrinsic origin of the nonlinear response is discussed in terms of the temperature dependence of material response. The influence of the crystallographic phase and of the phase boundaries on the material response are then reviewed. Subsequently, the impact of the defects created by doping in order to control the extrinsic contribution is discussed as a way of tuning material properties. Finally, some aspects related to the grain-size effect on the nonlinear response of piezoceramics are surveyed. PMID:28793681

Cellular burdens and biological effects on tissue level caused by inhaled radon progenies.

PubMed

Madas, B G; Balásházy, I; Farkas, Á; Szoke, I

2011-02-01

In the case of radon exposure, the spatial distribution of deposited radioactive particles is highly inhomogeneous in the central airways. The object of this research is to investigate the consequences of this heterogeneity regarding cellular burdens in the bronchial epithelium and to study the possible biological effects at tissue level. Applying computational fluid and particle dynamics techniques, the deposition distribution of inhaled radon daughters has been determined in a bronchial airway model for 23 min of work in the New Mexico uranium mine corresponding to 0.0129 WLM exposure. A numerical epithelium model based on experimental data has been utilised in order to quantify cellular hits and doses. Finally, a carcinogenesis model considering cell death-induced cell-cycle shortening has been applied to assess the biological responses. Present computations reveal that cellular dose may reach 1.5 Gy, which is several orders of magnitude higher than tissue dose. The results are in agreement with the histological finding that the uneven deposition distribution of radon progenies may lead to inhomogeneous spatial distribution of tumours in the bronchial airways. In addition, at the macroscopic level, the relationship between cancer risk and radiation burden seems to be non-linear.

Nonlinear response and avalanche behavior in metallic glasses

NASA Astrophysics Data System (ADS)

Riechers, B.; Samwer, K.

2017-08-01

The response to different stress amplitudes at temperatures below the glass transition temperature is analyzed by mechanical oscillatory excitation of Pd40Ni40P20 metallic glass samples in single cantilever bending geometry. While low amplitude oscillatory excitations are commonly used in mechanical spectroscopy to probe the relaxation spectrum, in this work the response to comparably high amplitudes is investigated. The strain response of the material is well below the critical yield stress even for highest stress amplitudes, implying the expectation of a linear relation between stress and strain according to Hooke's Law. However, a deviation from the linear behavior is evident, which is analyzed in terms of temperature dependence and influence of the applied stress amplitude by two different approaches of evaluation. The nonlinear approach is based on a nonlinear expansion of the stress-strain-relation, assuming an intrinsic nonlinear character of the shear or elastic modulus. The degree of nonlinearity is extracted by a period-by-period Fourier-analysis and connected to nonlinear coefficients, describing the intensity of nonlinearity at the fundamental and higher harmonic frequencies. The characteristic timescale to adapt to a significant change in stress amplitude in terms of a recovery timescale to a steady state value is connected to the structural relaxation time of the material, suggesting a connection between the observed nonlinearity and primary relaxation processes. The second approach of evaluation is termed the incremental analysis and relates the observed response behavior to avalanches, which occur due to the activation and correlation of local microstructural rearrangements. These rearrangements are connected with shear transformation zones and correspond to localized plastic events, which are superimposed on the linear response behavior of the material.

Non-destructive testing techniques based on nonlinear methods for assessment of debonding in single lap joints

NASA Astrophysics Data System (ADS)

Scarselli, G.; Ciampa, F.; Ginzburg, D.; Meo, M.

2015-04-01

Nonlinear ultrasonic non-destructive evaluation (NDE) methods can be used for the identification of defects within adhesive bonds as they rely on the detection of nonlinear elastic features for the evaluation of the bond strength. In this paper the nonlinear content of the structural response of a single lap joint subjected to ultrasonic harmonic excitation is both numerically and experimentally evaluated to identify and characterize the defects within the bonded region. Different metallic samples with the same geometry were experimentally tested in order to characterize the debonding between two plates by using two surface bonded piezoelectric transducers in pitch-catch mode. The dynamic response of the damaged samples acquired by the single receiver sensor showed the presence of higher harmonics (2nd and 3rd) and subharmonics of the fundamental frequencies. These nonlinear elastic phenomena are clearly due to nonlinear effects induced by the poor adhesion between the two plates. A new constitutive model aimed at representing the nonlinear material response generated by the interaction of the ultrasonic waves with the adhesive joint is also presented. Such a model is implemented in an explicit FE software and uses a nonlinear user defined traction-displacement relationship implemented by means of a cohesive material user model interface. The developed model is verified for the different geometrical and material configurations. Good agreement between the experimental and numerical nonlinear response showed that this model can be used as a simple and useful tool for understanding the quality of the adhesive joint.

A new modal superposition method for nonlinear vibration analysis of structures using hybrid mode shapes

NASA Astrophysics Data System (ADS)

Ferhatoglu, Erhan; Cigeroglu, Ender; Özgüven, H. Nevzat

2018-07-01

In this paper, a new modal superposition method based on a hybrid mode shape concept is developed for the determination of steady state vibration response of nonlinear structures. The method is developed specifically for systems having nonlinearities where the stiffness of the system may take different limiting values. Stiffness variation of these nonlinear systems enables one to define different linear systems corresponding to each value of the limiting equivalent stiffness. Moreover, the response of the nonlinear system is bounded by the confinement of these linear systems. In this study, a modal superposition method utilizing novel hybrid mode shapes which are defined as linear combinations of the modal vectors of the limiting linear systems is proposed to determine periodic response of nonlinear systems. In this method the response of the nonlinear system is written in terms of hybrid modes instead of the modes of the underlying linear system. This provides decrease of the number of modes that should be retained for an accurate solution, which in turn reduces the number of nonlinear equations to be solved. In this way, computational time for response calculation is directly curtailed. In the solution, the equations of motion are converted to a set of nonlinear algebraic equations by using describing function approach, and the numerical solution is obtained by using Newton's method with arc-length continuation. The method developed is applied on two different systems: a lumped parameter model and a finite element model. Several case studies are performed and the accuracy and computational efficiency of the proposed modal superposition method with hybrid mode shapes are compared with those of the classical modal superposition method which utilizes the mode shapes of the underlying linear system.

Estimation of the Nonlinear Random Coefficient Model when Some Random Effects Are Separable

ERIC Educational Resources Information Center

du Toit, Stephen H. C.; Cudeck, Robert

2009-01-01

A method is presented for marginal maximum likelihood estimation of the nonlinear random coefficient model when the response function has some linear parameters. This is done by writing the marginal distribution of the repeated measures as a conditional distribution of the response given the nonlinear random effects. The resulting distribution…

Dynamics of cochlear nonlinearity: Automatic gain control or instantaneous damping?

PubMed

Altoè, Alessandro; Charaziak, Karolina K; Shera, Christopher A

2017-12-01

Measurements of basilar-membrane (BM) motion show that the compressive nonlinearity of cochlear mechanical responses is not an instantaneous phenomenon. For this reason, the cochlear amplifier has been thought to incorporate an automatic gain control (AGC) mechanism characterized by a finite reaction time. This paper studies the effect of instantaneous nonlinear damping on the responses of oscillatory systems. The principal results are that (i) instantaneous nonlinear damping produces a noninstantaneous gain control that differs markedly from typical AGC strategies; (ii) the kinetics of compressive nonlinearity implied by the finite reaction time of an AGC system appear inconsistent with the nonlinear dynamics measured on the gerbil basilar membrane; and (iii) conversely, those nonlinear dynamics can be reproduced using an harmonic oscillator with instantaneous nonlinear damping. Furthermore, existing cochlear models that include instantaneous gain-control mechanisms capture the principal kinetics of BM nonlinearity. Thus, an AGC system with finite reaction time appears neither necessary nor sufficient to explain nonlinear gain control in the cochlea.

Modeling of Nonlinear Optical Response in Gaseous Media and Its Comparison with Experiment

NASA Astrophysics Data System (ADS)

Xia, Yi

This thesis demonstrates the model and application of nonlinear optical response with Metastable Electronic State Approach (MESA) in ultrashort laser propagation and verifies accuracy of MESA through extensive comparison with experimental data. The MESA is developed from quantum mechanics to describe the nonlinear off-resonant optical response together with strong-field ionization in gaseous medium. The conventional light-matter interaction models are based on a piece-wise approach where Kerr effect and multi-photon ionization are treated as independent nonlinear responses. In contrast, MESA is self-consistent as the response from freed electrons and bound electrons are microscopically linked. It also can be easily coupled to the Unidirectional Pulse Propagation Equations (UPPE) for large scale simulation of experiments. This work tests the implementation of MESA model in simulation of nonlinear phase transients of ultrashort pulse propagation in a gaseous medium. The phase transient has been measured through Single-Shot Supercontinuum Spectral Interferometry. This technique can achieve high temporal resolution (10 fs) and spatial resolution (5 mum). Our comparison between simulation and experiment gives a quantitive test of MESA model including post-adiabatic corrections. This is the first time such a comparison was achieved for a theory suitable for large scale numerical simulation of modern nonlinear-optics experiments. In more than one respect, ours is a first-of-a-kind achievement. In particular, • Large amount of data are compared. We compare the data of nonlinear response induced by different pump intensity in Ar and Nitrogen. The data sets are three dimensions including two transverse spacial dimensions and one axial temporal dimension which reflect the whole structure of nonlinear response including the interplay between Kerr and plasma-induced effects. The resolutions of spatial and temporal dimension are about a few micrometer and several femtosecond. • The regime of light-matter interaction investigated here is between the strong and perturbative, where the pulse intensity can induce nonlinear refractive index change and partial ionization of dielectric medium. Obviously, such regimes are difficult to study both experimentally and theoretically. • MESA is a quantum based model, but it retains the same computation complexity as conventional light-matter interaction model. MESA contains the response from both bound and continuum states in a single self-consistent "Package". So, it is fair to say that this experiment-theory comparison sets a new standard for nonlinear light-matter interaction models and their verification in the area of extreme nonlinear optics.

Smoking increases risks of all-cause and breast cancer specific mortality in breast cancer individuals: a dose-response meta-analysis of prospective cohort studies involving 39725 breast cancer cases

PubMed Central

Wang, Kang; Li, Feng; Zhang, Xiang; Li, Zhuyue; Li, Hongyuan

2016-01-01

Smoking is associated with the risks of mortality from breast cancer (BC) or all causes in BC survivors. Two-stage dose-response meta-analysis was conducted. A search of PubMed and Embase was performed, and a random-effect model was used to yield summary hazard ratios (HRs). Eleven prospective cohort studies were included. The summary HR per 10 cigarettes/day, 10 pack-years, 10 years increase were 1.10 (95% confidence interval (CI) = 1.04–1.16), 1.09 (95% CI = 1.06–1.12), 1.10 (95% CI = 1.06–1.14) for BC specific mortality, and 1.15 (95% CI = 1.10–1.19), 1.15 (95% CI = 1.10–1.20), 1.17 (95% CI = 1.11–1.23) for all-cause mortality, respectively. The linear or non-linear associations between smoking and risks of mortality from BC or all causes were revealed. Subgroup analyses suggested a positive association between ever or former smoking and the risk of all-cause mortality in BC patients, especially in high doses consumption. In conclusion, higher smoking intensity, more cumulative amount of cigarettes consumption and longer time for smoking is associated with elevated risk of mortality from BC and all causes in BC individuals. The results regarding smoking cessation and “ever or former” smokers should be treated with caution due to limited studies. PMID:27863414

Simple nonlinear modelling of earthquake response in torsionally coupled R/C structures: A preliminary study

NASA Astrophysics Data System (ADS)

Saiidi, M.

1982-07-01

The equivalent of a single degree of freedom (SDOF) nonlinear model, the Q-model-13, was examined. The study intended to: (1) determine the seismic response of a torsionally coupled building based on the multidegree of freedom (MDOF) and (SDOF) nonlinear models; and (2) develop a simple SDOF nonlinear model to calculate displacement history of structures with eccentric centers of mass and stiffness. It is shown that planar models are able to yield qualitative estimates of the response of the building. The model is used to estimate the response of a hypothetical six-story frame wall reinforced concrete building with torsional coupling, using two different earthquake intensities. It is shown that the Q-Model-13 can lead to a satisfactory estimate of the response of the structure in both cases.

Nonlinear rovibrational polarization response of water vapor to ultrashort long-wave infrared pulses

NASA Astrophysics Data System (ADS)

Schuh, K.; Rosenow, P.; Kolesik, M.; Wright, E. M.; Koch, S. W.; Moloney, J. V.

2017-10-01

We study the rovibrational polarization response of water vapor using a fully correlated optical Bloch equation approach employing data from the HITRAN database. For a 10 -μ m long-wave infrared pulse the resulting linear response is negative, with a negative nonlinear response at intermediate intensities and a positive value at higher intensities. For a model atmosphere comprised of the electronic response of argon combined with the rovibrational response of water vapor this leads to a weakened positive nonlinear response at intermediate intensities. Propagation simulations using a simplified noncorrelated approach show the resultant reduction in the peak filament intensity sustained during filamentation due to the presence of the water vapor.

Giant nonlinear response at a plasmonic nanofocus drives efficient four-wave mixing

NASA Astrophysics Data System (ADS)

Nielsen, Michael P.; Shi, Xingyuan; Dichtl, Paul; Maier, Stefan A.; Oulton, Rupert F.

2017-12-01

Efficient optical frequency mixing typically must accumulate over large interaction lengths because nonlinear responses in natural materials are inherently weak. This limits the efficiency of mixing processes owing to the requirement of phase matching. Here, we report efficient four-wave mixing (FWM) over micrometer-scale interaction lengths at telecommunications wavelengths on silicon. We used an integrated plasmonic gap waveguide that strongly confines light within a nonlinear organic polymer. The gap waveguide intensifies light by nanofocusing it to a mode cross-section of a few tens of nanometers, thus generating a nonlinear response so strong that efficient FWM accumulates over wavelength-scale distances. This technique opens up nonlinear optics to a regime of relaxed phase matching, with the possibility of compact, broadband, and efficient frequency mixing integrated with silicon photonics.

Reduced-Order Models Based on Linear and Nonlinear Aerodynamic Impulse Responses

NASA Technical Reports Server (NTRS)

Silva, Walter A.

1999-01-01

This paper discusses a method for the identification and application of reduced-order models based on linear and nonlinear aerodynamic impulse responses. The Volterra theory of nonlinear systems and an appropriate kernel identification technique are described. Insight into the nature of kernels is provided by applying the method to the nonlinear Riccati equation in a non-aerodynamic application. The method is then applied to a nonlinear aerodynamic model of RAE 2822 supercritical airfoil undergoing plunge motions using the CFL3D Navier-Stokes flow solver with the Spalart-Allmaras turbulence model. Results demonstrate the computational efficiency of the technique.

Reduced Order Models Based on Linear and Nonlinear Aerodynamic Impulse Responses

NASA Technical Reports Server (NTRS)

Silva, Walter A.

1999-01-01

This paper discusses a method for the identification and application of reduced-order models based on linear and nonlinear aerodynamic impulse responses. The Volterra theory of nonlinear systems and an appropriate kernel identification technique are described. Insight into the nature of kernels is provided by applying the method to the nonlinear Riccati equation in a non-aerodynamic application. The method is then applied to a nonlinear aerodynamic model of an RAE 2822 supercritical airfoil undergoing plunge motions using the CFL3D Navier-Stokes flow solver with the Spalart-Allmaras turbulence model. Results demonstrate the computational efficiency of the technique.

Pupil movements to light and accommodative stimulation - A comparative study.

NASA Technical Reports Server (NTRS)

Semmlow, J.; Stark, L.

1973-01-01

Isolation and definition of specific response components in pupil reflexes through comparison of the dynamic features of light-induced and accommodation-induced pupil movements. A quantitative analysis of the behavior of the complex nonlinear pupil responses reveals the presence of two independent nonlinear characteristics: a range-dependent gain and a direction dependence or movement asymmetry. These nonlinear properties are attributed to motor processes because they are observable in pupil responses to both light and accommodation stimuli. The possible mechanisms and consequences of these pupil response characteristics are quantitatively defined and discussed.

Nonlinear flutter analysis of composite panels

NASA Astrophysics Data System (ADS)

An, Xiaomin; Wang, Yan

2018-05-01

Nonlinear panel flutter is an interesting subject of fluid-structure interaction. In this paper, nonlinear flutter characteristics of curved composite panels are studied in very low supersonic flow. The composite panel with geometric nonlinearity is modeled by a nonlinear finite element method; and the responses are computed by the nonlinear Newmark algorithm. An unsteady aerodynamic solver, which contains a flux splitting scheme and dual time marching technology, is employed in calculating the unsteady pressure of the motion of the panel. Based on a half-step staggered coupled solution, the aeroelastic responses of two composite panels with different radius of R = 5 and R = 2.5 are computed and compared with each other at different dynamic pressure for Ma = 1.05. The nonlinear flutter characteristics comprising limited cycle oscillations and chaos are analyzed and discussed.

Modelling nonlinearity in piezoceramic transducers: From equations to nonlinear equivalent circuits.

PubMed

Parenthoine, D; Tran-Huu-Hue, L-P; Haumesser, L; Vander Meulen, F; Lematre, M; Lethiecq, M

2011-02-01

Quadratic nonlinear equations of a piezoelectric element under the assumptions of 1D vibration and weak nonlinearity are derived by the perturbation theory. It is shown that the nonlinear response can be represented by controlled sources that are added to the classical hexapole used to model piezoelectric ultrasonic transducers. As a consequence, equivalent electrical circuits can be used to predict the nonlinear response of a transducer taking into account the acoustic loads on the rear and front faces. A generalisation of nonlinear equivalent electrical circuits to cases including passive layers and propagation media is then proposed. Experimental results, in terms of second harmonic generation, on a coupled resonator are compared to theoretical calculations from the proposed model. Copyright © 2010 Elsevier B.V. All rights reserved.

Nonlinear tapping dynamics of multi-walled carbon nanotube tipped atomic force microcantilevers

NASA Astrophysics Data System (ADS)

Lee, S. I.; Howell, S. W.; Raman, A.; Reifenberger, R.; Nguyen, C. V.; Meyyappan, M.

2004-05-01

The nonlinear dynamics of an atomic force microcantilever (AFM) with an attached multi-walled carbon nanotube (MWCNT) tip is investigated experimentally and theoretically. We present the experimental nonlinear frequency response of a MWCNT tipped microcantilever in the tapping mode. Several unusual features in the response distinguish it from those traditionally observed for conventional tips. The MWCNT tipped AFM probe is apparently immune to conventional imaging instabilities related to the coexistence of attractive and repulsive tapping regimes. A theoretical interaction model for the system using an Euler elastica MWCNT model is developed and found to predict several unusual features of the measured nonlinear response.

Errors introduced by dose scaling for relative dosimetry

PubMed Central

Watanabe, Yoichi; Hayashi, Naoki

2012-01-01

Some dosimeters require a relationship between detector signal and delivered dose. The relationship (characteristic curve or calibration equation) usually depends on the environment under which the dosimeters are manufactured or stored. To compensate for the difference in radiation response among different batches of dosimeters, the measured dose can be scaled by normalizing the measured dose to a specific dose. Such a procedure, often called “relative dosimetry”, allows us to skip the time‐consuming production of a calibration curve for each irradiation. In this study, the magnitudes of errors due to the dose scaling procedure were evaluated by using the characteristic curves of BANG3 polymer gel dosimeter, radiographic EDR2 films, and GAFCHROMIC EBT2 films. Several sets of calibration data were obtained for each type of dosimeters, and a calibration equation of one set of data was used to estimate doses of the other dosimeters from different batches. The scaled doses were then compared with expected doses, which were obtained by using the true calibration equation specific to each batch. In general, the magnitude of errors increased with increasing deviation of the dose scaling factor from unity. Also, the errors strongly depended on the difference in the shape of the true and reference calibration curves. For example, for the BANG3 polymer gel, of which the characteristic curve can be approximated with a linear equation, the error for a batch requiring a dose scaling factor of 0.87 was larger than the errors for other batches requiring smaller magnitudes of dose scaling, or scaling factors of 0.93 or 1.02. The characteristic curves of EDR2 and EBT2 films required nonlinear equations. With those dosimeters, errors larger than 5% were commonly observed in the dose ranges of below 50% and above 150% of the normalization dose. In conclusion, the dose scaling for relative dosimetry introduces large errors in the measured doses when a large dose scaling is applied, and this procedure should be applied with special care. PACS numbers: 87.56.Da, 06.20.Dk, 06.20.fb PMID:22955658

Pharmacokinetic-pharmacodynamic modelling of the antihistaminic (H1) effect of bilastine.

PubMed

Jauregizar, Nerea; de la Fuente, Leire; Lucero, Maria Luisa; Sologuren, Ander; Leal, Nerea; Rodríguez, Mónica

2009-01-01

To model the pharmacokinetic and pharmacodynamic relationship of bilastine, a new histamine H(1) receptor antagonist, from single- and multiple-dose studies in healthy adult subjects. The pharmacokinetic model was developed from different single-dose and multiple-dose studies. In the single-dose studies, a total of 183 subjects received oral doses of bilastine 2.5, 5, 10, 20, 50, 100, 120, 160, 200 and 220 mg. In the multiple-dose studies, 127 healthy subjects received bilastine 10, 20, 40, 50, 80, 100, 140 or 200 mg/day as multiple doses during a 4-, 7- or 14-day period. The pharmacokinetic profile of bilastine was investigated using a simultaneous analysis of all concentration-time data by means of nonlinear mixed-effects modelling population pharmacokinetic software NONMEM version 6.1. Plasma concentrations were modelled according to a two-compartment open model with first-order absorption and elimination. For the pharmacodynamic analysis, the inhibitory effect of bilastine (inhibition of histamine-induced wheal and flare) was assessed on a preselected time schedule, and the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. An indirect response model was developed to describe the pharmacodynamic relationships between flare or wheal areas and bilastine plasma concentrations. Finally, once values of the concentration that produced 50% inhibition (IC(50)) had been estimated for wheal and flare effects, simulations were carried out to predict plasma concentrations for the doses of bilastine 5, 10 and 20 mg at steady state (72-96 hours). A non-compartmental analysis resulted in linear kinetics of bilastine in the dose range studied. Bilastine was characterized by two-compartmental kinetics with a rapid-absorption phase (first-order absorption rate constant = 1.50 h(-1)), plasma peak concentrations were observed at 1 hour following administration and the maximal response was observed at approximately 4 hours or later. Concerning the selected pharmacodynamic model to fit the data (type I indirect response model), this selection is attributable to the presence of inhibitory bilastine plasma concentrations that decrease the input response function, i.e. the production of the skin reaction. This model resulted in the best fit of wheal and flare data. The estimates (with relative standard errors expressed in percentages in parentheses) of the apparent zero-order rate constant for flare or wheal spontaneous appearance (k(in)), the first-order rate constant for flare or wheal disappearance (k(out)) and bilastine IC(50) values were 0.44 ng/mL/h (14.60%), 1.09 h(-1) (15.14%) and 5.15 ng/mL (16.16%), respectively, for wheal inhibition, and 11.10 ng/mL/h (8.48%), 1.03 h(-1) (8.35%) and 1.25 ng/mL (14.56%), respectively, for flare inhibition. The simulation results revealed that bilastine plasma concentrations do not remain over the IC(50) value throughout the inter-dose period for doses of 5 and 10 mg. However, with a dose of 20 mg of bilastine administered every 24 hours, plasma concentrations remained over the IC(50) value during the considered period for the flare effect, and up to 20 hours for the wheal effect. Pharmacokinetic and pharmacodynamic relationships of bilastine were reliably described with the use of an indirect response pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of bilastine.

Distinguishing graded and ultrasensitive signalling cascade kinetics by the shape of morphogen gradients in Drosophila.

PubMed

MacNamara, Shev; Baker, Ruth E; Maini, Philip K

2011-09-21

Recently, signalling gradients in cascades of two-state reaction-diffusion systems were described as a model for understanding key biochemical mechanisms that underlie development and differentiation processes in the Drosophila embryo. Diffusion-trapping at the exterior of the cell membrane triggers the mitogen-activated protein kinase (MAPK) cascade to relay an appropriate signal from the membrane to the inner part of the cytosol, whereupon another diffusion-trapping mechanism involving the nucleus reads out this signal to trigger appropriate changes in gene expression. Proposed mathematical models exhibit equilibrium distributions consistent with experimental measurements of key spatial gradients in these processes. A significant property of the formulation is that the signal is assumed to be relayed from one system to the next in a linear fashion. However, the MAPK cascade often exhibits nonlinear dose-response properties and the final remark of Berezhkovskii et al. (2009) is that this assumption remains an important property to be tested experimentally, perhaps via a new quantitative assay across multiple genetic backgrounds. In anticipation of the need to be able to sensibly interpret data from such experiments, here we provide a complementary analysis that recovers existing formulae as a special case but is also capable of handling nonlinear functional forms. Predictions of linear and nonlinear signal relays and, in particular, graded and ultrasensitive MAPK kinetics, are compared. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dietary mushroom intake may reduce the risk of breast cancer: evidence from a meta-analysis of observational studies.

PubMed

Li, Jiaoyuan; Zou, Li; Chen, Wei; Zhu, Beibei; Shen, Na; Ke, Juntao; Lou, Jiao; Song, Ranran; Zhong, Rong; Miao, Xiaoping

2014-01-01

Epidemiological studies have investigated the potential anticancer effects of mushroom intake. This review aims to clarify the evidence on the association of dietary mushroom intake with breast cancer risk and to quantify its dose-response relationship. Relevant studies were identified by a search of PubMed, Web of Science and Google Scholar up to December 31, 2013. Observational studies with relative risks (RRs) or hazard ratios (HRs) or odd ratios (ORs) and 95% confidence intervals (CIs) of breast cancer for three or more categories of mushroom intake were eligible. The quality of included studies was assessed by using Newcastle-Ottawa Scale. A dose-response meta-analysis was performed by utilizing generalized least squares trend estimation. Eight case-control studies and two cohort studies with a total of 6890 cases were ultimately included. For dose-response analysis, there was no evidence of non-linear association between mushroom consumption and breast cancer risk (P = 0.337) and a 1 g/d increment in mushroom intake conferred an RR of 0.97 (95% CI: 0.96-0.98) for breast cancer risk, with moderate heterogeneity (I(2) = 56.3%, P = 0.015). Besides, available menopause data extracted from included studies were used to evaluate the influence of menopausal statues. The summary RRs of mushroom consumption on breast cancer were 0.96 (95% CI: 0.91-1.00) for premenopausal women and 0.94 (95% CI: 0.91-0.97) for postmenopausal women, respectively. Our findings demonstrated that mushroom intake may be inversely associated with risk of breast cancer, which need to be confirmed with large-scale prospective studies further.

Predictors of Androgen Deprivation Therapy Efficacy Combined With Prostatic Irradiation: The Central Role of Tumor Stage and Radiation Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, Scott, E-mail: scott.williams@petermac.or; Buyyounouski, Mark; Kestin, Larry

2011-03-01

Purpose: To evaluate the response of clinically localized prostate cancer to various durations of planned androgen deprivation therapy (ADT) and to investigate subgroups predicting response. Methods and Materials: Data of 3,666 prostate cancer patients treated with either combined ADT and external beam radiotherapy (EBRT) or EBRT alone at four institutions were examined. ADT consisted of neoadjuvant, concurrent, or adjuvant ADT or combinations of these regimens. The primary endpoint was time to biochemical failure (nadir plus 2 ng/ml), assessed from the end of therapy. Factors predictive for the need for ADT were examined with interaction analyses. Results: The impact of increasingmore » ADT duration was nonlinear with, on average, 6 months of adjuvant ADT resulting in a reduction of the risk of biochemical failure by 38% (95% confidence interval [CI], 29%-46%), while 12, 24, and 36 months of ADT resulted in a 58% (95% CI, 47%-67%), 66% (95% CI, 55%-75%), and 66% (95% CI, 51%-77%) relative failure reduction, respectively. Patients with higher T stage cancers and those treated with lower radiation doses had a significantly greater benefit for increasing ADT duration (interaction, p = 0.016 and p = 0.007, respectively). Pretreatment prostate-specific antigen values, Gleason score, age, and risk group did not modify the response to ADT. Conclusions: The known ADT efficacy derived from randomized studies can be generalized to patients with different features, and individual predictions of potential benefit from ADT use and duration may be calculated to aid patient and physician decision making. Tumor stage and radiation dose variations were related to significantly different ADT duration effects. The validity of these predictive factors requires prospective evaluation.« less

Nonlinear dynamics of the patient’s response to drug effect during general anesthesia

NASA Astrophysics Data System (ADS)

Ionescu, Clara; Tenreiro Machado, Jose; De Keyser, Robin; Decruyenaere, Johan; Struys, Michel M. R. F.

2015-03-01

In today's healthcare paradigm, optimal sedation during anesthesia plays an important role both in patient welfare and in the socio-economic context. For the closed-loop control of general anesthesia, two drugs have proven to have stable, rapid onset times: propofol and remifentanil. These drugs are related to their effect in the bispectral index, a measure of EEG signal. In this paper wavelet time-frequency analysis is used to extract useful information from the clinical signals, since they are time-varying and mark important changes in patient's response to drug dose. Model based predictive control algorithms are employed to regulate the depth of sedation by manipulating these two drugs. The results of identification from real data and the simulation of the closed loop control performance suggest that the proposed approach can bring an improvement of 9% in overall robustness and may be suitable for clinical practice.

Nonlinear vibration and radiation from a panel with transition to chaos induced by acoustic waves

NASA Technical Reports Server (NTRS)

Maestrello, Lucio; Frendi, Abdelkader; Brown, Donald E.

1992-01-01

The dynamic response of an aircraft panel forced at resonance and off-resonance by plane acoustic waves at normal incidence is investigated experimentally and numerically. Linear, nonlinear (period doubling) and chaotic responses are obtained by increasing the sound pressure level of the excitation. The response time history is sensitive to the input level and to the frequency of excitation. The change in response behavior is due to a change in input conditions, triggered either naturally or by modulation of the bandwidth of the incident waves. Off-resonance, bifurcation is diffused and difficult to maintain, thus the panel response drifts into a linear behavior. The acoustic pressure emanated by the panel is either linear or nonlinear as is the vibration response. The nonlinear effects accumulate during the propagation with distance. Results are also obtained on the control of the panel response using damping tape on aluminum panel and using a graphite epoxy panel having the same size and weight. Good agreement is obtained between the experimental and numerical results.

Nonlinear vibration and radiation from a panel with transition to chaos

NASA Technical Reports Server (NTRS)

Maestrello, Lucio; Frendi, Abdelkader; Brown, Donald E.

1992-01-01

The dynamic response of an aircraft panel forced at resonance and off-resonance by plane acoustic waves at normal incidence is investigated experimentally and numerically. Linear, nonlinear (period doubling), and chaotic responses are obtained by increasing the sound pressure level of the excitation. The response time history is sensitive to the input level and to the frequency of excitation. The change in response behavior is due to a change in input conditions, triggered either naturally or by modulation of the bandwidth of the incident waves. Off-resonance bifurcation is diffused and difficult to maintain; thus the panel response drifts into a linear behavior. The acoustic pressure emanated by the panel is either linear or nonlinear as is the vibration response. The nonlinear effects accumulate during the propagation with distance. Results are also obtained on the control of the panel response using damping tape on an aluminum panel and a graphite epoxy panel having the same size and weight. Good agreement is obtained betwen the experimental and numerical results.

Enhanced Third-Order Optical Nonlinearity Driven by Surface-Plasmon Field Gradients.

PubMed

Kravtsov, Vasily; AlMutairi, Sultan; Ulbricht, Ronald; Kutayiah, A Ryan; Belyanin, Alexey; Raschke, Markus B

2018-05-18

Efficient nonlinear optical frequency mixing in small volumes is key for future on-chip photonic devices. However, the generally low conversion efficiency severely limits miniaturization to nanoscale dimensions. Here we demonstrate that gradient-field effects can provide for an efficient, conventionally dipole-forbidden nonlinear response. We show that a longitudinal nonlinear source current can dominate the third-order optical nonlinearity of the free electron response in gold in the technologically important near-IR frequency range where the nonlinearities due to other mechanisms are particularly small. Using adiabatic nanofocusing to spatially confine the excitation fields, from measurements of the 2ω_{1}-ω_{2} four-wave mixing response as a function of detuning ω_{1}-ω_{2}, we find up to 10^{-5} conversion efficiency with a gradient-field contribution to χ_{Au}^{(3)} of up to 10^{-19}  m^{2}/V^{2}. The results are in good agreement with the theory based on plasma hydrodynamics and underlying electron dynamics. The associated increase in the nonlinear conversion efficiency with a decreasing sample size, which can even overcompensate the volume decrease, offers a new approach for enhanced nonlinear nano-optics. This will enable more efficient nonlinear optical devices and the extension of coherent multidimensional spectroscopies to the nanoscale.

Enhanced Third-Order Optical Nonlinearity Driven by Surface-Plasmon Field Gradients

NASA Astrophysics Data System (ADS)

Kravtsov, Vasily; AlMutairi, Sultan; Ulbricht, Ronald; Kutayiah, A. Ryan; Belyanin, Alexey; Raschke, Markus B.

2018-05-01

Efficient nonlinear optical frequency mixing in small volumes is key for future on-chip photonic devices. However, the generally low conversion efficiency severely limits miniaturization to nanoscale dimensions. Here we demonstrate that gradient-field effects can provide for an efficient, conventionally dipole-forbidden nonlinear response. We show that a longitudinal nonlinear source current can dominate the third-order optical nonlinearity of the free electron response in gold in the technologically important near-IR frequency range where the nonlinearities due to other mechanisms are particularly small. Using adiabatic nanofocusing to spatially confine the excitation fields, from measurements of the 2 ω1-ω2 four-wave mixing response as a function of detuning ω1-ω2, we find up to 10-5 conversion efficiency with a gradient-field contribution to χAu(3 ) of up to 10-19 m2/V2 . The results are in good agreement with the theory based on plasma hydrodynamics and underlying electron dynamics. The associated increase in the nonlinear conversion efficiency with a decreasing sample size, which can even overcompensate the volume decrease, offers a new approach for enhanced nonlinear nano-optics. This will enable more efficient nonlinear optical devices and the extension of coherent multidimensional spectroscopies to the nanoscale.

Nonlinear Terahertz Absorption of Graphene Plasmons.

PubMed

Jadidi, Mohammad M; König-Otto, Jacob C; Winnerl, Stephan; Sushkov, Andrei B; Drew, H Dennis; Murphy, Thomas E; Mittendorff, Martin

2016-04-13

Subwavelength graphene structures support localized plasmonic resonances in the terahertz and mid-infrared spectral regimes. The strong field confinement at the resonant frequency is predicted to significantly enhance the light-graphene interaction, which could enable nonlinear optics at low intensity in atomically thin, subwavelength devices. To date, the nonlinear response of graphene plasmons and their energy loss dynamics have not been experimentally studied. We measure and theoretically model the terahertz nonlinear response and energy relaxation dynamics of plasmons in graphene nanoribbons. We employ a terahertz pump-terahertz probe technique at the plasmon frequency and observe a strong saturation of plasmon absorption followed by a 10 ps relaxation time. The observed nonlinearity is enhanced by 2 orders of magnitude compared to unpatterned graphene with no plasmon resonance. We further present a thermal model for the nonlinear plasmonic absorption that supports the experimental results. The model shows that the observed strong linearity is caused by an unexpected red shift of plasmon resonance together with a broadening and weakening of the resonance caused by the transient increase in electron temperature. The model further predicts that even greater resonant enhancement of the nonlinear response can be expected in high-mobility graphene, suggesting that nonlinear graphene plasmonic devices could be promising candidates for nonlinear optical processing.

On the dimension of complex responses in nonlinear structural vibrations

NASA Astrophysics Data System (ADS)

Wiebe, R.; Spottswood, S. M.

2016-07-01

The ability to accurately model engineering systems under extreme dynamic loads would prove a major breakthrough in many aspects of aerospace, mechanical, and civil engineering. Extreme loads frequently induce both nonlinearities and coupling which increase the complexity of the response and the computational cost of finite element models. Dimension reduction has recently gained traction and promises the ability to distill dynamic responses down to a minimal dimension without sacrificing accuracy. In this context, the dimensionality of a response is related to the number of modes needed in a reduced order model to accurately simulate the response. Thus, an important step is characterizing the dimensionality of complex nonlinear responses of structures. In this work, the dimensionality of the nonlinear response of a post-buckled beam is investigated. Significant detail is dedicated to carefully introducing the experiment, the verification of a finite element model, and the dimensionality estimation algorithm as it is hoped that this system may help serve as a benchmark test case. It is shown that with minor modifications, the method of false nearest neighbors can quantitatively distinguish between the response dimension of various snap-through, non-snap-through, random, and deterministic loads. The state-space dimension of the nonlinear system in question increased from 2-to-10 as the system response moved from simple, low-level harmonic to chaotic snap-through. Beyond the problem studied herein, the techniques developed will serve as a prescriptive guide in developing fast and accurate dimensionally reduced models of nonlinear systems, and eventually as a tool for adaptive dimension-reduction in numerical modeling. The results are especially relevant in the aerospace industry for the design of thin structures such as beams, panels, and shells, which are all capable of spatio-temporally complex dynamic responses that are difficult and computationally expensive to model.

Predicted Risk of Radiation-Induced Cancers After Involved Field and Involved Node Radiotherapy With or Without Intensity Modulation for Early-Stage Hodgkin Lymphoma in Female Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weber, Damien C., E-mail: damien.weber@unige.ch; Johanson, Safora; Peguret, Nicolas

2011-10-01

Purpose: To assess the excess relative risk (ERR) of radiation-induced cancers (RIC) in female patients with Hodgkin lymphoma (HL) female patients treated with conformal (3DCRT), intensity modulated (IMRT), or volumetric modulated arc (RA) radiation therapy. Methods and Materials: Plans for 10 early-stage HL female patients were computed for 3DCRT, IMRT, and RA with involved field RT (IFRT) and involvednode RT (INRT) radiation fields. Organs at risk dose--volume histograms were computed and inter-compared for IFRT vs. INRT and 3DCRT vs. IMRT/RA, respectively. The ERR for cancer induction in breasts, lungs, and thyroid was estimated using both linear and nonlinear models. Results:more » The mean estimated ERR for breast, lung, and thyroid were significantly lower (p < 0.01) with INRT than with IFRT planning, regardless of the radiation delivery technique used, assuming a linear dose-risk relationship. We found that using the nonlinear model, the mean ERR values were significantly (p < 0.01) increased with IMRT or RA compared to those with 3DCRT planning for the breast, lung, and thyroid, using an IFRT paradigm. After INRT planning, IMRT or RA increased the risk of RIC for lung and thyroid only. Conclusions: In this comparative planning study, using a nonlinear dose--risk model, IMRT or RA increased the estimated risk of RIC for breast, lung, and thyroid for HL female patients. This study also suggests that INRT planning, compared to IFRT planning, may reduce the ERR of RIC when risk is predicted using a linear model. Observing the opposite effect, with a nonlinear model, however, questions the validity of these biologically parameterized models.« less

Adaptive iterative design (AID): a novel approach for evaluating the interactive effects of multiple stressors on aquatic organisms.

PubMed

Glaholt, Stephen P; Chen, Celia Y; Demidenko, Eugene; Bugge, Deenie M; Folt, Carol L; Shaw, Joseph R

2012-08-15

The study of stressor interactions by eco-toxicologists using nonlinear response variables is limited by required amounts of a priori knowledge, complexity of experimental designs, the use of linear models, and the lack of use of optimal designs of nonlinear models to characterize complex interactions. Therefore, we developed AID, an adaptive-iterative design for eco-toxicologist to more accurately and efficiently examine complex multiple stressor interactions. AID incorporates the power of the general linear model and A-optimal criteria with an iterative process that: 1) minimizes the required amount of a priori knowledge, 2) simplifies the experimental design, and 3) quantifies both individual and interactive effects. Once a stable model is determined, the best fit model is identified and the direction and magnitude of stressors, individually and all combinations (including complex interactions) are quantified. To validate AID, we selected five commonly co-occurring components of polluted aquatic systems, three metal stressors (Cd, Zn, As) and two water chemistry parameters (pH, hardness) to be tested using standard acute toxicity tests in which Daphnia mortality is the (nonlinear) response variable. We found after the initial data input of experimental data, although literature values (e.g. EC-values) may also be used, and after only two iterations of AID, our dose response model was stable. The model ln(Cd)*ln(Zn) was determined the best predictor of Daphnia mortality response to the combined effects of Cd, Zn, As, pH, and hardness. This model was then used to accurately identify and quantify the strength of both greater- (e.g. As*Cd) and less-than additive interactions (e.g. Cd*Zn). Interestingly, our study found only binary interactions significant, not higher order interactions. We conclude that AID is more efficient and effective at assessing multiple stressor interactions than current methods. Other applications, including life-history endpoints commonly used by regulators, could benefit from AID's efficiency in assessing water quality criteria. Copyright © 2012 Elsevier B.V. All rights reserved.

Tracing the transition of a macro electron shuttle into nonlinear response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Chulki; Prada, Marta; Qin, Hua

We present a study on a macroscopic electron shuttle in the transition from linear to nonlinear response. The shuttle consists of a classical mechanical pendulum situated between two capacitor plates. The metallic pendulum enables mechanical transfer of electrons between the plates, hence allowing to directly trace electron shuttling in the time domain. By applying a high voltage to the plates, we drive the system into a controlled nonlinear response, where we observe period doubling.

WE-D-210-04: Radiation-Induced Polymerization of Ultrasound Contrast Agents in View of Non-Invasive Dosimetry in External Beam Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Callens, M; Verboven, E; Van Den Abeele, K

2015-06-15

Purpose: Ultrasound contrast agents (UCA’s) based on gas-filled microbubbles encapsulated by an amphiphilic shell are well established as safe and effective echo-enhancers in diagnostic imaging. In view of an alternative application of UCA’s, we investigated the use of targeted microbubbles as radiation sensors for external beam radiation therapy. As radiation induces permanent changes in the microbubble’s physico-chemical properties, a robust measure of these changes can provide a direct or indirect estimate of the applied radiation dose. For instance, by analyzing the ultrasonic dispersion characteristics of microbubble distributions before and after radiation treatment, an estimate of the radiation dose at themore » location of the irradiated volume can be made. To increase the radiation sensitivity of microbubbles, polymerizable diacetylene molecules can be incorporated into the shell. This study focuses on characterizing the acoustic response and quantifying the chemical modifications as a function of radiation dose. Methods: Lipid/diacetylene microbubbles were irradiated with a 6 MV photon beam using dose levels in the range of 0–150 Gy. The acoustic response of the microbubbles was monitored by ultrasonic through-transmission measurements in the range of 500 kHz to 20 MHz, thereby providing the dispersion relations of the phase velocity, attenuation and nonlinear coefficient. In addition, the radiation-induced chemical modifications were quantified using UV-VIS spectroscopy. Results: UV-VIS spectroscopy measurements indicate that ionizing radiation induces the polymerization of diacetylenes incorporated in the microbubble shell. The polymer yield strongly depends on the shell composition and the radiation-dose. The acoustic response is inherently related to the visco-elastic properties of the shell and is strongly influenced by the shell composition and the physico-chemical changes in the environment. Conclusion: Diacetylene-containing microbubbles are polymerizable under influence of ionizing radiation and are a promising design concept within the development of a novel non-invasive in-vivo radiation dosimeter for external beam radiation therapy. This work was funded by the Research Foundation - Flanders (FWO)« less

Nonlinear Dynamics of Electroelastic Dielectric Elastomers

DTIC Science & Technology

2018-01-30

research will significantly advance the basic science and fundamental understanding of how rate- dependent material response couples to large, nonlinear...experimental studies of constrained dielectric elastomer films, a transition in the surface instability mechanism depending on the elastocapillary number...fundamental understanding of how rate- dependent material response couples to large, nonlinear material deformation under applied electrostatic loading to

Estimation of Sonic Fatigue by Reduced-Order Finite Element Based Analyses

NASA Technical Reports Server (NTRS)

Rizzi, Stephen A.; Przekop, Adam

2006-01-01

A computationally efficient, reduced-order method is presented for prediction of sonic fatigue of structures exhibiting geometrically nonlinear response. A procedure to determine the nonlinear modal stiffness using commercial finite element codes allows the coupled nonlinear equations of motion in physical degrees of freedom to be transformed to a smaller coupled system of equations in modal coordinates. The nonlinear modal system is first solved using a computationally light equivalent linearization solution to determine if the structure responds to the applied loading in a nonlinear fashion. If so, a higher fidelity numerical simulation in modal coordinates is undertaken to more accurately determine the nonlinear response. Comparisons of displacement and stress response obtained from the reduced-order analyses are made with results obtained from numerical simulation in physical degrees-of-freedom. Fatigue life predictions from nonlinear modal and physical simulations are made using the rainflow cycle counting method in a linear cumulative damage analysis. Results computed for a simple beam structure under a random acoustic loading demonstrate the effectiveness of the approach and compare favorably with results obtained from the solution in physical degrees-of-freedom.

Accuracy of three-dimensional seismic ground response analysis in time domain using nonlinear numerical simulations

NASA Astrophysics Data System (ADS)

Liang, Fayun; Chen, Haibing; Huang, Maosong

2017-07-01

To provide appropriate uses of nonlinear ground response analysis for engineering practice, a three-dimensional soil column with a distributed mass system and a time domain numerical analysis were implemented on the OpenSees simulation platform. The standard mesh of a three-dimensional soil column was suggested to be satisfied with the specified maximum frequency. The layered soil column was divided into multiple sub-soils with a different viscous damping matrix according to the shear velocities as the soil properties were significantly different. It was necessary to use a combination of other one-dimensional or three-dimensional nonlinear seismic ground analysis programs to confirm the applicability of nonlinear seismic ground motion response analysis procedures in soft soil or for strong earthquakes. The accuracy of the three-dimensional soil column finite element method was verified by dynamic centrifuge model testing under different peak accelerations of the earthquake. As a result, nonlinear seismic ground motion response analysis procedures were improved in this study. The accuracy and efficiency of the three-dimensional seismic ground response analysis can be adapted to the requirements of engineering practice.

Colombeau algebra as a mathematical tool for investigating step load and step deformation of systems of nonlinear springs and dashpots

NASA Astrophysics Data System (ADS)

Průša, Vít; Řehoř, Martin; Tůma, Karel

2017-02-01

The response of mechanical systems composed of springs and dashpots to a step input is of eminent interest in the applications. If the system is formed by linear elements, then its response is governed by a system of linear ordinary differential equations. In the linear case, the mathematical method of choice for the analysis of the response is the classical theory of distributions. However, if the system contains nonlinear elements, then the classical theory of distributions is of no use, since it is strictly limited to the linear setting. Consequently, a question arises whether it is even possible or reasonable to study the response of nonlinear systems to step inputs. The answer is positive. A mathematical theory that can handle the challenge is the so-called Colombeau algebra. Building on the abstract result by Průša and Rajagopal (Int J Non-Linear Mech 81:207-221, 2016), we show how to use the theory in the analysis of response of nonlinear spring-dashpot and spring-dashpot-mass systems.

Nonlocal nonlinear refraction in Hibiscus sabdariffa with large phase shifts.

PubMed

Ramírez-Martínez, D; Alvarado-Méndez, E; Trejo-Durán, M; Vázquez-Guevara, M A

2014-10-20

In this work we present a study of nonlinear optical properties in organic materials (hibiscus sabdariffa). Our results demonstrate that the medium exhibits a highly nonlocal nonlinear response. We show preliminary numerical results of the transmittance as nonlocal response by considering, simultaneously, the nonlinear absorption and refraction in media. Numerical results are accord to measurement obtained by Z- scan technique where we observe large phase shifts. We also analyze the far field diffraction ring patterns of the sample.

Physical activity and the risk of gestational diabetes mellitus: a systematic review and dose-response meta-analysis of epidemiological studies.

PubMed

Aune, Dagfinn; Sen, Abhijit; Henriksen, Tore; Saugstad, Ola Didrik; Tonstad, Serena

2016-10-01

Physical activity has been inconsistently associated with risk of gestational diabetes mellitus in epidemiological studies, and questions remain about the strength and shape of the dose-response relationship between the two. We therefore conducted a systematic review and meta-analysis of cohort studies and randomized trials on physical activity and gestational diabetes mellitus. PubMed, Embase and Ovid databases were searched for cohort studies, and randomized controlled trials of physical activity and risk of gestational diabetes mellitus, up to August 5th 2015. Summary relative risks (RRs) were estimated using a random effects model. Twenty-five studies (26 publications) were included. For total physical activity the summary RR for high versus low activity was 0.62 (95 % CI 0.41-0.94, I 2  = 0 %, n = 4) before pregnancy, and 0.66 (95 % CI 0.36-1.21, I 2  = 0 %, n = 3) during pregnancy. For leisure-time physical activity the respective summary RRs for high versus low activity was 0.78 (95 % CI 0.61-1.00, I 2  = 47 %, n = 8) before pregnancy, and it was 0.80 (95 % CI 0.64-1.00, I 2  = 17 %, n = 17) during pregnancy. The summary RR for pre-pregnancy activity was 0.70 (95 % CI 0.49-1.01, I 2  = 72.6 %, n = 3) per increment of 5 h/week and for activity during pregnancy was 0.98 (95 % CI 0.87-1.09, I 2  = 0 %, n = 3) per 5 h/week. There was evidence of a nonlinear association between physical activity before pregnancy and the risk of gestational diabetes mellitus, p nonlinearity  = 0.005, with a slightly steeper association at lower levels of activity although further reductions in risk were observed up to 10 h/week. There was also evidence of nonlinearity for physical activity in early pregnancy, p nonlinearity  = 0.008, with no further reduction in risk above 8 h/week. There was some indication of inverse associations between walking (before and during pregnancy) and vigorous activity (before pregnancy) and the risk of gestational diabetes mellitus. This meta-analysis suggests that there is a significant inverse association between physical activity before pregnancy and in early pregnancy and the risk of gestational diabetes mellitus. Further studies are needed to clarify the association between specific types and intensities of activity and gestational diabetes mellitus.

Pre- and postnatal bisphenol A treatment results in persistent deficits in the sexual behavior of male rats, but not female rats, in adulthood.

PubMed

Jones, Bryan A; Shimell, Jordan J; Watson, Neil V

2011-02-01

Perinatal administration of the endocrine disruptor bisphenol A (BPA) reportedly inhibits the sexual behavior of sexually naïve adult male rats. In order to evaluate the effects of BPA administration during early development on later reproductive behavior, we administered one of five doses of bisphenol A daily to pregnant female rats throughout gestation and lactation, and quantified the appetitive and consummatory sexual behaviors of the resultant male and female offspring over multiple sexual encounters in adulthood. Males receiving low dose perinatal BPA (50 μg/kg bw/day) showed persistent deficits in sexual behavior in adulthood. Males receiving the highest dose (5 mg/kg bw/day), however, were indistinguishable from controls with respect to consummatory sexual behaviors but showed decreased latencies to engage in those behaviors when sexually naïve, with significant non-linear, or U-shaped, dose-response relationships observed on the first and last day of testing. Adult female sexual behavior was not affected by early BPA administration at any dose tested. These results are consistent with previous reports that BPA exerts behavioral effects especially at low doses, and further indicates that BPA can cause lasting impairment of sexual behavior in males, but does not alter the normal development of female appetitive or consummatory sexual behaviors. To our knowledge, this is the first report indicating that adult sexual performance is impaired in sexually experienced animals following perinatal exposure to bisphenol A. Copyright © 2010 Elsevier Inc. All rights reserved.

Coffee consumption and risk of all-cause, cardiovascular, and cancer mortality in smokers and non-smokers: a dose-response meta-analysis.

PubMed

Grosso, Giuseppe; Micek, Agnieszka; Godos, Justyna; Sciacca, Salvatore; Pajak, Andrzej; Martínez-González, Miguel A; Giovannucci, Edward L; Galvano, Fabio

2016-12-01

Coffee consumption has been associated with several benefits toward human health. However, its association with mortality risk has yielded contrasting results, including a non-linear relation to all-cause and cardiovascular disease (CVD) mortality and no association with cancer mortality. As smoking habits may affect the association between coffee and health outcomes, the aim of the present study was to update the latest dose-response meta-analysis of prospective cohort studies on the association between coffee consumption and mortality risk and conduct stratified analyses by smoking status and other potential confounders. A systematic search was conducted in electronic databases to identify relevant studies, risk estimates were retrieved from the studies, and dose-response analysis was modeled by using restricted cubic splines. A total of 31 studies comprising 1610,543 individuals and 183,991 cases of all-cause, 34,574 of CVD, and 40,991 of cancer deaths were selected. Analysis showed decreased all-cause [relative risk (RR) = 0.86, 95 % confidence interval (CI) = 0.82, 0.89)] and CVD mortality risk (RR = 0.85, 95 % CI = 0.77, 0.93) for consumption of up to 4 cups/day of coffee, while higher intakes were associated with no further lower risk. When analyses were restricted only to non-smokers, a linear decreased risk of all-cause (RR = 0.94, 95 % CI = 0.93, 0.96), CVD (RR = 0.94, 95 % CI = 0.91, 0.97), and cancer mortality (RR = 0.98, 95 % CI = 0.96, 1.00) for 1 cup/day increase was found. The search for other potential confounders, including dose-response analyses in subgroups by gender, geographical area, year of publication, and type of coffee, showed no relevant differences between strata. In conclusion, coffee consumption is associated with decreased risk of mortality from all-cause, CVD, and cancer; however, smoking modifies the observed risk when studying the role of coffee on human health.

Nonlinear dynamics in ecosystem response to climatic change: Case studies and policy implications

USGS Publications Warehouse

Burkett, Virginia R.; Wilcox, Douglas A.; Stottlemyer, Robert; Barrow, Wylie; Fagre, Dan; Baron, Jill S.; Price, Jeff; Nielsen, Jennifer L.; Allen, Craig D.; Peterson, David L.; Ruggerone, Greg; Doyle, Thomas

2005-01-01

Many biological, hydrological, and geological processes are interactively linked in ecosystems. These ecological phenomena normally vary within bounded ranges, but rapid, nonlinear changes to markedly different conditions can be triggered by even small differences if threshold values are exceeded. Intrinsic and extrinsic ecological thresholds can lead to effects that cascade among systems, precluding accurate modeling and prediction of system response to climate change. Ten case studies from North America illustrate how changes in climate can lead to rapid, threshold-type responses within ecological communities; the case studies also highlight the role of human activities that alter the rate or direction of system response to climate change. Understanding and anticipating nonlinear dynamics are important aspects of adaptation planning since responses of biological resources to changes in the physical climate system are not necessarily proportional and sometimes, as in the case of complex ecological systems, inherently nonlinear.

Model updating strategy for structures with localised nonlinearities using frequency response measurements

NASA Astrophysics Data System (ADS)

Wang, Xing; Hill, Thomas L.; Neild, Simon A.; Shaw, Alexander D.; Haddad Khodaparast, Hamed; Friswell, Michael I.

2018-02-01

This paper proposes a model updating strategy for localised nonlinear structures. It utilises an initial finite-element (FE) model of the structure and primary harmonic response data taken from low and high amplitude excitations. The underlying linear part of the FE model is first updated using low-amplitude test data with established techniques. Then, using this linear FE model, the nonlinear elements are localised, characterised, and quantified with primary harmonic response data measured under stepped-sine or swept-sine excitations. Finally, the resulting model is validated by comparing the analytical predictions with both the measured responses used in the updating and with additional test data. The proposed strategy is applied to a clamped beam with a nonlinear mechanism and good agreements between the analytical predictions and measured responses are achieved. Discussions on issues of damping estimation and dealing with data from amplitude-varying force input in the updating process are also provided.

Parametric Study on the Response of Compression-Loaded Composite Shells With Geometric and Material Imperfections

NASA Technical Reports Server (NTRS)

Hilburger, Mark W.; Starnes, James H., Jr.

2004-01-01

The results of a parametric study of the effects of initial imperfections on the buckling and postbuckling response of three unstiffened thinwalled compression-loaded graphite-epoxy cylindrical shells with different orthotropic and quasi-isotropic shell-wall laminates are presented. The imperfections considered include initial geometric shell-wall midsurface imperfections, shell-wall thickness variations, local shell-wall ply-gaps associated with the fabrication process, shell-end geometric imperfections, nonuniform applied end loads, and variations in the boundary conditions including the effects of elastic boundary conditions. A high-fidelity nonlinear shell analysis procedure that accurately accounts for the effects of these imperfections on the nonlinear responses and buckling loads of the shells is described. The analysis procedure includes a nonlinear static analysis that predicts stable response characteristics of the shells and a nonlinear transient analysis that predicts unstable response characteristics.

Nonlinear hybrid modal synthesis based on branch modes for dynamic analysis of assembled structure

NASA Astrophysics Data System (ADS)

Huang, Xing-Rong; Jézéquel, Louis; Besset, Sébastien; Li, Lin; Sauvage, Olivier

2018-01-01

This paper describes a simple and fast numerical procedure to study the steady state responses of assembled structures with nonlinearities along continuous interfaces. The proposed strategy is based on a generalized nonlinear modal superposition approach supplemented by a double modal synthesis strategy. The reduced nonlinear modes are derived by combining a single nonlinear mode method with reduction techniques relying on branch modes. The modal parameters containing essential nonlinear information are determined and then employed to calculate the stationary responses of the nonlinear system subjected to various types of excitation. The advantages of the proposed nonlinear modal synthesis are mainly derived in three ways: (1) computational costs are considerably reduced, when analyzing large assembled systems with weak nonlinearities, through the use of reduced nonlinear modes; (2) based on the interpolation models of nonlinear modal parameters, the nonlinear modes introduced during the first step can be employed to analyze the same system under various external loads without having to reanalyze the entire system; and (3) the nonlinear effects can be investigated from a modal point of view by analyzing these nonlinear modal parameters. The proposed strategy is applied to an assembled system composed of plates and nonlinear rubber interfaces. Simulation results have proven the efficiency of this hybrid nonlinear modal synthesis, and the computation time has also been significantly reduced.

A fast method to emulate an iterative POCS image reconstruction algorithm.

PubMed

Zeng, Gengsheng L

2017-10-01

Iterative image reconstruction algorithms are commonly used to optimize an objective function, especially when the objective function is nonquadratic. Generally speaking, the iterative algorithms are computationally inefficient. This paper presents a fast algorithm that has one backprojection and no forward projection. This paper derives a new method to solve an optimization problem. The nonquadratic constraint, for example, an edge-preserving denoising constraint is implemented as a nonlinear filter. The algorithm is derived based on the POCS (projections onto projections onto convex sets) approach. A windowed FBP (filtered backprojection) algorithm enforces the data fidelity. An iterative procedure, divided into segments, enforces edge-enhancement denoising. Each segment performs nonlinear filtering. The derived iterative algorithm is computationally efficient. It contains only one backprojection and no forward projection. Low-dose CT data are used for algorithm feasibility studies. The nonlinearity is implemented as an edge-enhancing noise-smoothing filter. The patient studies results demonstrate its effectiveness in processing low-dose x ray CT data. This fast algorithm can be used to replace many iterative algorithms. © 2017 American Association of Physicists in Medicine.

Response of Non-Linear Shock Absorbers-Boundary Value Problem Analysis

NASA Astrophysics Data System (ADS)

Rahman, M. A.; Ahmed, U.; Uddin, M. S.

2013-08-01

A nonlinear boundary value problem of two degrees-of-freedom (DOF) untuned vibration damper systems using nonlinear springs and dampers has been numerically studied. As far as untuned damper is concerned, sixteen different combinations of linear and nonlinear springs and dampers have been comprehensively analyzed taking into account transient terms. For different cases, a comparative study is made for response versus time for different spring and damper types at three important frequency ratios: one at r = 1, one at r > 1 and one at r <1. The response of the system is changed because of the spring and damper nonlinearities; the change is different for different cases. Accordingly, an initially stable absorber may become unstable with time and vice versa. The analysis also shows that higher nonlinearity terms make the system more unstable. Numerical simulation includes transient vibrations. Although problems are much more complicated compared to those for a tuned absorber, a comparison of the results generated by the present numerical scheme with the exact one shows quite a reasonable agreement

Generating giant and tunable nonlinearity in a macroscopic mechanical resonator from a single chemical bond.

PubMed

Huang, Pu; Zhou, Jingwei; Zhang, Liang; Hou, Dong; Lin, Shaochun; Deng, Wen; Meng, Chao; Duan, Changkui; Ju, Chenyong; Zheng, Xiao; Xue, Fei; Du, Jiangfeng

2016-05-26

Nonlinearity in macroscopic mechanical systems may lead to abundant phenomena for fundamental studies and potential applications. However, it is difficult to generate nonlinearity due to the fact that macroscopic mechanical systems follow Hooke's law and respond linearly to external force, unless strong drive is used. Here we propose and experimentally realize high cubic nonlinear response in a macroscopic mechanical system by exploring the anharmonicity in chemical bonding interactions. We demonstrate the high tunability of nonlinear response by precisely controlling the chemical bonding interaction, and realize, at the single-bond limit, a cubic elastic constant of 1 × 10(20) N m(-3). This enables us to observe the resonator's vibrational bi-states transitions driven by the weak Brownian thermal noise at 6 K. This method can be flexibly applied to a variety of mechanical systems to improve nonlinear responses, and can be used, with further improvements, to explore macroscopic quantum mechanics.

Generating giant and tunable nonlinearity in a macroscopic mechanical resonator from a single chemical bond

PubMed Central

Huang, Pu; Zhou, Jingwei; Zhang, Liang; Hou, Dong; Lin, Shaochun; Deng, Wen; Meng, Chao; Duan, Changkui; Ju, Chenyong; Zheng, Xiao; Xue, Fei; Du, Jiangfeng

2016-01-01

Nonlinearity in macroscopic mechanical systems may lead to abundant phenomena for fundamental studies and potential applications. However, it is difficult to generate nonlinearity due to the fact that macroscopic mechanical systems follow Hooke's law and respond linearly to external force, unless strong drive is used. Here we propose and experimentally realize high cubic nonlinear response in a macroscopic mechanical system by exploring the anharmonicity in chemical bonding interactions. We demonstrate the high tunability of nonlinear response by precisely controlling the chemical bonding interaction, and realize, at the single-bond limit, a cubic elastic constant of 1 × 1020 N m−3. This enables us to observe the resonator's vibrational bi-states transitions driven by the weak Brownian thermal noise at 6 K. This method can be flexibly applied to a variety of mechanical systems to improve nonlinear responses, and can be used, with further improvements, to explore macroscopic quantum mechanics. PMID:27225287

Influence of unbalance on the nonlinear dynamical response and stability of flexible rotor-bearing systems

NASA Technical Reports Server (NTRS)

Gunter, E. J.; Humphris, R. R.; Springer, H.

1983-01-01

In this paper, some of the effects of unbalance on the nonlinear response and stability of flexible rotor-bearing systems is presented from both a theoretical and experimental standpoint. In a linear system, operating above its stability threshold, the amplitude of motion grows exponentially with time and the orbits become unbounded. In an actual system, this is not necessarily the case. The actual amplitudes of motion may be bounded due to various nonlinear effects in the system. These nonlinear effects cause limit cycles of motion. Nonlinear effects are inherent in fluid film bearings and seals. Other contributors to nonlinear effects are shafts, couplings and foundations. In addition to affecting the threshold of stability, the nonlinear effects can cause jump phenomena to occur at not only the critical speeds, but also at stability onset or restabilization speeds.

On the Response of a Nonlinear Structure to High Kurtosis Non-Gaussian Random Loadings

NASA Technical Reports Server (NTRS)

Rizzi, Stephen A.; Przekop, Adam; Turner, Travis L.

2011-01-01

This paper is a follow-on to recent work by the authors in which the response and high-cycle fatigue of a nonlinear structure subject to non-Gaussian loadings was found to vary markedly depending on the nature of the loading. There it was found that a non-Gaussian loading having a steady rate of short-duration, high-excursion peaks produced essentially the same response as would have been incurred by a Gaussian loading. In contrast, a non-Gaussian loading having the same kurtosis, but with bursts of high-excursion peaks was found to elicit a much greater response. This work is meant to answer the question of when consideration of a loading probability distribution other than Gaussian is important. The approach entailed nonlinear numerical simulation of a beam structure under Gaussian and non-Gaussian random excitations. Whether the structure responded in a Gaussian or non-Gaussian manner was determined by adherence to, or violations of, the Central Limit Theorem. Over a practical range of damping, it was found that the linear response to a non-Gaussian loading was Gaussian when the period of the system impulse response is much greater than the rate of peaks in the loading. Lower damping reduced the kurtosis, but only when the linear response was non-Gaussian. In the nonlinear regime, the response was found to be non-Gaussian for all loadings. The effect of a spring-hardening type of nonlinearity was found to limit extreme values and thereby lower the kurtosis relative to the linear response regime. In this case, lower damping gave rise to greater nonlinearity, resulting in lower kurtosis than a higher level of damping.

Nonlinear Analysis of Airfoil High-Intensity Gust Response Using a High-Order Prefactored Compact Code

NASA Technical Reports Server (NTRS)

Crivellini, A.; Golubev, V.; Mankbadi, R.; Scott, J. R.; Hixon, R.; Povinelli, L.; Kiraly, L. James (Technical Monitor)

2002-01-01

The nonlinear response of symmetric and loaded airfoils to an impinging vortical gust is investigated in the parametric space of gust dimension, intensity, and frequency. The study, which was designed to investigate the validity limits for a linear analysis, is implemented by applying a nonlinear high-order prefactored compact code and comparing results with linear solutions from the GUST3D frequency-domain solver. Both the unsteady aerodynamic and acoustic gust responses are examined.

Nonlinear normal modes modal interactions and isolated resonance curves

DOE PAGES

Kuether, Robert J.; Renson, L.; Detroux, T.; ...

2015-05-21

The objective of the present study is to explore the connection between the nonlinear normal modes of an undamped and unforced nonlinear system and the isolated resonance curves that may appear in the damped response of the forced system. To this end, an energy balance technique is used to predict the amplitude of the harmonic forcing that is necessary to excite a specific nonlinear normal mode. A cantilever beam with a nonlinear spring at its tip serves to illustrate the developments. Furthermore, the practical implications of isolated resonance curves are also discussed by computing the beam response to sine sweepmore » excitations of increasing amplitudes.« less

Cytogenetic toxicity of vincristine.

PubMed

Choudhury, R C; Das, B; Misra, S; Jagdale, M B

2000-01-01

The anticancer drugs vincristine sulphate (VCR) and cyclophosphamide (CTX) were tested for their cytogenetic effects in the bone marrow cells of Swiss mice. The end points investigated were chromosomal aberrations and mitotic index at 24 hours posttreatment and micronuclei (MN) at 30 hours posttreatment in bone marrow cells of male and female mice after a single intraperitoneal exposure. The doses tested were VCR 0.25, 0.5, and 1.0 mg/kg and CTX 40 mg/kg b.w. of mice. Significant percentages of chromosomal aberrations and significant numbers of micronuclei per thousand polychromatic erythrocytes (PCEs) that were induced were recorded from bone marrow of each of the VCR-treated groups of mice. There were no significant differences between the percentages of dividing cells in the VCR-treated group and the vehicle control groups of mice. Peculiarly, in the chromosomal aberration study, the male mice were found to be more responsive to VCR than the females, and the aberrations per hundred metaphases were found to be decreased when the dose of VCR was increased. The percentage of dividing cells was also higher with the lowest dose of VCR tested. However, there was a dose-dependent, but nonlinear, increase in MN per thousand PCEs. The results were compared with the already available fragmentary and self-contradictory data on the genotoxicity of VCR in mice and in other mammalian test systems.

Acute radiation risk models

NASA Astrophysics Data System (ADS)

Smirnova, Olga

Biologically motivated mathematical models, which describe the dynamics of the major hematopoietic lineages (the thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems) in acutely/chronically irradiated humans are developed. These models are implemented as systems of nonlinear differential equations, which variables and constant parameters have clear biological meaning. It is shown that the developed models are capable of reproducing clinical data on the dynamics of these systems in humans exposed to acute radiation in the result of incidents and accidents, as well as in humans exposed to low-level chronic radiation. Moreover, the averaged value of the "lethal" dose rates of chronic irradiation evaluated within models of these four major hematopoietic lineages coincides with the real minimal dose rate of lethal chronic irradiation. The demonstrated ability of the models of the human thrombocytopoietic, lymphocytopoietic, granulocytopoietic, and erythropoietic systems to predict the dynamical response of these systems to acute/chronic irradiation in wide ranges of doses and dose rates implies that these mathematical models form an universal tool for the investigation and prediction of the dynamics of the major human hematopoietic lineages for a vast pattern of irradiation scenarios. In particular, these models could be applied for the radiation risk assessment for health of astronauts exposed to space radiation during long-term space missions, such as voyages to Mars or Lunar colonies, as well as for health of people exposed to acute/chronic irradiation due to environmental radiological events.

Experimental Investigation of the Acoustic Nonlinear Behavior in Granular Polymer Bonded Explosives with Progressive Fatigue Damage

PubMed Central

Yang, Zhanfeng; Tian, Yong; Li, Weibin; Zhou, Haiqiang; Zhang, Weibin; Li, Jingming

2017-01-01

The measurement of acoustic nonlinear response is known as a promising technique to characterize material micro-damages. In this paper, nonlinear ultrasonic approach is used to characterize the evolution of fatigue induced micro-cracks in polymer bonded explosives. The variations of acoustic nonlinearity with respect to fatigue cycles in the specimens are obtained in this investigation. The present results show a significant increase of acoustic nonlinearity with respect to fatigue cycles. The experimental observation of the correlation between the acoustic nonlinearity and fatigue cycles in carbon/epoxy laminates, verifies that an acoustic nonlinear response can be used to evaluate the progressive fatigue damage in the granular polymer bonded explosives. The sensitivity comparison of nonlinear and linear parameters of ultrasonic waves in the specimens shows that nonlinear acoustic parameters are more promising indicators to fatigue induced micro-damage than linear ones. The feasibility study of the micro-damage assessment of polymer bonded explosives by nonlinear ultrasonic technique in this work can be applied to damage identification, material degradation monitoring, and lifetime prediction of the explosive parts. PMID:28773017

Experimental Investigation of the Acoustic Nonlinear Behavior in Granular Polymer Bonded Explosives with Progressive Fatigue Damage.

PubMed

Yang, Zhanfeng; Tian, Yong; Li, Weibin; Zhou, Haiqiang; Zhang, Weibin; Li, Jingming

2017-06-16

The measurement of acoustic nonlinear response is known as a promising technique to characterize material micro-damages. In this paper, nonlinear ultrasonic approach is used to characterize the evolution of fatigue induced micro-cracks in polymer bonded explosives. The variations of acoustic nonlinearity with respect to fatigue cycles in the specimens are obtained in this investigation. The present results show a significant increase of acoustic nonlinearity with respect to fatigue cycles. The experimental observation of the correlation between the acoustic nonlinearity and fatigue cycles in carbon/epoxy laminates, verifies that an acoustic nonlinear response can be used to evaluate the progressive fatigue damage in the granular polymer bonded explosives. The sensitivity comparison of nonlinear and linear parameters of ultrasonic waves in the specimens shows that nonlinear acoustic parameters are more promising indicators to fatigue induced micro-damage than linear ones. The feasibility study of the micro-damage assessment of polymer bonded explosives by nonlinear ultrasonic technique in this work can be applied to damage identification, material degradation monitoring, and lifetime prediction of the explosive parts.

Nonlinear Response Of MSSS Bridges Under Earthquake Ground Motions: Case Studies

DOT National Transportation Integrated Search

1999-10-01

This report presents the results of the second phase of a comprehensive analytical study on the seismic response of highway bridges in New Jersey. The overall objective of this phase of the study was to evaluate the nonlinear seismic response of actu...

Dose-response association of physical activity with acute myocardial infarction: do amount and intensity matter?

PubMed

Elosua, Roberto; Redondo, Ana; Segura, Antonio; Fiol, Miquel; Aldasoro, Elena; Vega, Gema; Forteza, Jordi; Martí, Helena; Arteagoitia, José María; Marrugat, Jaume

2013-11-01

The aims of this study were to analyze the dose-response association between leisure time physical activity (PA) practice and myocardial infarction (MI), considering not only the total amount but also the amount of PA at different levels of intensity, and to determine whether these associations were modified by age. In a population-based age- and sex-matched case-control study, all first acute MI patients aged 25 to 74 years were prospectively registered in four Spanish hospitals between 2002 and 2004. Controls were randomly selected from population-based samples recruited during the same period of time. The Minnesota PA questionnaire was administered to assess total energy expenditure in PA and in light-, moderate-, and high-intensity PA. Finally, 1339 cases and 1339 controls were included. The association between PA and MI likelihood was non-linear, with significantly lower MI odds at low practice levels (≥ 500 MET·min/week), lowest odds around 1500 MET·min/week, and a plateau thereafter. Light- (in subjects older than 64 years), moderate-, and high-intensity PA produced similar benefits. Most of the population could reduce their likelihood of MI by engaging in PA at a moderate level of intensity or, in individuals older than 64 years, at a light level of intensity. © 2013.

Under which climate and soil conditions the plant productivity-precipitation relationship is linear or nonlinear?

PubMed

Ye, Jian-Sheng; Pei, Jiu-Ying; Fang, Chao

2018-03-01

Understanding under which climate and soil conditions the plant productivity-precipitation relationship is linear or nonlinear is useful for accurately predicting the response of ecosystem function to global environmental change. Using long-term (2000-2016) net primary productivity (NPP)-precipitation datasets derived from satellite observations, we identify >5600pixels in the North Hemisphere landmass that fit either linear or nonlinear temporal NPP-precipitation relationships. Differences in climate (precipitation, radiation, ratio of actual to potential evapotranspiration, temperature) and soil factors (nitrogen, phosphorous, organic carbon, field capacity) between the linear and nonlinear types are evaluated. Our analysis shows that both linear and nonlinear types exhibit similar interannual precipitation variabilities and occurrences of extreme precipitation. Permutational multivariate analysis of variance suggests that linear and nonlinear types differ significantly regarding to radiation, ratio of actual to potential evapotranspiration, and soil factors. The nonlinear type possesses lower radiation and/or less soil nutrients than the linear type, thereby suggesting that nonlinear type features higher degree of limitation from resources other than precipitation. This study suggests several factors limiting the responses of plant productivity to changes in precipitation, thus causing nonlinear NPP-precipitation pattern. Precipitation manipulation and modeling experiments should combine with changes in other climate and soil factors to better predict the response of plant productivity under future climate. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimisation of the vibrational response of ultrasonic cutting systems

NASA Astrophysics Data System (ADS)

Cartmell, M. P.; Lim, F. C. N.; Cardoni, A.; Lucas, M.

2005-10-01

This paper provides an account of an investigation into possible dynamic interactions between two coupled non-linear sub-systems, each possessing opposing non-linear overhang characteristics in the frequency domain in terms of positive and negative cubic stiffnesses. This system is a two-degree-of-freedom Duffing oscillator in which certain non-linear effects can be advantageously neutralised under specific conditions. This theoretical vehicle has been used as a preliminary methodology for understanding the interactive behaviour within typical industrial ultrasonic cutting components. Ultrasonic energy is generated within a piezoelectric exciter, which is inherently non-linear, and which is coupled to a bar- or block-horn, and to one or more material cutting blades, for example. The horn/blade configurations are also non-linear, and within the whole system there are response features which are strongly reminiscent of positive and negative cubic stiffness effects. The two-degree-of-freedom model is analysed and it is shown that a practically useful mitigating effect on the overall non-linear response of the system can be created under certain conditions when one of the cubic stiffnesses is varied. It has also been shown experimentally that coupling of ultrasonic components with different non-linear characteristics can strongly influence the performance of the system and that the general behaviour of the hypothetical theoretical model is indeed borne out in practice. Further experiments have shown that a multiple horn/blade configuration can, under certain circumstances, display autoparametric responses based on the forced response of the desired longitudinal mode parametrically exciting an undesired lateral mode. Typical autoparametric response phenomena have been observed and are presented at the end of the paper.

Single point estimation of phenytoin dosing: a reappraisal.

PubMed

Koup, J R; Gibaldi, M; Godolphin, W

1981-11-01

A previously proposed method for estimation of phenytoin dosing requirement using a single serum sample obtained 24 hours after intravenous loading dose (18 mg/Kg) has been re-evaluated. Using more realistic values for the volume of distribution of phenytoin (0.4 to 1.2 L/Kg), simulations indicate that the proposed method will fail to consistently predict dosage requirements. Additional simulations indicate that two samples obtained during the 24 hour interval following the iv loading dose could be used to more reliably predict phenytoin dose requirement. Because of the nonlinear relationship which exists between phenytoin dose administration rate (RO) and the mean steady state serum concentration (CSS), small errors in prediction of the required RO result in much larger errors in CSS.

Nonlinear system identification technique validation

NASA Astrophysics Data System (ADS)

Rudko, M.; Bussgang, J. J.

1982-01-01

This final technical report describes the results obtained by SIGNATRON, Inc. of Lexington MA on Air Force Contract F30602-80-C-0104 for Rome Air Development Center. The objective of this effort is to develop a technique for identifying system response of nonlinear circuits by measurements of output response to known inputs. The report describes results of a study into the system identification technique based on the pencil-of-function method previously explored by Jain (1974) and Ewen (1979). The procedure identified roles of the linear response and is intended as a first step in nonlinear response and is intended as a first step in nonlinear circuit identification. There are serious implementation problems associated with the original approach such as loss of accuracy due to repeated integrations, lack of good measures of accuracy and computational iteration to identify the number of poles.

Accuracy and efficiency of published film dosimetry techniques using a flat-bed scanner and EBT3 film.

PubMed

Spelleken, E; Crowe, S B; Sutherland, B; Challens, C; Kairn, T

2018-03-01

Gafchromic EBT3 film is widely used for patient specific quality assurance of complex treatment plans. Film dosimetry techniques commonly involve the use of transmission scanning to produce TIFF files, which are analysed using a non-linear calibration relationship between the dose and red channel net optical density (netOD). Numerous film calibration techniques featured in the literature have not been independently verified or evaluated. A range of previously published film dosimetry techniques were re-evaluated, to identify whether these methods produce better results than the commonly-used non-linear, netOD method. EBT3 film was irradiated at calibration doses between 0 and 4000 cGy and 25 pieces of film were irradiated at 200 cGy to evaluate uniformity. The film was scanned using two different scanners: The Epson Perfection V800 and the Epson Expression 10000XL. Calibration curves, uncertainty in the fit of the curve, overall uncertainty and uniformity were calculated following the methods described by the different calibration techniques. It was found that protocols based on a conventional film dosimetry technique produced results that were accurate and uniform to within 1%, while some of the unconventional techniques produced much higher uncertainties (> 25% for some techniques). Some of the uncommon methods produced reliable results when irradiated to the standard treatment doses (< 400 cGy), however none could be recommended as an efficient or accurate replacement for a common film analysis technique which uses transmission scanning, red colour channel analysis, netOD and a non-linear calibration curve for measuring doses up to 4000 cGy when using EBT3 film.

Efficient computational nonlinear dynamic analysis using modal modification response technique

NASA Astrophysics Data System (ADS)

Marinone, Timothy; Avitabile, Peter; Foley, Jason; Wolfson, Janet

2012-08-01

Generally, structural systems contain nonlinear characteristics in many cases. These nonlinear systems require significant computational resources for solution of the equations of motion. Much of the model, however, is linear where the nonlinearity results from discrete local elements connecting different components together. Using a component mode synthesis approach, a nonlinear model can be developed by interconnecting these linear components with highly nonlinear connection elements. The approach presented in this paper, the Modal Modification Response Technique (MMRT), is a very efficient technique that has been created to address this specific class of nonlinear problem. By utilizing a Structural Dynamics Modification (SDM) approach in conjunction with mode superposition, a significantly smaller set of matrices are required for use in the direct integration of the equations of motion. The approach will be compared to traditional analytical approaches to make evident the usefulness of the technique for a variety of test cases.

Equivalent circuit simulation of HPEM-induced transient responses at nonlinear loads

NASA Astrophysics Data System (ADS)

Kotzev, Miroslav; Bi, Xiaotang; Kreitlow, Matthias; Gronwald, Frank

2017-09-01

In this paper the equivalent circuit modeling of a nonlinearly loaded loop antenna and its transient responses to HPEM field excitations are investigated. For the circuit modeling the general strategy to characterize the nonlinearly loaded antenna by a linear and a nonlinear circuit part is pursued. The linear circuit part can be determined by standard methods of antenna theory and numerical field computation. The modeling of the nonlinear circuit part requires realistic circuit models of the nonlinear loads that are given by Schottky diodes. Combining both parts, appropriate circuit models are obtained and analyzed by means of a standard SPICE circuit simulator. It is the main result that in this way full-wave simulation results can be reproduced. Furthermore it is clearly seen that the equivalent circuit modeling offers considerable advantages with respect to computation speed and also leads to improved physical insights regarding the coupling between HPEM field excitation and nonlinearly loaded loop antenna.

Coupling between plate vibration and acoustic radiation

NASA Technical Reports Server (NTRS)

Frendi, Abdelkader; Maestrello, Lucio; Bayliss, Alvin

1992-01-01

A detailed numerical investigation of the coupling between the vibration of a flexible plate and the acoustic radiation is performed. The nonlinear Euler equations are used to describe the acoustic fluid while the nonlinear plate equation is used to describe the plate vibration. Linear, nonlinear, and quasi-periodic or chaotic vibrations and the resultant acoustic radiation are analyzed. We find that for the linear plate response, acoustic coupling is negligible. However, for the nonlinear and chaotic responses, acoustic coupling has a significant effect on the vibration level as the loading increases. The radiated pressure from a plate undergoing nonlinear or chaotic vibrations is found to propagate nonlinearly into the far-field. However, the nonlinearity due to wave propagation is much weaker than that due to the plate vibrations. As the acoustic wave propagates into the far-field, the relative difference in level between the fundamental and its harmonics and subharmonics decreases with distance.

Application of Nonlinear Elastic Resonance Spectroscopy For Damage Detection In Concrete: An Interesting Story

DOE Office of Scientific and Technical Information (OSTI.GOV)

Byers, Loren W.; Ten Cate, James A.; Johnson, Paul A.

2012-06-28

Nonlinear resonance ultrasound spectroscopy experiments conducted on concrete cores, one chemically and mechanically damaged by alkali-silica reactivity, and one undamaged, show that this material displays highly nonlinear wave behavior, similar to many other damaged materials. They find that the damaged sample responds more nonlinearly, manifested by a larger resonant peak and modulus shift as a function of strain amplitude. The nonlinear response indicates that there is a hysteretic influence in the stress-strain equation of state. Further, as in some other materials, slow dynamics are present. The nonlinear response they observe in concrete is an extremely sensitive indicator of damage. Ultimately,more » nonlinear wave methods applied to concrete may be used to guide mixing, curing, or other production techniques, in order to develop materials with particular desired qualities such as enhanced strength or chemical resistance, and to be used for damage inspection.« less

Population pharmacokinetics of busulfan in pediatric and young adult patients undergoing hematopoietic cell transplant: a model-based dosing algorithm for personalized therapy and implementation into routine clinical use.

PubMed

Long-Boyle, Janel R; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J; Dvorak, Christopher C

2015-04-01

Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared with conventional dose guidelines. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration at steady state) and implement a simple model-based tool for the initial dosing of busulfan in children undergoing hematopoietic cell transplantation. Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone hematopoietic cell transplantation with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the nonlinear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Modeling of busulfan time-concentration data indicates that busulfan clearance displays nonlinearity in children, decreasing up to approximately 20% between the concentrations of 250-2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan clearance were actual body weight and age. The percentage of individuals achieving a therapeutic concentration at steady state was significantly higher in subjects receiving initial doses based on the population PK model (81%) than in historical controls dosed on conventional guidelines (52%) (P = 0.02). When compared with the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults.

Computational Model of the Modulation of Gene Expression Following DNA Damage

NASA Technical Reports Server (NTRS)

Cucinotta, F. A.; Dicello, J. F.; Nikjoo, H.; Cherubini, R.

2002-01-01

High linear energy transfer (LET) radiation, such as heavy ions or neutrons, has an increased biological effectiveness compared to X rays for gene mutation, genomic instability, and carcinogenesis. In the traditional paradigm, mutations or chromosomal aberrations are causative of late effects. However, in recent years experimental evidence has demonstrated the important role of the description of the modification of gene expression by radiation in understanding the mechanisms of radiation action. In this report, approaches are discussed to the mathematical description of mRNA and protein expression kinetics following DNA damage. Several hypotheses for models of radiation modulation of protein expression are discussed including possible non-linear processes that evolve from the linear dose responses that follow the initial DNA damage produced by radiation.

The Influence of Assay Design, Blinding, and Gymnema sylvestre on Sucrose Detection by Humans.

PubMed

Aleman, Max G; Marconi, Lauren J; Nguyen, Nam H; Park, Jae M; Patino, Maria M; Wang, Yuchi; Watkins, Celeste S; Shelley, Chris

2016-01-01

The detection and grading of tastes corresponding to different taste modalities can be tested in engaging laboratory sessions using students themselves as test subjects. This article describes a series of experiments in which data pertaining to the detection of salty and sweet tastes are obtained, and the ability of the herb Gymnema sylvestre to disrupt the detection of sucrose is quantified. The effects of blinding and different assay designs on EC50 estimation are also investigated. The data obtained allow for substantial data analysis, including non-linear regression using fixed and free parameters to quantify dose-response relationships, and the use of often under-utilized permutation tests to determine significant differences when the underlying data display heteroscedasticity.

The Influence of Assay Design, Blinding, and Gymnema sylvestre on Sucrose Detection by Humans

PubMed Central

Aleman, Max G.; Marconi, Lauren J.; Nguyen, Nam H.; Park, Jae M.; Patino, Maria M.; Wang, Yuchi; Watkins, Celeste S.; Shelley, Chris

2016-01-01

The detection and grading of tastes corresponding to different taste modalities can be tested in engaging laboratory sessions using students themselves as test subjects. This article describes a series of experiments in which data pertaining to the detection of salty and sweet tastes are obtained, and the ability of the herb Gymnema sylvestre to disrupt the detection of sucrose is quantified. The effects of blinding and different assay designs on EC50 estimation are also investigated. The data obtained allow for substantial data analysis, including non-linear regression using fixed and free parameters to quantify dose-response relationships, and the use of often under-utilized permutation tests to determine significant differences when the underlying data display heteroscedasticity. PMID:27980466

Nonlinear Response and Residual Strength of Damaged Stiffened Shells Subjected to Combined Loads

NASA Technical Reports Server (NTRS)

Starnes, James H., Jr.; Britt, Vicki O.; Rose, Cheryl A.; Rankin, Charles C.

1996-01-01

The results of an analytical study of the nonlinear response of stiffened fuselage shells with long cracks are presented. The shells are modeled with a hierarchical modeling strategy and analyzed with a nonlinear shell analysis code that maintains the shell in a nonlinear equilibrium state while the crack is grown. The analysis accurately accounts for global and local structural response phenomena. Fuselage skins, frames stringers and failsafe straps are included in the models. Results are presented for various combinations of internal pressure and mechanical bending, vertical shear and torsion loads, and the effects of crack orientation and location on the shell response are described. These results indicate that the nonlinear interaction between the in-plane stress resultants and the out-of-plane displacements near a crack can significantly affect the structural response of the shell, and the stress-intensity factors associated with a crack that are used to predict residual strength. The effects of representative combined loading conditions on the stress-intensity factors associated with a crack are presented. The effects of varying structural parameters on the stress-intensity factors associated with a crack, and on self-similar and non-self-similar crack-growth are also presented.

Time-dependent behavior of passive skeletal muscle

NASA Astrophysics Data System (ADS)

Ahamed, T.; Rubin, M. B.; Trimmer, B. A.; Dorfmann, L.

2016-03-01

An isotropic three-dimensional nonlinear viscoelastic model is developed to simulate the time-dependent behavior of passive skeletal muscle. The development of the model is stimulated by experimental data that characterize the response during simple uniaxial stress cyclic loading and unloading. Of particular interest is the rate-dependent response, the recovery of muscle properties from the preconditioned to the unconditioned state and stress relaxation at constant stretch during loading and unloading. The model considers the material to be a composite of a nonlinear hyperelastic component in parallel with a nonlinear dissipative component. The strain energy and the corresponding stress measures are separated additively into hyperelastic and dissipative parts. In contrast to standard nonlinear inelastic models, here the dissipative component is modeled using an evolution equation that combines rate-independent and rate-dependent responses smoothly with no finite elastic range. Large deformation evolution equations for the distortional deformations in the elastic and in the dissipative component are presented. A robust, strongly objective numerical integration algorithm is used to model rate-dependent and rate-independent inelastic responses. The constitutive formulation is specialized to simulate the experimental data. The nonlinear viscoelastic model accurately represents the time-dependent passive response of skeletal muscle.

Biphasic Elimination of Tenofovir Diphosphate and Nonlinear Pharmacokinetics of Zidovudine Triphosphate in a Microdosing Study

PubMed Central

Chen, Jianmeng; Flexner, Charles; Liberman, Rosa G.; Skipper, Paul L.; Louissaint, Nicolette; Tannenbaum, Steven R.; Hendrix, Craig; Fuchs, Edward

2012-01-01

Objective Phase 0 studies can provide initial pharmacokinetics (PK) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of two antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens. Study Design We administered a microdose (100 μg) of 14C-labeled drug (ZDV or tenofovir disoproxil fumarate (TDF)) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in PBMCs and CD4+ cells were measured by AMS. Results The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg to 300 mg), while the intracellular TFV-DP PK were linear over the same dose range. ZDV-TP concentrations were lower in CD4+ cells versus total peripheral blood mononuclear cells (PBMCs), while TFV-DP concentrations were not different in CD4+ cells and PBMCs. Conclusion Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. AMS shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs. PMID:23187888

Enhanced nonlinear optical response of an endohedral metallofullerene through metal-to-cage charge transfer

NASA Astrophysics Data System (ADS)

Heflin, J. R.; Marciu, D.; Figura, C.; Wang, S.; Burbank, P.; Stevenson, S.; Dorn, H. C.

1998-06-01

A new mechanism for increasing the third-order nonlinear optical susceptibility, χ(3), is described for endohedral metallofullerenes. A two to three orders of magnitude increase in the nonlinear response is reported for degenerate four-wave mixing experiments conducted with solutions of Er2@C82 (isomer III) relative to empty-cage fullerenes. A value of -8.7×10-32esu is found for the molecular susceptibility, γxyyx, of Er2@C82 compared to previously reported values of γxxxx=3×10-34 esu and γxyyx=4×10-35 esu for C60. The results confirm the importance of the metal-to-cage charge-transfer mechanism for enhancing the nonlinear optical response in endohedral metallofullerenes.

Study on Nonlinear Vibration Analysis of Gear System with Random Parameters

NASA Astrophysics Data System (ADS)

Tong, Cao; Liu, Xiaoyuan; Fan, Li

2018-03-01

In order to study the dynamic characteristics of gear nonlinear vibration system and the influence of random parameters, firstly, a nonlinear stochastic vibration analysis model of gear 3-DOF is established based on Newton’s Law. And the random response of gear vibration is simulated by stepwise integration method. Secondly, the influence of stochastic parameters such as meshing damping, tooth side gap and excitation frequency on the dynamic response of gear nonlinear system is analyzed by using the stability analysis method such as bifurcation diagram and Lyapunov exponent method. The analysis shows that the stochastic process can not be neglected, which can cause the random bifurcation and chaos of the system response. This study will provide important reference value for vibration engineering designers.

Nonlinear response and bistability of driven ion acoustic waves

NASA Astrophysics Data System (ADS)

Akbari-Moghanjoughi, M.

2017-08-01

The hydrodynamic model is used to obtain a generalized pseudoforce equation through which the nonlinear response of periodically driven ion acoustic waves is studied in an electron-ion plasma with isothermal and adiabatic ion fluids. The pseudotime series, corresponding to different driving frequencies, indicates that nonlinearity effects appear more strongly for smaller frequency values. The existence of extra harmonic resonances in the nonlinear amplitude spectrum is a clear indication of the interaction of an external force with harmonic components of the nonlinear ion acoustic waves. It is shown that many plasma parameters significantly and differently affect the nonlinear resonance spectrum of ion acoustic excitations. A heuristic but accurate model for the foldover effect is used which quite satisfactorily predicts the bistability of driven plasma oscillations. It is remarked that the characteristic resonance peak of isothermal ion plasma oscillations appears at lower frequencies but is stronger compared to that of adiabatic ions. Comparison of the exact numerical results for fully nonlinear and approximate (weakly nonlinear) models indicates that a weakly nonlinear model exaggerates the hysteresis and jump phenomenon for higher values of the external force amplitude.

Ultrafast Optical Modulation of Second- and Third-Harmonic Generation from Cut-Disk-Based Metasurfaces

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sartorello, Giovanni; Olivier, Nicolas; Zhang, Jingjing

2016-08-17

We design and fabricate a metasurface composed of gold cut-disk resonators that exhibits a strong coherent nonlinear response. We experimentally demonstrate all-optical modulation of both second- and third-harmonic signals on a subpicosecond time scale. Pump probe experiments and numerical models show that the observed effects are due to the ultrafast response of the electronic excitations in the metal under external illumination. These effects pave the way for the development of novel active nonlinear metasurfaces with controllable and switchable coherent nonlinear response.

Evaluating the risk of death via the hematopoietic syndrome mode for prolonged exposure of nuclear workers to radiation delivered at very low rates.

PubMed

Scott, B R; Lyzlov, A F; Osovets, S V

1998-05-01

During a Phase-I effort, studies were planned to evaluate deterministic (nonstochastic) effects of chronic exposure of nuclear workers at the Mayak atomic complex in the former Soviet Union to relatively high levels (> 0.25 Gy) of ionizing radiation. The Mayak complex has been used, since the late 1940's, to produce plutonium for nuclear weapons. Workers at Site A of the complex were involved in plutonium breeding using nuclear reactors, and some were exposed to relatively large doses of gamma rays plus relatively small neutron doses. The Weibull normalized-dose model, which has been set up to evaluate the risk of specific deterministic effects of combined, continuous exposure of humans to alpha, beta, and gamma radiations, is here adapted for chronic exposure to gamma rays and neutrons during repeated 6-h work shifts--as occurred for some nuclear workers at Site A. Using the adapted model, key conclusions were reached that will facilitate a Phase-II study of deterministic effects among Mayak workers. These conclusions include the following: (1) neutron doses may be more important for Mayak workers than for Japanese A-bomb victims in Hiroshima and can be accounted for using an adjusted dose (which accounts for neutron relative biological effectiveness); (2) to account for dose-rate effects, normalized dose X (a dimensionless fraction of an LD50 or ED50) can be evaluated in terms of an adjusted dose; (3) nonlinear dose-response curves for the risk of death via the hematopoietic mode can be converted to linear dose-response curves (for low levels of risk) using a newly proposed dimensionless dose, D = X(V), in units of Oklad (where D is pronounced "deh"), and V is the shape parameter in the Weibull model; (4) for X < or = Xo, where Xo is the threshold normalized dose, D = 0; (5) unlike absorbed dose, the dose D can be averaged over different Mayak workers in order to calculate the average risk of death via the hematopoietic mode for the population exposed at Site A; and (6) the expected cases of death via the hematopoietic syndrome mode for Mayak workers chronically exposed during work shifts at Site A to gamma rays and neutrons can be predicted using ln(2)B M[D]; where B (pronounced "beh") is the number of workers at risk (criticality accident victims excluded); and M[D] is the average (mean) value of D (averaged over the worker population at risk, for Site A, for the time period considered). These results can be used to facilitate a Phase II study of deterministic radiation effects among Mayak workers chronically exposed to gamma rays and neutrons.

Apparent mass matrix of standing subjects exposed to multi-axial whole-body vibration.

PubMed

Tarabini, Marco; Solbiati, Stefano; Saggin, Bortolino; Scaccabarozzi, Diego

2016-08-01

This paper describes the experimental characterisation of the apparent mass matrix of eight male subjects in standing position and the identification of nonlinearities under both mono-axial and dual-axis whole-body vibration. The nonlinear behaviour of the response was studied using the conditioned response techniques considering models of increasing complexity. Results showed that the cross-axis terms are comparable to the diagonal terms. The contribution of the nonlinear effects are minor and can be endorsed to the change of modal parameters during the tests. The nonlinearity generated by the vibration magnitude is more evident in the subject response, since magnitude-dependent effects in the population are overlaid by the scatter in the subjects' biometric data. The biodynamic response is influenced by the addition of a secondary vibration axis and, in case of dual-axis vibrations, the overall magnitude has a marginal contribution. Practitioner Summary: We have measured both the diagonal and cross-axis elements of the apparent mass matrix. The effect of nonlinearities and the simultaneous presence of vibration along two axes are smaller than the inter-subject variability.

Nonlinear response of lipid-shelled microbubbles to coded excitation: implications for noninvasive atherosclerosis imaging

NASA Astrophysics Data System (ADS)

Shekhar, Himanshu; Doyley, Marvin M.

2013-03-01

Nonlinear (subharmonic/harmonic) imaging with ultrasound contrast agents (UCA) could characterize the vasa vasorum, which could help assess the risk associated with atherosclerosis. However, the sensitivity and specificity of high-frequency nonlinear imaging must be improved to enable its clinical translation. The current excitation scheme employs sine-bursts — a strategy that requires high-peak pressures to produce strong nonlinear response from UCA. In this paper, chirp-coded excitation was evaluated to assess its ability to enhance the subharmonic and harmonic response of UCA. Acoustic measurements were conducted with a pair of single-element transducers at 10-MHz transmit frequencies to evaluate the subharmonic and harmonic response of Targestar-P® (Targeson Inc., San Diego, CA, USA), a commercially available phospholipid-encapsulated contrast agent. The results of this study demonstrated a 2 - 3 fold reduction in the subharmonic threshold, and a 4 - 14 dB increase in nonlinear signal-to-noise ratio, with chirp-coded excitation. Therefore, chirp-coded excitation could be well suited for improving the imaging performance of high-frequency harmonic and subharmonic imaging.

Are Portuguese Echinochloa spp. populations still susceptible to propanil?

PubMed

Calha, I M; Matias, A; Neto, M; Rocha, F

2009-01-01

Propanil is the most important herbicide for rice weed management both at world and national level. Rice growers complains of poor control of Echinochloa was monitored in Mondego and Sorraia river valleys, Portugal. Seed samples were collected from the affected area and tested. After the first screening of 37 populations, the sensitivity of six Echinochloa spp. populations to propanil was assessed in a growth chamber dose response study (with seven rates: 0- 7200 g a.i. ha(-1)). Fresh weight was assessed 21 days after treatment and data was analysed using non-linear regression analysis and sensitivity indices (SI = ED80, less sensitive/ ED80, most sensitive) calculated for the two regions surveyed. The rates of 50% of plant growth inhibition (ED50) was calculated from the fitted equations. Four populations where confirmed susceptible with ED50 values ranging from 89 to 1866 g a.i. ha(-1). Two other populations presented ED50 values of 6538 and 9536 g a.i. ha(-1). Mondego and Sorraia SI were 2.35 and 53.55 respectively. The pattern of propanil use in the two regions could explain the higher sensitivity of Mondego populations compared to Sorraia populations. The response to a single dose Petri dish bioassay (360 g a.i. L(-1)) was similar among the six populations, denoting that this method was not so sensitive as the whole plant assay to discriminate between Echinochloa spp. populations. Further studies are needed with more doses and populations since this method allows for an answer within six days, compared with 41 days with the whole plant bioassay.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

PubMed

Bercu, J P; Galloway, S M; Parris, P; Teasdale, A; Masuda-Herrera, M; Dobo, K; Heard, P; Kenyon, M; Nicolette, J; Vock, E; Ku, W; Harvey, J; White, A; Glowienke, S; Martin, E A; Custer, L; Jolly, R A; Thybaud, V

2018-04-01

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication. Copyright © 2018. Published by Elsevier Inc.

Subpiosecond Third Order Nonlinear Response in Polythiophene and Thiopene Based Thin Films

NASA Technical Reports Server (NTRS)

Harris, D.; Royer, E.; Dorsinville, R.

1995-01-01

Ultrafast relaxation kinetics of the third order nonlinear susceptibility of polythiophene and polycondensed thiophene-based polymer was determined by the forward degenerate four-wave mixing technique. Deep into the absorption band the nonlinear response shows only a fast component (less than 900 fs at 587 nm) while at the edge of the absorption band at 642 nm a much slower and complex decay was measured.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

PubMed

Rosario, Maria; Wyant, Timothy; Leach, Timothy; Sankoh, Serap; Scholz, Catherine; Parikh, Asit; Fox, Irving; Feagan, Brian G

2016-11-01

Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Vedolizumab maximum observed serum concentration (C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC 0-inf ) and shorter terminal elimination half-life (t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab was well tolerated by healthy volunteers.

On the origin of nonlinear elasticity in disparate rocks

DOE PAGES

Riviere, Jacques Vincent; Shokouhi, Parisa; Guyer, Robert A.; ...

2015-03-31

Dynamic acousto-elastic (DAE) studies are performed on a set of 6 rock samples (four sandstones, one soapstone, and one granite). From these studies, at 20 strain levels 10 -7 < ϵ < 10 -5, four measures characterizing the nonlinear elastic response of each sample are found. Additionally, each sample is tested with nonlinear resonant ultrasonic spectroscopy (NRUS) and a fth measure of nonlinear elastic response is found. The ve measures of the nonlinear elastic response of the samples (approximately 3 x 6 x 20 x 5 numbers as each measurement is repeated 3 times) are subjected to careful analysis usingmore » model independent statistical methods, principal component analysis and fuzzy clustering. This analysis reveals di erences among the samples and di erences among the nonlinear measures. Four of the nonlinear measures are sensing much the same physical mechanism in the samples. The fth is seeing something di erent. This is the case for all samples. Although the same physical mechanisms (two) are operating in all samples there are distinctive features in the way the physical mechanisms present themselves from sample to sample. This suggests classi cation of the samples into two groups. The numbers in this study and the classi cation of the measures/samples constitute an empirical characterization of rock nonlinear elastic properties that can serve as a valuable testing ground for physically based theories that relate rock nonlinear elastic properties to microscopic elastic features.« less

Human middle-ear nonlinearity measurements using laser Doppler vibrometry

NASA Astrophysics Data System (ADS)

Gladiné, Kilian; Muyshondt, Pieter G. G.; Dirckx, Joris J. J.

2017-12-01

It has long been supposed that the middle-ear has near to perfect linear characteristics, and several attempts have been made to investigate this hypothesis. In conclusion, the middle-ear was regarded as a linear system at least up till sound pressure levels of 120 dB. Because of the linear relationship between Doppler shift of light and the vibration velocity of the object on which the light is reflected, laser Doppler vibrometry (LDV) is an intrinsically highly linear measurement technique. Therefore it allows straightforward detection of very small nonlinearities in a vibration response. In this paper, laser Doppler vibrometry and multisine stimulation are used to detect nonlinear distortions in the vibration response at the umbo of the tympanic membrane of seven human cadaver temporal bones. Nonlinear distortions were detected starting from sound pressure levels of 99 dB and measurements were performed up to 120 dB. These distortions can be subdivided into even degree (e.g. quadratic distortion tones) and odd degree nonlinear distortions (e.g. cubic distortion tones). We illustrate that with odd multisine stimulation the level of even and odd degree nonlinear distortions can be investigated separately. In conclusion, laser Doppler vibrometry is an adequate tool to detect nonlinear distortions in the middle-ear system and to quantify the level of such distortions even at 57 dB below the vibration response. The possibility to analyze even degree and odd degree nonlinear distortion levels separately can help in future work to pinpoint the source of the nonlinearity.

Nonlinear dynamical analysis of an aeroelastic system with multi-segmented moment in the pitch degree-of-freedom

NASA Astrophysics Data System (ADS)

Vasconcellos, Rui; Abdelkefi, Abdessattar

2015-01-01

The effects of a multi-segmented nonlinearity in the pitch degree of freedom on the behavior of a two-degree of freedom aeroelastic system are investigated. The aeroelastic system is free to plunge and pitch and is supported by linear translational and nonlinear torsional springs and is subjected to an incoming flow. The unsteady representation based on the Duhamel formulation is used to model the aerodynamic loads. Using modern method of nonlinear dynamics, a nonlinear characterization is performed to identify the system's response when increasing the wind speed. It is demonstrated that four sudden transitions take place with a change in the system's response. It is shown that, in the first transition, the system's response changes from simply periodic (only main oscillating frequency) to two periods (having the main oscillating frequency and its superharmonic of order 2). In the second transition, the response of the system changes from two periods (having the main oscillating frequency and its superharmonic of order 2) to a period-1. The results also show that the third transition is accompanied by a change in the system's response from simply periodic to two periods (having the main oscillating frequency and its superharmonic of order 3). After this transition, chaotic responses take place and then the fourth transition is accompanied by a sudden change in the system's response from chaotic to two periods (having the main oscillating frequency and its superharmonic of order 3). The results show that these transitions are caused by the tangential contact between the trajectory and the multi-segmented nonlinearity boundaries and with a zero-pitch speed incidence. This observation is associated with the definition of grazing bifurcation.

Classical Michaelis-Menten and system theory approach to modeling metabolite formation kinetics.

PubMed

Popović, Jovan

2004-01-01

When single doses of drug are administered and kinetics are linear, techniques, which are based on the compartment approach and the linear system theory approach, in modeling the formation of the metabolite from the parent drug are proposed. Unlike the purpose-specific compartment approach, the methodical, conceptual and computational uniformity in modeling various linear biomedical systems is the dominant characteristic of the linear system approach technology. Saturation of the metabolic reaction results in nonlinear kinetics according to the Michaelis-Menten equation. The two compartment open model with Michaelis-Menten elimination kinetics is theorethicaly basic when single doses of drug are administered. To simulate data or to fit real data using this model, one must resort to numerical integration. A biomathematical model for multiple dosage regimen calculations of nonlinear metabolic systems in steady-state and a working example with phenytoin are presented. High correlation between phenytoin steady-state serum levels calculated from individual Km and Vmax values in the 15 adult epileptic outpatients and the observed levels at the third adjustment of phenytoin daily dose (r=0.961, p<0.01) were found.

Study of The Non-linear Uv Dosimetry In Simulated Extraterrestrial Conditions

NASA Astrophysics Data System (ADS)

Berces, A.; Kerekgyarto, T.; Ronto, G.; Lammer, H.; Kargl, G.; Komle, N. I.

In UV biological dosimetry the UV dose scale is additive starting at a value of zero ac- cording to the definition of CIE (Technical Report TC-6-18). The biological dose can be defined by a measured end-effect. In our dosimeters (phage T7 and uracil dosime- ter) exposed to natural (terrestrial) UV radiation the proportion of pyrimidin photo- products among the total photoproducts is smaller than 10 and the linear correlation between the biological and physical dose is higher than 0.9. According to the experi- mental data this linear relationship is often not valid. We observed that UV radiation did not only induce dimerisation but shorter wavelengths caused monomerisation of pyrimidin dimers. Performing the irradiation in oxygen free environment and using a Deuterium lamp as UV source, we could increase monomerisation against dimerisa- tion thus the DNA-based dosimetrySs additivity rule is not fulfilled in these conditions. In this study we will demonstrate those non-linear experiments which constitute the basis of our biological experiments on the International Space Station.

Using physiologically based pharmacokinetic modeling to address nonlinear kinetics and changes in rodent physiology and metabolism due to aging and adaptation in deriving reference values for propylene glycol methyl ether and propylene glycol methyl ether acetate.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirman, C R.; Sweeney, Lisa M.; Corley, Rick A.

2005-04-01

Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based upon transient sedation observed in F344 rats and B6C3F1 mice during a two-year inhalation study. The dose-response relationship for sedation was characterized using internal dose measures as predicted by a physiologically based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during weeksmore » 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues was selected as the most appropriate internal dose measure based upon a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) based upon the presence or absence of sedation at each time-point, species, and sex in the two year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical-specific adjustment factors were derived to replace default uncertainty factor values of ten. Nonlinear kinetics are were predicted by the model in all species at PGME concentrations exceeding 100 ppm, which complicates interspecies and low-dose extrapolations. To address this complication, reference values were derived using two approaches which differ with respect to the order in which these extrapolations were performed: (1) uncertainty factor application followed by interspecies extrapolation (PBPK modeling); and (2) interspecies extrapolation followed by uncertainty factor application. The resulting reference values for these two approaches are substantially different, with values from the former approach being 7-fold higher than those from the latter approach. Such a striking difference between the two approaches reveals an underlying issue that has received little attention in the literature regarding the application of uncertainty factors and interspecies extrapolations to compounds where saturable kinetics occur in the range of the NOAEL. Until such discussions have taken place, reference values based on the latter approach are recommended for risk assessments involving human exposures to PGME and PGMEA.« less

Association of dairy products consumption with risk of obesity in children and adults: a meta-analysis of mainly cross-sectional studies.

PubMed

Wang, Weijing; Wu, Yili; Zhang, Dongfeng

2016-12-01

The association of dairy products consumption with risk of obesity remains controversial. Therefore, we reviewed and quantitatively synthesized the evidence from observational studies with a meta-analysis. A literature search was performed in relevant databases. Random-effects model was used to pool odds ratios with 95% confidence intervals. Dose-response relationship was assessed by restricted cubic spline model. Seventeen studies for total dairy products and 16 studies for milk with risk of obesity were eligible. The pooled odds ratios (95% confidence intervals) of obesity for the highest versus lowest category of total dairy products consumption were 0.54 (0.38-0.77) in children, 0.75 (0.69-0.81) in adults, and 0.74 (0.68-0.80) for both. Evidence of a nonlinear relationship was found (P for nonlinearity  = .009). Milk consumption was also associated with risk of obesity [0.81 (0.75-0.88)] both in children [0.87 (0.80-0.95)] and in adults [0.77 (0.68-0.87)], and a linear relationship (P for nonlinearity  = .598) suggested that risk of obesity decreased by 16% [0.84 (0.77-0.92)] for every 200 g/d increment of milk consumption. This meta-analysis indicates that dairy products consumption may be associated with a decreased risk of obesity. This association may be of public health significance. Copyright © 2016 Elsevier Inc. All rights reserved.

Skin grafting impairs postsynaptic cutaneous vasodilator and sweating responses.

PubMed

Davis, Scott L; Shibasaki, Manabu; Low, David A; Cui, Jian; Keller, David M; Purdue, Gary F; Hunt, John L; Arnoldo, Brett D; Kowalske, Karen J; Crandall, Craig G

2007-01-01

This study tested the hypothesis that postsynaptic cutaneous vascular responses to endothelial-dependent and -independent vasodilators, as well as sweat gland function, are impaired in split-thickness grafted skin 5 to 9 months after surgery. Intradermal microdialysis membranes were placed in grafted and adjacent control skin, thereby allowing local delivery of the endothelial-dependent vasodilator, acetylcholine (ACh; 1 x 10(-7) to 1 x 10(-1) M at 10-fold increments) and the endothelial-independent nitric oxide donor, sodium nitroprusside (SNP; 5 x 10(-8) to 5 x 10(-2) M at 10-fold increments). Skin blood flow and sweat rate were simultaneously assessed over the semipermeable portion of the membrane. Cutaneous vascular conductance (CVC) was calculated from the ratio of laser Doppler-derived skin blood flow to mean arterial blood pressure. deltaCVC responses from baseline to these drugs were modeled via nonlinear regression curve fitting to identify the dose of ACh and SNP causing 50% of the maximal vasodilator response (EC50). A rightward shift in the CVC dose response curve for ACh was observed in grafted (EC50 = -2.61 +/- 0.44 log M) compared to adjacent control skin (EC50 = -3.34 +/- 0.46 log M; P = .003), whereas the mean EC50 for SNP was similar between grafted (EC50 = -4.21 +/- 0.94 log M) and adjacent control skin (EC50 = -3.87 +/- 0.65 log M; P = 0.332). Only minimal sweating to exogenous ACh was observed in grafted skin whereas normal sweating was observed in control skin. Increased EC50 and decreased maximal CVC responses to the exogenous administration of ACh suggest impairment of endothelial-dependent cutaneous vasodilator responses in grafted skin 5 to 9 months after surgery. Greatly attenuated sweating responses to ACh suggests either abnormal or an absence of functional sweat glands in the grafted skin.

Coherent source interaction, third-order nonlinear response of synthesized PEG coated magnetite nanoparticles in polyethylene glycol and its application

NASA Astrophysics Data System (ADS)

Gopal, S. Veena; Chitrambalam, S.; Joe, I. Hubert

2018-01-01

Third-order nonlinear response of synthesized polyethylene glycol coated Fe3O4 nanoparticles dispersed in a suitable solvent, polyethylene glycol has been studied. The structural characterization of the synthesized magnetite nanoparticles were carried out. The linear optical property of the synthesized magnetite nanoparticles was investigated using UV-visible technique. Both closed and open aperture Z-scan techniques have been performed at 532 nm with pulse width 5 ns and repetition rate 10 Hz. It was found that polyethylene glycol coated magnetite exhibits reverse saturable absorption, with significant nonlinear absorption coefficient. Two-photon absorption intensity dependent positive nonlinear refraction coefficients indicate self focusing phenomena. Results show that higher concentration gives better nonlinear and optical limiting properties.

Nonlinear response of GaAs gratings in the extraordinary transmission regime.

PubMed

Vincenti, Maria Antonietta; de Ceglia, Domenico; Scalora, Michael

2011-12-01

We theoretically describe a way to enhance harmonic generation from subwavelength slits milled on semiconductor substrates in strongly absorptive regimes. The metal-like response typical of semiconductors, like GaAs and GaP, triggers enhanced transmission and nonlinear optical phenomena in the deep UV range. We numerically study correlations between linear and nonlinear responses and their intricacies in infinite arrays, and highlight differences between nonlinear surface and magnetic sources, and intrinsic χ((2)) and χ((3)) contributions to harmonic generation. The results show promising efficiencies at wavelengths below 120 nm, and reveal coupling of TE and TM polarizations for pump and harmonic signals. A downconversion process that can regenerate pump photons with polarization orthogonal to the incident pump is also discussed. © 2011 Optical Society of America

Maximized Gust Loads of a Closed-Loop, Nonlinear Aeroelastic System Using Nonlinear Systems Theory

NASA Technical Reports Server (NTRS)

Silva, Walter A.

1999-01-01

The problem of computing the maximized gust load for a nonlinear, closed-loop aeroelastic aircraft is discusses. The Volterra theory of nonlinear systems is applied in order to define a linearized system that provides a bounds on the response of the nonlinear system of interest. The method is applied to a simplified model of an Airbus A310.

Analytical investigations of seismic responses for reinforced concrete bridge columns subjected to strong near-fault ground motion

NASA Astrophysics Data System (ADS)

Su, Chin-Kuo; Sung, Yu-Chi; Chang, Shuenn-Yih; Huang, Chao-Hsun

2007-09-01

Strong near-fault ground motion, usually caused by the fault-rupture and characterized by a pulse-like velocity-wave form, often causes dramatic instantaneous seismic energy (Jadhav and Jangid 2006). Some reinforced concrete (RC) bridge columns, even those built according to ductile design principles, were damaged in the 1999 Chi-Chi earthquake. Thus, it is very important to evaluate the seismic response of a RC bridge column to improve its seismic design and prevent future damage. Nonlinear time history analysis using step-by-step integration is capable of tracing the dynamic response of a structure during the entire vibration period and is able to accommodate the pulsing wave form. However, the accuracy of the numerical results is very sensitive to the modeling of the nonlinear load-deformation relationship of the structural member. FEMA 273 and ATC-40 provide the modeling parameters for structural nonlinear analyses of RC beams and RC columns. They use three parameters to define the plastic rotation angles and a residual strength ratio to describe the nonlinear load-deformation relationship of an RC member. Structural nonlinear analyses are performed based on these parameters. This method provides a convenient way to obtain the nonlinear seismic responses of RC structures. However, the accuracy of the numerical solutions might be further improved. For this purpose, results from a previous study on modeling of the static pushover analyses for RC bridge columns (Sung et al. 2005) is adopted for the nonlinear time history analysis presented herein to evaluate the structural responses excited by a near-fault ground motion. To ensure the reliability of this approach, the numerical results were compared to experimental results. The results confirm that the proposed approach is valid.

Differential adaptation of the linear and nonlinear components of the horizontal vestibuloocular reflex in squirrel monkeys

NASA Technical Reports Server (NTRS)

Clendaniel, Richard A.; Lasker, David M.; Minor, Lloyd B.; Shelhamer, M. J. (Principal Investigator)

2002-01-01

Previous work in squirrel monkeys has demonstrated the presence of linear and nonlinear components to the horizontal vestibuloocular reflex (VOR) evoked by high-acceleration rotations. The nonlinear component is seen as a rise in gain with increasing velocity of rotation at frequencies more than 2 Hz (a velocity-dependent gain enhancement). We have shown that there are greater changes in the nonlinear than linear component of the response after spectacle-induced adaptation. The present study was conducted to determine if the two components of the response share a common adaptive process. The gain of the VOR, in the dark, to sinusoidal stimuli at 4 Hz (peak velocities: 20-150 degrees /s) and 10 Hz (peak velocities: 20 and 100 degrees /s) was measured pre- and postadaptation. Adaptation was induced over 4 h with x0.45 minimizing spectacles. Sum-of-sines stimuli were used to induce adaptation, and the parameters of the stimuli were adjusted to invoke only the linear or both linear and nonlinear components of the response. Preadaptation, there was a velocity-dependent gain enhancement at 4 and 10 Hz. In postadaptation with the paradigms that only recruited the linear component, there was a decrease in gain and a persistent velocity-dependent gain enhancement (indicating adaptation of only the linear component). After adaptation with the paradigm designed to recruit both the linear and nonlinear components, there was a decrease in gain and no velocity-dependent gain enhancement (indicating adaptation of both components). There were comparable changes in the response to steps of acceleration. We interpret these results to indicate that separate processes drive the adaptation of the linear and nonlinear components of the response.

On the effect of acoustic coupling on random and harmonic plate vibrations

NASA Technical Reports Server (NTRS)

Frendi, A.; Robinson, J. H.

1993-01-01

The effect of acoustic coupling on random and harmonic plate vibrations is studied using two numerical models. In the coupled model, the plate response is obtained by integration of the nonlinear plate equation coupled with the nonlinear Euler equations for the surrounding acoustic fluid. In the uncoupled model, the nonlinear plate equation with an equivalent linear viscous damping term is integrated to obtain the response of the plate subject to the same excitation field. For a low-level, narrow-band excitation, the two models predict the same plate response spectra. As the excitation level is increased, the response power spectrum predicted by the uncoupled model becomes broader and more shifted towards the high frequencies than that obtained by the coupled model. In addition, the difference in response between the coupled and uncoupled models at high frequencies becomes larger. When a high intensity harmonic excitation is used, causing a nonlinear plate response, both models predict the same frequency content of the response. However, the level of the harmonics and subharmonics are higher for the uncoupled model. Comparisons to earlier experimental and numerical results show that acoustic coupling has a significant effect on the plate response at high excitation levels. Its absence in previous models may explain the discrepancy between predicted and measured responses.

Cognitive-behavioral therapy for eating disorders in primary care settings: Does it work, and does a greater dose make it more effective?

PubMed

Rose, Charlotte; Waller, Glenn

2017-12-01

This study aimed to determine whether cognitive-behavioral therapy (CBT) for eating disorders can be effective in a routine, primary care clinical setting, and to assess dose response. The participants were 47 patients who commenced treatment with a publicly-funded primary care eating disorder service. They attended 7-33 sessions of individual CBT (mean = 17), using an evidence-based approach. Routine measures were collected pre- and post-therapy. Three-quarters of the patients completed treatment. Using intention to treat analysis (multiple imputation), the patients showed substantial improvements in eating attitudes, bulimic behaviors, and depression. However, there was no association between the level of improvement and the length of therapy past the 8th to 12th session. The level of effectiveness shown here is comparable to that previously demonstrated by more specialist services in secondary and tertiary care. The nonlinear association between number of sessions and recovery highlights the importance of early change, across the eating disorders. © 2017 Wiley Periodicals, Inc.

Extreme Nonlinear Optics of High Intensity Laser Pulse Filamentation in Gases

DTIC Science & Technology

2016-05-12

of energy from femtosecond filaments. Published * absolute measurements of electronic, vibrational, and rotational nonlinear response in H2 and D2 ...coefficients in the fastest rotating molecules H2 and D2 , which can serve as a benchmark for theory of high field molecule interactions. One of the...17. Absolute measurement of the ultrafast nonlinear electronic and rovibrational response in H2 and D2 J. K. Wahlstrand, S. Zahedpour, Y.-H

Experimental Comparison of Speed : Fuel-flow and Speed-area Controls on a Turbojet Engine for Small Step Disturbances

NASA Technical Reports Server (NTRS)

Wenzel, L M; Hart, C E; Craig, R T

1957-01-01

Optimum proportional-plus-integral control settings for speed - fuel-flow control, determined by minimization of integral criteria, correlated well with analytically predicted optimum settings. Engine response data are given for a range of control settings around the optimum. An inherent nonlinearity in the speed-area loop necessitated the use of nonlinear controls. Response data for two such nonlinear control schemes are presented.

A Parametric Study of Nonlinear Seismic Response Analysis of Transmission Line Structures

PubMed Central

Wang, Yanming; Yi, Zhenhua

2014-01-01

A parametric study of nonlinear seismic response analysis of transmission line structures subjected to earthquake loading is studied in this paper. The transmission lines are modeled by cable element which accounts for the nonlinearity of the cable based on a real project. Nonuniform ground motions are generated using a stochastic approach based on random vibration analysis. The effects of multicomponent ground motions, correlations among multicomponent ground motions, wave travel, coherency loss, and local site on the responses of the cables are investigated using nonlinear time history analysis method, respectively. The results show the multicomponent seismic excitations should be considered, but the correlations among multicomponent ground motions could be neglected. The wave passage effect has a significant influence on the responses of the cables. The change of the degree of coherency loss has little influence on the response of the cables, but the responses of the cables are affected significantly by the effect of coherency loss. The responses of the cables change little with the degree of the difference of site condition changing. The effect of multicomponent ground motions, wave passage, coherency loss, and local site should be considered for the seismic design of the transmission line structures. PMID:25133215

Measuring nonlinear signal combination using EEG.

PubMed

Cunningham, Darren G M; Baker, Daniel H; Peirce, Jonathan W

2017-05-01

Relatively little is known about the processes, both linear and nonlinear, by which signals are combined beyond V1. By presenting two stimulus components simultaneously, flickering at different temporal frequencies (frequency tagging) while measuring steady-state visual evoked potentials, we can assess responses to the individual components, including direct measurements of suppression on each other, and various nonlinear responses to their combination found at intermodulation frequencies. The result is a rather rich dataset of frequencies at which responses can be found. We presented pairs of sinusoidal gratings at different temporal frequencies, forming plaid patterns that were "coherent" (looking like a checkerboard) and "noncoherent" (looking like a pair of transparently overlaid gratings), and found clear intermodulation responses to compound stimuli, indicating nonlinear summation. This might have been attributed to cross-orientation suppression except that the pattern of intermodulation responses differed for coherent and noncoherent patterns, whereas the effects of suppression (measured at the component frequencies) did not. A two-stage model of nonlinear summation involving conjunction detection with a logical AND gate described the data well, capturing the difference between coherent and noncoherent plaids over a wide array of possible response frequencies. Multistimulus frequency-tagged EEG in combination with computational modeling may be a very valuable tool in studying the conjunction of these signals. In the current study the results suggest a second-order mechanism responding selectively to coherent plaid patterns.

Dynamic analysis of nonlinear rotor-housing systems

NASA Technical Reports Server (NTRS)

Noah, Sherif T.

1988-01-01

Nonlinear analysis methods are developed which will enable the reliable prediction of the dynamic behavior of the space shuttle main engine (SSME) turbopumps in the presence of bearing clearances and other local nonlinearities. A computationally efficient convolution method, based on discretized Duhamel and transition matrix integral formulations, is developed for the transient analysis. In the formulation, the coupling forces due to the nonlinearities are treated as external forces acting on the coupled subsystems. Iteration is utilized to determine their magnitudes at each time increment. The method is applied to a nonlinear generic model of the high pressure oxygen turbopump (HPOTP). As compared to the fourth order Runge-Kutta numerical integration methods, the convolution approach proved to be more accurate and more highly efficient. For determining the nonlinear, steady-state periodic responses, an incremental harmonic balance method was also developed. The method was successfully used to determine dominantly harmonic and subharmonic responses fo the HPOTP generic model with bearing clearances. A reduction method similar to the impedance formulation utilized with linear systems is used to reduce the housing-rotor models to their coordinates at the bearing clearances. Recommendations are included for further development of the method, for extending the analysis to aperiodic and chaotic regimes and for conducting critical parameteric studies of the nonlinear response of the current SSME turbopumps.

A nonlinear dynamics of trunk kinematics during manual lifting tasks.

PubMed

Khalaf, Tamer; Karwowski, Waldemar; Sapkota, Nabin

2015-01-01

Human responses at work may exhibit nonlinear properties where small changes in the initial task conditions can lead to large changes in system behavior. Therefore, it is important to study such nonlinearity to gain a better understanding of human performance under a variety of physical, perceptual, and cognitive tasks conditions. The main objective of this study was to investigate whether the human trunk kinematics data during a manual lifting task exhibits nonlinear behavior in terms of determinist chaos. Data related to kinematics of the trunk with respect to the pelvis were collected using Industrial Lumbar Motion Monitor (ILMM), and analyzed applying the nonlinear dynamical systems methodology. Nonlinear dynamics quantifiers of Lyapunov exponents and Kaplan-Yorke dimensions were calculated and analyzed under different task conditions. The study showed that human trunk kinematics during manual lifting exhibits chaotic behavior in terms of trunk sagittal angular displacement, velocity and acceleration. The findings support the importance of accounting for nonlinear dynamical properties of biomechanical responses to lifting tasks.

Nonlinear optical response in narrow graphene nanoribbons

NASA Astrophysics Data System (ADS)

Karimi, Farhad; Knezevic, Irena

We present an iterative method to calculate the nonlinear optical response of armchair graphene nanoribbons (aGNRs) and zigzag graphene nanoribbons (zGNRs) while including the effects of dissipation. In contrast to methods that calculate the nonlinear response in the ballistic (dissipation-free) regime, here we obtain the nonlinear response of an electronic system to an external electromagnetic field while interacting with a dissipative environment (to second order). We use a self-consistent-field approach within a Markovian master-equation formalism (SCF-MMEF) coupled with full-wave electromagnetic equations, and we solve the master equation iteratively to obtain the higher-order response functions. We employ the SCF-MMEF to calculate the nonlinear conductance and susceptibility, as well as to calculate the dependence of the plasmon dispersion and plasmon propagation length on the intensity of the electromagnetic field in GNRs. The electron scattering mechanisms included in this work are scattering with intrinsic phonons, ionized impurities, surface optical phonons, and line-edge roughness. Unlike in wide GNRs, where ionized-impurity scattering dominates dissipation, in ultra-narrow nanoribbons on polar substrates optical-phonon scattering and ionized-impurity scattering are equally prominent. Support by the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering under Award DE-SC0008712.

Frequency Response of Synthetic Vocal Fold Models with Linear and Nonlinear Material Properties

ERIC Educational Resources Information Center

Shaw, Stephanie M.; Thomson, Scott L.; Dromey, Christopher; Smith, Simeon

2012-01-01

Purpose: The purpose of this study was to create synthetic vocal fold models with nonlinear stress-strain properties and to investigate the effect of linear versus nonlinear material properties on fundamental frequency (F[subscript 0]) during anterior-posterior stretching. Method: Three materially linear and 3 materially nonlinear models were…

Population response to climate change: linear vs. non-linear modeling approaches.

PubMed

Ellis, Alicia M; Post, Eric

2004-03-31

Research on the ecological consequences of global climate change has elicited a growing interest in the use of time series analysis to investigate population dynamics in a changing climate. Here, we compare linear and non-linear models describing the contribution of climate to the density fluctuations of the population of wolves on Isle Royale, Michigan from 1959 to 1999. The non-linear self excitatory threshold autoregressive (SETAR) model revealed that, due to differences in the strength and nature of density dependence, relatively small and large populations may be differentially affected by future changes in climate. Both linear and non-linear models predict a decrease in the population of wolves with predicted changes in climate. Because specific predictions differed between linear and non-linear models, our study highlights the importance of using non-linear methods that allow the detection of non-linearity in the strength and nature of density dependence. Failure to adopt a non-linear approach to modelling population response to climate change, either exclusively or in addition to linear approaches, may compromise efforts to quantify ecological consequences of future warming.

Parametric Identification of Nonlinear Dynamical Systems

NASA Technical Reports Server (NTRS)

Feeny, Brian

2002-01-01

In this project, we looked at the application of harmonic balancing as a tool for identifying parameters (HBID) in a nonlinear dynamical systems with chaotic responses. The main idea is to balance the harmonics of periodic orbits extracted from measurements of each coordinate during a chaotic response. The periodic orbits are taken to be approximate solutions to the differential equations that model the system, the form of the differential equations being known, but with unknown parameters to be identified. Below we summarize the main points addressed in this work. The details of the work are attached as drafts of papers, and a thesis, in the appendix. Our study involved the following three parts: (1) Application of the harmonic balance to a simulation case in which the differential equation model has known form for its nonlinear terms, in contrast to a differential equation model which has either power series or interpolating functions to represent the nonlinear terms. We chose a pendulum, which has sinusoidal nonlinearities; (2) Application of the harmonic balance to an experimental system with known nonlinear forms. We chose a double pendulum, for which chaotic response were easily generated. Thus we confronted a two-degree-of-freedom system, which brought forth challenging issues; (3) A study of alternative reconstruction methods. The reconstruction of the phase space is necessary for the extraction of periodic orbits from the chaotic responses, which is needed in this work. Also, characterization of a nonlinear system is done in the reconstructed phase space. Such characterizations are needed to compare models with experiments. Finally, some nonlinear prediction methods can be applied in the reconstructed phase space. We developed two reconstruction methods that may be considered if the common method (method of delays) is not applicable.

Irrationality and Quasiperiodicity in Driven Nonlinear Systems

NASA Astrophysics Data System (ADS)

Cubero, David; Casado-Pascual, Jesús; Renzoni, Ferruccio

2014-05-01

We analyze the relationship between irrationality and quasiperiodicity in nonlinear driven systems. To that purpose, we consider a nonlinear system whose steady-state response is very sensitive to the periodic or quasiperiodic character of the input signal. In the infinite time limit, an input signal consisting of two incommensurate frequencies will be recognized by the system as quasiperiodic. We show that this is, in general, not true in the case of finite interaction times. An irrational ratio of the driving frequencies of the input signal is not sufficient for it to be recognized by the nonlinear system as quasiperiodic, resulting in observations which may differ by several orders of magnitude from the expected quasiperiodic behavior. Thus, the system response depends on the nature of the irrational ratio, as well as the observation time. We derive a condition for the input signal to be identified by the system as quasiperiodic. Such a condition also takes into account the sub-Fourier response of the nonlinear system.

Experiments and numerical simulations of nonlinear vibration responses of an assembly with friction joints - Application on a test structure named "Harmony"

NASA Astrophysics Data System (ADS)

Claeys, M.; Sinou, J.-J.; Lambelin, J.-P.; Todeschini, R.

2016-03-01

In presence of friction, the frequency response function of a metallic assembly is strongly dependent on the excitation level. The local stick-slip behavior at the friction interfaces induces energy dissipation and local stiffness softening. These phenomena are studied both experimentally and numerically on a test structure named "Harmony". Concerning the numerical part, a classical complete methodology from the finite element and friction modeling to the prediction of the nonlinear vibrational response is implemented. The well-known Harmonic Balance Method with a specific condensation process on the nonlinear frictional elements is achieved. Also, vibration experiments are performed to validate not only the finite element model of the test structure named "Harmony" at low excitation levels but also to investigate the nonlinear behavior of the system on several excitation levels. A scanning laser vibrometer is used to measure the nonlinear behavior and the local stick-slip movement near the contacts.

The analysis of non-linear dynamic behavior (including snap-through) of postbuckled plates by simple analytical solution

NASA Technical Reports Server (NTRS)

Ng, C. F.

1988-01-01

Static postbuckling and nonlinear dynamic analysis of plates are usually accomplished by multimode analyses, although the methods are complicated and do not give straightforward understanding of the nonlinear behavior. Assuming single-mode transverse displacement, a simple formula is derived for the transverse load displacement relationship of a plate under in-plane compression. The formula is used to derive a simple analytical expression for the static postbuckling displacement and nonlinear dynamic responses of postbuckled plates under sinusoidal or random excitation. Regions with softening and hardening spring behavior are identified. Also, the highly nonlinear motion of snap-through and its effects on the overall dynamic response can be easily interpreted using the single-mode formula. Theoretical results are compared with experimental results obtained using a buckled aluminum panel, using discrete frequency and broadband point excitation. Some important effects of the snap-through motion on the dynamic response of the postbuckled plates are found.

Identification of Linear and Nonlinear Aerodynamic Impulse Responses Using Digital Filter Techniques

NASA Technical Reports Server (NTRS)

Silva, Walter A.

1997-01-01

This paper discusses the mathematical existence and the numerically-correct identification of linear and nonlinear aerodynamic impulse response functions. Differences between continuous-time and discrete-time system theories, which permit the identification and efficient use of these functions, will be detailed. Important input/output definitions and the concept of linear and nonlinear systems with memory will also be discussed. It will be shown that indicial (step or steady) responses (such as Wagner's function), forced harmonic responses (such as Theodorsen's function or those from doublet lattice theory), and responses to random inputs (such as gusts) can all be obtained from an aerodynamic impulse response function. This paper establishes the aerodynamic impulse response function as the most fundamental, and, therefore, the most computationally efficient, aerodynamic function that can be extracted from any given discrete-time, aerodynamic system. The results presented in this paper help to unify the understanding of classical two-dimensional continuous-time theories with modern three-dimensional, discrete-time theories. First, the method is applied to the nonlinear viscous Burger's equation as an example. Next the method is applied to a three-dimensional aeroelastic model using the CAP-TSD (Computational Aeroelasticity Program - Transonic Small Disturbance) code and then to a two-dimensional model using the CFL3D Navier-Stokes code. Comparisons of accuracy and computational cost savings are presented. Because of its mathematical generality, an important attribute of this methodology is that it is applicable to a wide range of nonlinear, discrete-time problems.

Identification of Linear and Nonlinear Aerodynamic Impulse Responses Using Digital Filter Techniques

NASA Technical Reports Server (NTRS)

Silva, Walter A.

1997-01-01

This paper discusses the mathematical existence and the numerically-correct identification of linear and nonlinear aerodynamic impulse response functions. Differences between continuous-time and discrete-time system theories, which permit the identification and efficient use of these functions, will be detailed. Important input/output definitions and the concept of linear and nonlinear systems with memory will also be discussed. It will be shown that indicial (step or steady) responses (such as Wagner's function), forced harmonic responses (such as Tbeodorsen's function or those from doublet lattice theory), and responses to random inputs (such as gusts) can all be obtained from an aerodynamic impulse response function. This paper establishes the aerodynamic impulse response function as the most fundamental, and, therefore, the most computationally efficient, aerodynamic function that can be extracted from any given discrete-time, aerodynamic system. The results presented in this paper help to unify the understanding of classical two-dimensional continuous-time theories with modem three-dimensional, discrete-time theories. First, the method is applied to the nonlinear viscous Burger's equation as an example. Next the method is applied to a three-dimensional aeroelastic model using the CAP-TSD (Computational Aeroelasticity Program - Transonic Small Disturbance) code and then to a two-dimensional model using the CFL3D Navier-Stokes code. Comparisons of accuracy and computational cost savings are presented. Because of its mathematical generality, an important attribute of this methodology is that it is applicable to a wide range of nonlinear, discrete-time problems.

[Microplate luminometry for toxicity bioassay of chemicals on luciferase].

PubMed

Ge, Hui-Lin; Liu, Shu-Shen; Chen, Fu; Luo, Jin-Hui; Lü, Dai-Zhu; Su, Bing-Xia

2013-10-01

A new microplate luminometry for the toxicity bioassay of chemicals on firefly luciferase, was developed using the multifunctional microplate reader (SpectraMax M5) to measure the luminous intensity of luciferase. Efects of luciferase concentration, luciferin concentration, ATP concentration, pH, temperature, and reaction time on the luminescence were systematically investigated. It was found that ATP exerted a biphasic response on the luciferase luminescence and the maximum relative light units (RLU) occurred at an ATP concentration of 1.1 x 10(-4) mol x L(-1). The method was successfully employed in the toxic effect test of NaF, NaCl, KBr and NaBF4 on luciferase. Using nonlinear least square technique, the dose-response curves (DRC) of the 4 chemicals were accurately fitted with the coefficient of determination (R2) between the fitted and observed responses being greater than 0.99. The median effective concentration (EC50) of the 4 chemicals were accurately measured from the DRC models. Compared with some literatures, the bioassay is a fast easy-operate and cost-effective method with high accuracy.

Recent Applications of Higher-Order Spectral Analysis to Nonlinear Aeroelastic Phenomena

NASA Technical Reports Server (NTRS)

Silva, Walter A.; Hajj, Muhammad R.; Dunn, Shane; Strganac, Thomas W.; Powers, Edward J.; Stearman, Ronald

2005-01-01

Recent applications of higher-order spectral (HOS) methods to nonlinear aeroelastic phenomena are presented. Applications include the analysis of data from a simulated nonlinear pitch and plunge apparatus and from F-18 flight flutter tests. A MATLAB model of the Texas A&MUniversity s Nonlinear Aeroelastic Testbed Apparatus (NATA) is used to generate aeroelastic transients at various conditions including limit cycle oscillations (LCO). The Gaussian or non-Gaussian nature of the transients is investigated, related to HOS methods, and used to identify levels of increasing nonlinear aeroelastic response. Royal Australian Air Force (RAAF) F/A-18 flight flutter test data is presented and analyzed. The data includes high-quality measurements of forced responses and LCO phenomena. Standard power spectral density (PSD) techniques and HOS methods are applied to the data and presented. The goal of this research is to develop methods that can identify the onset of nonlinear aeroelastic phenomena, such as LCO, during flutter testing.

Topological nature of nonlinear optical effects in solids.

PubMed

Morimoto, Takahiro; Nagaosa, Naoto

2016-05-01

There are a variety of nonlinear optical effects including higher harmonic generations, photovoltaic effects, and nonlinear Kerr rotations. They are realized by strong light irradiation to materials that results in nonlinear polarizations in the electric field. These are of great importance in studying the physics of excited states of the system as well as for applications to optical devices and solar cells. Nonlinear properties of materials are usually described by nonlinear susceptibilities, which have complex expressions including many matrix elements and energy denominators. On the other hand, a nonequilibrium steady state under an electric field periodic in time has a concise description in terms of the Floquet bands of electrons dressed by photons. We show theoretically, using the Floquet formalism, that various nonlinear optical effects, such as the shift current in noncentrosymmetric materials, photovoltaic Hall response, and photo-induced change of order parameters under the continuous irradiation of monochromatic light, can be described in a unified fashion by topological quantities involving the Berry connection and Berry curvature. We found that vector fields defined with the Berry connections in the space of momentum and/or parameters govern the nonlinear responses. This topological view offers a route to designing nonlinear optical materials.

Topological nature of nonlinear optical effects in solids

PubMed Central

Morimoto, Takahiro; Nagaosa, Naoto

2016-01-01

There are a variety of nonlinear optical effects including higher harmonic generations, photovoltaic effects, and nonlinear Kerr rotations. They are realized by strong light irradiation to materials that results in nonlinear polarizations in the electric field. These are of great importance in studying the physics of excited states of the system as well as for applications to optical devices and solar cells. Nonlinear properties of materials are usually described by nonlinear susceptibilities, which have complex expressions including many matrix elements and energy denominators. On the other hand, a nonequilibrium steady state under an electric field periodic in time has a concise description in terms of the Floquet bands of electrons dressed by photons. We show theoretically, using the Floquet formalism, that various nonlinear optical effects, such as the shift current in noncentrosymmetric materials, photovoltaic Hall response, and photo-induced change of order parameters under the continuous irradiation of monochromatic light, can be described in a unified fashion by topological quantities involving the Berry connection and Berry curvature. We found that vector fields defined with the Berry connections in the space of momentum and/or parameters govern the nonlinear responses. This topological view offers a route to designing nonlinear optical materials. PMID:27386523

A Comparison of Measurement Equivalence Methods Based on Confirmatory Factor Analysis and Item Response Theory.

ERIC Educational Resources Information Center

Flowers, Claudia P.; Raju, Nambury S.; Oshima, T. C.

Current interest in the assessment of measurement equivalence emphasizes two methods of analysis, linear, and nonlinear procedures. This study simulated data using the graded response model to examine the performance of linear (confirmatory factor analysis or CFA) and nonlinear (item-response-theory-based differential item function or IRT-Based…

A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation.

PubMed

Ding, Junjie; Wang, Yi; Lin, Weiwei; Wang, Changlian; Zhao, Limei; Li, Xingang; Zhao, Zhigang; Miao, Liyan; Jiao, Zheng

2015-03-01

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy. A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM(®) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models. The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model. The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.

Characterizing driver-response relationships in marine pelagic ecosystems for improved ocean management.

PubMed

Hunsicker, Mary E; Kappel, Carrie V; Selkoe, Kimberly A; Halpern, Benjamin S; Scarborough, Courtney; Mease, Lindley; Amrhein, Alisan

2016-04-01

Scientists and resource managers often use methods and tools that assume ecosystem components respond linearly to environmental drivers and human stressors. However, a growing body of literature demonstrates that many relationships are-non-linear, where small changes in a driver prompt a disproportionately large ecological response. We aim to provide a comprehensive assessment of the relationships between drivers and ecosystem components to identify where and when non-linearities are likely to occur. We focused our analyses on one of the best-studied marine systems, pelagic ecosystems, which allowed us to apply robust statistical techniques on a large pool of previously published studies. In this synthesis, we (1) conduct a wide literature review on single driver-response relationships in pelagic systems, (2) use statistical models to identify the degree of non-linearity in these relationships, and (3) assess whether general patterns exist in the strengths and shapes of non-linear relationships across drivers. Overall we found that non-linearities are common in pelagic ecosystems, comprising at least 52% of all driver-response relation- ships. This is likely an underestimate, as papers with higher quality data and analytical approaches reported non-linear relationships at a higher frequency (on average 11% more). Consequently, in the absence of evidence for a linear relationship, it is safer to assume a relationship is non-linear. Strong non-linearities can lead to greater ecological and socioeconomic consequences if they are unknown (and/or unanticipated), but if known they may provide clear thresholds to inform management targets. In pelagic systems, strongly non-linear relationships are often driven by climate and trophodynamic variables but are also associated with local stressors, such as overfishing and pollution, that can be more easily controlled by managers. Even when marine resource managers cannot influence ecosystem change, they can use information about threshold responses to guide how other stressors are managed and to adapt to new ocean conditions. As methods to detect and reduce uncertainty around threshold values improve, managers will be able to better understand and account for ubiquitous non-linear relationships.

Multimodal nonlinear nanophotonics (Conference Presentation)

NASA Astrophysics Data System (ADS)

Kivshar, Yuri S.

2017-05-01

Nonlinear nanophotonics is a rapidly developing field of research with many potential applications for the design of nonlinear nanoantennas, light sources, nanolasers, and ultrafast miniature metadevices. A tight confinement of the local electromagnetic fields in resonant photonic nanostructures can boost nonlinear optical effects, thus offering versatile opportunities for the subwavelength control of light. To achieve the desired functionalities, it is essential to gain flexible control over the near- and far-field properties of nanostructures. To engineer nonlinear scattering from resonant nanoscale elements, both modal and multipolar control of the nonlinear response are widely exploited for enhancing the near-field interaction and optimizing the radiation directionality. Motivated by the recent progress of all-dielectric nanophotonics, where the electric and magnetic multipolar contributions may become comparable, here we review the advances in the recently emerged field of multipolar nonlinear nanophotonics, starting from earlier relevant studies of metallic and metal-dielectric structures supporting localized plasmonic resonances to then discussing the latest results for all-dielectric nanostructures driven by Mie-type multipolar resonances and optically induced magnetic response. These recent developments suggest intriguing opportunities for a design of nonlinear subwavelength light sources with reconfigurable radiation characteristics and engineering large effective optical nonlinearities at the nanoscale, which could have important implications for novel nonlinear photonic devices operating beyond the diffraction limit.

A theoretical and experimental investigation of the linear and nonlinear impulse responses from a magnetoplasma column

NASA Technical Reports Server (NTRS)

Grody, N. C.

1973-01-01

Linear and nonlinear responses of a magnetoplasma resulting from inhomogeneity in the background plasma density are studied. The plasma response to an impulse electric field was measured and the results are compared with the theory of an inhomogeneous cold plasma. Impulse responses were recorded for the different plasma densities, static magnetic fields, and neutral pressures and generally appeared as modulated, damped oscillations. The frequency spectra of the waveforms consisted of two separated resonance peaks. For weak excitation, the results correlate with the linear theory of a cold, inhomogeneous, cylindrical magnetoplasma. The damping mechanism is identified with that of phase mixing due to inhomogeneity in plasma density. With increasing excitation voltage, the nonlinear impulse responses display stronger damping and a small increase in the frequency of oscillation.

Nonlinear dynamic response of a uni-directional model for the tile/pad space shuttle thermal protection system

NASA Technical Reports Server (NTRS)

Housner, J. M.; Edighoffer, H. H.; Park, K. C.

1980-01-01

A unidirectional analysis of the nonlinear dynamic behavior of the space shuttle tile/pad thermal protection system is developed and examined for imposed sinusoidal and random motions of the shuttle skin and/or applied tile pressure. The analysis accounts for the highly nonlinear stiffening hysteresis and viscous behavior of the pad which joins the tile to the shuttle skin. Where available, experimental data are used to confirm the validity of the analysis. Both analytical and experimental studies reveal that the system resonant frequency is very high for low amplitude oscillations but decreases rapidly to a minimum value with increasing amplitude. Analytical studies indicate that with still higher amplitude the resonant frequency increases slowly. The nonlinear pad is also responsible for the analytically and experimentally observed distorted response wave shapes having high sharp peaks when the system is subject to sinusoidal loads. Furthermore, energy dissipation in the pad is studied analytically and it is found that the energy dissipated is sufficiently high to cause rapid decay of dynamic transients. Nevertheless, the sharp peaked nonlinear responses of the system lead to higher magnification factors than would be expected in such a highly damped linear system.

Novel procedure for characterizing nonlinear systems with memory: 2017 update

NASA Astrophysics Data System (ADS)

Nuttall, Albert H.; Katz, Richard A.; Hughes, Derke R.; Koch, Robert M.

2017-05-01

The present article discusses novel improvements in nonlinear signal processing made by the prime algorithm developer, Dr. Albert H. Nuttall and co-authors, a consortium of research scientists from the Naval Undersea Warfare Center Division, Newport, RI. The algorithm, called the Nuttall-Wiener-Volterra or 'NWV' algorithm is named for its principal contributors [1], [2],[ 3] . The NWV algorithm significantly reduces the computational workload for characterizing nonlinear systems with memory. Following this formulation, two measurement waveforms are required in order to characterize a specified nonlinear system under consideration: (1) an excitation input waveform, x(t) (the transmitted signal); and, (2) a response output waveform, z(t) (the received signal). Given these two measurement waveforms for a given propagation channel, a 'kernel' or 'channel response', h= [h0,h1,h2,h3] between the two measurement points, is computed via a least squares approach that optimizes modeled kernel values by performing a best fit between measured response z(t) and a modeled response y(t). New techniques significantly diminish the exponential growth of the number of computed kernel coefficients at second and third order and alleviate the Curse of Dimensionality (COD) in order to realize practical nonlinear solutions of scientific and engineering interest.

Subharmonic response of a single-degree-of-freedom nonlinear vibro-impact system to a narrow-band random excitation.

PubMed

Haiwu, Rong; Wang, Xiangdong; Xu, Wei; Fang, Tong

2009-08-01

The subharmonic response of single-degree-of-freedom nonlinear vibro-impact oscillator with a one-sided barrier to narrow-band random excitation is investigated. The narrow-band random excitation used here is a filtered Gaussian white noise. The analysis is based on a special Zhuravlev transformation, which reduces the system to one without impacts, or velocity jumps, thereby permitting the applications of asymptotic averaging over the "fast" variables. The averaged stochastic equations are solved exactly by the method of moments for the mean-square response amplitude for the case of linear system with zero offset. A perturbation-based moment closure scheme is proposed and the formula of the mean-square amplitude is obtained approximately for the case of linear system with nonzero offset. The perturbation-based moment closure scheme is used once again to obtain the algebra equation of the mean-square amplitude of the response for the case of nonlinear system. The effects of damping, detuning, nonlinear intensity, bandwidth, and magnitudes of random excitations are analyzed. The theoretical analyses are verified by numerical results. Theoretical analyses and numerical simulations show that the peak amplitudes may be strongly reduced at large detunings or large nonlinear intensity.

Nonlinear ultrasound imaging of nanoscale acoustic biomolecules

NASA Astrophysics Data System (ADS)

Maresca, David; Lakshmanan, Anupama; Lee-Gosselin, Audrey; Melis, Johan M.; Ni, Yu-Li; Bourdeau, Raymond W.; Kochmann, Dennis M.; Shapiro, Mikhail G.

2017-02-01

Ultrasound imaging is widely used to probe the mechanical structure of tissues and visualize blood flow. However, the ability of ultrasound to observe specific molecular and cellular signals is limited. Recently, a unique class of gas-filled protein nanostructures called gas vesicles (GVs) was introduced as nanoscale (˜250 nm) contrast agents for ultrasound, accompanied by the possibilities of genetic engineering, imaging of targets outside the vasculature and monitoring of cellular signals such as gene expression. These possibilities would be aided by methods to discriminate GV-generated ultrasound signals from anatomical background. Here, we show that the nonlinear response of engineered GVs to acoustic pressure enables selective imaging of these nanostructures using a tailored amplitude modulation strategy. Finite element modeling predicted a strongly nonlinear mechanical deformation and acoustic response to ultrasound in engineered GVs. This response was confirmed with ultrasound measurements in the range of 10 to 25 MHz. An amplitude modulation pulse sequence based on this nonlinear response allows engineered GVs to be distinguished from linear scatterers and other GV types with a contrast ratio greater than 11.5 dB. We demonstrate the effectiveness of this nonlinear imaging strategy in vitro, in cellulo, and in vivo.

An approximation technique for predicting the transient response of a second order nonlinear equation

NASA Technical Reports Server (NTRS)

Laurenson, R. M.; Baumgarten, J. R.

1975-01-01

An approximation technique has been developed for determining the transient response of a nonlinear dynamic system. The nonlinearities in the system which has been considered appear in the system's dissipation function. This function was expressed as a second order polynomial in the system's velocity. The developed approximation is an extension of the classic Kryloff-Bogoliuboff technique. Two examples of the developed approximation are presented for comparative purposes with other approximation methods.

Cochlear microphonic responses to acoustic clicks in guinea pig and their relation with microphonic responses to pure tones.

PubMed

Echeverría, E L; Robles, L W

1983-02-01

Cochlear microphonic (CM) responses to acoustic transient stimuli were studied at the three more basal turns of the cochlea in the guinea pig. The responses to rarefaction and condensation pressure pulses of less than 100-mus duration were recorded using the differential electrode technique. In some animals the CM response to pure tones was recorded at the same position at which the transient response was obtained. The transient responses recorded at the three turns of the cochlea displayed a damped oscillation at a frequency consistent with the values of cutoff frequency already known for the electrode positions. Some of the responses were significantly less damped than click responses previously reported. There was a good correlation between the cutoff frequency in the frequency response curve and the frequency of oscillation in the transient response for recordings obtained at the same position in the cochlea. A nonlinear effect was observed for changes in stimulus intensity. There was a less than proportional decrease in amplitude of the initial part of the damped oscillation for a decrease of the stimulus intensity, while the late part of the response behaved almost linearly. This nonlinearity observed in the CM transient response could not be explained by a nonlinear characteristic of the sort reported in the basilar membrane of the squirrel monkey by Robles et al. [J. Acoust. Soc. Am. 59, 926-939 (1976)]; rather it seems to be a saturation nonlinearity similar to the one known for sinusoidal stimulation.

Theoretical and Analog Studies of the Effects of Nonlinear Stability Derivatives on the Longitudinal Motions of an Aircraft in Response to Step Control Deflections and to the Influence of Proportional Automatic Control

NASA Technical Reports Server (NTRS)

Curfman, Howard J , Jr

1955-01-01

Through theoretical and analog results the effects of two nonlinear stability derivatives on the longitudinal motions of an aircraft have been investigated. Nonlinear functions of pitching-moment and lift coefficients with angle of attack were considered. Analog results of aircraft motions in response to step elevator deflections and to the action of the proportional control systems are presented. The occurrence of continuous hunting oscillations was predicted and demonstrated for the attitude stabilization system with proportional control for certain nonlinear pitching-moment variations and autopilot adjustments.

Vortex-induced vibrations mitigation through a nonlinear energy sink

NASA Astrophysics Data System (ADS)

Dai, H. L.; Abdelkefi, A.; Wang, L.

2017-01-01

The passive suppression mechanism of the vortex-induced vibrations (VIV) of the cylinder by means of an essentially nonlinear element, the nonlinear energy sink (NES) is investigated. The flow-induced loads on the cylinder are modeled using a prevalent van der Pol oscillator which is experimentally validated, coupling to the structural vibrations in the presence of the NES structure. Based on the coupled nonlinear governing equations of motion, the performed analysis indicates that the mass and damping of NES have significant effects on the coupled frequency and damping of the aero-elastic system, leading to the shift of synchronization region and mitigation of vibration responses. It is demonstrated that the coupled system of flow-cylinder-NES behaves resonant interactions, showing periodic, aperiodic, and multiple stable responses which depend on the values of the NES parameters. In addition, it is found that the occurrence of multiple stable responses can enhance the nonlinear energy pumping effect, resulting in the increment of transferring energy from the flow via the cylinder to the NES, which is related to the essential nonlinearity of the sink stiffness. This results in a significant reduction in the VIV amplitudes of the primary circular cylinder for appropriate NES parameter values.

The Recommendations for Linear Measurement Techniques on the Measurements of Nonlinear System Parameters of a Joint.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Scott A; Catalfamo, Simone; Brake, Matthew R. W.

2017-01-01

In the study of the dynamics of nonlinear systems, experimental measurements often convolute the response of the nonlinearity of interest and the effects of the experimental setup. To reduce the influence of the experimental setup on the deduction of the parameters of the nonlinearity, the response of a mechanical joint is investigated under various experimental setups. These experiments first focus on quantifying how support structures and measurement techniques affect the natural frequency and damping of a linear system. The results indicate that support structures created from bungees have negligible influence on the system in terms of frequency and damping ratiomore » variations. The study then focuses on the effects of the excitation technique on the response for a linear system. The findings suggest that thinner stingers should not be used, because under the high force requirements the stinger bending modes are excited adding unwanted torsional coupling. The optimal configuration for testing the linear system is then applied to a nonlinear system in order to assess the robustness of the test configuration. Finally, recommendations are made for conducting experiments on nonlinear systems using conventional/linear testing techniques.« less

A 1-D model of the nonlinear dynamics of the human lumbar intervertebral disc

NASA Astrophysics Data System (ADS)

Marini, Giacomo; Huber, Gerd; Püschel, Klaus; Ferguson, Stephen J.

2017-01-01

Lumped parameter models of the spine have been developed to investigate its response to whole body vibration. However, these models assume the behaviour of the intervertebral disc to be linear-elastic. Recently, the authors have reported on the nonlinear dynamic behaviour of the human lumbar intervertebral disc. This response was shown to be dependent on the applied preload and amplitude of the stimuli. However, the mechanical properties of a standard linear elastic model are not dependent on the current deformation state of the system. The aim of this study was therefore to develop a model that is able to describe the axial, nonlinear quasi-static response and to predict the nonlinear dynamic characteristics of the disc. The ability to adapt the model to an individual disc's response was a specific focus of the study, with model validation performed against prior experimental data. The influence of the numerical parameters used in the simulations was investigated. The developed model exhibited an axial quasi-static and dynamic response, which agreed well with the corresponding experiments. However, the model needs further improvement to capture additional peculiar characteristics of the system dynamics, such as the change of mean point of oscillation exhibited by the specimens when oscillating in the region of nonlinear resonance. Reference time steps were identified for specific integration scheme. The study has demonstrated that taking into account the nonlinear-elastic behaviour typical of the intervertebral disc results in a predicted system oscillation much closer to the physiological response than that provided by linear-elastic models. For dynamic analysis, the use of standard linear-elastic models should be avoided, or restricted to study cases where the amplitude of the stimuli is relatively small.

Modulational-instability-induced supercontinuum generation with saturable nonlinear response

NASA Astrophysics Data System (ADS)

Raja, R. Vasantha Jayakantha; Porsezian, K.; Nithyanandan, K.

2010-07-01

We theoretically investigate the supercontinuum generation (SCG) on the basis of modulational instability (MI) in liquid-core photonic crystal fibers (LCPCF) with CS2-filled central core. The effect of saturable nonlinearity of LCPCF on SCG in the femtosecond regime is studied using an appropriately modified nonlinear Schrödinger equation. We also compare the MI induced spectral broadening with SCG obtained by soliton fission. To analyze the quality of the pulse broadening, we study the coherence of the SC pulse numerically. It is evident from the numerical simulation that the response of the saturable nonlinearity suppresses the broadening of the pulse. We also observe that the MI induced SCG in the presence of saturable nonlinearity degrades the coherence of the SCG pulse when compared to unsaturated medium.

Modulational-instability-induced supercontinuum generation with saturable nonlinear response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raja, R. Vasantha Jayakantha; Porsezian, K.; Nithyanandan, K.

2010-07-15

We theoretically investigate the supercontinuum generation (SCG) on the basis of modulational instability (MI) in liquid-core photonic crystal fibers (LCPCF) with CS{sub 2}-filled central core. The effect of saturable nonlinearity of LCPCF on SCG in the femtosecond regime is studied using an appropriately modified nonlinear Schroedinger equation. We also compare the MI induced spectral broadening with SCG obtained by soliton fission. To analyze the quality of the pulse broadening, we study the coherence of the SC pulse numerically. It is evident from the numerical simulation that the response of the saturable nonlinearity suppresses the broadening of the pulse. We alsomore » observe that the MI induced SCG in the presence of saturable nonlinearity degrades the coherence of the SCG pulse when compared to unsaturated medium.« less

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer

PubMed Central

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang

2016-01-01

Lessons Learned This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity. These findings provide clinicians with evidence for application of higher-dose icotinib. Background. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100–200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Methods. Twenty-six patients with advanced NSCLC were treated at doses of 250–625 mg three times daily The EGFR mutation test was not mandatory in this study. Results. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (Tmax) ranged from 1 to 3 hours (1.5–4 hours) after multiple doses. The t1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. Conclusion. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. PMID:27789778

A Phase I Study of the Safety and Pharmacokinetics of Higher-Dose Icotinib in Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Liu, Jian; Wu, Lihua; Wu, Guolan; Hu, Xingjiang; Zhou, Huili; Chen, Junchun; Zhu, Meixiang; Xu, Wei; Tan, Fenlai; Ding, Lieming; Wang, Yinxiang; Shentu, Jianzhong

2016-11-01

This phase I study evaluated the maximum tolerated dose, dose-limiting toxicities, safety, pharmacokinetics, and efficacy of icotinib with a starting dose of 250 mg in pretreated, advanced non-small cell lung cancer patients. We observed a maximum tolerated dose of 500 mg with a favorable pharmacokinetics profile and antitumor activity.These findings provide clinicians with evidence for application of higher-dose icotinib. Icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has shown favorable tolerability and antitumor activity at 100-200 mg in previous studies without reaching the maximum tolerated dose (MTD). In July 2011, icotinib was approved by the China Food and Drug Administration at a dose of 125 mg three times daily for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one platinum-based chemotherapy regimen. This study investigated the MTD, tolerability, and pharmacokinetics of higher-dose icotinib in patients with advanced NSCLC. Twenty-six patients with advanced NSCLC were treated at doses of 250-625 mg three times daily The EGFR mutation test was not mandatory in this study. Twenty-four (92.3%) of 26 patients experienced at least one adverse event (AE); rash (61.5%), diarrhea (23.1%), and oral ulceration (11.5%) were most frequent AEs. Dose-limiting toxicities were seen in 2 of 6 patients in the 625-mg group, and the MTD was established at 500 mg. Icotinib was rapidly absorbed and eliminated. The amount of time that the drug was present at the maximum concentration in serum (T max ) ranged from 1 to 3 hours (1.5-4 hours) after multiple doses. The t 1/2 was similar after single- and multiple-dose administration (7.11 and 6.39 hours, respectively). A nonlinear relationship was observed between dose and drug exposure. Responses were seen in 6 (23.1%) patients, and 8 (30.8%) patients had stable disease. This study demonstrated that higher-dose icotinib was well-tolerated, with a MTD of 500 mg. Favorable antitumor activity and pharmacokinetic profile were observed in patients with heavily pretreated, advanced NSCLC. ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Dependence of pentobarbital kinetics upon the dose of the drug and its pharmacodynamic effects.

PubMed

Kozlowski, K H; Szaykowski, A; Danysz, A

1977-01-01

Pentobarbital (PB), at dose range of 20--50 mg/kg, displays in rabbits non-linear, dose-dependent kinetics. Pharmacokinetics parameters of drug elimination depend largely upon the dose, while the distribution phase is dose-independent. The rate of disappearance of PB from the central compartment (plasma) decreases with the increase of the dose. The analysis of pharmacodynamic parameters has shown that this dose-dependent retardation of PB elimination is probably caused by an impairment of metabolic processes, resulting from disturbance of the circulatory system. A close correlation has been found between the hypotensive effect of PB and the elimination constant, k13, and also between the hypotensive effect and beta.Vd(extrap), a coefficient proportional to the rate of metabolism of PB [23, 29]. The results indicate the necessity of considering the changes in the functional state of the organism, related to the action of a drug, in pharmacokinetic studies.

Implications of Nonlinear Concentration Response Curve for Ozone related Mortality on Health Burden Assessment

EPA Science Inventory

We characterize the sensitivity of the ozone attributable health burden assessment with respect to different modeling strategies of concentration-response function. For this purpose, we develop a flexible Bayesian hierarchical model allowing for a nonlinear ozone risk curve with ...

Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation

PubMed Central

Frey, N; Laveille, C; Paraire, M; Francillard, M; Holford, N H G; Jochemsen, Roeline

2003-01-01

Aims To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability. Methods A PKPD database of 634 Type 2 diabetic patients with a total of 5258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR. Results Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l−1 year−1 (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control. Conclusions This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control. PMID:12580986

Grain size effects on stability of nonlinear vibration with nanocrystalline NiTi shape memory alloy

NASA Astrophysics Data System (ADS)

Xia, Minglu; Sun, Qingping

2017-10-01

Grain size effects on stability of thermomechanical responses for a nonlinear torsional vibration system with nanocrystalline superelastic NiTi bar are investigated in the frequency and amplitude domains. NiTi bars with average grain size from 10 nm to 100 nm are fabricated through cold-rolling and subsequent annealing. Thermomechanical responses of the NiTi bar as a softening nonlinear damping spring in the torsional vibration system are obtained by synchronised acquisition of rotational angle and temperature under external sinusoidal excitation. It is shown that nonlinearity and damping capacity of the NiTi bar decrease as average grain size of the material is reduced below 100 nm. Therefore jump phenomena of thermomechanical responses become less significant or even vanish and the vibration system becomes more stable. The work in this paper provides a solid experimental base for manipulating the undesired jump phenomena of thermomechanical responses and stabilising the mechanical vibration system through grain refinement of NiTi SMA.

Nonlinear rotordynamics analysis. [Space Shuttle Main Engine turbopumps

NASA Technical Reports Server (NTRS)

Noah, Sherif T.

1991-01-01

Effective analysis tools were developed for predicting the nonlinear rotordynamic behavior of the Space Shuttle Main Engine (SSME) turbopumps under steady and transient operating conditions. Using these methods, preliminary parametric studies were conducted on both generic and actual HPOTP (high pressure oxygen turbopump) models. In particular, a novel modified harmonic balance/alternating Fourier transform (HB/AFT) method was developed and used to conduct a preliminary study of the effects of fluid, bearing and seal forces on the unbalanced response of a multi-disk rotor in the presence of bearing clearances. The method makes it possible to determine periodic, sub-, super-synchronous and chaotic responses of a rotor system. The method also yields information about the stability of the obtained response, thus allowing bifurcation analyses. This provides a more effective capability for predicting the response under transient conditions by searching in proximity of resonance peaks. Preliminary results were also obtained for the nonlinear transient response of an actual HPOTP model using an efficient, newly developed numerical method based on convolution integration. Currently, the HB/AFT is being extended for determining the aperiodic response of nonlinear systems. Initial results show the method to be promising.

Buckling Behavior of Compression-Loaded Composite Cylindrical Shells With Reinforced Cutouts

NASA Technical Reports Server (NTRS)

Hilburger, Mark W.; Sarnes, James H., Jr.

2004-01-01

Results from a numerical study of the response of thin-walled compression-loaded quasi-isotropic laminated composite cylindrical shells with unreinforced and reinforced square cutouts are presented. The effects of cutout reinforcement orthotropy, size, and thickness on the nonlinear response of the shells are described. A nonlinear analysis procedure has been used to predict the nonlinear response of the shells. The results indicate that a local buckling response occurs in the shell near the cutout when subjected to load and is caused by a nonlinear coupling between local shell-wall deformations and in-plane destabilizing compression stresses near the cutout. In general, reinforcement around a cutout in a compression-loaded shell is shown to retard or eliminate the local buckling response near the cutout and increase the buckling load of the shell. However, some results show that certain reinforcement configurations can cause an unexpected increase in the magnitude of local deformations and stresses in the shell and cause a reduction in the buckling load. Specific cases are presented that suggest that the orthotropy, thickness, and size of a cutout reinforcement in a shell can be tailored to achieve improved buckling response characteristics.

OSL and thermally assisted OSL response in dental enamel for its possible application in retrospective dosimetry.

PubMed

Soni, Anuj; Mishra, D R; Polymeris, G S; Bhatt, B C; Kulkarni, M S

2014-11-01

Dental enamel was studied for its thermoluminescence (TL) and optically stimulated luminescence (OSL) defects. The TL studies showed a wide glow curve with multiple peaks. The thermally assisted OSL (TA-OSL) studies showed that the integrated TA-OSL and thus OSL signal increases with readout temperature between 100 and 250 °C, due to the temperature dependence of OSL. The thermally assisted energy E A associated with this increase is found to be 0.21 ± 0.015 eV. On the other hand, the signal intensity decreases with temperature between 260 and 450 °C. This decrease could be due to depletion of OSL active traps or possible thermal quenching. The increase of the OSL signal at increased temperature can be used to enhance the sensitivity of dental enamel for ex vivo measurements in retrospective dosimetry. The emission and excitation spectra of its luminescence centers were studied by photoluminescence and were found to be at 412 and 324 nm, respectively. It was found to possess multiple OSL active traps having closely lying photoionization cross sections characterized by continuous wave OSL and nonlinear OSL methods. The investigated dental enamel samples showed a linear OSL dose response up to 500 Gy. The dose threshold was found to be 100 mGy using a highly sensitive compact OSL reader with blue LED (470 nm) stimulation.

Resonant third-order optical nonlinearities of thin films containing J-aggregates of a cyanine dye or a squarylium dye

NASA Astrophysics Data System (ADS)

Li, Zhongyu; Jin, Zhaohui; Kasatani, Kazuo

2005-01-01

The third-order optical nonlinearities and responses of thin films containing the J-aggregates of a cyanine dye or a squarylium dye were measured using the degenerate four-wave mixing (DFWM) technique under resonant conditions. The sol-gel silica coating films containing the J-aggregates of the cyanine dye, NK-3261, are stable at room temperature and durable against laser beam irradiation. The temporal profiles of the DFWM signal were measured with a time resolution of 0.3 ps, and were found to consist of at least three components, i.e., the coherent instantaneous nonlinear response and the two slow responses with delay time constants of ca. 1.0 ps and ca. 5.6 ps. The contribution of the later was small. The electronic component of the effective third-order optical nonlinear susceptibility of the film had value of as high as ca. 3.0 x 10-7 esu. We also studied the neat film of a squarylium dye J-aggregates. The temporal profile of the DFWM signal of the neat film of squarylium dye was also found to consist of at least three components, the coherent instantaneous nonlinear response and the delayed response with decay time constants of ca. 0.6 ps and ca. 6.5 ps. The contribution of the slow tail was also very small. The electronic component of effective third-order optical nonlinear susceptibility of the neat film of squarylium dye had value of as high as ca. 3.6 x 10-8 esu.

Laminar and orientation-dependent characteristics of spatial nonlinearities: implications for the computational architecture of visual cortex.

PubMed

Victor, Jonathan D; Mechler, Ferenc; Ohiorhenuan, Ifije; Schmid, Anita M; Purpura, Keith P

2009-12-01

A full understanding of the computations performed in primary visual cortex is an important yet elusive goal. Receptive field models consisting of cascades of linear filters and static nonlinearities may be adequate to account for responses to simple stimuli such as gratings and random checkerboards, but their predictions of responses to complex stimuli such as natural scenes are only approximately correct. It is unclear whether these discrepancies are limited to quantitative inaccuracies that reflect well-recognized mechanisms such as response normalization, gain controls, and cross-orientation suppression or, alternatively, imply additional qualitative features of the underlying computations. To address this question, we examined responses of V1 and V2 neurons in the monkey and area 17 neurons in the cat to two-dimensional Hermite functions (TDHs). TDHs are intermediate in complexity between traditional analytic stimuli and natural scenes and have mathematical properties that facilitate their use to test candidate models. By exploiting these properties, along with the laminar organization of V1, we identify qualitative aspects of neural computations beyond those anticipated from the above-cited model framework. Specifically, we find that V1 neurons receive signals from orientation-selective mechanisms that are highly nonlinear: they are sensitive to phase correlations, not just spatial frequency content. That is, the behavior of V1 neurons departs from that of linear-nonlinear cascades with standard modulatory mechanisms in a qualitative manner: even relatively simple stimuli evoke responses that imply complex spatial nonlinearities. The presence of these findings in the input layers suggests that these nonlinearities act in a feedback fashion.

New pharmacokinetic methods. III. Two simple test for deep pool effect

DOE Office of Scientific and Technical Information (OSTI.GOV)

Browne, T.R.; Greenblatt, D.J.; Schumacher, G.E.

1990-08-01

If a portion of administered drug is distributed into a deep peripheral compartment, the drug's actual elimination half-life during the terminal exponential phase of elimination may be longer than determined by a single dose study or a tracer dose study (deep pool effect). Two simple methods of testing for deep pool effect applicable to drugs with either linear or nonlinear pharmacokinetic properties are described. The methods are illustrated with stable isotope labeled (13C15N2) tracer dose studies of phenytoin. No significant (P less than .05) deep pool effect was detected.

Graphene-clad tapered fiber: effective nonlinearity and propagation losses.

PubMed

Gorbach, A V; Marini, A; Skryabin, D V

2013-12-15

We derive a pulse propagation equation for a graphene-clad optical fiber, treating the optical response of the graphene and nonlinearity of the dielectric fiber core as perturbations in asymptotic expansion of Maxwell equations. We analyze the effective nonlinear and attenuation coefficients due to the graphene layer. Based on the recent experimental measurements of the nonlinear graphene conductivity, we predict considerable enhancement of the effective nonlinearity for subwavelength fiber core diameters.

A computer program for predicting nonlinear uniaxial material responses using viscoplastic models

NASA Technical Reports Server (NTRS)

Chang, T. Y.; Thompson, R. L.

1984-01-01

A computer program was developed for predicting nonlinear uniaxial material responses using viscoplastic constitutive models. Four specific models, i.e., those due to Miller, Walker, Krieg-Swearengen-Rhode, and Robinson, are included. Any other unified model is easily implemented into the program in the form of subroutines. Analysis features include stress-strain cycling, creep response, stress relaxation, thermomechanical fatigue loop, or any combination of these responses. An outline is given on the theoretical background of uniaxial constitutive models, analysis procedure, and numerical integration methods for solving the nonlinear constitutive equations. In addition, a discussion on the computer program implementation is also given. Finally, seven numerical examples are included to demonstrate the versatility of the computer program developed.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Scott, Bobby, R., Ph.D.

2003-06-27

OAK - B135 This project final report summarizes modeling research conducted in the U.S. Department of Energy (DOE), Low Dose Radiation Research Program at the Lovelace Respiratory Research Institute from October 1998 through June 2003. The modeling research described involves critically evaluating the validity of the linear nonthreshold (LNT) risk model as it relates to stochastic effects induced in cells by low doses of ionizing radiation and genotoxic chemicals. The LNT model plays a central role in low-dose risk assessment for humans. With the LNT model, any radiation (or genotoxic chemical) exposure is assumed to increase one¡¯s risk of cancer.more » Based on the LNT model, others have predicted tens of thousands of cancer deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Our research has focused on developing biologically based models that explain the shape of dose-response curves for low-dose radiation and genotoxic chemical-induced stochastic effects in cells. Understanding the shape of the dose-response curve for radiation and genotoxic chemical-induced stochastic effects in cells helps to better understand the shape of the dose-response curve for cancer induction in humans. We have used a modeling approach that facilitated model revisions over time, allowing for timely incorporation of new knowledge gained related to the biological basis for low-dose-induced stochastic effects in cells. Both deleterious (e.g., genomic instability, mutations, and neoplastic transformation) and protective (e.g., DNA repair and apoptosis) effects have been included in our modeling. Our most advanced model, NEOTRANS2, involves differing levels of genomic instability. Persistent genomic instability is presumed to be associated with nonspecific, nonlethal mutations and to increase both the risk for neoplastic transformation and for cancer occurrence. Our research results, based on applications of NEOTRANS2, indicate that nonlinear threshold-type, dose-response relationships for excess stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected after exposure to low linear energy transfer (LET) gamma rays or gamma rays in combination with high-LET alpha radiation. Similar thresholds are expected for low-dose-rate low-LET beta irradiation. We attribute the thresholds to low-dose, low-LET radiation induced protection against spontaneous mutations and neoplastic transformations. The protection is presumed mainly to involve selective elimination of problematic cells via apoptosis. Low-dose, low-LET radiation is presumed to trigger wide-area cell signaling, which in turn leads to problematic bystander cells (e.g., mutants, neoplastically transformed cells) selectively undergoing apoptosis. Thus, this protective bystander effect leads to selective elimination of problematic cells (a tissue cleansing process in vivo). However, this protective bystander effects is a different process from low-dose stimulation of the immune system. Low-dose, low-LET radiation stimulation of the immune system may explain why thresholds for inducing excess cancer appear much larger (possibly more than 100-fold larger) than thresholds for inducing excess mutations and neoplastic transformations, when the dose rate is low. For ionizing radiation, the current risk assessment paradigm is such that the relative risk (RR) is always ¡Ý 1, no matter how small the dose. Our research results indicate that for low-dose or low-dose-rate, low-LET irradiation, RR < 1 may be more the rule than the exception. Directly tied to the current RR paradigm are the billion-dollar cleanup costs for radionuclide-contaminated DOE sites. Our research results suggest that continued use of the current RR paradigm for which RR ¡Ý 1 could cause more harm than benefit to society (e.g., by spreading unwarranted fear about phantom excess risks associated with low-dose low-LET radiation). Such phantom risks also may arise from risk assessments conducted for combined exposure to low- and high-LET radiations when based on the LNT or other models that exclude RR < 1. Our results for high-LET radiation are consistent with the LNT hypothesis but only where there is no additional low-LET contribution (e.g., gamma rays) to the total dose. For high-LET neutron sources, gamma rays arise (especially in vivo) for large mammals such as humans from neutron interactions with tissue. The gamma rays might provide some protection from low-dose-related stochastic effects via inducing the protective bystander apoptosis effect that is considered to contribute to tissue cleansing via removal of problematic cells.« less

Bistability in mushroom-type metamaterials

NASA Astrophysics Data System (ADS)

Fernandes, David E.; Silveirinha, Mário G.

2017-07-01

Here, we study the electromagnetic response of asymmetric mushroom-type metamaterials loaded with nonlinear elements. It is shown that near a Fano resonance, these structures may have a strong tunable, bistable, and switchable response and enable giant nonlinear effects. By using an effective medium theory and full wave simulations, it is proven that the nonlinear elements may allow the reflection and transmission coefficients to follow hysteresis loops, and to switch the metamaterial between "go" and "no-go" states similar to an ideal electromagnetic switch.

Method for conducting nonlinear electrochemical impedance spectroscopy

DOEpatents

Adler, Stuart B.; Wilson, Jamie R.; Huff, Shawn L.; Schwartz, Daniel T.

2015-06-02

A method for conducting nonlinear electrochemical impedance spectroscopy. The method includes quantifying the nonlinear response of an electrochemical system by measuring higher-order current or voltage harmonics generated by moderate-amplitude sinusoidal current or voltage perturbations. The method involves acquisition of the response signal followed by time apodization and fast Fourier transformation of the data into the frequency domain, where the magnitude and phase of each harmonic signal can be readily quantified. The method can be implemented on a computer as a software program.

Analyses of Multishaft Rotor-Bearing Response

NASA Technical Reports Server (NTRS)

Nelson, H. D.; Meacham, W. L.

1985-01-01

Method works for linear and nonlinear systems. Finite-element-based computer program developed to analyze free and forced response of multishaft rotor-bearing systems. Acronym, ARDS, denotes Analysis of Rotor Dynamic Systems. Systems with nonlinear interconnection or support bearings or both analyzed by numerically integrating reduced set of coupledsystem equations. Linear systems analyzed in closed form for steady excitations and treated as equivalent to nonlinear systems for transient excitation. ARDS is FORTRAN program developed on an Amdahl 470 (similar to IBM 370).

Response of composite plates subjected to acoustic loading

NASA Technical Reports Server (NTRS)

Moyer, E. Thomas, Jr.

1989-01-01

The objectives of the project were to investigate numerical methodology for the determination of narrowband response in the geometrically nonlinear regime, to determine response characteristics for geometrically nonlinear plates subjected to random loading and to compare the predictions with experiments to be performed at NASA-Langley. The first two objectives were met. The response of composite plates subjected to both narrowband and broadband excitation were studied and the results are presented and discussed.

Pressure-coupled combustion response model for solid propellants based on Zeldovich-Novozhilov approach

NASA Technical Reports Server (NTRS)

Harstad, K. G.; Strand, L. D.

1987-01-01

An exact analytical solution is given to the problem of long-time propellant thermal response to a specified pressure oscillation. Coupling to the gas phase is made using the quasisteady Zeldovich-Novozhilov approximation. Explicit linear and lowest order (quadratic) nonlinear expressions for propellant response are obtained from the implicit nonlinear solutions. Using these expressions, response curves are presented for an ammonium perchlorate composite propellant and HMX monopropellant.

Non-parametric estimation of low-concentration benzene metabolism.

PubMed

Cox, Louis A; Schnatter, A Robert; Boogaard, Peter J; Banton, Marcy; Ketelslegers, Hans B

2017-12-25

Two apparently contradictory findings in the literature on low-dose human metabolism of benzene are as follows. First, metabolism is approximately linear at low concentrations, e.g., below 10 ppm. This is consistent with decades of quantitative modeling of benzene pharmacokinetics and dose-dependent metabolism. Second, measured benzene exposure and metabolite concentrations for occupationally exposed benzene workers in Tianjin, China show that dose-specific metabolism (DSM) ratios of metabolite concentrations per ppm of benzene in air decrease steadily with benzene concentration, with the steepest decreases below 3 ppm. This has been interpreted as indicating that metabolism at low concentrations of benzene is highly nonlinear. We reexamine the data using non-parametric methods. Our main conclusion is that both findings are correct; they are not contradictory. Low-concentration metabolism can be linear, with metabolite concentrations proportional to benzene concentrations in air, and yet DSM ratios can still decrease with benzene concentrations. This is because a ratio of random variables can be negatively correlated with its own denominator even if the mean of the numerator is proportional to the denominator. Interpreting DSM ratios that decrease with air benzene concentrations as evidence of nonlinear metabolism is therefore unwarranted when plots of metabolite concentrations against benzene ppm in air show approximately straight-line relationships between them, as in the Tianjin data. Thus, an apparent contradiction that has fueled heated discussions in the recent literature can be resolved by recognizing that highly nonlinear, decreasing DSM ratios are consistent with linear metabolism. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Step responses of a torsional system with multiple clearances: Study of vibro-impact phenomenon using experimental and computational methods

NASA Astrophysics Data System (ADS)

Oruganti, Pradeep Sharma; Krak, Michael D.; Singh, Rajendra

2018-01-01

Recently Krak and Singh (2017) proposed a scientific experiment that examined vibro-impacts in a torsional system under a step down excitation and provided preliminary measurements and limited non-linear model studies. A major goal of this article is to extend the prior work with a focus on the examination of vibro-impact phenomena observed under step responses in a torsional system with one, two or three controlled clearances. First, new measurements are made at several locations with a higher sampling frequency. Measured angular accelerations are examined in both time and time-frequency domains. Minimal order non-linear models of the experiment are successfully constructed, using piecewise linear stiffness and Coulomb friction elements; eight cases of the generic system are examined though only three are experimentally studied. Measured and predicted responses for single and dual clearance configurations exhibit double sided impacts and time varying periods suggest softening trends under the step down torque. Non-linear models are experimentally validated by comparing results with new measurements and with those previously reported. Several metrics are utilized to quantify and compare the measured and predicted responses (including peak to peak accelerations). Eigensolutions and step responses of the corresponding linearized models are utilized to better understand the nature of the non-linear dynamic system. Finally, the effect of step amplitude on the non-linear responses is examined for several configurations, and hardening trends are observed in the torsional system with three clearances.

A semi-active H∞ control strategy with application to the vibration suppression of nonlinear high-rise building under earthquake excitations.

PubMed

Yan, Guiyun; Chen, Fuquan; Wu, Yingxiong

2016-01-01

Different from previous researches which mostly focused on linear response control of seismically excited high-rise buildings, this study aims to control nonlinear seismic response of high-rise buildings. To this end, a semi-active control strategy, in which H∞ control algorithm is used and magneto-rheological dampers are employed for an actuator, is presented to suppress the nonlinear vibration. In this strategy, a modified Kalman-Bucy observer which is suitable for the proposed semi-active strategy is developed to obtain the state vector from the measured semi-active control force and acceleration feedback, taking into account of the effects of nonlinearity, disturbance and uncertainty of controlled system parameters by the observed nonlinear accelerations. Then, the proposed semi-active H∞ control strategy is applied to the ASCE 20-story benchmark building when subjected to earthquake excitation and compared with the other control approaches by some control criteria. It is indicated that the proposed semi-active H∞ control strategy provides much better control performances by comparison with the semi-active MPC and Clipped-LQG control approaches, and can reduce nonlinear seismic response and minimize the damage in the buildings. Besides, it enhances the reliability of the control performance when compared with the active control strategy. Thus, the proposed semi-active H∞ control strategy is suitable for suppressing the nonlinear vibration of high-rise buildings.

Harmonic Phase Response of Nonlinear Radar Targets

DTIC Science & Technology

2015-10-01

while allowing its harmonics to pass through. The weak harmonic responses are then amplified to allow for easier detection and measurement . 4...where the phase of the 2nd and 3rd harmonic of the received electromagnetic wave from nonlinear targets was measured and plotted against the frequency

Nonlinear structural joint model updating based on instantaneous characteristics of dynamic responses

NASA Astrophysics Data System (ADS)

Wang, Zuo-Cai; Xin, Yu; Ren, Wei-Xin

2016-08-01

This paper proposes a new nonlinear joint model updating method for shear type structures based on the instantaneous characteristics of the decomposed structural dynamic responses. To obtain an accurate representation of a nonlinear system's dynamics, the nonlinear joint model is described as the nonlinear spring element with bilinear stiffness. The instantaneous frequencies and amplitudes of the decomposed mono-component are first extracted by the analytical mode decomposition (AMD) method. Then, an objective function based on the residuals of the instantaneous frequencies and amplitudes between the experimental structure and the nonlinear model is created for the nonlinear joint model updating. The optimal values of the nonlinear joint model parameters are obtained by minimizing the objective function using the simulated annealing global optimization method. To validate the effectiveness of the proposed method, a single-story shear type structure subjected to earthquake and harmonic excitations is simulated as a numerical example. Then, a beam structure with multiple local nonlinear elements subjected to earthquake excitation is also simulated. The nonlinear beam structure is updated based on the global and local model using the proposed method. The results show that the proposed local nonlinear model updating method is more effective for structures with multiple local nonlinear elements. Finally, the proposed method is verified by the shake table test of a real high voltage switch structure. The accuracy of the proposed method is quantified both in numerical and experimental applications using the defined error indices. Both the numerical and experimental results have shown that the proposed method can effectively update the nonlinear joint model.

Nonlinear response of dense colloidal suspensions under oscillatory shear: mode-coupling theory and Fourier transform rheology experiments.

PubMed

Brader, J M; Siebenbürger, M; Ballauff, M; Reinheimer, K; Wilhelm, M; Frey, S J; Weysser, F; Fuchs, M

2010-12-01

Using a combination of theory, experiment, and simulation we investigate the nonlinear response of dense colloidal suspensions to large amplitude oscillatory shear flow. The time-dependent stress response is calculated using a recently developed schematic mode-coupling-type theory describing colloidal suspensions under externally applied flow. For finite strain amplitudes the theory generates a nonlinear response, characterized by significant higher harmonic contributions. An important feature of the theory is the prediction of an ideal glass transition at sufficiently strong coupling, which is accompanied by the discontinuous appearance of a dynamic yield stress. For the oscillatory shear flow under consideration we find that the yield stress plays an important role in determining the nonlinearity of the time-dependent stress response. Our theoretical findings are strongly supported by both large amplitude oscillatory experiments (with Fourier transform rheology analysis) on suspensions of thermosensitive core-shell particles dispersed in water and Brownian dynamics simulations performed on a two-dimensional binary hard-disk mixture. In particular, theory predicts nontrivial values of the exponents governing the final decay of the storage and loss moduli as a function of strain amplitude which are in good agreement with both simulation and experiment. A consistent set of parameters in the presented schematic model achieves to jointly describe linear moduli, nonlinear flow curves, and large amplitude oscillatory spectroscopy.

Trajectory Control for Very Flexible Aircraft

DTIC Science & Technology

2006-10-30

aircraft are coupled with the aeroelastic equations that govern the geometrically nonlinear structural response of the vehicle. A low -order strain...nonlinear structural formulation, the finite state aerodynamic model, and the nonlinear rigid body equations together provide a low -order complete...nonlinear aircraft analysis tool. Due to the inherent flexibility of the aircraft modeling, the low order structural fre- quencies are of the same order

Exact modelling of the optical bistability in ferroelectics via two-wave mixing: A system with full nonlinearity

NASA Astrophysics Data System (ADS)

Khushaini, Muhammad Asif A.; Ibrahim, Abdel-Baset M. A.; Choudhury, P. K.

2018-05-01

In this paper, we provide a complete mathematical model of the phenomenon of optical bistability (OB) resulting from the degenerate two-wave mixing (TWM) process of laser beams interacting with a single nonlinear layer of ferroelectric material. Starting with the electromagnetic wave equation for optical wave propagating in nonlinear media, a nonlinear coupled wave (CW) system with both self-phase modulation (SPM) and cross-phase modulation (XPM) sources of nonlinearity are derived. The complete CW system with full nonlinearity is solved numerically and a comparison between both the cases of with and without SPM at various combinations of design parameters is given. Furthermore, to provide a reliable theoretical model for the OB via TWM process, the results obtained theoretically are compared with the available experimental data. We found that the nonlinear system without SPM fails to predict the bistable response at lower combinations of the input parameters. However, at relatively higher values, the solution without SPM shows a reduction in the switching contrast and period in the OB response. A comparison with the experimental results shows better agreement with the system with full nonlinearity.

Six different roles for crossover inhibition in the retina: correcting the nonlinearities of synaptic transmission.

PubMed

Werblin, Frank S

2010-03-01

Early retinal studies categorized ganglion cell behavior as either linear or nonlinear and rectifying as represented by the familiar X- and Y-type ganglion cells in cat. Nonlinear behavior is in large part a consequence of the rectifying nonlinearities inherent in synaptic transmission. These nonlinear signals underlie many special functions in retinal processing, including motion detection, motion in motion, and local edge detection. But linear behavior is also required for some visual processing tasks. For these tasks, the inherently nonlinear signals are "linearized" by "crossover inhibition." Linearization utilizes a circuitry whereby nonlinear ON inhibition adds with nonlinear OFF excitation or ON excitation adds with OFF inhibition to generate a more linear postsynaptic voltage response. Crossover inhibition has now been measured in most bipolar, amacrine, and ganglion cells. Functionally crossover inhibition enhances edge detection, allows ganglion cells to recognize luminance-neutral patterns with their receptive fields, permits ganglion cells to distinguish contrast from luminance, and maintains a more constant conductance during the light response. In some cases, crossover extends the operating range of cone-driven OFF ganglion cells into the scotopic levels. Crossover inhibition is also found in neurons of the lateral geniculate nucleus and V1.

Milk and dairy consumption and risk of cardiovascular diseases and all-cause mortality: dose-response meta-analysis of prospective cohort studies.

PubMed

Guo, Jing; Astrup, Arne; Lovegrove, Julie A; Gijsbers, Lieke; Givens, David I; Soedamah-Muthu, Sabita S

2017-04-01

With a growing number of prospective cohort studies, an updated dose-response meta-analysis of milk and dairy products with all-cause mortality, coronary heart disease (CHD) or cardiovascular disease (CVD) have been conducted. PubMed, Embase and Scopus were searched for articles published up to September 2016. Random-effect meta-analyses with summarised dose-response data were performed for total (high-fat/low-fat) dairy, milk, fermented dairy, cheese and yogurt. Non-linear associations were investigated using the spine models and heterogeneity by subgroup analyses. A total of 29 cohort studies were available for meta-analysis, with 938,465 participants and 93,158 mortality, 28,419 CHD and 25,416 CVD cases. No associations were found for total (high-fat/low-fat) dairy, and milk with the health outcomes of mortality, CHD or CVD. Inverse associations were found between total fermented dairy (included sour milk products, cheese or yogurt; per 20 g/day) with mortality (RR 0.98, 95% CI 0.97-0.99; I 2  = 94.4%) and CVD risk (RR 0.98, 95% CI 0.97-0.99; I 2  = 87.5%). Further analyses of individual fermented dairy of cheese and yogurt showed cheese to have a 2% lower risk of CVD (RR 0.98, 95% CI 0.95-1.00; I 2  = 82.6%) per 10 g/day, but not yogurt. All of these marginally inverse associations of totally fermented dairy and cheese were attenuated in sensitivity analyses by removing one large Swedish study. This meta-analysis combining data from 29 prospective cohort studies demonstrated neutral associations between dairy products and cardiovascular and all-cause mortality. For future studies it is important to investigate in more detail how dairy products can be replaced by other foods.

Comparative Evaluation of a Silicone Membrane as an Alternative to Skin for Testing Mosquito Repellents.

PubMed

Agramonte, Natasha M; Gezan, Salvador A; Bernier, Ulrich R

2017-05-01

Repellents prevent mosquito bites and help reduce mosquito-borne disease, a global public health issue. Laboratory-based repellent bioassays predict the ability of compounds to deter mosquito feeding, but the variety of repellent bioassays and statistical analysis methods makes it difficult to compare results across methodologies. The most realistic data are collected when repellents are applied on the skin; however, this method exposes volunteers to chemicals and mosquito bites. Silicone membranes were investigated as an alternative to human skin in assays of repellent efficacy. Results from module system bioassays conducted in vitro with a silicone membrane were compared with in vivo bioassays conducted with N,N-diethyl-3-methylbenzamide (referred to as DEET), 1-piperidinecarboxylic acid 2-(2-hydroxyethyl)-1-methylpropylester (referred to as Picaridin), ethyl 3-[acetyl(butyl)amino]propanoate (referred to as IR3535), and para-menthane-3,8-diol (referred to as PMD) applied directly on the skin of the leg. No significant difference in mosquito feeding was found when comparing skin and volunteer-worn membrane controls using blood; however, feeding was significantly lower in unworn membrane controls using either 10% sucrose or blood, indicating that worn membranes are a possible surrogate for untreated human skin. Pooled data from six volunteers were used to generate dose-response curves of blood-feeding activity. Results from skin-applied repellents were modeled to determine if membranes could provide a predictive correlate for skin. Goodness-of-fit comparisons indicated that the nonlinear dose-response curves for the skin and membrane differed significantly for DEET and Picaridin, but did not differ significantly for IR3535 and PMD. With knowledge of the dose-response relationships and further modifications to this system, the membrane-based tests could be used for standardized repellent testing with infected vectors. Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.

Association between sugar-sweetened and artificially sweetened soft drinks and type 2 diabetes: systematic review and dose-response meta-analysis of prospective studies.

PubMed

Greenwood, D C; Threapleton, D E; Evans, C E L; Cleghorn, C L; Nykjaer, C; Woodhead, C; Burley, V J

2014-09-14

The intake of sugar-sweetened soft drinks has been reported to be associated with an increased risk of type 2 diabetes, but it is unclear whether this is because of the sugar content or related lifestyle factors, whether similar associations hold for artificially sweetened soft drinks, and how these associations are related to BMI. We aimed to conduct a systematic literature review and dose-response meta-analysis of evidence from prospective cohorts to explore these issues. We searched multiple sources for prospective studies on sugar-sweetened and artificially sweetened soft drinks in relation to the risk of type 2 diabetes. Data were extracted from eleven publications on nine cohorts. Consumption values were converted to ml/d, permitting the exploration of linear and non-linear dose-response trends. Summary relative risks (RR) were estimated using a random-effects meta-analysis. The summary RR for sugar-sweetened and artificially sweetened soft drinks were 1·20/330 ml per d (95 % CI 1·12, 1·29, P< 0·001) and 1·13/330 ml per d (95 % CI 1·02, 1·25, P= 0·02), respectively. The association with sugar-sweetened soft drinks was slightly lower in studies adjusting for BMI, consistent with BMI being involved in the causal pathway. There was no evidence of effect modification, though both these comparisons lacked power. Overall between-study heterogeneity was high. The included studies were observational, so their results should be interpreted cautiously, but findings indicate a positive association between sugar-sweetened soft drink intake and type 2 diabetes risk, attenuated by adjustment for BMI. The trend was less consistent for artificially sweetened soft drinks. This may indicate an alternative explanation, such as lifestyle factors or reverse causality. Future research should focus on the temporal nature of the association and whether BMI modifies or mediates the association.

Coffee and caffeine consumption and depression: A meta-analysis of observational studies.

PubMed

Wang, Longfei; Shen, Xiaoli; Wu, Yili; Zhang, Dongfeng

2016-03-01

The results from observation studies on the relationship between coffee intake and risk of depression and the relationship between caffeine consumption and depression remain controversial. We conducted a meta-analysis with a dose-response analysis to quantitatively summarize the evidence about the association between coffee and caffeine intakes and risk of depression. Relevant articles were identified by researching PubMed, Web of Science, China National Knowledge Infrastructure and WANFANG DATA in English or Chinese from 1 January 1980 to 1 May 2015. Case-control, cohort or cross-sectional studies evaluating coffee or caffeine consumption and depression were included. A random-effects model was used to combine study-specific relative risk and 95% confidence interval. Dose-response relationship was assessed by restricted cubic spline functions. Data were obtained from 11 observation articles; 330,677 participants from seven studies in seven articles were included in the coffee-depression analysis, while 38,223 participants from eight studies in seven articles were involved in the caffeine-depression analysis. Compared with the lowest level consumption, the pooled relative risk (95% confidence interval) for coffee-depression and caffeine-depression was 0.757 [0.624, 0.917] and 0.721 [0.522, 0.997], respectively. For dose-response analysis, evidence of a linear association was found between coffee consumption and depression, and the risk of depression decreased by 8% (relative risk = 0.92, 95% confidence interval = [0.87, 0.97], p = 0.002) for each cup/day increment in coffee intake; a nonlinear association was found between caffeine consumption and depression, the risk of depression decreased faster and the association became significant when the caffeine consumption was above 68 mg/day and below 509 mg/day. Coffee and caffeine consumption were significantly associated with decreased risk of depression. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Maternal blood, plasma, and breast milk lead: lactational transfer and contribution to infant exposure.

PubMed

Ettinger, Adrienne S; Roy, Ananya; Amarasiriwardena, Chitra J; Smith, Donald; Lupoli, Nicola; Mercado-García, Adriana; Lamadrid-Figueroa, Hector; Tellez-Rojo, Martha Maria; Hu, Howard; Hernández-Avila, Mauricio

2014-01-01

Human milk is a potential source of lead exposure. Yet lactational transfer of lead from maternal blood into breast milk and its contribution to infant lead burden remains poorly understood. We explored the dose-response relationships between maternal blood, plasma, and breast milk to better understand lactational transfer of lead from blood and plasma into milk and, ultimately, to the breastfeeding infant. We measured lead in 81 maternal blood, plasma, and breast milk samples at 1 month postpartum and in 60 infant blood samples at 3 months of age. Milk-to-plasma (M/P) lead ratios were calculated. Multivariate linear, piecewise, and generalized additive models were used to examine dose-response relationships between blood, plasma, and milk lead levels. Maternal lead levels (mean±SD) were as follows: blood: 7.7±4.0 μg/dL; plasma: 0.1±0.1 μg/L; milk: 0.8±0.7 μg/L. The average M/P lead ratio was 7.7 (range, 0.6-39.8) with 97% of the ratios being >1. The dose-response relationship between plasma lead and M/P ratio was nonlinear (empirical distribution function=6.5, p=0.0006) with the M/P ratio decreasing by 16.6 and 0.6 per 0.1 μg/L of plasma lead, respectively, below and above 0.1 μg/L plasma lead. Infant blood lead level (3.4±2.2 μg/dL) increased by 1.8 μg/dL per 1 μg/L milk lead (p<0.0001, R2=0.3). The M/P ratio for lead in humans is substantially higher than previously reported, and transfer of lead from plasma to milk may be higher at lower levels of plasma lead. Breast milk is an important determinant of lead burden among breastfeeding infants.

Predominant nonlinear atmospheric response to meridional shift of the Gulf Stream path from the WRF atmospheric model simulations

NASA Astrophysics Data System (ADS)

Seo, H.; Kwon, Y. O.; Joyce, T. M.

2016-02-01

A remarkably strong nonlinear behavior of the atmospheric circulation response to North Atlantic SST anomalies (SSTA) is revealed from a set of large-ensemble, high-resolution, and hemispheric-scale Weather Research and Forecasting (WRF) model simulations. The model is forced with the SSTA associated with meridional shift of the Gulf Stream (GS) path, constructed from a lag regression of the winter SST on a GS Index from observation. Analysis of the systematic set of experiments with SSTAs of varied amplitudes and switched signs representing various GS-shift scenarios provides unique insights into mechanism for emergence and evolution of transient and equilibrium response of atmospheric circulation to extratropical SSTA. Results show that, independent of sign of the SSTA, the equilibrium response is characterized by an anomalous trough over the North Atlantic Ocean and the Western Europe concurrent with enhanced storm track, increased rainfall, and reduced blocking days. To the north of the anomalous low, an anomalous ridge emerges over the Greenland, Iceland, and Norwegian Seas accompanied by weakened storm track, reduced rainfall and increased blocking days. This nonlinear component of the total response dominates the weak and oppositely signed linear response that is directly forced by the SSTA, yielding an anomalous ridge (trough) downstream of the warm (cold) SSTA. The amplitude of the linear response is proportional to that of the SSTA, but this is masked by the overwhelmingly strong nonlinear behavior showing no clear correspondence to the SSTA amplitude. The nonlinear pattern emerges 3-4 weeks after the model initialization in November and reaches its first peak amplitude in December/January. It appears that altered baroclinic wave activity due to the GS SSTA in November lead to low-frequency height responses in December/January through transient eddy vorticity flux convergence.

Geometrically Nonlinear Shell Analysis of Wrinkled Thin-Film Membranes with Stress Concentrations

NASA Technical Reports Server (NTRS)

Tessler, Alexander; Sleight, David W.

2006-01-01

Geometrically nonlinear shell finite element analysis has recently been applied to solar-sail membrane problems in order to model the out-of-plane deformations due to structural wrinkling. Whereas certain problems lend themselves to achieving converged nonlinear solutions that compare favorably with experimental observations, solutions to tensioned membranes exhibiting high stress concentrations have been difficult to obtain even with the best nonlinear finite element codes and advanced shell element technology. In this paper, two numerical studies are presented that pave the way to improving the modeling of this class of nonlinear problems. The studies address the issues of mesh refinement and stress-concentration alleviation, and the effects of these modeling strategies on the ability to attain converged nonlinear deformations due to wrinkling. The numerical studies demonstrate that excessive mesh refinement in the regions of stress concentration may be disadvantageous to achieving wrinkled equilibrium states, causing the nonlinear solution to lock in the membrane response mode, while totally discarding the very low-energy bending response that is necessary to cause wrinkling deformation patterns.

Dynamic Nonlinear Elastic Stability of Helicopter Rotor Blades in Hover and in Forward Flight

NASA Technical Reports Server (NTRS)

Friedmann, P.; Tong, P.

1972-01-01

Equations for large coupled flap-lag motion of hingeless elastic helicopter blades are consistently derived. Only torsionally-rigid blades excited by quasi-steady aerodynamic loads are considered. The nonlinear equations of motion in the time and space variables are reduced to a system of coupled nonlinear ordinary differential equations with periodic coefficients, using Galerkin's method for the space variables. The nonlinearities present in the equations are those arising from the inclusion of moderately large deflections in the inertia and aerodynamic loading terms. The resulting system of nonlinear equations has been solved, using an asymptotic expansion procedure in multiple time scales. The stability boundaries, amplitudes of nonlinear response, and conditions for existence of limit cycles are obtained analytically. Thus, the different roles played by the forcing function, parametric excitation, and nonlinear coupling in affecting the solution can be easily identified, and the basic physical mechanism of coupled flap-lag response becomes clear. The effect of forward flight is obtained with the requirement of trimmed flight at fixed values of the thrust coefficient.

Multiple-mode nonlinear free and forced vibrations of beams using finite element method

NASA Technical Reports Server (NTRS)

Mei, Chuh; Decha-Umphai, Kamolphan

1987-01-01

Multiple-mode nonlinear free and forced vibration of a beam is analyzed by the finite element method. The geometric nonlinearity is investigated. Inplane displacement and inertia (IDI) are also considered in the formulation. Harmonic force matrix is derived and explained. Nonlinear free vibration can be simply treated as a special case of the general forced vibration by setting the harmonic force matrix equal to zero. The effect of the higher modes is more pronouced for the clamped supported beam than the simply supported one. Beams without IDI yield more effect of the higher modes than the one with IDI. The effects of IDI are to reduce nonlinearity. For beams with end supports restrained from axial movement (immovable cases), only the hardening type nonlinearity is observed. However, beams of small slenderness ratio (L/R = 20) with movable end supports, the softening type nonlinearity is found. The concentrated force case yields a more severe response than the uniformly distributed force case. Finite element results are in good agreement with the solution of simple elliptic response, harmonic balance method, and Runge-Kutte method and experiment.

Fast novel nonlinear optical NLC system with local response

NASA Astrophysics Data System (ADS)

Iljin, Andrey; Residori, Stefania; Bortolozzo, Umberto

2017-06-01

Nonlinear optical performance of a novel liquid crystalline (LC) cell has been studied in two-wave mixing experiments revealing high diffraction efficiency within extremely wide intensity range, fast recording times and spatial resolution. Photo-induced modulation of the LC order parameter resulting from trans-cis isomerisation of dye molecules causes consequent changes of refractive indices of the medium (Light-Induced Order Modification, LIOM-mechanism) and is proved to be the main mechanism of optical nonlinearity. The proposed arrangement of the electric-field-stabilised homeotropic alignment hinders the LC director reorientation, prevents appearance of surface effects and ensures the optical cell quality. The LIOM-type nonlinearity, characterised with the substantially local nonlinear optical response, could also be extended for the recording of arbitrary phase profiles as requested in several applications for light-beam manipulation, recording of dynamic volume holograms and photonic lattices.

Using surface lattice resonances to engineer nonlinear optical processes in metal nanoparticle arrays

NASA Astrophysics Data System (ADS)

Huttunen, Mikko J.; Rasekh, Payman; Boyd, Robert W.; Dolgaleva, Ksenia

2018-05-01

Collective responses of localized surface plasmon resonances, known as surface lattice resonances (SLRs) in metal nanoparticle arrays, can lead to high quality factors (˜100 ), large local-field enhancements, and strong light-matter interactions. SLRs have found many applications in linear optics, but little work of the influence of SLRs on nonlinear optics has been reported. Here we show how SLRs could be utilized to enhance nonlinear optical interactions. We devote special attention to the sum-frequency, difference-frequency, and third-harmonic generation processes because of their potential for the realization of novel sources of light. We also demonstrate how such arrays could be engineered to enhance higher-order nonlinear optical interactions through cascaded nonlinear processes. In particular, we demonstrate how the efficiency of third-harmonic generation could be engineered via cascaded second-order responses.

The Generation of Harmonic Distortion and Distortion Products in a Computational Model of the Cochlea

NASA Astrophysics Data System (ADS)

Meaud, Julien; Li, Yizeng; Grosh, Karl

2011-11-01

It is generally agreed that the nonlinear response of the cochlea is due to the forward transduction of the outer hair cell (OHC) hair bundle (HB) and subsequent alteration of the active force applied to the cochlear structures, including the basilar membrane (BM). A mechanical-acoustical-electrical model of the cochlea with three-dimensional fluid representation, and feedback from OHC somatic motility coupled to nonlinear HB mechanotransduction is used to predict nonlinear distortion of the BM response to acoustic stimulus. An efficient alternating frequency time scheme is implemented to solve for the nonlinear stationary dynamics of the cochlea. The model is used to predict the location of maximum generation of nonlinear distortion during pure tone and two-tone stimulation as well as the propagation of the distortion components on the BM.

An F1-extended one-generation reproductive toxicity study in Crl:CD(SD) rats with 2,4-dichlorophenoxyacetic acid.

PubMed

Marty, Mary Sue; Neal, Barbara H; Zablotny, Carol L; Yano, Barry L; Andrus, Amanda K; Woolhiser, Michael R; Boverhof, Darrell R; Saghir, Shakil A; Perala, Adam W; Passage, Julie K; Lawson, Marie A; Bus, James S; Lamb, James C; Hammond, Larry

2013-12-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10-12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The "No Observed Adverse Effect Level" for systemic toxicity was 300 ppm in both males (16.6 mg/kg/day) and females (20.6 mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies.

An F1-Extended One-Generation Reproductive Toxicity Study in Crl:CD(SD) Rats With 2,4-Dichlorophenoxyacetic Acid

PubMed Central

Marty, Mary Sue

2013-01-01

2,4-Dichlorophenoxyacetic acid (2,4-D) was assessed for systemic toxicity, reproductive toxicity, developmental neurotoxicity (DNT), developmental immunotoxicity (DIT), and endocrine toxicity. CD rats (27/sex/dose) were exposed to 0, 100, 300, 600 (female), or 800 (male) ppm 2,4-D in diet. Nonlinear toxicokinetic behavior was shown at high doses; the renal clearance saturation threshold for 2,4-D was exceeded markedly in females and slightly exceeded in males. Exposure was 4 weeks premating, 7 weeks postmating for P1 males and through lactation for P1 females. F1 offspring were examined for survival and development, and at weaning, pups were divided in cohorts, by sex and dose, and by systemic toxicity (10), DNT (10), DIT (20), and reproductive toxicity (≥ 23). Remaining weanlings were evaluated for systemic toxicity and neuropathology (10–12). Body weight decreased during lactation in high-dose P1 females and in F1 pups. Kidney was the primary target organ, with slight degeneration of proximal convoluted tubules observed in high-dose P1 males and in high-dose F1 males and females. A slight intergenerational difference in kidney toxicity was attributed to increased intake of 2,4-D in F1 offspring. Decreased weanling testes weights and delayed preputial separation in F1 males were attributed to decreased body weights. Endocrine-related effects were limited to slight thyroid hormone changes and adaptive histopathology in high-dose GD 17 dams seen only at a nonlinear toxicokinetic dose. 2,4-D did not cause reproductive toxicity, DNT, or DIT. The “No Observed Adverse Effect Level” for systemic toxicity was 300 ppm in both males (16.6mg/kg/day) and females (20.6mg/kg/day), which is approximately 6700- to 93 000-fold higher than that reported for 2,4-D exposures in human biomonitoring studies. PMID:24072463

Population Pharmacokinetics of Busulfan in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplant: A Model-Based Dosing Algorithm for Personalized Therapy and Implementation into Routine Clinical Use

PubMed Central

Long-Boyle, Janel; Savic, Rada; Yan, Shirley; Bartelink, Imke; Musick, Lisa; French, Deborah; Law, Jason; Horn, Biljana; Cowan, Morton J.; Dvorak, Christopher C.

2014-01-01

Background Population pharmacokinetic (PK) studies of busulfan in children have shown that individualized model-based algorithms provide improved targeted busulfan therapy when compared to conventional dosing. The adoption of population PK models into routine clinical practice has been hampered by the tendency of pharmacologists to develop complex models too impractical for clinicians to use. The authors aimed to develop a population PK model for busulfan in children that can reliably achieve therapeutic exposure (concentration-at-steady-state, Css) and implement a simple, model-based tool for the initial dosing of busulfan in children undergoing HCT. Patients and Methods Model development was conducted using retrospective data available in 90 pediatric and young adult patients who had undergone HCT with busulfan conditioning. Busulfan drug levels and potential covariates influencing drug exposure were analyzed using the non-linear mixed effects modeling software, NONMEM. The final population PK model was implemented into a clinician-friendly, Microsoft Excel-based tool and used to recommend initial doses of busulfan in a group of 21 pediatric patients prospectively dosed based on the population PK model. Results Modeling of busulfan time-concentration data indicates busulfan CL displays non-linearity in children, decreasing up to approximately 20% between the concentrations of 250–2000 ng/mL. Important patient-specific covariates found to significantly impact busulfan CL were actual body weight and age. The percentage of individuals achieving a therapeutic Css was significantly higher in subjects receiving initial doses based on the population PK model (81%) versus historical controls dosed on conventional guidelines (52%) (p = 0.02). Conclusion When compared to the conventional dosing guidelines, the model-based algorithm demonstrates significant improvement for providing targeted busulfan therapy in children and young adults. PMID:25162216

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ganguly, Jayanta; Ghosh, Manas, E-mail: pcmg77@rediffmail.com

We investigate the profiles of diagonal components of frequency-dependent first nonlinear (β{sub xxx} and β{sub yyy}) optical response of repulsive impurity doped quantum dots. We have assumed a Gaussian function to represent the dopant impurity potential. This study primarily addresses the role of noise on the polarizability components. We have invoked Gaussian white noise consisting of additive and multiplicative characteristics (in Stratonovich sense). The doped system has been subjected to an oscillating electric field of given intensity, and the frequency-dependent first nonlinear polarizabilities are computed. The noise characteristics are manifested in an interesting way in the nonlinear polarizability components. Inmore » case of additive noise, the noise strength remains practically ineffective in influencing the optical responses. The situation completely changes with the replacement of additive noise by its multiplicative analog. The replacement enhances the nonlinear optical response dramatically and also causes their maximization at some typical value of noise strength that depends on oscillation frequency.« less