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Sample records for linear dose response

  1. Cancer risk assessment: Optimizing human health through linear dose-response models.

    PubMed

    Calabrese, Edward J; Shamoun, Dima Yazji; Hanekamp, Jaap C

    2015-07-01

    This paper proposes that generic cancer risk assessments be based on the integration of the Linear Non-Threshold (LNT) and hormetic dose-responses since optimal hormetic beneficial responses are estimated to occur at the dose associated with a 10(-4) risk level based on the use of a LNT model as applied to animal cancer studies. The adoption of the 10(-4) risk estimate provides a theoretical and practical integration of two competing risk assessment models whose predictions cannot be validated in human population studies or with standard chronic animal bioassay data. This model-integration reveals both substantial protection of the population from cancer effects (i.e. functional utility of the LNT model) while offering the possibility of significant reductions in cancer incidence should the hormetic dose-response model predictions be correct. The dose yielding the 10(-4) cancer risk therefore yields the optimized toxicologically based "regulatory sweet spot". PMID:25916915

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

    SciTech Connect

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

    2012-08-15

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

  3. Origin of the linearity no threshold (LNT) dose-response concept.

    PubMed

    Calabrese, Edward J

    2013-09-01

    This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673-674, 1928) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201-213, 1929; Oliver in Science 71:44-46, 1930), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose-response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide. PMID:23887208

  4. Non-linear dose-response of DNA-reactive genotoxins: recommendations for data analysis.

    PubMed

    Johnson, George E; Doak, Shareen H; Griffiths, Sioned M; Quick, Emma L; Skibinski, David O F; Zaïr, Zoulikha M; Jenkins, Gareth J

    2009-08-01

    Until recently, there has only been a limited amount of data available on the kinetics of mutation induction in the low dose region of exposure. In our publication Doak et al. [S.H. Doak, G.J. Jenkins, G.E. Johnson, E. Quick, E.M. Parry, J.M. Parry, Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens, Cancer Res. 67 (2007) 3904-3911] we showed that the two alkylating agents methyl-methanesulfonate (MMS) and ethyl-methanesulfonate (EMS) possess non-linear dose-response curves with no observed effect levels (NOEL) for mutation or chromosomal damage in vitro. These experiments were carried out in the AHH-1 human lymphoblastoid cell line, using the hypoxanthine phosphoribosyl transferase (HPRT) assay and the cytokinesis-block micronucleus (CBMN) assay, respectively. We have now carried out more advanced statistical analyses to define threshold values, which is critical as it has a dramatic impact on hazard and risk assessment. To do this, we re-analysed the data to see if the linear model or a more complex model (hockey stick or quadratic) gave a significant better fit of the data. For both EMS and MMS cytokinesis-block micronucleus data sets, the hockey stick model gave the most significant fit. The same was true for EMS, MMS and surprisingly ethylnitrosourea (ENU) in the HPRT assay in human AHH-1 cells. However, methylnitrosourea (MNU) was linear in both assays. These further analyses have shown that EMS and MMS have clear thresholds for both gene mutation and chromosome damage, as does ENU for gene mutation in AHH-1 cells. MNU was linear for gene and chromosome mutation and so was ENU for chromosome mutations at the concentrations tested. These findings correlate closely with those in vivo findings of Gocke et al. [E. Gocke, L. Müller, In vivo studies in the mouse to define a threshold for the genotoxicity of EMS and ENU, Mutat. Res. (this issue)] and together these data show a true threshold for EMS both in vitro and in

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

    PubMed Central

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

    2015-01-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334

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

    PubMed

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

    2015-10-01

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

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

    PubMed

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

    2015-10-01

    Biological dosimetry (biodosimetry) is based on the investigation of radiation-induced biological effects (biomarkers), mainly dicentric chromosomes, in order to correlate them with radiation dose. To interpret the dicentric score in terms of absorbed dose, a calibration curve is needed. Each curve should be constructed with respect to basic physical parameters, such as the type of ionizing radiation characterized by low or high linear energy transfer (LET) and dose rate. This study was designed to obtain dose calibration curves by scoring of dicentric chromosomes in peripheral blood lymphocytes irradiated in vitro with a 6 MV electron linear accelerator (Mevatron M, Siemens, USA). Two software programs, CABAS (Chromosomal Aberration Calculation Software) and Dose Estimate, were used to generate the curve. The two software programs are discussed; the results obtained were compared with each other and with other published low LET radiation curves. Both software programs resulted in identical linear and quadratic terms for the curve presented here, which was in good agreement with published curves for similar radiation quality and dose rates. PMID:26445334

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

    PubMed Central

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

    2016-01-01

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

  9. EMS in Viracept--initial ('traditional') assessment of risk to patients based on linear dose response relations.

    PubMed

    Gocke, Elmar; Müller, Lutz; Pfister, Thomas

    2009-11-12

    Prior to having performed in depth toxicological, genotoxicological and DMPK studies on ethyl methanesulfonate (EMS) providing solid evidence for a thresholded dose response relationship, we had prepared and shared with regulatory authorities a preliminary risk estimate based on standard linear dose-effect projections. We estimated that maximal lifetime cancer risk was in the order of 10(-3) (for lifetime ingestion of the maximally contaminated tablets) or 10(-4) for the exposure lasting for 3 months. This estimate was based on a lifetime cancer study with methyl methanesulfonate (MMS; as insufficient data were available for EMS) in rodents and default linear back extrapolation. Analogous estimates were made specifically for breast cancer based on short term tumorigenicity studies with EMS in rats, for the induction of heritable mutations based on specific locus and dominant lethal tests in mice and for the induction of birth defects based on teratogenicity studies in mice. We concluded that even under worst case assumptions of linear dose relations the chance of experiencing these adverse effects would be very small, comprising at most a minute additional burden among the background incidence of the patients.

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

    SciTech Connect

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

    2000-11-15

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

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

    SciTech Connect

    Calabrese, Edward J.; Kostecki, Paul T.

    2002-05-28

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

  12. Dose-response relationship between total cadmium intake and prevalence of renal dysfunction using general linear models.

    PubMed

    Hochi, Y; Kido, T; Nogawa, K; Kito, H; Shaikh, Z A

    1995-01-01

    To determine the maximum allowable intake limits for chronic dietary exposure to cadmium (Cd), the dose-response relationship between total Cd intake and prevalence of renal dysfunction was examined using general linear models considering the effect of age as a confounder. The target population comprised 1850 Cd-exposed and 294 non-exposed inhabitants of Ishikawa, Japan. They were divided into 96 subgroups by sex, age (four categories) cadmium concentrations in rice (three categories) and length of residence (four categories). As indicators of the cadmium-induced renal dysfunction, glucose, total protein, amino nitrogen, beta 2-microglobulin and metallothionein in urine were employed. General linear models were fitted statistically to the relationship among prevalence of renal dysfunction, sex, age and total Cd intake. Prevalence of abnormal urinary findings other than glucosuria had significant associations with total Cd intake. When total Cd intake corresponding to the mean prevalence of each abnormal urinary finding in the non-exposed subjects was calculated using general linear models, total Cd intakes corresponding to glucosuria, proteinuria, aminoaciduria (men only) and proteinuria with glucosuria were determined to be ca. 2.2-3.8 g and those corresponding to prevalence of metallothioneinuria were calculated as ca. 1.5-2.6 g. The low-molecular-weight protein in urine was confirmed to be a more sensitive indicator of renal dysfunction, and these total Cd intake values were close to those calculated previously by simple regression analysis, suggesting them to be reasonable values as the maximum allowable intake of Cd.

  13. Dose-response relationships in chemical carcinogenesis: superposition of different mechanisms of action, resulting in linear-nonlinear curves, practical thresholds, J-shapes.

    PubMed

    Lutz, W K

    1998-09-20

    The shape of a carcinogen dose-cancer incidence curve is discussed as the result of a superposition of dose-response relationships for various effects of the carcinogen on the process of carcinogenesis. Effects include direct DNA damage, e.g., by covalent binding, indirect DNA damage, e.g., by increased formation of reactive oxygen species or interaction with DNA replication or chromosome integrity. The 'fixation' of a DNA adduct as a heritable mutation depends on its pro-mutagenic potency and on the rates of DNA repair and DNA replication. Endogenous and unavoidable DNA damage is responsible for a background rate of the process of mutagenesis and carcinogenesis and forms the basis of spontaneous cancer incidence. For DNA-reactive carcinogens, linearity of the dose response at the low-dose end is expected. With increasing dose, saturation of DNA repair can introduce a sublinearity (example: dimethylnitrosamine). Stimulation of cell division as a result of high-dose toxicity and regenerative proliferation also results in a sublinear deviation from low-dose linearity. If the DNA-damaging potency of the carcinogen is low in comparison with the high-dose effects, the linear part of the low dose-cancer incidence curve might be hidden within the background variability. Under such conditions, 'practical thresholds' could be discussed (formaldehyde). If a carcinogen increases the rate of cell division or the level of oxidative stress at high dose but has an antimitogenic or antioxidative effect at low dose, a J-shaped (or: U-shaped) curve with a decrease of the spontaneous tumor incidence at low dose could result (caffeic acid; TCDD). This phenomenon has been observed even under conditions of a genotoxic contribution (ionizing radiation; diesel exhaust particles). For a mechanism-based assessment of a low-dose cancer risk, information on the various modes of action and modulations should be available over the full dose range, and models should be refined to incorporate the

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-05-01

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

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

    PubMed Central

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

    2016-01-01

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

  19. Dose Rate Effects in Linear Bipolar Transistors

    NASA Technical Reports Server (NTRS)

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

    2011-01-01

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

  20. Linear response at criticality

    NASA Astrophysics Data System (ADS)

    Svenkeson, Adam; Bologna, Mauro; Grigolini, Paolo

    2012-10-01

    We study a set of cooperatively interacting units at criticality, and we prove with analytical and numerical arguments that they generate the same renewal non-Poisson intermittency as that produced by blinking quantum dots, thereby giving a stronger support to the results of earlier investigation. By analyzing how this out-of-equilibrium system responds to harmonic perturbations, we find that the response can be described only using a new form of linear response theory that accounts for aging and the nonergodic behavior of the underlying process. We connect the undamped response of the system at criticality to the decaying response predicted by the recently established nonergodic fluctuation-dissipation theorem for dichotomous processes using information about the second moment of the fluctuations. We demonstrate that over a wide range of perturbation frequencies the response of the cooperative system is greatest when at criticality.

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

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

    PubMed

    Seong, Ki Moon; Seo, Songwon; Lee, Dalnim; Kim, Min-Jeong; Lee, Seung-Sook; Park, Sunhoo; Jin, Young Woo

    2016-02-01

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

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

    PubMed Central

    2016-01-01

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

  4. Investigation of Non-Linear Adaptive Responses and Split Dose Recovery Induced by Ionizing Radiation in Three Human Epithelial Derived Cell Lines

    PubMed Central

    Ryan, Lorna A.; Seymour, Colin B.; Mothersill, Carmel E.

    2009-01-01

    Two almost completely exclusive fields in radiobiology deal with splitting doses of radiation and comparing the effect to a similar total dose given in one exposure. In radiotherapy, dose “fractionation” is used to “spare” normal tissue and in the low dose field, the adaptive response is well documented as a phenomenon where a small “priming” dose administered before the larger “challenge “ dose reduces the effect of the large dose. There have been very few studies where these fields overlap, thus it is not possible to ascertain whether common or distinct mechanisms underlie both phenomena but this is certainly an interesting question and relevant to our understanding of high and low dose radiobiology. This paper presents data for three human cell lines with varying p53 status and radiation responses, treated at a range of times between first and second dose and for 3 different first doses (0.1, 0.5 and 2Gy). The data show that time between doses is critical. Protective (adaptive) effects were seen in each cell line but most prominently in the malignant HT 29 cell line. Surprisingly none of the cell lines showed pronounced split dose recovery. This suggests different mechanisms may underlie the two phenomena. PMID:20011650

  5. The Impact of Adaptive and Non-targeted Effects in the Biological Responses to Low Dose/Low Fluence Ionizing-Radiation: The Modulating Effect of Linear Energy Transfer

    PubMed Central

    de Toledo, Sonia M.; Buonanno, Manuela; Li, Min; Asaad, Nesrin; Qin, Yong; Zhang, Jie; Azzam, Edouard I.

    2011-01-01

    A large volume of laboratory and human epidemiological studies have shown that high doses of ionizing radiation engender significant health risks. In contrast, the health risks of low level radiation remain ambiguous and have been the subject of intense debate. To reduce the uncertainty in evaluating these risks, research advances in cellular and molecular biology are being used to characterize the biological effects of low dose radiation exposures and their underlying mechanisms. Radiation type, dose rate, genetic susceptibility, cellular redox environment, stage of cell growth, level of biological organization and environmental parameters are among the factors that modulate interactions among signaling processes that determine short- and long-term outcomes of low dose exposures. Whereas, recommended radiation protection guidelines assume a linear dose-response relationship in estimating radiation cancer risk, in vitro and in vivo investigations of phenomena such as adaptive responses and non-targeted effects, namely bystander effects and genomic instability, suggest that low dose/low fluence-induced signaling events act to alter linearity of the dose-response relation as supported by the biophysical argument. The latter predicts that increases in dose simply increase the probability that a given cell in a tissue will be intersected by an electron track, and by corollary, each unit of radiation, no matter how small would increases risk. These predictions assume that similar molecular events mediate both low and high dose radiobiological effects, and the cumulative risk from two sequential radiation exposures can never be less than one alone. PMID:21512606

  6. Estimation of absorbed dose in irradiated dates ( Phoenix dactylifera L.). Test of ESR response function by a weighted linear least-squares regression analysis

    NASA Astrophysics Data System (ADS)

    Ghelawi, M. A.; Moore, J. S.; Bisby, R. H.; Dodd, N. J. F.

    2001-01-01

    Food spoilage is caused by infestation by insects, contamination by bacteria and fungi and by deterioration by enzymes. In the third world, it has been estimated that 25% of agricultural products are lost before they reach the market. One way to decrease such losses is by treatment with ionising radiation and maximum permitted doses have been established for treatment of a wide variety of foods. For dates this dose is 2.0 kGy. Detection of irradiated foods is now essential and here we have used ESR to detect and estimate the dose received by a single date. The ESR spectrum of unirradiated date stone contains a single line g=2.0045 (signal A). Irradiation up to 2.0 kGy induces radical formation with g=1.9895, g=2.0159 (signal C) and g=1.9984 (signal B) high field. The lines with g=1.9895 and 2.0159 are readily detected and stable at room temperature for at least 27 months for samples irradiated up to this dose. The yield of the radicals resulting in these lines increase linearly up to a dose of 5.0 kGy as is evidenced by the linear increase in their intensity. In blind trials of 21 unirradiated and irradiated dates we are able to identify with 100% accuracy an irradiated sample and to estimate the dose to which the sample was irradiated to within ˜0.5 kGy.

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

    PubMed Central

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

    2014-01-01

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

  8. 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.

  9. The Dose Response Relationship for Radiation Carcinogenesis

    NASA Astrophysics Data System (ADS)

    Hall, Eric

    2008-03-01

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

  10. Linear Response for Intermittent Maps

    NASA Astrophysics Data System (ADS)

    Baladi, Viviane; Todd, Mike

    2016-11-01

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

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

    PubMed Central

    Zhao, Yuchao; Ricci, Paolo F.

    2010-01-01

    For ionization radiation (IR) induced cancer, a linear non-threshold (LNT) model at very low doses is the default used by a number of national and international organizations and in regulatory law. This default denies any positive benefit from any level of exposure. However, experimental observations and theoretical biology have found that both linear and J-shaped IR dose-response curves can exist at those very low doses. We develop low dose J-shaped dose-response, based on systems biology, and thus justify its use regarding exposure to IR. This approach incorporates detailed, molecular and cellular descriptions of biological/toxicological mechanisms to develop a dose-response model through a set of nonlinear, differential equations describing the signaling pathways and biochemical mechanisms of cell cycle checkpoint, apoptosis, and tumor incidence due to IR. This approach yields a J-shaped dose response curve while showing where LNT behaviors are likely to occur. The results confirm the hypothesis of the J-shaped dose response curve: the main reason is that, at low-doses of IR, cells stimulate protective systems through a longer cell arrest time per unit of IR dose. We suggest that the policy implications of this approach are an increasingly correct way to deal with precautionary measures in public health. PMID:21191485

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

    PubMed

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

    2016-06-01

    In evaluating the risk of exposure to health hazards, characterizing the dose-response relationship and estimating acceptable exposure levels are the primary goals. In analyses of health risks associated with exposure to ionizing radiation, while there is a clear agreement that moderate to high radiation doses cause harmful effects in humans, little has been known about the possible biological effects at low doses, for example, below 0.1 Gy, which is the dose range relevant to most radiation exposures of concern today. A conventional approach to radiation dose-response estimation based on simple parametric forms, such as the linear nonthreshold model, can be misleading in evaluating the risk and, in particular, its uncertainty at low doses. As an alternative approach, we consider a Bayesian semiparametric model that has a connected piece-wise-linear dose-response function with prior distributions having an autoregressive structure among the random slope coefficients defined over closely spaced dose categories. With a simulation study and application to analysis of cancer incidence data among Japanese atomic bomb survivors, we show that this approach can produce smooth and flexible dose-response estimation while reasonably handling the risk uncertainty at low doses and elsewhere. With relatively few assumptions and modeling options to be made by the analyst, the method can be particularly useful in assessing risks associated with low-dose radiation exposures. PMID:26581473

  13. LINEARIZING THE RESPONSE OF THE NSRL SYNCHRONOUS RECYCLING-INTEGRATORS.

    SciTech Connect

    ODDO, P.; RUSEK, A.; RUSSO, T.

    2005-05-16

    The Lawrence Berkeley National Laboratory (LBNL) designed recycling-integrators used for the NASA Space Radiation Laboratory (NSRL) dosimetry feature excellent linearity. However, switching transients in the balancing source add a duty-cycle dependence to the response that manifests as a non-linearity near mid-scale and a slope-change above mid-scale. The onset of this non-linearity limits the typical usable dynamic range. Measurements during a recent run showed that at higher intensities the recycling-integrators would operate in the non-linear region enough to exceed the desired tolerance and over count the dose. This report will show how a FPGA, which implements the scalars, was used to compensate the non-linearity allowing higher dose-rates by effectively doubling the dynamic range of the dosimetry system.

  14. Exploring the dose response of radiochromic dosimeters

    NASA Astrophysics Data System (ADS)

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

    2013-06-01

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

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

    NASA Technical Reports Server (NTRS)

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

    2007-01-01

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

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

    PubMed

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

    2011-01-01

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

  17. Simultaneous measurements of absorbed dose and linear energy transfer in therapeutic proton beams.

    PubMed

    Granville, Dal A; Sahoo, Narayan; Sawakuchi, Gabriel O

    2016-02-21

    The biological response resulting from proton therapy depends on both the absorbed dose in the irradiated tissue and the linear energy transfer (LET) of the beam. Currently, optimization of proton therapy treatment plans is based only on absorbed dose. However, recent advances in proton therapy delivery have made it possible to vary the LET distribution for potential therapeutic gain, leading to investigations of using LET as an additional parameter in plan optimization. Having a method to measure and verify both absorbed dose and LET as part of a quality assurance program would be ideal for the safe delivery of such plans. Here we demonstrated the potential of an optically stimulated luminescence (OSL) technique to simultaneously measure absorbed dose and LET. We calibrated the ratio of ultraviolet (UV) to blue emission intensities from Al2O3:C OSL detectors as a function of LET to facilitate LET measurements. We also calibrated the intensity of the blue OSL emission for absorbed dose measurements and introduced a technique to correct for the LET-dependent dose response of OSL detectors exposed to therapeutic proton beams. We demonstrated the potential of our OSL technique by using it to measure LET and absorbed dose under new irradiation conditions, including patient-specific proton therapy treatment plans. In the beams investigated, we found the OSL technique to measure dose-weighted LET within 7.9% of Monte Carlo-simulated values and absorbed dose within 2.5% of ionization chamber measurements.

  18. Simultaneous measurements of absorbed dose and linear energy transfer in therapeutic proton beams.

    PubMed

    Granville, Dal A; Sahoo, Narayan; Sawakuchi, Gabriel O

    2016-02-21

    The biological response resulting from proton therapy depends on both the absorbed dose in the irradiated tissue and the linear energy transfer (LET) of the beam. Currently, optimization of proton therapy treatment plans is based only on absorbed dose. However, recent advances in proton therapy delivery have made it possible to vary the LET distribution for potential therapeutic gain, leading to investigations of using LET as an additional parameter in plan optimization. Having a method to measure and verify both absorbed dose and LET as part of a quality assurance program would be ideal for the safe delivery of such plans. Here we demonstrated the potential of an optically stimulated luminescence (OSL) technique to simultaneously measure absorbed dose and LET. We calibrated the ratio of ultraviolet (UV) to blue emission intensities from Al2O3:C OSL detectors as a function of LET to facilitate LET measurements. We also calibrated the intensity of the blue OSL emission for absorbed dose measurements and introduced a technique to correct for the LET-dependent dose response of OSL detectors exposed to therapeutic proton beams. We demonstrated the potential of our OSL technique by using it to measure LET and absorbed dose under new irradiation conditions, including patient-specific proton therapy treatment plans. In the beams investigated, we found the OSL technique to measure dose-weighted LET within 7.9% of Monte Carlo-simulated values and absorbed dose within 2.5% of ionization chamber measurements. PMID:26859539

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

    EPA Science Inventory

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

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

    SciTech Connect

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

    2014-02-15

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

  1. BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants

    PubMed Central

    Sen, Abhijit; Prasad, Manya; Norat, Teresa; Janszky, Imre; Tonstad, Serena; Romundstad, Pål; Vatten, Lars J

    2016-01-01

    Objective To conduct a systematic review and meta-analysis of cohort studies of body mass index (BMI) and the risk of all cause mortality, and to clarify the shape and the nadir of the dose-response curve, and the influence on the results of confounding from smoking, weight loss associated with disease, and preclinical disease. Data sources PubMed and Embase databases searched up to 23 September 2015. Study selection Cohort studies that reported adjusted risk estimates for at least three categories of BMI in relation to all cause mortality. Data synthesis Summary relative risks were calculated with random effects models. Non-linear associations were explored with fractional polynomial models. Results 230 cohort studies (207 publications) were included. The analysis of never smokers included 53 cohort studies (44 risk estimates) with >738 144 deaths and >9 976 077 participants. The analysis of all participants included 228 cohort studies (198 risk estimates) with >3 744 722 deaths among 30 233 329 participants. The summary relative risk for a 5 unit increment in BMI was 1.18 (95% confidence interval 1.15 to 1.21; I2=95%, n=44) among never smokers, 1.21 (1.18 to 1.25; I2=93%, n=25) among healthy never smokers, 1.27 (1.21 to 1.33; I2=89%, n=11) among healthy never smokers with exclusion of early follow-up, and 1.05 (1.04 to 1.07; I2=97%, n=198) among all participants. There was a J shaped dose-response relation in never smokers (Pnon-linearity <0.001), and the lowest risk was observed at BMI 23-24 in never smokers, 22-23 in healthy never smokers, and 20-22 in studies of never smokers with ≥20 years’ follow-up. In contrast there was a U shaped association between BMI and mortality in analyses with a greater potential for bias including all participants, current, former, or ever smokers, and in studies with a short duration of follow-up (<5 years or <10 years), or with moderate study quality scores. Conclusion Overweight and obesity is associated

  2. Optically isolated signal coupler with linear response

    DOEpatents

    Kronberg, James W.

    1994-01-01

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

  3. 5-ASA Dose-Response

    PubMed Central

    Katz, Seymour; Lichtenstein, Gary R; Safdi, Michael A

    2010-01-01

    Mesalamine (5-aminosalicylic acid; 5-ASA) represents the cornerstone of first-line therapy for mild-to-moderate ulcerative colitis (UC). Current guidelines suggest that the combination of oral and rectal therapies provide optimal symptom resolution and effectively maintain remission in the majority of these patients. Although effective, most oral 5-ASA formulations have a high pill burden and rectal therapies are associated with low adherence. Recent research has examined patterns of compliance, as well as the efficacy of different dose levels of 5-ASA in terms of symptom resolution, the maintenance of remission, and improvements in quality of life. The ASCEND I, II, and III trials found that doses of 4.8 g/day are more effective than 2.4 g/day doses in patients with moderate disease, those with previous steroid use, and those with a history of multiple medications. The benefits of effective long-term 5-ASA therapy include the avoidance of more costly and potentially toxic drugs (such as corticosteroids and biologic therapies), as well as improvements in quality of life, reductions in the need for future colectomy, and a lower risk of developing colorectal cancer. PMID:20567558

  4. Linear ubiquitination signals in adaptive immune responses

    PubMed Central

    Ikeda, Fumiyo

    2015-01-01

    Summary Ubiquitin can form eight different linkage types of chains using the intrinsic Met 1 residue or one of the seven intrinsic Lys residues. Each linkage-type of ubiquitin chain has a distinct three-dimensional topology, functioning as a tag to attract specific signaling molecules, which are so-called ubiquitin readers, and regulates various biological functions. Ubiquitin chains linked via Met 1 in a head-to-tail manner are called linear ubiquitin chains. Linear ubiquitination plays an important role in the regulation of cellular signaling, including the best-characterized Tumor Necrosis Factor (TNF) -induced canonical nuclear factor-kappa B (NF-κB) pathway. Linear ubiquitin chains are specifically generated by an E3 ligase complex called the linear ubiquitin chain assembly complex (LUBAC) and hydrolyzed by a deubiquitinase (DUB) called ovarian tumor (OTU) DUB with linear linkage specificity (OTULIN). LUBAC linearly ubiquitinates critical molecules in the TNF pathway, such as NEMO and RIPK1. The linear ubiquitin chains are then recognized by the ubiquitin readers, including NEMO, which control the TNF pathway. Accumulating evidence indicates an importance of the LUBAC complex in the regulation of apoptosis, development, and inflammation in mice. In this article, I focus on the role of linear ubiquitin chains in adaptive immune responses with an emphasis on the TNF-induced signaling pathways. PMID:26085218

  5. Solution of the multiple dosing problem using linear programming.

    PubMed

    Hacisalihzade, S S; Mansour, M

    1985-07-01

    A system theoretical approach to drug concentration-time data analysis is introduced after the discussion of some relevant concepts as they are used in system theory. The merits of this approach are demonstrated in multiple dosing problem. It is shown that dosage minimization without stringent constraints does not result in the desired therapeutic effect. In a different optimization the discrepancy between the actual and the desired time-histories of the relevant substance's plasma concentration is minimized. It is shown that both of these optimizations can be reduced to linear programming problems which are easily solvable with today's computers. These methods are demonstrated in a case study of dopaminergic substitution in Parkinson's disease where computer simulations show them to yield excellent results. Finally, the limits of this approach are also discussed.

  6. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

  8. Shared dosimetry error in epidemiological dose-response analyses

    SciTech Connect

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

    2015-03-23

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

  9. Shared dosimetry error in epidemiological dose-response analyses

    DOE PAGESBeta

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

    2015-03-23

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

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

    PubMed

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

    2015-01-01

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

  11. Shared Dosimetry Error in Epidemiological Dose-Response Analyses

    SciTech Connect

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

    2015-03-23

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

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

    PubMed

    Aleta, C R

    2009-01-01

    Current radiation protection regulatory limits are based on the linear non-threshold (LNT) theory using health data from atomic bombing survivors. Studies in recent years sparked debate on the validity of the theory, especially at low doses. The present LNT overestimates radiation risks since the dosimetry included only acute gammas and neutrons; the role of other bomb-caused factors, e.g. fallout, induced radioactivity, thermal radiation (UVR), electromagnetic pulse (EMP), and blast, were excluded. Studies are proposed to improve the dose-response relationship. PMID:19299154

  13. Linear Response Laws and Causality in Electrodynamics

    ERIC Educational Resources Information Center

    Yuffa, Alex J.; Scales, John A.

    2012-01-01

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

  14. Dose-Response Analysis Using R

    PubMed Central

    Ritz, Christian; Baty, Florent; Streibig, Jens C.; Gerhard, Daniel

    2015-01-01

    Dose-response analysis can be carried out using multi-purpose commercial statistical software, but except for a few special cases the analysis easily becomes cumbersome as relevant, non-standard output requires manual programming. The extension package drc for the statistical environment R provides a flexible and versatile infrastructure for dose-response analyses in general. The present version of the package, reflecting extensions and modifications over the last decade, provides a user-friendly interface to specify the model assumptions about the dose-response relationship and comes with a number of extractors for summarizing fitted models and carrying out inference on derived parameters. The aim of the present paper is to provide an overview of state-of-the-art dose-response analysis, both in terms of general concepts that have evolved and matured over the years and by means of concrete examples. PMID:26717316

  15. Biologically effective dose distribution based on the linear quadratic model and its clinical relevance

    SciTech Connect

    Lee, S.P.; Smathers, J.B.; Withers, H.R.

    1995-09-30

    Radiotherapy plans based on physical dose distributions do not necessarily entirely reflect the biological effects under various fractionation schemes. Over the past decade, the linear-quadratic (LQ) model has emerged as a convenient tool to quantify biological effects for radiotherapy. In this work, we set out to construct a mechanism to display biologically oriented dose distribution based on the LQ model. A computer program that converts a physical dose distribution calculated by a commercially available treatment planning system to a biologically effective dose (BED) distribution has been developed and verified against theoretical calculations. This software accepts a user`s input of biological parameters for each structure of interest (linear and quadratic dose-response and repopulation kinetic parameters), as well as treatment scheme factors (number of fractions, fractional dose, and treatment time). It then presents a two-dimensional BED display in conjunction with anatomical structures. Furthermore, to facilitate clinicians` intuitive comparison with conventional fractionation regimen, a conversion of BED to normalized isoeffective dose (NID) is also allowed. We have demonstrated the feasibility of constructing a biologically oriented dose distribution for clinical practice of radiotherapy. The discordance between physical dose distributions and the biological counterparts based on the given treatment schemes was quantified. The computerized display of BED at nonprescription points greatly enhanced the versatility of this tool. Although the routine use of this implementation in clinical radiotherapy should be cautiously done, depending largely on the accuracy of the published biological parameters, it may, nevertheless, help the clinicians derive an optimal treatment plan with a particular fractionation scheme or use it as a quantitative tool for outcome analysis in clinical research. 45 refs., 3 figs., 5 tabs.

  16. A broadly applicable function for describing luminescence dose response

    SciTech Connect

    Burbidge, C. I.

    2015-07-28

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

  17. Code System for Emergency Response Dose Assessment.

    2002-01-16

    Version: 00 A dose assessment model for emergency response applications. Dose pathways represented in the model are those that are most likely to be important during and immediately following a release (hours) rather than over an extended time frame (days or weeks). The doses computed include: external dose resulting from exposure to radiation emitted by radionuclides in the air and deposited on the ground, internal dose commitment resulting from inhalation, and total whole-body dose. Threemore » preprocessors are included. RSFPREP generates the MESORAD run specification (input) file, METWR creates the meteorological data file, and RELPREP prepares the release definition file. PRNT is a postprocessor for generating printer or screen-compatible output. All four programs run interactively. MESORAD was developed from version 2.0 of the MESOI atmospheric dispersion model (NESC 9862) retaining its modular nature.« less

  18. Total dose responses and reliability issues of 65 nm NMOSFETs

    NASA Astrophysics Data System (ADS)

    Dezhao, Yu; Qiwen, Zheng; Jiangwei, Cui; Hang, Zhou; Xuefeng, Yu; Qi, Guo

    2016-06-01

    In this paper, total dose responses and reliability issues of MOSFETs fabricated by 65 nm CMOS technology were examined. “Radiation-induced narrow channel effect” is observed in a narrow channel device. Similar to total dose responses of NMOSFETs, narrow channel NMOSFEs have larger hot-carrier-induced degradation than wide channel devices. Step Time-Dependent Dielectric Breakdown (TDDB) stresses are applied, and narrow channel devices have higher breakdown voltage than wide channel devices, which agree with “weakest link” theory of TDDB. Experimental results show that linear current, transconductance, saturated drain current and subthreshold swing are superposed degenerated by total dose irradiation and reliability issues, which may result in different lifetime from that considering total dose irradiation reliability issues separately. Project supported by “Light of West China” Program of CAS (No. XBBS201219).

  19. Dose-response-a challenge for allelopathy?

    PubMed

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

    2005-04-01

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

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

    PubMed

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

    2016-05-01

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

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

    PubMed

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

    2016-05-01

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

  2. Responses to Low Doses of Ionizing Radiation in Biological Systems

    PubMed Central

    Feinendegen, Ludwig E.; Pollycove, Myron; Sondhaus, Charles A.

    2004-01-01

    Biological tissues operate through cells that act together within signaling networks. These assure coordinated cell function in the face of constant exposure to an array of potentially toxic agents, externally from the environment and endogenously from metabolism. Living tissues are indeed complex adaptive systems. To examine tissue effects specific for low-dose radiation, (1) absorbed dose in tissue is replaced by the sum of the energies deposited by each track event, or hit, in a cell-equivalent tissue micromass (1 ng) in all micromasses exposed, that is, by the mean energy delivered by all microdose hits in the exposed micromasses, with cell dose expressing the total energy per micromass from multiple microdoses; and (2) tissue effects are related to cell damage and protective cellular responses per average microdose hit from a given radiation quality for all such hits in the exposed micromasses. The probability of immediate DNA damage per low-linear-energy-transfer (LET) average micro-dose hit is extremely small, increasing over a certain dose range in proportion to the number of hits. Delayed temporary adaptive protection (AP) involves (a) induced detoxification of reactive oxygen species, (b) enhanced rate of DNA repair, (c) induced removal of damaged cells by apoptosis followed by normal cell replacement and by cell differentiation, and (d) stimulated immune response, all with corresponding changes in gene expression. These AP categories may last from less than a day to weeks and be tested by cell responses against renewed irradiation. They operate physiologically against nonradiogenic, largely endogenous DNA damage, which occurs abundantly and continually. Background radiation damage caused by rare microdose hits per micromass is many orders of magnitude less frequent. Except for apoptosis, AP increasingly fails above about 200 mGy of low-LET radiation, corresponding to about 200 microdose hits per exposed micromass. This ratio appears to exceed

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

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

    SciTech Connect

    Rai, K.; Van Ryzin, J.

    1985-03-01

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

  6. Dose-response relationship of fibrous dusts in intraperitoneal studies.

    PubMed Central

    Roller, M; Pott, F; Kamino, K; Althoff, G H; Bellmann, B

    1997-01-01

    The relationship between the number of fibers injected intraperitoneally and the occurrence of peritoneal mesotheliomas in rats was investigated using data from a series of carcinogenicity studies with several fibrous dusts. Based on observed tumor incidences ranging between 10 and 90%, the hypothesis of a common slope of dose-response relationships (parallel probit lines in probit analysis) cannot be rejected. In general, parallelism of probit lines is considered an indication of a common mode of action. Analysis of the shape of the dose-response relationship, with one apparent exception, shows virtually linear or superlinear behavior, i.e., from these data, there is no indication of a decrease in carcinogenic potency of an elementary carcinogenic unit at lower doses. PMID:9400733

  7. Random Response of Linear Hysteretic Damping

    SciTech Connect

    Floris, Claudio

    2008-07-08

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

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

    SciTech Connect

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

    1998-12-31

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

  9. Shortcuts to adiabaticity from linear response theory

    SciTech Connect

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

    2015-10-23

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

  10. Shortcuts to adiabaticity from linear response theory

    DOE PAGESBeta

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

    2015-10-23

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

  11. Hydration thermodynamics beyond the linear response approximation.

    PubMed

    Raineri, Fernando O

    2016-10-19

    The solvation energetics associated with the transformation of a solute molecule at infinite dilution in water from an initial state A to a final state B is reconsidered. The two solute states have different potentials energies of interaction, [Formula: see text] and [Formula: see text], with the solvent environment. Throughout the A [Formula: see text] B transformation of the solute, the solvation system is described by a Hamiltonian [Formula: see text] that changes linearly with the coupling parameter ξ. By focusing on the characterization of the probability density [Formula: see text] that the dimensionless perturbational solute-solvent interaction energy [Formula: see text] has numerical value y when the coupling parameter is ξ, we derive a hierarchy of differential equation relations between the ξ-dependent cumulant functions of various orders in the expansion of the appropriate cumulant generating function. On the basis of this theoretical framework we then introduce an inherently nonlinear solvation model for which we are able to find analytical results for both [Formula: see text] and for the solvation thermodynamic functions. The solvation model is based on the premise that there is an upper or a lower bound (depending on the nature of the interactions considered) to the amplitude of the fluctuations of Y in the solution system at equilibrium. The results reveal essential differences in behavior for the model when compared with the linear response approximation to solvation, particularly with regards to the probability density [Formula: see text]. The analytical expressions for the solvation properties show, however, that the linear response behavior is recovered from the new model when the room for the thermal fluctuations in Y is not restricted by the existence of a nearby bound. We compare the predictions of the model with the results from molecular dynamics computer simulations for aqueous solvation, in which either (1) the solute

  12. Hydration thermodynamics beyond the linear response approximation.

    PubMed

    Raineri, Fernando O

    2016-10-19

    The solvation energetics associated with the transformation of a solute molecule at infinite dilution in water from an initial state A to a final state B is reconsidered. The two solute states have different potentials energies of interaction, [Formula: see text] and [Formula: see text], with the solvent environment. Throughout the A [Formula: see text] B transformation of the solute, the solvation system is described by a Hamiltonian [Formula: see text] that changes linearly with the coupling parameter ξ. By focusing on the characterization of the probability density [Formula: see text] that the dimensionless perturbational solute-solvent interaction energy [Formula: see text] has numerical value y when the coupling parameter is ξ, we derive a hierarchy of differential equation relations between the ξ-dependent cumulant functions of various orders in the expansion of the appropriate cumulant generating function. On the basis of this theoretical framework we then introduce an inherently nonlinear solvation model for which we are able to find analytical results for both [Formula: see text] and for the solvation thermodynamic functions. The solvation model is based on the premise that there is an upper or a lower bound (depending on the nature of the interactions considered) to the amplitude of the fluctuations of Y in the solution system at equilibrium. The results reveal essential differences in behavior for the model when compared with the linear response approximation to solvation, particularly with regards to the probability density [Formula: see text]. The analytical expressions for the solvation properties show, however, that the linear response behavior is recovered from the new model when the room for the thermal fluctuations in Y is not restricted by the existence of a nearby bound. We compare the predictions of the model with the results from molecular dynamics computer simulations for aqueous solvation, in which either (1) the solute

  13. Hydration thermodynamics beyond the linear response approximation

    NASA Astrophysics Data System (ADS)

    Raineri, Fernando O.

    2016-10-01

    The solvation energetics associated with the transformation of a solute molecule at infinite dilution in water from an initial state A to a final state B is reconsidered. The two solute states have different potentials energies of interaction, {{\\Psi}\\text{A}} and {{\\Psi}\\text{B}} , with the solvent environment. Throughout the A \\to B transformation of the solute, the solvation system is described by a Hamiltonian H≤ft(ξ \\right) that changes linearly with the coupling parameter ξ. By focusing on the characterization of the probability density {{\\wp}ξ}≤ft( y\\right) that the dimensionless perturbational solute-solvent interaction energy Y=β ≤ft({{\\Psi}\\text{B}}-{{\\Psi}\\text{A}}\\right) has numerical value y when the coupling parameter is ξ, we derive a hierarchy of differential equation relations between the ξ-dependent cumulant functions of various orders in the expansion of the appropriate cumulant generating function. On the basis of this theoretical framework we then introduce an inherently nonlinear solvation model for which we are able to find analytical results for both {{\\wp}ξ} ≤ft( y\\right) and for the solvation thermodynamic functions. The solvation model is based on the premise that there is an upper or a lower bound (depending on the nature of the interactions considered) to the amplitude of the fluctuations of Y in the solution system at equilibrium. The results reveal essential differences in behavior for the model when compared with the linear response approximation to solvation, particularly with regards to the probability density {{\\wp}ξ} ≤ft( y\\right) . The analytical expressions for the solvation properties show, however, that the linear response behavior is recovered from the new model when the room for the thermal fluctuations in Y is not restricted by the existence of a nearby bound. We compare the predictions of the model with the results from molecular dynamics computer simulations for aqueous solvation, in

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

    MedlinePlus

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

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

    NASA Technical Reports Server (NTRS)

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

    2011-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1972-01-01

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

  17. Gastroduodenal response to low-dose glucagon.

    PubMed

    Feczko, P J; Simms, S M; Iorio, J; Halpert, R

    1983-05-01

    A prospective, double-blind clinical study of the double-contrast upper gastrointestinal examination involving 240 patients was performed using glucagon in doses from 0.025 to 0.125 mg, in 0.025 mg increments. Although motility was diminished, neither gastric distension or coating was improved with the use of glucagon. However, duodenal distension and coating were markedly enhanced. The response of the pylorus was individualistic. The pylorus remained patent in most patients, and glucagon would not prevent barium spillage in the duodenum. However, in those patients with a "competent" pylorus, increasing glucagon doses produced a delay in gastric emptying. Several other variables, including weight, age, and gender, were studied and were not believed to be of clinical significance. Spontaneous gastroesophageal reflux was also increased with the use of glucagon. Glucagon mainly enhanced duodenal visualization but had no beneficial effect on the stomach or pylorus. Absolute dose is the most important factor, and all observable changes can be seen once a certain threshold dose (0.05 mg) is reached.

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

    PubMed

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

    2016-01-01

    Out-of-field doses from radiotherapy can cause harmful side effects or eventually lead to secondary cancers. Scattered doses outside the applicator field, neutron source strength values, and neutron dose equivalents have not been broadly investigated for high-energy electron beams. To better understand the extent of these exposures, we measured out-of-field dose characteristics of electron applicators for high-energy electron beams on two Varian 21iXs, a Varian TrueBeam, and an Elekta Versa HD operating at various energy levels. Out-of-field dose profiles and percent depth-dose curves were measured in a Wellhofer water phantom using a Farmer ion chamber. Neutron dose was assessed using a combination of moderator buckets and gold activation foils placed on the treatment couch at various locations in the patient plane on both the Varian 21iX and Elekta Versa HD linear accelerators. Our findings showed that out-of-field electron doses were highest for the highest electron energies. These doses typically decreased with increasing distance from the field edge but showed substantial increases over some distance ranges. The Elekta linear accelerator had higher electron out-of-field doses than the Varian units examined, and the Elekta dose profiles exhibited a second dose peak about 20 to 30 cm from central-axis, which was found to be higher than typical out-of-field doses from photon beams. Electron doses decreased sharply with depth before becoming nearly constant; the dose was found to decrease to a depth of approximately E(MeV)/4 in cm. With respect to neutron dosimetry, Q values and neutron dose equivalents increased with electron beam energy. Neutron contamination from electron beams was found to be much lower than that from photon beams. Even though the neutron dose equivalent for electron beams represented a small portion of neutron doses observed under photon beams, neutron doses from electron beams may need to be considered for special cases. PMID:27455499

  19. Laboratory measurement error in external dose estimates and its effects on dose-response analyses of Hanford worker mortality data

    SciTech Connect

    Gilbert, E.S.; Fix, J.J.

    1996-08-01

    This report addresses laboratory measurement error in estimates of external doses obtained from personnel dosimeters, and investigates the effects of these errors on linear dose-response analyses of data from epidemiologic studies of nuclear workers. These errors have the distinguishing feature that they are independent across time and across workers. Although the calculations made for this report were based on Hanford data, the overall conclusions are likely to be relevant for other epidemiologic studies of workers exposed to external radiation.

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

    NASA Technical Reports Server (NTRS)

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

    2011-01-01

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

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

    SciTech Connect

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

    2005-09-01

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

  2. Implications of dose-dependent target tissue absorption for linear and non-linear/threshold approaches in development of a cancer-based oral toxicity factor for hexavalent chromium.

    PubMed

    Haney, J

    2015-07-01

    Dose-dependent changes in target tissue absorption have important implications for determining the most defensible approach for developing a cancer-based oral toxicity factor for hexavalent chromium (CrVI). For example, mouse target tissue absorption per unit dose is an estimated 10-fold lower at the CrVI dose corresponding to the federal maximum contaminant level (MCL) than at the USEPA draft oral slope factor (SFo) point of departure dose. This decreasing target tissue absorption as doses decrease to lower, more environmentally-relevant doses is inconsistent with linear low-dose extrapolation. The shape of the dose-response curve accounting for this toxicokinetic phenomenon would clearly be non-linear. Furthermore, these dose-dependent differences in absorption indicate that the magnitude of risk overestimation by a linear low-dose extrapolation approach (e.g., SFo) increases and is likely to span one or perhaps more orders of magnitude as it is used to predict risk at progressively lower, more environmentally-relevant doses. An additional apparent implication is that no single SFo can reliably predict risk across potential environmental doses (e.g., doses corresponding to water concentrations⩽the federal MCL). A non-linear approach, consistent with available mode of action data, is most scientifically defensible for derivation of an oral toxicity factor for CrVI-induced carcinogenesis.

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

    EPA Science Inventory

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

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

    SciTech Connect

    Scott, Bobby, R., Ph.D.

    2003-06-27

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

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

    NASA Technical Reports Server (NTRS)

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

    2008-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    2003-01-01

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

  7. 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.

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

    SciTech Connect

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

    2015-12-09

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

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

    DOE PAGESBeta

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

    2015-12-09

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

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

    PubMed

    Little, M P; Muirhead, C R

    1997-12-01

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

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

    SciTech Connect

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

    2012-02-15

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

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

    PubMed

    Nakashima, Eiji

    2015-07-01

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

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

    SciTech Connect

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

    2013-08-15

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

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

    PubMed

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

    2016-03-01

    It has been suggested that a mechanistic understanding of the cellular responses to low dose and dose rate may be valuable in reducing some of the uncertainties involved in current risk estimates for cancer- and non-cancer-related radiation effects that are inherited in the linear no-threshold hypothesis. In this study, the effects of low-dose radiation on the proteome in both human fibroblasts and stem cells were investigated. Particular emphasis was placed on examining: 1. the dose-response relationships for the differential expression of proteins in the low-dose range (40-140 mGy) of low-linear energy transfer (LET) radiation; and 2. the effect on differential expression of proteins of a priming dose given prior to a challenge dose (adaptive response effects). These studies were performed on cultured human fibroblasts (VH10) and human adipose-derived stem cells (ADSC). The results from the VH10 cell experiments demonstrated that low-doses of low-LET radiation induced unique patterns of differentially expressed proteins for each dose investigated. In addition, a low priming radiation dose significantly changed the protein expression induced by the subsequent challenge exposure. In the ADSC the number of differentially expressed proteins was markedly less compared to VH10 cells, indicating that ADSC differ in their intrinsic response to low doses of radiation. The proteomic results are further discussed in terms of possible pathways influenced by low-dose irradiation. PMID:26934482

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

    PubMed Central

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

    1987-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

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

  17. Evidence for curvilinearity in the cancer incidence dose-response in the Japanese atomic bomb survivors.

    PubMed

    Little, M P; Muirhead, C R

    1996-07-01

    The recently released data on cancer incidence in the Japanese atomic bomb survivors are analysed using a variety of relative risk models which take account of errors in estimates of dose to assess the dose-response at low doses. For all solid cancers analysed together there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the solid cancer data, a threshold of more than about 0.2 Sv is inconsistent with the data, whereas these data are consistent with there being no threshold. Linear-quadratic models and linear-quadratic models with an exponential cell-sterilization term provide no better fit than the linear model. For the three main radiation-inducible leukaemia subtypes analysed together (acute lymphatic leukaemia, acute myeloid leukaemia and chronic myeloid leukaemia) there is a significant positive dose-response (at the one-sided 2.5% significance level) if all survivors who received < 0.5 Sv are considered, but the significance vanishes if doses of < 0.2 Sv are considered. If a relative risk model with a threshold (the dose-response being assumed linear above the threshold) is fitted to the leukaemia data, a thresh-old of more than about 0.3 Sv is inconsistent with the data. In contrast with the solid cancer data, the best estimate for the threshold level in the leukaemia data is significantly different from zero, even when allowance is made for a possible quadratic term in the dose-response, albeit at borderline levels of statistical significance (p = 0.04). There is little evidence for curvature in the leukaemia dose-response from 0.2 Sv upwards. However, the possible underestimation of the errors in the estimates of the dose threshold as a result of confounding and uncertainties not taken

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

    PubMed Central

    Nascarella, Marc A.; Calabrese, Edward J.

    2012-01-01

    The term hormesis describes a dose-response relationship that is characterized by a response that is opposite above and below the toxicological or pharmacological threshold. Previous reports have shown that this relationship is ubiquitous in the response of pharmaceuticals, metals, organic chemicals, radiation, and physical stressor agents. Recent reports have also indicated that certain nanoparticles (NPs) may also exhibit a hormetic dose-response. We describe the application of three previously described methods to quantify the magnitude of the hormetic biphasic dose-responses in nanotoxicology studies. This methodology is useful in screening assays that attempt to parse the observed toxicological dose-response data into categories based on the magnitude of hormesis in the evaluation of NPs. For example, these methods may be used to quickly identify NP induced hormetic responses that are either desirably enhanced (e.g., neuronal cell viability) or undesirably stimulated (e.g., low dose stimulation of tumor cells). PMID:22942868

  19. Air pollution exposure-DNA adduct dosimetry in humans and rodents: evidence for non-linearity at high doses.

    PubMed

    Lewtas, J; Walsh, D; Williams, R; Dobiás, L

    1997-08-01

    form of non-linearity at high doses that has been described by Lutz (W.K. Lutz, Dose-response relationship and low dose extrapolation in chemical carcinogenesis, Carcinogenesis, 11 (1990) 1243-1247) as a superlinear dose response. This superlinear response may be due to saturation of metabolic activation enzymes, induction of either DNA repair processes or detoxification enzymes, or other mechanisms. Regardless of the mechanism, this decrease in the DNA-binding potency at moderate to high doses of PAH has important implications for dose-response extrapolation in risk assessment.

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

    PubMed

    Vinnikov, Volodymyr A; Maznyk, Nataliya A

    2013-04-01

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

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

    SciTech Connect

    Levy, R.P.

    1991-01-01

    An in vitro system using neuroglia from neonatal rat brain was developed to examining the morphologic, immunocytochemical and biochemical response of oligodendroglia to ionizing radiation. Following acute [gamma]-radiation at day-in-culture (DIC) 8, oligodendrocyte counts at DIC 14 were 55% to 65% of control values after 2 Gy, and 29% to 36% after 5 Gy. Counts increased to near-normal levels at DIC 21 in the 2 Gy group and to 75% of normal in the 5 Gy group. Myelin basic protein levels (MBP) at DIC 14 were 60% of control values after 2 Gy, and 40% after 5 Gy. At DIC 21, MBP after 2 Gy was 45% greater than that observed at DIC 14, but MBP, as a fraction of age-matched control values, dropped from 60% to 50%. Following 5 Gy, absolute MBP changed little between DIC 14 and DIC 21, but decreased from 40% to 25% of control cultures. It was concluded that oligodendrocytes in irradiated cultures had significantly lower functional capacity than did unirradiated controls. The response to split-dose irradiation indicated that nearly all sublethal damage in the oligodendrocyte population (and its precursors) was repaired within 3 h to 4 h. At DIC 14, the group irradiated in a single fraction had significantly lower oligodendrocyte counts than any group given split doses; all irradiated cultures had marked depression of MBP synthesis, but to significant differences referable to time interval between doses. At DIC 21, cultures irradiated at intervals of 0 h to 2 h had similar oligodendrocyte counts to one another, but these counts were significantly lower than in cultures irradiated at intervals of 4 h to 6 h; MBP levels remained depressed at DIC 21 for all irradiated cultures. The oligodendrocyte response to dose rate (0.03 to 1.97 Gy/min) was evaluated at DIC 14 and DIC 21. Exposure at 0.03 Gy/min suppressed oligodendrocyte counts at DIC 21 less than did higher dose rates in 5-Gy irradiated cultures.

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

    EPA Science Inventory

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

  3. Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

    PubMed

    Upton, A C

    1983-10-01

    The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell.

  4. Dose-Response Calculator for ArcGIS

    USGS Publications Warehouse

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

    2011-01-01

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

  5. 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

  6. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses.

    PubMed

    Vandenberg, Laura N; 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; Myers, John Peterson

    2012-06-01

    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

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

    PubMed

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

    2015-12-01

    This paper describes modelling, application and validation of a filtration technique for a linear slot-scanning digital X-ray system to reduce radiation dose to paediatric patients while preserving diagnostic image quality. A dose prediction model was implemented, which calculates patient entrance doses using variable input parameters. Effective dose is calculated using a Monte Carlo simulation. An added filter of 1.8-mm aluminium was predicted to lower the radiation dose significantly. An objective image quality study was conducted using detective quantum efficiency (DQE). The PTW Normi 4FLU test phantom was used for quantitative assessment, showing that image contrast and spatial resolution were maintained with the proposed filter. A paediatric cadaver full-body imaging trial assessed the diagnostic quality of the images and measured the dose reduction using a 1.8-mm aluminium filter. Assessment by radiologists indicated that diagnostic quality was maintained with the added filtration, despite a reduction in DQE. A new filtration technique for full-body paediatric scanning on the Lodox Statscan has been validated, reducing entrance dose for paediatric patients by 36 % on average and effective dose by 27 % on average, while maintaining image quality. PMID:25433049

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

    NASA Technical Reports Server (NTRS)

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

    1998-01-01

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

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

    PubMed Central

    2016-01-01

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

  10. Role of initial quantum correlation in transient linear response

    SciTech Connect

    Uchiyama, Chikako; Aihara, Masaki

    2010-10-15

    The linear transient response of a two-level system coupled with an environmental system is studied under correlated and factorized initial conditions. We find that the transient responses in these cases differ significantly from each other, especially for strong system-environment interaction at intermediate temperatures. This means that it is necessary to pay attention to the initial conditions chosen when analyzing experiments on transient linear response, because the conventional factorized initial condition results in an incorrect response, in which the quantum correlation between the relevant system and the environmental system is disregarded.

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

    PubMed

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

    2016-03-01

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

  12. Linear and non-linear forced response of a conical, ducted, laminar premixed flame

    SciTech Connect

    Karimi, Nader; Brear, Michael J.; Jin, Seong-Ho; Monty, Jason P.

    2009-11-15

    This paper presents an experimental study on the dynamics of a ducted, conical, laminar premixed flame subjected to acoustic excitation of varying amplitudes. The flame transfer function is measured over a range of forcing frequencies and equivalence ratios. In keeping with previous works, the measured flame transfer function is in good agreement with that predicted by linear kinematic theory at low amplitudes of acoustic velocity excitation. However, a systematic departure from linear behaviour is observed as the amplitude of the velocity forcing upstream of the flame increases. This non-linearity is mostly in the phase of the transfer function and manifests itself as a roughly constant phase at high forcing amplitude. Nonetheless, as predicted by non-linear kinematic arguments, the response always remains close to linear at low forcing frequencies, regardless of the forcing amplitude. The origin of this phase behaviour is then sought through optical data post-processing. (author)

  13. Response properties of pigeon otolith afferents to linear acceleration

    NASA Technical Reports Server (NTRS)

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

    1997-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

  15. Linear energy transfer dependence of a normoxic polymer gel dosimeter investigated using proton beam absorbed dose measurements

    NASA Astrophysics Data System (ADS)

    Gustavsson, Helen; Bäck, Sven Å. J.; Medin, Joakim; Grusell, Erik; Olsson, Lars E.

    2004-09-01

    Three-dimensional dosimetry with good spatial resolution can be performed using polymer gel dosimetry, which has been investigated for dosimetry of different types of particles. However, there are only sparse data concerning the influence of the linear energy transfer (LET) properties of the radiation on the gel absorbed dose response. The purpose of this study was to investigate possible LET dependence for a polymer gel dosimeter using proton beam absorbed dose measurements. Polymer gel containing the antioxidant tetrakis(hydroxymethyl)phosphonium (THP) was irradiated with 133 MeV monoenergetic protons, and the gel absorbed dose response was evaluated using MRI. The LET distribution for a monoenergetic proton beam was calculated as a function of depth using the Monte Carlo code PETRA. There was a steep increase in the Monte Carlo calculated LET starting at the depth corresponding to the front edge of the Bragg peak. This increase was closely followed by a decrease in the relative detector sensitivity (Srel = Dgel/Ddiode), indicating that the response of the polymer gel detector was dependent on LET. The relative sensitivity was 0.8 at the Bragg peak, and reached its minimum value at the end of the proton range. No significant effects in the detector response were observed for LET < 4.9 keV µm-1, thus indicating that the behaviour of the polymer gel dosimeter would not be altered for the range of LET values expected in the case of photons or electrons in a clinical range of energies.

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

    SciTech Connect

    Hübener, Hannes; Giustino, Feliciano

    2014-07-28

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

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

    PubMed

    Hübener, Hannes; Giustino, Feliciano

    2014-07-28

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

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

    SciTech Connect

    Simpkins, A.A.

    2003-07-21

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

  19. Dose Effects of Ion Beam Exposure on Deinococcus Radiodurans: Survival and Dose Response

    NASA Astrophysics Data System (ADS)

    Song, Dao-jun; Wu, Li-fang; Wu, Li-jun; Yu, Zeng-liang

    2001-02-01

    To explore the survival and dose response of organism for different radiation sources is of great importance in the research of radiobiology. In this study, the survival-dose response of Deinococcus radiodurans (E.coli, as the control) for ultra-violet (UV), γ-rays radiation and ion beam exposure was investigated. The shoulder type of survival curves were found for both UV and γ-ray ionizing radiation, but the saddle type of survival curves were shown for H+, N+(20keV and 30keV) and Ar+ beam exposure. This dose effect of the survival initially decreased with the increase in dose and then increased in the high dose range and finally decreased again in the higher dose range. Our experimental results suggest that D. radiodurans, which is considerably radio-resistant to UV and x-ray and γ-ray ionizing radiation, do not resist ion beam exposure.

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

    SciTech Connect

    Levy, R.P.

    1991-12-01

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

  1. A two-stage sequential linear programming approach to IMRT dose optimization

    PubMed Central

    Zhang, Hao H; Meyer, Robert R; Wu, Jianzhou; Naqvi, Shahid A; Shi, Leyuan; D’Souza, Warren D

    2010-01-01

    The conventional IMRT planning process involves two stages in which the first stage consists of fast but approximate idealized pencil beam dose calculations and dose optimization and the second stage consists of discretization of the intensity maps followed by intensity map segmentation and a more accurate final dose calculation corresponding to physical beam apertures. Consequently, there can be differences between the presumed dose distribution corresponding to pencil beam calculations and optimization and a more accurately computed dose distribution corresponding to beam segments that takes into account collimator-specific effects. IMRT optimization is computationally expensive and has therefore led to the use of heuristic (e.g., simulated annealing and genetic algorithms) approaches that do not encompass a global view of the solution space. We modify the traditional two-stage IMRT optimization process by augmenting the second stage via an accurate Monte-Carlo based kernel-superposition dose calculations corresponding to beam apertures combined with an exact mathematical programming based sequential optimization approach that uses linear programming (SLP). Our approach was tested on three challenging clinical test cases with multileaf collimator constraints corresponding to two vendors. We compared our approach to the conventional IMRT planning approach, a direct-aperture approach and a segment weight optimization approach. Our results in all three cases indicate that the SLP approach outperformed the other approaches, achieving superior critical structure sparing. Convergence of our approach is also demonstrated. Finally, our approach has also been integrated with a commercial treatment planning system and may be utilized clinically. PMID:20071764

  2. Analytic characterization of linear accelerator radiosurgery dose distributions for fast optimization.

    PubMed

    Meeks, S L; Bova, F J; Buatti, J M; Friedman, W A; Eyster, B; Kendrick, L A

    1999-11-01

    Linear accelerator (linac) radiosurgery utilizes non-coplanar arc therapy delivered through circular collimators. Generally, spherically symmetric arc sets are used, resulting in nominally spherical dose distributions. Various treatment planning parameters may be manipulated to provide dose conformation to irregular lesions. Iterative manipulation of these variables can be a difficult and time-consuming task, because (a) understanding the effect of these parameters is complicated and (b) three-dimensional (3D) dose calculations are computationally expensive. This manipulation can be simplified, however, because the prescription isodose surface for all single isocentre distributions can be approximated by conic sections. In this study, the effects of treatment planning parameter manipulation on the dimensions of the treatment isodose surface were determined empirically. These dimensions were then fitted to analytic functions, assuming that the dose distributions were characterized as conic sections. These analytic functions allowed real-time approximation of the 3D isodose surface. Iterative plan optimization, either manual or automated, is achieved more efficiently using this real time approximation of the dose matrix. Subsequent to iterative plan optimization, the analytic function is related back to the appropriate plan parameters, and the dose distribution is determined using conventional dosimetry calculations. This provides a pseudo-inverse approach to radiosurgery optimization, based solely on geometric considerations.

  3. Accumulation of cocaine in maternal and fetal hair; the dose response curve.

    PubMed

    Forman, R; Schneiderman, J; Klein, J; Graham, K; Greenwald, M; Koren, G

    1992-01-01

    Cocaine and its major metabolites are incorporated into hair during the growth of the shaft and stay there for the whole life of the hair. Cocaine crosses the placenta and its metabolites for example Benzoylecgonine (BZ), have been found in neonatal urine, meconium and hair. In order to utilize hair measurements of cocaine as a biological marker of systemic exposure, we conducted both animal and human investigations on the dose response characteristics of this phenomenon. Our data suggest that both maternal and fetal accumulation of cocaine and its metabolite follow a linear pattern within the clinically used doses. Similarly, a good correlation was observed in animals between maternal dose and fetal hair accumulation.

  4. Quetiapine: dose-response relationship in schizophrenia.

    PubMed

    Sparshatt, Anna; Jones, Sarah; Taylor, David

    2008-01-01

    Quetiapine is a widely used second-generation antipsychotic that is effective in the treatment of schizophrenia and bipolar mania. In recent years, various publications have suggested the possibility that, in some patients, higher than licensed dosages are necessary for full therapeutic effect. A 'high-dose' theory of quetiapine activity has developed, leading many prescribers to disregard the formal upper limit of the quetiapine dosage range (750 or 800 mg/day, depending on local labelling). In this review, we examine the clinical and neuroimaging data relating to the use of quetiapine in acute exacerbations of schizophrenia. Fixed-dose efficacy studies of immediate-release (IR) quetiapine suggest dosages of quetiapine of 150-450 mg/day are more effective than placebo and no less effective than dosages of 600 or 750 mg/day. A fixed-dose study of extended-release quetiapine indicated that dosages of 600 and 800 mg/day were equally efficacious and numerically superior to 400 mg/day. Dosages of IR quetiapine averaging between 254 and 525 mg/day have been shown to be equivalent in efficacy to standard dosages of conventional and other atypical antipsychotics. Pooled data support these findings. Effectiveness studies using quetiapine in daily doses averaging between 565 and 653 mg revealed quetiapine to be somewhat less effective than some comparator drugs. Support for the use of high-dosage quetiapine (>800 mg/day) is very limited: case reports, albeit numerous, describe quetiapine as showing therapeutic effects only at dosages above the licensed range; some data suggest widespread use of higher dosages in practice; and neuroimaging data suggest inadequate dopamine receptor occupancy at standard dosages (although these findings may reflect the low affinity of quetiapine for dopamine receptors). Overall, robust controlled data strongly suggest that the standard dosage range for quetiapine is appropriate for clinical use. The balance of evidence does not support the

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

    PubMed

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

    2016-01-01

    In VMAT treatment delivery the ability of the linear accelerator (linac) to accurately control dose versus gantry angle is critical to delivering the plan correctly. A new VMAT test delivery was developed to specifically test the dose versus gantry angle with the full range of allowed gantry speeds and dose rates. The gantry-mounted IBA MatriXX with attached inclinometer was used in movie mode to measure the instantaneous relative dose versus gantry angle during the plan every 0.54 s. The results were compared to the expected relative dose at each gantry angle calculated from the plan. The same dataset was also used to compare the instantaneous gan-try speeds throughout the delivery compared to the expected gantry speeds from the plan. Measurements performed across four linacs generally show agreement between measurement and plan to within 1.5% in the constant dose rate regions and dose rate modulation within 0.1 s of the plan. Instantaneous gantry speed was measured to be within 0.11°/s of the plan (1 SD). An error in one linac was detected in that the nominal gantry speed was incorrectly calibrated. This test provides a practical method to quality-assure critical aspects of VMAT delivery including dose versus gantry angle and gantry speed control. The method can be performed with any detector that can acquire time-resolved dosimetric information that can be synchronized with a measurement of gantry angle. The test fulfils several of the aims of the recent Netherlands Commission on Radiation Dosimetry (NCS) Report 24, which provides recommendations for comprehensive VMAT quality assurance. PMID:27167282

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  8. The effects of heating rate on the dose response characteristics of TLD-200, TLD-300 and TLD-400

    NASA Astrophysics Data System (ADS)

    Kafadar, V. Emir; Necmeddin Yazici, A.; Güler Yildirim, R.

    2009-10-01

    In the given study; the effects of heating rates on the dose response characteristics of CaF 2:Dy (TLD-200), CaF 2:Tm (TLD-300) and CaF 2:Mn (TLD-400) crystals have been investigated using the dose dependence curve and dose response function f( D). It was observed from the dose response functions that the linearity and behaviour of the TL glow peaks of TLD-200 and TLD-400 are affected, but the TLD-300 is not affected from the heating rate.

  9. Response of Biological Systems to Low Doses of Ionizing Radiation.

    PubMed

    Hei, Tom K

    2016-03-01

    Radiation is ubiquitous in the environment. Biological effects of exposure to low doses of ionizing radiation are subjected to several modulating factors. Two of these, bystander response and adaptive protections, are discussed briefly. PMID:26808883

  10. Dose calibrator linearity test: 99mTc versus 18F radioisotopes*

    PubMed Central

    Willegaignon, José; Sapienza, Marcelo Tatit; Coura-Filho, George Barberio; Garcez, Alexandre Teles; Alves, Carlos Eduardo Gonzalez Ribeiro; Cardona, Marissa Anabel Rivera; Gutterres, Ricardo Fraga; Buchpiguel, Carlos Alberto

    2015-01-01

    Objective The present study was aimed at evaluating the viability of replacing 18F with 99mTc in dose calibrator linearity testing. Materials and Methods The test was performed with sources of 99mTc (62 GBq) and 18F (12 GBq) whose activities were measured up to values lower than 1 MBq. Ratios and deviations between experimental and theoretical 99mTc and 18F sources activities were calculated and subsequently compared. Results Mean deviations between experimental and theoretical 99mTc and 18F sources activities were 0.56 (± 1.79)% and 0.92 (± 1.19)%, respectively. The mean ratio between activities indicated by the device for the 99mTc source as measured with the equipment pre-calibrated to measure 99mTc and 18F was 3.42 (± 0.06), and for the 18F source this ratio was 3.39 (± 0.05), values considered constant over the measurement time. Conclusion The results of the linearity test using 99mTc were compatible with those obtained with the 18F source, indicating the viability of utilizing both radioisotopes in dose calibrator linearity testing. Such information in association with the high potential of radiation exposure and costs involved in 18F acquisition suggest 99mTc as the element of choice to perform dose calibrator linearity tests in centers that use 18F, without any detriment to the procedure as well as to the quality of the nuclear medicine service. PMID:25798005

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

    PubMed

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

    2016-01-01

    Diamond detectors (DD) are preferred in small field dosimetry of radiation beams because of small dose profile penumbras, better spatial resolution, and tissue-equivalent properties. We investigated a commercially available 'microdiamond' detector in realizing absorbed dose from first principles. A microdiamond detector, type TM 60019 with tandem electrometer is used to measure absorbed doses in water, nylon, and PMMA phantoms. With sensitive volume 0.004 mm3, radius 1.1mm, thickness 1 x10(-3) mm, the nominal response is 1 nC/Gy. It is assumed that the diamond detector could collect total electric charge (nC) developed during irradiation at 0 V bias. We found that dose rate effect is less than 0.7% for changing dose rate by 500 MU/min. The reproducibility in obtaining readings with diamond detector is found to be ± 0.17% (1 SD) (n = 11). The measured absorbed doses for 6 MV and 15 MV photons arrived at using mass energy absorption coefficients and stop-ping power ratios compared well with Nd, water calibrated ion chamber measured absorbed doses within 3% in water, PMMA, and nylon media. The calibration factor obtained for diamond detector confirmed response variation is due to sensitivity due to difference in manufacturing process. For electron beams, we had to apply ratio of electron densities of water to carbon. Our results qualify diamond dosimeter as a transfer standard, based on long-term stability and reproducibility. Based on micro-dimensions, we recommend these detectors for pretreatment dose verifications in small field irradiations like stereotactic treatments with image guidance. PMID:27074452

  12. The Increase in Animal Mortality Risk following Exposure to Sparsely Ionizing Radiation Is Not Linear Quadratic with Dose

    PubMed Central

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

    2015-01-01

    Introduction The US government regulates allowable radiation exposures relying, in large part, on the seventh report from the committee to estimate the Biological Effect of Ionizing Radiation (BEIR VII), which estimated that most contemporary exposures- protracted or low-dose, carry 1.5 fold less risk of carcinogenesis and mortality per Gy than acute exposures of atomic bomb survivors. This correction is known as the dose and dose rate effectiveness factor for the life span study of atomic bomb survivors (DDREFLSS). It was calculated by applying a linear-quadratic dose response model to data from Japanese atomic bomb survivors and a limited number of animal studies. Methods and Results We argue that the linear-quadratic model does not provide appropriate support to estimate the risk of contemporary exposures. In this work, we re-estimated DDREFLSS using 15 animal studies that were not included in BEIR VII’s original analysis. Acute exposure data led to a DDREFLSS estimate from 0.9 to 3.0. By contrast, data that included both acute and protracted exposures led to a DDREFLSS estimate from 4.8 to infinity. These two estimates are significantly different, violating the assumptions of the linear-quadratic model, which predicts that DDREFLSS values calculated in either way should be the same. Conclusions Therefore, we propose that future estimates of the risk of protracted exposures should be based on direct comparisons of data from acute and protracted exposures, rather than from extrapolations from a linear-quadratic model. The risk of low dose exposures may be extrapolated from these protracted estimates, though we encourage ongoing debate as to whether this is the most valid approach. We also encourage efforts to enlarge the datasets used to estimate the risk of protracted exposures by including both human and animal data, carcinogenesis outcomes, a wider range of exposures, and by making more radiobiology data publicly accessible. We believe that these steps will

  13. Radiation Dose-Response Relationships and Risk Assessment

    SciTech Connect

    Strom, Daniel J.

    2005-07-05

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

  14. Updating Dosimetry for Emergency Response Dose Projections.

    PubMed

    DeCair, Sara

    2016-02-01

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

  15. Updating Dosimetry for Emergency Response Dose Projections.

    PubMed

    DeCair, Sara

    2016-02-01

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

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

    SciTech Connect

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

    2006-06-01

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

  17. Dose-response relationship for supraglottic laryngeal carcinoma

    SciTech Connect

    Peters, L.J.; Thomas, H.D. Jr.

    1983-03-01

    In this editorial, two important issues in the treatment of cancers of the supraglottic larynx which had been raised by other authors, Harwood et al., are discussed. The first is the technique of elective irradiation of clinically uninvolved neck nodes. The second is the question of dose-response relationships for local control of tumors of this site. The present authors do not believe that the data of Harwood et al. can be construed as convincing evidence against a dose-response relationship, because of the heterogeneity of the clinical material and the narrow range of doses represented.(KRM)

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

    EPA Science Inventory

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

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

    PubMed

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

    2012-12-01

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

  20. Site-specific dose-response relationships for cancer induction from the combined Japanese A-bomb and Hodgkin cohorts for doses relevant to radiotherapy

    PubMed Central

    2011-01-01

    Background and Purpose Most information on the dose-response of radiation-induced cancer is derived from data on the A-bomb survivors. Since, for radiation protection purposes, the dose span of main interest is between zero and one Gy, the analysis of the A-bomb survivors is usually focused on this range. However, estimates of cancer risk for doses larger than one Gy are becoming more important for radiotherapy patients. Therefore in this work, emphasis is placed on doses relevant for radiotherapy with respect to radiation induced solid cancer. Materials and methods For various organs and tissues the analysis of cancer induction was extended by an attempted combination of the linear-no-threshold model from the A-bomb survivors in the low dose range and the cancer risk data of patients receiving radiotherapy for Hodgkin's disease in the high dose range. The data were fitted using organ equivalent dose (OED) calculated for a group of different dose-response models including a linear model, a model including fractionation, a bell-shaped model and a plateau-dose-response relationship. Results The quality of the applied fits shows that the linear model fits best colon, cervix and skin. All other organs are best fitted by the model including fractionation indicating that the repopulation/repair ability of tissue is neither 0 nor 100% but somewhere in between. Bone and soft tissue sarcoma were fitted well by all the models. In the low dose range beyond 1 Gy sarcoma risk is negligible. For increasing dose, sarcoma risk increases rapidly and reaches a plateau at around 30 Gy. Conclusions In this work OED for various organs was calculated for a linear, a bell-shaped, a plateau and a mixture between a bell-shaped and plateau dose-response relationship for typical treatment plans of Hodgkin's disease patients. The model parameters (α and R) were obtained by a fit of the dose-response relationships to these OED data and to the A-bomb survivors. For any three

  1. Testing Linear Models for Ability Parameters in Item Response Models

    ERIC Educational Resources Information Center

    Glas, Cees A. W.; Hendrawan, Irene

    2005-01-01

    Methods for testing hypotheses concerning the regression parameters in linear models for the latent person parameters in item response models are presented. Three tests are outlined: A likelihood ratio test, a Lagrange multiplier test and a Wald test. The tests are derived in a marginal maximum likelihood framework. They are explicitly formulated…

  2. Chaos pass filter: Linear response of synchronized chaotic systems

    NASA Astrophysics Data System (ADS)

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

    2013-04-01

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

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

    PubMed Central

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

    2016-01-01

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

  4. A Bayesian network model for biomarker-based dose response.

    PubMed

    Hack, C Eric; Haber, Lynne T; Maier, Andrew; Shulte, Paul; Fowler, Bruce; Lotz, W Gregory; Savage, Russell E

    2010-07-01

    A Bayesian network model was developed to integrate diverse types of data to conduct an exposure-dose-response assessment for benzene-induced acute myeloid leukemia (AML). The network approach was used to evaluate and compare individual biomarkers and quantitatively link the biomarkers along the exposure-disease continuum. The network was used to perform the biomarker-based dose-response analysis, and various other approaches to the dose-response analysis were conducted for comparison. The network-derived benchmark concentration was approximately an order of magnitude lower than that from the usual exposure concentration versus response approach, which suggests that the presence of more information in the low-dose region (where changes in biomarkers are detectable but effects on AML mortality are not) helps inform the description of the AML response at lower exposures. This work provides a quantitative approach for linking changes in biomarkers of effect both to exposure information and to changes in disease response. Such linkage can provide a scientifically valid point of departure that incorporates precursor dose-response information without being dependent on the difficult issue of a definition of adversity for precursors.

  5. Skyshine photon doses from 6 and 10 MV medical linear accelerators.

    PubMed

    de Paiva, Eduardo; da Rosa, Luiz A R

    2012-01-01

    The skyshine radiation phenomenon consists of the scattering of primary photon beams in the atmosphere above the roof of a medical linear accelerator facility, generating an additional dose at ground level in the vicinity of the treatment room. Thus, with respect to radioprotection, this situation plays an important role when the roof is designed with little shielding and there are buildings next to the radiotherapy treatment room. In literature, there are few reported skyshine-measured doses and these contain poor agreement with empirical calculations. In this work, we carried out measurements of skyshine photon dose rates produced from eight different 6 and 10 MV medical accelerators. Each measurement was performed outside the room facility, with the beam positioned in the upward direction, at a horizontal distance from the target and for a 40 cm × 40 cm maximum photon field size at the accelerator isocenter. Measured dose-equivalent rates results were compared with calculations obtained by an empirical expression, and differences between them deviated in one or more order of magnitude.

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

    PubMed

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

    2012-04-01

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

  7. Analytical modelling of regional radiotherapy dose response of lung

    NASA Astrophysics Data System (ADS)

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

    2012-06-01

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

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2014-03-01

    Dose-response relationships for most addictive substances are "inverted U"-shaped. Addictive substances produce both positive features that include reward, euphoria, anxiolysis, withdrawal-relief, and negative features that include aversion, dysphoria, anxiety and withdrawal symptoms. A simple model differentially associates ascending and descending limbs of dose-response curves with rewarding and aversive influences, respectively. However, Diagnostic and Statistical Manual (DSM) diagnoses of substance dependence fail to incorporate dose-response criteria and don't directly consider balances between euphoric and dysphoric drug effects. Classical genetic studies document substantial heritable influences on DSM substance dependence. Linkage and genome-wide association studies identify modest-sized effects at any locus. Nevertheless, clusters of SNPs within selected genes display 10(-2)>p>10(-8) associations with dependence in many independent samples. For several of these genes, evidence for cis-regulatory, level-of-expression differences supports the validity of mouse models in which levels of expression are also altered. This review documents surprising, recently defined cases in which convergent evidence from humans and mouse models supports central influences of altered dose-response relationships in mediating the impact of relevant genomic variation on addiction phenotypes. For variation at loci for the α5 nicotinic acetylcholine receptor, cadherin 13, receptor type protein tyrosine phosphatase Δ and neuronal cell adhesion molecule genes, changed dose-response relationships conferred by gene knockouts in mice are accompanied by supporting human data. These observations emphasize desirability of carefully elucidating dose-response relationships for both rewarding and aversive features of abused substances wherever possible. They motivate consideration of individual differences in dose-response relationships in addiction nosology and therapeutics. PMID:24189489

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

    PubMed

    Speck, Thomas

    2016-08-01

    We study the linear response in systems driven away from thermal equilibrium into a nonequilibrium steady state with nonvanishing entropy production rate. A simple derivation of a general response formula is presented under the condition that the generating function describes a transformation that (to lowest order) preserves normalization and thus describes a physical stochastic process. For Markov processes we explicitly construct the conjugate quantities and discuss their relation with known response formulas. Emphasis is put on the formal analogy with thermodynamic potentials and some consequences are discussed. PMID:27627270

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

    NASA Astrophysics Data System (ADS)

    Speck, Thomas

    2016-08-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2009-01-01

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

  13. Computer Simulation of Quantal Dose-Response Relationships.

    ERIC Educational Resources Information Center

    McGilliard, Kip L.

    1985-01-01

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

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

    SciTech Connect

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

    2010-03-15

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

  15. A linear chromatic mechanism drives the pupillary response.

    PubMed Central

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

    2001-01-01

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

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

    PubMed

    Kinhikar, Rajesh A

    2008-10-01

    The purpose of this study was to estimate the surface dose for five telecobalt machines (four from Best Theratronics Limited, Canada, one from Panacea Medical Technologies, India), 6 MV photon beam (static) from four linear accelerators (three Varian linear accelerators and one Siemens) and Hi-Art Tomotherapy unit. The surface dose was measured with Thermoluminescent dosimeters in phantom slabs. For Tomotherapy 6 MV beam the surface dose was estimated as 32% while it was 35%, 33%, and 36% for Clinac 6EX, Clinac 2100CD, and Clinac 2100C linear accelerators, respectively. Similarly, the surface dose for 6 MV photon beam from Primus linear accelerator was estimated as 35%. Surface doses from telecobalt machines Equinox-80, Elite-80, Th-780C, Th-780, and Bhabhatron-II was found to be 30%, 29.1%, 27.8%, 29.3%, and 29.9% for 10 cm x 10 field size, respectively. Measured surface dose from all four linear accelerators were in good agreement with that of the Tomotherapy. The surface dose measurements were useful for Tomotherapy to predict the superficial dose during helical IMRT treatments. PMID:18783288

  17. Dose-Response Curves for Radish Seedling Phototropism 12

    PubMed Central

    Everett, Marylee

    1974-01-01

    Radish seedlings (Raphanus sativus L.) were grown for 4 days in complete darkness, or in white light, or for 3 days in darkness followed by 1 day of red light. Phototropic dose-response curves for the seedlings grown in these three ways were determined with 460-nm light. The dark-grown and red light-treated seedlings responded with positive curvatures of no more than 10° to energy doses in the first positive range and with larger positive curvatures in the second positive dose range. No indifferent or negative curvature was seen with the light intensity used. White light-grown seedlings did not respond to first positive energy doses, but responded as strongly to second positive doses as the other types of seedlings. PMID:16658864

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

    PubMed

    Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian E; Simon, Steven L

    2016-02-10

    Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure.

  19. Maximum likelihood estimation for cytogenetic dose-response curves

    SciTech Connect

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

    1986-03-01

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

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

    PubMed

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

    2015-12-01

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

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

    PubMed

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

    2013-05-01

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

  2. Gaussian fluctuations and linear response in an electron transfer protein

    PubMed Central

    Simonson, Thomas

    2002-01-01

    In response to charge separation or transfer, polar liquids respond in a simple linear fashion. A similar linear response for proteins might be expected from the central limit theorem and is postulated in widely used theories of protein electrostatics, including the Marcus electron transfer theory and dielectric continuum theories. Although these theories are supported by a variety of experimental data, the exact validity of a linear protein dielectric response has been difficult to determine. Molecular dynamics simulations are presented that establish a linear dielectric response of both protein and surrounding solvent over the course of a biologically relevant electron transfer reaction: oxido-reduction of yeast cytochrome c in solution. Using an umbrella-sampling free energy approach with long simulations, an accurate treatment of long-range electrostatics and both classical and quantum models of the heme, good agreement is obtained with experiment for the redox potential relative to a heme–octapeptide complex. We obtain a reorganization free energy that is only half that for heme–octapeptide and is reproduced with a dielectric continuum model where the heme vicinity has a dielectric constant of only 1.1. This value implies that the contribution of protein reorganization to the electron transfer free energy barrier is reduced almost to the theoretical limit (a dielectric of one), and that the fluctuations of the electrostatic potential on the heme have a simple harmonic form, in accord with Marcus theory, even though the fluctuations of many individual protein groups (especially at the protein surface) are anharmonic. PMID:12011418

  3. Linear response of tripartite entanglement to infinitesimal noise

    SciTech Connect

    Zhang, Fu-Lin; Chen, Jing-Ling

    2014-10-15

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

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

    SciTech Connect

    Schultheiss, Timothy E.

    2008-08-01

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

  5. Dose response of xylitol and sorbitol for EPR retrospective dosimetry with applications to chewing gum.

    PubMed

    Israelsson, A; Gustafsson, H; Lund, E

    2013-04-01

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

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

    PubMed

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

    2015-07-01

    Avian egg yolks contain various amounts of maternally derived androgens that can modify offspring phenotype and adjust their development to the post-hatching environment. Seemingly adaptive variation in yolk androgen levels with respect to breeding density conditions or male attractiveness has been found in numerous studies. One important consideration that has been overlooked in previous research is the likely non-linear nature of hormone effects. To examine possible complex dose-response effects of maternal androgens on chick development, we experimentally administered three different androgen doses of the naturally occurring mixture of yolk testosterone and androstenedione to spotless starling eggs (Sturnus unicolor). We found that yolk androgens induce a non-linear dose-response pattern in several traits. Androgens had a stimulatory effect on hatchling body mass and nestling skeletal growth, but maximum values were found at intermediate doses, whereas our highest dose resulted in a decrease. However, the opposite U-shaped effect was found on nestling body mass. We also detected linear negative and positive effects on embryonic development period and nestling gape width, respectively. Our results suggest differential tissue responsiveness to yolk androgens, which may result in compromises in maternal allocation to produce adapted phenotypes. Because of the non-linear dose-response pattern, future investigations should carefully consider a wide range of concentrations, as the balance of costs and benefits may strongly differ depending on concentration. PMID:25987739

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

    PubMed

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

    2014-03-01

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

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

    PubMed

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

    2015-10-21

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

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

    PubMed

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

    2015-10-21

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

  10. Maximum likelihood estimation for cytogenetic dose-response curves

    SciTech Connect

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

    1983-10-01

    In vitro dose-response curves are used to describe the relation between the yield of dicentric chromosome aberrations and radiation dose for human lymphocytes. The dicentric yields follow the Poisson distribution, and the expected yield depends on both the magnitude and the temporal distribution of the dose for low LET radiation. A general dose-response model that describes this relation has been obtained by Kellerer and Rossi using the theory of dual radiation action. The yield of elementary lesions is kappa(..gamma..d + g(t, tau)d/sup 2/), where t is the time and d is dose. The coefficient of the d/sup 2/ term is determined by the recovery function and the temporal mode of irradiation. Two special cases of practical interest are split-dose and continuous exposure experiments, and the resulting models are intrinsically nonlinear in the parameters. A general purpose maximum likelihood estimation procedure is described and illustrated with numerical examples from both experimental designs. Poisson regression analysis is used for estimation, hypothesis testing, and regression diagnostics. Results are discussed in the context of exposure assessment procedures for both acute and chronic human radiation exposure.

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

    PubMed

    Mougabure-Cueto, G; Sfara, V

    2016-04-25

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

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

    PubMed

    Mougabure-Cueto, G; Sfara, V

    2016-04-25

    Dose-response relations can be obtained from systems at any structural level of biological matter, from the molecular to the organismic level. There are two types of approaches for analyzing dose-response curves: a deterministic approach, based on the law of mass action, and a statistical approach, based on the assumed probabilities distribution of phenotypic characters. Models based on the law of mass action have been proposed to analyze dose-response relations across the entire range of biological systems. The purpose of this paper is to discuss the principles that determine the dose-response relations. Dose-response curves of simple systems are the result of chemical interactions between reacting molecules, and therefore are supported by the law of mass action. In consequence, the shape of these curves is perfectly sustained by physicochemical features. However, dose-response curves of bioassays with quantal response are not explained by the simple collision of molecules but by phenotypic variations among individuals and can be interpreted as individual tolerances. The expression of tolerance is the result of many genetic and environmental factors and thus can be considered a random variable. In consequence, the shape of its associated dose-response curve has no physicochemical bearings; instead, they are originated from random biological variations. Due to the randomness of tolerance there is no reason to use deterministic equations for its analysis; on the contrary, statistical models are the appropriate tools for analyzing these dose-response relations. PMID:26952004

  13. Dose response of chlorhexidine against plaque and comparison with triclosan.

    PubMed

    Jenkins, S; Addy, M; Newcombe, R G

    1994-04-01

    The optimum dose of chlorhexidine delivered by mouthrinse, which balances efficacy against local side-effects, is generally considered to be in the region of 20 mg 2 x daily. Unfortunately, there have been few dose-response studies for chlorhexidine mouthrinses and for these, only limited details are published. The aims of this study were to determine the dose response of chlorhexidine to plaque inhibition and position a 0.1% triclosan rinse within this model. 28 subjects took part in this 7-treatment, double-blind, randomised cross-over 4-day plaque regrowth study. The rinses were 0.01%, 0.05%, 0.1% and 0.2% chlorhexidine, 0.1% triclosan and minus active controls for chlorhexidine and triclosan. On day 1 from a zero plaque baseline, volunteers suspended tooth-cleaning and commenced supervised 2 x daily rinsing with 10 ml volumes of the allocated rinses. On Day 5, plaque was scored by index and area. Treatment differences between the 7 rinses were highly significant. A clear dose-response pattern was seen for chlorhexidine with mean plaque scores decreasing with increasing dose. Even at 0.01%, chlorhexidine showed considerable and significant plaque inhibition compared to control. Triclosan at 0.1% showed limited plaque inhibition and less than 0.01% chlorhexidine. The findings of this study suggest that consideration could be given to low concentration chlorhexidine rinses as adjuncts to oral hygiene.

  14. Linear response to long wavelength fluctuations using curvature simulations

    NASA Astrophysics Data System (ADS)

    Baldauf, Tobias; Seljak, Uroš; Senatore, Leonardo; Zaldarriaga, Matias

    2016-09-01

    We study the local response to long wavelength fluctuations in cosmological N-body simulations, focusing on the matter and halo power spectra, halo abundance and non-linear transformations of the density field. The long wavelength mode is implemented using an effective curved cosmology and a mapping of time and distances. The method provides an alternative, more direct, way to measure the isotropic halo biases. Limiting ourselves to the linear case, we find generally good agreement between the biases obtained from the curvature method and the traditional power spectrum method at the level of a few percent. We also study the response of halo counts to changes in the variance of the field and find that the slope of the relation between the responses to density and variance differs from the naïve derivation assuming a universal mass function by approximately 8–20%. This has implications for measurements of the amplitude of local non-Gaussianity using scale dependent bias. We also analyze the halo power spectrum and halo-dark matter cross-spectrum response to long wavelength fluctuations and derive second order halo bias from it, as well as the super-sample variance contribution to the galaxy power spectrum covariance matrix.

  15. Linear response to long wavelength fluctuations using curvature simulations

    NASA Astrophysics Data System (ADS)

    Baldauf, Tobias; Seljak, Uroš; Senatore, Leonardo; Zaldarriaga, Matias

    2016-09-01

    We study the local response to long wavelength fluctuations in cosmological N-body simulations, focusing on the matter and halo power spectra, halo abundance and non-linear transformations of the density field. The long wavelength mode is implemented using an effective curved cosmology and a mapping of time and distances. The method provides an alternative, more direct, way to measure the isotropic halo biases. Limiting ourselves to the linear case, we find generally good agreement between the biases obtained from the curvature method and the traditional power spectrum method at the level of a few percent. We also study the response of halo counts to changes in the variance of the field and find that the slope of the relation between the responses to density and variance differs from the naïve derivation assuming a universal mass function by approximately 8-20%. This has implications for measurements of the amplitude of local non-Gaussianity using scale dependent bias. We also analyze the halo power spectrum and halo-dark matter cross-spectrum response to long wavelength fluctuations and derive second order halo bias from it, as well as the super-sample variance contribution to the galaxy power spectrum covariance matrix.

  16. Dose-response analyses of the carcinogenic effects of trichloroethylene in experimental animals.

    PubMed Central

    Rhomberg, L R

    2000-01-01

    In lifetime bioassays, trichloroethylene (TCE, CAS No. 79-01-6) causes liver tumors in mice following gavage, liver and lung tumors in mice following inhalation, and kidney tumors in rats following gavage or inhalation. Recently developed pharmacokinetic models provide estimates of internal, target-organ doses of the TCE metabolites thought responsible for these tumor responses. Dose-response analyses following recently proposed methods for carcinogen risk assessment from the U.S. Environmental Protection Agency (U.S. EPA) are conducted on the animal tumor data using the pharmacokinetic dosimeters to derive a series of alternative projections of the potential carcinogenic potency of TCE in humans exposed to low environmental concentrations. Although mechanistic considerations suggest action of possibly nonlinear processes, dose-response shapes in the observable range of tumor incidence evince little sign of such patterns. Results depend on which of several alternative pharmacokinetic analyses are used to define target-organ doses. Human potency projections under the U.S. EPA linear method based on mouse liver tumors and internal dosimetry equal or somewhat exceed calculations based on administered dose, and projections based on mouse liver tumors exceed those from mouse lung or rat kidney tumors. Estimates of the carcinogenic potency of the two primary oxidative metabolites of TCE--trichloroacetic acid and dichloroacetic acid, which are mouse liver carcinogens in their own right--are also made, but it is not clear whether the carcinogenic potency of TCE can be quantitatively ascribed to metabolic generation of these metabolites. PMID:10807564

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

    SciTech Connect

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

    2011-04-15

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

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

    EPA Science Inventory

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

  19. Linear optical response of Si1-xGex compounds

    NASA Astrophysics Data System (ADS)

    Ferriera da Silva, A.; Souza Dantas, N.; Ahuja, R.; Pepe, I.; da Silva, Eronides F., Jr.; Nur, O.; Willander, M.; Persson, C.

    2005-03-01

    Si1-xGex is a good candidate as a substitute material for Si in a low-power and high-speed semiconductor device technologies. Optical devices, such as heterojunction bipolar transistors, are already in industrial production. The samples are grown on Si(001) with both n- and p-type impurities and with different Ge concentrations. The linear optical response of Si1-xGex is investigated theoretically using a full-potential linearized augmented plane wave method with respect to composition x. The calculated real and imaginary parts of the dielectric function ɛ(ω) = ɛ1(ω) + iɛ2(ω) were found to be in good agreement with recent spectroscopic ellipsometry measurements performed by Bahng et al., J. Phys.: Condens. Matter 13, 777 (2001). We also perform absorption measurements for different type of samples showing the variation of energy gaps as a function of Ge concentrations.

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

    SciTech Connect

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

    2013-04-19

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

  1. Flexible dose-response models for Japanese atomic bomb survivor data: Bayesian estimation and prediction of cancer risk.

    PubMed

    Bennett, James; Little, Mark P; Richardson, Sylvia

    2004-12-01

    Generalised absolute risk models were fitted to the latest Japanese atomic bomb survivor cancer incidence data using Bayesian Markov Chain Monte Carlo methods, taking account of random errors in the DS86 dose estimates. The resulting uncertainty distributions in the relative risk model parameters were used to derive uncertainties in population cancer risks for a current UK population. Because of evidence for irregularities in the low-dose dose response, flexible dose-response models were used, consisting of a linear-quadratic-exponential model, used to model the high-dose part of the dose response, together with piecewise-linear adjustments for the two lowest dose groups. Following an assumed administered dose of 0.001 Sv, lifetime leukaemia radiation-induced incidence risks were estimated to be 1.11 x 10(-2) Sv(-1) (95% Bayesian CI -0.61, 2.38) using this model. Following an assumed administered dose of 0.001 Sv, lifetime solid cancer radiation-induced incidence risks were calculated to be 7.28 x 10(-2) Sv(-1) (95% Bayesian CI -10.63, 22.10) using this model. Overall, cancer incidence risks predicted by Bayesian Markov Chain Monte Carlo methods are similar to those derived by classical likelihood-based methods and which form the basis of established estimates of radiation-induced cancer risk.

  2. Bayesian multimodel inference for dose-response studies

    USGS Publications Warehouse

    Link, W.A.; Albers, P.H.

    2007-01-01

    Statistical inference in dose?response studies is model-based: The analyst posits a mathematical model of the relation between exposure and response, estimates parameters of the model, and reports conclusions conditional on the model. Such analyses rarely include any accounting for the uncertainties associated with model selection. The Bayesian inferential system provides a convenient framework for model selection and multimodel inference. In this paper we briefly describe the Bayesian paradigm and Bayesian multimodel inference. We then present a family of models for multinomial dose?response data and apply Bayesian multimodel inferential methods to the analysis of data on the reproductive success of American kestrels (Falco sparveriuss) exposed to various sublethal dietary concentrations of methylmercury.

  3. Microbial dose response modeling: past, present, and future.

    PubMed

    Haas, Charles N

    2015-02-01

    The understanding of the risk to humans from exposure to pathogens has been firmly put into a risk assessment framework. A key element of applying this approach is the understanding of the relationship between dose and response for particular pathogens. This understanding has progressed from early use of threshold concepts ("minimal infectious dose") thru multiple generations of models. Generation 1 models describe probability of response to exposed dose. Generation 2 models incorporate host factors (e.g., age) and/or pathogen factors (e.g., particle size of inhaled agents). Generation 3 models describe the rate at which effects develop, i.e. the epidemic curve. These (generation 1 through three models) have been developed and used in multiple contexts. Beyond Generation 3 lies an opportunity for the deep incorporation of in vivo physiological responses and the coupling of the individual host dynamics to the dynamics of spread of contagious diseases in the population. This would enable more direct extrapolation from controlled dosing studies to estimate population level effects. There remain also needs to understand broader categories of infectious agents, including pathogenic amoebae and fungi. More advanced models need to be validated against well-characterized human outbreak data.

  4. Dose response of alanine detectors irradiated with carbon ion beams

    SciTech Connect

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

    2011-04-15

    Purpose: The dose response of the alanine detector shows a dependence on particle energy and type when irradiated with ion beams. The purpose of this study is to investigate the response behavior of the alanine detector in clinical carbon ion beams and compare the results to model predictions. Methods: Alanine detectors have been irradiated with carbon ions with an energy range of 89-400 MeV/u. The relative effectiveness of alanine has been measured in this regime. Pristine and spread out Bragg peak depth-dose curves have been measured with alanine dosimeters. The track structure based alanine response model developed by Hansen and Olsen has been implemented in the Monte Carlo code FLUKA and calculations were compared to experimental results. Results: Calculations of the relative effectiveness deviate less than 5% from the measured values for monoenergetic beams. Measured depth-dose curves deviate from predictions in the peak region, most pronounced at the distal edge of the peak. Conclusions: The used model and its implementation show a good overall agreement for quasimonoenergetic measurements. Deviations in depth-dose measurements are mainly attributed to uncertainties of the detector geometry implemented in the Monte Carlo simulations.

  5. Systemic response to low-dose endotoxin infusion in cats.

    PubMed

    DeClue, Amy E; Williams, Kurt J; Sharp, Claire; Haak, Carol; Lechner, Elizabeth; Reinero, Carol R

    2009-12-15

    Sepsis is a common problem in feline patients and is associated with substantial morbidity and mortality. There has been little research investigating the physiologic response to bacterial infection in cats, in part because appropriate models have not been developed. The objective of this study was to characterize the response to low-dose LPS infusion in conscious, healthy cats. Measures of systemic inflammation, hemodynamic stability, coagulation, metabolic function, and organ damage were compared between placebo and low-dose LPS infusion (2mcg/kg/hx4h, IV) in cats, with each cat serving as its own control. Markers of systemic inflammation including temperature, plasma TNF activity, IL-6, CXCL-8 and IL-10 concentrations were significantly increased and white blood cell counts were significantly decreased after LPS infusion. A biphasic hypotensive response was observed after initiation of LPS infusion without concurrent tachycardia. Additionally, LPS administration significantly increased blood glucose, lactate and creatinine concentrations. Patchy alveolar congestion, multifocal acute alveolar epithelial necrosis, and mild pulmonary edema were noted in the lungs along with acute centrilobular hepatocellular necrosis, and mild lymphocyte apoptosis in the spleen and/or intestinal Peyer's patches. No biologically significant alterations in coagulation parameters developed after LPS infusion. Low-dose LPS infusion in cats induced systemic inflammation, hemodynamic derangement, metabolic alterations and mild organ damage. Low-dose endotoxin infusion is a viable pre-clinical model to study naturally developing sepsis in cats.

  6. Linear response theory for magnon transport in ferromagnetic insulators

    NASA Astrophysics Data System (ADS)

    Murakami, Shuichi; Matsumoto, Ryo

    2012-02-01

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

  7. Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose response using different monomers

    NASA Astrophysics Data System (ADS)

    Senden, R. J.; DeJean, P.; McAuley, K. B.; Schreiner, L. J.

    2006-07-01

    In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies.

  8. Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose-response using different monomers.

    PubMed

    Senden, R J; De Jean, P; McAuley, K B; Schreiner, L J

    2006-07-21

    In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies. PMID:16825731

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

    SciTech Connect

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

    1987-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  11. Molecular circuits, biological switches, and nonlinear dose-response relationships.

    PubMed Central

    Andersen, Melvin E; Yang, Raymond S H; French, C Tenley; Chubb, Laura S; Dennison, James E

    2002-01-01

    Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment. PMID:12634127

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

    PubMed Central

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

    2016-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

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

  14. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab

    PubMed Central

    Pouliquen, Isabelle J.; Kornmann, Oliver; Barton, Sharon V.; Price, Jeffrey A.; Ortega, Hector G.

    2015-01-01

    Objective: Mepolizumab is a humanized IgG1 monoclonal antibody that blocks human IL-5 from binding to the IL-5 receptor, which is mainly expressed on eosinophils. Eosinophils are key cells in the inflammatory cascade of various diseases, including asthma. This study investigated the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between exposure of mepolizumab subcutaneous (SC) administration and blood eosinophil reduction compared with intravenous (IV) administration in adult subjects with asthma. Methods: In this multi-center, randomized, open-label, parallel-group, repeat-dose study, 70 adult subjects received one of four possible treatment regimens: mepolizumab 12.5, 125, or 250 mg SC or 75 mg IV. In addition to analyzing the dose and PK/PD relationship, absolute bioavailability, safety, tolerability, and incidence of anti-mepolizumab antibodies were evaluated. Results: Blood eosinophil levels decreased in a dose-dependent manner with the lowest (12.5 mg) dose clearly differentiating from the other doses. A non-linear inhibition Imax model based on blood eosinophil levels at week 12 identified that the SC doses providing 50% and 90% of maximal blood eosinophil inhibition were 11 mg (95% confidence interval (CI): 5.19 – 16.85) and 99 mg (95% CI: 47 – 152), respectively. The route of administration did not affect the exposure-response relationship. The estimated mepolizumab SC absolute bioavailability (arm) was 74% (90% CI: 54 – 102%). The safety profile of mepolizumab was favorable. Conclusions: A dose-dependent reduction in blood eosinophils across all mepolizumab doses investigated was observed. The subcutaneous absolute bioavailability was 74%. The route of administration did not affect the mepolizumab exposure eosinophil response relationship. PMID:26445140

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

    PubMed Central

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

    2015-01-01

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

  16. Dose-response patterns for vibration-induced white finger

    PubMed Central

    Griffin, M; Bovenzi, M; Nelson, C

    2003-01-01

    Aims: To investigate alternative relations between cumulative exposures to hand-transmitted vibration (taking account of vibration magnitude, lifetime exposure duration, and frequency of vibration) and the development of white finger (Raynaud's phenomenon). Methods: Three previous studies have been combined to provide a group of 1557 users of powered vibratory tools in seven occupational subgroups: stone grinders, stone carvers, quarry drillers, dockyard caulkers, dockyard boilermakers, dockyard painters, and forest workers. The estimated total operating duration in hours was thus obtained for each subject, for each tool, and for all tools combined. From the vibration magnitudes and exposure durations, seven alternative measurements of cumulative exposure were calculated for each subject, using expressions of the form: dose = ∑amiti, where ai is the acceleration magnitude on tool i, ti is the lifetime exposure duration for tool i, and m = 0, 1, 2, or 4. Results: For all seven alternative dose measures, an increase in dose was associated with a significant increase in the occurrence of vibration-induced white finger, after adjustment for age and smoking. However, dose measures with high powers of acceleration (m > 1) faired less well than measures in which the weighted or unweighted acceleration, and lifetime exposure duration, were given equal weight (m = 1). Dose determined solely by the lifetime exposure duration (without consideration of the vibration magnitude) gave better predictions than measures with m greater than unity. All measures of dose calculated from the unweighted acceleration gave better predictions than the equivalent dose measures using acceleration frequency-weighted according to current standards. Conclusions: Since the total duration of exposure does not discriminate between exposures accumulated over the day and those accumulated over years, a linear relation between vibration magnitude and exposure duration seems appropriate for predicting

  17. Blood glucose concentration and risk of pancreatic cancer: systematic review and dose-response meta-analysis

    PubMed Central

    Liao, Wei-Chih; Wu, Ming-Shiang; Lin, Jaw-Town; Wang, Hsiu-Po

    2015-01-01

    Objective To evaluate potential linear and non-linear dose-response relations between blood glucose and risk of pancreatic cancer. Design Systematic review and dose-response meta-analysis of prospective observational studies. Data sources Search of PubMed, Scopus, and related reviews before 30 November 2013 without language restriction. Eligibility criteria Prospective studies evaluating the association between blood glucose concentration and pancreatic cancer. Retrospective and cross sectional studies excluded to avoid reverse causality. Data extraction and synthesis Two reviewers independently extracted relevant information and assessed study quality with the Newcastle-Ottawa scale. Random effects dose-response meta-analysis was conducted to assess potential linear and non-linear dose-response relations. Results Nine studies were included for analysis, with a total of 2408 patients with pancreatic cancer. There was a strong linear dose-response association between fasting blood glucose concentration and the rate of pancreatic cancer across the range of prediabetes and diabetes. No non-linear association was detected. The pooled rate ratio of pancreatic cancer per 0.56 mmol/L (10 mg/dL) increase in fasting blood glucose was 1.14 (95% confidence interval 1.06 to 1.22; P<0.001) without significant heterogeneity. Sensitivity analysis excluding blood glucose categories in the range of diabetes showed similar results (pooled rate ratio per 0.56 mmol/L increase in fasting blood glucose was 1.15, 95% confidence interval 1.05 to 1.27; P=0.003), strengthening the association between prediabetes and pancreatic cancer. Conclusions Every 0.56 mmol/L increase in fasting blood glucose is associated with a 14% increase in the rate of pancreatic cancer. As prediabetes can be improved or even reversed through lifestyle changes, early detection of prediabetes coupled with lifestyle changes could represent a viable strategy to curb the increasing incidence of pancreatic cancer. PMID

  18. Biphasic Dose Response in Low Level Light Therapy

    PubMed Central

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

    2009-01-01

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

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

    SciTech Connect

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

    1987-02-01

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

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

    PubMed

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

    2015-11-01

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

  1. 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.

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

    NASA Astrophysics Data System (ADS)

    Berejka, Anthony J.

    2007-08-01

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

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

    EPA Science Inventory

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

  4. Bayesian Dose-Response Modeling in Sparse Data

    NASA Astrophysics Data System (ADS)

    Kim, Steven B.

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

  5. How linear features alter predator movement and the functional response.

    PubMed

    McKenzie, Hannah W; Merrill, Evelyn H; Spiteri, Raymond J; Lewis, Mark A

    2012-04-01

    In areas of oil and gas exploration, seismic lines have been reported to alter the movement patterns of wolves (Canis lupus). We developed a mechanistic first passage time model, based on an anisotropic elliptic partial differential equation, and used this to explore how wolf movement responses to seismic lines influence the encounter rate of the wolves with their prey. The model was parametrized using 5 min GPS location data. These data showed that wolves travelled faster on seismic lines and had a higher probability of staying on a seismic line once they were on it. We simulated wolf movement on a range of seismic line densities and drew implications for the rate of predator-prey interactions as described by the functional response. The functional response exhibited a more than linear increase with respect to prey density (type III) as well as interactions with seismic line density. Encounter rates were significantly higher in landscapes with high seismic line density and were most pronounced at low prey densities. This suggests that prey at low population densities are at higher risk in environments with a high seismic line density unless they learn to avoid them. PMID:22419990

  6. Linear and nonlinear optical response of spherical anisotropic semiconductor microcrystallites

    NASA Astrophysics Data System (ADS)

    Ramaniah, Lavanya M.; Nair, Selvakumar V.; Rustagi, Kailash C.

    1989-12-01

    We present a phenomenological theory of the linear and nonlinear optical properties associated with the Fröhlich resonances of an optically anisotropic, spherical semiconductor crystallite. Using the Maxwell-Garnett approach, we calculate the effective dielectric function of a composite medium containing such crystallites. To study the effect of anisotropy, we take CdS and CdSe quantum dots as examples for the inclusions, and use a two-resonance model for the dielectric function. Even for randomly oriented inclusions, the Fröhlich resonances split as a result of anisotropic local-field corrections. At higher laser intensities, absorption saturation leads to bistability or tristability in the optical response of individual crystallites, while the response of the composite medium with randomly oriented inclusions shows multistability, with many intermediate branches. The nonlinear response of such a composite medium also exhibits a new kind of orientation-induced broadening of resonances. We also find that tristability is possible in another kind of inhomogeneous material, viz., a composite medium containing two types of isotropic spherical crystallites.

  7. 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

  8. Finite orbit energetic particle linear response to toroidal Alfven eigenmodes

    SciTech Connect

    Berk, H.L.; Ye, Huanchun . Inst. for Fusion Studies); Breizman, B.N. . Inst. Yadernoj Fiziki)

    1991-07-01

    The linear response of energetic particles to the TAE modes is calculated taking into account their finite orbit excursion from the flux surfaces. The general expression reproduces the previously derived theory for small banana width: when the banana width {triangle}{sub b} is much larger than the mode thickness {triangle}{sub m}, we obtain a new compact expression for the linear power transfer. When {triangle}{sub m}/{triangle}{sub b} {much lt} 1, the banana orbit effect reduces the power transfer by a factor of {triangle}{sub m}/{triangle}{sub b} from that predicted by the narrow orbit theory. A comparison is made of the contribution to the TAE growth rate of energetic particles with a slowing-down distribution arising from an isotropic source, and a balance-injected beam source when the source speed is close to the Alfven speed. For the same stored energy density, the contribution from the principal resonances ({vert bar}{upsilon}{sub {parallel}}{vert bar} = {upsilon}{sub A} is substantially enhanced in the beam case compared to the isotropic case, while the contribution at the higher sidebands ({vert bar}{upsilon}{sub {parallel}}{vert bar}) = {upsilon}{sub A}/(2{ell} {minus} 1) with {ell} {ge} 2) is substantially reduced. 10 refs.

  9. Nonequilibrium thermal transport and its relation to linear response

    NASA Astrophysics Data System (ADS)

    Karrasch, C.; Ilan, R.; Moore, J. E.

    2013-11-01

    We study the real-time dynamics of spin chains driven out of thermal equilibrium by an initial temperature gradient TL≠TR using density matrix renormalization group methods. We demonstrate that the nonequilibrium energy current saturates fast to a finite value if the linear-response thermal conductivity is infinite, i.e., if the Drude weight D is nonzero. Our data suggest that a nonintegrable dimerized chain might support such dissipationless transport (D>0). We show that the steady-state value JE of the current for arbitrary TL≠TR is of the functional form JE=f(TL)-f(TR), i.e., it is completely determined by the linear conductance. We argue for this functional form, which is essentially a Stefan-Boltzmann law in this integrable model; for the XXX ferromagnet, f can be computed via the thermodynamic Bethe ansatz in good agreement with the numerics. Inhomogeneous systems exhibiting different bulk parameters as well as Luttinger liquid boundary physics induced by single impurities are discussed briefly.

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Chang, Yu-Kai; Etnier, Jennifer L

    2009-10-01

    The purpose of this study was to explore the dose-response relationship between resistance exercise intensity and cognitive performance. Sixty-eight participants were randomly assigned into control, 40%, 70%, or 100% of 10-repetition maximal resistance exercise groups. Participants were tested on Day 1 (baseline) and on Day 2 (measures were taken relative to performance of the treatment). Heart rate, ratings of perceived exertion, self-reported arousal, and affect were assessed on both days. Cognitive performance was assessed on Day 1 and before and following treatment on Day 2. Results from regression analyses indicated that there is a significant linear effect of exercise intensity on information processing speed, and a significant quadratic trend for exercise intensity on executive function. Thus, there is a dose-response relationship between the intensity of resistance exercise and cognitive performance such that high-intensity exercise benefits speed of processing, but moderate intensity exercise is most beneficial for executive function. PMID:20016113

  12. Hall Viscosity I: Linear Response Theory for Viscosity

    NASA Astrophysics Data System (ADS)

    Bradlyn, Barry; Goldstein, Moshe; Read, Nicholas

    2012-02-01

    In two dimensional systems with broken time-reversal symmetry, there can exist a non-dissipative viscosity coefficient [1,2,3]. This Hall viscosity is similar in nature to the non-dissipative Hall conductivity. In order to investigate this phenomenon further, we develop a linear response formalism for viscosity. We derive a Kubo formula for the frequency dependent viscosity tensor in the long wavelength limit. We compute the viscosity tensor for the free electron gas, integer quantum Hall systems, and two-dimensional paired superfluids. In the zero frequency limit, we show how the known results [3,4] for the Hall viscosity are recovered.[4pt] [1] J. Avron, R. Seiler, and P. Zograf, Phys. Rev. Lett. 75, 697 (1995).[0pt] [2] P. Levay, J. Math. Phys. 36, 2792 (1995).[0pt] [3] N. Read, Phys. Rev. B 79, 045308 (2009).[0pt] [4] N. Read and E. Rezayi, Phys. Rev. B 84, 085316 (2011).

  13. Portable polarimetric underwater imaging system with a linear response

    NASA Astrophysics Data System (ADS)

    Karpel, Nir; Schechner, Yoav Y.

    2004-07-01

    Polarized light plays an important role in the underwater environment. Light that is scattered within the water is partially polarized. Biological and artificial systems can exploit this phenomenon. We aim to utilize this phenomenon in a new generation of underwater imaging systems in order to partially compensate for the loss of color and visibility. In order to obtain quantitative measurement of radiance and polarization, the imaging system should have a linear radiometric response and low noise. In addition, the interface of the camera with the water should have a minimum effect on the polarization. In this paper, we describe a portable lightweight imaging system that addresses these conditions. We detail the design considerations and empirical verifications.

  14. Linear Response Screening Models for Dense, Strongly-Coupled Plasmas

    NASA Astrophysics Data System (ADS)

    Stanton, Liam; Murillo, Michael; Benage, John; Graziani, Frank

    2011-10-01

    Needs for accurate EOS and transport models of warm/hot dense matter have increased with the advent of new experiments that are able to more accurately probe these areas of phase-space. Molecular dynamics (MD) methods are often used for this, as they are apt for strongly-coupled systems. Unfortunately, the traditional Coulomb and Yukawa pair-potentials begin to fail at lower temperatures as degeneracy effects of the electron gas arise, and a more sophisticated treatment is required. We present a class of effective ion-ion interactions derived within the framework of linear response, which go beyond screening in the long-wavelength limit. These new potentials not only improve the accuracy of screening effects without contributing to the computational complexity of the model, but they also add physics entirely missing from Yukawa models (such as the onset of Friedel oscillations). Prepared by LLNL under Contract DE-AC52-07NA27344. LLNL-ABS-490713.

  15. Cellular Response to Linear and Branched Poly(acrylic acid).

    PubMed

    Whitty, Elizabeth G; Maniego, Alison R; Bentwitch, Sharon A; Guillaneuf, Yohann; Jones, Mark R; Gaborieau, Marianne; Castignolles, Patrice

    2015-12-01

    Poly(acrylic acid-co-sodium acrylate) (PNaA) is a pH-responsive polymer with potential in anticancer drug delivery. The cytotoxicity and intracellular effects of 3-arm star, hyperbranched and linear PNaA were investigated with L1210 progenitor leukemia cells and L6 myoblast cells. Free solution capillary electrophoresis demonstrated interactions of PNaA with serum proteins. In a 72 h MTT assay most PNaAs exhibited a IC50 between 7 and 14 mmol L(-1), showing that precipitation may be a sufficient purification for PNaA dilute solutions. Dialyzed 3-arm star and hyperbranched PNaA caused an increase in L6 cell viability, challenging the suitability of MTT as cytotoxicity assay for PNaA. Fluorescent confocal microscopy revealed merging of cellular lipids after exposure to PNaA, likely caused by serum starvation.

  16. Linear versus nonlinear response of a forced wave turbulence system.

    PubMed

    Cadot, Olivier; Touzé, Cyril; Boudaoud, Arezki

    2010-10-01

    A vibrating plate is set into a chaotic state of wave turbulence by a forcing having periodic and random components. Both components are weighted in order to explore continuously intermediate forcing from the periodic to the random one, but keeping constant its rms value. The transverse velocity of the plate is measured at the application point of the force. It is found that whatever the detail of the forcing is, the velocity spectra exhibit a universal cascade for frequencies larger than the forcing frequency range. In contrast, the velocity spectra strongly depend on the nature of the forcing within the range of forcing frequencies. The coherence function is used to extract the contribution of the velocity fluctuations that display a linear relationship with the forcing. The nonlinear contribution to the velocity fluctuations is found to be almost constant, about 55% of the total velocity fluctuations whatever the nature of the forcing from random to periodic. On the other hand, the nonlinear contribution to the fluctuations of the injected power depends on the nature of the forcing; it is significantly larger for the periodic forcing (60%) and decreases continuously as the randomness is increased, reaching a value of 40% for the pure random forcing. For all the cases of intermediate forcing from random to periodic, a simple model of the velocity response recovers in a fairly good agreement the probability density function of the injected power. The consequence of the existence of a linear-response component is discussed in the context of the fluctuation-dissipation theorem validation in experiments of out-of-equilibrium systems. PMID:21230369

  17. Modeling Effective Dosages in Hormetic Dose-Response Studies

    PubMed Central

    Belz, Regina G.; Piepho, Hans-Peter

    2012-01-01

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

  18. 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.

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

    SciTech Connect

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

    2013-03-15

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

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

    PubMed

    Rosier, Bob T; Lazova, Milena D

    2016-01-01

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

  1. Characterization of a developmental toxicity dose-response model

    SciTech Connect

    Faustman, E.M.; Wellington, D.G.; Smith, W.P.; Kimmel, C.A.

    1989-02-01

    The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.

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

    SciTech Connect

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

    1995-12-31

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

  3. Quantum optimal control theory in the linear response formalism

    SciTech Connect

    Castro, Alberto; Tokatly, I. V.

    2011-09-15

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

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

    SciTech Connect

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

    2005-11-01

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

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

    SciTech Connect

    Daila S. Gridley, PhD

    2012-03-30

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

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

    PubMed

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

    2007-07-01

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

  7. Responses of proteins to different ionic environment are linearly interrelated.

    PubMed

    Ferreira, Luisa A; Madeira, Pedro P; Uversky, Alexey V; Uversky, Vladimir N; Zaslavsky, Boris Y

    2015-03-27

    Protein partitioning in aqueous two-phase systems (ATPS) is widely used as a convenient, inexpensive, and readily scaled-up separation technique. Protein partition behavior in ATPS is known to be readily manipulated by ionic composition. However, the available data on the effects of salts and buffer concentrations on protein partitioning are very limited. To fill this gap, partitioning of 15 proteins was examined in dextran-poly(ethylene glycol) ATPSs with different salt additives (Na2SO4, NaClO4, NaSCN, CsCl) in 0.11 M sodium phosphate buffer, pH 7.4. This analysis reveals that there is a linear relationship between the logarithms of the protein partition coefficients determined in the presence of different salts. This relationship suggests that the protein response to ionic environment is determined by the protein structure and type and concentrations of the ions present. Analysis of the differences between protein structures (described in terms of proteins responses to different salts) and that of cytochrome c chosen as a reference showed that the peculiarities of the protein surface structure and B-factor used as a measure of the protein flexibility are the determining parameters. Our results provide better insight into the use of different salts in manipulating protein partitioning in aqueous two-phase systems. These data also demonstrate that the protein responses to different ionic environments are interrelated and are determined by the structural peculiarities of protein surface. It is suggested that changes in ionic microenvironment of proteins may regulate protein transport and behavior in biological systems.

  8. Optical and NMR dose response of N-isopropylacrylamide normoxic polymer gel for radiation therapy dosimetry

    PubMed Central

    Mesbahi, Asghar; Jafarzadeh, Vahid; Gharehaghaji, Nahideh

    2012-01-01

    Background Application of less toxic normoxic polymer gel of N-isopropyl acrylamide (NIPAM) for radiation therapy has been studied in recent years. Aim In the current study the optical and NMR properties of NIPAM were studied for radiation therapy dosimetry application. Materials and methods NIPAM normoxic polymer gel was prepared and irradiated by 9 MV photon beam of a medical linac. The optical absorbance was measured using a conventional laboratory spectrophotometer in different wavelengths ranging from 390 to 860 nm. R2 measurements of NIPAM gels were performed using a 1.5 T scanner and R2–dose curve was obtained. Results Our results showed R2 dose sensitivity of 0.193 ± 0.01 s−1 Gy−1 for NIPAM gel. Both R2 and optical absorbance showed a linear relationship with dose from 1.5 to 11 Gy for NIPAM gel dosimeter. Moreover, absorbance–dose response varied considerably with light wavelength and highest sensitivity was seen for the blue part of the spectrum. Conclusion Our results showed that both optical and NMR approaches have acceptable sensitivity and accuracy for dose determination with NIPAM gel. However, for optical reading of the gel, utilization of an optimum optical wavelength is recommended. PMID:24377016

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

    EPA Science Inventory

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

  10. Isometric exercise and cognitive function: an investigation of acute dose-response effects during submaximal fatiguing contractions.

    PubMed

    Brown, Denver M Y; Bray, Steven R

    2015-01-01

    The purpose of this study was to explore the dose-response relationship between exercise and cognitive performance using an acute bout of isometric exercise. University students (N = 55) were randomly assigned to control, 30%, 50% and 70% of maximum voluntary handgrip contraction groups. Participants performed a modified Stroop task before and after completion of an isometric handgrip endurance trial at their assigned exercise intensity. Ratings of perceived exertion (RPE) and forearm muscle activation (EMG) showed linear trends of progressively greater RPE and muscle activation at greater exercise intensity levels. Regression analysis showed significant (P < .05) linear degradations in frequency of errors on the Stroop task with increasing exercise intensity. We conclude that performing isometric exercise until exhaustion is associated with reduced cognitive performance and that higher intensity isometric exercise leads to greater performance impairments in a linear dose-response manner.

  11. A consistent, linear-response approach to LDA+U

    NASA Astrophysics Data System (ADS)

    Cococcioni, Matteo

    2006-03-01

    Hubbard U-correction to LDA or GGA has proven very effective in describing several strongly-correlated systems for which these approximations to DFT otherwise fail. Constrained DFT or semiempirical approaches have been often used to compute the Hubbard U. I introduce here an alternative scheme to evaluate the effective electronic interaction in a fully consistent way. This approach is based on the linear response of the system under consideration to a potential shift acting on the localized orbitals of the correlated sites. Using the occupations of these orbitals as the relevant electronic degrees of freedom we compute the on-site electronic coupling as the difference between the inverse of the bare and of the fully-interacting response matrices. The U computed in this way thus corresponds to the effective, atomically-averaged kernel of the Hartree-exchange-correlation interaction, in agreement with the second quantization expression of the "+U" energy functional. In this way the strength of the "+U" correction is evaluated from the same DFT scheme we aim to correct so that LDA+U becomes a consistent non-parametric method, with no need for semiempirical evaluations of the effective coupling. With this approach we successfully studied the structural, electronic, chemical and electrochemical properties of several transition-metal compounds. Examples will include minerals in the Earth's interior^1, cathode materials for next-generation lithium batteries^2 and metal-organic complexes ^3. 1) M. Cococcioni and S. de Gironcoli, PRB (2005). 2) F. Zhou, M. Cococcioni, A. C. Marianetti, D. Morgan and G. Ceder, PRB (2004). 3) H. J. Kulik, M. Cococcioni, D. Scherlis and N. Marzari, submitted to PRL.

  12. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    PubMed

    Cornelissen, Jan B W J; van der Giessen, Joke W B; Takumi, Katsuhisa; Teunis, Peter F M; Wisselink, Henk J

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.

  13. An Experimental Toxoplasma gondii Dose Response Challenge Model to Study Therapeutic or Vaccine Efficacy in Cats

    PubMed Central

    Cornelissen, Jan B. W. J.; van der Giessen, Joke W. B.; Takumi, Katsuhisa; Teunis, Peter F. M.; Wisselink, Henk J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10), and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application. PMID:25184619

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

    EPA Science Inventory

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

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

    NASA Technical Reports Server (NTRS)

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

    1996-01-01

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

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

    PubMed

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

    2015-11-01

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

  17. 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. PMID:27036068

  18. 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.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-01-01

    Polymer gels are regarded as a potential dosimeter for independent validation of absorbed doses in clinical radiotherapy. Several imaging modalities have been used to convert radiation-induced polymerization to absorbed doses from a macro-scale viewpoint. This study developed a novel dose conversion mechanism by texture analysis of scanning electron microscopy (SEM) images. The modified N-isopropyl-acrylamide (NIPAM) gels were prepared under normoxic conditions, and were administered radiation doses from 5 to 20 Gy. After freeze drying, the gel samples were sliced for SEM scanning with 50×, 500×, and 3500× magnifications. Four texture indices were calculated based on the gray level co-occurrence matrix (GLCM). The results showed that entropy and homogeneity were more suitable than contrast and energy as dose indices for higher linearity and sensitivity of the dose response curves. After parameter optimization, an R (2) value of 0.993 can be achieved for homogeneity using 500× magnified SEM images with 27 pixel offsets and no outlier exclusion. For dose verification, the percentage errors between the prescribed dose and the measured dose for 5, 10, 15, and 20 Gy were -7.60%, 5.80%, 2.53%, and -0.95%, respectively. We conclude that texture analysis can be applied to the SEM images of gel dosimeters to accurately convert micro-scale structural features to absorbed doses. The proposed method may extend the feasibility of applying gel dosimeters in the fields of diagnostic radiology and radiation protection. PMID:23843998

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

    PubMed

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

    2016-02-01

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

  2. Dose response and post-irradiation characteristics of the Sunna 535-nm photo-fluorescent film dosimeter

    NASA Astrophysics Data System (ADS)

    Murphy, M. K.; Kovács, A.; Miller, S. D.; McLaughlin, W. L.

    2003-12-01

    Results of characterization studies on one of the first versions of the Sunna photo-fluorescent dosimeter™ have previously been reported, and the performance of the red fluorescence component described. This present paper describes dose response and post-irradiation characteristics of the green fluorescence component from the same dosimeter film ( Sunna Model γ), which is manufactured using the injection molding technique. This production method may supply batch sizes on the order of 1 million dosimeter film elements while maintaining a signal precision (1 σ) on the order of ±1% without the need to correct for variability of film thickness. The dosimeter is a 1 cm×3 cm polymeric film of 0.5-mm thickness that emits green fluorescence at intensities increasing almost linearly with dose. The data presented include dose response, post-irradiation growth, heat treatment, dosimeter aging, dose rate dependence, energy dependence, dose fractionation, variation of response within a batch, and the stability of the fluorimeter response. The results indicate that, as a routine dosimeter, the green signal provides a broad range of response at food irradiation (0.3-5 kGy), medical sterilization (5-40 kGy), and polymer cross-linking (40-250 kGy) dose levels.

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

    PubMed

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

    2015-09-25

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

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

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

    SciTech Connect

    Rowland, R.E.; Stehney, A.F.; Lucas, H.F. Jr.

    1981-01-01

    The incidence of bone sarcomas among 3055 female radium-dial workers who entered the dial industry before 1950 was used to determine dose-response relationships for the induction of bone sarcomas by radium. Two subpopulations were analyzed: all measured cases who survived at last five years after the start of employment and all cases who survived at least two years after first measurement. The first constituted a group based on year of entry; it contained 1468 women who experienced 42 bone sarcomas; the expected number was 0.4. The second comprised a group based on first measurement; it contained 1257 women who experienced 13 bone sarcomas; the expected number was 0.2. The dose-response function, I = (C + ..cap alpha..D + ..beta..D/sup 2/)e/sup -..gamma..D/, and simplifications of this general form, were fit to each data set. Two functions, I = (C + ..cap alpha..D + ..beta..D/sup 2/)e/sup -..gamma..D/ and I = (C + ..beta..D/sup 2/)e/sup -..gamma..D/, fit the data for year of entry (p greater than or equal to 0.05); both these functions and I = (C + ..cap alpha..D) fit the data for first measurement. The function I = (C + ..beta..D/sup 2/)e/sup -..gamma..D/ was used to predict the number of bone sarcomas in all other pre-1950 radium cases (medical, laboratory, and other exposure); fewer were actually observed than the fit of this function to the female dial workers predicted.

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

    Cancer.gov

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

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

    PubMed

    Little, M P

    2010-05-01

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

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

    EPA Science Inventory

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

  9. Peripheral dose measurements for 6 and 18 MV photon beams on a linear accelerator with multileaf collimator

    SciTech Connect

    Mazonakis, Michalis; Zacharopoulou, Fotini; Varveris, Haralambos; Damilakis, John

    2008-10-15

    Peripheral dose (PD) to critical structures outside treatment volume is of clinical importance. The aim of the current study was to estimate PD on a linear accelerator equipped with multileaf collimator (MLC). Dose measurements were carried out using an ionization chamber embedded in a water phantom for 6 and 18 MV photon beams. PD values were acquired for field sizes from 5x5 to 20x20 cm{sup 2} in increments of 5 cm at distances up to 24 cm from the field edge. Dose data were obtained at two collimator orientations where the measurement points are shielded by MLC and jaws. The variation of PD with the source to skin distance (SSD), depth, and lateral displacement of the measurement point was evaluated. To examine the dependence of PD upon the tissue thickness at the entrance point of the beam, scattered dose was measured using thermoluminescent dosemeters placed on three anthropomorphic phantoms simulating 5- and 10-year-old children and an average adult patient. PD from 6 MV photons varied from 0.13% to 6.75% of the central-axis maximum dose depending upon the collimator orientation, extent of irradiated area, and distance from the treatment field. The corresponding dose range from 18 MV x rays was 0.09% to 5.61%. The variation of PD with depth and with lateral displacements up to 80% of the field dimension was very small. The scattered dose from both photon beams increased with the increase of SSD or tissue thickness along beam axis. The presented dosimetric data set allows the estimation of scattered dose outside the primary beam.

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

    SciTech Connect

    Plataniotis, George A. Dale, Roger G.

    2009-10-01

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

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

    EPA Science Inventory

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

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

    PubMed

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

    2012-05-01

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

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

    PubMed

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

    2012-05-01

    The non-cancer mortality data for cerebrovascular disease (CVD) and cardiovascular diseases from Report 13 on the atomic bomb survivors published by the Radiation Effects Research Foundation were analysed to investigate the dose-response for the influence of radiation on these detrimental health effects. Various parametric and categorical models (such as linear-no-threshold (LNT) and a number of threshold and step models) were analysed with a statistical selection protocol that rated the model description of the data. Instead of applying the usual approach of identifying one preferred model for each data set, a set of plausible models was applied, and a sub-set of non-nested models was identified that all fitted the data about equally well. Subsequently, this sub-set of non-nested models was used to perform multi-model inference (MMI), an innovative method of mathematically combining different models to allow risk estimates to be based on several plausible dose-response models rather than just relying on a single model of choice. This procedure thereby produces more reliable risk estimates based on a more comprehensive appraisal of model uncertainties. For CVD, MMI yielded a weak dose-response (with a risk estimate of about one-third of the LNT model) below a step at 0.6 Gy and a stronger dose-response at higher doses. The calculated risk estimates are consistent with zero risk below this threshold-dose. For mortalities related to cardiovascular diseases, an LNT-type dose-response was found with risk estimates consistent with zero risk below 2.2 Gy based on 90% confidence intervals. The MMI approach described here resolves a dilemma in practical radiation protection when one is forced to select between models with profoundly different dose-responses for risk estimates. PMID:22437350

  14. Thermally-induced structural dynamic response of flexural configurations influenced by linear/non-linear thermal effects

    NASA Technical Reports Server (NTRS)

    Namburu, Raju R.; Tamma, Kumar K.

    1991-01-01

    The thermally-induced strucural dynamic response of flexural configurations influenced by linear/nonlinear thermal effects is presented in conjunction with 'unified' transient approaches for effectively tackling this class of interdisciplinary problems. For illustrative purposes, the flexural structural models are assumed to be of the Euler-Bernoulli type. The purpose of the present paper is to not only provide an understanding of the influence of general linear/nonlinear thermal effects on flexural configurations, but also to provide to the analyst effective computational tools which help preserve a unified technology for the interdisciplinary areas encompassing structural mechanics/dynamics and thermal sciences. Several numerical test models illustrate the representative thermally-induced structural dynamic response of flexural configurations subjected to general linear/nonlinear temperature effects.

  15. The effect of a paraffin screen on the neutron dose at the maze door of a 15 MV linear accelerator

    SciTech Connect

    Krmar, M.; Kuzmanović, A.; Nikolić, D.; Kuzmanović, Z.; Ganezer, K.

    2013-08-15

    Purpose: The purpose of this study was to explore the effects of a paraffin screen located at various positions in the maze on the neutron dose equivalent at the maze door.Methods: The neutron dose equivalent was measured at the maze door of a room containing a 15 MV linear accelerator for x-ray therapy. Measurements were performed for several positions of the paraffin screen covering only 27.5% of the cross-sectional area of the maze. The neutron dose equivalent was also measured at all screen positions. Two simple models of the neutron source were considered in which the first assumed that the source was the cross-sectional area at the inner entrance of the maze, radiating neutrons in an isotropic manner. In the second model the reduction in the neutron dose equivalent at the maze door due to the paraffin screen was considered to be a function of the mean values of the neutron fluence and energy at the screen.Results: The results of this study indicate that the equivalent dose at the maze door was reduced by a factor of 3 through the use of a paraffin screen that was placed inside the maze. It was also determined that the contributions to the dosage from areas that were not covered by the paraffin screen as viewed from the dosimeter, were 2.5 times higher than the contributions from the covered areas. This study also concluded that the contributions of the maze walls, ceiling, and floor to the total neutron dose equivalent were an order of magnitude lower than those from the surface at the far end of the maze.Conclusions: This study demonstrated that a paraffin screen could be used to reduce the neutron dose equivalent at the maze door by a factor of 3. This paper also found that the reduction of the neutron dose equivalent was a linear function of the area covered by the maze screen and that the decrease in the dose at the maze door could be modeled as an exponential function of the product φ·E at the screen.

  16. The hormetic dose-response model is more common than the threshold model in toxicology.

    PubMed

    Calabrese, Edward J; Baldwin, Linda A

    2003-02-01

    The threshold dose-response model is widely viewed as the most dominant model in toxicology. The present study was designed to test the validity of the threshold model by assessing the responses of doses below the toxicological NOAEL (no observed adverse effect level) in relationship to the control response (i.e., unexposed group). Nearly 1,800 doses below the NOAEL, from 664 dose-response relationships derived from a previously published database that satisfied a priori entry criteria, were evaluated. While the threshold model predicts a 1:1 ratio of responses "greater than" to "less than" the control response (i.e., a random distribution), a 2.5:1 ratio (i.e., 1171:464) was observed, reflecting 31% more responses above the control value than expected (p < 0.0001). The mean response (calculated as % control response) of doses below the NOAEL was 115.0% +/- 1.5 standard error of the mean (SEM). These findings challenge the long-standing belief in the primacy of the threshold model in toxicology (and other areas of biology involving dose-response relationships) and provide strong support for the hormetic-like biphasic dose-response model characterized by a low-dose stimulation and a high-dose inhibition. These findings may affect numerous aspects of toxicological and biological/biomedical research related to dose-response relationships, including study design, risk assessment, as well as chemotherapeutic strategies.

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

    PubMed

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

    2015-04-01

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

  18. A comparative study of the peripheral doses from a linear accelerator with a multileaf collimator system.

    PubMed

    Acun, Hediye; Zubaroglu, Ali; Kemikler, Gönül; Bozkurt, Ahmet

    2014-01-01

    This study presents a comparison of peripheral doses (PDs) measured using an ionisation chamber with treatment planning system (TPS) data and a Monte Carlo (MC) simulation of a 6-MV photon beam. The ion chamber measurements and MC simulation produced similar results for all out-of-field distances and field sizes considered in this study. For the 0° and 90° collimation angles, the average local per cent dose differences between the MC and TPS calculations were 2.7 % (range: -2.4, +22.6) and -1.7 % (range: -12.2, +10.8), respectively. The corresponding differences between the MC calculations and the ion chamber measurements were 2.2 % (range: -2.4, 24.7) and -1.8 % (range: -17, 15.2) for all field sizes and depths, respectively. Whereas the PDs increased with field sizes, the variations with depth were negligible at large distances. The TPS calculations usually yielded higher PDs than ion chamber measurements at distances close to the field edge. In contrast, at the farther distances, the TPS results indicated lower doses than both the ion chamber and the MC data. TPS data are not sufficient for use in calculating the out-of-field doses. These results can be used to estimate non-target organ doses to patients.

  19. Linear optical response of carbon nanotubes under axial magnetic field

    NASA Astrophysics Data System (ADS)

    Moradian, Rostam; Chegel, Raad; Behzad, Somayeh

    2010-04-01

    We considered single walled carbon naotubes (SWCNTs) as real three dimensional (3D) systems in a cylindrical coordinate. The optical matrix elements and linear susceptibility, χ(ω), in the tight binding approximation in terms of one-dimensional wave vector, kz and subband index, l are calculated. In an external axial magnetic field optical frequency dependence of linear susceptibility are investigated. We found that axial magnetic field has two effects on the imaginary part of the linear susceptibility spectrum, in agreement with experimental results. The first effect is broadening and the second, splitting. Also we found that for all metallic zigzag and armchair SWCNTs, the axial magnetic field leads to the creation of a peak with energy less than 1.5 eV, contrary to what is observed in the absence of a magnetic field.

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

    EPA Science Inventory

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

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

    PubMed

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

    2015-10-07

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

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

    NASA Astrophysics Data System (ADS)

    Kalita, J. M.; Wary, G.

    2016-09-01

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

  3. Linear response, multi-order grating interferometry using a reversal shearing imaging system.

    PubMed

    Tao, Zhang; Tan, Jiubin; Cui, Jiwen

    2015-10-01

    Linear response, multi-order grating interferometry is proposed to measure grating displacement. The system, a combination of a reversal shearing interferometer and an imaging system, enables calculating multi-order, integrated intensity signals with a linear waveform response. A theoretical multi-order model for the linear response signal analysis is presented with a Fourier series expansion. The results of the experiment, which prove the validity of the theoretical model, indicate a linear response to displacement with a linearity of 98.7% and a resolution of 10 nm. We conclude that the proposed method enables the development of a new class of potent linear response grating interferometry for displacement metrology.

  4. Inorganic arsenic in drinking water and bladder cancer: a meta-analysis for dose-response assessment.

    PubMed

    Chu, Huei-An; Crawford-Brown, Douglas J

    2006-12-01

    Most arsenic cancer risk assessments have been based solely on epidemiological studies to characterize the dose-response relationship for arsenic-associated cancer and to perform risk calculations. However, current epidemiological evidence is too inconsistent and fraught with uncertainty regarding arsenic exposure to provide reliable estimates. This makes it hard to draw a firm conclusion about the shape and slope of the dose-response relationship from individual studies. Meta-analysis is a statistical approach to combining results across studies and offers expanded opportunities for obtaining an improved dose-response relationship. In this study, a meta-analysis of arsenic studies was conducted by combining seven epidemiological studies from different regions to get an overall dose-response relationship between the amount of arsenic intake and the excess probability of bladder cancer. Both the fixed-effect and random-effect models were used to calculate the averaged coefficient of the linear-logistic regression model. A homogeneity test was also conducted. The final product of this research is an aggregated dose-response model in the range of empirical observation of arsenic. Considering the most recent arsenic MCL (maximum contaminant level, i.e. 10microg/L), the associated bladder cancer risk (lifetime excess probability) at this MCL is 2.29 x 10-5.

  5. Dose-Response Relationship between Exercise and Respiratory Disease Mortality

    PubMed Central

    Williams, Paul T.

    2014-01-01

    Purpose To assess prospectively the dose-response relationship between respiratory disease (ICD10: J1-99), pneumonia (ICD10: J12.0-18.9), and asperation pneumonia mortality (ICD10: J69) vs. baseline walking and running energy expenditure (MET-hours/d, 1 MET = 3.5 ml O2/kg/min). Methods Cox proportional hazard analyses of 109,352 runners and 40,798 walkers adjusted for age, sex, smoking, diet, alcohol, and education. Results There were 236 deaths with respiratory disease listed as the underlying cause, and 833 deaths that were respiratory disease related (entity axis diagnosis). Included among these were 79 deaths with pneumonia listed as the underlying cause and 316 pneumonia-related deaths, and 77 deaths due to aspiration pneumonia. There was no significant difference in the effect of running compared to walking (per MET-hours/d) on mortality, thus runners and walkers were combined for analysis. Respiratory disease mortality decreased 7.9% per MET-hours/d as the underlying cause (95%CI: 1.6% to 14.0%, P=0.01) and 7.3% for all respiratory disease-related deaths (95%CI: 4.2% to 10.4%, P=10-5). Pneumonia mortality decreased 13.1% per MET-hours/d as the underlying cause (95%CI: 2.6% to 23.2%, P=0.01) and 10.5% per MET-hours/d for all pneumonia-related deaths (95%CI: 5.4% to 15.5%, P=0.0001). The risk for aspiration pneumonia mortality also did not differ between running and walking, and decreased 19.9% per MET-hours/d run or walked (95%CI: 8.9% to 30.2%, P=0.0004). These results remained significant when additionally adjusted for BMI. Conclusions Higher doses of running and walking were associated with lower risk of respiratory disease, pneumonia, and aspiration pneumonia mortality in a dose-dependent manner, and the effects of running and walking appear equivalent. These effects appear to be independent of the effects of exercise on cardiovascular disease. PMID:24002349

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

    SciTech Connect

    Catt, B; Snyder, M

    2014-06-15

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

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

    PubMed

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

    2014-02-15

    Critical habitats of at-risk populations of northeast Pacific "resident" killer whales can be heavily trafficked by large ships, with transits occurring on average once every hour in busy shipping lanes. We modeled behavioral responses of killer whales to ship transits during 35 "natural experiments" as a dose-response function of estimated received noise levels in both broadband and audiogram-weighted terms. Interpreting effects is contingent on a subjective and seemingly arbitrary decision about severity threshold indicating a response. Subtle responses were observed around broadband received levels of 130 dB re 1 μPa (rms); more severe responses are hypothesized to occur at received levels beyond 150 dB re 1 μPa, where our study lacked data. Avoidance responses are expected to carry minor energetic costs in terms of increased energy expenditure, but future research must assess the potential for reduced prey acquisition, and potential population consequences, under these noise levels. PMID:24373666

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

    PubMed

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

    2014-02-15

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

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

    NASA Technical Reports Server (NTRS)

    Jamison, J. W.

    1994-01-01

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

  10. Dose-response analysis of cadmium in man: body burden vs kidney dysfunction

    SciTech Connect

    Ellis, K.J.; Yuen, K.; Yasumura, S.; Cohn, S.H.

    1984-02-01

    The primary objective of this study was to develop dose-response relationships of cadmium in human beings. In vivo measurements of kidney, liver, urine, and blood cadmium, and urinary levels of ..beta../sub 2/-microglobulin and total protein were obtained in 82 industrially exposed workers and 30 control subjects. The values of 200 ..mu..g/g creatinine for urinary ..beta../sub 2/-microglobulin and 250 mg/g creatinine for urinary total protein were used to define the upper limit for normal kidney function. Forty-one of the cadmium workers (18 active, 23 retired) were classified as having abnormal kidney function; all control subjects had normal kidney function. Most workers with Cd above 70 ppm in the liver were judged to have some evidence of kidney abnormalities. The dose-response relationship for liver cadmium for the actively employed workers could be described by a linear logistic regression model: In p/(1-p) = 0.118 x liver cadmium (ppm) - 5.00 where p is the individual's probability of having kidney dysfunction. The loss of cadmium from the kidney following dysfunction prohibited a direct logistic analysis of the kidney cadmium data. However, when the linear relationship between kidney and liver cadmium for the subjects with normal kidney function was combined with the logistic equation for the liver, a predicted-response curve was obtained for the kidney. The logistic models predict a 50% probability of having kidney dysfunction at 38.4 mg for the kidney and 42.3 ppm for the liver, respectively.

  11. Dose response of CaF2:Tm to charged particles of different LET.

    PubMed

    Moyers, M F; Nelson, G A

    2009-08-01

    Thermoluminescent dosimeters are well established for performing calibrations in radiotherapy and for monitoring dose to personnel exposed to low linear energy transfer (LET) ionizing radiation. Patients undergoing light ion therapy and astronauts engaged in space flight are, however, exposed to radiation fields consisting of a mix of low- and high-LET charged particles. In this study, glow curves from CaF2:Tm chips were examined after exposure to various electron and ion beams. The annealing and readout procedures for these chips were optimized for these beams. After a 10 min prereadout annealing at 100 degrees C, the optimized glow curve samples the light output between 95 and 335 degrees C with a heating rate of 2 degrees C/s. The ratio of the integral of the glow curve under peaks 4-6 to the integral under peak 3 was approximately 0.9 for electrons, 1.0 for entrance protons, 1.6 for peak protons, and 2.2 for entrance carbon, silicon, and iron ions. The integral light output per unit dose in water for the iron exposures was about half as much as for the electron exposures. The peak-area-ratio can be used to determine a dose response factor for different LET radiations. PMID:19746804

  12. Response of silicon-Based Linear Energy Transfer Spectrometers

    NASA Technical Reports Server (NTRS)

    Aman, A.; Bman, B.; Badhwar, G. D.; ONeill, P. M. O.

    2000-01-01

    Silicon-based linear energy transfer (LET) telescope,(e. g., DOSTEL and RRMD) have recently been flown in space. LET spectra measured using tissue equivalent proportional counters show differences that need to be fully understood. A Monte Carlo technique based on: 1. radiation transport cluster intra-cascade model. 2. Landau-Vavilov distribution, 3. telescope geometry and detector coincidence & discriminator settings, 4. spacecraft shielding geometry, and 5. the external free space radiation environment, including recent albedo measurements, was developed.

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

    ERIC Educational Resources Information Center

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

    2007-01-01

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

  14. The Simplest Complete Model of Choice Response Time: Linear Ballistic Accumulation

    ERIC Educational Resources Information Center

    Brown, Scott D.; Heathcote, Andrew

    2008-01-01

    We propose a linear ballistic accumulator (LBA) model of decision making and reaction time. The LBA is simpler than other models of choice response time, with independent accumulators that race towards a common response threshold. Activity in the accumulators increases in a linear and deterministic manner. The simplicity of the model allows…

  15. The Generalized Logit-Linear Item Response Model for Binary-Designed Items

    ERIC Educational Resources Information Center

    Revuelta, Javier

    2008-01-01

    This paper introduces the generalized logit-linear item response model (GLLIRM), which represents the item-solving process as a series of dichotomous operations or steps. The GLLIRM assumes that the probability function of the item response is a logistic function of a linear composite of basic parameters which describe the operations, and the…

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

    NASA Astrophysics Data System (ADS)

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

    2004-08-01

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

  17. Dose response studies of bevantolol in hypertensive patients.

    PubMed

    Okawa, K K

    1986-03-01

    This multicenter study, conducted to determine the antihypertensive efficacy of bevantolol at different fixed doses compared with placebo was carried out at four separate institutions using a common protocol. One hundred thirty-nine patients with mild to moderate essential hypertension were enrolled. At doses of 200 to 400 mg/day bevantolol was clearly effective in lowering diastolic blood pressure and in maintaining this effect over the eight weeks of this double-blind study. Twice a day dosing is indicated since efficacy was evident 12 hours post-dosing. Bevantolol was well tolerated.

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

    SciTech Connect

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

    2015-04-01

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

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

    PubMed

    Tomita, Masanori; Maeda, Munetoshi

    2015-03-01

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

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

    EPA Science Inventory

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

  1. 3'-deoxy-3'-[{sup 18}F]fluorothymidine PET Quantification of Bone Marrow Response to Radiation Dose

    SciTech Connect

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

    2011-11-01

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

  2. Salvage Radiotherapy for Rising Prostate-Specific Antigen Levels After Radical Prostatectomy for Prostate Cancer: Dose-Response Analysis

    SciTech Connect

    Bernard, Johnny Ray; Buskirk, Steven J.; Heckman, Michael G.; Diehl, Nancy N.; Ko, Stephen J.; Macdonald, Orlan K.; Schild, Steven E.; Pisansky, Thomas M.

    2010-03-01

    Purpose: To investigate the association between external beam radiotherapy (EBRT) dose and biochemical failure (BcF) of prostate cancer in patients who received salvage prostate bed EBRT for a rising prostate-specific antigen (PSA) level after radical prostatectomy. Methods and Materials: We evaluated patients with a rising PSA level after prostatectomy who received salvage EBRT between July 1987 and October 2007. Patients receiving pre-EBRT androgen suppression were excluded. Cox proportional hazards models were used to investigate the association between EBRT dose and BcF. Dose was considered as a numeric variable and as a categoric variable (low, <64.8 Gy; moderate, 64.8-66.6 Gy; high, >66.6 Gy). Results: A total of 364 men met study selection criteria and were followed up for a median of 6.0 years (range, 0.1-19.3 years). Median pre-EBRT PSA level was 0.6 ng/mL. The estimated cumulative rate of BcF at 5 years after EBRT was 50% overall and 57%, 46%, and 39% for the low-, moderate-, and high-dose groups, respectively. In multivariable analysis adjusting for potentially confounding variables, there was evidence of a linear trend between dose and BcF, with risk of BcF decreasing as dose increased (relative risk [RR], 0.77 [5.0-Gy increase]; p = 0.05). Compared with the low-dose group, there was evidence of a decreased risk of BcF for the high-dose group (RR, 0.60; p = 0.04), but no difference for the moderate-dose group (RR, 0.85; p = 0.41). Conclusions: Our results suggest a dose response for salvage EBRT. Doses higher than 66.6 Gy result in decreased risk of BcF.

  3. Estradiol valerate and alcohol intake: dose-response assessments

    PubMed Central

    Quirarte, Gina L; Reid, Larry D; de la Teja, I Sofía Ledesma; Reid, Meta L; Sánchez, Marco A; Díaz-Trujillo, Arnulfo; Aguilar-Vazquez, Azucena; Prado-Alcalá, Roberto A

    2007-01-01

    Background An injection of estradiol valerate (EV) provides estradiol for a prolonged period. Recent research indicates that a single 2.0 mg injection of EV modifies a female rat's appetite for alcoholic beverages. This research extends the initial research by assessing 8 doses of EV (from .001 to 2.0 mg/female rat), as well assessing the effects of 2.0 mg EV in females with ovariectomies. Results With the administration of EV, there was a dose-related loss of bodyweight reaching the maximum loss, when it occurred, at about 4 days after injections. Subsequently, rats returned to gaining weight regularly. Of the doses tested, only the 2.0 mg dose produced a consistent increase in intake of ethanol during the time previous research indicated that the rats would show enhanced intakes. There was, however, a dose-related trend for smaller doses to enhance intakes. Rats with ovariectomies showed a similar pattern of effects, to intact rats, with the 2 mg dose. After extensive histories of intake of alcohol, both placebo and EV-treated females had estradiol levels below the average measured in females without a history of alcohol-intake. Conclusion The data support the conclusion that pharmacological doses of estradiol can produce enduring changes that are manifest as an enhanced appetite for alcoholic beverages. The effect can occur among females without ovaries. PMID:17335585

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

    PubMed Central

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

    2016-01-01

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

  5. Forecasting Cell Death Dose-Response from Early Signal Transduction Responses In Vitro

    PubMed Central

    Vrana, Julie A.; Currie, Holly N.; Han, Alice A.; Boyd, Jonathan

    2014-01-01

    The rapid pharmacodynamic response of cells to toxic xenobiotics is primarily coordinated by signal transduction networks, which follow a simple framework: the phosphorylation/dephosphorylation cycle mediated by kinases and phosphatases. However, the time course from initial pharmacodynamic response(s) to cell death following exposure can have a vast range. Viewing this time lag between early signaling events and the ultimate cellular response as an opportunity, we hypothesize that monitoring the phosphorylation of proteins related to cell death and survival pathways at key, early time points may be used to forecast a cell's eventual fate, provided that we can measure and accurately interpret the protein responses. In this paper, we focused on a three-phased approach to forecast cell death after exposure: (1) determine time points relevant to important signaling events (protein phosphorylation) by using estimations of adenosine triphosphate production to reflect the relationship between mitochondrial-driven energy metabolism and kinase response, (2) experimentally determine phosphorylation values for proteins related to cell death and/or survival pathways at these significant time points, and (3) use cluster analysis to predict the dose-response relationship between cellular exposure to a xenobiotic and plasma membrane degradation at 24 h post-exposure. To test this approach, we exposed HepG2 cells to two disparate treatments: a GSK-3β inhibitor and a MEK inhibitor. After using our three-phased approach, we were able to accurately forecast the 24 h HepG2 plasma membrane degradation dose-response from protein phosphorylation values as early as 20 min post-MEK inhibitor exposure and 40 min post-GSK-3β exposure. PMID:24824809

  6. Forecasting cell death dose-response from early signal transduction responses in vitro.

    PubMed

    Vrana, Julie A; Currie, Holly N; Han, Alice A; Boyd, Jonathan

    2014-08-01

    The rapid pharmacodynamic response of cells to toxic xenobiotics is primarily coordinated by signal transduction networks, which follow a simple framework: the phosphorylation/dephosphorylation cycle mediated by kinases and phosphatases. However, the time course from initial pharmacodynamic response(s) to cell death following exposure can have a vast range. Viewing this time lag between early signaling events and the ultimate cellular response as an opportunity, we hypothesize that monitoring the phosphorylation of proteins related to cell death and survival pathways at key, early time points may be used to forecast a cell's eventual fate, provided that we can measure and accurately interpret the protein responses. In this paper, we focused on a three-phased approach to forecast cell death after exposure: (1) determine time points relevant to important signaling events (protein phosphorylation) by using estimations of adenosine triphosphate production to reflect the relationship between mitochondrial-driven energy metabolism and kinase response, (2) experimentally determine phosphorylation values for proteins related to cell death and/or survival pathways at these significant time points, and (3) use cluster analysis to predict the dose-response relationship between cellular exposure to a xenobiotic and plasma membrane degradation at 24 h post-exposure. To test this approach, we exposed HepG2 cells to two disparate treatments: a GSK-3β inhibitor and a MEK inhibitor. After using our three-phased approach, we were able to accurately forecast the 24 h HepG2 plasma membrane degradation dose-response from protein phosphorylation values as early as 20 min post-MEK inhibitor exposure and 40 min post-GSK-3β exposure.

  7. MODELING STREAM-AQUIFIER INTERACTIONS WITH LINEAR RESPONSE FUNCTIONS

    EPA Science Inventory

    The problem of stream-aquifer interactions is pertinent to conjunctive-use management of water resources and riparian zone hydrology. Closed form solutions are derived for stream-aquifer interactions in rates and volumes expressed as convolution integrals of impulse response and ...

  8. Item Response Theory Using Hierarchical Generalized Linear Models

    ERIC Educational Resources Information Center

    Ravand, Hamdollah

    2015-01-01

    Multilevel models (MLMs) are flexible in that they can be employed to obtain item and person parameters, test for differential item functioning (DIF) and capture both local item and person dependence. Papers on the MLM analysis of item response data have focused mostly on theoretical issues where applications have been add-ons to simulation…

  9. Total Dose Effects on Single Event Transients in Digital CMOS and Linear Bipolar Circuits

    NASA Technical Reports Server (NTRS)

    Buchner, S.; McMorrow, D.; Sibley, M.; Eaton, P.; Mavis, D.; Dusseau, L.; Roche, N. J-H.; Bernard, M.

    2009-01-01

    This presentation discusses the effects of ionizing radiation on single event transients (SETs) in circuits. The exposure of integrated circuits to ionizing radiation changes electrical parameters. The total ionizing dose effect is observed in both complementary metal-oxide-semiconductor (CMOS) and bipolar circuits. In bipolar circuits, transistors exhibit grain degradation, while in CMOS circuits, transistors exhibit threshold voltage shifts. Changes in electrical parameters can cause changes in single event upset(SEU)/SET rates. Depending on the effect, the rates may increase or decrease. Therefore, measures taken for SEU/SET mitigation might work at the beginning of a mission but not at the end following TID exposure. The effect of TID on SET rates should be considered if SETs cannot be tolerated.

  10. Efficient Algorithms for Estimating the Absorption Spectrum within Linear Response TDDFT

    SciTech Connect

    Brabec, Jiri; Lin, Lin; Shao, Meiyue; Govind, Niranjan; Yang, Chao; Saad, Yousef; Ng, Esmond

    2015-10-06

    We present two iterative algorithms for approximating the absorption spectrum of molecules within linear response of time-dependent density functional theory (TDDFT) framework. These methods do not attempt to compute eigenvalues or eigenvectors of the linear response matrix. They are designed to approximate the absorption spectrum as a function directly. They take advantage of the special structure of the linear response matrix. Neither method requires the linear response matrix to be constructed explicitly. They only require a procedure that performs the multiplication of the linear response matrix with a vector. These methods can also be easily modified to efficiently estimate the density of states (DOS) of the linear response matrix without computing the eigenvalues of this matrix. We show by computational experiments that the methods proposed in this paper can be much more efficient than methods that are based on the exact diagonalization of the linear response matrix. We show that they can also be more efficient than real-time TDDFT simulations. We compare the pros and cons of these methods in terms of their accuracy as well as their computational and storage cost.

  11. Cosolvent-free polymer gel dosimeters with improved dose sensitivity and resolution for x-ray CT dose response

    NASA Astrophysics Data System (ADS)

    Chain, J. N. M.; Jirasek, A.; Schreiner, L. J.; McAuley, K. B.

    2011-04-01

    This study reports new N-isopropylacrylamide (NIPAM) polymer gel recipes with increased dose sensitivity and improved dose resolution for x-ray CT readout. NIPAM can be used to increase the solubility of N, N'-methylenebisacrylamide (Bis) in aqueous solutions from approximately 3% to 5.5% by weight, enabling the manufacture of dosimeters containing up to 19.5%T, which is the total concentration of NIPAM and Bis by weight. Gelatin is shown to have a mild influence on dose sensitivity when gels are imaged using x-ray CT, and a stronger influence when gels are imaged optically. Phantoms that contain only 3% gelatin and 5 mM tetrakis hydroxymethyl phosphonium chloride are sufficiently stiff for dosimetry applications. The best cosolvent-free gel formulation has a dose sensitivity in the linear range (~0.88 H Gy-1) that is a small improvement compared to the best NIPAM-based gels that incorporate isopropanol as a cosolvent (~0.80 H Gy-1). This new gel formulation results in enhanced dose resolution (~0.052 Gy) for x-ray CT readout, making clinical applications of this imaging modality more feasible.

  12. Response verification of dose rate and time dependence of PAGAT polymer gel dosimeters by photon beams using magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Azadbakht, B.; Hadad, K.; Zahmatkesh, M. H.

    2009-05-01

    The purpose of this study was to evaluate dependence of PAGAT polymer gel dosimeter 1/T2 on different post time imaging as well as on different mean dose rates for a standard clinically used Co-60 therapy unit and an electa linear accelerator. Using MRI, the formulation to give the maximum change in the transverse relaxation rate R2(1/T2) was determined to be 4.5% N,N'-methylen-bis-acrylamide(bis), 4.5% acrylamid(AA), 5% gelatine, 5 mM tetrakis (hydroxymethyl) phosphonium chloride (THPC), 0.01 mM hydroquinone (HQ) and 86% HPLC(Water).When the preparation of final polymer gel solution is completed, it is transferred into phantoms and allowed to set by storage in a refrigerator at about 4°C. The sensitivity of the dosimeter was represented by the slope of calibration curve in the linear region measured for each modality. A calibration curve (in the linear region) based on 16 dosimeters (15 irradiated and one background) was obtained for 1.25 MV photon beam. To determine the calibration curve of the PAGAT polymer gel dosimeter, there are two linear responses between 2-10Gy and 10-30Gy and the R2-dose sensitivity showed stability with imaging post time after 38 days. Dose rate of dependence was studied in 6 MV photon beam with the use of dose rates 80, 160, 240, 320, 400 and 480 cGy/min. Evaluation of dosimeters were performed on Siemens Symphony, Germany 1.5T Scanner in the head coil. A multi echo sequence with 32 equidistant echoes was used for the evaluation of irradiated polymer gel dosimeters. The parameters of the sequence were as follows: TR 3000ms, TE 20ms, Slice Thickness 4 mm and FOV 256mm. No trend in polymer-gel dosimeter 1/T2 dependence was found on mean dose rate for photon beams.

  13. High-dose vitamin D supplements are not associated with linear growth in a large Finnish cohort.

    PubMed

    Hyppönen, Elina; Fararouei, Mohammad; Sovio, Ulla; Hartikainen, Anna-Liisa; Pouta, Anneli; Robertson, Claire; Whittaker, John C; Jarvelin, Marjo-Riitta

    2011-05-01

    High vitamin D intake in childhood has been suggested to have an adverse influence on linear growth. In Finland, in the mid-1960s the official recommendation for infant vitamin D supplementation was 2000 IU/d (50 μg/d). We investigated whether high-dose vitamin D supplementation in infancy was associated with subsequent growth in height. We used data from a prospective population-based birth cohort study including all children due to be born in the 2 northernmost provinces in Finland in 1966 (12,058 live-births, coverage 96%). Information on each participant's height was collected at birth and ages 1, 14, and 31 y, as were possible confounding factors (data for analyses available from 10,060 singletons). Information on the frequency and dose of vitamin D supplementation was collected in 1967 when participants were 1 y of age. A weak association was found between frequency of vitamin D supplementation with greater height at age 1 y (P = 0.005), which was explained by birth characteristics and maternal and social factors (adjusted P = 0.34). Neither frequency nor dose of vitamin D supplementation was associated with height at 14 or 31 y (P > 0.13). To conclude, contrary to proposed evidence suggesting that vitamin D has a negative influence on growth rate at a dosage of ~2000 IU/d, supplementation at this level in the Northern Finland Birth Cohort was not associated with reduced height at any age studied.

  14. [MEASUREMENT OF SPACE RADIATION DOSES AND LINEAR ENERGY TRANSFER SPECTRA INSIDE BIOLOGICAL SATELLITE BION-M1].

    PubMed

    Inozemtsev, K O; Kushin, V V; Tolochek, R V; Shurshakov, V A

    2015-01-01

    The paper presents the results of measuring biologically significant characteristics of space radiation (spectra of linear energy transfer (LET), absorbed and equivalent doses and averaged quality factors) inside the descend capsule of biosatellite Bion-M1 in space experiment Bioradiation. Measurements combined the use of thermoluminescent detectors DTG-4 (TDL) and solid state nuclear track detectors CR-39 (Tastrak) (SSNTD). Differential and integral LET spectra of high-LET space radiation were determined in 4 points inside spacecraft using passive detectors assembles (PDA). Total absorbed dose rates for PDA boxes No 1-4 made up 2.4 ± 0.2; 1.1 ± 0.1; 1.6 ± 0.2; 2.0 ± 0.1 mGy/d respectively, whereas total equivalent dose rates estimated based on ICRP Publication 60 recommendations made up 3.4 ± 0.2; 2.0 ± 0.1; 2.6 ± 0.2; 3.1 ± 0.1 mSv/d respectively. Values of the averaged quality factor for different PDSs were in the range between 1.4 and 1.8. PMID:26087582

  15. Dissolution and subsequent re-crystallization as zeroing mechanism, thermal properties and component resolved dose response of salt (NaCl) for retrospective dosimetry.

    PubMed

    Polymeris, George S; Kitis, George; Kiyak, Nafiye G; Sfamba, Ioanna; Subedi, Bhagawan; Pagonis, Vasilis

    2011-09-01

    In the present study we report dosimetric properties of iodized salt aiming at using it as an accidental luminescent dosimeter. It was found that the very good sensitivity of its main dosimetric peak is strongly affected by thermal treatments. This is also the case for OSL emission. The sensitivity loss due to heating implies that caution should be exercised while applying single aliquot protocols for dose evaluation. The sequence of dissolution and subsequent re-crystallization was established to be an extremely effective zeroing mechanism for the TL signal. The linearity in the dose response was also monitored in the case of dissolved and subsequently re-crystallized salt. In the case of naturally occurring salt, zeroing of the TL signal due to dissolution as well as the linearity of dose response up to doses as large as 100 Gy were found to be very promising features for dating applications.

  16. The linearity and selectivity of neuronal responses in awake visual cortex

    PubMed Central

    Chen, Yao; Anand, Sanjiv; Martinez-Conde, Susana; Macknik, Stephen L.; Bereshpolova, Yulia; Swadlow, Harvey A.; Alonso, Jose-Manuel

    2011-01-01

    Neurons in primary visual cortex (V1) are frequently classified based on their response linearity: the extent in which their visual responses to drifting gratings resemble a linear replica of the stimulus. This classification is supported by the finding that response linearity is bimodally distributed across neurons in area V1 of anesthetized animals. However, recent studies suggest that such bimodal distribution may not reflect two neuronal types but a nonlinear relationship between the membrane potential and the spike output. A main limitation of these previous studies is that they measured response linearity in anesthetized animals, where the distance between the neuronal membrane potential and spike threshold is artificially increased by anesthesia. Here, we measured V1 response linearity in the awake brain and its correlation with the neuronal spontaneous firing rate, which is related to the distance between membrane potential and threshold. Our results demonstrate that response linearity is bimodally distributed in awake V1 but that it is poorly correlated with spontaneous firing rate. In contrast, the spontaneous firing rate is best correlated to the response selectivity and response latency to stimuli. PMID:19761345

  17. Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X-rays with different levels of hardness.

    PubMed

    Kong, Eva Yi; Cheng, Shuk Han; Yu, Kwan Ngok

    2016-07-01

    The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead.

  18. Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X-rays with different levels of hardness

    PubMed Central

    Kong, Eva Yi; Cheng, Shuk Han; Yu, Kwan Ngok

    2016-01-01

    The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead. PMID:26951078

  19. A dose homogeneity and conformity evaluation between ViewRay and pinnacle-based linear accelerator IMRT treatment plans.

    PubMed

    Saenz, Daniel L; Paliwal, Bhudatt R; Bayouth, John E

    2014-04-01

    ViewRay, a novel technology providing soft-tissue imaging during radiotherapy is investigated for treatment planning capabilities assessing treatment plan dose homogeneity and conformity compared with linear accelerator plans. ViewRay offers both adaptive radiotherapy and image guidance. The combination of cobalt-60 (Co-60) with 0.35 Tesla magnetic resonance imaging (MRI) allows for magnetic resonance (MR)-guided intensity-modulated radiation therapy (IMRT) delivery with multiple beams. This study investigated head and neck, lung, and prostate treatment plans to understand what is possible on ViewRay to narrow focus toward sites with optimal dosimetry. The goal is not to provide a rigorous assessment of planning capabilities, but rather a first order demonstration of ViewRay planning abilities. Images, structure sets, points, and dose from treatment plans created in Pinnacle for patients in our clinic were imported into ViewRay. The same objectives were used to assess plan quality and all critical structures were treated as similarly as possible. Homogeneity index (HI), conformity index (CI), and volume receiving <20% of prescription dose (DRx) were calculated to assess the plans. The 95% confidence intervals were recorded for all measurements and presented with the associated bars in graphs. The homogeneity index (D5/D95) had a 1-5% inhomogeneity increase for head and neck, 3-8% for lung, and 4-16% for prostate. CI revealed a modest conformity increase for lung. The volume receiving 20% of the prescription dose increased 2-8% for head and neck and up to 4% for lung and prostate. Overall, for head and neck Co-60 ViewRay treatments planned with its Monte Carlo treatment planning software were comparable with 6 MV plans computed with convolution superposition algorithm on Pinnacle treatment planning system. PMID:24872603

  20. A dose homogeneity and conformity evaluation between ViewRay and pinnacle-based linear accelerator IMRT treatment plans.

    PubMed

    Saenz, Daniel L; Paliwal, Bhudatt R; Bayouth, John E

    2014-04-01

    ViewRay, a novel technology providing soft-tissue imaging during radiotherapy is investigated for treatment planning capabilities assessing treatment plan dose homogeneity and conformity compared with linear accelerator plans. ViewRay offers both adaptive radiotherapy and image guidance. The combination of cobalt-60 (Co-60) with 0.35 Tesla magnetic resonance imaging (MRI) allows for magnetic resonance (MR)-guided intensity-modulated radiation therapy (IMRT) delivery with multiple beams. This study investigated head and neck, lung, and prostate treatment plans to understand what is possible on ViewRay to narrow focus toward sites with optimal dosimetry. The goal is not to provide a rigorous assessment of planning capabilities, but rather a first order demonstration of ViewRay planning abilities. Images, structure sets, points, and dose from treatment plans created in Pinnacle for patients in our clinic were imported into ViewRay. The same objectives were used to assess plan quality and all critical structures were treated as similarly as possible. Homogeneity index (HI), conformity index (CI), and volume receiving <20% of prescription dose (DRx) were calculated to assess the plans. The 95% confidence intervals were recorded for all measurements and presented with the associated bars in graphs. The homogeneity index (D5/D95) had a 1-5% inhomogeneity increase for head and neck, 3-8% for lung, and 4-16% for prostate. CI revealed a modest conformity increase for lung. The volume receiving 20% of the prescription dose increased 2-8% for head and neck and up to 4% for lung and prostate. Overall, for head and neck Co-60 ViewRay treatments planned with its Monte Carlo treatment planning software were comparable with 6 MV plans computed with convolution superposition algorithm on Pinnacle treatment planning system.

  1. BY HOW MUCH DO SHAPES OF TOXICOLOGICAL DOSE-RESPONSE RELATIONSHIPS VARY? (SOT)

    EPA Science Inventory

    A re-analysis of a large number of historical dose-response data for continuous endpoints showed that the shapes of the dose-response relationships were surprisingly homogenous. The datasets were selected on the sole criterion that they were expected to provide relatively good in...

  2. Molecular dissection of the roles of the SOD genes in mammalian response to low dose irradiation

    SciTech Connect

    Li, Chuan-Yaun

    2009-01-27

    “Molecular dissection of the roles of the SOD genes in mammalian response to low dose irradiation " was started on 09/01/03 and ended on 08/31/07. The primary objective of the project was to carry out mechanistic studies of the roles of the anti-oxidant SOD genes in mammalian cellular response to low dose ionizing radiation.

  3. NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

    EPA Science Inventory

    Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
    S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

    Dose-response estimation is a critical feature of risk assessment. It can be...

  4. Estimation of dose-response models for discrete and continuous data in weed science

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dose-response analysis is widely used in biological sciences and has application to a variety of risk assessment, bioassay, and calibration problems. In weed science, dose-response methodologies have typically relied on least squares estimation under an assumption of normality. Advances in computati...

  5. USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

    EPA Science Inventory

    Use of Mechanistic Data to Help Define Dose-Response Curves

    The cancer risk assessment process described by the U.S. EPA necessitates a description of the dose-response curve for tumors in humans at low (environmental) exposures. This description can either be a default l...

  6. Statistical strategies for averaging EC50 from multiple dose-response experiments.

    PubMed

    Jiang, Xiaoqi; Kopp-Schneider, Annette

    2015-11-01

    In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

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

    EPA Science Inventory

    Endocrine Active Substances and Dose-Response for Individuals and Populations
    Hugh A. Barton

    Abstract for IUPAC-SCOPE article

    Dose-response characteristics for endocrine disruption have been major focuses in efforts to understand potential impacts on human and ec...

  8. LARGE SCALE CARCINOGEN DOSE RESPONSE STUDIES WITH JAPANESE MEDAKA (ORYZIAS LATIPES)

    EPA Science Inventory

    To investigate the responses to low carcinogen doses in animal models, large sample sizes are needed and it is an advantage if the model has a low spontaneous tumor rate. Three large scale dose response studies were conducted using Japanese medaka and the carcinogen diethylnitros...

  9. Dose-response and risk assessment of airborne hexavalent chromium and lung cancer mortality.

    PubMed

    Crump, Casey; Crump, Kenny; Hack, Eric; Luippold, Rose; Mundt, Kenneth; Liebig, Elizabeth; Panko, Julie; Paustenbach, Dennis; Proctor, Deborah

    2003-12-01

    This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).

  10. A Linear Variable-[theta] Model for Measuring Individual Differences in Response Precision

    ERIC Educational Resources Information Center

    Ferrando, Pere J.

    2011-01-01

    Models for measuring individual response precision have been proposed for binary and graded responses. However, more continuous formats are quite common in personality measurement and are usually analyzed with the linear factor analysis model. This study extends the general Gaussian person-fluctuation model to the continuous-response case and…

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

    PubMed

    Urbain, Paul; Jakobsen, Jette

    2015-09-23

    The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P < 0.0001), which is equivalent to 17.6 μg (704 IU) vitamin D2 per 100 g of fresh mushrooms and comparable to levels found in fatty fish like the Atlantic salmon.

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

    PubMed

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

    2015-11-01

    To derive O3 dose-response relationships (DRR) for five European forest trees species and broadleaf deciduous and needleleaf tree plant functional types (PFTs), phytotoxic O3 doses (PODy) were related to biomass reductions. PODy was calculated using a stomatal flux model with a range of cut-off thresholds (y) indicative of varying detoxification capacities. Linear regression analysis showed that DRR for PFT and individual tree species differed in their robustness. A simplified parameterisation of the flux model was tested and showed that for most non-Mediterranean tree species, this simplified model led to similarly robust DRR as compared to a species- and climate region-specific parameterisation. Experimentally induced soil water stress was not found to substantially reduce PODy, mainly due to the short duration of soil water stress periods. This study validates the stomatal O3 flux concept and represents a step forward in predicting O3 damage to forests in a spatially and temporally varying climate. PMID:26164201

  13. Linear Ordinary Differential Equations with Constant Coefficients. Revisiting the Impulsive Response Method Using Factorization

    ERIC Educational Resources Information Center

    Camporesi, Roberto

    2011-01-01

    We present an approach to the impulsive response method for solving linear constant-coefficient ordinary differential equations based on the factorization of the differential operator. The approach is elementary, we only assume a basic knowledge of calculus and linear algebra. In particular, we avoid the use of distribution theory, as well as of…

  14. Adiabatic Hamiltonian deformation, linear response theory, and nonequilibrium molecular dynamics

    SciTech Connect

    Hoover, W.G.

    1980-05-28

    Although Hamiltonians of various kinds have previously been used to derive Green-Kubo relations for the transport coefficients, the particular choice described is uniquely related to thermodynamics. This nonequilibrium Hamiltonian formulation of fluid flow provides pedagogically simple routes to nonequilibrium fluxes and distribution functions, to theoretical understanding of long-time effects, and to new numerical methods for simulating systems far from equilibrium. The same methods are now being applied to solid-phase problems. At the relatively high frequencies used in the viscous fluid calculations described, solids typically behave elastically. Lower frequencies lead to the formation of dislocations and other defects, making it possible to study plastic flow. A property of the nonequilibrium equations of motion which might be profitably explored is their effective irreversibility. Because only a few particles are necessary to generate irreversible behavior, simulations using adiabatic deformations of the kind described here could perhaps elucidate the instability in the equations of motion responsible for irreversibility.

  15. [Modeling and simulation of responses from ultrasonic linear phased array].

    PubMed

    He, Wenjing; Zhu, Yuanzhong; Wang, Yufeng; He, Lingli; Lai, Siyu

    2012-10-01

    Phased array transducers are very attractive because the beam generated by the arrays can be electronically focused and steered. The present work characterizes far-field 2D properties of phased array system by functions that are deduced from rectangle source, rectangle line array and phased array based on point source. Results are presented for the distribution of ultrasound intensity on plane xoz and on x-axis by simulation using numerical calculation. It is shown that the shape of response of rectangle line array is modulated by the single array element. It is also demonstrated that the delay time of phased array is the key to steer the beam, sacrificing the value of main lobe and increasing the number of side lobes.

  16. Linear response to a heat-driven spin torque

    NASA Astrophysics Data System (ADS)

    Fitoussi, Lucas; Vetro, Francesco Antonio; Caspers, Christian; Gravier, Laurent; Yu, Haiming; Ansermet, Jean-Philippe

    2015-04-01

    The existence of a heat-driven spin torque is demonstrated using Co/Cu/Co spin valves embedded in metallic nanowires. Heat currents flowing in one direction or its opposite were obtained by heating optically one end or the other of the nanowires. The spin torque associated with the heat-driven spin current pushes the magnetization out of equilibrium, resulting in a change of the magnetoresistance, which is detected using a charge current small enough not to cause heating or induced fields of any significance. The giant magnetoresistance response to this torque peaks with the magnetic susceptibility, whereas the spurious signal coming from the temperature dependence of the resistance produces merely a field independent baseline.

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

    SciTech Connect

    Schwartz, J.; Landrigan, P.J.; Baker, E.L. Jr.; Orenstein, W.A.; von Lindern, I.H. )

    1990-02-01

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

  18. Oxidative Stress and Skeletal Health with Low-Dose, Low-LET (Linear Energy Transfer) Ionizing Radiation

    SciTech Connect

    Globus, Ruth K.

    2014-11-03

    month after irradiation (IR). At four months post-IR, these animals were comparable to sham-treated controls with regards to the abovementioned structural parameters. Irradation at 1 or 10 cGy did not result in any significant changes in bone structural parameters. (3) Irradiation of 16-wk old male mice with high doses of 56Fe or proton (50 or 200cGy), but not at low doses (5 or 10cGy), showed a similar loss of cancellous BV/TV and trabecular number at five weeks post-IR. (4) Age-related bone loss overtook acute radiation-induced decrements in bone structure within four months post-IR with 100 cGy gamma and 12 months post-IR with 200 cGy iron. Transgenic mice globally overexpressing human catalase gene in mitochondria did not exhibit cancellous bone loss as assessed at four month post-IR with 10 cGy proton, 50 cGy iron, or in combination. (5) The cellular and molecular mechanisms responsible for loss of bone with radiation are mediated primarily through increased osteoclastogenesis. Our data provide evidence that there are increases in gene expression of TNF alpha and MCP1 in the bone marrow cells 24 hours post-IR and of osteoclastogenic differentiation factor RANKL by day 3. These cytokines in the marrow may stimulate mature osteoclasts or drive osteoclastogenesis from precursors. (6) Osteoblastogenesis from marrow progenitors evaluated ex vivo decreased following whole body 56Fe irradiation at a dose threshold between 20 and 50 cGy whereas osteoclastogenesis ex vivo increased with doses as low as 10cGy two days post-IR of mice. However, the latter finding was not observed in more than a single experiment. (7) Gamma irradiation of cells in vitro requires relatively high doses (200cGy) to disturb normal osteoblastogenesis and osteoclastogenesis as evidenced by decrements in mineralized nodule formation, osteoclast counts, and expression of osteoblast related genes such as runx2, col1a1. (8) We also investigated the effect of antioxidants on osteoblastogenesis following

  19. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    SciTech Connect

    Mossman, K.L.

    1983-08-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated with /sup 60/Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response.

  20. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy

    SciTech Connect

    Mossman, K.L.

    1983-08-01

    A quantitative dose-response curve for salivary gland function in patients during radiotherapy is presented. Salivary-function data used in this study were obtained from four previously published reports. All patients were treated wih /sup 60/Co teletherapy to the head and neck using conventional treatment techniques. Salivary dysfunction was determined at specific dose levels by comparing salivary flow rates before therapy with flow rates at specific dose intervals during radiotherapy up to a total dose of 6000 cGy. Fifty percent salivary dysfunction occurred after 1000 cGy and eighty percent dysfunction was observed by the end of the therapy course (6000 cGy). The salivary-function curve was also compared to the previously published dose-response curve for taste function. Comparisons of the two curves indicate that salivary dysfunction precedes taste loss and that the shapes of the dose-response curves are different. A new term, tissue tolerance ratio, defined as the ratio of responses of two tissues given the same radiation dose, was used to make the comparisons between gustatory and salivary gland tissue effects. Measurements of salivary gland function and analysis of dose-response curves may be useful in evaluating chemical modifiers of radiation response.

  1. Normal Liver Tissue Density Dose Response in Patients Treated With Stereotactic Body Radiation Therapy for Liver Metastases

    SciTech Connect

    Howells, Christopher C.; Stinauer, Michelle A.; Diot, Quentin; Westerly, David C.; Schefter, Tracey E.; Kavanagh, Brian D.; Miften, Moyed

    2012-11-01

    Purpose: To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT). Methods and Materials: Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change ({Delta}HU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue. Results: Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, -0.65 {Delta}HU/5 Gy). The threshold for significant change (-7 {Delta}HU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated. Conclusions: SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

  2. Linear and nonlinear piezoelectric response of charged cellular polypropylene

    NASA Astrophysics Data System (ADS)

    Kressmann, Reiner

    2001-10-01

    Piezoelectricity in a charged cellular polypropylene, called EMFi, is investigated with respect to nonlinearities to explain the strong differences in longitudinal piezoelectric constants published in the literature and ranging from 90 to 250 pC/N. The inverse constant was measured interferometrically to be 90 pm/V. Quasistatic and dynamic measurements with small loads yielded the same value for the direct constant. The direct constant was also investigated with respect to large-signal behavior becoming noticeable at static and dynamic loads higher than 10 kPa. Both the quasistatic and the dynamic constant increase up to 130 pC/N at such loads. Furthermore, an additional resonance appears under strong loading in the range of about 10 Hz shifting down with increasing load. In addition, the piezoelectric constant increases also with increasing dynamic load under constant static load. The nonlinearity also results in the generation of harmonics. Finally, boundary effects can be detected if just a small area of the sample is loaded. This effect appearing mainly at frequencies below 20 Hz is attributed to airflow between the air bubbles. A load-dependent Young's modulus, mainly responsible for the nonlinear behavior, is calculated from the experiments. It diminishes from 2 to 1.5 MPa at a load of 60 kPa.

  3. Dose response of elastase-induced emphysema in hamsters.

    PubMed

    Raub, J A; Mercer, R R; Miller, F J; Graham, J A; O'Neil, J J

    1982-04-01

    Elastase-induced emphysema in hamsters was studied using pulmonary function tests in an effort to develop techniques for determining the effects of air pollutants on the progression of this disease. Single intratracheal injections of 6, 12, or 24 units of porcine pancreatic elastase produced dose-related changes in pulmonary function after 4 wk when compared with sham-injected control animals. Boyle's law end-expiratory volume and residual volume, measured by gas dilution, increased (p less than 0.05) at 12 and 24 units, respectively, whereas vital capacity, determined plethysmographically, and total lung capacity wee increased (p less than 0.05) at all 3 elastase doses. Respiratory system compliance, calculated by a nonlinear least squares regression fit of the deflation pressure-volume curve, increased (p less than 0.05) at 24 units only. The multiple-breath nitrogen washout slope (N2 slope) and the single-breath diffusing capacity for carbon monoxide (DLCO) decreased (p less than 0.05) at all 3 doses of elastase. Both histologic and physiologic evaluation showed dose-related pulmonary impairment. It appears, therefore, that as little as 6 units of elastase produces mild emphysema in hamsters, which is detectable by pulmonary function testing. Of these tests, the DLCO and N2 slope were the most effective in detecting the degree of impairment. PMID:6918202

  4. Linear and nonlinear light scattering and absorption in free-electron nanoclusters with diffuse surface: General considerations and linear response

    SciTech Connect

    Fomichev, S. V.; Becker, W.

    2010-06-15

    Both linear and nonlinear scattering and absorption of a laser pulse by spherical nanoclusters with free electrons and with a diffuse surface are considered in the collisionless hydrodynamics approximation. The developed model of forced collective motion of electrons confined to a cluster permits one consistently to introduce into the theory all the sources of nonlinearity, as well as the inhomogeneity of the cluster near its boundary. Two different perturbation theories corresponding to different laser intensity ranges are developed in this context, and both cold metal clusters and hot laser-heated or -ionized clusters are considered within the same approach. In the present article, after developing the full nonlinear model, the linear response to the laser field of the free-electron cluster with diffuse surface is investigated in detail, especially the properties of the linear Mie resonance (width and position). Under certain conditions, depending on the various cluster parameters secondary resonances are found. The properties of resonance-enhanced third-order harmonic generation and nonlinear laser absorption and their dependence on the shape of the diffuse surface will be presented separately.

  5. Linear ordinary differential equations with constant coefficients. Revisiting the impulsive response method using factorization

    NASA Astrophysics Data System (ADS)

    Camporesi, Roberto

    2011-06-01

    We present an approach to the impulsive response method for solving linear constant-coefficient ordinary differential equations based on the factorization of the differential operator. The approach is elementary, we only assume a basic knowledge of calculus and linear algebra. In particular, we avoid the use of distribution theory, as well as of the other more advanced approaches: Laplace transform, linear systems, the general theory of linear equations with variable coefficients and the variation of constants method. The approach presented here can be used in a first course on differential equations for science and engineering majors.

  6. ACB-PCR MEASUREMENT OF K-RAS CODON 12 MUTATION IN A/J MOUSE LUNG EXPOSED TO BENZO[A]PYRENE: A DOSE-RESPONSE ASSESSMENT

    EPA Science Inventory

    Benzo[a]pyrene (B[a]P) is a known human carcinogen and environmental contaminant. The direct measurement of K-Ras mutant fraction (MF) was developed as a metric with which to examine the default assumption of low dose linearity in the mutational response to B...

  7. Physiological responses to linear treadmill and cycle ergometer exercise in COPD.

    PubMed

    Hsia, D; Casaburi, R; Pradhan, A; Torres, E; Porszasz, J

    2009-09-01

    Incremental cardiopulmonary exercise testing work rate ideally increases linearly to the subject's tolerance within approximately 10 min. Widely used treadmill protocols often yield shorter exercise times in debilitated patients. We compared a recently described treadmill protocol featuring linear work rate increase, weight adjustments and a priori exercise tolerance estimates with standard cycle and treadmill protocols. We also compared treadmill and cycle responses to examine mechanisms of oxyhaemoglobin desaturation differences. In total, 16 subjects with chronic obstructive pulmonary disease (COPD; mean+/-sd forced expiratory volume in 1 s of 36.5+/-10.9% predicted) performed incremental exercise using cycle, linear treadmill and modified Bruce protocols. Initial linear treadmill speed and grade yielded oxygen uptake (V'(O(2))) similar to cycle unloaded pedalling; Bruce protocol first stage elicited much higher V'(O(2)). Exercise duration was much shorter in Bruce than in cycle or linear treadmill protocols. At peak exercise, greater desaturation was noted in linear treadmill and Bruce protocols compared with cycle (-8.9+/-4.9 versus -8.5+/-4.7 versus -3.7+/-3.3%; p<0.001); at iso-V'(O(2)) values this difference widened as exercise proceeded. Iso-V'(O(2)) desaturation differences were largely related to higher ventilatory response to cycle than to treadmill exercise. The linear incremental treadmill protocol generates responses similar to cycle ergometry in severe COPD. However, cycle ergometry elicits less desaturation than does ambulation, making the linear treadmill protocol advantageous when evaluating COPD patients.

  8. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies.

    PubMed

    Yang, Wan-Shui; Deng, Qin; Fan, Wen-Yan; Wang, Wei-Ye; Wang, Xin

    2014-07-01

    Evidence from observational studies on light at night (LAN) exposure, sleep duration, endogenous melatonin levels, and risk for breast cancer in women is conflicting. This led us to conduct a dose-response analysis of published observational data. Pertinent studies were identified by searching Medline, Web of Science, and EMBASE through April 2013. The dose-response relationship between sleep duration, urinary 6-sulphatoxymelatonin levels, and breast cancer was assessed using the restricted cubic spline model and by multivariate random-effects metaregression. A separate meta-analysis was also carried out to calculate the relative risks (RRs) with 95% confidence intervals (CIs) for breast cancer for the comparable categories or highest levels of exposure versus the lowest levels. Twelve case-control and four cohort studies were included in the analysis. High artificial LAN exposure is associated with an increased risk for breast cancer (RR=1.17, 95% CI: 1.11-1.23), but not ambient LAN exposure (RR=0.91, 95% CI: 0.78-1.07). The summary RR for breast cancer is 1.00 (95% CI: 0.995-1.01) for an increment of 1 h of sleep per night. No significant dose-response relationship between sleep duration and breast cancer was found either for the linearity test (Ptrend=0.725) or for the nonlinearity (Ptrend=0.091) test. An increasein of 15 ng/mg creatinine in urinary 6-sulphatoxymelatonin is associated with a 14% reduced risk for breast cancer (RR=0.86, 95% CI: 0.78-0.95), with a linear dose-response trend (Ptrend=0.003). There was no evidence of substantial heterogeneity or publication bias in the analysis. Our study adds to the evidence of LAN breast cancer theory. Further research in this area is warranted.

  9. Light exposure at night, sleep duration, melatonin, and breast cancer: a dose-response analysis of observational studies.

    PubMed

    Yang, Wan-Shui; Deng, Qin; Fan, Wen-Yan; Wang, Wei-Ye; Wang, Xin

    2014-07-01

    Evidence from observational studies on light at night (LAN) exposure, sleep duration, endogenous melatonin levels, and risk for breast cancer in women is conflicting. This led us to conduct a dose-response analysis of published observational data. Pertinent studies were identified by searching Medline, Web of Science, and EMBASE through April 2013. The dose-response relationship between sleep duration, urinary 6-sulphatoxymelatonin levels, and breast cancer was assessed using the restricted cubic spline model and by multivariate random-effects metaregression. A separate meta-analysis was also carried out to calculate the relative risks (RRs) with 95% confidence intervals (CIs) for breast cancer for the comparable categories or highest levels of exposure versus the lowest levels. Twelve case-control and four cohort studies were included in the analysis. High artificial LAN exposure is associated with an increased risk for breast cancer (RR=1.17, 95% CI: 1.11-1.23), but not ambient LAN exposure (RR=0.91, 95% CI: 0.78-1.07). The summary RR for breast cancer is 1.00 (95% CI: 0.995-1.01) for an increment of 1 h of sleep per night. No significant dose-response relationship between sleep duration and breast cancer was found either for the linearity test (Ptrend=0.725) or for the nonlinearity (Ptrend=0.091) test. An increasein of 15 ng/mg creatinine in urinary 6-sulphatoxymelatonin is associated with a 14% reduced risk for breast cancer (RR=0.86, 95% CI: 0.78-0.95), with a linear dose-response trend (Ptrend=0.003). There was no evidence of substantial heterogeneity or publication bias in the analysis. Our study adds to the evidence of LAN breast cancer theory. Further research in this area is warranted. PMID:24858716

  10. Dose-dependent hepatic transcriptional responses in Atlantic salmon (Salmo salar) exposed to sublethal doses of gamma radiation.

    PubMed

    Song, You; Salbu, Brit; Teien, Hans-Christian; Heier, Lene Sørlie; Rosseland, Bjørn Olav; Tollefsen, Knut Erik

    2014-11-01

    Due to the production of free radicals, gamma radiation may pose a hazard to living organisms. The high-dose radiation effects have been extensively studied, whereas the ecotoxicity data on low-dose gamma radiation is still limited. The present study was therefore performed using Atlantic salmon (Salmo salar) to characterize effects of low-dose (15, 70 and 280 mGy) gamma radiation after short-term (48h) exposure. Global transcriptional changes were studied using a combination of high-density oligonucleotide microarrays and quantitative real-time reverse transcription polymerase chain reaction (qPCR). Differentially expressed genes (DEGs; in this article the phrase gene expression is taken as a synonym of gene transcription, although it is acknowledged that gene expression can also be regulated, e.g., at protein stability and translational level) were determined and linked to their biological meanings predicted using both Gene Ontology (GO) and mammalian ortholog-based functional analyses. The plasma glucose level was also measured as a general stress biomarker at the organism level. Results from the microarray analysis revealed a dose-dependent pattern of global transcriptional responses, with 222, 495 and 909 DEGs regulated by 15, 70 and 280 mGy gamma radiation, respectively. Among these DEGs, only 34 were commonly regulated by all radiation doses, whereas the majority of differences were dose-specific. No GO functions were identified at low or medium doses, but repression of DEGs associated with GO functions such as DNA replication, cell cycle regulation and response to reactive oxygen species (ROS) were observed after 280mGy gamma exposure. Ortholog-based toxicity pathway analysis further showed that 15mGy radiation affected DEGs associated with cellular signaling and immune response; 70mGy radiation affected cell cycle regulation and DNA damage repair, cellular energy production; and 280mGy radiation affected pathways related to cell cycle regulation and DNA

  11. Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies.

    PubMed

    Melia, Umberto; Vallverdú, Montserrat; Borrat, Xavier; Valencia, Jose Fernando; Jospin, Mathieu; Jensen, Erik Weber; Gambus, Pedro; Caminal, Pere

    2015-01-01

    The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands.

  12. Prediction of Nociceptive Responses during Sedation by Linear and Non-Linear Measures of EEG Signals in High Frequencies

    PubMed Central

    Melia, Umberto; Vallverdú, Montserrat; Borrat, Xavier; Valencia, Jose Fernando; Jospin, Mathieu; Jensen, Erik Weber; Gambus, Pedro; Caminal, Pere

    2015-01-01

    The level of sedation in patients undergoing medical procedures evolves continuously, affected by the interaction between the effect of the anesthetic and analgesic agents and the pain stimuli. The monitors of depth of anesthesia, based on the analysis of the electroencephalogram (EEG), have been progressively introduced into the daily practice to provide additional information about the state of the patient. However, the quantification of analgesia still remains an open problem. The purpose of this work is to improve the prediction of nociceptive responses with linear and non-linear measures calculated from EEG signal filtered in frequency bands higher than the traditional bands. Power spectral density and auto-mutual information function was applied in order to predict the presence or absence of the nociceptive responses to different stimuli during sedation in endoscopy procedure. The proposed measures exhibit better performances than the bispectral index (BIS). Values of prediction probability of Pk above 0.75 and percentages of sensitivity and specificity above 70% were achieved combining EEG measures from the traditional frequency bands and higher frequency bands. PMID:25901571

  13. Influence of high doses γ-irradiation on oxygen permeability of linear low-density polyethylene and cast polypropylene films

    NASA Astrophysics Data System (ADS)

    Klepac, Damir; Ščetar, Mario; Baranović, Goran; Galić, Kata; Valić, Srećko

    2014-04-01

    Linear low density polyethylene (PE-LLD) and cast polypropylene (PPcast) films were irradiated in a 60Co γ-source. The total irradiation dose varied from 0 kGy (unirradiated samples) to 200 kGy. Oxygen transport was investigated by a manometric method and the structural changes were studied by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Free radicals decay as a function of time was monitored by electron spin resonance (ESR) spectroscopy. The results show that the γ-irradiation reduces oxygen permeability coefficient in both films. The reduction was associated with an increase in crystallinity. DSC thermograms revealed a decrease in PPcast melting point with increasing irradiation dose, indicating higher degradation compared to PE-LLD. The observed peak in FTIR spectra for both samples at 1716 cm-1 corresponds to the stretching of the carbonyl and carboxylic groups which arise from the reaction of oxygen with the free radicals produced in the polymer matrix as a result of irradiation.

  14. Responses of astrocytes in culture after low dose laser irradiation

    SciTech Connect

    Yew, D.T.; Zheng, D.R.; Au, C.; Li, W.W. )

    1990-03-01

    The effect of Helium-Neon low dose laser on astrocytes was investigated in cultures of isolated astrocytes from albino neonatal rats. The laser appeared to inhibit the growth of astrocytes as exemplified by the smaller sizes of the cells and the decreased leucine uptake in each cell after treatment. Temporary decrease in the number of mitoses was also observed, but this trend was reversed soon after. Electron microscopic studies revealed an increase in buddings from cell bodies and processes (branches) after irradiation.

  15. Ligand-Induced Protein Responses and Mechanical Signal Propagation Described by Linear Response Theories

    PubMed Central

    Yang, Lee-Wei; Kitao, Akio; Huang, Bang-Chieh; Gō, Nobuhiro

    2014-01-01

    In this study, a general linear response theory (LRT) is formulated to describe time-dependent and -independent protein conformational changes upon CO binding with myoglobin. Using the theory, we are able to monitor protein relaxation in two stages. The slower relaxation is found to occur from 4.4 to 81.2 picoseconds and the time constants characterized for a couple of aromatic residues agree with those observed by UV Resonance Raman (UVRR) spectrometry and time resolved x-ray crystallography. The faster “early responses”, triggered as early as 400 femtoseconds, can be best described by the theory when impulse forces are used. The newly formulated theory describes the mechanical propagation following ligand-binding as a function of time, space and types of the perturbation forces. The “disseminators”, defined as the residues that propagate signals throughout the molecule the fastest among all the residues in protein when perturbed, are found evolutionarily conserved and the mutations of which have been shown to largely change the CO rebinding kinetics in myoglobin. PMID:25229149

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

    SciTech Connect

    Calabrese, Edward J. . E-mail: edwardc@schoolph.umass.edu; Blain, Robyn

    2005-02-01

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

  17. Comparison of particulate matter dose and acute heart rate variability response in cyclists, pedestrians, bus and train passengers.

    PubMed

    Nyhan, Marguerite; McNabola, Aonghus; Misstear, Bruce

    2014-01-15

    Exposure to airborne particulate matter (PM) has been linked to cardiovascular morbidity and mortality. Heart rate variability (HRV) is a measure of the change in cardiac autonomic function, and consistent links between PM exposure and decreased HRV have been documented in studies. This study quantitatively assesses the acute relative variation of HRV with predicted PM dose in the lungs of commuters. Personal PM exposure, HR and HRV were monitored in 32 young healthy cyclists, pedestrians, bus and train passengers. Inhaled and lung deposited PM doses were determined using a numerical model of the human respiratory tract which accounted for varying ventilation rates between subjects and during commutes. Linear mixed models were used to examine air pollution dose and HRV response relationships in 122 commutes sampled. Elevated PM2.5 and PM10 inhaled and lung deposited doses were significantly (p<0.05) associated with decreased HRV indices. Percent declines in SDNN (standard deviation of normal RR intervals) relative to resting, due to an inter-quartile range increase in PM10 lung deposited dose were stronger in cyclists (-6.4%, 95% CI: -11.7, -1.3) and pedestrians (-5.8%, 95% CI: -11.3, -0.5), in comparison to bus (-3.2%, 95% CI: -6.4, -0.1) and train (-1.8%, -7.5, 3.8) passengers. A similar trend was observed in the case of PM2.5 lung deposited dose and results for rMSSD (the square root of the squared differences of successive normal RR intervals) followed similar trends to SDNN. Inhaled and lung deposited doses accounting for varying ventilation rates between modes, individuals and during commutes have been neglected in other studies relating PM to HRV. The findings here indicate that exercise whilst commuting has an influence on inhaled PM and PM lung deposited dose, and these were significantly associated with acute declines in HRV, especially in pedestrians and cyclists.

  18. Explicit solvent simulations of the aqueous oxidation potential and reorganization energy for neutral molecules: gas phase, linear solvent response, and non-linear response contributions.

    PubMed

    Guerard, Jennifer J; Tentscher, Peter R; Seijo, Marianne; Samuel Arey, J

    2015-06-14

    First principles simulations were used to predict aqueous one-electron oxidation potentials (Eox) and associated half-cell reorganization energies (λaq) for aniline, phenol, methoxybenzene, imidazole, and dimethylsulfide. We employed quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations of the oxidized and reduced species in an explicit aqueous solvent, followed by EOM-IP-CCSD computations with effective fragment potentials for diabatic energy gaps of solvated clusters, and finally thermodynamic integration of the non-linear solvent response contribution using classical MD. A priori predicted Eox and λaq values exhibit mean absolute errors of 0.17 V and 0.06 eV, respectively, compared to experiment. We also disaggregate Eox into several well-defined free energy properties, including the gas phase adiabatic free energy of ionization (7.73 to 8.82 eV), the solvent-induced shift in the free energy of ionization due to linear solvent response (-2.01 to -2.73 eV), and the contribution from non-linear solvent response (-0.07 to -0.14 eV). The linear solvent response component is further apportioned into contributions from the solvent-induced shift in vertical ionization energy of the reduced species (ΔVIEaq) and the solvent-induced shift in negative vertical electron affinity of the ionized species (ΔNVEAaq). The simulated ΔVIEaq and ΔNVEAaq are found to contribute the principal sources of uncertainty in computational estimates of Eox and λaq. Trends in the magnitudes of disaggregated solvation properties are found to correlate with trends in structural and electronic features of the solute. Finally, conflicting approaches for evaluating the aqueous reorganization energy are contrasted and discussed, and concluding recommendations are given.

  19. The Maturing of Hormesis as a Credible Dose-Response Model

    PubMed Central

    Calabrese, Edward J.

    2003-01-01

    Hormesis is a dose-response phenomenon that has received little recognition, credibility and acceptance as evidenced by its absence from major toxicological/risk assessment texts, governmental regulatory dose-response modeling for risk assessment, and non-visibility in major professional toxicological society national meetings. This paper traces the historical evolution of the hormetic dose-response hypothesis, why this model is not only credible but also more common than the widely accepted threshold model in direct comparative evaluation, and how the toxicological community made a critical error in rejecting hormesis, a rejection sustained over 70 years. PMID:19330138

  20. Quantitative radiation dose-response relationships for normal tissues in man - I. Gustatory tissues response during photon and neutron radiotherapy

    SciTech Connect

    Mossman, K.L.

    1982-08-01

    Quantitative radiation dose-response curves for normal gustatory tissue in man were studied. Taste function, expressed as taste loss, was evaluated in 84 patients who were given either photon or neutron radiotherapy for tumors in the head and neck region. Patients were treated to average tumor doses of 6600 cGy (photon) or 2200 cGy intervals for photon patients and 320-cGy intervals for neutron patients during radiotherapy. The dose-response curves for photons and neutrons were analyzed by fitting a four-parameter logistic equation to the data. Photon and neutron curves differed principally in their relative position along the dose axis. Comparison of the dose-response curves were made by determination of RBE. At 320 cGy, the lowest neutron dose at which taste measurements were made, RBE = 5.7. If this RBE is correct, then the therapeutic gain factor may be equal to or less than 1, indicating no biological advantage in using neutrons over photons for this normal tissue. These studies suggest measurements of taste function and evaluation of dose-response relationships may also be useful in quantitatively evaluating the efficacy of chemical modifiers of radiation response such as hypoxic cell radiosensitizers and radioprotectors.

  1. Dose Response of MARV/Angola Infection in Cynomolgus Macaques following IM or Aerosol Exposure

    PubMed Central

    Johnston, Sara C.; Lin, Kenny L.; Twenhafel, Nancy A.; Raymond, Jo Lynne W.; Shamblin, Joshua D.; Wollen, Suzanne E.; Wlazlowski, Carly B.; Wilkinson, Eric R.; Botto, Miriam A.; Goff, Arthur J.

    2015-01-01

    Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies. PMID:26413900

  2. A resource conservative procedure for comparison of dose-response relationships

    USGS Publications Warehouse

    Link, W.A.; Hill, E.F.; Hines, J.E.; Henry, P.F.P.

    1996-01-01

    The evaluation of effects of toxicants on a wildlife community can be complicated by varying responses among the community's constituent populations. Even within populations, considerable variability in dose-response relations may result from different avenues of exposure to the toxicant. Full scale investigations of the dose-response relations among a variety of species and avenues of exposure can therefore be prohibitively expensive, whether this expense is measured by the number of experimental animals needed, by the human resources committed to the study, or by laboratory expenses. We propose an abbreviated protocol for investigations of multiple dose-response relations that is designed to limit these expenses. The protocol begins with the judicious choice of a baseline dose-response relation to be estimated by a full scale study involving a minimum of 5 doses levels, with 10 subjects per dose level. This relation is then used as the basis for rapid screening of subsequent dose-response relations, which are compared to the baseline relation by testing for differences in the median effective dosages. These secondary studies can consist of as few as 14 animals exposed to the estimated LC50 from the baseline study. We describe MS-DOS compatible software available from the authors which can be used to analyze these data.

  3. No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

    SciTech Connect

    Sheehan, Daniel M. . E-mail: dansheeh@swbell.net

    2006-01-15

    We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated on a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.

  4. Dose response of benzo(a)pyrene-induced mutagenesis using the BigBlue{reg_sign} transgenic mouse assay

    SciTech Connect

    Kotturi, G.; Holcroft, J.; Boer, J. de

    1997-10-01

    To investigate the dose response of benzo(a)pyrene-induced mutagenesis, groups of five BigBlue{reg_sign} transgenic mice were injected with a single intra-peritoneal dose were injected with corn oil containing benzo(a)pyrene to achieve the following concentrations: 0, 62.5, 125, 250, 500 mg/kg. Tissues were harvested after a 14 day expression time and analysed for mutational events. DNA adducts were measured in the liver of mice that were sacrificed 1 day after injection. The mutant frequency in the mouse liver linearly increased from 5.2 to 53.5 x 10{sup -5} in a dose-specific manner from 0 to 500 mg/kg benzo(a)pyrene. Mutants were sequenced to give an estimate of the number of clonal events as a function of benzo(a) pyrene with a total of 20 exposed animals (4 doses and five animals/dose), we established frequently mutated sites or `mutational hotspots` as well as a full mutational spectrum. Various other factors associated with the BigBlue{reg_sign} assay were analysed such as the effect of plating density on the purity of mutant plaques during the phage purification step.

  5. NMR nuclear magnetic shielding anisotropy of linear molecules within the linear response within the elimination of the small component approach.

    PubMed

    Ruiz de Azúa, MartínC; Giribet, Claudia G; Melo, Juan I

    2011-01-21

    The influence of the spin-Zeeman (SZ) operator in the evaluation of the spin-orbit effect on the nuclear magnetic shielding tensor in the context of the linear response within the elimination of the small component approach is critically discussed. It is shown that such term yields no contribution to the isotropic nuclear magnetic shielding constant, but it may be of great importance in the determination of individual tensor components, and particularly of the tensor anisotropy. In particular, an interesting relation between the SZ and orbital Zeeman contributions to the spin-orbit effect for the case of linear molecules is shown to hold. Numerical examples for the BrH, IH, and XeF(2) molecules are presented which show that, provided the SZ term is taken into account, results of the individual shielding tensor components and the tensor anisotropy are in good agreement with those obtained by other theoretical methods, and particularly by the Dirac-Hartree-Fock approach.

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

    EPA Science Inventory

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

  7. Dose-Response Issues Concerning the Relations between Regular Physical Activity and Health.

    ERIC Educational Resources Information Center

    Rankinen, Tuomo; Bouchard, Claude

    2002-01-01

    This paper categorizes the many benefits of physical activity, offering information concerning the type of dose necessary to get that benefit. In 2000, Health Canada and the United States Centers for Disease Control and Prevention, along with other agencies, sponsored a symposium to determine whether there was a dose-response relationship between…

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

    ERIC Educational Resources Information Center

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

    2012-01-01

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

  9. RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R828035)

    EPA Science Inventory

    Three dose¯response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID50) using a simple cumulative perce...

  10. BUMP: a FORTRAN program for identifying dose-response curves subject to downturns.

    PubMed

    Simpson, D G; Dallal, G E

    1989-02-01

    BUMP is a FORTRAN implementation of a modified Jonckheere-Terpstra test, proposed by Simpson and Margolin, to test nonparametrically for a dose-response curve when a downturn is possible at high doses. The Jonckheere-Terpstra statistic is commonly used to test for increasing or decreasing trends in dose-response relationships. In many experimental settings, however, a test agent has more than one effect, and a "bump"-shaped dose-response can occur. For instance, increasing the concentration of a certain nutrient on a petri dish may increase the growth rate at low doses yet decrease the growth rate at high doses because of toxicity. The modified test allows one to assess the significance of the initial increase in the dose-response curve and yet to minimize the effect on the conclusions of any downturn at higher doses. A complete system which operates directly on SYSTAT/MYSTAT files is available for the IBM-PC and compatibles; it includes a utility which converts ASCII data files to the SYSTAT/MYSTAT format. The FORTRAN 77 source code is available for those who would like to run BUMP on other machines.

  11. Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors

    EPA Science Inventory

    Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC ...

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

    NASA Technical Reports Server (NTRS)

    Chappell, Lori J.; Cucinotta, Francis A.

    2010-01-01

    There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies.

  13. Effect of daily linear acceleration training on the hypergravity-induced vomiting response in house musk shrew (Suncus murinus).

    PubMed

    Abe, Chikara; Iwata, Chihiro; Shiina, Takahiko; Shimizu, Yasutake; Morita, Hironobu

    2011-09-20

    The effects of repeated linear acceleration training and the antimotion sickness drug, promethazine, on hypergravity-induced motion sickness were examined in musk shrew (Suncus murinus), which is known to show a vomiting response to motion stimulation. Animals were assigned into five groups: vestibular intact, untreated animals (Sham), vestibular lesioned (VL) animals, vestibular intact animals with promethazine hydrochloride administered as daily drinking water (Prom), vestibular intact animals who underwent horizontal linear accelerator motion training (Train), and vestibular intact animals treated with both promethazine hydrochloride and linear acceleration training (Prom+Train). In Sham animals, the number of vomiting episodes was 14±2 during 2 G exposure for 10min, and was accompanied by intense Fos expression in the medial vestibular nucleus (MVe), the nucleus of the solitary tract (NTS), the area postrema (AP), and the paraventricular hypothalamic nucleus (PVN). The vomiting response and Fos expression were completely abolished in VL animals, indicating that these responses are mediated via the vestibular system. Although Train and Prom animals experienced a significantly reduced number of hypergravity-induced vomiting episodes compared with Sham animals, the effect was significantly greater in Train animals than in Prom animals. Fos expression in the NTS, AP, and PVN were significantly more reduced in Train animals than in Prom animals. Higher dose of bolus injection of promethazine (50mg/kg, i.p.) completely abolished the vomiting episodes, although the animals were drowsy and sedated due to side effects. In conclusion, daily linear acceleration training and promethazine could prevent the hypergravity-induced vomiting episodes.

  14. Disentangling linear and nonlinear brain responses to evoked deep tissue pain.

    PubMed

    Loggia, Marco L; Edwards, Robert R; Kim, Jieun; Vangel, Mark G; Wasan, Ajay D; Gollub, Randy L; Harris, Richard E; Park, Kyungmo; Napadow, Vitaly

    2012-10-01

    Pain stimuli evoke widespread responses in the brain. However, our understanding of the physiological significance underlying heterogeneous response within different pain-activated and -deactivated regions is still limited. Using functional magnetic resonance imaging, we evaluated brain responses to a wide range of stimulus intensity levels (1 innocuous, 7 painful) in order to estimate region-specific stimulus-response functions, which we hypothesized could illuminate that region's functional relationship to pain. Linear and nonlinear brain responses to pain were estimated through independent Legendre polynomial transformations of pain ratings within a general linear model. This approach identified at least 5 different, regionally specific activity profiles in the brain. Linearly increasing (eg, primary somatosensory/motor cortex, insulae) and intensity-independent (eg, secondary somatosensory cortex) activation was noted in traditional pain-processing areas, potentially reflecting sensory encoding and all-or-none salience responses, respectively. Multiple activity profiles were seen in areas of the default mode network (DMN): intensity-independent deactivation (eg, posterior cingulate cortex), linearly decreasing (eg, contralateral inferior parietal lobule), and quadratic (U-shaped; eg, medial prefrontal cortex). The latter observation suggests that: (1) different DMN subregions exhibit functional heterogeneity and (2) some DMN subregions respond in a percept-related manner to pain, suggesting closer linkage between the DMN and pain processing than previously thought. Future studies should apply a similar approach using innocuous stimuli of multiple intensities to evaluate whether the response profiles reported here can also be generalized to nonpainful somatosensory processing.

  15. The spin polarized linear response from density functional theory: theory and application to atoms.

    PubMed

    Fias, Stijn; Boisdenghien, Zino; De Proft, Frank; Geerlings, Paul

    2014-11-14

    Within the context of spin polarized conceptual density functional theory, the spin polarized linear response functions are introduced both in the [N, N(s)] and [N(α), N(β)] representations. The mathematical relations between the spin polarized linear response functions in both representations are examined and an analytical expression for the spin polarized linear response functions in the [N(α), N(β)] representation is derived. The spin polarized linear response functions were calculated for all atoms up to and including argon. To simplify the plotting of our results, we integrated χ(r, r') to a quantity χ(r, r'), circumventing the θ and ϕ dependence. This allows us to plot and to investigate the periodicity throughout the first three rows in the periodic table within the two different representations. For the first time, χ(αβ)(r, r'), χ(βα)(r, r'), and χ(SS)(r, r') plots have been calculated and discussed. By integration of the spin polarized linear response functions, different components to the polarisability, α(αα), α(αβ), α(βα), and α(ββ) have been calculated. PMID:25399132

  16. The spin polarized linear response from density functional theory: Theory and application to atoms

    SciTech Connect

    Fias, Stijn Boisdenghien, Zino; De Proft, Frank; Geerlings, Paul

    2014-11-14

    Within the context of spin polarized conceptual density functional theory, the spin polarized linear response functions are introduced both in the [N, N{sub s}] and [N{sub α}, N{sub β}] representations. The mathematical relations between the spin polarized linear response functions in both representations are examined and an analytical expression for the spin polarized linear response functions in the [N{sub α}, N{sub β}] representation is derived. The spin polarized linear response functions were calculated for all atoms up to and including argon. To simplify the plotting of our results, we integrated χ(r, r′) to a quantity χ(r, r{sup ′}), circumventing the θ and ϕ dependence. This allows us to plot and to investigate the periodicity throughout the first three rows in the periodic table within the two different representations. For the first time, χ{sub αβ}(r, r{sup ′}), χ{sub βα}(r, r{sup ′}), and χ{sub SS}(r, r{sup ′}) plots have been calculated and discussed. By integration of the spin polarized linear response functions, different components to the polarisability, α{sub αα}, α{sub αβ}, α{sub βα}, and α{sub ββ} have been calculated.

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

    SciTech Connect

    Appelt, Ane L.; Ploen, John; Vogelius, Ivan R.; Bentzen, Soren M.; Jakobsen, Anders

    2013-01-01

    Purpose: Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. Methods and Materials: A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D{sub 50,i}, and the normalized dose-response gradient, {gamma}{sub 50,i}. Results: A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D{sub 50,TRG1} = 92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), {gamma}{sub 50,TRG1} = 0.982 (CI 0.533-1.429), and for major response (TRG1-2) D{sub 50,TRG1} and {sub 2} = 72.1 Gy (CI 65.3-94.0 Gy), {gamma}{sub 50,TRG1} and {sub 2} = 0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. Conclusions: This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.

  18. Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose-volume outcome relationships.

    PubMed

    El Naqa, I; Suneja, G; Lindsay, P E; Hope, A J; Alaly, J R; Vicic, M; Bradley, J D; Apte, A; Deasy, J O

    2006-11-21

    Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearman's rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

  19. The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events

    EPA Science Inventory

    The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Act...

  20. Mouse bioassay for palytoxin. Specific symptoms and dose-response against dose-death time relationships.

    PubMed

    Riobó, P; Paz, B; Franco, J M; Vázquez, J A; Murado, M A; Cacho, E

    2008-08-01

    Nowadays, a variety of protocols are applied to quantitate palytoxin. However, there is not desirable agreement among them, the confidence intervals of the basic toxicological parameters are too wide and the formal descriptions lack the necessary generality to establish comparisons. Currently, the mouse bioassay is the most accepted one to categorize marine toxins and it must constitute the reference for other methods. In the present work, the mouse bioassay for palytoxin is deeply analyzed and carefully described showing the initial symptoms of injected mice which are presented here in the first time. These symptoms clearly differ from the more common marine toxins described up to now. Regarding to the toxicological aspects two considerations are taking into account: (i) the empiric models based in the dose-death time relationships cause serious ambiguities and (ii) the traditional moving average method contains in its regular use any inaccuracy elements. Herein is demonstrated that the logistic equation and the accumulative function of Weibull's distribution (with the modifications proposed) generate satisfactory toxicological descriptions in all the respects.

  1. Linear-response calculation in the time-dependent density functional theory

    SciTech Connect

    Nakatsukasa, Takashi; Inakura, Tsunenori; Avogadro, Paolo; Ebata, Shuichiro; Sato, Koichi; Yabana, Kazuhiro

    2012-11-12

    Linear response calculations based on the time-dependent density-functional theory are presented. Especially, we report results of the finite amplitude method which we have recently proposed as an alternative and feasible approach to the (quasiparticle-)random-phase approximation. Calculated properties of the giant resonances and low-energy E1 modes are discussed. We found a universal linear correlation between the low-energy E1 strength and the neutron skin thickness.

  2. Predictive Bayesian microbial dose-response assessment based on suggested self-organization in primary illness response: Cryptosporidium parvum.

    PubMed

    Englehardt, James D; Swartout, Jeff

    2006-04-01

    The probability of illness caused by very low doses of pathogens cannot generally be tested due to the numbers of subjects that would be needed, though such assessments of illness dose response are needed to evaluate drinking water standards. A predictive Bayesian dose-response assessment method was proposed previously to assess the unconditional probability of illness from available information and avoid the inconsistencies of confidence-based approaches. However, the method uses knowledge of the conditional dose-response form, and this form is not well established for the illness endpoint. A conditional parametric dose-response function for gastroenteric illness is proposed here based on simple numerical models of self-organized host-pathogen systems and probabilistic arguments. In the models, illnesses terminate when the host evolves by processes of natural selection to a self-organized critical value of wellness. A generalized beta-Poisson illness dose-response form emerges for the population as a whole. Use of this form is demonstrated in a predictive Bayesian dose-response assessment for cryptosporidiosis. Results suggest that a maximum allowable dose of 5.0 x 10(-7) oocysts/exposure (e.g., 2.5 x 10(-7) oocysts/L water) would correspond with the original goals of the U.S. Environmental Protection Agency Surface Water Treatment Rule, considering only primary illnesses resulting from Poisson-distributed pathogen counts. This estimate should be revised to account for non-Poisson distributions of Cryptosporidium parvum in drinking water and total response, considering secondary illness propagation in the population. PMID:16573639

  3. Toward a unified approach to dose-response modeling in ecotoxicology.

    PubMed

    Ritz, Christian

    2010-01-01

    This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

  4. Characterizing dose-responses of catalase to nitrofurazone exposure in model ciliated protozoan Euplotes vannus for ecotoxicity assessment: enzyme activity and mRNA expression.

    PubMed

    Li, Jiqiu; Zhou, Liang; Lin, Xiaofeng; Yi, Zhenzhen; Al-Rasheid, Khaled A S

    2014-02-01

    In environmental studies, some biological responses, known as biomarkers, have been used as a powerful bioassay tool for more than four decades. Disparity between enzyme activity and mRNA abundance leads to correlation equivocality, which makes the application of biomarkers for environmental risk assessment more complicated. This study investigates this disparity in the case of catalase when used as a biomarker for detecting ecotoxicity induced by antibiotics in aquatic ecosystems. In particular, dose-responses for catalase activity and mRNA expression abundance were investigated in Euplotes vannus which were exposed to graded doses of nitrofurazone for several discrete durations, and dose-response models were developed to characterize the dose-response dynamics. Significant differences were found in both catalase activity and mRNA expression abundance among the E. vannus treated with nitrofurazone. Catalase activity showed a hormetic-like effect in terms of dose-response, characterized by a biphasic relationship which was more clearly evident after a longer exposure period, while mRNA expression abundance increased linearly with the exposure duration. Additionally, the correlation between catalase activity and mRNA expression abundance reversed along with the duration of exposure to nitrofurazone. Taken together, our results demonstrate that catalase mRNA expression offers a more straightforward dose-response model than enzyme activity. Our findings suggest that both catalase enzyme activity and mRNA expression abundance can be used jointly as bioassay tools for detecting ecotoxicity induced by nitrofurazone in aquatic ecosystems.

  5. 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

  6. Joint detection of important biomarkers and optimal dose-response model using penalties.

    PubMed

    Vandenhende, F; Eilers, P; Ledent, E; Renard, D; Tibaldi, F

    2007-11-30

    We propose a method to jointly detect influential biomarkers and estimate how they change with dose. The assessment is made in dose-ranging trials collecting multiple outcomes for efficacy, safety, pharmacokinetics or pharmacodynamics. We regress all these outcomes versus a non-parametric transformation of the dose. The regression coefficients and the parameters from the dose-response model are simultaneously estimated using a penalized alternating least-squares method. We illustrate the technique with a phase I clinical trial and a metabonomic experiment in rats. PMID:17579922

  7. Linear response theory for symmetry improved two particle irreducible effective actions

    NASA Astrophysics Data System (ADS)

    Brown, Michael J.; Whittingham, Ian B.; Kosov, Daniel S.

    2016-05-01

    We investigate the linear response of an O (N ) scalar quantum field theory subject to external perturbations using the symmetry-improved two-particle irreducible effective action (SI-2PIEA) formalism [A. Pilaftsis and D. Teresi, Nucl. Phys. B874, 594 (2013)]. Despite satisfactory equilibrium behavior, we find a number of unphysical effects at the linear response level. Goldstone boson field fluctuations are overdetermined, with the only consistent solution being to set the fluctuations and their driving sources to zero, except for momentum modes where the Higgs and Goldstone self-energies obey a particular relationship. Also Higgs field fluctuations propagate masslessly, despite the Higgs propagator having the correct mass. These pathologies are independent of any truncation of the effective action and still exist even if we relax the overdetermining Ward identities, so long as the constraint is formulated O (N ) covariantly. We discuss possible reasons for the apparent incompatibility of the constraints and linear response approximation and possible ways forward.

  8. Quasi-Linear Cochlear Responses to Noise Can Result from Instantaneous Nonlinearities

    NASA Astrophysics Data System (ADS)

    Liu, Yi-Wen; Neely, Stephen T.

    2011-11-01

    Responses to acoustic stimuli in the cochlea are known to be nonlinear. Many existing models of cochlear mechanics were built upon three basic assumptions: traveling-wave amplification is provided by active mechanisms in the outer hair cells (OHCs). Second, as the stimulus level increases, the gain decreases due to saturation nonlinearity in the OHCs. Finally, the saturation non-linearity is "instantaneous"; its input-output relation does not possess memory. These assumptions were recently challenged by reports that basilar-membrane (BM) responses to noise can be predicted well by level-dependent Wiener filters and are thus quasi-linear. It was argued that the quasi-linear responses could not result from instantaneous nonlinearity. In this paper, we present a model of cochlear mechanics which has instantaneous OHC saturation nonlinearity but produces quasi-linear responses to noise. Correlation coefficients were consistently greater than 0.9 between simulated noise responses and the responses predicted by equivalent Wiener filters. Further, Gaussianity in the acoustic stimuli was preserved on the BM. We conclude that the results support the common understandings and assumptions of cochlear mechanics.

  9. DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES TO PENICILLIUM CHRYSOGENUM

    EPA Science Inventory

    ABSTRACT
    Indoor mold has been associated with development of allergic asthma. Penicillium chrysogenum, a common indoor mold, is known to have several allergens and its viable conidia can induce allergic responses in a mouse model of allergic penicilliosis. The hypothesis o...

  10. Radiation-Induced Bystander Effects: Evidence for an Adaptive Response to Low Dose Exposures?

    PubMed Central

    Mothersill, Carmel; Seymour, Colin

    2006-01-01

    This paper reviews our current knowledge of the mechanisms underlying the induction of bystander effects by low dose, low-LET ionizing radiation and discusses how they may be related to observed adaptive responses or other protective effects of low dose exposures. Bystander effects appear to be the result of a generalized stress response in tissues or cells. The signals may be produced by all exposed cells, but the response appears to require a quorum in order to be expressed. The major response involving low LET radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but is p53 independent. While a death response might appear to be adverse, the position is argued in this paper that it is in fact protective and removes damaged cells from the population. Since many cell populations carry damaged cells without being exposed to radiation, so called “background damage”, it is possible that low doses exposures cause removal of cells damaged by agents other than the test dose of radiation. This mechanism would lead to the production of “U-shaped” dose response curves. In this scenario, the level of “adaptive” or beneficial response will be related to the background damage carried by the cell population. This model may be important when attempting to predict the consequences of mixed exposures involving radiation and other environmental stressors. PMID:18648593

  11. The energy dependence and dose response of a commercial optically stimulated luminescent detector for kilovoltage photon, megavoltage photon, and electron, proton, and carbon beams

    SciTech Connect

    Reft, Chester S.

    2009-05-15

    Optically stimulated luminescent detectors, which are widely used in radiation protection, offer a number of potential advantages for application in radiation therapy dosimetry. Their introduction into this field has been somewhat hampered by the lack of information on their radiation response in megavoltage beams. Here the response of a commercially available optically stimulated luminescent detector (OSLD) is determined as a function of energy, absorbed dose to water, and linear energy transfer (LET). The detector response was measured as a function of energy for absorbed doses from 0.5 to 4.0 Gy over the following ranges: 125 kVp to18 MV for photons, 6-20 MeV for electrons, 50-250 MeV for protons, and 290 MeV/u for the carbon ions. For the low LET beams, the response of the detector was linear up to 2 Gy with supralinearity occurring at higher absorbed doses. For the kilovoltage photons, the detector response relative to 6 MV increased with decreasing energy due to the higher atomic number of aluminum oxide (11.2) relative to water (7.4). For the megavoltage photons and electrons, the response was independent of energy. The response for protons was also independent of energy, but it was about 6% higher than its response to 6 MV photons. For the carbon ions, the dose response was linear for a given LET from 0.5 to 4.0 Gy, and no supralinearity was observed. However, it did exhibit LET dependence on the response relative to 6 MV photons decreasing from 1.02 at 1.3 keV/{mu}m to 0.41 at 78 keV/{mu}m. These results provide additional information on the dosimetric properties for this particular OSL detector and also demonstrate the potential for their use in photon, electron, and proton radiotherapy dosimetry with a more limited use in high LET radiotherapy dosimetry.

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

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

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

  13. Beyond the Death of Linear Response: 1/f Optimal Information Transport

    NASA Astrophysics Data System (ADS)

    Aquino, Gerardo; Bologna, Mauro; Grigolini, Paolo; West, Bruce J.

    2010-07-01

    Nonergodic renewal processes have recently been shown by several authors to be insensitive to periodic perturbations, thereby apparently sanctioning the death of linear response, a building block of nonequilibrium statistical physics. We show that it is possible to go beyond the “death of linear response” and establish a permanent correlation between an external stimulus and the response of a complex network generating nonergodic renewal processes, by taking as stimulus a similar nonergodic process. The ideal condition of 1/f noise corresponds to a singularity that is expected to be relevant in several experimental conditions.

  14. Application of linear response theory to magnetotransport properties of dense plasmas.

    PubMed

    Adams, J R; Reinholz, H; Redmer, R

    2010-03-01

    Linear response theory, as developed within the Zubarev formalism, is a quantum statistical approach for describing systems out of but close to equilibrium, which has been successfully applied to a wide variety of plasmas in an external electric field and/or containing a temperature gradient. We present here an extension of linear response theory to include the effects of an external magnetic field. General expressions for the complete set of relevant transport properties are given. In particular, the Hall effect and the influence of a magnetic field on the dc electrical conductivity are discussed. Low-density limits including electron-electron scattering are presented as well as results for arbitrary degeneracy.

  15. Application of linear response theory to magnetotransport properties of dense plasmas

    SciTech Connect

    Adams, J. R.; Redmer, R.; Reinholz, H.

    2010-03-15

    Linear response theory, as developed within the Zubarev formalism, is a quantum statistical approach for describing systems out of but close to equilibrium, which has been successfully applied to a wide variety of plasmas in an external electric field and/or containing a temperature gradient. We present here an extension of linear response theory to include the effects of an external magnetic field. General expressions for the complete set of relevant transport properties are given. In particular, the Hall effect and the influence of a magnetic field on the dc electrical conductivity are discussed. Low-density limits including electron-electron scattering are presented as well as results for arbitrary degeneracy.

  16. A dose-response study of triclosan mouthrinses on plaque regrowth.

    PubMed

    Jenkins, S; Addy, M; Newcombe, R J

    1993-09-01

    Triclosan is used in toothpastes and mouthrinses as a plaque inhibitory agent. The concentrations used and therefore the dose of triclosan varies between products and there is, as with most plaque inhibitory agents, little information on the dose response of this agent. The purpose of this investigation was to measure the plaque inhibitory properties of triclosan in a simple mouthrinse formulation over a range of concentrations and therefore doses. The study was a 5 treatment, double-blind, Latin-square randomised, minus-active controlled design balanced for residual effects. The formulations were 0.01%, 0.05%, 0.1% and 0.2% triclosan in 0.5% sodium carbonate and 5% alcohol aqueous solutions, used as 10 ml, 1-min rinses 2 x daily, without tooth-brushing. 2 groups each of 15 healthy volunteers rinsed during alternate 4-day treatment, 1-week washout periods with the allocated rinses. From a zero-plaque baseline on Day 1, plaque was scored by index and area on Day 5. A dose response pattern of decreasing plaque indices and particularly areas, with increasing triclosan dose was observed. However, by far the largest sequential drop in plaque scores occurred between 0.1% and 0.2% triclosan treatments. Extending the dose-response study to higher concentrations is considered impractical if not unjustifiable, because of potential harmful local side-effects and compliance difficulties. Dose-response studies to assess the agents thought to potentiate triclosan would seem warranted.

  17. Dose-response measurement in gel dosimeter using various imaging modalities

    NASA Astrophysics Data System (ADS)

    Fujibuchi, T.; Kawamura, H.; Yamanashi, K.; Hiroki, A.; Yamashita, S.; Taguchi, M.; Sato, Y.; Mimura, K.; Ushiba, H.; Okihara, T.

    2013-06-01

    Measurement methods that accurately measure radiation dose distribution in a three dimensional manner in order to allow comparisons of treatment plans are needed for quality assurance. One such measurement method involves the use of a polymer gel dosimeter to measure the dose distribution in three dimensions. During irradiation, a polymerization reaction makes new chemical bonds and induces changes of the chemical structure of the gel of the gel dosimeter. In the present study, dose-response measurement of an environment-friendly material used in the gel dosimeter was performed by imaging with computed tomography (CT) and R1, R2, and fluid-attenuated inversion-recovery (FLAIR) magnetic resonance imaging (MRI) under various imaging conditions. Dose-response characteristics in the gel dosimeter used in the experiment were observed at doses of 5-20 Gy administered by X-ray CT and MRI. Although the FLAIR signal was a relative value, the dose-response values with FLAIR were excellent compared to those with R1, R2, and CT. Determination of more appropriate imaging conditions could help expand the dose-response parameters of each measurement method.

  18. Bystander responses in low dose irradiated cells treated with plasma from gamma irradiated blood

    NASA Astrophysics Data System (ADS)

    Acheva, A.; Georgieva, R.; Rupova, I.; Boteva, R.; Lyng, F.

    2008-02-01

    There are two specific low-dose radiation-induced responses that have been the focus of radiobiologists' interest in recent years. These are the bystander effect in non-irradiated cells and the adaptive response to a challenge dose after prior low dose irradiation. In the present study we have investigated if plasma from irradiated blood can act as a 'challenge dose' on low dose irradiated reporter epithelial cells (HaCaT cell line). The main aim was to evaluate the overall effect of low dose irradiation (0.05 Gy) of reporter cells and the influence of bystander factors in plasma from 0.5 Gy gamma irradiated blood on these cells. The effects were estimated by clonogenic survival of the reporter cells. We also investigated the involvement of reactive oxygen species (ROS) as potential factors involved in the bystander signaling. Calcium fluxes and mitochondrial membrane potential (MMP) depolarization were also examined as a marker for initiation of apoptosis in the reporter cells. The results show that there are large individual differences in the production of bystander effects and adaptive responses between different donors. These may be due to the specific composition of the donor plasma. The observed effects generally could be divided into two groups: adaptive responses and additive effects. ROS appeared to be involved in the responses of the low dose pretreated reporter cells. In all cases there was a significant decrease in MMP which may be an early event in the apoptotic process. Calcium signaling also appeared to be involved in triggering apoptosis in the low dose pretreated reporter cells. The heterogeneity of the bystander responses makes them difficult to be modulated for medical uses. Specific plasma characteristics that cause these large differences in the responses would need to be identified to make them useful for radiotherapy.

  19. Meta-analysis of dioxin cancer dose response for three occupational cohorts.

    PubMed Central

    Crump, Kenny S; Canady, Richard; Kogevinas, Manolis

    2003-01-01

    This article presents a meta analysis of data from three cohorts occupationally exposed to TCDD and related compounds. A statistically significant (p = 0.02) trend was found in total cancer mortality with increasing dioxin exposure. The trend tests show an increase in total cancer at cumulative TEQ (unit of measurement for TCDD-like compounds that is defined as the amount of TCDD that would produce the same toxicity as a mixture of TCDD-like compounds) serum levels that would result from lifetime intake of 7 pg TEQ/kg body weight/day, with no increase at 6 pg/kg/day. A linear dose response provided a good fit to the combined data and predicted an ED(01) (dioxin exposure resulting in a 0.01 increase in lifetime risk of cancer mortality) of 45 pg/kg/day (95% confidence interval, 21-324). The U.S. Environmental Protection Agency estimates that current lifetime human exposures to dioxin average approximately 1 pg/kg/day (99% percentile: 3 pg/kg/day). Although it appears unlikely that current exposures through foods would reach either 7 pg/kg/day or the ED(01), our analysis argues for careful consideration of the upper ranges of long-term average exposures for dioxins. PMID:12727594

  20. Cognition-Enhancing Doses of Methylphenidate Preferentially Increase Prefrontal Cortical Neuronal Responsiveness

    PubMed Central

    Devilbiss, David M.; Berridge, Craig W.

    2008-01-01

    Background Despite widespread use of low-dose psychostimulants for the treatment of attention deficit hyperactivity disorder (ADHD), the neural basis for the therapeutic actions of these drugs are not well-understood. We recently demonstrated that low-dose methylphenidate (MPH) increases catecholamine efflux preferentially within the prefrontal cortex (PFC), suggesting the PFC is a principal site of action in the behavioral-calming and cognition-enhancing effects of low-dose psychostimulants. To better understand the neural mechanisms involved in the behavioral actions of low-dose stimulants, the current study examined the effects of low-dose MPH on the discharge properties of individual and ensembles of PFC neurons. Methods Extracellular activity of multiple individual PFC neurons was recorded in freely moving rats using multi-channel recording techniques. Behavioral studies identified optimal, working memory-enhancing doses of intraperitoneal MPH. The effects of these low-doses of MPH on PFC neuronal discharge properties were compared to: 1) the effects of high-dose MPH on PFC neuronal discharge; 2) the effects of low-dose MPH on neuronal discharge within the somatosensory cortex. Results Only working memory-enhancing doses of MPH increased the responsivity of individual PFC neurons and altered neuronal ensemble responses within the PFC. These effects were not observed outside the PFC (i.e. within somatosensory cortex). In contrast, high-dose MPH profoundly suppressed evoked discharge of PFC neurons. Conclusions These observations suggest that preferential enhancement of signal processing within the PFC, including alterations in the discharge properties of individual PFC neurons and PFC neuronal ensembles, underlie the behavioral/cognitive actions of low-dose psychostimulants. PMID:18585681

  1. Dose--response of initial G2-chromatid breaks induced in normal human fibroblasts by heavy ions

    NASA Technical Reports Server (NTRS)

    Kawata, T.; Durante, M.; Furusawa, Y.; George, K.; Takai, N.; Wu, H.; Cucinotta, F. A.; Dicello, J. F. (Principal Investigator)

    2001-01-01

    PURPOSE: To investigate initial chromatid breaks in prematurely condensed G2 chromosomes following exposure to heavy ions of different LET. MATERIAL AND METHODS: Exponentially growing human fibroblast cells AG1522 were irradiated with gamma-rays, energetic carbon (13 keV/ microm, 80 keV/microm), silicon (55 keV/microm) and iron (140 keV/microm, 185keV/microm, 440keV/microm) ions. Chromosomes were prematurely condensed using calyculin-A. Initial chromatid-type and isochromatid breaks in G2 cells were scored. RESULTS: The dose response curves for total chromatid breaks were linear regardless of radiation type. The relative biological effectiveness (RBE) showed a LET-dependent increase, peaking around 2.7 at 55-80keV/microm and decreasing at higher LET. The dose response curves for isochromatid-type breaks were linear for high-LET radiations, but linear-quadratic for gamma-rays and 13 keV/microm carbon ions. The RBE for the induction of isochromatid breaks obtained from linear components increased rapidly between 13keV/microm (about 7) and 80keV/microm carbon (about 71), and decreased gradually until 440 keV/microm iron ions (about 66). CONCLUSIONS: High-LET radiations are more effective at inducing isochromatid breaks, while low-LET radiations are more effective at inducing chromatid-type breaks. The densely ionizing track structures of heavy ions and the proximity of sister chromatids in G2 cells result in an increase in isochromatid breaks.

  2. Near-linear response of mean monsoon strength to a broad range of radiative forcings.

    PubMed

    Boos, William R; Storelvmo, Trude

    2016-02-01

    Theoretical models have been used to argue that seasonal mean monsoons will shift abruptly and discontinuously from wet to dry stable states as their radiative forcings pass a critical threshold, sometimes referred to as a "tipping point." Further support for a strongly nonlinear response of monsoons to radiative forcings is found in the seasonal onset of the South Asian summer monsoon, which is abrupt compared with the annual cycle of insolation. Here it is shown that the seasonal mean strength of monsoons instead exhibits a nearly linear dependence on a wide range of radiative forcings. First, a previous theory that predicted a discontinuous, threshold response is shown to omit a dominant stabilizing term in the equations of motion; a corrected theory predicts a continuous and nearly linear response of seasonal mean monsoon strength to forcings. A comprehensive global climate model is then used to show that the seasonal mean South Asian monsoon exhibits a near-linear dependence on a wide range of isolated greenhouse gas, aerosol, and surface albedo forcings. This model reproduces the observed abrupt seasonal onset of the South Asian monsoon but produces a near-linear response of the mean monsoon by changing the duration of the summer circulation and the latitude of that circulation's ascent branch. Thus, neither a physically correct theoretical model nor a comprehensive climate model support the idea that seasonal mean monsoons will undergo abrupt, nonlinear shifts in response to changes in greenhouse gas concentrations, aerosol emissions, or land surface albedo. PMID:26811462

  3. Dose and developmental responses of Anopheles merus larvae to salinity.

    PubMed

    White, Bradley J; Kundert, Peter N; Turissini, David A; Van Ekeris, Leslie; Linser, Paul J; Besansky, Nora J

    2013-09-15

    Saltwater tolerance is a trait that carries both ecological and epidemiological significance for Anopheles mosquitoes that transmit human malaria, as it plays a key role in determining their habitat use and ecological distribution, and thus their local contribution to malaria transmission. Here, we lay the groundwork for genetic dissection of this trait by quantifying saltwater tolerance in three closely related cryptic species and malaria vectors from the Afrotropical Anopheles gambiae complex that are known to differ starkly in their tolerance to salinity: the obligate freshwater species A. gambiae and A. coluzzii, and the saltwater-tolerant species A. merus. We performed detailed comparisons of survivorship under varying salinities, using multiple strains of A. gambiae, A. coluzzii and A. merus, as well as F1 progeny from reciprocal crosses of A. merus and A. coluzzii. Additionally, using immunohistochemistry, we compared the location of three ion regulatory proteins (Na(+)/K(+)-ATPase, carbonic anhydrase and Na(+)/H(+)-antiporter) in the recta of A. coluzzii and A. merus reared in freshwater or saline water. As expected, we found that A. merus survives exposure to high salinities better than A. gambiae and A. coluzzii. Further, we found that exposure to a salinity level of 15.85 g NaCl l(-1) is a discriminating dose that kills all A. gambiae, A. coluzzii and A. coluzzii-A. merus F1 larvae, but does not negatively impact the survival of A. merus. Importantly, phenotypic expression of saltwater tolerance by A. merus is highly dependent upon the developmental time of exposure, and based on immunohistochemistry, salt tolerance appears to involve a major shift in Na(+)/K+-ATPase localization in the rectum, as observed previously for the distantly related saline-tolerant species A. albimanus. PMID:23966587

  4. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans.

    PubMed

    Greer, Monte A; Goodman, Gay; Pleus, Richard C; Greer, Susan E

    2002-09-01

    Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect

  5. Health effects assessment for environmental perchlorate contamination: the dose response for inhibition of thyroidal radioiodine uptake in humans.

    PubMed Central

    Greer, Monte A; Goodman, Gay; Pleus, Richard C; Greer, Susan E

    2002-01-01

    Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect

  6. Dose-response investigation into glucose facilitation of memory performance and mood in healthy young adults.

    PubMed

    Sünram-Lea, Sandra I; Owen, Lauren; Finnegan, Yvonne; Hu, Henglong

    2011-08-01

    It has been suggested that the memory enhancing effect of glucose follows an inverted U-shaped curve, with 25 g resulting in optimal facilitation in healthy young adults. The aim of this study was to further investigate the dose dependency of the glucose facilitation effect in this population across different memory domains and to assess moderation by interindividual differences in glucose regulation and weight. Following a double-blind, repeated measures design, 30 participants were administered drinks containing five different doses of glucose (0 g, 15 g, 25 g, 50 g, and 60 g) and were tested across a range of memory tasks. Glycaemic response and changes in mood state were assessed following drink administration. Analysis of the data showed that glucose administration did not affect mood, but significant glucose facilitation of several memory tasks was observed. However, dose-response curves differed depending on the memory task with only performance on the long-term memory tasks adhering largely to the previously observed inverted U-shaped dose-response curve. Moderation of the response profiles by interindividual differences in glucose regulation and weight was observed. The current data suggest that dose-response function and optimal dose might depend on cognitive domain and are moderated by interindividual differences in glucose regulation and weight.

  7. A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer.

    PubMed

    Wang, F; Yeung, K L; Chan, W C; Kwok, C C H; Leung, S L; Wu, C; Chan, E Y Y; Yu, I T S; Yang, X R; Tse, L A

    2013-11-01

    This study aimed to conduct a systematic review to sum up evidence of the associations between different aspects of night shift work and female breast cancer using a dose-response meta-analysis approach. We systematicly searched all cohort and case-control studies published in English on MEDLINE, Embase, PSYCInfo, APC Journal Club and Global Health, from January 1971 to May 2013. We extracted effect measures (relative risk, RR; odd ratio, OR; or hazard ratio, HR) from individual studies to generate pooled results using meta-analysis approaches. A log-linear dose-response regression model was used to evaluate the relationship between various indicators of exposure to night shift work and breast cancer risk. Downs and Black scale was applied to assess the methodological quality of included studies. Ten studies were included in the meta-analysis. A pooled adjusted relative risk for the association between 'ever exposed to night shift work' and breast cancer was 1.19 [95% confidence interval (CI) 1.05-1.35]. Further meta-analyses on dose-response relationship showed that every 5-year increase of exposure to night shift work would correspondingly enhance the risk of breast cancer of the female by 3% (pooled RR = 1.03, 95% CI 1.01-1.05; Pheterogeneity < 0.001). Our meta-analysis also suggested that an increase in 500-night shifts would result in a 13% (RR = 1.13, 95% CI 1.07-1.21; Pheterogeneity = 0.06) increase in breast cancer risk. This systematic review updated the evidence that a positive dose-response relationship is likely to present for breast cancer with increasing years of employment and cumulative shifts involved in the work.

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

    PubMed

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

    2016-04-15

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

  9. Non-linear relationships between aflatoxin B₁ levels and the biological response of monkey kidney vero cells.

    PubMed

    Rasooly, Reuven; Hernlem, Bradley; He, Xiaohua; Friedman, Mendel

    2013-08-01

    Aflatoxin-producing fungi contaminate food and feed during pre-harvest, storage and processing periods. Once consumed, aflatoxins (AFs) accumulate in tissues, causing illnesses in animals and humans. Most human exposure to AF seems to be a result of consumption of contaminated plant and animal products. The policy of blending and dilution of grain containing higher levels of aflatoxins with uncontaminated grains for use in animal feed implicitly assumes that the deleterious effects of low levels of the toxins are linearly correlated to concentration. This assumption may not be justified, since it involves extrapolation of these nontoxic levels in feed, which are not of further concern. To develop a better understanding of the significance of low dose effects, in the present study, we developed quantitative methods for the detection of biologically active aflatoxin B₁ (AFB1) in Vero cells by two independent assays: the green fluorescent protein (GFP) assay, as a measure of protein synthesis by the cells, and the microculture tetrazolium (MTT) assay, as a measure of cell viability. The results demonstrate a non-linear dose-response relationship at the cellular level. AFB1 at low concentrations has an opposite biological effect to higher doses that inhibit protein synthesis. Additional studies showed that heat does not affect the stability of AFB1 in milk and that the Vero cell model can be used to determine the presence of bioactive AFB1 in spiked beef, lamb and turkey meat. The implication of the results for the cumulative effects of low amounts of AFB1 in numerous foods is discussed. PMID:23949006

  10. Non-Linear Relationships between Aflatoxin B1 Levels and the Biological Response of Monkey Kidney Vero Cells

    PubMed Central

    Rasooly, Reuven; Hernlem, Bradley; He, Xiaohua; Friedman, Mendel

    2013-01-01

    Aflatoxin-producing fungi contaminate food and feed during pre-harvest, storage and processing periods. Once consumed, aflatoxins (AFs) accumulate in tissues, causing illnesses in animals and humans. Most human exposure to AF seems to be a result of consumption of contaminated plant and animal products. The policy of blending and dilution of grain containing higher levels of aflatoxins with uncontaminated grains for use in animal feed implicitly assumes that the deleterious effects of low levels of the toxins are linearly correlated to concentration. This assumption may not be justified, since it involves extrapolation of these nontoxic levels in feed, which are not of further concern. To develop a better understanding of the significance of low dose effects, in the present study, we developed quantitative methods for the detection of biologically active aflatoxin B1 (AFB1) in Vero cells by two independent assays: the green fluorescent protein (GFP) assay, as a measure of protein synthesis by the cells, and the microculture tetrazolium (MTT) assay, as a measure of cell viability. The results demonstrate a non-linear dose-response relationship at the cellular level. AFB1 at low concentrations has an opposite biological effect to higher doses that inhibit protein synthesis. Additional studies showed that heat does not affect the stability of AFB1 in milk and that the Vero cell model can be used to determine the presence of bioactive AFB1 in spiked beef, lamb and turkey meat. The implication of the results for the cumulative effects of low amounts of AFB1 in numerous foods is discussed. PMID:23949006

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

    PubMed

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

    2012-11-01

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

  12. 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.

  13. Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

    SciTech Connect

    Hall, Matthew D.; Schultheiss, Timothy E.; Smith, David D.; Nguyen, Khanh H.; Wong, Jeffrey Y.C.

    2015-01-01

    Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the

  14. Flutter and Forced Response Analyses of Cascades using a Two-Dimensional Linearized Euler Solver

    NASA Technical Reports Server (NTRS)

    Reddy, T. S. R.; Srivastava, R.; Mehmed, O.

    1999-01-01

    Flutter and forced response analyses for a cascade of blades in subsonic and transonic flow is presented. The structural model for each blade is a typical section with bending and torsion degrees of freedom. The unsteady aerodynamic forces due to bending and torsion motions. and due to a vortical gust disturbance are obtained by solving unsteady linearized Euler equations. The unsteady linearized equations are obtained by linearizing the unsteady nonlinear equations about the steady flow. The predicted unsteady aerodynamic forces include the effect of steady aerodynamic loading due to airfoil shape, thickness and angle of attack. The aeroelastic equations are solved in the frequency domain by coupling the un- steady aerodynamic forces to the aeroelastic solver MISER. The present unsteady aerodynamic solver showed good correlation with published results for both flutter and forced response predictions. Further improvements are required to use the unsteady aerodynamic solver in a design cycle.

  15. VIBRA: An interactive computer program for steady-state vibration response analysis of linear damped structures

    NASA Technical Reports Server (NTRS)

    Bowman, L. M.

    1984-01-01

    An interactive steady state frequency response computer program with graphics is documented. Single or multiple forces may be applied to the structure using a modal superposition approach to calculate response. The method can be reapplied to linear, proportionally damped structures in which the damping may be viscous or structural. The theoretical approach and program organization are described. Example problems, user instructions, and a sample interactive session are given to demonstate the program's capability in solving a variety of problems.

  16. Dose-Response Evaluation of Braslet-M Occlusion Cuffs

    NASA Technical Reports Server (NTRS)

    Ebert, Douglas; Garcia, Kathleen; Sargsyan, Ashot E.; Ham, David; Hamilton, Douglas; Dulchavsky, Scott A.

    2010-01-01

    Introduction: Braslet-M is a set of special elasticized thigh cuffs used by the Russian space agency to reduce the effects of the head-ward fluid shift during early adaptation to microgravity by sequestering fluid in the lower extremities. Currently, no imaging modalities are used in the calibration of the device, and the pressure required to produce a predictable physiological response is unknown. This investigation intends to relate the pressure exerted by the cuffs to the extent of fluid redistribution and commensurate physiological effects. Materials and Methods: Ten healthy subjects with standardized fluid intake participated in the study. Data collection included femoral and internal jugular vein imaging in two orthogonal planes, pulsed Doppler of cervical and femoral vessels and middle cerebral artery, optic nerve imaging, and echocardiography. Braslet-M cuff pressure was monitored at the skin interface using pre-calibrated pressure sensors. Using 6 and 30 head-down tilt in two separate sessions, the effect of Braslet-M was assessed while incrementally tightening the cuffs. Cuffs were then simultaneously released to document the resulting hemodynamic change. Results: Preliminary analysis shows correlation between physical pressure exerted by the Braslet-M device and several parameters such as jugular and femoral vein cross-sections, resistivity of the lower extremity vascular bed, and others. A number of parameters reflect blood redistribution and will be used to determine the therapeutic range of the device and to prevent unsafe application. Conclusion: Braslet-M exerts a physical effect that can be measured and correlated with many changes in central and peripheral hemodynamics. Analysis of the full data set will be required to make definitive recommendations regarding the range of safe therapeutic application. Objective data and subjective responses suggest that a safer and equally effective use of Braslet can be achieved when compared with the current

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

    SciTech Connect

    Reynolds, M.; Fallone, B. G.; Rathee, S.

    2014-09-15

    Purpose: MR-Linac devices under development worldwide will require standard calibration, commissioning, and quality assurance. Solid state radiation detectors are often used for dose profiles and percent depth dose measurements. The dose response of selected solid state detectors is therefore evaluated in varying transverse and longitudinal magnetic fields for this purpose. Methods: The Monte Carlo code PENELOPE was used to model irradiation of a PTW 60003 diamond detector and IBA PFD diode detector in the presence of a magnetic field. The field itself was varied in strength, and oriented both transversely and longitudinally with respect to the incident photon beam. The long axis of the detectors was oriented either parallel or perpendicular to the photon beam. The dose to the active volume of each detector in air was scored, and its ratio to dose with zero magnetic field strength was determined as the “dose response” in magnetic field. Measurements at low fields for both detectors in transverse magnetic fields were taken to evaluate the accuracy of the simulations. Additional simulations were performed in a water phantom to obtain few representative points for beam profile and percent depth dose measurements. Results: Simulations show significant dose response as a function of magnetic field in transverse field geometries. This response can be near 20% at 1.5 T, and it is highly dependent on the detectors’ relative orientation to the magnetic field, the energy of the photon beam, and detector composition. Measurements at low transverse magnetic fields verify the simulations for both detectors in their relative orientations to radiation beam. Longitudinal magnetic fields, in contrast, show little dose response, rising slowly with magnetic field, and reaching 0.5%–1% at 1.5 T regardless of detector orientation. Water tank and in air simulation results were the same within simulation uncertainty where lateral electronic equilibrium is present and expectedly

  18. Evaluating and interpreting the chemical relevance of the linear response kernel for atoms II: open shell.

    PubMed

    Boisdenghien, Zino; Fias, Stijn; Van Alsenoy, Christian; De Proft, Frank; Geerlings, Paul

    2014-07-28

    Most of the work done on the linear response kernel χ(r,r') has focussed on its atom-atom condensed form χAB. Our previous work [Boisdenghien et al., J. Chem. Theory Comput., 2013, 9, 1007] was the first effort to truly focus on the non-condensed form of this function for closed (sub)shell atoms in a systematic fashion. In this work, we extend our method to the open shell case. To simplify the plotting of our results, we average our results to a symmetrical quantity χ(r,r'). This allows us to plot the linear response kernel for all elements up to and including argon and to investigate the periodicity throughout the first three rows in the periodic table and in the different representations of χ(r,r'). Within the context of Spin Polarized Conceptual Density Functional Theory, the first two-dimensional plots of spin polarized linear response functions are presented and commented on for some selected cases on the basis of the atomic ground state electronic configurations. Using the relation between the linear response kernel and the polarizability we compare the values of the polarizability tensor calculated using our method to high-level values. PMID:24837234

  19. On the Linear Relation between the Mean and the Standard Deviation of a Response Time Distribution

    ERIC Educational Resources Information Center

    Wagenmakers, Eric-Jan; Brown, Scott

    2007-01-01

    Although it is generally accepted that the spread of a response time (RT) distribution increases with the mean, the precise nature of this relation remains relatively unexplored. The authors show that in several descriptive RT distributions, the standard deviation increases linearly with the mean. Results from a wide range of tasks from different…

  20. Determining polarizable force fields with electrostatic potentials from quantum mechanical linear response theory

    NASA Astrophysics Data System (ADS)

    Wang, Hao; Yang, Weitao

    2016-06-01

    We developed a new method to calculate the atomic polarizabilities by fitting to the electrostatic potentials (ESPs) obtained from quantum mechanical (QM) calculations within the linear response theory. This parallels the conventional approach of fitting atomic charges based on electrostatic potentials from the electron density. Our ESP fitting is combined with the induced dipole model under the perturbation of uniform external electric fields of all orientations. QM calculations for the linear response to the external electric fields are used as input, fully consistent with the induced dipole model, which itself is a linear response model. The orientation of the uniform external electric fields is integrated in all directions. The integration of orientation and QM linear response calculations together makes the fitting results independent of the orientations and magnitudes of the uniform external electric fields applied. Another advantage of our method is that QM calculation is only needed once, in contrast to the conventional approach, where many QM calculations are needed for many different applied electric fields. The molecular polarizabilities obtained from our method show comparable accuracy with those from fitting directly to the experimental or theoretical molecular polarizabilities. Since ESP is directly fitted, atomic polarizabilities obtained from our method are expected to reproduce the electrostatic interactions better. Our method was used to calculate both transferable atomic polarizabilities for polarizable molecular mechanics' force fields and nontransferable molecule-specific atomic polarizabilities.

  1. Determining polarizable force fields with electrostatic potentials from quantum mechanical linear response theory.

    PubMed

    Wang, Hao; Yang, Weitao

    2016-06-14

    We developed a new method to calculate the atomic polarizabilities by fitting to the electrostatic potentials (ESPs) obtained from quantum mechanical (QM) calculations within the linear response theory. This parallels the conventional approach of fitting atomic charges based on electrostatic potentials from the electron density. Our ESP fitting is combined with the induced dipole model under the perturbation of uniform external electric fields of all orientations. QM calculations for the linear response to the external electric fields are used as input, fully consistent with the induced dipole model, which itself is a linear response model. The orientation of the uniform external electric fields is integrated in all directions. The integration of orientation and QM linear response calculations together makes the fitting results independent of the orientations and magnitudes of the uniform external electric fields applied. Another advantage of our method is that QM calculation is only needed once, in contrast to the conventional approach, where many QM calculations are needed for many different applied electric fields. The molecular polarizabilities obtained from our method show comparable accuracy with those from fitting directly to the experimental or theoretical molecular polarizabilities. Since ESP is directly fitted, atomic polarizabilities obtained from our method are expected to reproduce the electrostatic interactions better. Our method was used to calculate both transferable atomic polarizabilities for polarizable molecular mechanics' force fields and nontransferable molecule-specific atomic polarizabilities.

  2. A study of non-linearity in rainfall-runoff response using 120 UK catchments

    NASA Astrophysics Data System (ADS)

    Mathias, Simon A.; McIntyre, Neil; Oughton, Rachel H.

    2016-09-01

    This study presents a catchment characteristic sensitivity analysis concerning the non-linearity of rainfall-runoff response in 120 UK catchments. Two approaches were adopted. The first approach involved, for each catchment, regression of a power-law to flow rate gradient data for recession events only. This approach was referred to as the recession analysis (RA). The second approach involved calibrating a rainfall-runoff model to the full data set (both recession and non-recession events). The rainfall-runoff model was developed by combining a power-law streamflow routing function with a one parameter probability distributed model (PDM) for soil moisture accounting. This approach was referred to as the rainfall-runoff model (RM). Step-wise linear regression was used to derive regionalization equations for the three parameters. An advantage of the RM approach is that it utilizes much more of the observed data. Results from the RM approach suggest that catchments with high base-flow and low annual precipitation tend to exhibit greater non-linearity in rainfall-runoff response. In contrast, the results from the RA approach suggest that non-linearity is linked to low evaporative demand. The difference in results is attributed to the aggregation of storm-flow and base-flow into a single system giving rise to a seemingly more non-linear response when applying the RM approach to catchments that exhibit a strongly dual storm-flow base-flow response. The study also highlights the value and limitations in a regionlization context of aggregating storm-flow and base-flow pathways into a single non-linear routing function.

  3. Optical measurement of the weak non-linearity in the eardrum vibration response to auditory stimuli

    NASA Astrophysics Data System (ADS)

    Aerts, Johan

    The mammalian hearing organ consists of the external ear (auricle and ear canal) followed by the middle ear (eardrum and ossicles) and the inner ear (cochlea). Its function is to convert the incoming sound waves and convert them into nerve pulses which are processed in the final stage by the brain. The main task of the external and middle ear is to concentrate the incoming sound waves on a smaller surface to reduce the loss that would normally occur in transmission from air to inner ear fluid. In the past it has been shown that this is a linear process, thus without serious distortions, for sound waves going up to pressures of 130 dB SPL (˜90 Pa). However, at large pressure changes up to several kPa, the middle ear movement clearly shows non-linear behaviour. Thus, it is possible that some small non-linear distortions are also present in the middle ear vibration at lower sound pressures. In this thesis a sensitive measurement set-up is presented to detect this weak non-linear behaviour. Essentially, this set-up consists of a loud-speaker which excites the middle ear, and the resulting vibration is measured with an heterodyne vibrometer. The use of specially designed acoustic excitation signals (odd random phase multisines) enables the separation of the linear and non-linear response. The application of this technique on the middle ear demonstrates that there are already non-linear distortions present in the vibration of the middle ear at a sound pressure of 93 dB SPL. This non-linear component also grows strongly with increasing sound pressure. Knowledge of this non-linear component can contribute to the improvement of modern hearing aids, which operate at higher sound pressures where the non-linearities could distort the signal considerably. It is also important to know the contribution of middle ear non-linearity to otoacoustic emissions. This are non-linearities caused by the active feedback amplifier in the inner ear, and can be detected in the external and

  4. Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

    PubMed

    Moens, An L; Ketner, Elizabeth A; Takimoto, Eiki; Schmidt, Tim S; O'Neill, Charles A; Wolin, Michael S; Alp, Nicholas J; Channon, Keith M; Kass, David A

    2011-10-01

    The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.'' PMID:21645517

  5. Dose-Responsive Gene Expression in Suberoylanilide Hydroxamic Acid (SAHA) Treated Resting CD4+ T Cells

    PubMed Central

    Reardon, Brian; Beliakova-Bethell, Nadejda; Spina, Celsa A.; Singhania, Akul; Margolis, David M.; Richman, Douglas R.; Woelk, Christopher H.

    2015-01-01

    Design Persistent latently infected CD4+ T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a proposed activation therapy. However, off-target effects on expression in host immune cells are poorly understood. We hypothesized that HDACi-modulated genes would be best identified with dose-response analysis. Methods Resting primary CD4+ T cells were treated with 0.34, 1, 3, or 10 μM of the HDACi, SAHA, for 24 hours and subjected to microarray gene expression analysis. Genes with dose-correlated expression were filtered to identify a subset with consistent up or downregulation at each SAHA dose. Histone modifications were characterized in 6 SAHA dose-responsive genes by chromatin immunoprecipitation (ChIP-RT-qPCR). Results A large number of genes were shown to be up (N=657) or downregulated (N=725) by SAHA in a dose-responsive manner (FDR p-value < 0.05, fold change ≥ |2|). Several genes (CTNNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in vivo biomarkers of SAHA activity. SAHA dose-responsive genes included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV. Pathway analysis suggested net downregulation of T cell activation with increasing SAHA dose. Histone acetylation was not correlated with host gene expression, but plausible alternative mechanisms for SAHA-modulated gene expression were identified. Conclusions Numerous genes in CD4+ T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone modification, and altered expression and activity of transcription factors. PMID:26258524

  6. Dose-response relationship of ozone-induced airway hyperresponsiveness in unanesthetized guinea pigs

    SciTech Connect

    Nishikawa, M.; Suzuki, S.; Ikeda, H.; Fukuda, T.; Suzuki, J.; Okubo, T. )

    1990-06-01

    The effect of ozone dose (the product of ozone concentration and exposure time) on airway responsiveness was examined in unanesthetized, spontaneously breathing guinea pigs. Airway responsiveness was assessed by measuring specific airway resistance (sRaw) as a function of increasing concentration of inhaled methacholine (Mch) aerosol (the concentration of Mch required in order to double the baseline sRaw: PC200Mch). The airway responsiveness was measured before and at 5 min, 5 h, and 24 h after exposure. A 30-min exposure to 1 ppm ozone (dose 30 ppm.min) did not change PC200Mch at any time after exposure. Both a 90-min exposure to 1 ppm ozone and a 30-min exposure to 3 ppm ozone, which are identical in terms of ozone dose (90 ppm.min), decreased PC200Mch to a similar degree. A 120-min exposure to 3 ppm ozone (360 ppm.min) produced a much greater decrease of PC200Mch at 5 min and 5 h after exposure, compared with low-dose exposure. There was a significant correlation between ozone dose and the change in airway responsiveness. In all groups, the baseline sRaw was increased by approximately 50% at 5 min after exposure, but there was no correlation between the changes in PC200Mch and the baseline sRaw. This study suggests that ozone-induced airway hyperresponsiveness in guinea pigs is closely related to ozone dose.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

  9. AN EXTRACT OF PENICILLIUM CHRYSOGENUM INDUCES DOSE-DEPENDENT ALLERGIC ASTHMA RESPONSES IN MICE

    EPA Science Inventory

    Rationale: Penicillium chrysogenum, a common indoor mold, is known to have several allergens and can induce allergic responses in a mouse model of allergic penicilliosis. Our hypothesis is that soluble components of P. chrysogenum (PCE) can dose-dependently induce responses typ...

  10. Modeling and regression analysis of semiochemical dose-response curves of insect antennal reception and behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dose-response curves with semiochemicals are reported in many articles in insect chemical ecology regarding neurophysiology and behavioral bioassays. Most such curves are shown in figures where the x-axis has order of magnitude increases in dosages versus responses on the y-axis represented by point...

  11. The Hematopoietic Syndrome of the Acute Radiation Syndrome in Rhesus Macaques: A Systematic Review of the Lethal Dose Response Relationship.

    PubMed

    MacVittie, Thomas J; Farese, Ann M; Jackson, William

    2015-11-01

    Well characterized animal models that mimic the human response to potentially lethal doses of radiation are required to assess the efficacy of medical countermeasures under the criteria of the U.S. Food and Drug Administration "animal rule." Development of a model requires the determination of the radiation dose response relationship and time course of mortality and morbidity across the hematopoietic acute radiation syndrome. The nonhuman primate, rhesus macaque, is a relevant animal model that may be used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality at selected lethal doses of total body irradiation. A systematic review of relevant studies that determined the dose response relationship for the hematopoietic acute radiation syndrome in the rhesus macaque relative to radiation quality, dose rate, and exposure uniformity has never been performed. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and U.S. HHS REPORT (2002 to present). The following terms were used: Rhesus, total body-irradiation, total body x irradiation, TBI, irradiation, gamma radiation, hematopoiesis, LD50/60, Macaca mulatta, whole-body irradiation, nonhuman primate, NHP, monkey, primates, hematopoietic radiation syndrome, mortality, and nuclear radiation. The reference lists of all studies, published and unpublished, were reviewed for additional studies. The total number of hits across all search sites was 3,001. There were a number of referenced, unpublished, non-peer reviewed government reports that were unavailable for review. Fifteen studies, 11 primary (n = 863) and four secondary (n = 153) studies [n = 1,016 total nonhuman primates (NHP), rhesus Macaca mulatta] were evaluated to provide an informative and consistent review. The dose response relationships (DRRs) were determined for uniform or non-uniform total

  12. CCL2 mediates the circadian response to low dose endotoxin.

    PubMed

    Duhart, José M; Brocardo, Lucila; Mul Fedele, Malena L; Guglielmotti, Angelo; Golombek, Diego A

    2016-09-01

    The mammalian circadian system is mainly originated in a master oscillator located in the suprachiasmatic nuclei (SCN) in the hypothalamus. Previous reports from our and other groups have shown that the SCN are sensitive to systemic immune activation during the early night, through a mechanism that relies on the action of proinflammatory factors within this structure. Chemokine (C-C motif) ligand 2 (CCL2) is induced in the brain upon peripheral immune activation, and it has been shown to modulate neuronal physiology. In the present work we tested whether CCL2 might be involved in the response of the circadian clock to peripheral endotoxin administration. The CCL2 receptor, C-C chemokine receptor type 2 (CCR2), was detected in the SCN of mice, with higher levels of expression during the early night, when the clock is sensitive to immune activation. Ccl2 was induced in the SCN upon intraperitoneal lipopolysaccharide (LPS) administration. Furthermore, mice receiving an intracerebroventricular (Icv) administration of a CCL2 synthesis inhibitor (Bindarit), showed a reduction LPS-induced circadian phase changes and Icv delivery of CCL2 led to phase delays in the circadian clock. In addition, we tested the possibility that CCL2 might also be involved in the photic regulation of the clock. Icv administration of Bindarit did not modify the effects of light pulses on the circadian clock. In summary, we found that CCL2, acting at the SCN level is important for the circadian effects of immune activation.

  13. Application of Low Dose Radiation Adaptive Response to Control Aging-Related Disease

    SciTech Connect

    Doss, Mohan

    2013-11-01

    Oxidative damage has been implicated in the pathogenesis of most aging-related diseases including neurodegenerative diseases. Antioxidant supplementation has been found to be ineffective in reducing such diseases, but increased endogenous production of antioxidants from the adaptive response due to physical and cognitive exercises (which increase oxidative metabolism and oxidative stress) has been effective in reducing some of the diseases. Low dose radiation (LDR), which increases oxidative stress and results in adaptive response of increased antioxidants, may provide an alternative method of controlling the aging-related diseases. We have studied the effect of LDR on the induction of adaptive response in rat brains and the effectiveness of the LDR in reducing the oxidative damage caused by subsequent high dose radiation. We have also investigated the effect of LDR on apomorphine-induced rotations in the 6-hydroxydopamine (6-OHDA) unilaterally-lesioned rat model of Parkinson?s disease (PD). LDR was observed to initiate an adaptive response in the brain, and reduce the oxidative damage from subsequent high dose radiation exposure, confirming the effectiveness of LDR adaptive response in reducing the oxidative damage from the free radicals due to high dose radiation. LDR resulted in a slight improvement in Tyrosine hydroxylase expression on the lesioned side of substantia nigra (indicative of its protective effect on the dopaminergic neurons), and reduced the behavioral symptoms in the 6-OHDA rat model of PD. Translation of this concept to humans, if found to be applicable, may be a possible approach for controlling the progression of PD and other neurodegenerative diseases. Since any translation of the concept to humans would be hindered by the currently prevalent carcinogenic concerns regarding LDR based on the linear no-threshold (LNT) model, we have also studied the justifications for the use of the LNT model. One of the shortcomings of the LNT model is that it

  14. A study of the shape of dose-response curves for acute lethality at low response: a megadaphnia study'

    SciTech Connect

    Sebaugh, J.L.; Wilson, J.D.; Tucker, M.W.; Adams, W.J. )

    1991-12-01

    Dose-response curves were developed for the immobilization response in Daphnia magna to four toxicants. The purpose of this work was to study the effect of the form of the model and the number of concentration levels used on the estimates of typical low-dose effective concentrations (1%, 5%, 10%). The generalized four-parameter logistic model was used as the reference. When using 12 concentration levels, one of the logistic family two- or three-parameter models was shown reliably to represent each of these various sets of dose-response data, and to provide adequate estimates of EC01 and EC05, as well as EC10 and EC50. For two of the toxicants, an asymmetric model was required. When reducing the number of concentrations to five, the EC10 and EC50 were well estimated by the probit model, with acceptable results at the EC05 level.

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

    SciTech Connect

    Schmitz, T.; Bassler, N.; Blaickner, M.; Ziegner, M.; Hsiao, M. C.; Liu, Y. H.; Koivunoro, H.; Auterinen, I.; Serén, T.; Kotiluoto, P.; Palmans, H.; Sharpe, P.; Langguth, P.; Hampel, G.

    2015-01-15

    Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particle spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The

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

    SciTech Connect

    Olson, J.J.; Friedman, R.; Orr, K.; Delaney, T.; Oldfield, E.H. )

    1990-05-01

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

  17. Responses of the central nervous system to high linear energy transfer radiation: NSCOR project highlights

    PubMed Central

    Nelson, Gregory; Fike, John; Limoli, Charles; Obenaus, André; Raber, Jacob; Soltesz, Ivan; Vlkolinský, Roman

    2014-01-01

    Overview: The five-university NSCOR project investigates the responses of the central nervous system to space-like charged particle exposure by evaluating: synaptic function, in vitro and in vivo neurogenesis, behavior and behaviorally induced gene expression, and oxidative stress of the mouse hippocampus and cultured neural precursor cells. To test the role of reactive oxygen species in mediating the effects of radiation exposure, we compare responses in a catalase overexpressing transgenic mouse strain to wild type. We also use computational models of the hippocampus in three dimensions, informed by experimental measurements, to provide insight into network behavior. Radiation exposure protocols include single, acute whole-body exposures to 1H, 28Si and 56Fe ions and mixed field exposures using 1H + 56Fe ions (24 h later). The animal models are 10-week-old C57BL/6J and MCATtg males which are evaluated at 30 and 90 days postirradiation. In vitro models are cultured murine and human neural stem cells irradiated with 1H, 16O, 28Si and 56Fe ions at multiple energies and are evaluated at times from days to weeks. Highlights: Neural stem cells organized into neurospheres were irradiated with several ions at doses as low as 0.75 cGy. Data show that significant oxidative stress occurs that alters survival, proliferation and differentiation. Overall trends indicate that changes in oxidative stress (persisting for weeks) correlate with particle linear energy transfer (LET). 56Fe ions elicited the largest and most persistent changes in stress markers, including antioxidant enzyme expression levels. The hippocampus-dependent contextual fear conditioning (CFC) and novel object recognition (NOR) paradigms were used to assess cognition and showed cognitive deficits after irradiation with the NOR paradigm more sensitive than CFC. Analysis of neurogenesis indicates that overall neurogenesis is inhibited at doses ≥1 Gy, but newly born activated microglia are significantly

  18. Airfoil wake and linear theory gust response including sub and superresonant flow conditions

    NASA Technical Reports Server (NTRS)

    Henderson, Gregory H.; Fleeter, Sanford

    1992-01-01

    The unsteady aerodynamic gust response of a high solidity stator vane row is examined in terms of the fundamental gust modeling assumptions with particular attention given to the effects near an acoustic resonance. A series of experiments was performed with gusts generated by rotors comprised of perforated plates and airfoils. It is concluded that, for both the perforated plate and airfoil wake generated gusts, the unsteady pressure responses do not agree with the linear-theory gust predictions near an acoustic resonance. The effects of the acoustic resonance phenomena are clearly evident on the airfoil surface unsteady pressure responses. The transition of the measured lift coefficients across the acoustic resonance from the subresonant regime to the superresonant regime occurs in a simple linear fashion.

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

    SciTech Connect

    Little, Mark P.; Kleinerman, Ruth A.; Stovall, Marilyn; Smith, Susan A.; Mabuchi, Kiyohiko

    2012-12-01

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

  20. Time and dose-response effects of honokiol on UVB-induced skin cancer development.

    PubMed

    Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

    2012-06-01

    Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

  1. Correction of the nonlinear dose response improves the viability of adenoviral vectors for gene therapy of Fabry disease.

    PubMed

    Ziegler, Robin J; Li, Chester; Cherry, Maribeth; Zhu, Yunxiang; Hempel, Donna; van Rooijen, Nico; Ioannou, Yiannis A; Desnick, Robert J; Goldberg, Mark A; Yew, Nelson S; Cheng, Seng H

    2002-05-20

    Systemic administration of recombinant adenoviral vectors for gene therapy of chronic diseases such as Fabry disease can be limited by dose-dependent toxicity. Because administration of a high dose of Ad2/CMVHI-alpha gal encoding human alpha-galactosidase A results in expression of supraphysiological levels of the enzyme, we sought to determine whether lower doses would suffice to correct the enzyme deficiency and lysosomal storage abnormality observed in Fabry mice. Reducing the dose of Ad2/CMVHI-alpha gal by 10-fold (from 10(11) to 10(10) particles/mouse) resulted in a greater than 200-fold loss in transgene expression. In Fabry mice, the reduced expression of alpha-galactosidase A, using the lower dose of Ad2/CMVHI-alpha gal, was associated with less than optimal clearance of the accumulated glycosphingolipid (GL-3) from the affected lysosomes. It was determined that this lack of linearity in dose response was not due to an inability to deliver the recombinant viral vectors to the liver but rather to sequestration, at least in part, of the viral vectors by the Kupffer cells. This lack of correlation between dose and expression levels could be obviated by supplementing the low dose of Ad2/CMVHI-alpha gal with an unrelated adenoviral vector or by depleting the Kupffer cells before administration of Ad2/CMVHI-alpha gal. Prior removal of the Kupffer cells, using clodronate liposomes, facilitated the use of a 100-fold lower dose of Ad2/CMVHI-alpha gal (10(9) particles/mouse) to effect the nearly complete clearance of GL-3 from the affected organs of Fabry mice. These results suggest that practical strategies that minimize the interaction between the recombinant adenoviral vectors and the reticuloendothelial system (RES) may improve the therapeutic window of this vector system. In this regard, we showed that pretreatment of mice with gamma globulins also resulted in significantly enhanced adenovirus-mediated transduction and expression of alpha-galactosidase A in the

  2. Vestibular afferent responses to linear accelerations in the alert squirrel monkey

    NASA Technical Reports Server (NTRS)

    Somps, Christopher J.; Schor, Robert H.; Tomko, David L.

    1994-01-01

    The spontaneous activity of 40 otolith afferents and 44 canal afferents was recorded in 4 alert, intact squirrel monkeys. Polarization vectors and response properties of otolith afferents were determined during static re-orientations relative to gravity and during Earth-horizontal, sinusoidal, linear oscillations. Canal afferents were tested for sensitivity to linear accelerations. For regular otolith afferents, a significant correlation between upright discharge rate and sensitivity to dynamic acceleration in the horizontal plane was observed. This correlation was not present in irregular units. The sensitivity of otolith afferents to both static tilts and dynamic linear acceleration was much greater in irregularly discharging units than in regularly discharging units. The spontaneous activity and static and dynamic response properties of regularly discharging otolith afferents were similar to those reported in barbiturate-anesthetized squirrel monkeys. Irregular afferents also had similar dynamic response properties when compared to anesthetized monkeys. However, this sample of irregular afferents in alert animals had higher resting discharge rates and greater sensitivity to static tilts. The majority of otolith polarization vectors were oriented near the horizontal in the plane of the utricular maculae; however, directions of maximum sensitivity were different during dynamic and static testing. Canal afferents were not sensitive to static tilts or linear oscillations of the head.

  3. Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate.

    PubMed

    Spiering, Barry A; Kraemer, William J; Vingren, Jakob L; Hatfield, Disa L; Fragala, Maren S; Ho, Jen-Yu; Maresh, Carl M; Anderson, Jeffrey M; Volek, Jeff S

    2007-02-01

    L-carnitine L-tartrate (LCLT) supplementation beneficially affects markers of postexercise metabolic stress and muscle damage. However, to date, no study has determined the dose response of LCLT to elicit such responses. Therefore, the purpose of this study was to determine the effects of different doses of LCLT on criterion variables previously shown to be responsive to LCLT supplementation. Eight healthy men (22 +/- 3 y, 174 +/- 5 cm, 83.0 +/- 15.3 kg) were supplemented with 0 g, 1 g, and 2 g of LCLT for 3 weeks and then performed a bout of resistance exercise (5 sets of 15-20 repetition maximum with a 2-min rest between sets) with associated blood draws. This procedure was performed in a balanced, randomized, repeated measures design. Serum carnitine concentrations increased (p < or = 0.05) following the 1 g and 2 g doses, with the 2-g dose providing the highest carnitine concentrations. The 1- and 2-g doses reduced postexercise serum hypoxanthine, serum xanthine oxidase, serum myoglobin, and perceived muscle soreness. In conclusion, both the 1- and 2-g doses were effective in mediating various markers of metabolic stress and of muscle soreness. Use of LCLT appears to attenuate metabolic stress and the hypoxic chain of events leading to muscle damage after exercise.

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

    EPA Science Inventory

    Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? Leon Earl Gray Jr, USEPA, ORD, NHEERL, TAD, RTB. RTP, NC, USA The shape of the dose response curve in the low dose region has been debated since th...

  5. Modeling the low-LET dose-response of BCR-ABL formation: predicting stem cell numbers from A-bomb data.

    PubMed

    Radivoyevitch, T; Hoel, D G

    1999-01-01

    Formation of the BCR-ABL chromosomal translocation t(9;22)(q34;q11) is essential to the genesis of chronic myeloid leukemia (CML). An interest in the dose-response of radiation induced CML therefore leads naturally to an interest in the dose-response of BCR-ABL formation. To predict the BCR-ABL dose-response to low-linear energy transfer (LET) ionizing radiation, three models valid over three different dose ranges are examined: the first for doses greater than 80 Gy, the second for doses less than 5 Gy and the third for doses greater than 2 Gy. The first of the models, due to Holley and Chatterjee, ignores the accidental binary eurejoining of DNA double-strand break (DSB) free ends ('eurejoining' refers to the accidental restitution of DSB free ends with their own proper mates). As a result, the model is valid only in the limit of high doses. The second model is derived directly from cytogenetic data. This model has the attractive feature that it implicitly accounts for single-track effects at low doses. The third model, based on the Sax-Markov binary eurejoining/misrejoining (SMBE) algorithm, does not account for single-track effects and is therefore limited to moderate doses greater than approximately 2 Gy. Comparing the second model to lifetime excess CML risks expected after 1 Gy, estimates of the number of hematopoietic stem cells capable of causing CML were obtained for male and female atomic bomb survivors in Hiroshima and Nagasaki. The stem cell number estimates lie in the range of 5 x 10(7)-3 x 10(8) cells. PMID:10616282

  6. Induction of IgG memory responses with polyvinylpyrrolidone (PVP) is antigen dose dependent

    SciTech Connect

    Lite, H.S.; Braley-Mullen, H.

    1981-03-01

    Irradiated recipients of spleen cells from mice primed with a very low dose (0.0025 ..mu../g) of the thymus-independent (TI) antigen polyvinylpyrrolidone (PVP) produced PVP-specific IgG memory responses after secondary challenge with a T-dependent (TD) form of PVP, PVP-HRBC. The IgG memory responses induced by low doses of PVP were similar in magnitude to those induced by the TD antigen PVP-HRBC. The induction of IgG memory by the TI form of antigen was markedly dependent on the dose of PVP used to prime donor mice. Spleen cells from mice primed with an amount of PVP (0.25 ..mu..g) that induces an optimal primary IgM response did not produce significant IgG antibody after challenge with PVP-HRBC. The inability of higher doses of PVP to induce IgG memory may be due, at least in part, to the fact that such doses of PVP were found to induce tolerance in PVP-specific B cells and could suppress the induction of memory induced by PVP-HRBC. Low doses of PVP did not interfere with the induction of memory by PVP-HRBC. Expression of IgG memory responses in recipients of PVP-HRBC or low-dose PVP-primed cells was found to be T cell dependent. Moreover, only primed T cells could reconstitute the respnse of recipients of primed B cells, suggesting that the ability of PVP to induce IgG memory may be related to its ability to prime T helper cells. Expression of the IgG memory response in recipient mice also required the use of a TD antigen for secondary challenge, i.e., mice challenged with PVP did not develop IgG.

  7. Effects of ozone on pulmonary function: the relationship of response to dose

    SciTech Connect

    Kleinman, M.T. )

    1991-07-01

    A dose-response relationship for the effects of ozone on pulmonary function in humans has been derived using the concept of internal thoracic dose. This quantity, which represents the dose of inhaled pollutant capable of reaching and affecting target sites in the lower respiratory tract, was estimated using a mathematical model derived in part from theory and in part from data obtained using human and animal subjects. The model was applied to ozone exposures of individuals ranging in age from infants to adults over age 65 and for exercise conditions ranging from rest to heavy exercise (greater than 6 times resting minute ventilation). The dose model was successfully used to compare results from clinical studies in which subjects were exposed under disparate conditions of exercise, exposure concentration and exposure duration. The model can also be applied to estimate doses to populations exposed to ambient pollution. The effects of ozone on pulmonary function in adults and children were evaluated using the model. On the basis of dose of ozone (micrograms O3 per kg body mass), children, aged 8 to 15 years, and adults were equally sensitive. When dose is analyzed as a function of age, the data suggest that children, under the age of 6 years, receive greater doses to respiratory tract tissues than do older children or adults, under equivalent conditions of exposure.

  8. Beneficial effects of low dose radiation in response to the oncogenic KRAS induced cellular transformation.

    PubMed

    Kim, Rae-Kwon; Kim, Min-Jung; Seong, Ki Moon; Kaushik, Neha; Suh, Yongjoon; Yoo, Ki-Chun; Cui, Yan-Hong; Jin, Young Woo; Nam, Seon Young; Lee, Su-Jae

    2015-01-01

    Recently low dose irradiation has gained attention in the field of radiotherapy. For lack of understanding of the molecular consequences of low dose irradiation, there is much doubt concerning its risks on human beings. In this article, we report that low dose irradiation is capable of blocking the oncogenic KRAS-induced malignant transformation. To address this hypothesis, we showed that low dose irradiation, at doses of 0.1 Gray (Gy); predominantly provide defensive response against oncogenic KRAS -induced malignant transformation in human cells through the induction of antioxidants without causing cell death and acts as a critical regulator for the attenuation of reactive oxygen species (ROS). Importantly, we elucidated that knockdown of antioxidants significantly enhanced ROS generation, invasive and migratory properties and abnormal acini formation in KRAS transformed normal as well as cancer cells. Taken together, this study demonstrates that low dose irradiation reduces the KRAS induced malignant cellular transformation through diminution of ROS. This interesting phenomenon illuminates the beneficial effects of low dose irradiation, suggesting one of contributory mechanisms for reducing the oncogene induced carcinogenesis that intensify the potential use of low dose irradiation as a standard regimen. PMID:26515758

  9. Poster — Thur Eve — 27: Flattening Filter Free VMAT Quality Assurance: Dose Rate Considerations for Detector Response

    SciTech Connect

    Viel, Francis; Duzenli, Cheryl; Camborde, Marie-Laure; Strgar, Vincent; Horwood, Ron; Atwal, Parmveer; Gete, Ermias; Karan, Tania

    2014-08-15

    Introduction: Radiation detector responses can be affected by dose rate. Due to higher dose per pulse and wider range of mu rates in FFF beams, detector responses should be characterized prior to implementation of QA protocols for FFF beams. During VMAT delivery, the MU rate may also vary dramatically within a treatment fraction. This study looks at the dose per pulse variation throughout a 3D volume for typical VMAT plans and the response characteristics for a variety of detectors, and makes recommendations on the design of QA protocols for FFF VMAT QA. Materials and Methods: Linac log file data and a simplified dose calculation algorithm are used to calculate dose per pulse for a variety of clinical VMAT plans, on a voxel by voxel basis, as a function of time in a cylindrical phantom. Diode and ion chamber array responses are characterized over the relevant range of dose per pulse and dose rate. Results: Dose per pulse ranges from <0.1 mGy/pulse to 1.5 mGy/pulse in a typical VMAT treatment delivery using the 10XFFF beam. Diode detector arrays demonstrate increased sensitivity to dose (+./− 3%) with increasing dose per pulse over this range. Ion chamber arrays demonstrate decreased sensitivity to dose (+/− 1%) with increasing dose rate over this range. Conclusions: QA protocols should be designed taking into consideration inherent changes in detector sensitivity with dose rate. Neglecting to account for changes in detector response with dose per pulse can lead to skewed QA results.

  10. Encoding of head acceleration in vestibular neurons. I. Spatiotemporal response properties to linear acceleration

    NASA Technical Reports Server (NTRS)

    Bush, G. A.; Perachio, A. A.; Angelaki, D. E.

    1993-01-01

    1. Extracellular recordings were made in and around the medial vestibular nuclei in decerebrated rats. Neurons were functionally identified according to their semicircular canal input on the basis of their responses to angular head rotations around the yaw, pitch, and roll head axes. Those cells responding to angular acceleration were classified as either horizontal semicircular canal-related (HC) or vertical semicircular canal-related (VC) neurons. The HC neurons were further characterized as either type I or type II, depending on the direction of rotation producing excitation. Cells that lacked a response to angular head acceleration, but exhibited sensitivity to a change in head position, were classified as purely otolith organ-related (OTO) neurons. All vestibular neurons were then tested for their response to sinusoidal linear translation in the horizontal head plane. 2. Convergence of macular and canal inputs onto central vestibular nuclei neurons occurred in 73% of the type I HC, 79% of the type II HC, and 86% of the VC neurons. Out of the 223 neurons identified as receiving macular input, 94 neurons were further studied, and their spatiotemporal response properties to sinusoidal stimulation with pure linear acceleration were quantified. Data were obtained from 33 type I HC, 22 type II HC, 22 VC, and 17 OTO neurons. 3. For each neuron the angle of the translational stimulus vector was varied by 15, 30, or 45 degrees increments in the horizontal head plane. In all tested neurons, a direction of maximum sensitivity was identified. An interesting difference among neurons was their response to translation along the direction perpendicular to that that produced the maximum response ("null" direction). For the majority of neurons tested, it was possible to evoke a nonzero response during stimulation along the null direction always had response phases that varied as a function of stimulus direction. 4. These spatiotemporal response properties were quantified in two

  11. Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

    SciTech Connect

    Munira A Kadhim

    2010-03-05

    To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim

  12. Hematopoietic responses under protracted exposures to low daily dose gamma irradiation

    NASA Astrophysics Data System (ADS)

    Seed, T. M.; Fritz, T. E.; Tolle, D. V.; Jackson, W. E.

    In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d -1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d -1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (> 1yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d -1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d -1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.

  13. Thermal dose and time-temperature factors for biological responses to heat shock.

    PubMed

    Gerner, E W

    1987-01-01

    The application of hyperthermia in human cancer therapy, especially by radiotherapists who are accustomed to prescribing ionizing radiation treatments in physical dose units, has stimulated workers in this area to consider the possibility and utility of defining a unit of 'thermal dose'. Previous thermal dose definitions have, primarily, been based on biological isoeffect response relationships, which attempt to relate exposure times that elicit a given biological response at one temperature to exposure times at another temperature that elicit the same biological response. This 'equivalent time' method is shown to have certain limitations. For both 42.4 and 45 degrees C hyperthermia, these relationships accurately describe cell survival responses only when the heating rate is rapid (greater than 0.5 degrees C min-1 from ambient to hyperthermic temperature). Further, the form of these isoeffect relationships appears to be temperature range and cell/tissue-type dependent, and it is suggested that these relationships be referred to as a 'time-temperature factor' (TTF) to help distinguish them from possible physical thermal dose definitions. Two physical dose definitions are discussed, one being simply exposure time at some temperature and the other being a more fundamental definition, the free energy change which is a temperature-dependent driving force for chemical reactions.

  14. Hematopoietic responses under protracted exposures to low daily dose gamma irradiation.

    PubMed

    Seed, T M; Fritz, T E; Tolle, D V; Jackson, W E

    2002-01-01

    In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.

  15. Evaluating quantitative formulas for dose-response assessment of chemical mixtures.

    PubMed Central

    Hertzberg, Richard C; Teuschler, Linda K

    2002-01-01

    Risk assessment formulas are often distinguished from dose-response models by being rough but necessary. The evaluation of these rough formulas is described here, using the example of mixture risk assessment. Two conditions make the dose-response part of mixture risk assessment difficult, lack of data on mixture dose-response relationships, and the need to address risk from combinations of chemicals because of public demands and statutory requirements. Consequently, the U.S. Environmental Protection Agency has developed methods for carrying out quantitative dose-response assessment for chemical mixtures that require information only on the toxicity of single chemicals and of chemical pair interactions. These formulas are based on plausible ideas and default parameters but minimal supporting data on whole mixtures. Because of this lack of mixture data, the usual evaluation of accuracy (predicted vs. observed) cannot be performed. Two approaches to the evaluation of such formulas are to consider fundamental biological concepts that support the quantitative formulas (e.g., toxicologic similarity) and to determine how well the proposed method performs under simplifying constraints (e.g., as the toxicologic interactions disappear). These ideas are illustrated using dose addition and two weight-of-evidence formulas for incorporating toxicologic interactions. PMID:12634126

  16. Immunological responses following experimental endobronchial infection of badgers (Meles meles) with different doses of Mycobacterium bovis.

    PubMed

    Lesellier, Sandrine; Corner, Leigh; Costello, Eamon; Sleeman, Paddy; Lyashchenko, Konstantin P; Greenwald, Rena; Esfandiari, Javan; Glyn Hewinson, R; Chambers, Mark; Gormley, Eamonn

    2009-01-15

    The Eurasian badger (Meles meles) is a wildlife reservoir for Mycobacterium bovis infection in Ireland and Great Britain and has been implicated in the transmission of tuberculosis to cattle. Vaccination of badgers is an option that could be used as part of a strategy to control the disease. In this study we used an endobronchial infection procedure to inoculate groups of badgers with three different doses (3x10(3), 2x10(2) and <10 Colony Forming Units (CFUs)) of M. bovis. After 17 weeks the disease status of each animal was determined by post-mortem pathology and culture for M. bovis. Each of the inoculum doses resulted in establishment of infection in the badgers. The cell-mediated immune (CMI) responses were measured by lymphocyte transformation assay (LTA) of peripheral blood mononuclear cells (PBMCs) cultured with bovine tuberculin (PPD-B). In each infected group the CMI responses increased with a kinetic profile corresponding to the delivered dose and the post-mortem pathology. The serological responses were measured by ELISA and a multi-antigen print immunoassay (MAPIA) in order to investigate any changes in the antigenic repertoire associated with different infective doses. In contrast to the CMI responses, the ELISA and MAPIA showed that the recognition of antigens by the badgers was intermittent and not strongly influenced by the dose of M. bovis.

  17. Study of the dose response of the system ferrous ammonium sulfate-sucrose-xylenol orange in acid aqueous solution

    NASA Astrophysics Data System (ADS)

    Juarez-Calderon, J. M.; Negron-Mendoza, A.; Ramos-Bernal, S.

    2014-11-01

    An aqueous solution of ammonium ferrous sulfate-sucrose-xylenol orange in sulfuric acid (FSX) is proposed as a dosimetric system for the processes of gamma irradiation in a range between 0.3 and 6 Gy. This system is based on the indirect oxidation of ferrous ion by an organic compound (sucrose) to ferric ion and on the formation of a color complex of Fe3+ in an acidic medium with xylenol orange (a dye). After gamma radiation, an observable change occurs in the color of the system. Irradiation was executed at three different temperatures (13 °C, 22 °C, and 40 °C). A spectrometric readout method at 585 nm was employed to evaluate the system's dose response. In all of the cases analyzed, the responses had a linear behavior, and a slight effect of irradiation temperature was observed. Post-irradiation response was also evaluated and showed the stability of the solutions 24 h after the irradiation. The results obtained suggest that FSX might be used as a dosimeter for low doses of gamma irradiation because it provides a stable signal, good reproducibility, and an accessible technique for analysis.

  18. Serological and bacteriological responses of water buffalo (Bubalus bubalis) vaccinated with two doses of Brucella abortus strain RB51 vaccine.

    PubMed

    Ramnanan, Anil; Diptee, Michael; Asgarali, Zinora; Campbell, Mervyn; Adesiyun, Abiodun Adewale

    2012-10-01

    Thirty-two water buffalo (Bubalus bubalis) calves aged 6–10 months were used to evaluate serological responses to Brucella abortus strain RB51 (RB51) vaccination in a dose-response study and to compare the use of two selective media for the isolation of RB51. The animals were randomly divided into three treatment groups. Groups I-III received the recommended vaccine dose (RD) twice 4 weeks apart, RD twice 18 weeks apart and saline once, respectively. Lymph nodes were excised from the three groups and subjected to bacteriological examination to determine the frequency of detection of RB51. Pre- and post-vaccination blood samples were collected and tested for B. abortus antibodies using the buffered plate agglutination test (BPAT), complement fixation test (CFT), and dot-blot assay. Sera taken at all post-inoculation weeks (PIW) were negative for field strain B. abortus using the BPAT. Antibody responses to RB51 were demonstrated in all vaccinates but not in controls by CFT and dot-blot assay from 1 PIW up to 16 weeks following booster vaccination. The agreement for both assays was 80.7% and there was a linear interdependence with a Pearson's correlation coefficient value of 0.578. The frequency of isolation of RB51 from the two selective media used was not significantly different (P > 0.05).

  19. The non-linear response of a superconductor to a few-cycle THz pulse

    NASA Astrophysics Data System (ADS)

    Carr, G. L.; Xi, Xiaoxiang

    2015-03-01

    We present a time-domain analysis of the response of a BCS superconductor (in the low temperature limit) to a few cycle THz pulse whose spectral content may span the absorption threshold for pair breaking. The analysis is based on the finite-difference time-domain (FDTD) approach, in combination with a model susceptibility for a superconductor that includes an explicit dependence on the energy gap. The FDTD approach allows us to calculate the THz induced current density, from which we determine the modified energy gap at each instant of time during the THz wave's passage. The resulting non-linear susceptibility causes up-conversion of the incident THz wave into odd harmonics. The model results are compared with experiment for thin NbN films in both linear and non-linear regimes. Research supported by the U.S. Dep't of Energy under Contract DE-AC02-98CH10886.

  20. Linear response as a singular limit for a periodically driven closed quantum system

    NASA Astrophysics Data System (ADS)

    Russomanno, Angelo; Silva, Alessandro; Santoro, Giuseppe E.

    2013-09-01

    We address the issue of the validity of linear response theory for a closed quantum system subject to a periodic external driving. Linear response theory (LRT) predicts energy absorption at frequencies of the external driving where the imaginary part of the appropriate response function is different from zero. Here we show that, for a fairly general nonlinear many-body system on a lattice subject to an extensive perturbation, this approximation should be expected to be valid only up to a time t* depending on the strength of the driving, beyond which the true coherent Schrödinger evolution departs from the linear response prediction and the system stops absorbing energy from the driving. We exemplify this phenomenon in detail with the example of a quantum Ising chain subject to a time-periodic modulation of the transverse field, by comparing an exact Floquet analysis with the standard results of LRT. In this context, we also show that if the perturbation is just local, the system is expected in the thermodynamic limit to keep absorbing energy, and LRT works at all times. We finally argue more generally the validity of the scenario presented for closed quantum many-body lattice systems with a bound on the energy-per-site spectrum, discussing the experimental relevance of our findings in the context of cold atoms in optical lattices and ultra-fast spectroscopy experiments.

  1. Near-linear response of mean monsoon strength to a broad range of radiative forcings

    PubMed Central

    Boos, William R.; Storelvmo, Trude

    2016-01-01

    Theoretical models have been used to argue that seasonal mean monsoons will shift abruptly and discontinuously from wet to dry stable states as their radiative forcings pass a critical threshold, sometimes referred to as a “tipping point.” Further support for a strongly nonlinear response of monsoons to radiative forcings is found in the seasonal onset of the South Asian summer monsoon, which is abrupt compared with the annual cycle of insolation. Here it is shown that the seasonal mean strength of monsoons instead exhibits a nearly linear dependence on a wide range of radiative forcings. First, a previous theory that predicted a discontinuous, threshold response is shown to omit a dominant stabilizing term in the equations of motion; a corrected theory predicts a continuous and nearly linear response of seasonal mean monsoon strength to forcings. A comprehensive global climate model is then used to show that the seasonal mean South Asian monsoon exhibits a near-linear dependence on a wide range of isolated greenhouse gas, aerosol, and surface albedo forcings. This model reproduces the observed abrupt seasonal onset of the South Asian monsoon but produces a near-linear response of the mean monsoon by changing the duration of the summer circulation and the latitude of that circulation’s ascent branch. Thus, neither a physically correct theoretical model nor a comprehensive climate model support the idea that seasonal mean monsoons will undergo abrupt, nonlinear shifts in response to changes in greenhouse gas concentrations, aerosol emissions, or land surface albedo. PMID:26811462

  2. Improving linear accelerator service response with a real- time electronic event reporting system.

    PubMed

    Hoisak, Jeremy D P; Pawlicki, Todd; Kim, Gwe-Ya; Fletcher, Richard; Moore, Kevin L

    2014-09-08

    To track linear accelerator performance issues, an online event recording system was developed in-house for use by therapists and physicists to log the details of technical problems arising on our institution's four linear accelerators. In use since October 2010, the system was designed so that all clinical physicists would receive email notification when an event was logged. Starting in October 2012, we initiated a pilot project in collaboration with our linear accelerator vendor to explore a new model of service and support, in which event notifications were also sent electronically directly to dedicated engineers at the vendor's technical help desk, who then initiated a response to technical issues. Previously, technical issues were reported by telephone to the vendor's call center, which then disseminated information and coordinated a response with the Technical Support help desk and local service engineers. The purpose of this work was to investigate the improvements to clinical operations resulting from this new service model. The new and old service models were quantitatively compared by reviewing event logs and the oncology information system database in the nine months prior to and after initiation of the project. Here, we focus on events that resulted in an inoperative linear accelerator ("down" machine). Machine downtime, vendor response time, treatment cancellations, and event resolution were evaluated and compared over two equivalent time periods. In 389 clinical days, there were 119 machine-down events: 59 events before and 60 after introduction of the new model. In the new model, median time to service response decreased from 45 to 8 min, service engineer dispatch time decreased 44%, downtime per event decreased from 45 to 20 min, and treatment cancellations decreased 68%. The decreased vendor response time and reduced number of on-site visits by a service engineer resulted in decreased downtime and decreased patient treatment cancellations.

  3. Improving linear accelerator service response with a real- time electronic event reporting system.

    PubMed

    Hoisak, Jeremy D P; Pawlicki, Todd; Kim, Gwe-Ya; Fletcher, Richard; Moore, Kevin L

    2014-01-01

    To track linear accelerator performance issues, an online event recording system was developed in-house for use by therapists and physicists to log the details of technical problems arising on our institution's four linear accelerators. In use since October 2010, the system was designed so that all clinical physicists would receive email notification when an event was logged. Starting in October 2012, we initiated a pilot project in collaboration with our linear accelerator vendor to explore a new model of service and support, in which event notifications were also sent electronically directly to dedicated engineers at the vendor's technical help desk, who then initiated a response to technical issues. Previously, technical issues were reported by telephone to the vendor's call center, which then disseminated information and coordinated a response with the Technical Support help desk and local service engineers. The purpose of this work was to investigate the improvements to clinical operations resulting from this new service model. The new and old service models were quantitatively compared by reviewing event logs and the oncology information system database in the nine months prior to and after initiation of the project. Here, we focus on events that resulted in an inoperative linear accelerator ("down" machine). Machine downtime, vendor response time, treatment cancellations, and event resolution were evaluated and compared over two equivalent time periods. In 389 clinical days, there were 119 machine-down events: 59 events before and 60 after introduction of the new model. In the new model, median time to service response decreased from 45 to 8 min, service engineer dispatch time decreased 44%, downtime per event decreased from 45 to 20 min, and treatment cancellations decreased 68%. The decreased vendor response time and reduced number of on-site visits by a service engineer resulted in decreased downtime and decreased patient treatment cancellations. PMID

  4. Probiotics reduce symptoms of antibiotic use in a hospital setting: a randomized dose response study.

    PubMed

    Ouwehand, Arthur C; DongLian, Cai; Weijian, Xu; Stewart, Morgan; Ni, Jiayi; Stewart, Tad; Miller, Larry E

    2014-01-16

    Probiotics are known to reduce antibiotic associated diarrhea (AAD) and Clostridium difficile associated diarrhea (CDAD) risk in a strain-specific manner. The aim of this study was to determine the dose-response effect of a four strain probiotic combination (HOWARU(®) Restore) on the incidence of AAD and CDAD and severity of gastrointestinal symptoms in adult in-patients requiring antibiotic therapy. Patients (n=503) were randomized among three study groups: HOWARU(®) Restore probiotic 1.70×10(10) CFU (high-dose, n=168), HOWARU(®) Restore probiotic 4.17×10(9) CFU (low-dose, n=168), or placebo (n=167). Subjects were stratified by gender, age, and duration of antibiotic treatment. Study products were administered daily up to 7 days after the final antibiotic dose. The primary endpoint of the study was the incidence of AAD. Secondary endpoints included incidence of CDAD, diarrhea duration, stools per day, bloody stools, fever, abdominal cramping, and bloating. A significant dose-response effect on AAD was observed with incidences of 12.5, 19.6, and 24.6% with high-dose, low-dose, and placebo, respectively (p=0.02). CDAD was the same in both probiotic groups (1.8%) but different from the placebo group (4.8%; p=0.04). Incidences of fever, abdominal pain, and bloating were lower with increasing probiotic dose. The number of daily liquid stools and average duration of diarrhea decreased with higher probiotic dosage. The tested four strain probiotic combination appears to lower the risk of AAD, CDAD, and gastrointestinal symptoms in a dose-dependent manner in adult in-patients.

  5. Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

    SciTech Connect

    Balajee, A.S.; Meador, J.A.; Su, Y.

    2011-03-24

    It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellular mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the

  6. Comparison of the modified relative dose response (MRDR) and the relative dose response (RDR) in the assessment of vitamin A status in malnourished children.

    PubMed

    Wahed, M A; Alvarez, J O; Khaled, M A; Mahalanabis, D; Rahman, M M; Habte, D

    1995-06-01

    The modified-relative-dose-response (MRDR) test and the relative-dose-response (RDR) test were compared in 49 mildly to moderately malnourished Bangladeshi children. The MRDR test had a significantly lower sensitivity, detecting only 71% of children with very low serum retinol (< or = 0.35 mumol/L) and 33% of children with low serum retinol (0.355-0.70 mumol/L) compared with 100% and 80% for the RDR test, respectively. The MRDR test showed a very strong dependency on retinol-binding protein (RBP) saturation (ie, percent saturation of RBP with retinol) compared with the RDR test. Only 3 (23%) of 13 children with RBP saturation > or = 55% but low vitamin A stores were diagnosed as abnormal by the MRDR test. This suggests that when apo-RBP concentration is limiting, as it is in malnourished children, didehydroretinol, the analog used in the MRDR test cannot effectively compete with retinol for binding to apo-RBP. Under these circumstances, the MRDR test is rendered ineffective. The possibility of increasing the sensitivity of the test by using a high dose of didehydroretinol needs to be investigated. PMID:7762526

  7. The adequate stimulus for avian short latency vestibular responses to linear translation

    NASA Technical Reports Server (NTRS)

    Jones, T. A.; Jones, S. M.; Colbert, S.

    1998-01-01

    Transient linear acceleration stimuli have been shown to elicit eighth nerve vestibular compound action potentials in birds and mammals. The present study was undertaken to better define the nature of the adequate stimulus for neurons generating the response in the chicken (Gallus domesticus). In particular, the study evaluated the question of whether the neurons studied are most sensitive to the maximum level of linear acceleration achieved or to the rate of change in acceleration (da/dt, or jerk). To do this, vestibular response thresholds were measured as a function of stimulus onset slope. Traditional computer signal averaging was used to record responses to pulsed linear acceleration stimuli. Stimulus onset slope was systematically varied. Acceleration thresholds decreased with increasing stimulus onset slope (decreasing stimulus rise time). When stimuli were expressed in units of jerk (g/ms), thresholds were virtually constant for all stimulus rise times. Moreover, stimuli having identical jerk magnitudes but widely varying peak acceleration levels produced virtually identical responses. Vestibular response thresholds, latencies and amplitudes appear to be determined strictly by stimulus jerk magnitudes. Stimulus attributes such as peak acceleration or rise time alone do not provide sufficient information to predict response parameter quantities. Indeed, the major response parameters were shown to be virtually independent of peak acceleration levels or rise time when these stimulus features were isolated and considered separately. It is concluded that the neurons generating short latency vestibular evoked potentials do so as "jerk encoders" in the chicken. Primary afferents classified as "irregular", and which traditionally fall into the broad category of "dynamic" or "phasic" neurons, would seem to be the most likely candidates for the neural generators of short latency vestibular compound action potentials.

  8. Prediction analysis of dose equivalent responses of neutron dosemeters used at a MOX fuel facility.

    PubMed

    Tsujimura, N; Yoshida, T; Takada, C

    2011-07-01

    To predict how accurately neutron dosemeters can measure the neutron dose equivalent (rate) in MOX fuel fabrication facility work environments, the dose equivalent responses of neutron dosemeters were calculated by the spectral folding method. The dosemeters selected included two types of personal dosemeter, namely a thermoluminescent albedo neutron dosemeter and an electronic neutron dosemeter, three moderator-based neutron survey meters, and one special instrument called an H(p)(10) monitor. The calculations revealed the energy dependences of the responses expected within the entire range of neutron spectral variations observed in neutron fields at workplaces. PMID:21498409

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

    NASA Technical Reports Server (NTRS)

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

    2000-01-01

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

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

    PubMed

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

    2016-05-01

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

  11. Linear response range characterization and in vivo application of laser speckle imaging of blood flow dynamics

    NASA Astrophysics Data System (ADS)

    Choi, Bernard; Ramírez-San-Juan, Julio C.; Lotfi, Justin; Nelson, J. S.

    2006-07-01

    Noninvasive blood flow imaging can provide critical information on the state of biological tissue and the efficacy of approaches to treat disease. With laser speckle imaging (LSI), relative changes in blood flow are typically reported, with the assumption that the measured values are on a linear scale. A linear relationship between the measured and actual flow rate values has been suggested. The actual flow rate range, over which this linear relationship is valid, is unknown. Herein we report the linear response range and velocity dynamic range (VDR) of our LSI instrument at two relevant camera integration times. For integration times of 1 and 10 ms, the best case VDR was 80 and 60 dB, respectively, and the worst case VDR was 20 and 50 dB. The best case VDR values were similar to those reported in the literature for optical Doppler tomography. We also demonstrate the potential of LSI for monitoring blood flow dynamics in the rodent dorsal skinfold chamber model. These findings imply that LSI can provide accurate wide-field maps of microvascular blood flow rate dynamics and highlight heterogeneities in flow response to the application of exogenous agents.

  12. Linear response to leadership, effective temperature, and decision making in flocks

    NASA Astrophysics Data System (ADS)

    Pearce, Daniel J. G.; Giomi, Luca

    2016-08-01

    Large collections of autonomously moving agents, such as animals or micro-organisms, are able to flock coherently in space even in the absence of a central control mechanism. While the direction of the flock resulting from this critical behavior is random, this can be controlled by a small subset of informed individuals acting as leaders of the group. In this article we use the Vicsek model to investigate how flocks respond to leadership and make decisions. Using a combination of numerical simulations and continuous modeling we demonstrate that flocks display a linear response to leadership that can be cast in the framework of the fluctuation-dissipation theorem, identifying an effective temperature reflecting how promptly the flock reacts to the initiative of the leaders. The linear response to leadership also holds in the presence of two groups of informed individuals with competing interests, indicating that the flock's behavioral decision is determined by both the number of leaders and their degree of influence.

  13. Linear response to leadership, effective temperature and decision making in flocks

    NASA Astrophysics Data System (ADS)

    Pearce, Daniel; Giomi, Luca

    The Vicsek model is the prototypical system for studying collective behavior of interacting self propelled particles (SPPs). It has formed the basis for models explaining the collective behavior of many active systems including flocks of birds and swarms of insects. To the standard Vicsek model we introduce a small angular torque to a subset of the particles and observe how this effects the direction of polarisation of the entire swarm. This is analogous to a few informed birds trying to lead the rest of a large flock by initiating a turn. We find a linear response to this perturbation and fluctuations that are in agreement with fluctuation dissipation theorem. This allows the identification of an effective temperature for the Vicsek model that follows a power law with the noise amplitude. The linear response can also be extended to the process of decision-making, wherein flocks must decide between the behaviors of two competing subgroups of individuals.

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

    PubMed

    Pedersen, Eja; Waye, Kerstin Persson

    2004-12-01

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

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

    PubMed

    Pedersen, Eja; Waye, Kerstin Persson

    2004-12-01

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

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

    NASA Astrophysics Data System (ADS)

    Pedersen, Eja; Persson Waye, Kerstin

    2004-12-01

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

  17. Monte Carlo simulation of the dose response of a novel 2D silicon diode array for use in hybrid MRI–LINAC systems

    SciTech Connect

    Gargett, Maegan Rosenfeld, Anatoly; Oborn, Brad; Metcalfe, Peter

    2015-02-15

    Purpose: MRI-guided radiation therapy systems (MRIgRT) are being developed to improve online imaging during treatment delivery. At present, the operation of single point dosimeters and an ionization chamber array have been characterized in such systems. This work investigates a novel 2D diode array, named “magic plate,” for both single point calibration and 2D positional performance, the latter being a key element of modern radiotherapy techniques that will be delivered by these systems. Methods: GEANT4 Monte Carlo methods have been employed to study the dose response of a silicon diode array to 6 MV photon beams, in the presence of in-line and perpendicularly aligned uniform magnetic fields. The array consists of 121 silicon diodes (dimensions 1.5 × 1.5 × 0.38 mm{sup 3}) embedded in kapton substrate with 1 cm pitch, spanning a 10 × 10 cm{sup 2} area in total. A geometrically identical, water equivalent volume was simulated concurrently for comparison. The dose response of the silicon diode array was assessed for various photon beam field shapes and sizes, including an IMRT field, at 1 T. The dose response was further investigated at larger magnetic field strengths (1.5 and 3 T) for a 4 × 4 cm{sup 2} photon field size. Results: The magic plate diode array shows excellent correspondence (< ± 1%) to water dose in the in-line orientation, for all beam arrangements and magnetic field strengths investigated. The perpendicular orientation, however, exhibits a dose shift with respect to water at the high-dose-gradient beam edge of jaw-defined fields [maximum (4.3 ± 0.8)% over-response, maximum (1.8 ± 0.8)% under-response on opposing side for 1 T, uncertainty 1σ]. The trend is not evident in areas with in-field dose gradients typical of IMRT dose maps. Conclusions: A novel 121 pixel silicon diode array detector has been characterized by Monte Carlo simulation for its performance inside magnetic fields representative of current prototype and proposed MRI–linear

  18. Dose-Response Analysis of Factors Involved in Germination and Secondary Dormancy of Seeds of Sisymbrium officinale

    PubMed Central

    Hilhorst, Henk W. M.

    1990-01-01

    The role of nitrate as a promoter of germination of Sisymbrium officinale seeds was examined in optimal light conditions. It was shown that the requirement for nitrate was absolute. This was true for all seed lots used. The probit of germination in water was log-linearly related to the level of endogenous nitrate. Preincubation at 15°C resulted in an immediate decrease in germination, whereas in 25 millimolar KNO3 the decrease was delayed. The decline of germination in water was strongly correlated with the rate at which nitrate leached from the seeds. The germination response to a range of KNO3 concentrations was followed during preincubation at 24-hour intervals. During the entire 264-hour preincubation period increasingly higher nitrate concentrations were required to maintain a response. This resulted in a right-hand shift of the dose-response curve parallel to the x axis. After 120 hours the high maximum germination level started to decline. The dose-response curves could be simulated by an equation from the receptor-occupancy theory. It is proposed that induction of secondary dormancy is a result of a decrease of the number of nitrate receptors. After 24 and 48 hours of preincubation, the nitrate-response curves were biphasic. The biphasic character could be related to the level of endogenous nitrate and to a differential requirement for nitrate of two fractions of the seed population. Similarities with the behavior of fluence-response curves after prolonged dark incubation led to the hypothesis that phytochrome and nitrate share the same site of action. PMID:16667802

  19. Evidence from retractor bulbi EMG for linearized motor control of conditioned nictitating membrane responses.

    PubMed

    Lepora, N F; Mavritsaki, E; Porrill, J; Yeo, C H; Evinger, C; Dean, P

    2007-10-01

    Classical conditioning of nictitating membrane (NM) responses in rabbits is a robust model learning system, and experimental evidence indicates that conditioned responses (CRs) are controlled by the cerebellum. It is unknown whether cerebellar control signals deal directly with the complex nonlinearities of the plant (blink-related muscles and peripheral tissues) or whether the plant is linearized to ensure a simple relation between cerebellar neuronal firing and CR profile. To study this question, the retractor bulbi muscle EMG was recorded with implanted electrodes during NM conditioning. Pooled activity in accessory abducens motoneurons was estimated from spike trains extracted from the EMG traces, and its temporal profile was found to have an approximately Gaussian shape with peak amplitude linearly related to CR amplitude. The relation between motoneuron activity and CR profiles was accurately fitted by a first-order linear filter, with each spike input producing an exponentially decaying impulse response with time constant of order 0.1 s. Application of this first-order plant model to CR data from other laboratories suggested that, in these cases also, motoneuron activity had a Gaussian profile, with time-of-peak close to unconditioned stimulus (US) onset and SD proportional to the interval between conditioned stimulus and US onsets. These results suggest that for conditioned NM responses the cerebellum is presented with a simplified "virtual" plant that is a linearized version of the underlying nonlinear biological system. Analysis of a detailed plant model suggests that one method for linearising the plant would be appropriate recruitment of motor units.

  20. Challenges within the linear response approximation when studying enzyme catalysis and effects of mutations.

    PubMed

    Sharir-Ivry, Avital; Varatharaj, Rajapandian; Shurki, Avital

    2015-01-13

    Various aspects of the linear response approximation (LRA) approach were examined when calculating reaction barriers within an enzyme and its different mutants. Scaling the electrostatic interactions is shown to slightly affect the absolute values of the barriers but not the overall trend when comparing wild-type and mutants. Convergence of the overall energetics was shown to depend on the sampling. Finally, the contribution of particular residues was shown to be significant, despite its small value. PMID:26574227

  1. Excited states with internally contracted multireference coupled-cluster linear response theory

    NASA Astrophysics Data System (ADS)

    Samanta, Pradipta Kumar; Mukherjee, Debashis; Hanauer, Matthias; Köhn, Andreas

    2014-04-01

    In this paper, the linear response (LR) theory for the variant of internally contracted multireference coupled cluster (ic-MRCC) theory described by Hanauer and Köhn [J. Chem. Phys. 134, 204211 (2011)] has been formulated and implemented for the computation of the excitation energies relative to a ground state of pronounced multireference character. We find that straightforward application of the linear-response formalism to the time-averaged ic-MRCC Lagrangian leads to unphysical second-order poles. However, the coupling matrix elements that cause this behavior are shown to be negligible whenever the internally contracted approximation as such is justified. Hence, for the numerical implementation of the method, we adopt a Tamm-Dancoff-type approximation and neglect these couplings. This approximation is also consistent with an equation-of-motion based derivation, which neglects these couplings right from the start. We have implemented the linear-response approach in the ic-MRCC singles-and-doubles framework and applied our method to calculate excitation energies for a number of molecules ranging from CH2 to p-benzyne and conjugated polyenes (up to octatetraene). The computed excitation energies are found to be very accurate, even for the notoriously difficult case of doubly excited states. The ic-MRCC-LR theory is also applicable to systems with open-shell ground-state wavefunctions and is by construction not biased towards a particular reference determinant. We have also compared the linear-response approach to the computation of energy differences by direct state-specific ic-MRCC calculations. We finally compare to Mk-MRCC-LR theory for which spurious roots have been reported [T.-C. Jagau and J. Gauss, J. Chem. Phys. 137, 044116 (2012)], being due to the use of sufficiency conditions to solve the Mk-MRCC equations. No such problem is present in ic-MRCC-LR theory.

  2. Linear response subordination to intermittent energy release in off-equilibrium aging dynamics

    NASA Astrophysics Data System (ADS)

    Christiansen, Simon; Sibani, Paolo

    2008-03-01

    The interpretation of experimental and numerical data describing off-equilibrium aging dynamics crucially depends on the connection between spontaneous and induced fluctuations. The hypothesis that linear response fluctuations are statistically subordinated to irreversible outbursts of energy, so-called quakes, leads to predictions for the average values and the fluctuation spectra of physical observables in reasonable agreement with experimental results (see e.g. Sibani et al 2006 Phys. Rev. B 74 224407). Using simulational data from a simple but representative Ising model with plaquette interactions, direct statistical evidence supporting the subordination hypothesis is presented and discussed in this work. Both energy and magnetic fluctuations are analyzed, with and without an external magnetic field present. In all cases, fluctuation spectra have a Gaussian zero centered component. For large negative values, the energy spectrum additionally features an intermittent tail describing the quakes. In the magnetization spectrum, two intermittent tails are present. These are symmetric around zero for zero-field, but asymmetric in other cases. The field has thus a biasing effect on the spontaneous intermittent magnetic fluctuations. Furthermore, the field has a negligible effect on the energy fluctuation spectra. From the observed strict temporal correlation between quakes and intermittent magnetization fluctuations, it is possible to conclude that the linear response is controlled by the quakes and inherits their temporal statistics. On this basis, the information culled from intermittent linear response data can be analyzed in the same way as spontaneous thermal energy fluctuations. The latter have a central rôle in thermally activated dynamics, but are harder to measure than linear response data.

  3. A Response Surface Model Exploration of Dosing Strategies in Gastrointestinal Endoscopies Using Midazolam and Opioids

    PubMed Central

    Liou, Jing-Yang; Ting, Chien-Kun; Hou, Ming-Chih; Tsou, Mei-Yung

    2016-01-01

    Abstract Classical midazolam–opioid combination for gastrointestinal endoscopy sedation has been adopted for decades. Dosing regimens have been studied but most require fixed dosing intervals. We intend to use a sophisticated pharmacodynamic tool, response surface model (RSM), to simulate sedation using different regimens. RSM can predict patient's response during different phases of the examination and predict patient's wake-up time with precision and without the need for fixed dosing intervals. We believe it will aid physicians in guiding their dosing strategy and timing. The study is divided into 2 parts. The first part is the full Greco RSMs development for 3 distinct phases: esophagogastroduodenoscopy (EGD), colonoscopy, and intersession (the time lapse between procedures). Observer's Assessment of Alertness Score (OAA/S) is used to assess patient response. The second part simulates 6 regimens with different characteristics us