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

PubMed

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

2016-12-01

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

Effects of head-only or whole-body exposure to very low doses of 4HE (1000 MeV/n) particles

USDA-ARS?s Scientific Manuscript database

INTRODUCTION On exploratory class missions, astronauts will be exposed to a range of heavy particles which vary in linear energy transfer (LET). Previous research has shown a direct relationship between particle LET and cognitive performance such that, as particle LET decreases the dose needed to af...

Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP

PubMed Central

Kusuhara, Hiroyuki; Furuie, Hidetoshi; Inano, Akihiro; Sunagawa, Akihiro; Yamada, Saiko; Wu, Chunyong; Fukizawa, Shinya; Morimoto, Nozomi; Ieiri, Ichiro; Morishita, Mariko; Sumita, Kiminobu; Mayahara, Hiroshi; Fujita, Takuya; Maeda, Kazuya; Sugiyama, Yuichi

2012-01-01

BACKGROUND AND PURPOSE An ATP-binding cassette (ABC) transporter, breast cancer resistance protein (BCRP)/ABCG2, limits oral bioavailability of sulphasalazine. Here we examined the effect of curcumin, the principal curcuminoid of turmeric, on oral bioavailability of microdoses and therapeutic doses of sulphasalazine in humans. EXPERIMENTAL APPROACH Effects of curcumin were measured on the ATP-dependent sulphasalazine uptake by hBCRP-expressing membrane vesicles and on oral bioavailability of sulphasalazine in wild-type and Bcrp(–/–) mice. Eight healthy Japanese subjects received an oral dose of sulphasalazine suspension (100 µg) or tablets (2 g) alone or after curcumin tablets (2 g). Uptake of sulphasalazine was studied in HEK293 cells transfected with the influx transporter (OATP)2B1. KEY RESULTS Curcumin was a potent hBCRP inhibitor in vitro (Ki 0.70 ± 0.41 µM). Curcumin increased the area under the curve (AUC)0–8 of plasma sulphasalazine eightfold in wild-type mice at 300 and 400 mg·kg−1, but not in Bcrp(–/–) mice. Curcumin increased AUC0–24 of plasma sulphasalazine 2.0-fold at microdoses and 3.2-fold at therapeutic doses in humans. Non-linearity of the dose–exposure relationship was observed between microdoses and therapeutic doses of sulphasalazine. Sulphasalazine was a substrate for OATP2B1 (Km 1.7 ± 0.3 µM). Its linear index (dose/Km) at the therapeutic dose was high and may saturate OATP2B1. CONCLUSIONS AND IMPLICATIONS Curcumin can be used to investigate effects of BCRP on oral bioavailability of drugs in humans. Besides the limited dissolution, OATP2B1 saturation is a possible mechanism underlying non-linearity in the dose–exposure relationship of sulphasalazine. PMID:22300367

Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses.

PubMed

Marchand, Sandrine; Lamarche, Isabelle; Gobin, Patrice; Couet, William

2010-08-01

The aim of this study was to evaluate the effect of colistin methanesulphonate (CMS) dose on CMS and colistin pharmacokinetics in rats. Three rats per group received an intravenous bolus of CMS at a dose of 5, 15, 30, 60 or 120 mg/kg. Arterial blood samples were drawn at 0, 5, 15, 30, 60, 90, 120, 150 and 180 min. CMS and colistin plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of CMS and colistin were calculated by non-compartmental analysis. Linear relationships were observed between CMS and colistin AUCs to infinity and CMS doses, as well as between CMS and colistin C(max) and CMS doses. CMS and colistin pharmacokinetics were linear for a range of colistin concentrations covering the range of values encountered and recommended in patients even during treatment with higher doses.

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

Otake, M.; Schull, W.J.

This paper investigates the quantitative relationship of ionizing radiation to the occurrence of posterior lenticular opacities among the survivors of the atomic bombings of Hiroshima and Nagasaki suggested by the DS86 dosimetry system. DS86 doses are available for 1983 (93.4%) of the 2124 atomic bomb survivors analyzed in 1982. The DS86 kerma neutron component for Hiroshima survivors is much smaller than its comparable T65DR component, but still 4.2-fold higher (0.38 Gy at 6 Gy) than that in Nagasaki (0.09 Gy at 6 Gy). Thus, if the eye is especially sensitive to neutrons, there may yet be some useful information onmore » their effects, particularly in Hiroshima. The dose-response relationship has been evaluated as a function of the separately estimated gamma-ray and neutron doses. Among several different dose-response models without and with two thresholds, we have selected as the best model the one with the smallest x2 or the largest log likelihood value associated with the goodness of fit. The best fit is a linear gamma-linear neutron relationship which assumes different thresholds for the two types of radiation. Both gamma and neutron regression coefficients for the best fitting model are positive and highly significant for the estimated DS86 eye organ dose.« less

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

PubMed

Guckenberger, Matthias; Klement, Rainer Johannes; Allgäuer, Michael; Appold, Steffen; Dieckmann, Karin; Ernst, Iris; Ganswindt, Ute; Holy, Richard; Nestle, Ursula; Nevinny-Stickel, Meinhard; Semrau, Sabine; Sterzing, Florian; Wittig, Andrea; Andratschke, Nicolaus; Flentje, Michael

2013-10-01

To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Role of genetic background in induced instability

NASA Technical Reports Server (NTRS)

Kadhim, Munira A.; Nelson, G. A. (Principal Investigator)

2003-01-01

Genomic instability is effectively induced by ionizing radiation. Recently, evidence has accumulated supporting a relationship between genetic background and the radiation-induced genomic instability phenotype. This is possibly due to alterations in proteins responsible for maintenance of genomic integrity or altered oxidative metabolism. Studies in human cell lines, human primary cells, and mouse models have been performed predominantly using high linear energy transfer (LET) radiation, or high doses of low LET radiation. The interplay between genetics, radiation response, and genomic instability has not been fully determined at low doses of low LET radiation. However, recent studies using low doses of low LET radiation suggest that the relationship between genetic background and radiation-induced genomic instability may be more complicated than these same relationships at high LET or high doses of low LET radiation. The complexity of this relationship at low doses of low LET radiation suggests that more of the population may be at risk than previously recognized and may have implications for radiation risk assessment.

Aspirin as a potential modality for the chemoprevention of breast cancer: A dose-response meta-analysis of cohort studies from 857,831 participants

PubMed Central

Lu, Liming; Shi, Leiyu; Zeng, Jingchun; Wen, Zehuai

2017-01-01

Background Previous meta-analyses on the relationship between aspirin use and breast cancer risk have drawn inconsistent results. In addition, the threshold effect of different doses, frequencies and durations of aspirin use in preventing breast cancer have yet to be established. Results The search yielded 13 prospective cohort studies (N=857,831 participants) that reported an average of 7.6 cases/1,000 person-years of breast cancer during a follow-up period of from 4.4 to 14 years. With a random effects model, a borderline significant inverse association was observed between overall aspirin use and breast cancer risk, with a summarized RR = 0.94 (P = 0.051, 95% CI 0.87-1.01). The linear regression model was a better fit for the dose-response relationship, which displayed a potential relationship between the frequency of aspirin use and breast cancer risk (RR = 0.97, 0.95 and 0.90 for 5, 10 and 20 times/week aspirin use, respectively). It was also a better fit for the duration of aspirin use and breast cancer risk (RR = 0.86, 0.73 and 0.54 for 5, 10 and 20 years of aspirin use). Methods We searched MEDLINE, EMBASE and CENTRAL databases through early October 2016 for relevant prospective cohort studies of aspirin use and breast cancer risk. Meta-analysis of relative risks (RR) estimates associated with aspirin intake were presented by fixed or random effects models. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Conclusion Our study confirmed a dose-response relationship between aspirin use and breast cancer risk. For clinical prevention, long term (>5 years) consistent use (2-7 times/week) of aspirin appears to be more effective in achieving a protective effect against breast cancer. PMID:28418881

Aspirin as a potential modality for the chemoprevention of breast cancer: A dose-response meta-analysis of cohort studies from 857,831 participants.

PubMed

Lu, Liming; Shi, Leiyu; Zeng, Jingchun; Wen, Zehuai

2017-06-20

Previous meta-analyses on the relationship between aspirin use and breast cancer risk have drawn inconsistent results. In addition, the threshold effect of different doses, frequencies and durations of aspirin use in preventing breast cancer have yet to be established. The search yielded 13 prospective cohort studies (N=857,831 participants) that reported an average of 7.6 cases/1,000 person-years of breast cancer during a follow-up period of from 4.4 to 14 years. With a random effects model, a borderline significant inverse association was observed between overall aspirin use and breast cancer risk, with a summarized RR = 0.94 (P = 0.051, 95% CI 0.87-1.01). The linear regression model was a better fit for the dose-response relationship, which displayed a potential relationship between the frequency of aspirin use and breast cancer risk (RR = 0.97, 0.95 and 0.90 for 5, 10 and 20 times/week aspirin use, respectively). It was also a better fit for the duration of aspirin use and breast cancer risk (RR = 0.86, 0.73 and 0.54 for 5, 10 and 20 years of aspirin use). We searched MEDLINE, EMBASE and CENTRAL databases through early October 2016 for relevant prospective cohort studies of aspirin use and breast cancer risk. Meta-analysis of relative risks (RR) estimates associated with aspirin intake were presented by fixed or random effects models. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Our study confirmed a dose-response relationship between aspirin use and breast cancer risk. For clinical prevention, long term (>5 years) consistent use (2-7 times/week) of aspirin appears to be more effective in achieving a protective effect against breast cancer.

SU-G-TeP3-01: A New Approach for Calculating Variable Relative Biological Effectiveness in IMPT Optimization

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

Cao, W; Randeniya, K; Grosshans, D

2016-06-15

Purpose: To investigate the impact of a new approach for calculating relative biological effectiveness (RBE) in intensity-modulated proton therapy (IMPT) optimization on RBE-weighted dose distributions. This approach includes the nonlinear RBE for the high linear energy transfer (LET) region, which was revealed by recent experiments at our institution. In addition, this approach utilizes RBE data as a function of LET without using dose-averaged LET in calculating RBE values. Methods: We used a two-piece function for calculating RBE from LET. Within the Bragg peak, RBE is linearly correlated to LET. Beyond the Bragg peak, we use a nonlinear (quadratic) RBE functionmore » of LET based on our experimental. The IMPT optimization was devised to incorporate variable RBE by maximizing biological effect (based on the Linear Quadratic model) in tumor and minimizing biological effect in normal tissues. Three glioblastoma patients were retrospectively selected from our institution in this study. For each patient, three optimized IMPT plans were created based on three RBE resolutions, i.e., fixed RBE of 1.1 (RBE-1.1), variable RBE based on linear RBE and LET relationship (RBE-L), and variable RBE based on linear and quadratic relationship (RBE-LQ). The RBE weighted dose distributions of each optimized plan were evaluated in terms of different RBE values, i.e., RBE-1.1, RBE-L and RBE-LQ. Results: The RBE weighted doses recalculated from RBE-1.1 based optimized plans demonstrated an increasing pattern from using RBE-1.1, RBE-L to RBE-LQ consistently for all three patients. The variable RBE (RBE-L and RBE-LQ) weighted dose distributions recalculated from RBE-L and RBE-LQ based optimization were more homogenous within the targets and better spared in the critical structures than the ones recalculated from RBE-1.1 based optimization. Conclusion: We implemented a new approach for RBE calculation and optimization and demonstrated potential benefits of improving tumor coverage and normal sparing in IMPT planning.« less

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

PubMed

Qi, Hui; Li, Shixue

2014-04-01

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

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

PubMed

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

2016-05-01

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

Analysis of pharmacokinetics of Gd-DTPA for dynamic contrast-enhanced magnetic resonance imaging.

PubMed

Taheri, Saeid; Shah, N Jon; Rosenberg, Gary A

2016-09-01

The pharmacokinetics (PK) of the contrast agent Gd-DTPA administered intravenously (i.v.) for contrast-enhanced MR imaging (DCE-MRI) is an important factor for quantitative data acquisition. We studied the effect of various initial bolus doses on the PK of Gd-DTPA and analyzed population PK of a lower dose for intra-subject variations in DCE-MRI. First, fifteen subjects (23-85years, M/F) were randomly divided into four groups for DCE-MRI with different Gd-DTPA dose: group-I, 0.1mmol/kg, n=4; group-II, 0.05mmol/kg, n=4; group-III, 0.025mmol/kg, n=4; and group-IV, 0.0125mmol/kg, n=3. Sequential fast T1 mapping sequence, after a bolus i.v. Gd-DTPA administered, and a linear T1-[Gd-DTPA] relationship were used to estimate the PK of Gd-DTPA. Secondly, MR-acquired PKs of Gd-DTPA from 58 subjects (28-80years, M/F) were collected retrospectively, from an ongoing study of the brain using DCE-MRI with Gd-DTPA at 0.025mmol/kg, to statistically analyze population PK of Gd-DTPA. We found that the PK of Gd-DTPA (i.v. 0.025mmol/kg) had a half-life of 37.3±6.6min, and was a better fit into a linear T1-[Gd-DTPA] relationship than higher doses (up to 0.1mmol/kg). The area under the curve (AUC) for 0.025mmol/kg was 3.37±0.46, which was a quarter of AUC of 0.1mmol/kg. In population analysis, a dose of 0.025mmol/kg of Gd-DTPA provided less than 5% subject-dependent variation in the PK of Gd-DTPA. Administration of 0.025mmol/kg Gd-DTPA enabled us to estimate [Gd-DTPA] from T1 by using a linear relationship that has a lower estimation error compared to a non-linear relationship. DCE-MRI with a quarter dose of Gd-DTPA is more sensitive to detect changes in [Gd-DTPA]. Copyright © 2016 Elsevier Inc. All rights reserved.

Technical Note: Statistical dependences between channels in radiochromic film readings. Implications in multichannel dosimetry.

PubMed

González-López, Antonio; Vera-Sánchez, Juan Antonio; Ruiz-Morales, Carmen

2016-05-01

This note studies the statistical relationships between color channels in radiochromic film readings with flatbed scanners. The same relationships are studied for noise. Finally, their implications for multichannel film dosimetry are discussed. Radiochromic films exposed to wedged fields of 6 MV energy were read in a flatbed scanner. The joint histograms of pairs of color channels were used to obtain the joint and conditional probability density functions between channels. Then, the conditional expectations and variances of one channel given another channel were obtained. Noise was extracted from film readings by means of a multiresolution analysis. Two different dose ranges were analyzed, the first one ranging from 112 to 473 cGy and the second one from 52 to 1290 cGy. For the smallest dose range, the conditional expectations of one channel given another channel can be approximated by linear functions, while the conditional variances are fairly constant. The slopes of the linear relationships between channels can be used to simplify the expression that estimates the dose by means of the multichannel method. The slopes of the linear relationships between each channel and the red one can also be interpreted as weights in the final contribution to dose estimation. However, for the largest dose range, the conditional expectations of one channel given another channel are no longer linear functions. Finally, noises in different channels were found to correlate weakly. Signals present in different channels of radiochromic film readings show a strong statistical dependence. By contrast, noise correlates weakly between channels. For the smallest dose range analyzed, the linear behavior between the conditional expectation of one channel given another channel can be used to simplify calculations in multichannel film dosimetry.

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

PubMed

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

2016-05-01

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

Effect of hydrogen fluoride on pollen germination and pollen tube growth in Prunus avium L. cv. Royal Ann

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

Facteau, T.J.; Wang, S.Y.; Rowe, K.E.

1973-05-01

Increased fluoride (F) fumigation levels resulted in decrease in percent Royal Ann pollen germination and pollen tube growth. As dose (hour x concentration in ..mu.. gF/m/sup 3/) increased, Van pollen tube growth in vivo decreased. A linear relationship between increased dose and fluoride residue in the flowers was shown. 14 references, 5 figures.

Micronucleus induction in Vicia faba roots. Part 2. Biological effects of neutrons below 1 cGy.

PubMed

Marshall, I; Bianchi, M

1983-08-01

A dose-effect relationship has been established for high-energy neutrons (maximum energy 600 MeV) within a dose range of 0.2 to 80 cGy and for low-energy neutrons produced by a 252Cf source (mean energy 2.35 MeV) for doses between 0.2 and 5 cGy. The frequency of micronuclei was found to increase linearly with dose. The relative biological effectiveness (r.b.e) values calculated using 60Co radiation as a reference were, in the high-dose region, 4.7 +/- 0.4 and 11.8 +/- 1.3 for the high- and low-energy neutrons, respectively. At doses below 1 cGy constant values of 25.4 +/- 4.4 and 63.7 +/- 12 were reached for the respective neutron energies.

Dose-Effect Relationships for Recurrence of Keloid and Pterygium After Surgery and Radiotherapy

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

Kal, Henk B.; Veen, Ronald E.; Juergenliemk-Schulz, Ina M.

2009-05-01

Purpose: To show radiation dose-response relationships for recurrence of keloid and pterygium after radiotherapy following surgery. Methods and Materials: Using PubMed, we performed a retrospective review of articles reporting incidences and/or dose-response relationships for recurrence of keloid and pterygium after radiotherapy following surgery. The irradiation regimens identified were normalized by use of the linear-quadratic model; biologically effective doses (BEDs) were calculated. Results: For keloid recurrence after radiotherapy following keloid removal, with either teletherapy or brachytherapy, the recurrence rate after having delivered a BED greater than 30 Gy is less than 10%. For pterygium recurrence after bare sclera surgery and {supmore » 90}Sr {beta}-irradiation, a BED of about 30 Gy seems to be sufficient also to reduce the recurrence rate to less than 10%. Conclusions: Most of the doses in the radiotherapy schemes used for prevention of keloid recurrence after surgery are too low. In contrast, the doses applied in most regimens to prevent pterygium recurrence are too high. A scheme with a BED of 30 to 40 Gy seems to be sufficient to prevent recurrences of keloid as well as pterygium.« less

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.

Consequences of synergy between environmental carcinogens

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

Berenbaum, M.C.

1985-12-01

As it is generally impossible to determine dose-response relationships for carcinogens at the low concentrations in which they occur in the environment, risk-benefit considerations are by consensus based on the linear, no-threshold model, on the assumption that this represents the worst case. However, this assumption does not take into account the possibility of synergistic interactions between carcinogens. It is shown here that, as a result of such interactions, the dose-response curve for added risk due to any individual carcinogen will generally be steeper at lower doses than at higher doses, and consequently the risk at low environmental levels will bemore » higher than would be expected from a linear response. Moreover, this excess risk at low doses is shown to increase as the general level of environmental carcinogens rises and, independently of this effect, it may also increase with the number of carcinogens present.« less

Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune.

PubMed

Hall, E J

2001-01-01

The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.

Genomic instability, bystander effect, cytoplasmic irradiation and other phenomena that may achieve fame without fortune

NASA Technical Reports Server (NTRS)

Hall, E. J.

2001-01-01

The possible risk of induced malignancies in astronauts, as a consequence of the radiation environment in space, is a factor of concern for long term missions. Cancer risk estimates for high doses of low LET radiation are available from the epidemiological studies of the A-bomb survivors. Cancer risks at lower doses cannot be detected in epidemiological studies and must be inferred by extrapolation from the high dose risks. The standard setting bodies, such as the ICRP recommend a linear, no-threshold extrapolation of risks from high to low doses, but this is controversial. A study of mechanisms of carcinogenesis may shed some light on the validity of a linear extrapolation. The multi-step nature of carcinogenesis suggests that the role of radiation may be to induce a mutation leading to a mutator phenotype. High energy Fe ions, such as those encountered in space are highly effective in inducing genomic instability. Experiments involving the single particle microbeam have demonstrated a "bystander effect", ie a biological effect in cells not themselves hit, but in close proximity to those that are, as well as the induction of mutations in cells where only the cytoplasm, and not the nucleus, have been traversed by a charged particle. These recent experiments cast doubt on the validity of a simple linear extrapolation, but the data are so far fragmentary and conflicting. More studies are necessary. While mechanistic studies cannot replace epidemiology as a source of quantitative risk estimates, they may shed some light on the shape of the dose response relationship and therefore on the limitations of a linear extrapolation to low doses.

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

PubMed

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

2009-06-01

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

Technical Note: Statistical dependences between channels in radiochromic film readings. Implications in multichannel dosimetry

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

González-López, Antonio, E-mail: antonio.gonzalez7@carm.es; Vera-Sánchez, Juan Antonio; Ruiz-Morales, Carmen

Purpose: This note studies the statistical relationships between color channels in radiochromic film readings with flatbed scanners. The same relationships are studied for noise. Finally, their implications for multichannel film dosimetry are discussed. Methods: Radiochromic films exposed to wedged fields of 6 MV energy were read in a flatbed scanner. The joint histograms of pairs of color channels were used to obtain the joint and conditional probability density functions between channels. Then, the conditional expectations and variances of one channel given another channel were obtained. Noise was extracted from film readings by means of a multiresolution analysis. Two different dosemore » ranges were analyzed, the first one ranging from 112 to 473 cGy and the second one from 52 to 1290 cGy. Results: For the smallest dose range, the conditional expectations of one channel given another channel can be approximated by linear functions, while the conditional variances are fairly constant. The slopes of the linear relationships between channels can be used to simplify the expression that estimates the dose by means of the multichannel method. The slopes of the linear relationships between each channel and the red one can also be interpreted as weights in the final contribution to dose estimation. However, for the largest dose range, the conditional expectations of one channel given another channel are no longer linear functions. Finally, noises in different channels were found to correlate weakly. Conclusions: Signals present in different channels of radiochromic film readings show a strong statistical dependence. By contrast, noise correlates weakly between channels. For the smallest dose range analyzed, the linear behavior between the conditional expectation of one channel given another channel can be used to simplify calculations in multichannel film dosimetry.« less

TGF-beta in human milk is associated with wheeze in infancy.

PubMed

Oddy, Wendy H; Halonen, Marilyn; Martinez, F D; Lohman, I Carla; Stern, Debra A; Kurzius-Spencer, Margaret; Guerra, Stefano; Wright, Anne L

2003-10-01

Cytokines secreted in human milk might play important roles in newborn health and in the development of infant immune responses. We investigated the relationship of the concentration and dose of cytokines in human milk to infant wheeze at 1 year of age. Our objective was to test whether the cytokines in milk could account for some of the apparent protective effect of breast-feeding against wheeze in the first year of life. Data on breast-feeding and infant wheeze were collected prospectively from birth to 1 year from 243 mothers participating in the Infant Immune Study in Tucson, Arizona. Breast milk samples obtained at a mean age of 11 days postpartum were assayed by means of ELISA for concentrations of TGF-beta1, IL-10, TNF-alpha, and the soluble form of CD14. The dose of each cytokine was assessed for a relationship with wheeze in bivariate and logistic regression analyses. Increasing duration of breast-feeding was significantly associated with a decreased prevalence of wheeze (P =.039). There was wide variability in levels of each cytokine in milk, as well as variability between women in the amount of each cytokine produced. There was a significant inverse association between the dose of TGF-beta1 received through milk with the percentage of wheeze (P =.017), and the relationship was linear (P =.006). None of the other cytokines showed a linear relationship with wheeze. In multivariate analyses the risk of wheeze was significantly decreased (odds ratio, 0.22; 95% CI 0.05-0.89; P =.034) with increasing TGF-beta1 dose (long breast-feeding and medium-high TGF-beta1 level compared with short breast-feeding and low TGF-beta. This analysis shows that the dose of TGF-beta1 received from milk has a significant relationship with infant wheeze, which might account for at least some of the protective effect of breast-feeding against wheeze.

BENCHMARK DOSE TECHNICAL GUIDANCE DOCUMENT ...

EPA Pesticide Factsheets

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

Cancer risk above 1 Gy and the impact for space radiation protection

NASA Astrophysics Data System (ADS)

Schneider, Uwe; Walsh, Linda

2009-07-01

Analyses of the epidemiological data on the Japanese A-bomb survivors, who were exposed to γ-rays and neutrons, provide most current information on the dose-response of radiation-induced cancer. Since the dose span of main interest is usually between 0 and 1 Gy, for radiation protection purposes, the analysis of the A-bomb survivors is often focused on this range. However, estimates of cancer risk for doses larger than 1 Gy are becoming more important for long-term manned space missions. Therefore in this work, emphasis is placed on doses larger than 1 Gy with respect to radiation-induced solid cancer and leukemia mortality. The present analysis of the A-bomb survivors data was extended by including two extra high-dose categories and applying organ-averaged dose instead of the colon-weighted dose. In addition, since there are some recent indications for a high neutron dose contribution, the data were fitted separately for three different values for the relative biological effectiveness (RBE) of the neutrons (10, 35 and 100) and a variable RBE as a function of dose. The data were fitted using a linear and a linear-exponential dose-response relationship using a dose and dose-rate effectiveness factor (DDREF) of both one and two. The work presented here implies that the use of organ-averaged dose, a dose-dependent neutron RBE and the bending-over of the dose-response relationship for radiation-induced cancer could result in a reduction of radiation risk by around 50% above 1 Gy. This could impact radiation risk estimates for space crews on long-term mission above 500 days who might be exposed to doses above 1 Gy. The consequence of using a DDREF of one instead of two increases cancer risk by about 40% and would therefore balance the risk decrease described above.

My older sibling was drunk - younger siblings' drunkenness in relation to parental monitoring and the parent-adolescent relationship.

PubMed

Gossrau-Breen, Diana; Kuntsche, Emmanuel; Gmel, Gerhard

2010-10-01

This study explored the links between having older siblings who get drunk, satisfaction with the parent-adolescent relationship, parental monitoring, and adolescents' risky drinking. Regression models were conducted based on a national representative sample of 3725 8th to 10th graders in Switzerland (mean age 15.0, SD = .93) who indicated having older siblings. Results showed that both parental factors and older siblings' drinking behaviour shape younger siblings' frequency of risky drinking. Parental monitoring showed a linear dose-response relationship, and siblings' influence had an additive effect. There was a non-linear interaction effect between parent-adolescent relationship and older sibling's drunkenness. The findings suggest that, apart from avoiding an increasingly unsatisfactory relationship with their children, parental monitoring appears to be important in preventing risky drinking by their younger children, even if the older sibling drinks in such a way. However, a satisfying relationship with parents does not seem to be sufficient to counterbalance older siblings' influence.

Pain and anxiety and their relationship with medication doses in the intensive care unit.

PubMed

Park, Sunyoung; Na, Se Hee; Oh, Jooyoung; Lee, Jong Seok; Oh, Seung-Taek; Kim, Jae-Jin; Park, Jin Young

2018-06-02

Pain and anxiety are understudied despite their importance to the general medical condition. The aim of the present study was to examine the effects of pain and anxiety and their relationship to the doses of opioids and anxiolytics administered in intensive care unit (ICU) patients. The subjects included 1349 conscious, critically ill patients admitted to an ICU. Psychiatrists evaluated the patients daily for pain and anxiety. Data regarding the doses of opioids and benzodiazepines administered were gathered. Linear mixed model was used for analysis. The pain and anxiety experienced by patients in the ICU were significantly correlated. Pain had significant main effects on the dose of opioids administered. No significant effects of anxiety on the daily dose of anxiolytics or opioids given were detected. Due to their closely linked relationship, pain and anxiety, can affect one another, and one can influence the other to appear more severe. In addition, anxiety can be underestimated in ICU patients. The present study suggests the need for precise evaluation and a comprehensive approach to the management of pain and anxiety. In addition, this study implies that management of anxiety may affect pain reduction, given the close correlation between the two. Copyright © 2018 Elsevier Inc. All rights reserved.

Effects of acute beta-adrenergic antagonism on verbal problem solving in autism spectrum disorder and exploration of treatment response markers.

PubMed

Zamzow, Rachel M; Ferguson, Bradley J; Ragsdale, Alexandra S; Lewis, Morgan L; Beversdorf, David Q

2017-08-01

Autism spectrum disorder (ASD) is characterized by impairments in social communication as well as restricted, repetitive behaviors. Evidence suggests that some individuals with ASD have cognitive impairments related to weak central coherence and hyperrestricted processing. Reducing noradrenergic activity may improve aspects of network processing and thus improve cognitive abilities, such as verbal problem solving, in individuals with ASD. The present pilot study explores the effects of acute administration of the beta-adrenergic antagonist propranolol on verbal problem solving in adults and adolescents with ASD. In a within-subject crossover-design, 20 participants with ASD received a single dose of propranolol or placebo on one of two sessions in a double-blinded, counterbalanced manner. Verbal problem solving was assessed via an anagram task. Baseline measurements of autonomic nervous system functioning were obtained, and anxiety was assessed at baseline and following drug administration. Participants solved the anagrams more quickly in the propranolol condition, as compared to the placebo condition, suggesting a potential cognitive benefit of this agent. Additionally, we observed a negative linear relationship between response to propranolol on the anagram task and two measures of baseline autonomic activity, as well as a positive linear relationship between drug response and baseline anxiety. These relationships propose potential markers for treatment response, as propranolol influences both autonomic functioning and anxiety. Further investigation is needed to expand on the present single-dose psychopharmacological challenge and explore the observed effects of propranolol in a serial-dose setting.

The relationship between organ dose and patient size in tube current modulated adult thoracic CT scans

NASA Astrophysics Data System (ADS)

Khatonabadi, Maryam; Zhang, Di; Yang, Jeffrey; DeMarco, John J.; Cagnon, Chris C.; McNitt-Gray, Michael F.

2012-03-01

Recently published AAPM Task Group 204 developed conversion coefficients that use scanner reported CTDIvol to estimate dose to the center of patient undergoing fixed tube current body exam. However, most performed CT exams use TCM to reduce dose to patients. Therefore, the purpose of this study was to investigate the correlation between organ dose and a variety of patient size metrics in adult chest CT scans that use tube current modulation (TCM). Monte Carlo simulations were performed for 32 voxelized models with contoured lungs and glandular breasts tissue, consisting of females and males. These simulations made use of patient's actual TCM data to estimate organ dose. Using image data, different size metrics were calculated, these measurements were all performed on one slice, at the level of patient's nipple. Estimated doses were normalized by scanner-reported CTDIvol and plotted versus different metrics. CTDIvol values were plotted versus different metrics to look at scanner's output versus size. The metrics performed similarly in terms of correlating with organ dose. Looking at each gender separately, for male models normalized lung dose showed a better linear correlation (r2=0.91) with effective diameter, while female models showed higher correlation (r2=0.59) with the anterior-posterior measurement. There was essentially no correlation observed between size and CTDIvol-normalized breast dose. However, a linear relationship was observed between absolute breast dose and size. Dose to lungs and breasts were consistently higher in females with similar size as males which could be due to shape and composition differences between genders in the thoracic region.

High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances.

PubMed

Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

1987-12-01

Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment.

High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances.

PubMed Central

Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

1987-01-01

Recent investigations on mechanism of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment. PMID:3447904

Organometallic exposure dependence on organic–inorganic hybrid material formation in polyethylene terephthalate and polyamide 6 polymer fibers

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

Akyildiz, Halil I.; Jur, Jesse S., E-mail: jsjur@ncsu.edu

2015-03-15

The effect of exposure conditions and surface area on hybrid material formation during sequential vapor infiltrations of trimethylaluminum (TMA) into polyamide 6 (PA6) and polyethylene terephthalate (PET) fibers is investigated. Mass gain of the fabric samples after infiltration was examined to elucidate the reaction extent with increasing number of sequential TMA single exposures, defined as the times for a TMA dose and a hold period. An interdependent relationship between dosing time and holding time on the hybrid material formation is observed for TMA exposure PET, exhibited as a linear trend between the mass gain and total exposure (dose time ×more » hold time × number of sequential exposures). Deviation from this linear relationship is only observed under very long dose or hold times. In comparison, amount of hybrid material formed during sequential exposures to PA6 fibers is found to be highly dependent on amount of TMA dosed. Increasing the surface area of the fiber by altering its cross-sectional dimension is shown to have little on the reaction behavior but does allow for improved diffusion of the TMA into the fiber. This work allows for the projection of exposure parameters necessary for future high-throughput hybrid modifications to polymer materials.« less

Study of The Non-linear Uv Dosimetry In Simulated Extraterrestrial Conditions

NASA Astrophysics Data System (ADS)

Berces, A.; Kerekgyarto, T.; Ronto, G.; Lammer, H.; Kargl, G.; Komle, N. I.

In UV biological dosimetry the UV dose scale is additive starting at a value of zero ac- cording to the definition of CIE (Technical Report TC-6-18). The biological dose can be defined by a measured end-effect. In our dosimeters (phage T7 and uracil dosime- ter) exposed to natural (terrestrial) UV radiation the proportion of pyrimidin photo- products among the total photoproducts is smaller than 10 and the linear correlation between the biological and physical dose is higher than 0.9. According to the experi- mental data this linear relationship is often not valid. We observed that UV radiation did not only induce dimerisation but shorter wavelengths caused monomerisation of pyrimidin dimers. Performing the irradiation in oxygen free environment and using a Deuterium lamp as UV source, we could increase monomerisation against dimerisa- tion thus the DNA-based dosimetrySs additivity rule is not fulfilled in these conditions. In this study we will demonstrate those non-linear experiments which constitute the basis of our biological experiments on the International Space Station.

Straightening Beta: Overdispersion of Lethal Chromosome Aberrations following Radiotherapeutic Doses Leads to Terminal Linearity in the Alpha–Beta Model

PubMed Central

Shuryak, Igor; Loucas, Bradford D.; Cornforth, Michael N.

2017-01-01

Recent technological advances allow precise radiation delivery to tumor targets. As opposed to more conventional radiotherapy—where multiple small fractions are given—in some cases, the preferred course of treatment may involve only a few (or even one) large dose(s) per fraction. Under these conditions, the choice of appropriate radiobiological model complicates the tasks of predicting radiotherapy outcomes and designing new treatment regimens. The most commonly used model for this purpose is the venerable linear-quadratic (LQ) formalism as it applies to cell survival. However, predictions based on the LQ model are frequently at odds with data following very high acute doses. In particular, although the LQ predicts a continuously bending dose–response relationship for the logarithm of cell survival, empirical evidence over the high-dose region suggests that the survival response is instead log-linear with dose. Here, we show that the distribution of lethal chromosomal lesions among individual human cells (lymphocytes and fibroblasts) exposed to gamma rays and X rays is somewhat overdispersed, compared with the Poisson distribution. Further, we show that such overdispersion affects the predicted dose response for cell survival (the fraction of cells with zero lethal lesions). This causes the dose response to approximate log-linear behavior at high doses, even when the mean number of lethal lesions per cell is well fitted by the continuously curving LQ model. Accounting for overdispersion of lethal lesions provides a novel, mechanistically based explanation for the observed shapes of cell survival dose responses that, in principle, may offer a tractable and clinically useful approach for modeling the effects of high doses per fraction. PMID:29312888

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

PubMed

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

2016-12-01

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

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

PubMed

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

2017-03-01

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

Bisphenol-A exposures and behavioural aberrations: median and linear spline and meta-regression analyses of 12 toxicity studies in rodents.

PubMed

Peluso, Marco E M; Munnia, Armelle; Ceppi, Marcello

2014-11-05

Exposures to bisphenol-A, a weak estrogenic chemical, largely used for the production of plastic containers, can affect the rodent behaviour. Thus, we examined the relationships between bisphenol-A and the anxiety-like behaviour, spatial skills, and aggressiveness, in 12 toxicity studies of rodent offspring from females orally exposed to bisphenol-A, while pregnant and/or lactating, by median and linear splines analyses. Subsequently, the meta-regression analysis was applied to quantify the behavioural changes. U-shaped, inverted U-shaped and J-shaped dose-response curves were found to describe the relationships between bisphenol-A with the behavioural outcomes. The occurrence of anxiogenic-like effects and spatial skill changes displayed U-shaped and inverted U-shaped curves, respectively, providing examples of effects that are observed at low-doses. Conversely, a J-dose-response relationship was observed for aggressiveness. When the proportion of rodents expressing certain traits or the time that they employed to manifest an attitude was analysed, the meta-regression indicated that a borderline significant increment of anxiogenic-like effects was present at low-doses regardless of sexes (β)=-0.8%, 95% C.I. -1.7/0.1, P=0.076, at ≤120 μg bisphenol-A. Whereas, only bisphenol-A-males exhibited a significant inhibition of spatial skills (β)=0.7%, 95% C.I. 0.2/1.2, P=0.004, at ≤100 μg/day. A significant increment of aggressiveness was observed in both the sexes (β)=67.9,C.I. 3.4, 172.5, P=0.038, at >4.0 μg. Then, bisphenol-A treatments significantly abrogated spatial learning and ability in males (P<0.001 vs. females). Overall, our study showed that developmental exposures to low-doses of bisphenol-A, e.g. ≤120 μg/day, were associated to behavioural aberrations in offspring. Copyright © 2014. Published by Elsevier Ireland Ltd.

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

PubMed Central

Vollet, Kaitlin; Dietrich, Kim N.

2016-01-01

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

Studies of Inhibition of Intestinal Absorption of Radioactive Strontium

PubMed Central

Skoryna, Stanley C.; Paul, T. M.; Waldron-Edward, Deirdre

1965-01-01

A method is reported which permits selective suppression of absorption of radioactive strontium from ingested food material, allowing calcium to be available to the body. Studies were carried out on the inhibitory effect of various amounts of sodium alginate and the dose-response relationship of Sr89 and bone uptake. The results obtained indicated that under laboratory conditions sodium alginate effectively reduces Sr89 uptake in a constant proportion. This effect was observed at the three levels of administration of 1.4%, 12% and 24% of sodium alginate. The linear relationship between the dosage of the radioisotope and the bone uptake in the presence of sodium alginate suggests that the same proportion is maintained at the lower levels of intake of radioactive strontium. Previous studies with small constant doses of sodium alginate were extended in rats to a period corresponding approximately to three years of human life span. Low doses were sufficient to reduce appreciably bone uptake of radiostrontium. PMID:14341649

Measuring and statistically testing the size of the effect of a chemical compound on a continuous in-vitro pharmacological response through a new statistical model of response detection limit

PubMed Central

Diaz, Francisco J.; McDonald, Peter R.; Pinter, Abraham; Chaguturu, Rathnam

2018-01-01

Biomolecular screening research frequently searches for the chemical compounds that are most likely to make a biochemical or cell-based assay system produce a strong continuous response. Several doses are tested with each compound and it is assumed that, if there is a dose-response relationship, the relationship follows a monotonic curve, usually a version of the median-effect equation. However, the null hypothesis of no relationship cannot be statistically tested using this equation. We used a linearized version of this equation to define a measure of pharmacological effect size, and use this measure to rank the investigated compounds in order of their overall capability to produce strong responses. The null hypothesis that none of the examined doses of a particular compound produced a strong response can be tested with this approach. The proposed approach is based on a new statistical model of the important concept of response detection limit, a concept that is usually neglected in the analysis of dose-response data with continuous responses. The methodology is illustrated with data from a study searching for compounds that neutralize the infection by a human immunodeficiency virus of brain glioblastoma cells. PMID:24905187

SU-F-18C-12: On the Relationship of the Weighted Dose to the Surface Dose In Abdominal CT - Patient Size Dependency

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

Zhou, Y; Scott, A; Allahverdian, J

2014-06-15

Purpose: It is possible to measure the patient surface dose non-invasively using radiolucent dosimeters. However, the patient size specific weighted dose remains unknown. We attempted to study the weighted dose to surface dose relationship as the patient size varies in abdominal CT. Methods: Seven abdomen phantoms (CIRS TE series) simulating patients from an infant to a large adult were used. Size specific doses were measured with a 100 mm CT chamber under axial scans using a Siemens Sensation 64 (mCT) and a GE 750 HD. The scanner settings were 120 kVp, 200 mAs with fully opened collimations. Additional kVps (80,more » 100, 140) were added depending on the phantom sizes. The ratios (r) of the weighted CT dose (Dw) to the surface dose (Ds) were related to the phantom size (L) defined as the diameter resulting the equivalent cross-sectional area. Results: The Dw versus Ds ratio (r) was fitted to a linear relationship: r = 1.083 − 0.007L (R square = 0.995), and r = 1.064 − 0.007L (R square = 0.953), for Siemens Sensation 64 and GE 750 HD, respectively. The relationship appears to be independent of the scanner specifics. Conclusion: The surface dose to the weighted dose ratio decreases linearly as the patient size increases. The result is independent of the scanner specifics. The result can be used to obtain in vivo CT dosimetry in abdominal CT.« less

Dose-effect relationships, epidemiological analysis and the derivation of low dose risk.

PubMed

Leenhouts, H P; Chadwick, K H

2011-03-01

This paper expands on our recent comments in a letter to this journal about the analysis of epidemiological studies and the determination of low dose RBE of low LET radiation (Chadwick and Leenhouts 2009 J. Radiol. Prot. 29 445-7). Using the assumption that radiation induced cancer arises from a somatic mutation (Chadwick and Leenhouts 2011 J. Radiol. Prot. 31 41-8) a model equation is derived to describe cancer induction as a function of dose. The model is described briefly, evidence is provided in support of it, and it is applied to a set of experimental animal data. The results are compared with a linear fit to the data as has often been done in epidemiological studies. The article presents arguments to support several related messages which are relevant to epidemiological analysis, the derivation of low dose risk and the weighting factor of sparsely ionising radiations. The messages are: (a) cancer incidence following acute exposure should, in principle, be fitted to a linear-quadratic curve with cell killing using all the data available; (b) the acute data are dominated by the quadratic component of dose; (c) the linear fit of any acute data will essentially be dependent on the quadratic component and will be unrelated to the effectiveness of the radiation at low doses; consequently, (d) the method used by ICRP to derive low dose risk from the atomic bomb survivor data means that it is unrelated to the effectiveness of the hard gamma radiation at low radiation doses; (e) the low dose risk value should, therefore, not be used as if it were representative for hard gamma rays to argue for an increased weighting factor for tritium and soft x-rays even though there are mechanistic reasons to expect this; (f) epidemiological studies of chronically exposed populations supported by appropriate cellular radiobiological studies have the best chance of revealing different RBE values for different sparsely ionising radiations.

Iodine-131 treatment and chromosomal damage: in vivo dose-effect relationship.

PubMed

Erselcan, Taner; Sungu, Selma; Ozdemir, Semra; Turgut, Bulent; Dogan, Derya; Ozdemir, Ozturk

2004-05-01

Although it is well known that radiation induces chromosomal aberrations, there is a lack of information on the in vivo dose-effect relationship in patients receiving iodine-131 treatment, and the results of previous studies are controversial. In this study, the sister chromatid exchange (SCE) method was employed to investigate acute and late chromosomal damage (CD) in the peripheral lymphocytes of 15 patients who received various doses of (131)I (259-3,700 MBq), either for thyrotoxicosis (TTX) or for ablation treatment in differentiated thyroid cancer (DTC). The SCE frequencies in cultured peripheral lymphocytes were determined before treatment (to assess basal SCE frequencies), on the 3rd day (to assess acute SCE frequencies) and 6 months later (to assess late SCE frequencies). The basal, acute and late SCE frequencies (mean+/-SD) were 3.19+/-0.93, 10.83+/-1.72 and 5.75+/-2.06, respectively, in the whole group, and these values differed significantly from each other ( P<0.001). In order to perform a quantitative evaluation of the present data and a comparative analysis with the results of previous studies reported in the literature, we defined acute and late effects using a "damage ratio" (DR) and a "recovery ratio" (RR), based on the basal, acute and late data for individual patients. No statistically significant difference was found in the DR between DTC and TTX patients (76.4%+/-11.5% vs 67.6%+/-9.0%), while the mean RR was higher in TTX patients than in the DTC group (75.2%+/-24.4% vs 36.8%+/-13.7%). The DR on the 3rd day was not related to the administered (131)I dose in the whole group, but a negative correlation was found between the (131)I dose and the RR at the 6th month (r=-0.60, P=0.04). The best fit for this relationship was obtained by a linear-quadratic model, as y=104.89x-28.4x(2)+38.1 ( R(2)=0.51, P=0.04). On the other hand, comparative analysis with the results of previous studies with comparable sampling times revealed that the best fit for the relationships between the administered dose of (131)I and DR and RR were obtained with a linear-quadratic model (Y=alpha D+beta D(2)) rather than a linear one. However, there was an interesting difference in comparison with in vitro studies, in that we found the coefficient beta to have a negative value, suggesting the disappearance of damaged lymphocytes from the peripheral circulation in a dose-dependent manner following (131)I treatment. Further studies are therefore needed to clarify the effect of the negative beta value on the biological dosimetry approach in continuous internal low LET radiation, as in the case of (131)I treatment.

Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats

PubMed Central

Teitelbaum, Susan L.; Li, Qian; Lambertini, Luca; Belpoggi, Fiorella; Manservisi, Fabiana; Falcioni, Laura; Bua, Luciano; Silva, Manori J.; Ye, Xiaoyun; Calafat, Antonia M.; Chen, Jia

2015-01-01

Background Exposure to environmental chemicals, including phthalates and phenols such as parabens and triclosan, is ubiquitous within the U.S. general population. Objective This proof-of-concept rodent study examined the relationship between oral doses of three widely used personal care product ingredients [diethyl phthalate (DEP), methyl paraben (MPB), and triclosan] and urine and serum concentrations of their respective biomarkers. Methods Using female Sprague-Dawley rats, we carried out two rounds of experiments with oral gavage doses selected in accordance with no observed adverse effect levels (NOAELs) derived from previous studies: 1,735 (DEP), 1,050 (MPB), 50 (triclosan) mg/kg/day. Administered doses ranged from 0.005 to 173 mg/kg/day, 10–100,000 times below the NOAEL for each chemical. Controls for the MPB and triclosan experiments were animals treated with olive oil (vehicle) only; controls for the DEP serum experiments were animals treated with the lowest doses of MPB and triclosan. Doses were administered for 5 days with five rats in each treatment group. Urine and blood serum, collected on the last day of exposure, were analyzed for biomarkers. Relationships between oral dose and biomarker concentrations were assessed using linear regression. Results Biomarkers were detected in all control urine samples at parts-per-billion levels, suggesting a low endemic environmental exposure to the three chemicals that could not be controlled even with all of the precautionary measures undertaken. Among the exposed animals, urinary concentrations of all three biomarkers were orders of magnitude higher than those in serum. A consistently positive linear relationship between oral dose and urinary concentration was observed (R2 > 0.80); this relationship was inconsistent in serum. Conclusions Our study highlights the importance of carefully considering the oral dose used in animal experiments and provides useful information in selecting doses for future studies. Citation Teitelbaum SL, Li Q, Lambertini L, Belpoggi F, Manservisi F, Falcioni L, Bua L, Silva MJ, Ye X, Calafat AM, Chen J. 2016. Paired serum and urine concentrations of biomarkers of diethyl phthalate, methyl paraben, and triclosan in rats. Environ Health Perspect 124:39–45; http://dx.doi.org/10.1289/ehp.1409586 PMID:26047088

Single toxin dose-response models revisited

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

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

The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the fourmore » models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.« less

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

PubMed

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

2015-12-01

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

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.

Human salmonellosis: estimation of dose-illness from outbreak data.

PubMed

Bollaerts, Kaatje; Aerts, Marc; Faes, Christel; Grijspeerdt, Koen; Dewulf, Jeroen; Mintiens, Koen

2008-04-01

The quantification of the relationship between the amount of microbial organisms ingested and a specific outcome such as infection, illness, or mortality is a key aspect of quantitative risk assessment. A main problem in determining such dose-response models is the availability of appropriate data. Human feeding trials have been criticized because only young healthy volunteers are selected to participate and low doses, as often occurring in real life, are typically not considered. Epidemiological outbreak data are considered to be more valuable, but are more subject to data uncertainty. In this article, we model the dose-illness relationship based on data of 20 Salmonella outbreaks, as discussed by the World Health Organization. In particular, we model the dose-illness relationship using generalized linear mixed models and fractional polynomials of dose. The fractional polynomial models are modified to satisfy the properties of different types of dose-illness models as proposed by Teunis et al. Within these models, differences in host susceptibility (susceptible versus normal population) are modeled as fixed effects whereas differences in serovar type and food matrix are modeled as random effects. In addition, two bootstrap procedures are presented. A first procedure accounts for stochastic variability whereas a second procedure accounts for both stochastic variability and data uncertainty. The analyses indicate that the susceptible population has a higher probability of illness at low dose levels when the combination pathogen-food matrix is extremely virulent and at high dose levels when the combination is less virulent. Furthermore, the analyses suggest that immunity exists in the normal population but not in the susceptible population.

[Optimizing staff radiation protection in radiology by minimizing the effective dose].

PubMed

von Boetticher, H; Lachmund, J; Hoffmann, W; Luska, G

2006-03-01

In the present study the optimization of radiation protection devices is achieved by minimizing the effective dose of the staff members since the stochastic radiation effects correlate to the effective dose. Radiation exposure dosimetry was performed with TLD measurements using one Alderson Phantom in the patient position and a second phantom in the typical position of the personnel. Various types of protective clothing as well as fixed shields were considered in the calculations. It was shown that the doses of the unshielded organs (thyroid, parts of the active bone marrow) contribute significantly to the effective dose of the staff. Therefore, there is no linear relationship between the shielding factors for protective garments and the effective dose. An additional thyroid protection collar reduces the effective dose by a factor of 1.7 - 3.0. X-ray protective clothing with a 0.35 mm lead equivalent and an additional thyroid protection collar provides better protection against radiation than an apron with a 0.5 mm lead equivalent but no collar. The use of thyroid protection collars is an effective preventive measure against exceeding occupational organ dose limits, and a thyroid shield also considerably reduces the effective dose. Therefore, thyroid protection collars should be a required component of anti-X protection.

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

PubMed

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

2018-06-01

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

Assessing the relative potency of (S)- and (R)-warfarin with a new PK-PD model, in relation to VKORC1 genotypes.

PubMed

Ferrari, Myriam; Pengo, Vittorio; Barolo, Massimiliano; Bezzo, Fabrizio; Padrini, Roberto

2017-06-01

The purpose of this study is to develop a new pharmacokinetic-pharmacodynamic (PK-PD) model to characterise the contribution of (S)- and (R)-warfarin to the anticoagulant effect on patients in treatment with rac-warfarin. Fifty-seven patients starting warfarin (W) therapy were studied, from the first dose and during chronic treatment at INR stabilization. Plasma concentrations of (S)- and (R)-W and INRs were measured 12, 36 and 60 h after the first dose and at steady state 12-14 h after dosing. Patients were also genotyped for the G>A VKORC1 polymorphism. The PK-PD model assumed a linear relationship between W enantiomer concentration and INR and included a scaling factor k to account for a different potency of (R)-W. Two parallel compartment chains with different transit times (MTT 1 and MTT 2 ) were used to model the delay in the W effect. PD parameters were estimated with the maximum likelihood approach. The model satisfactorily described the mean time-course of INR, both after the initial dose and during long-term treatment. (R)-W contributed to the rac-W anticoagulant effect with a potency of about 27% that of (S)-W. This effect was independent of VKORC1 genotype. As expected, the slope of the PK/PD linear correlation increased stepwise from GG to GA and from GA to AA VKORC1 genotype (0.71, 0.90 and 1.49, respectively). Our PK-PD linear model can quantify the partial pharmacodynamic activity of (R)-W in patients contemporaneously exposed to therapeutic (S)-W plasma levels. This concept may be useful in improving the performance of future algorithms aiming at identifying the most appropriate W maintenance dose.

Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs.

PubMed

Andreasen, Nancy C; Pressler, Marcus; Nopoulos, Peg; Miller, Del; Ho, Beng-Choon

2010-02-01

A standardized quantitative method for comparing dosages of different drugs is a useful tool for designing clinical trials and for examining the effects of long-term medication side effects such as tardive dyskinesia. Such a method requires establishing dose equivalents. An expert consensus group has published charts of equivalent doses for various antipsychotic medications for first- and second-generation medications. These charts were used in this study. Regression was used to compare each drug in the experts' charts to chlorpromazine and haloperidol and to create formulas for each relationship. The formulas were solved for chlorpromazine 100 mg and haloperidol 2 mg to derive new chlorpromazine and haloperidol equivalents. The formulas were incorporated into our definition of dose-years such that 100 mg/day of chlorpromazine equivalent or 2 mg/day of haloperidol equivalent taken for 1 year is equal to one dose-year. All comparisons to chlorpromazine and haloperidol were highly linear with R(2) values greater than .9. A power transformation further improved linearity. By deriving a unique formula that converts doses to chlorpromazine or haloperidol equivalents, we can compare otherwise dissimilar drugs. These equivalents can be multiplied by the time an individual has been on a given dose to derive a cumulative value measured in dose-years in the form of (chlorpromazine equivalent in mg) x (time on dose measured in years). After each dose has been converted to dose-years, the results can be summed to provide a cumulative quantitative measure of lifetime exposure. Copyright 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.

PubMed

Zhao, Yan; Guo, Chenyang; Hu, Hongtao; Zheng, Lin; Ma, Junli; Jiang, Li; Zhao, Erjiang; Li, Hailiang

2017-02-07

Previously reported findings on the association between folate intake or serum folate levels and esophageal cancer risk have been inconsistent. This study aims to summarize the evidence regarding these relationships using a dose-response meta-analysis approach. We performed electronic searches of the Pubmed, Medline and Cochrane Library electronic databases to identify studies examining the effect of folate on the risk of esophageal cancer. Ultimately, 19 studies were included in the meta-analysis. Summary odds ratios (ORs) were estimated using a random effects model. A linear regression analysis of the natural logarithm of the OR was carried out to assess the possible dose-response relationship between folate intake and esophageal cancer risk. The pooled ORs for esophageal cancer in the highest vs. lowest levels of dietary folate intake and serum folate were 0.63 (95% CI: 0.56-0.71) and 0.71 (95% CI: 0.55-0.92), respectively. The dose-response meta-analysis indicated that a 100 μg/day increment in dietary folate intake reduced the estimate risk of esophageal cancer by 12%. These findings suggest that dietary and serum folate exert a protective effect against esophageal carcinogenesis.

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

PubMed

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

2017-06-01

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

Renal dysfunction after total body irradiation: Dose-effect relationship

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

Kal, Henk B.; Kempen-Harteveld, M. Loes van

2006-07-15

Purpose: Late complications related to total body irradiation (TBI) as part of the conditioning regimen for hematopoietic stem cell transplantation have been increasingly noted. We reviewed and compared the results of treatments with various TBI regimens and tried to derive a dose-effect relationship for the endpoint of late renal dysfunction. The aim was to find the tolerance dose for the kidney when TBI is performed. Methods and Materials: A literature search was performed using PubMed for articles reporting late renal dysfunction. For intercomparison, the various TBI regimens were normalized using the linear-quadratic model, and biologically effective doses (BEDs) were calculated.more » Results: Eleven reports were found describing the frequency of renal dysfunction after TBI. The frequency of renal dysfunction as a function of the BED was obtained. For BED >16 Gy an increase in the frequency of dysfunction was observed. Conclusions: The tolerance BED for kidney tissue undergoing TBI is about 16 Gy. This BED can be realized with highly fractionated TBI (e.g., 6 x 1.7 Gy or 9 x 1.2 Gy at dose rates >5 cGy/min). To prevent late renal dysfunction, the TBI regimens with BED values >16 Gy (almost all found in published reports) should be applied with appropriate shielding of the kidneys.« less

Response Inhibition Impairments Predict Alcohol-Induced Sedation

PubMed Central

Shannon, Erin E.; Staniforth, Elizabeth R.; McNamara, Juliette; Bernosky-Smith, Kimberly A.; Liguori, Anthony

2011-01-01

Aims: The aim of this study was to probe the relationship between the subjective effects of alcohol and impulsive behavior in social drinkers. Methods: Fifty social drinkers performed a response-inhibition task before consuming alcohol. A 0.8-g/kg dose of alcohol was administered in a binge-like fashion (0.2 g/kg every 30 min) to the participants over a 2-h time period. Participants then completed questionnaires measuring stimulation, sedation and mood following consumption of alcohol. Linear regression analyses were performed by examining the relationship between performance on the response inhibition impulsivity task and subjective responses to alcohol (i.e. stimulation, sedation and arousal). Results: There was a significant positive relationship found between impulsive responding and self-reported sedation following alcohol consumption. Additionally, there was a significant negative relationship between behavioral impulsivity and self-reported stimulation and arousal following alcohol consumption. Conclusion: These results suggest that higher levels of impulsivity are associated with experiencing greater sedating than stimulating effects of alcohol. Individuals with high levels of impulsivity may be less sensitive to the stimulating effects of a specified dose of alcohol, which could lead to these individuals consuming more alcohol to experience the stimulating effects of alcohol. PMID:21127353

Modelling carcinogenesis after radiotherapy using Poisson statistics: implications for IMRT, protons and ions.

PubMed

Jones, Bleddyn

2009-06-01

Current technical radiotherapy advances aim to (a) better conform the dose contours to cancers and (b) reduce the integral dose exposure and thereby minimise unnecessary dose exposure to normal tissues unaffected by the cancer. Various types of conformal and intensity modulated radiotherapy (IMRT) using x-rays can achieve (a) while charged particle therapy (CPT)-using proton and ion beams-can achieve both (a) and (b), but at greater financial cost. Not only is the long term risk of radiation related normal tissue complications important, but so is the risk of carcinogenesis. Physical dose distribution plans can be generated to show the differences between the above techniques. IMRT is associated with a dose bath of low to medium dose due to fluence transfer: dose is effectively transferred from designated organs at risk to other areas; thus dose and risk are transferred. Many clinicians are concerned that there may be additional carcinogenesis many years after IMRT. CPT reduces the total energy deposition in the body and offers many potential advantages in terms of the prospects for better quality of life along with cancer cure. With C ions there is a tail of dose beyond the Bragg peaks, due to nuclear fragmentation; this is not found with protons. CPT generally uses higher linear energy transfer (which varies with particle and energy), which carries a higher relative risk of malignant induction, but also of cell death quantified by the relative biological effect concept, so at higher dose levels the frank development of malignancy should be reduced. Standard linear radioprotection models have been used to show a reduction in carcinogenesis risk of between two- and 15-fold depending on the CPT location. But the standard risk models make no allowance for fractionation and some have a dose limit at 4 Gy. Alternatively, tentative application of the linear quadratic model and Poissonian statistics to chromosome breakage and cell kill simultaneously allows estimation of relative changes in carcinogenesis that incorporate fractionation and relative biological effects (RBE). This alternative modelling approach allows absolute and relative risk estimations per cell and can be extended to tissues. The classical turnover point in carcinogenesis occurring after a single exposure is a feature of the model; also, the dose-response relationship becomes pseudo-linear with extended fractionation and when heterogeneity of the radiosensitivity parameters is introduced; there is also an inverse relationship between dose per fraction and cancer induction. In principle, this new approach might influence the conduct of proton and ion beam therapy, particularly beam placements and fractionation policies. The theoretical implications for future radiotherapy are considerable, but these predictions should be subjected to cellular and tissue experiments that simulate these forms of treatment, including any secondary neutron production in some cases depending on the beam delivery technique, e.g. in tissue equivalent humanoid phantoms using cell transformation techniques. Since the UK has no working high energy particle beam facility over 100 MeV, British scientists would require use of particle beam facilities in Europe, USA or Japan to perform experiments.

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

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

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

1990-02-01

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

Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases.

PubMed

Ozasa, Kotaro; Shimizu, Yukiko; Suyama, Akihiko; Kasagi, Fumiyoshi; Soda, Midori; Grant, Eric J; Sakata, Ritsu; Sugiyama, Hiromi; Kodama, Kazunori

2012-03-01

This is the 14th report in a series of periodic general reports on mortality in the Life Span Study (LSS) cohort of atomic bomb survivors followed by the Radiation Effects Research Foundation to investigate the late health effects of the radiation from the atomic bombs. During the period 1950-2003, 58% of the 86,611 LSS cohort members with DS02 dose estimates have died. The 6 years of additional follow-up since the previous report provide substantially more information at longer periods after radiation exposure (17% more cancer deaths), especially among those under age 10 at exposure (58% more deaths). Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, and effect modification by gender, age at exposure, and attained age. The risk of all causes of death was positively associated with radiation dose. Importantly, for solid cancers the additive radiation risk (i.e., excess cancer cases per 10(4) person-years per Gy) continues to increase throughout life with a linear dose-response relationship. The sex-averaged excess relative risk per Gy was 0.42 [95% confidence interval (CI): 0.32, 0.53] for all solid cancer at age 70 years after exposure at age 30 based on a linear model. The risk increased by about 29% per decade decrease in age at exposure (95% CI: 17%, 41%). The estimated lowest dose range with a significant ERR for all solid cancer was 0 to 0.20 Gy, and a formal dose-threshold analysis indicated no threshold; i.e., zero dose was the best estimate of the threshold. The risk of cancer mortality increased significantly for most major sites, including stomach, lung, liver, colon, breast, gallbladder, esophagus, bladder and ovary, whereas rectum, pancreas, uterus, prostate and kidney parenchyma did not have significantly increased risks. An increased risk of non-neoplastic diseases including the circulatory, respiratory and digestive systems was observed, but whether these are causal relationships requires further investigation. There was no evidence of a radiation effect for infectious or external causes of death.

Clozapine-Related EEG Changes and Seizures: Dose and Plasma-Level Relationships

PubMed Central

Varma, Seema; Bishara, Delia; Besag, Frank M. C.; Taylor, David

2011-01-01

Clozapine is a widely used atypical antipsychotic with a unique effectiveness in treatment-resistant schizophrenia. An important adverse effect is seizures, which have been observed at all stages of clozapine treatment. Valproate has traditionally been considered the drug of choice for the prophylaxis of clozapine seizures, however it may not be the most suitable choice for all patients. There is disagreement as to the best point to prescribe valproate or a suitable antiepileptic: as seizure prophylaxis at a certain clozapine dose or level, or only as remedial treatment. In this review, we examine the relevant literature with an aim to evaluate the following relationships: clozapine dose and electroencephalogram (EEG) abnormalities, plasma levels and EEG abnormalities, dose and occurrence of seizures and plasma levels and occurrence of seizures. Weighted linear regression models were fitted to investigate these relationships. There was a strong relationship between clozapine dose and plasma level and occurrence of clozapine-induced EEG abnormalities. However, a statistically significant relationship between dose and occurrence of seizures was not found. A relationship between clozapine plasma level and occurrence of seizures was not established because of the scarcity of useful data although our review found three case reports which suggested that there is a very substantial risk of seizures with clozapine plasma levels exceeding 1300 μg/l. Seizures are more common during the initiation phase of clozapine treatment, suggesting a slow titration to target plasma levels is desirable. An antiepileptic drug should be considered when the clozapine plasma level exceeds 500 μg/l, if the EEG shows clear epileptiform discharges, if seizures, myoclonic jerks or speech difficulties occur and when there is concurrent use of epileptogenic medication. The antiepileptics of choice for the treatment and prophylaxis of clozapine-induced seizures are valproate (particularly where there is mood disturbance) and lamotrigine (where there is resistance to clozapine). PMID:23983927

Dose-response effects of aerobic exercise on estrogen among women at high risk for breast cancer: a randomized controlled trial.

PubMed

Schmitz, Kathryn H; Williams, Nancy I; Kontos, Despina; Domchek, Susan; Morales, Knashawn H; Hwang, Wei-Ting; Grant, Lorita L; DiGiovanni, Laura; Salvatore, Domenick; Fenderson, Desire'; Schnall, Mitchell; Galantino, Mary Lou; Stopfer, Jill; Kurzer, Mindy S; Wu, Shandong; Adelman, Jessica; Brown, Justin C; Good, Jerene

2015-11-01

Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18-50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m(2). 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise <75 min/week. Area under curve (AUC) for urinary estrogen. Secondary measures: urinary progesterone, quantitative digitized breast dynamic contrast-enhanced magnetic resonance imaging background parenchymal enhancement. Mean age 34 years, mean BMI 26.8 kg/m(2). A linear dose-response relationship was observed such that every 100 min of exercise is associated with 3.6 % lower follicular phase estrogen AUC (linear trend test, p = 0.03). No changes in luteal phase estrogen or progesterone levels. There was also a dose-response effect noted: for every 100 min of exercise, there was a 9.7 % decrease in background parenchymal enhancement as measured by imaging (linear trend test, p = 0.009). Linear dose-response effect observed to reduce follicular phase estrogen exposure measured via urine and hormone sensitive breast tissue as measured by imaging. Future research should explore maintenance of effects and extent to which findings are repeatable in lower risk women. Given the high benefit to risk ratio, clinicians can inform young women at increased risk that exercise may blunt estrogen exposure while considering whether to try other preventive therapies.

Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats.

PubMed

Dahan, A; Yassen, A; Bijl, H; Romberg, R; Sarton, E; Teppema, L; Olofsen, E; Danhof, M

2005-06-01

There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats. In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1). In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa). Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

Design considerations and analysis planning of a phase 2a proof of concept study in rheumatoid arthritis in the presence of possible non-monotonicity.

PubMed

Liu, Feng; Walters, Stephen J; Julious, Steven A

2017-10-02

It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings.

PubMed

Noel, Gary J; Goodman, Daniel B; Chien, Shuchean; Solanki, Bhavna; Padmanabhan, Mukund; Natarajan, Jaya

2004-05-01

A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value, particularly with drugs that might influence HR.

Caffeinated and decaffeinated coffee consumption and melanoma risk: a dose-response meta-analysis of prospective cohort studies.

PubMed

Micek, Agnieszka; Godos, Justyna; Lafranconi, Alessandra; Marranzano, Marina; Pajak, Andrzej

2018-06-01

To determine the association between total, caffeinated and decaffeinated coffee consumption and melanoma risk a dose-response meta-analysis on prospective cohort studies were performed. Eligible studies were identified searching PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by random-effects meta-analysis and the shape of the exposure-outcome curve was modelled linearly and using restricted cubic splines. A total of seven studies eligible for meta-analysis were identified that comprised 1,418,779 participants and 9211 melanoma cases. A linear dose-response meta-analysis showed a significant association between total coffee consumption and melanoma risk. An increase in coffee consumption of one cup per day was associated with a 3% reduction in melanoma risk (RR 0.97; 95% CI 0.95-0.99). Our findings suggest that coffee intake may be inversely associated with incidence of melanoma. Nevertheless, further studies exploring also the role of confounding factors are needed to explain the heterogeneity among studies.

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

PubMed

Zhou, Yunping; Tian, Changwei; Jia, Chongqi

2012-08-01

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

Occupational dust and radiation exposure and mortality from stomach cancer among German uranium miners, 1946-2003.

PubMed

Kreuzer, M; Straif, K; Marsh, J W; Dufey, F; Grosche, B; Nosske, D; Sogl, M

2012-03-01

'Dusty occupations' and exposure to low-dose radiation have been suggested as potential risk factors for stomach cancer. Data from the German uranium miner cohort study are used to further evaluate this topic. The cohort includes 58 677 miners with complete information on occupational exposure to dust, arsenic and radiation dose based on a detailed job-exposure matrix. A total of 592 stomach cancer deaths occurred in the follow-up period from 1946 to 2003. A Poisson regression model stratified by age and calendar year was used to calculate the excess relative risk (ERR) per unit of cumulative exposure to fine dust or from cumulative absorbed dose to stomach from α or low-LET (low linear energy transfer) radiation. For arsenic exposure, a binary quadratic model was applied. After adjustment for each of the three other variables, a statistically non-significant linear relationship was observed for absorbed dose from low-LET radiation (ERR/Gy=0.30, 95% CI -1.26 to 1.87), α radiation (ERR/Gy=22.5, 95% CI -26.5 to 71.5) and fine dust (ERR/dust-year=0.0012, 95% CI -0.0020 to 0.0043). The relationship between stomach cancer and arsenic exposure was non-linear with a 2.1-fold higher RR (95% CI 0.9 to 3.3) in the exposure category above 500 compared with 0 dust-years. Positive statistically non-significant relationships between stomach cancer and arsenic dust, fine dust and absorbed dose from α and low-LET radiation were found. Overall, low statistical power due to low doses from radiation and dust are of concern.

Ventilation/Perfusion Positron Emission Tomography—Based Assessment of Radiation Injury to Lung

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

Siva, Shankar, E-mail: shankar.siva@petermac.org; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville; Hardcastle, Nicholas

2015-10-01

Purpose: To investigate {sup 68}Ga-ventilation/perfusion (V/Q) positron emission tomography (PET)/computed tomography (CT) as a novel imaging modality for assessment of perfusion, ventilation, and lung density changes in the context of radiation therapy (RT). Methods and Materials: In a prospective clinical trial, 20 patients underwent 4-dimensional (4D)-V/Q PET/CT before, midway through, and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT, and isodose volumes were averaged into 10-Gy bins. Within each dose bin, relative loss in standardized uptake value (SUV) was recorded for ventilation andmore » perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models, and goodness of fit was assessed with Akaike Information Criterion (AIC). Results: A total of 179 imaging datasets were available for analysis (1 scan was unrecoverable). An almost perfectly linear negative dose-response relationship was observed for perfusion and air-filled fraction (r{sup 2}=0.99, P<.01), with ventilation strongly negatively linear (r{sup 2}=0.95, P<.01). Logistic models did not provide a better fit as evaluated by AIC. Perfusion, ventilation, and the air-filled fraction decreased 0.75 ± 0.03%, 0.71 ± 0.06%, and 0.49 ± 0.02%/Gy, respectively. Within high-dose regions, higher baseline perfusion SUV was associated with greater rate of loss. At 50 Gy and 60 Gy, the rate of loss was 1.35% (P=.07) and 1.73% (P=.05) per SUV, respectively. Of 8/20 patients with peritumoral reperfusion/reventilation during treatment, 7/8 did not sustain this effect after treatment. Conclusions: Radiation-induced regional lung functional deficits occur in a dose-dependent manner and can be estimated by simple linear models with 4D-V/Q PET/CT imaging. These findings may inform future studies of functional lung avoidance using V/Q PET/CT.« less

In vitro function of the aryl hydrocarbon receptor predicts in ...

EPA Pesticide Factsheets

Differences in sensitivity to dioxin-like compounds (DLCs) among species and taxa presents a major challenge to ecological risk assessments. Activation of the aryl hydrocarbon receptor (AHR) regulates adverse effects associated with exposure to DLCs in vertebrates. Prior investigations demonstrated that sensitivity to activation of the AHR1 (50% effect concentration; EC50) in an in vitro luciferase reporter gene (LRG) assay was predictive of the sensitivity of embryos (lethal dose to cause 50% lethality; LD50) across all species of birds for all DLCs. However, nothing was known about whether sensitivity to activation of the AHR is predictive of sensitivity of embryos of fishes to DLCs. Therefore, this study investigated in vitro sensitivities of AHR1s and AHR2s to the model DLC, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), among eight species of fish of known sensitivities of embryos to TCDD. AHR1s and AHR2s of all fishes were activated by TCDD in vitro. There was no significant linear relationship between in vitro sensitivity of AHR1 and in vivo sensitivity among the investigated fishes (R2 = 0.33, p = 0.23). However, there was a significant linear relationship between in vitro sensitivity of AHR2 and in vivo sensitivity among the investigated fishes (R2 = 0.97, p = < 0.0001). The linear relationship between in vitro sensitivity of AHR2 and in vivo sensitivity of embryos among fishes was compared to the previously generated linear relationship between in vitro s

Population Genetic-Based Pharmacokinetic Modeling of Methadone and its Relationship with the QTc Interval in Opioid-Dependent Patients.

PubMed

Csajka, Chantal; Crettol, Séverine; Guidi, Monia; Eap, Chin B

2016-12-01

Methadone is a μ-opioid agonist widely used for the treatment of pain, and for detoxification or maintenance treatment in opioid addiction. It has been shown to exhibit large pharmacokinetic variability and concentration-QTc relationships. In this study we investigated the relative influence of genetic polymorphism and other variables on the dose concentration-QTc relationship. A population model for methadone enantiomers in 251 opioid-dependent patients was developed using non-linear mixed effect modeling (NONMEM ® ). Various models were tested to characterize the pharmacokinetics of (R)- and (S)-methadone and the pharmacokinetic-pharmacodynamic relationship, while including demographics, physiological conditions, co-medications, and genetic variants as covariates. Model-based simulations were performed to assess the relative increase in QTc with dose upon stratification according to genetic polymorphisms involved in methadone disposition. A two-compartment model with first-order absorption and lag time provided the best model fit for (R)- and (S)-methadone pharmacokinetics. (S)-methadone clearance was influenced by cytochrome P450 (CYP) 2B6 activity, ABCB1 3435C>T, and α-1 acid glycoprotein level, while (R)-methadone clearance was influenced by CYP2B6 activity, POR*28, and CYP3A4*22. A linear model described the methadone concentration-QTc relationship, with a mean QTc increase of 9.9 ms and 19.2 ms per 1000 ng/ml of (R)- and (S)-methadone, respectively. Simulations with different methadone doses up to 240 mg/day showed that <8 % of patients presented with a QTc interval above 450 ms; however, this might reach 12 to 18 % for (R)- and (S)-methadone, respectively, in patients with a genetic status associated with a decreased methadone elimination at doses exceeding 240 mg/day. Risk factor assessment, electrocardiogram monitoring, and therapeutic drug monitoring are beneficial to optimize treatment in methadone patients, especially for those who have low levels despite high methadone doses, or who are at risk of overdosing.

Effects and dose-response relationships of resistance training on physical performance in youth athletes: a systematic review and meta-analysis.

PubMed

Lesinski, Melanie; Prieske, Olaf; Granacher, Urs

2016-07-01

To quantify age, sex, sport and training type-specific effects of resistance training on physical performance, and to characterise dose-response relationships of resistance training parameters that could maximise gains in physical performance in youth athletes. Systematic review and meta-analysis of intervention studies. Studies were identified by systematic literature search in the databases PubMed and Web of Science (1985-2015). Weighted mean standardised mean differences (SMDwm) were calculated using random-effects models. Only studies with an active control group were included if these investigated the effects of resistance training in youth athletes (6-18 years) and tested at least one physical performance measure. 43 studies met the inclusion criteria. Our analyses revealed moderate effects of resistance training on muscle strength and vertical jump performance (SMDwm 0.8-1.09), and small effects on linear sprint, agility and sport-specific performance (SMDwm 0.58-0.75). Effects were moderated by sex and resistance training type. Independently computed dose-response relationships for resistance training parameters revealed that a training period of >23 weeks, 5 sets/exercise, 6-8 repetitions/set, a training intensity of 80-89% of 1 repetition maximum (RM), and 3-4 min rest between sets were most effective to improve muscle strength (SMDwm 2.09-3.40). Resistance training is an effective method to enhance muscle strength and jump performance in youth athletes, moderated by sex and resistance training type. Dose-response relationships for key training parameters indicate that youth coaches should primarily implement resistance training programmes with fewer repetitions and higher intensities to improve physical performance measures of youth athletes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

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

PubMed Central

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

1978-01-01

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

The nematode C. elegans - A model animal system for the detection of genetic and developmental lesions

NASA Technical Reports Server (NTRS)

Nelson, Gregory A.; Marshall, Tamara M.; Schubert, Wayne W.

1989-01-01

The effects of ionizing and nonionizing radiation effects on cell reproduction, differentiation, and mutation in vivo are studied using the nematode C. elegans. The relationships between fluence/dose and response and quality factor and linear energy transfer are analyzed. The data reveal that there is a complex repair pathway in the nematode and that mutants can be used to direct the sensitivity of the system to specific mutagens/radiation types.

Continuing evaluation of bipolar linear devices for total dose bias dependency and ELDRS effects

NASA Technical Reports Server (NTRS)

McClure, Steven S.; Gorelick, Jerry L.; Yui, Candice; Rax, Bernard G.; Wiedeman, Michael D.

2003-01-01

We present results of continuing efforts to evaluate total dose bias dependency and ELDRS effects in bipolar linear microcircuits. Several devices were evaluated, each exhibiting moderate to significant bias and/or dose rate dependency.

Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

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

Inskip, Peter D., E-mail: inskippeter@gmail.com; Sigurdson, Alice J.; Veiga, Lene

Objectives: The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose–response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. Methods: This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands,more » and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site–specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Results: Linear dose–response relationships over a wide range of radiation dose (0-50 Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy > 1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy = 0.27-0.36). The relative risk for thyroid cancer increased up to 15-20 Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5 Gy or more to the ovaries. Conclusions: The results suggest that the effect of high-dose irradiation is consistent with a linear dose–response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment.« less

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 case of radiation oncology, modern innovations such as Intensity Modulated Radiation Oncology or Proton Therapy both result in a substantial total-body dose to the patient, which must result in an increased incidence of second cancers. The technology exists to reduce these total body doses and the problem needs to be addressed.

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

PubMed

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

2015-10-14

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

Development of a Bayesian response-adaptive trial design for the Dexamethasone for Excessive Menstruation study.

PubMed

Holm Hansen, Christian; Warner, Pamela; Parker, Richard A; Walker, Brian R; Critchley, Hilary Od; Weir, Christopher J

2017-12-01

It is often unclear what specific adaptive trial design features lead to an efficient design which is also feasible to implement. This article describes the preparatory simulation study for a Bayesian response-adaptive dose-finding trial design. Dexamethasone for Excessive Menstruation aims to assess the efficacy of Dexamethasone in reducing excessive menstrual bleeding and to determine the best dose for further study. To maximise learning about the dose response, patients receive placebo or an active dose with randomisation probabilities adapting based on evidence from patients already recruited. The dose-response relationship is estimated using a flexible Bayesian Normal Dynamic Linear Model. Several competing design options were considered including: number of doses, proportion assigned to placebo, adaptation criterion, and number and timing of adaptations. We performed a fractional factorial study using SAS software to simulate virtual trial data for candidate adaptive designs under a variety of scenarios and to invoke WinBUGS for Bayesian model estimation. We analysed the simulated trial results using Normal linear models to estimate the effects of each design feature on empirical type I error and statistical power. Our readily-implemented approach using widely available statistical software identified a final design which performed robustly across a range of potential trial scenarios.

Dose-response relationships for environmentally mediated infectious disease transmission models

PubMed Central

Eisenberg, Joseph N. S.

2017-01-01

Environmentally mediated infectious disease transmission models provide a mechanistic approach to examining environmental interventions for outbreaks, such as water treatment or surface decontamination. The shift from the classical SIR framework to one incorporating the environment requires codifying the relationship between exposure to environmental pathogens and infection, i.e. the dose–response relationship. Much of the work characterizing the functional forms of dose–response relationships has used statistical fit to experimental data. However, there has been little research examining the consequences of the choice of functional form in the context of transmission dynamics. To this end, we identify four properties of dose–response functions that should be considered when selecting a functional form: low-dose linearity, scalability, concavity, and whether it is a single-hit model. We find that i) middle- and high-dose data do not constrain the low-dose response, and different dose–response forms that are equally plausible given the data can lead to significant differences in simulated outbreak dynamics; ii) the choice of how to aggregate continuous exposure into discrete doses can impact the modeled force of infection; iii) low-dose linear, concave functions allow the basic reproduction number to control global dynamics; and iv) identifiability analysis offers a way to manage multiple sources of uncertainty and leverage environmental monitoring to make inference about infectivity. By applying an environmentally mediated infectious disease model to the 1993 Milwaukee Cryptosporidium outbreak, we demonstrate that environmental monitoring allows for inference regarding the infectivity of the pathogen and thus improves our ability to identify outbreak characteristics such as pathogen strain. PMID:28388665

Nutritive Supplements - Help or Harm for Breast Cancer Patients?

PubMed

Muenstedt, Karsten; El-Safadi, Samer

2010-01-01

SUMMARY: Considerable numbers of patients and physicians believe that micronutrients may be useful with respect to prevention and treatment of breast cancer. However, the analysis of the literature shows that basic information on nutritional demands in cancer patients is lacking. It is unknown whether there is an increased demand of micro-nutrients in cancer patients in general and if there is an even more increased demand during the various types of treatment. As a result, there are only limited positive findings. Higher calcium intake in premenopausal women and higher intake of vitamin D seem to be able to lower breast cancer incidence. Vitamin E (800 IU per day) was found to have a modest effect on hot flashes during tamoxifen treatment. However, there are potential side effects especially when micronutrients are administered in high or very high doses. There is increasing evidence that dose-effect relationships are not linear but U-shaped. It seems that two thresholds exist for adverse effect, one at low doses for undersupply, and another at high doses for toxicity. Thus, arbitrary high-dose administration of micronutrients should be avoided. Supplementation of normal doses seems to be safe and acceptable from the medical point of view.

Characteristics of fiber-optic radiation sensor for passive scattering proton beams

NASA Astrophysics Data System (ADS)

Son, J.; Kim, M.; Jeong, J.; Lim, Y.; Lee, S. B.; Shin, D.; Yoon, M.

2017-11-01

The aims of this study were to investigate the characteristics of a fiber-optic radiation sensor (FORS) that detects the fluorescence light produced by proton beam and to verify its effectiveness in proton therapy quality assurance (QA). Various characteristics of the FORS were investigated, such as the linearity of its relationships to the sensitive length of fiber for the proton beams of intermediate ranges (165.46 and 178.37 MeV) and to the measured dose, as well as its dose rate dependence. In addition, patient specific precription dose QA was conducted for five patients actually undergoing proton therapy and the results were compared with the doses measured using an ion chamber. The results show that the signal of the FORS is linearly related to the sensitive length of fiber and to the irradiated dose in the range from 1 to 500 cGy. The QA results obtained using the FORS system showed good agreement with the corresponding ion chamber results, with an average difference of 0.40% and a standard deviation of 0.35%. The FORS was dose-rate independent for proton currents up to 5 Gy/min. The profiles of various proton beams obtained using an array of FORS, which were measured as an application of the developed dosimetric system, closely agreed with the profiles acquired using EBT3 film. In summary, the experimental results of FORS demonstrated its effectiveness for use in various proton therapy QA tests.

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

PubMed

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

2008-01-01

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

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

PubMed

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

2013-04-10

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

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...

Meta-analysis of thirty-two case-control and two ecological radon studies of lung cancer.

PubMed

Dobrzynski, Ludwik; Fornalski, Krzysztof W; Reszczynska, Joanna

2018-03-01

A re-analysis has been carried out of thirty-two case-control and two ecological studies concerning the influence of radon, a radioactive gas, on the risk of lung cancer. Three mathematically simplest dose-response relationships (models) were tested: constant (zero health effect), linear, and parabolic (linear-quadratic). Health effect end-points reported in the analysed studies are odds ratios or relative risk ratios, related either to morbidity or mortality. In our preliminary analysis, we show that the results of dose-response fitting are qualitatively (within uncertainties, given as error bars) the same, whichever of these health effect end-points are applied. Therefore, we deemed it reasonable to aggregate all response data into the so-called Relative Health Factor and jointly analysed such mixed data, to obtain better statistical power. In the second part of our analysis, robust Bayesian and classical methods of analysis were applied to this combined dataset. In this part of our analysis, we selected different subranges of radon concentrations. In view of substantial differences between the methodology used by the authors of case-control and ecological studies, the mathematical relationships (models) were applied mainly to the thirty-two case-control studies. The degree to which the two ecological studies, analysed separately, affect the overall results when combined with the thirty-two case-control studies, has also been evaluated. In all, as a result of our meta-analysis of the combined cohort, we conclude that the analysed data concerning radon concentrations below ~1000 Bq/m3 (~20 mSv/year of effective dose to the whole body) do not support the thesis that radon may be a cause of any statistically significant increase in lung cancer incidence.

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

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

Calabrese, Edward J.; Kostecki, Paul T.

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

Radiation Dose Index of Renal Colic Protocol CT Studies in the United States

PubMed Central

Lukasiewicz, Adam; Bhargavan-Chatfield, Mythreyi; Coombs, Laura; Ghita, Monica; Weinreb, Jeffrey; Gunabushanam, Gowthaman; Moore, Christopher L.

2016-01-01

Purpose To determine radiation dose indexes for computed tomography (CT) performed with renal colic protocols in the United States, including frequency of reduced-dose technique usage and any institutional-level factors associated with high or low dose indexes. Materials and Methods The Dose Imaging Registry (DIR) collects deidentified CT data, including examination type and dose indexes, for CT performed at participating institutions; thus, the DIR portion of the study was exempt from institutional review board approval and was HIPAA compliant. CT dose indexes were examined at the institutional level for CT performed with a renal colic protocol at institutions that contributed at least 10 studies to the registry as of January 2013. Additionally, patients undergoing CT for renal colic at a single institution (with institutional review board approval and informed consent from prospective subjects and waiver of consent from retrospective subjects) were studied to examine individual renal colic CT dose index patterns and explore relationships between patient habitus, demographics, and dose indexes. Descriptive statistics were used to analyze dose indexes, and linear regression and Spearman correlations were used to examine relationships between dose indexes and institutional factors. Results There were 49 903 renal colic protocol CT examinations conducted at 93 institutions between May 2011 and January 2013. Mean age ± standard deviation was 49 years ± 18, and 53.9% of patients were female. Institutions contributed a median of 268 (interquartile range, 77–699) CT studies. Overall mean institutional dose-length product (DLP) was 746 mGy · cm (effective dose, 11.2 mSv), with a range of 307–1497 mGy · cm (effective dose, 4.6–22.5 mSv) for mean DLPs. Only 2% of studies were conducted with a DLP of 200 mGy · cm or lower (a “reduced dose”) (effective dose, 3 mSv), and only 10% of institutions kept DLP at 400 mGy · cm (effective dose, 6 mSv) or less in at least 50% of patients. Conclusion Reduced-dose renal protocol CT is used infrequently in the United States. Mean dose index is higher than reported previously, and institutional variation is substantial. PMID:24484064

Dose Response Data for Hormonally Active Chemicals ...

EPA Pesticide Factsheets

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the default assumption is that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDS), which act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses: responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and nonmonotonic dose response relationships from case studies of chemicals that disrupt reproductive development and function via the ER, AR and AhR pathways and will include in vitro and in vivo multigenerational data. The in vivo studies in this discussion include only robust, well designed, comprehensive studies that administered the chemical via a relevant route(s) of exposure over a broad dose response range, including low dose(s) in the microgram/kg/d range. The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters and 2,3,7,8 TCDD. The objective is to critically evaluate the data from well done studies in this field to address concerns that current multigenerational reproductive test gui

[Determination of morroniside concentration in beagle plasma and its pharmacokinetics by high performance liquid chromatography-tandem mass spectrometry].

PubMed

Xiong, Shan; Li, Jinglai; Zhu, Xiuqing; Wang, Xiaoying; Lü, Guiyuan; Zhang, Zhenqing

2014-03-01

A sensitive, simple and specific high performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS) method was developed for the determination of morroniside in the plasma of beagles administered via intragastric (ig) doses of morroniside. The method employed paeoniflorin as the internal standard and extracted by simple protein precipitation. The separation was achieved using an Inertsil ODS-SP column (50 mm x 2.1 mm, 5 microm) with mobile phases of 1 mmol/L sodium formate aqueous solution and acetonitrile (gradient elution) at a flow rate of 0.4 mL/min. The detection was accomplished by a mass spectrometer using multiple reaction monitoring (MRM) in positive mode. Pharmacokinetic parameters were fitted by software DAS 2.0. The methodological study showed a good linear relationship of 2-5 000 microg/L (r = 0.996 6) with a sensitivity of 2 microg/L as the limit of quantification. The precision, accuracy, mean recoveries and the matrix effects were satisfied with the requirements of biological sample measurement. The method described above was successfully applied to the pharmacokinetic study of morroniside in the beagle plasma samples. The area under the plasma concentration-time curves (AUC(0-infinity)) of morroniside after single ig administration doses of 5, 15 and 45 mg/kg were (1 631.20 +/- 238.50), (3 984.05 +/- 750.38) and (10 397.64 +/- 3 156.34) microg/L x h. The relationship between dose and AUC showed a good linearity. The pharmacokinetic property of morroniside was proposed to be linear pharmacokinetics.

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 results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.

Harderian Gland Tumorigenesis: Low-Dose and LET Response

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

Chang, Polly Y.; Cucinotta, Francis A.; Bjornstad, Kathleen A.

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 mSvmore » 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 results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.« less

Modern dosimetric tools for 60Co irradiation at high containment laboratories

PubMed Central

Twardoski, Barri; Feldmann, Heinz; Bloom, Marshall E.; Ward, Joe

2011-01-01

Purpose To evaluate an innovative photo-fluorescent film as a routine dosimetric tool during 60Co irradiations at a high containment biological research laboratory, and to investigate whether manufacturer-provided chamber exposure rates can be used to accurately administer a prescribed dose to biological specimens. Materials and methods Photo-fluorescent, lithium fluoride film dosimeters and National Institutes of Standards and Technology (NIST) transfer dosimeters were co-located in a self-shielded 60Co irradiator and exposed to γ-radiation with doses ranging from 5–85 kGy. Film dose-response relationships were developed for varying temperatures simulating conditions present when irradiating infectious biological specimens. Dose measurement results from NIST transfer dosimeters were compared to doses predicted using manufacturer-provided irradiator chamber exposure rates. Results The film dosimeter exhibited a photo-fluorescent response signal that was consistent and nearly linear in relationship to γ-radiation exposure over a wide dose range. The dosimeter response also showed negligible effects from dose fractionization and humidity. Significant disparities existed between manufacturer-provided chamber exposure rates and actual doses administered. Conclusion This study demonstrates the merit of utilizing dosimetric tools to validate the process of exposing dangerous and exotic biological agents to γ-radiation at high containment laboratories. The film dosimeter used in this study can be utilized to eliminate potential for improperly administering γ-radiation doses. PMID:21961968

RADIATION EXPOSURE OF THE POPULATION FROM 222Rn AND OTHER NATURAL RADIONUCLIDES AROUND MOCHOVCE NUCLEAR POWER PLANT, SLOVAKIA.

PubMed

Bulko, Martin; Holý, Karol; Pohronská, Žofia; Mullerová, Monika; Böhm, Radoslav; Holá, Ol'ga

2017-11-01

In this article, the effective dose to the population from natural sources of ionizing radiation in the vicinity of Mochovce nuclear power plant in Slovakia is presented. All major contributions to the effective dose were taken into account, including the contributions from gamma radiation of soil and rocks, cosmic radiation, and indoor and outdoor radon and thoron. On the basis of recent indoor radon measurements in Slovak cities and publicly available data about radon concentration in the soil air, a roughly linear relationship was found between these variables. Consequently, the annual effective dose from indoor radon and thoron was conservatively estimated. For the area of interest, a map of conservatively estimated potential effective doses was created. For the villages in the vicinity of Mochovce, the conservatively estimated effective dose to the population from natural sources ranged from 5.4 to 14.6 mSv, which is four orders of magnitude higher than the contribution of radioactive discharges from Mochovce nuclear power plant. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Patient-specific dose calculations for pediatric CT of the chest, abdomen and pelvis

PubMed Central

Fraser, Nicholas D.; Carver, Diana E.; Pickens, David R.; Price, Ronald R.; Hernanz-Schulman, Marta; Stabin, Michael G.

2015-01-01

Background Organ dose is essential for accurate estimates of patient dose from CT. Objective To determine organ doses from a broad range of pediatric patients undergoing diagnostic chest–abdomen–pelvis CT and investigate how these relate to patient size. Materials and methods We used a previously validated Monte Carlo simulation model of a Philips Brilliance 64 multi-detector CT scanner (Philips Healthcare, Best, The Netherlands) to calculate organ doses for 40 pediatric patients (M:F=21:19; range 0.6–17 years). Organ volumes and positions were determined from the images using standard segmentation techniques. Non-linear regression was performed to determine the relationship between volume CT dose index (CTDIvol)-normalized organ doses and abdominopelvic diameter. We then compared results with values obtained from independent studies. Results We found that CTDIvol-normalized organ dose correlated strongly with exponentially decreasing abdominopelvic diameter (R2>0.8 for most organs). A similar relationship was determined for effective dose when normalized by dose-length product (R2=0.95). Our results agreed with previous studies within 12% using similar scan parameters (i.e. bowtie filter size, beam collimation); however results varied up to 25% when compared to studies using different bowtie filters. Conclusion Our study determined that organ doses can be estimated from measurements of patient size, namely body diameter, and CTDIvol prior to CT examination. This information provides an improved method for patient dose estimation. PMID:26142256

DOSE-RESPONSE RELATIONSHIPS FOR MOLECULAR ALTERATIONS INDUCED BY B[ A ]P IN STRAIN A/J MOUSE LUNG

EPA Science Inventory

Benzo[a]pyrene (B[a]P) induces tumors in rodents at doses much higher than those found in the environment. Current cancer risk assessment of B[a]P assumes that the risk posed by low level exposure to B[a]P is linear with respect to dose. We have measur...

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

Otake, M.; Schull, W.J.

The occurrence of lenticular opacities among atomic bomb survivors in Hiroshima and Nagasaki detected in 1963-1964 has been examined in reference to their ..gamma.. and neutron doses. A lenticular opacity in this context implies an ophthalmoscopic and slit lamp biomicroscopic defect in the axial posterior aspect of the lens which may or may not interfere measureably with visual acuity. Several different dose-response models were fitted to the data after the effects of age at time of bombing (ATB) were examined. Some postulate the existence of a threshold(s), others do not. All models assume a ''background'' exists, that is, that somemore » number of posterior lenticular opacities are ascribable to events other than radiation exposure. Among these alternatives we can show that a simple linear ..gamma..-neutron relationship which assumes no threshold does not fit the data adequately under the T65 dosimetry, but does fit the recent Oak Ridge and Lawrence Livermore estimates. Other models which envisage quadratic terms in gamma and which may or may not assume a threshold are compatible with the data. The ''best'' fit, that is, the one with the smallest X/sup 2/ and largest tail probability, is with a ''linear gamma:linear neutron'' model which postulates a ..gamma.. threshold but no threshold for neutrons. It should be noted that the greatest difference in the dose-response models associated with the three different sets of doses involves the neutron component, as is, of course, to be expected. No effect of neutrons on the occurrence of lenticular opacities is demonstrable with either the Lawrence Livermore or Oak Ridge estimates.« less

Population pharmacokinetic/pharmacodynamic model of clozapine for characterizing the relationship between accumulated exposure and PANSS scores in patients with schizophrenia.

PubMed

Shang, De-Wei; Li, Li-Jun; Wang, Xi-Pei; Wen, Yu-Guan; Ren, Yu-Peng; Guo, Wei; Li, Wen-Biao; Li, Liang; Zhou, Tian-Yan; Lu, Wei; Wang, Chuan-Yue

2014-06-01

The aim of this study was to characterize the relationship between accumulated exposure of clozapine and changes in Positive and Negative Syndrome Scale (PANSS) score in Chinese patients with schizophrenia by pharmacokinetic/pharmacodynamic (PK/PD) modeling. Sparse clozapine PK data and PANSS scores were collected from 2 clinical studies of Chinese inpatients with schizophrenia. Two other rich PK data sets were included for more accurate assessment of clozapine PK characteristics. The relationship between clozapine-accumulated exposure and PANSS score was investigated using linear, log-linear, E(max), and sigmoid models, and each model was evaluated using visual predictive condition and normalized prediction distribution error methods. Simulations based on the final PK/PD model were preformed to investigate the effect of clozapine on PANSS scores under different dose regimens. A total of 1391 blood clozapine concentrations from 198 subjects (180 patients and 18 healthy volunteers) and 576 PANSS scores from 137 patients were included for PK and PK/PD analysis. A first-order 2-compartment PK model with covariates gender and smoking status influencing systemic clearance adequately described the PK profile of clozapine. The decrease in total PANSS score during treatment was best characterized using cumulated clozapine area under the curve (AUC) data in the E(max) model. The maximum decrease in PANSS during clozapine treatment (Emax) was 55.4%, and the cumulated AUC(50) (cAUC(50)) required to attain half of E(max) was 296 mg·L(-1)·h(-1)·d(-1). The simulations demonstrated that the accelerated dose titration and constant dose regimens achieved a similar maximum drug response but with a slower relief of symptoms in dose titration regimen. The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients.

The New Radiobiology: Returning to Our Roots

PubMed Central

Ulsh, Brant A.

2012-01-01

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

X-ray induced dominant lethal mutations in mature and immature oocytes of guinea-pigs and golden hamsters.

PubMed

Cox, B D; Lyon, M F

1975-06-01

The induction of dominant lethal mutations by doses of 100-400 rad X-rays in oocytes of the guinea-pig and golden hamster was studied using criteria of embryonic mortality. For both species higher yields were obtained from mature than from immature oocytes, in contrast to results for the mouse. Data on fertility indicated that in the golden hamster, as in the mouse, immature oocytes were more sensitive to killing by X-rays than mature oocytes but that the converse was true in the guinea-pig. The dose-response relationship for mutation to dominant lethals in pre-ovulatory oocytes of guinea-pig and golden hamsters was linear, both when based on pre- and post-implantation loss and when on post-implantation loss only. The rate per unit dose was higher for the golden hamster, and the old golden hamsters were possibly slightly more sensitive than young ones. The mutation rate data for mature oocytes of the mouse, using post-implantation loss alone, also fitted a linear dose-response relationship, except that the rate per unit dose was lower than for the other two species.

Effect of gamma irradiation on the color, structure and morphology of nickel-doped polyvinyl alcohol films: Alternative use as dosimeter or irradiation indicator

NASA Astrophysics Data System (ADS)

Raouafi, A.; Daoudi, M.; Jouini, K.; Charradi, K.; Hamzaoui, A. H.; Blaise, P.; Farah, K.; Hosni, F.

2018-06-01

Nickel-doped poly vinyl alcohol (PVA) films were developed for potential application in industrial sectors like radiation processing. We report in this paper the results of an experimental investigation of 60Co source γ-radiation effect on colorimetric, structural and morphological properties of PVA films doped with 0.5% Ni2+ ions (PVA/Ni2+). The PVA/Ni2+ films were irradiated by different gamma-radiation doses varying from 5 to 100 kGy. Color modification of films were studied using L∗, a∗ and b∗ color space measurements as function of the γ-dose and post-irradiation time. The visual change in all samples was verified by microstructure analysis, Fourier transforms infrared (FTIR) spectroscopy, X-Rays diffraction (XRD) and scanning electron microscopy (SEM). The color space exhibited a linear dose response at a dose ranging from 5 to 50 kGy, and then it reached saturation for higher γ-doses. The calculated color changes (ΔE) show a linear dose response relationship from 9.90 to 115.02 in the dose range from 0 to 50 kGy. It showed also the activation of stable color centers. The variability of the color change did not exceed 3% during 80 h (h) post-irradiation. Furthermore, the microstructure analysis evidenced that the color modification due to the optical activation of nickel-oxide (NiO) color center were obtained by complexing Ni2+ ions in irradiated PVA films. The obtained results inspire the possibility to use PVA films for the control process in industrial radiation facilities in dose range 5-50 kGy.

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 the estimation process rendered results from the BLQ model questionable. Importantly, accounting for heterogeneous variance enhanced inferential precision as the breadth of the confidence interval for the mean breakpoint decreased by approximately 44%. In summary, the article illustrates the use of linear and nonlinear mixed models for dose-response relationships accounting for heterogeneous residual variances, discusses important diagnostics and their implications for inference, and provides practical recommendations for computational troubleshooting.

Effects of ionizing radiation on the light sensing elements of the retina. [Structural and physiological effects of carbon, helium, and neon ions on rods and cones of salamanders and mice

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

Malachowski, M.J.

1978-07-01

This investigation was undertaken to quantitate possible morphological and physiological effects of particles of high linear energy transfer on the retina, in comparison with x-ray effects. The particles used were accelerated atomic nuclei of helium, carbon, and neon at kinetic energies of several hundred MeV/nucleon. For morphological studies, scanning and transmission electron microscopy and light microscopy were used. Physiological studies consisted of autoradiographic data of the rate of incorporation of labeled protein in the structures (opsin) of the outer segment of visual cells. Structural changes were found in the nuclei, as well as the inner and outer segments of visualmore » cells, rods and cones. At a low dose of 10 rad, x rays and helium had no statistically significant morphological effects, but carbon and neon beams did cause significant degeneration of individual cells, pointing to the existence of a linear dose--effect relationship. At high doses of several hundred rads, a Pathologic Index determined the relative biological effectiveness of neon against alpha particles to have a value of greater than 6. The severity of effects per particle increased with atomic number. Labeling studies demonstrated a decreased rate of incorporation of labeled proteins in the structural organization of the outer segments of visual rods. The rate of self-renewal of visual rod discs was punctuated by irradiation and the structures themselves were depleted of amino acids. A model of rod discs (metabolic and catabolic) was postulated for correlated early and late effects to high and low doses.« less

Depressive symptoms, lifestyle structure, and ART adherence among HIV-infected individuals: a longitudinal mediation analysis.

PubMed

Magidson, Jessica F; Blashill, Aaron J; Safren, Steven A; Wagner, Glenn J

2015-01-01

Despite the well-documented relationship between depression and antiretroviral therapy (ART) nonadherence, few studies have identified explanatory pathways through which depression affects adherence. The current study tested lifestyle structure-the degree of organization and routinization of daily activities-as a mediator of this relationship, given previous evidence of lifestyle structure being associated with both depression and ART nonadherence. HIV-infected individuals starting or re-starting ART in the California Collaborative Treatment Group 578 study (n = 199) were assessed over 48 weeks. Adherence was measured using electronic monitoring caps to determine dose timing and doses taken, and viral load was assessed. The mediating role of lifestyle structure was tested using generalized linear mixed-effects modeling and bootstrapping. Lifestyle significantly mediated the relationship between depression and both measures of ART adherence behavior. Interventions that minimize disruptions to lifestyle structure and link adherence to daily activities may be useful for individuals with depression and ART nonadherence.

SU-F-T-35: Optimization of Bladder and Rectal Doses Using a Multi-Lumen Intracavitary Applicator for Gynecological Brachytherapy

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

Laoui, S; Dietrich, S; Sehgal, V

2016-06-15

Purpose: Radiation dose delivery for endometrial cancer using HDR techniques is limited by dose to bladder and rectum. A dosimetric study was performed using Varian Capri vaginal brachytherapy applicator to determine the optimal channel configuration which minimizes dose to bladder and rectum, while providing good target coverage. Methods: A total of 17 patients, 63 plans clinically delivered, and 252 simulated plans using Varian BrachyVision planning system were generated to investigate optimal channel configuration which results in minimum dose to bladder and rectum while providing adequate target coverage. The Capri applicator consists of 13 lumens arranged in two concentric rings, onemore » central lumen and six lumens per ring. Manual dose shaping is invariably required to lower the dose to critical organs. Three-dimensional plans were simulated for 4 channel arrangements, all 13 channels, channel 12 o’clock (close to bladder) and 6 o’clock (close to rectum) deactivated, central channel deactivated, and central channel in addition to 12 o’clock and 6 o’clock deactivated. A relationship between V100, the volume that receives the prescribed dose, and the amount of curie-seconds required to deliver it, was established. Results: Using all 13 channels results in maximum dose to bladder and rectum. Deactivating central channel in addition to 12 o’clock and 6 o’clock resulted in minimizing bladder and rectum doses but compromised target coverage. The relationship between V100, the volume that receives the prescribed dose, and the curie seconds was found to be linear. Conclusion: Deactivating channels 12 o’clock and 6 o’clock was shown to be the optimal configuration leading to minimum dose to bladder and rectum without compromising target coverage. The linear relationship between V100 and the curie- seconds can be used as a verification parameter.« less

Strong relationship between oral dose and tenofovir hair levels in a randomized trial: hair as a potential adherence measure for pre-exposure prophylaxis (PrEP).

PubMed

Liu, Albert Y; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P; Greenblatt, Ruth M; Gandhi, Monica

2014-01-01

Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60-93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. ClinicalTrials.gov NCT00903084.

Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP)

PubMed Central

Liu, Albert Y.; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L.; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P.; Greenblatt, Ruth M.; Gandhi, Monica

2014-01-01

Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084. PMID:24421901

Interpretation of the margin of exposure for genotoxic carcinogens - elicitation of expert knowledge about the form of the dose response curve at human relevant exposures.

PubMed

Boobis, Alan; Flari, Villie; Gosling, John Paul; Hart, Andy; Craig, Peter; Rushton, Lesley; Idahosa-Taylor, Ehi

2013-07-01

The general approach to risk assessment of genotoxic carcinogens has been to advise reduction of exposure to "as low as reasonably achievable/practicable" (ALARA/P). However, whilst this remains the preferred risk management option, it does not provide guidance on the urgency or extent of risk management actions necessary. To address this, the "Margin of Exposure" (MOE) approach has been proposed. The MOE is the ratio between the point of departure for carcinogenesis and estimated human exposure. However, interpretation of the MOE requires implicit or explicit consideration of the shape of the dose-response curve at human relevant exposures. In a structured elicitation exercise, we captured expert opinion on available scientific evidence for low dose-response relationships for genotoxic carcinogens. This allowed assessment of: available evidence for the nature of dose-response relationships at human relevant exposures; the generality of judgments about such dose-response relationships; uncertainties affecting judgments on the nature of such dose-response relationships; and whether this last should differ for different classes of genotoxic carcinogens. Elicitation results reflected the variability in experts' views on the form of the dose-response curve for low dose exposure and major sources of uncertainty affecting the assumption of a linear relationship. Copyright © 2013 Elsevier Ltd. All rights reserved.

Total dose bias dependency and ELDRS effects in bipolar linear devices

NASA Technical Reports Server (NTRS)

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

2002-01-01

Total dose tests of several bipolar linear devices show sensitivity to both dose rate and bias during exposure. All devices exhibited Enhanced Low Dose Rate Sensitivity (ELDRS). An accelerated ELDRS test method for three different devices demonstrate results similar to tests at low dose rate. Behavior and critical parameters from these tests are compared and discussed.

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

PubMed Central

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

2015-01-01

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

Minisatellite and Hprt mutations in V79 cells irradiated with helium ions and gamma rays.

PubMed

Cherubinit, R; Canova, S; Favaretto, S; Bruna, V; Battivelli, P; Celotti, L

2002-09-01

To evaluate and compare cytotoxic and mutational effects of graded doses of gamma-rays and 4He++ ions at different LET values (nominally 80 and 123 keV/microm) in V79 cells. 4He++ ion beams at 80 and 123 keV/microm were supplied by the 7 MV Van de Graaff CN accelerator of the INFN-LNL in the dose range 0.3 2.4 Gy at a dose rate of 1 Gy/min. Gamma-irradiation was performed by the 60Co 'gamma beam' of CNR-FRAE (at the INFN-LNL) in the dose range 0.5 6.0 Gy at a dose rate of 1 Gy/min. After irradiation, the cells were seeded to measure surviving fraction (SF) and mutant frequency (MF) at the Hprt locus on the basis of 6-thioguanine resistance. Alterations at minisatellite sequences (MS) of clones derived from irradiated and unirradiated cells were detected by Southern blot analysis using a multi-locus probe (DNA fingerprinting). Survival data from 4He++ irradiation at two LET values (80 and 123 keV/microm) yielded similar results: alpha = (1.08 +/- 0.04)/Gy and (0.90 +/- 0.03)/Gy, respectively. The best fit for mutant induction at the Hprt locus after 80keV/microm 4He++ was a linear function of the dose in the dose-interval 0-1.5 Gy: alpha= (47.77 +/- 16.01) x 10(-6)/Gy. The best fit for mutant induction after 123 keV/microm 4He++ in the dose-interval 0-1.2 Gv was a linear-quadratic function: alpha=(86.01 +/- 13.80) x 10(-6)/Gy; beta = (42.87 +/- 11.03) x 10(-6)/Gy2. For gamma-irradiation, the best fit of Hprt mutation data gave: alpha = (4.14+2.67)x 10(-6)/Gy: beta = (0.63 +/- 0.86) x 10(-6)/Gy2. The best fitting of MS alteration data with linear-quadratic or linear relationships gave: for gamma-rays, alpha = 0.56 mutants/Gy and beta = 0.52 mutants/Gy2; for 80 keV/microm 4He++, alpha = 3.70 mutants/Gy and beta = 9.00 mutants/Gy2; for 123keV/microm 4He++, alpha = 4.36 mutants/Gy. The results reported here confirmed the higher cytotoxic and mutagenic effects of helium ions in comparison with gamma-irradiation and the ability of DNA fingerprint analysis to investigate DNA damage induced by different ionizing radiations. The results of the mutagenic effects measured by the two tests are in agreement.

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

PubMed

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

2017-12-08

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

Gamma radiation effects on seed germination, growth and pigment content, and ESR study of induced free radicals in maize (Zea mays).

PubMed

Marcu, Delia; Damian, Grigore; Cosma, Constantin; Cristea, Victoria

2013-09-01

The effects of gamma radiation are investigated by studying plant germination, growth and development, and biochemical characteristics of maize. Maize dry seeds are exposed to a gamma source at doses ranging from 0.1 to 1 kGy. Our results show that the germination potential, expressed through the final germination percentage and the germination index, as well as the physiological parameters of maize seedlings (root and shoot lengths) decreased by increasing the irradiation dose. Moreover, plants derived from seeds exposed at higher doses (≤0.5 kGy) did not survive more than 10 days. Biochemical differences based on photosynthetic pigment (chlorophyll a, chlorophyll b, carotenoids) content revealed an inversely proportional relationship to doses of exposure. Furthermore, the concentration of chlorophyll a was higher than chlorophyll b in both irradiated and non-irradiated seedlings. Electron spin resonance spectroscopy used to evaluate the amount of free radicals induced by gamma ray treatment demonstrates that the relative concentration of radiation-induced free radicals depends linearly on the absorbed doses.

Improving power and robustness for detecting genetic association with extreme-value sampling design.

PubMed

Chen, Hua Yun; Li, Mingyao

2011-12-01

Extreme-value sampling design that samples subjects with extremely large or small quantitative trait values is commonly used in genetic association studies. Samples in such designs are often treated as "cases" and "controls" and analyzed using logistic regression. Such a case-control analysis ignores the potential dose-response relationship between the quantitative trait and the underlying trait locus and thus may lead to loss of power in detecting genetic association. An alternative approach to analyzing such data is to model the dose-response relationship by a linear regression model. However, parameter estimation from this model can be biased, which may lead to inflated type I errors. We propose a robust and efficient approach that takes into consideration of both the biased sampling design and the potential dose-response relationship. Extensive simulations demonstrate that the proposed method is more powerful than the traditional logistic regression analysis and is more robust than the linear regression analysis. We applied our method to the analysis of a candidate gene association study on high-density lipoprotein cholesterol (HDL-C) which includes study subjects with extremely high or low HDL-C levels. Using our method, we identified several SNPs showing a stronger evidence of association with HDL-C than the traditional case-control logistic regression analysis. Our results suggest that it is important to appropriately model the quantitative traits and to adjust for the biased sampling when dose-response relationship exists in extreme-value sampling designs. © 2011 Wiley Periodicals, Inc.

High dose psilocybin is associated with positive subjective effects in healthy volunteers.

PubMed

Nicholas, Christopher R; Henriquez, Kelsey M; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Hetzel, Scott; Brown, Randall T; Cozzi, Nicholas V; Thomas, Chantelle; Hutson, Paul R

2018-06-01

The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects. Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire. There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience. High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.

Nicotine dose-concentration relationship and pregnancy outcomes in rat: Biologic plausibility and implications for future research

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

Hussein, Jabeen; Farkas, Svetlana; MacKinnon, Yolanda

Cigarette smoke (CS) exposure during pregnancy can lead to profound adverse effects on fetal development. Although CS contains several thousand chemicals, nicotine has been widely used as its surrogate as well as in its own right as a neuroteratogen. The justification for the route and dose of nicotine administration is largely based on inferential data suggesting that nicotine 6 mg/kg/day infused continuously via osmotic mini pumps (OMP) would mimic maternal CS exposure. We provide evidence that 6 mg/kg/day nicotine dose as commonly administered to pregnant rats leads to plasma nicotine concentrations that are 3-10-fold higher than those observed in moderatemore » to heavy smokers and pregnant mothers, respectively. Furthermore, the cumulative daily nicotine dose exceeds by several hundred fold the amount consumed by human heavy smokers. Our study does not support the widely accepted notion that regardless of the nicotine dose, a linear nicotine dose-concentration relationship exists in a steady-state OMP model. We also show that total nicotine clearance increases with advancing pregnancy but no significant change is observed between the 2nd and 3rd trimester. Furthermore, nicotine infusion even at this extremely high dose has little effect on a number of maternal and fetal biologic variables and pregnancy outcome suggesting that CS constituents other than nicotine mediate the fetal growth restriction in infants born to smoking mothers. Our current study has major implications for translational research in developmental toxicology and pharmacotherapy using nicotine replacement treatment as an aid to cessation of cigarette smoking in pregnant mothers.« less

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

PubMed

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

2017-01-01

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

Reinvestigation of the relationship between the amplitude of the first heart sound to cardiac dynamics.

PubMed

Tang, Hong; Ruan, Chengjie; Qiu, Tianshuang; Park, Yongwan; Xiao, Shouzhong

2013-08-01

The relationships between the amplitude of the first heart sound (S1) and the rising rate of left ventricular pressure (LVP) concluded in previous studies were not consistent. Some researchers believed the relationship was positively linear; others stated the relationship was only positively correlated. To further investigate this relationship, this study simultaneously sampled the external phonocardiogram, electrocardiogram, and intracardiac pressure in the left ventricle in three anesthetized dogs, while invoking wide hemodynamic changes using various doses of epinephrine. The relationship between the maximum amplitude of S1 and the maximum rising rate of LVP and the relationship between the amplitude of dominant peaks/valleys and the corresponding rising rate of LVP were examined by linear, quadratic, cubic, and exponential models. The results showed that the relationships are best fit by nonlinear exponential models.

Introduction to methodology of dose-response meta-analysis for binary outcome: With application on software.

PubMed

Zhang, Chao; Jia, Pengli; Yu, Liu; Xu, Chang

2018-05-01

Dose-response meta-analysis (DRMA) is widely applied to investigate the dose-specific relationship between independent and dependent variables. Such methods have been in use for over 30 years and are increasingly employed in healthcare and clinical decision-making. In this article, we give an overview of the methodology used in DRMA. We summarize the commonly used regression model and the pooled method in DRMA. We also use an example to illustrate how to employ a DRMA by these methods. Five regression models, linear regression, piecewise regression, natural polynomial regression, fractional polynomial regression, and restricted cubic spline regression, were illustrated in this article to fit the dose-response relationship. And two types of pooling approaches, that is, one-stage approach and two-stage approach are illustrated to pool the dose-response relationship across studies. The example showed similar results among these models. Several dose-response meta-analysis methods can be used for investigating the relationship between exposure level and the risk of an outcome. However the methodology of DRMA still needs to be improved. © 2018 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.

IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?

EPA Science Inventory

IS THE DOSE-RESPONSE LINEAR OR NONLINEAR FOR GENOTOXIC EFFECTS?
Preston, RJ. Environmental Carcinogenesis Division, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711

For considerations of cancer risk assessment from exposure to environmenta...

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.

Introduction of risk size in the determination of uncertainty factor UFL in risk assessment

NASA Astrophysics Data System (ADS)

Xue, Jinling; Lu, Yun; Velasquez, Natalia; Yu, Ruozhen; Hu, Hongying; Liu, Zhengtao; Meng, Wei

2012-09-01

The methodology for using uncertainty factors in health risk assessment has been developed for several decades. A default value is usually applied for the uncertainty factor UFL, which is used to extrapolate from LOAEL (lowest observed adverse effect level) to NAEL (no adverse effect level). Here, we have developed a new method that establishes a linear relationship between UFL and the additional risk level at LOAEL based on the dose-response information, which represents a very important factor that should be carefully considered. This linear formula makes it possible to select UFL properly in the additional risk range from 5.3% to 16.2%. Also the results remind us that the default value 10 may not be conservative enough when the additional risk level at LOAEL exceeds 16.2%. Furthermore, this novel method not only provides a flexible UFL instead of the traditional default value, but also can ensure a conservative estimation of the UFL with fewer errors, and avoid the benchmark response selection involved in the benchmark dose method. These advantages can improve the estimation of the extrapolation starting point in the risk assessment.

TU-C-18A-01: Models of Risk From Low-Dose Radiation Exposures: What Does the Evidence Say?

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

Bushberg, J; Boreham, D; Ulsh, B

2014-06-15

At dose levels of (approximately) 500 mSv or more, increased cancer incidence and mortality have been clearly demonstrated. However, at the low doses of radiation used in medical imaging, the relationship between dose and cancer risk is not well established. As such, assumptions about the shape of the dose-response curve are made. These assumptions, or risk models, are used to estimate potential long term effects. Common models include 1) the linear non-threshold (LNT) model, 2) threshold models with either a linear or curvilinear dose response above the threshold, and 3) a hormetic model, where the risk is initially decreased belowmore » background levels before increasing. The choice of model used when making radiation risk or protection calculations and decisions can have significant implications on public policy and health care decisions. However, the ongoing debate about which risk model best describes the dose-response relationship at low doses of radiation makes informed decision making difficult. This symposium will review the two fundamental approaches to determining the risk associated with low doses of ionizing radiation, namely radiation epidemiology and radiation biology. The strengths and limitations of each approach will be reviewed, the results of recent studies presented, and the appropriateness of different risk models for various real world scenarios discussed. Examples of well-designed and poorly-designed studies will be provided to assist medical physicists in 1) critically evaluating publications in the field and 2) communicating accurate information to medical professionals, patients, and members of the general public. Equipped with the best information that radiation epidemiology and radiation biology can currently provide, and an understanding of the limitations of such information, individuals and organizations will be able to make more informed decisions regarding questions such as 1) how much shielding to install at medical facilities, 2) at what dose level are risk vs. benefit discussions with patients appropriate, 3) at what dose level should we tell a pregnant woman that the baby’s health risk from a prenatal radiation exposure is “significant”, 4) is informed consent needed for patients undergoing medical imaging, and 5) at what dose level is evacuation appropriate after a radiological accident. Examples of the tremendous impact that choosing different risks models can have on the answers to these types of questions will be given.A moderated panel discussion will allow audience members to pose questions to the faculty members, each of whom is an established expert in his respective discipline. Learning Objectives: Understand the fundamental principles, strengths and limitations of radiation epidemiology and radiation biology for determining the risk from exposures to low doses of ionizing radiation Become familiar with common models of risk used to describe the dose-response relationship at low dose levels Learn to identify strengths and weaknesses in studies designed to measure the effect of low doses of ionizing radiation Understand the implications of different risk models on public policy and health care decisions.« less

Thyroid Cancer Following Childhood Low-Dose Radiation Exposure: A Pooled Analysis of Nine Cohorts.

PubMed

Lubin, Jay H; Adams, M Jacob; Shore, Roy; Holmberg, Erik; Schneider, Arthur B; Hawkins, Michael M; Robison, Leslie L; Inskip, Peter D; Lundell, Marie; Johansson, Robert; Kleinerman, Ruth A; de Vathaire, Florent; Damber, Lena; Sadetzki, Siegal; Tucker, Margaret; Sakata, Ritsu; Veiga, Lene H S

2017-07-01

The increased use of diagnostic and therapeutic procedures that involve radiation raises concerns about radiation effects, particularly in children and the radiosensitive thyroid gland. Evaluation of relative risk (RR) trends for thyroid radiation doses <0.2 gray (Gy); evidence of a threshold dose; and possible modifiers of the dose-response, e.g., sex, age at exposure, time since exposure. Pooled data from nine cohort studies of childhood external radiation exposure and thyroid cancer with individualized dose estimates, ≥1000 irradiated subjects or ≥10 thyroid cancer cases, with data limited to individuals receiving doses <0.2 Gy. Cohorts included the following: childhood cancer survivors (n = 2); children treated for benign diseases (n = 6); and children who survived the atomic bombings in Japan (n = 1). There were 252 cases and 2,588,559 person-years in irradiated individuals and 142 cases and 1,865,957 person-years in nonirradiated individuals. There were no interventions. Incident thyroid cancers. For both <0.2 and <0.1 Gy, RRs increased with thyroid dose (P < 0.01), without significant departure from linearity (P = 0.77 and P = 0.66, respectively). Estimates of threshold dose ranged from 0.0 to 0.03 Gy, with an upper 95% confidence bound of 0.04 Gy. The increasing dose-response trend persisted >45 years after exposure, was greater at younger age at exposure and younger attained age, and was similar by sex and number of treatments. Our analyses reaffirmed linearity of the dose response as the most plausible relationship for "as low as reasonably achievable" assessments for pediatric low-dose radiation-associated thyroid cancer risk. Copyright © 2017 Endocrine Society

SU-F-T-113: Inherent Functional Dependence of Spinal Cord Doses of Variable Irradiated Volumes in Spine SBRT

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

Ma, L; Braunstein, S; Chiu, J

2016-06-15

Purpose: Spinal cord tolerance for SBRT has been recommended for the maximum point dose level or at irradiated volumes such as 0.35 mL or 10% of contoured volumes. In this study, we investigated an inherent functional relationship that associates these dose surrogates for irradiated spinal cord volumes of up to 3.0 mL. Methods: A hidden variable termed as Effective Dose Radius (EDR) was formulated based on a dose fall-off model to correlate dose at irradiated spinal cord volumes ranging from 0 mL (point maximum) to 3.0 mL. A cohort of 15 spine SBRT cases was randomly selected to derive anmore » EDR-parameterized formula. The mean prescription dose for the studied cases was 21.0±8.0 Gy (range, 10–40Gy) delivered in 3±1 fractions with target volumes of 39.1 ± 70.6 mL. Linear regression and variance analysis were performed for the fitting parameters of variable EDR values. Results: No direct correlation was found between the dose at maximum point and doses at variable spinal cord volumes. For example, Pearson R{sup 2} = 0.643 and R{sup 2}= 0.491 were obtained when correlating the point maximum dose with the spinal cord dose at 1 mL and 3 mL, respectively. However, near perfect correlation (R{sup 2} ≥0.99) was obtained when corresponding parameterized EDRs. Specifically, Pearson R{sup 2}= 0.996 and R{sup 2} = 0.990 were obtained when correlating EDR (maximum point dose) with EDR (dose at 1 mL) and EDR(dose at 3 mL), respectively. As a result, high confidence level look-up tables were established to correlate spinal cord doses at the maximum point to any finite irradiated volumes. Conclusion: An inherent functional relationship was demonstrated for spine SBRT. Such a relationship unifies dose surrogates at variable cord volumes and proves that a single dose surrogate (e.g. point maximum dose) is mathematically sufficient in constraining the overall spinal cord dose tolerance for SBRT.« less

Experience of micromultileaf collimator linear accelerator based single fraction stereotactic radiosurgery: Tumor dose inhomogeneity, conformity, and dose fall off

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

Hong, Linda X.; Garg, Madhur; Lasala, Patrick

2011-03-15

Purpose: Sharp dose fall off outside a tumor is essential for high dose single fraction stereotactic radiosurgery (SRS) plans. This study explores the relationship among tumor dose inhomogeneity, conformity, and dose fall off in normal tissues for micromultileaf collimator (mMLC) linear accelerator (LINAC) based cranial SRS plans. Methods: Between January 2007 and July 2009, 65 patients with single cranial lesions were treated with LINAC-based SRS. Among them, tumors had maximum diameters {<=}20 mm: 31; between 20 and 30 mm: 21; and >30 mm: 13. All patients were treated with 6 MV photons on a Trilogy linear accelerator (Varian Medical Systems,more » Palo Alto, CA) with a tertiary m3 high-resolution mMLC (Brainlab, Feldkirchen, Germany), using either noncoplanar conformal fixed fields or dynamic conformal arcs. The authors also created retrospective study plans with identical beam arrangement as the treated plan but with different tumor dose inhomogeneity by varying the beam margins around the planning target volume (PTV). All retrospective study plans were normalized so that the minimum PTV dose was the prescription dose (PD). Isocenter dose, mean PTV dose, RTOG conformity index (CI), RTOG homogeneity index (HI), dose gradient index R{sub 50}-R{sub 100} (defined as the difference between equivalent sphere radius of 50% isodose volume and prescription isodose volume), and normal tissue volume (as a ratio to PTV volume) receiving 50% prescription dose (NTV{sub 50}) were calculated. Results: HI was inversely related to the beam margins around the PTV. CI had a ''V'' shaped relationship with HI, reaching a minimum when HI was approximately 1.3. Isocenter dose and mean PTV dose (as percentage of PD) increased linearly with HI. R{sub 50}-R{sub 100} and NTV{sub 50} initially declined with HI and then reached a plateau when HI was approximately 1.3. These trends also held when tumors were grouped according to their maximum diameters. The smallest tumor group (maximum diameters {<=}20 mm) had the most HI dependence for dose fall off. For treated plans, CI averaged 2.55{+-}0.79 with HI 1.23{+-}0.06; the average R{sub 50}-R{sub 100} was 0.41{+-}0.08, 0.55{+-}0.10, and 0.65{+-}0.09 cm, respectively, for tumors {<=}20 mm, between 20 and 30 mm, and >30 mm. Conclusions: Tumor dose inhomogeneity can be used as an important and convenient parameter to evaluate mMLC LINAC-based SRS plans. Sharp dose fall off in the normal tissue is achieved with sufficiently high tumor dose inhomogeneity. By adjusting beam margins, a homogeneity index of approximately 1.3 would provide best conformity for the authors' SRS system.« less

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.

A generalized target theory and its applications.

PubMed

Zhao, Lei; Mi, Dong; Hu, Bei; Sun, Yeqing

2015-09-28

Different radiobiological models have been proposed to estimate the cell-killing effects, which are very important in radiotherapy and radiation risk assessment. However, most applied models have their own scopes of application. In this work, by generalizing the relationship between "hit" and "survival" in traditional target theory with Yager negation operator in Fuzzy mathematics, we propose a generalized target model of radiation-induced cell inactivation that takes into account both cellular repair effects and indirect effects of radiation. The simulation results of the model and the rethinking of "the number of targets in a cell" and "the number of hits per target" suggest that it is only necessary to investigate the generalized single-hit single-target (GSHST) in the present theoretical frame. Analysis shows that the GSHST model can be reduced to the linear quadratic model and multitarget model in the low-dose and high-dose regions, respectively. The fitting results show that the GSHST model agrees well with the usual experimental observations. In addition, the present model can be used to effectively predict cellular repair capacity, radiosensitivity, target size, especially the biologically effective dose for the treatment planning in clinical applications.

Relationship between changes in vasomotor symptoms and changes in menopause-specific quality of life and sleep parameters.

PubMed

Pinkerton, JoAnn V; Abraham, Lucy; Bushmakin, Andrew G; Cappelleri, Joseph C; Komm, Barry S

2016-10-01

This study characterizes and quantifies the relationship of vasomotor symptoms (VMS) of menopause with menopause-specific quality of life (MSQOL) and sleep parameters to help predict treatment outcomes and inform treatment decision-making. Data were derived from a 12-week randomized, double-blind, placebo-controlled phase 3 trial that evaluated effects of two doses of conjugated estrogens/bazedoxifene on VMS in nonhysterectomized postmenopausal women (N = 318, mean age = 53.39) experiencing at least seven moderate to severe hot flushes (HFs) per day or at least 50 per week. Repeated measures models were used to determine relationships between HF frequency and severity and outcomes on the Menopause-Specific Quality of Life questionnaire and the Medical Outcomes Study sleep scale. Sensitivity analyses were performed to check assumptions of linearity between VMS and outcomes. Frequency and severity of HFs showed approximately linear relationships with MSQOL and sleep parameters. Sensitivity analyses supported assumptions of linearity. The largest changes associated with a reduction of five HFs and a 0.5-point decrease in severity occurred in the Menopause-Specific Quality of Life vasomotor functioning domain (0.78 for number of HFs and 0.98 for severity) and the Medical Outcomes Study sleep disturbance (7.38 and 4.86) and sleep adequacy (-5.60 and -4.66) domains and the two overall sleep problems indices (SPI: 5.17 and 3.63; SPII: 5.82 and 3.83). Frequency and severity of HFs have an approximately linear relationship with MSQOL and sleep parameters-that is, improvements in HFs are associated with improvements in MSQOL and sleep. Such relationships may enable clinicians to predict changes in sleep and MSQOL expected from various VMS treatments.

RBE of quasi-monoenergetic 60 MeV neutron radiation for induction of dicentric chromosomes in human lymphocytes.

PubMed

Nolte, R; Mühlbradt, K-H; Meulders, J P; Stephan, G; Haney, M; Schmid, E

2005-12-01

The production of dicentric chromosomes in human lymphocytes by high-energy neutron radiation was studied using a quasi-monoenergetic 60 MeV neutron beam. The average yield coefficient [see text] of the linear dose-response relationship for dicentric chromosomes was measured to be (0.146+/-0.016) Gy-1. This confirms our earlier observations that above 400 keV, the yield of dicentric chromosomes decreases with increasing neutron energy. Using the linear-quadratic dose-response relationship for dicentric chromosomes established in blood of the same donor for 60Co gamma-rays as a reference radiation, an average maximum low-dose RBE (RBEM) of 14+/-4 for 60 MeV quasi-monoenergetic neutrons with a dose-weighted average energy [see text] of 41.0 MeV is obtained. A correction procedure was applied, to account for the low-energy continuum of the quasi-monoenergetic spectral neutron distribution, and the yield coefficient alpha for 60 MeV neutrons was determined from the measured average yield coefficient [see text]. For alpha, a value of (0.115+/-0.026) Gy-1 was obtained corresponding to an RBEM of 11+/-4. The present experiments extend earlier investigations with monoenergetic neutrons to higher energies.

Biological effects and equivalent doses in radiotherapy: A software solution

PubMed Central

Voyant, Cyril; Julian, Daniel; Roustit, Rudy; Biffi, Katia; Lantieri, Céline

2013-01-01

Background The limits of TDF (time, dose, and fractionation) and linear quadratic models have been known for a long time. Medical physicists and physicians are required to provide fast and reliable interpretations regarding delivered doses or any future prescriptions relating to treatment changes. Aim We, therefore, propose a calculation interface under the GNU license to be used for equivalent doses, biological doses, and normal tumor complication probability (Lyman model). Materials and methods The methodology used draws from several sources: the linear-quadratic-linear model of Astrahan, the repopulation effects of Dale, and the prediction of multi-fractionated treatments of Thames. Results and conclusions The results are obtained from an algorithm that minimizes an ad-hoc cost function, and then compared to an equivalent dose computed using standard calculators in seven French radiotherapy centers. PMID:24936319

Treatment dose-response in amblyopia therapy: the Monitored Occlusion Treatment of Amblyopia Study (MOTAS).

PubMed

Stewart, Catherine E; Moseley, Merrick J; Stephens, David A; Fielder, Alistair R

2004-09-01

Amblyopia is the commonest visual disorder of childhood. Yet the contributions of the two principal treatments (spectacle wear and occlusion) to outcome are unknown. This study was undertaken to investigate the dose-response relationship of amblyopia therapy. The study comprised three distinct phases: baseline, in which repeat measures of visual function were undertaken to confirm the initial visual deficit; refractive adaptation: an 18-week period of spectacle wear with six weekly measurements of logarithm of the minimum angle of resolution (logMAR) visual acuity; occlusion: in which participants were prescribed 6 hours of "patching" per day. In the latter phase, occlusion was objectively monitored and logMAR visual acuity recorded at 2-week intervals until any observed gains had ceased. Data were obtained from 94 participants (mean age, 5.1 +/- 1.4 years) with amblyopia associated with strabismus (n = 34), anisometropia (n = 23), and both anisometropia and strabismus (n = 37). Eighty-six underwent refractive adaptation. Average concordance with patching was 48%. The relationship between logMAR visual acuity gain and total occlusion dose was monotonic and linear. Increasing dose rate beyond 2 h/d hastened the response but did not improve outcome. More than 80% of the improvement during occlusion occurred within 6 weeks. Treatment outcome was significantly better for children younger than 4 years (n = 17) than in those older than 6 years (n = 24; P = 0.0014). Continuous objective monitoring of the amount of patching therapy received has provided insight into the dose-response relationship of occlusion therapy for amblyopia. Patching is most effective within the first few weeks of treatment, even for those in receipt of a relatively small dose. Further studies are needed to elucidate the neural basis for the dose-response functions. Copyright Association for Research in Vision and Ophthalmology

Radiation and breast cancer: a review of current evidence

PubMed Central

Ronckers, Cécile M; Erdmann, Christine A; Land, Charles E

2005-01-01

This paper summarizes current knowledge on ionizing radiation-associated breast cancer in the context of established breast cancer risk factors, the radiation dose–response relationship, and modifiers of dose response, taking into account epidemiological studies and animal experiments. Available epidemiological data support a linear dose–response relationship down to doses as low as about 100 mSv. However, the magnitude of risk per unit dose depends strongly on when radiation exposure occurs: exposure before the age of 20 years carries the greatest risk. Other characteristics that may influence the magnitude of dose-specific risk include attained age (that is, age at observation for risk), age at first full-term birth, parity, and possibly a history of benign breast disease, exposure to radiation while pregnant, and genetic factors. PMID:15642178

Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria.

PubMed

Wattanakul, Thanaporn; Teerapong, Pramote; Plewes, Katherine; Newton, Paul N; Chierakul, Wirongrong; Silamut, Kamolrat; Chotivanich, Kesinee; Ruengweerayut, Ronnatrai; White, Nicholas J; Dondorp, Arjen M; Tarning, Joel

2016-04-27

Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular paracetamol given to patients with acute falciparum malaria and high body temperature was performed. A randomized, open-label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic model was used for dose optimization simulations. Relationships between paracetamol concentrations with temperature and parasite half-life were investigated using linear and non-linear regression analyses. The population pharmacokinetic properties of paracetamol were best described by a two-compartment disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively. The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2-95.1 %) compared to intramuscular administration. Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic steady state concentrations for antipyresis, but more favourable concentration-time profiles were achieved with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations and temperature or parasite half-life were found. Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2-95.1 %). Dosing simulations showed that a loading dose followed by six-hourly dosing intervals reduced the time delay to reach therapeutic drug levels after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now needs to be established in larger studies.

A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation derived from the effects of terfenadine, cisapride and E-4031 in the conscious chronic av node--ablated, His bundle-paced dog.

PubMed

Nolan, Emily R; Feng, Meihua Rose; Koup, Jeffrey R; Liu, Jing; Turluck, Daniel; Zhang, Yiqun; Paulissen, Jerome B; Olivier, N Bari; Miller, Teresa; Bailie, Marc B

2006-01-01

Terfenadine, cisapride, and E-4031, three drugs that prolong ventricular repolarization, were selected to evaluate the sensitivity of the conscious chronic atrioventricular node--ablated, His bundle-paced Dog for defining drug induced cardiac repolarization prolongation. A novel predictive pharmacokinetic/pharmacodynamic model of repolarization prolongation was generated from these data. Three male beagle dogs underwent radiofrequency AV nodal ablation, and placement of a His bundle-pacing lead and programmable pacemaker under anesthesia. Each dog was restrained in a sling for a series of increasing dose infusions of each drug while maintained at a constant heart rate of 80 beats/min. RT interval, a surrogate for QT interval in His bundle-paced dogs, was recorded throughout the experiment. E-4031 induced a statistically significant RT prolongation at the highest three doses. Cisapride resulted in a dose-dependent increase in RT interval, which was statistically significant at the two highest doses. Terfenadine induced a dose-dependent RT interval prolongation with a statistically significant change occurring only at the highest dose. The relationship between drug concentration and RT interval change was described by a sigmoid E(max) model with an effect site. Maximum RT change (E(max)), free drug concentration at half of the maximum effect (EC(50)), and free drug concentration associated with a 10 ms RT prolongation (EC(10 ms)) were estimated. A linear correlation between EC(10 ms) and HERG IC(50) values was identified. The conscious dog with His bundle-pacing detects delayed cardiac repolarization related to I(Kr) inhibition, and detects repolarization change induced by drugs with activity at multiple ion channels. A clinically relevant sensitivity and a linear correlation with in vitro HERG data make the conscious His bundle-paced dog a valuable tool for detecting repolarization effect of new chemical entities.

Toxicity of o,p′-DDE to medaka d-rR strain after a one-time embryonic exposure by in ovo nanoinjection: An early through juvenile life cycle assessment

USGS Publications Warehouse

Villalobos, Sergio A.; Papoulias, Diana M.; Pastva, Stephanie D.; Blankenship, Alan L.; Meadows, John C.; Tillitt, Donald E.; Giesy, John P.

2003-01-01

The toxicity of o,p′-DDE (1,1-dichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl) ethylene) was evaluated in embryos of medaka (Oryzias latipes) following a one time exposure via nanoinjection. Medaka eggs (early gastrula) were injected with 0.5 nl of triolein (vehicle control) or 0.5 nl of 4 graded doses (0.0005-0.5 ng/egg) of o,p′-DDE in triolein. Embryos were allowed to develop, and fry were reared. Embryonic survival was monitored daily during the first 10 d until hatching and thereafter, on a weekly basis until day 59, at which time the fish were monitored for sexual maturity until day 107. In general, o,p′-DDE caused a dose- and time-dependent mortality. No changes in mortality were observed between the last two time points (day 38 and 59, respectively), and hence a 59 day-LD50 of 346 ng o,p′-DDE/egg was derived from the linear dose-response relationship. Prior to late stage death, only isolated cases of cardiovascular lesions and spinal deformities were observed, but were not dose-dependent. The lowest observable adverse effect level (LOAEL), based on upper 95% CI for regression line=0.0018 mg/kg, and the LOAEL based on exposure doses=0.5 mg/kg. Likewise, the no observable adverse effect level (NOAEL) based on linear extrapolation to 100% survival=0.0000388 mg/kg, while the NOAEL based on exposure doses=0.05 mg/kg. The nanoinjection medaka model has potential in the study of hormonally active compounds in the environment.

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.

Response of biological uv dosimeters to the simulated extraterrestrial uv radiation

NASA Astrophysics Data System (ADS)

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

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

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

NASA Astrophysics Data System (ADS)

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

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

Organ Doses Associated with Partial-Body Irradiation with 2.5% Bone Marrow Sparing of the Non-Human Primate: A Retrospective Study.

PubMed

Prado, C; MacVittie, T J; Bennett, A W; Kazi, A; Farese, A M; Prado, K

2017-12-01

A partial-body irradiation model with approximately 2.5% bone marrow sparing (PBI/BM2.5) was established to determine the radiation dose-response relationships for the prolonged and delayed multi-organ effects of acute radiation exposure. Historically, doses reported to the entire body were assumed to be equal to the prescribed dose at some defined calculation point, and the dose-response relationship for multi-organ injury has been defined relative to the prescribed dose being delivered at this point, e.g., to a point at mid-depth at the level of the xiphoid of the non-human primate (NHP). In this retrospective-dose study, the true distribution of dose within the major organs of the NHP was evaluated, and these doses were related to that at the traditional dose-prescription point. Male rhesus macaques were exposed using the PBI/BM2.5 protocol to a prescribed dose of 10 Gy using 6-MV linear accelerator photons at a rate of 0.80 Gy/min. Point and organ doses were calculated for each NHP from computed tomography (CT) scans using heterogeneous density data. The prescribed dose of 10.0 Gy to a point at midline tissue assuming homogeneous media resulted in 10.28 Gy delivered to the prescription point when calculated using the heterogeneous CT volume of the NHP. Respective mean organ doses to the volumes of nine organs, including the heart, lung, bowel and kidney, were computed. With modern treatment planning systems, utilizing a three-dimensional reconstruction of the NHP's CT images to account for the variations in body shape and size, and using density corrections for each of the tissue types, bone, water, muscle and air, accurate determination of the differences in dose to the NHP can be achieved. Dose and volume statistics can be ascertained for any body structure or organ that has been defined using contouring tools in the planning system. Analysis of the dose delivered to critical organs relative to the total-body target dose will permit a more definitive analysis of organ-specific effects and their respective influence in multiple organ injury.

Determination of the quenching correction factors for plastic scintillation detectors in therapeutic high-energy proton beams

PubMed Central

Wang, L L W; Perles, L A; Archambault, L; Sahoo, N; Mirkovic, D; Beddar, S

2013-01-01

The plastic scintillation detectors (PSD) have many advantages over other detectors in small field dosimetry due to its high spatial resolution, excellent water equivalence and instantaneous readout. However, in proton beams, the PSDs will undergo a quenching effect which makes the signal level reduced significantly when the detector is close to Bragg peak where the linear energy transfer (LET) for protons is very high. This study measures the quenching correction factor (QCF) for a PSD in clinical passive-scattering proton beams and investigates the feasibility of using PSDs in depth-dose measurements in proton beams. A polystyrene based PSD (BCF-12, ϕ0.5mm×4mm) was used to measure the depth-dose curves in a water phantom for monoenergetic unmodulated proton beams of nominal energies 100, 180 and 250 MeV. A Markus plane-parallel ion chamber was also used to get the dose distributions for the same proton beams. From these results, the QCF as a function of depth was derived for these proton beams. Next, the LET depth distributions for these proton beams were calculated by using the MCNPX Monte Carlo code, based on the experimentally validated nozzle models for these passive-scattering proton beams. Then the relationship between the QCF and the proton LET could be derived as an empirical formula. Finally, the obtained empirical formula was applied to the PSD measurements to get the corrected depth-dose curves and they were compared to the ion chamber measurements. A linear relationship between QCF and LET, i.e. Birks' formula, was obtained for the proton beams studied. The result is in agreement with the literature. The PSD measurements after the quenching corrections agree with ion chamber measurements within 5%. PSDs are good dosimeters for proton beam measurement if the quenching effect is corrected appropriately. PMID:23128412

Determination of the quenching correction factors for plastic scintillation detectors in therapeutic high-energy proton beams

NASA Astrophysics Data System (ADS)

Wang, L. L. W.; Perles, L. A.; Archambault, L.; Sahoo, N.; Mirkovic, D.; Beddar, S.

2012-12-01

Plastic scintillation detectors (PSDs) have many advantages over other detectors in small field dosimetry due to their high spatial resolution, excellent water equivalence and instantaneous readout. However, in proton beams, the PSDs undergo a quenching effect which makes the signal level reduced significantly when the detector is close to the Bragg peak where the linear energy transfer (LET) for protons is very high. This study measures the quenching correction factor (QCF) for a PSD in clinical passive-scattering proton beams and investigates the feasibility of using PSDs in depth-dose measurements in proton beams. A polystyrene-based PSD (BCF-12, ϕ0.5 mm × 4 mm) was used to measure the depth-dose curves in a water phantom for monoenergetic unmodulated proton beams of nominal energies 100, 180 and 250 MeV. A Markus plane-parallel ion chamber was also used to get the dose distributions for the same proton beams. From these results, the QCF as a function of depth was derived for these proton beams. Next, the LET depth distributions for these proton beams were calculated by using the MCNPX Monte Carlo code, based on the experimentally validated nozzle models for these passive-scattering proton beams. Then the relationship between the QCF and the proton LET could be derived as an empirical formula. Finally, the obtained empirical formula was applied to the PSD measurements to get the corrected depth-dose curves and they were compared to the ion chamber measurements. A linear relationship between the QCF and LET, i.e. Birks' formula, was obtained for the proton beams studied. The result is in agreement with the literature. The PSD measurements after the quenching corrections agree with ion chamber measurements within 5%. PSDs are good dosimeters for proton beam measurement if the quenching effect is corrected appropriately.

Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma.

PubMed

van Nimwegen, Frederika A; Schaapveld, Michael; Cutter, David J; Janus, Cècile P M; Krol, Augustinus D G; Hauptmann, Michael; Kooijman, Karen; Roesink, Judith; van der Maazen, Richard; Darby, Sarah C; Aleman, Berthe M P; van Leeuwen, Flora E

2016-01-20

Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors. We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive. The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy(<27.5years), 20.0%; ERR/Gy(27.5-36.4years), 8.8%; ERR/Gy(36.5-50.9years), 4.2%; P(interaction) = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8). The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors. © 2015 by American Society of Clinical Oncology.

The mass-action law based algorithms for quantitative econo-green bio-research.

PubMed

Chou, Ting-Chao

2011-05-01

The relationship between dose and effect is not random, but rather governed by the unified theory based on the median-effect equation (MEE) of the mass-action law. Rearrangement of MEE yields the mathematical form of the Michaelis-Menten, Hill, Henderson-Hasselbalch and Scatchard equations of biochemistry and biophysics, and the median-effect plot allows linearization of all dose-effect curves regardless of potency and shape. The "median" is the universal common-link and reference-point for the 1st-order to higher-order dynamics, and from single-entities to multiple-entities and thus, it allows the all for one and one for all unity theory to "integrate" simple and complex systems. Its applications include the construction of a dose-effect curve with a theoretical minimum of only two data points if they are accurately determined; quantification of synergism or antagonism at all dose and effect levels; the low-dose risk assessment for carcinogens, toxic substances or radiation; and the determination of competitiveness and exclusivity for receptor binding. Since the MEE algorithm allows the reduced requirement of the number of data points for small size experimentation, and yields quantitative bioinformatics, it points to the deterministic, efficient, low-cost biomedical research and drug discovery, and ethical planning for clinical trials. It is concluded that the contemporary biomedical sciences would greatly benefit from the mass-action law based "Green Revolution".

In vivo dose response relationship between physostigmine and cholinesterase activity in RBC and tissues of rats

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

Somani, S.M.; Dube, S.N.

1989-01-01

Dose response of physostigmine (Phy) was studied in rat using various doses. Rats were sacrificed 15 min after Phy administration. Blood and tissues were analyzed for ChE activity by radiometric method and Phy concentration by HPLC method. A comparison of ChE values in different tissues of rats indicated that ChE activity was highest in brain and least in diaphragm. The enzyme activity was eleven times more in brain as compared to diaphragm. Phy produced a dose-dependent inhibition of ChE in RBC, brain and diaphragm from 50 to 200 {mu}g/kg, then ChE inhibition was plateaued from 200 to 500 {mu}g/kg inmore » these tissues. A dose related ChE inhibition was seen in heart and thigh muscle from 50 to 500 {mu}g/kg. Phy concentration increased linearly from 50 to 400 {mu}g/kg in plasma, brain, heart and thigh muscle. These results indicate that ChE inhibition is linear up to 200 {mu}g/kg in RBC, 150 {mu}g/kg in brain and 300 {mu}g/kg in heart. This linearity is not consistent in other tissues.« less

Induction of Chromosomal Aberrations at Fluences of Less Than One HZE Particle per Cell Nucleus

NASA Technical Reports Server (NTRS)

Hada, Megumi; Chappell, Lori J.; Wang, Minli; George, Kerry A.; Cucinotta, Francis A.

2014-01-01

The assumption of a linear dose response used to describe the biological effects of high LET radiation is fundamental in radiation protection methodologies. We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high energy and charge (HZE) nuclei. Human fibroblast and lymphocyte cells where irradiated with several low doses of <0.1 Gy, and several higher doses of up to 1 Gy with O (77 keV/ (long-s)m), Si (99 keV/ (long-s)m), Fe (175 keV/ (long-s)m), Fe (195 keV/ (long-s)m) or Fe (240 keV/ (long-s)m) particles. Chromosomal aberrations at first mitosis were scored using fluorescence in situ hybridization (FISH) with chromosome specific paints for chromosomes 1, 2 and 4 and DAPI staining of background chromosomes. Non-linear regression models were used to evaluate possible linear and non-linear dose response models based on these data. Dose responses for simple exchanges for human fibroblast irradiated under confluent culture conditions were best fit by non-linear models motivated by a non-targeted effect (NTE). Best fits for the dose response data for human lymphocytes irradiated in blood tubes were a NTE model for O and a linear response model fit best for Si and Fe particles. Additional evidence for NTE were found in low dose experiments measuring gamma-H2AX foci, a marker of double strand breaks (DSB), and split-dose experiments with human fibroblasts. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high LET radiation at the relevant range of low doses.

A nonhuman primate model of the hematopoietic acute radiation syndrome plus medical management.

PubMed

Farese, Ann M; Cohen, Melanie V; Katz, Barry P; Smith, Cassandra P; Jackson, William; Cohen, Daniel M; MacVittie, Thomas J

2012-10-01

The development of medical countermeasures against the hematopoietic subsyndrome of the acute radiation syndrome requires well characterized and validated animal models. The model must define the radiation dose- and time-dependent relationships for mortality and major signs of morbidity to include other organ damage that may contribute to morbidity and mortality. Herein, the authors define these parameters for a nonhuman primate exposed to total body radiation and administered medical management. A blinded, randomized study (n = 48 rhesus macaques) determined the lethal dose-response relationship using bilateral 6 MV linear accelerator photon radiation to doses in the range of 7.20 to 8.90 Gy at 0.80 Gy min(-1). Following irradiation, animals were monitored for complete bloodcounts, body weight, temperature, diarrhea, and hydration status for 60 d. Animals were administered medical management consisting of intravenous fluids, prophylactic antibiotics, blood transfusions, anti-diarrheals, analgesics, and nutrition. The primary endpoint was survival at 60 d post-irradiation; secondary endpoints included hematopoietic-related parameters, number of transfusions, incidence of documented infection, febrile neutropenia, severity of diarrhea, mean survival time of decedents, and tissue histology. The study defined an LD30/60 of 7.06 Gy, LD50/60 of 7.52 Gy, and an LD70/60 of 7.99 Gy with a relatively steep slope of 1.13 probits per linear dose. This study establishes a rhesus macaque model of the hematopoietic acute radiation syndrome and shows the marked effect of medical management on increased survival and overall mean survival time for decedents. Furthermore, following a nuclear terrorist event, medical management may be the only treatment administered at its optimal schedule.

Association between tea consumption and risk of cognitive disorders: A dose-response meta-analysis of observational studies

PubMed Central

Liu, Xueying; Du, Xiaoyuan; Han, Guanying; Gao, Wenyuan

2017-01-01

Background The epidemiological evidence for a dose-response relationship between tea consumption and risk of cognitive disorders is sparse. The aim of the study was to summarize the evidence for the association of tea consumption with risk of cognitive disorders and assess the dose-response relationship. Methods We searched electronic databases of Pubmed, Embase, and Cochrane Library (from 1965 to Jan 19, 2017) for eligible studies that published in the international journals. A random-effects model was used to pool the most adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Results Seventeen studies involving 48,435 participants were included in our study. The meta-analysis showed that a higher tea consumption was associated with a significant reduction in the risk of cognitive disorders (OR=0.73, 95% CI: 0.65-0.82). When considering the specific types of tea consumption, the significantly inverse association is only found in green tea consumption (OR=0.64, 95% CI: 0.53-0.77) but not in black/oolong tea consumption (OR=0.75, 95% CI: 0.55-1.01). Dose-response meta-analysis indicated that tea consumption is linearly associated with a reduced risk of cognitive disorders. An increment of 100 ml/day, 300 ml/day, and 500 ml/day of tea consumption was associated with a 6% (OR=0.94, 95% CI: 0.92-0.96), 19% (OR=0.81, 95% CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82) lower risk of cognitive disorders. Conclusions Tea consumption is inversely and linearly related to the risk of cognitive disorders. More studies are needed to further confirm our findings. PMID:28496007

Association between tea consumption and risk of cognitive disorders: A dose-response meta-analysis of observational studies.

PubMed

Liu, Xueying; Du, Xiaoyuan; Han, Guanying; Gao, Wenyuan

2017-06-27

The epidemiological evidence for a dose-response relationship between tea consumption and risk of cognitive disorders is sparse. The aim of the study was to summarize the evidence for the association of tea consumption with risk of cognitive disorders and assess the dose-response relationship. We searched electronic databases of Pubmed, Embase, and Cochrane Library (from 1965 to Jan 19, 2017) for eligible studies that published in the international journals. A random-effects model was used to pool the most adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Seventeen studies involving 48,435 participants were included in our study. The meta-analysis showed that a higher tea consumption was associated with a significant reduction in the risk of cognitive disorders (OR=0.73, 95% CI: 0.65-0.82). When considering the specific types of tea consumption, the significantly inverse association is only found in green tea consumption (OR=0.64, 95% CI: 0.53-0.77) but not in black/oolong tea consumption (OR=0.75, 95% CI: 0.55-1.01). Dose-response meta-analysis indicated that tea consumption is linearly associated with a reduced risk of cognitive disorders. An increment of 100 ml/day, 300 ml/day, and 500 ml/day of tea consumption was associated with a 6% (OR=0.94, 95% CI: 0.92-0.96), 19% (OR=0.81, 95% CI: 0.74-0.88), and 29% (OR=0.71, 95% CI: 0.62-0.82) lower risk of cognitive disorders. Tea consumption is inversely and linearly related to the risk of cognitive disorders. More studies are needed to further confirm our findings.

[15 years after the accident at the Chernobyl Nuclear Power Plant].

PubMed

Buldakov, L A; Gus'kova, A K

2002-01-01

Health effects as a result of the accident at the Chernobyl nuclear power plant occurred in 1986 are considered in the paper. Wrong prognosis of the health effects with respect to mortality and morbidity among the population exposed to low radiation doses is shown. Proven increase in thyroid cancer cases among people who were children aged from 0 to 18 at the time of the accident is shown. Linear relationship between thyroid cancer cases and dose to thyroid ranged from 0.2 to 4.0 Gy is considered. An additional absolute risk of thyroid cancer in children varies in the range 1.9-2.6 cases per 10(4) person-year Gy. During the fifteen years following the accident no cases of acute and chronic radiation sickness have been revealed because the population living in contaminated areas received low radiation doses. Also, exposures to low radiation doses did not result in excess of malignant tumors among population. In some cases the outcomes of acute radiation sickness were as follows: radiation damages to the skin, cancer cataracts, development of oncopathology.

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.

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

PubMed

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

2017-05-01

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

The Dose-Effect Relationship in Psychodynamic Psychotherapy with People with Intellectual Disabilities

ERIC Educational Resources Information Center

Beail, Nigel; Kellett, Stephen; Newman, David W.; Warden, Sharon

2007-01-01

Background: Although there is an established body of evidence attesting to the dose-effect relationship in psychotherapy with non-disabled adults, the issue as to whether such a relationship exists for persons with intellectual disabilities has not been previously examined. Dose-effect essentially concerns the amount of psychotherapy required to…

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

PubMed Central

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

2013-01-01

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

Using spatial information about recurrence risk for robust optimization of dose-painting prescription functions

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

Bender, Edward T.

Purpose: To develop a robust method for deriving dose-painting prescription functions using spatial information about the risk for disease recurrence. Methods: Spatial distributions of radiobiological model parameters are derived from distributions of recurrence risk after uniform irradiation. These model parameters are then used to derive optimal dose-painting prescription functions given a constant mean biologically effective dose. Results: An estimate for the optimal dose distribution can be derived based on spatial information about recurrence risk. Dose painting based on imaging markers that are moderately or poorly correlated with recurrence risk are predicted to potentially result in inferior disease control when comparedmore » the same mean biologically effective dose delivered uniformly. A robust optimization approach may partially mitigate this issue. Conclusions: The methods described here can be used to derive an estimate for a robust, patient-specific prescription function for use in dose painting. Two approximate scaling relationships were observed: First, the optimal choice for the maximum dose differential when using either a linear or two-compartment prescription function is proportional to R, where R is the Pearson correlation coefficient between a given imaging marker and recurrence risk after uniform irradiation. Second, the predicted maximum possible gain in tumor control probability for any robust optimization technique is nearly proportional to the square of R.« less

Individual variations in dose response for spatial memory learning among outbred wistar rats exposed from 5 to 20 cGy of (56) Fe particles.

PubMed

Wyrobek, Andrew J; Britten, Richard A

2016-06-01

Exposures of brain tissue to ionizing radiation can lead to persistent deficits in cognitive functions and behaviors. However, little is known about the quantitative relationships between exposure dose and neurological risks, especially for lower doses and among genetically diverse individuals. We investigated the dose relationship for spatial memory learning among genetically outbred male Wistar rats exposed to graded doses of (56) Fe particles (sham, 5, 10, 15, and 20 cGy; 1 GeV/n). Spatial memory learning was assessed on a Barnes maze using REL3 ratios measured at three months after exposure. Irradiated animals showed dose-dependent declines in spatial memory learning that were fit by a linear regression (P for slope <0.0002). The irradiated animals showed significantly impaired learning at 10 cGy exposures, no detectable learning between 10 and 15 cGy, and worsened performances between 15 and 20 cGy. The proportions of poor learners and the magnitude of their impairment were fit by linear regressions with doubling doses of ∼10 cGy. In contrast, there were no detectable deficits in learning among the good learners in this dose range. Our findings suggest that genetically diverse individuals can vary substantially in their spatial memory learning, and that exposures at low doses appear to preferentially impact poor learners. This hypothesis invites future investigations of the genetic and physiological mechanisms of inter-individual variations in brain function related to spatial memory learning after low-dose HZE radiation exposures and to determine whether it also applies to physical trauma to brain tissue and exposures to chemical neurotoxicants. Environ. Mol. Mutagen. 57:331-340, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Clustered DNA damages induced in human hematopoietic cells by low doses of ionizing radiation

NASA Technical Reports Server (NTRS)

Sutherland, Betsy M.; Bennett, Paula V.; Cintron-Torres, Nela; Hada, Megumi; Trunk, John; Monteleone, Denise; Sutherland, John C.; Laval, Jacques; Stanislaus, Marisha; Gewirtz, Alan

2002-01-01

Ionizing radiation induces clusters of DNA damages--oxidized bases, abasic sites and strand breaks--on opposing strands within a few helical turns. Such damages have been postulated to be difficult to repair, as are double strand breaks (one type of cluster). We have shown that low doses of low and high linear energy transfer (LET) radiation induce such damage clusters in human cells. In human cells, DSB are about 30% of the total of complex damages, and the levels of DSBs and oxidized pyrimidine clusters are similar. The dose responses for cluster induction in cells can be described by a linear relationship, implying that even low doses of ionizing radiation can produce clustered damages. Studies are in progress to determine whether clusters can be produced by mechanisms other than ionizing radiation, as well as the levels of various cluster types formed by low and high LET radiation.

A plausible radiobiological model of cardiovascular disease at low or fractionated doses

NASA Astrophysics Data System (ADS)

Little, Mark; Vandoolaeghe, Wendy; Gola, Anna; Tzoulaki, Ioanna

Atherosclerosis is the main cause of coronary heart disease and stroke, the two major causes of death in developed society. There is emerging evidence of excess risk of cardiovascular disease at low radiation doses in various occupationally-exposed groups receiving small daily radia-tion doses. Assuming that they are causal, the mechanisms for effects of chronic fractionated radiation exposures on cardiovascular disease are unclear. We outline a spatial reaction-diffusion model for atherosclerosis, and perform stability analysis, based wherever possible on human data. We show that a predicted consequence of multiple small radiation doses is to cause mean chemo-attractant (MCP-1) concentration to increase linearly with cumulative dose. The main driver for the increase in MCP-1 is monocyte death, and consequent reduction in MCP-1 degradation. The radiation-induced risks predicted by the model are quantitatively consistent with those observed in a number of occupationally-exposed groups. The changes in equilibrium MCP-1 concentrations with low density lipoprotein cholesterol concentration are also consistent with experimental and epidemiologic data. This proposed mechanism would be experimentally testable. If true, it also has substantive implications for radiological protection, which at present does not take cardiovascular disease into account. The Japanese A-bomb survivor data implies that cardiovascular disease and can-cer mortality contribute similarly to radiogenic risk. The major uncertainty in assessing the low-dose risk of cardiovascular disease is the shape of the dose response relationship, which is unclear in the Japanese data. The analysis of the present paper suggests that linear extrapo-lation would be appropriate for this endpoint.

Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers.

PubMed

Wei, Randy L; Jung, Brian C; Manzano, Wilfred; Sehgal, Varun; Klempner, Samuel J; Lee, Steve P; Ramsinghani, Nilam S; Lall, Chandana

2016-03-01

To investigate the relationship between abdominal chemoradiation (CRT) for locally advanced cancers and bone mineral density (BMD) reduction in the vertebral spine. Data from 272 patients who underwent abdominal radiation therapy from January 1997 to May 2015 were retrospectively reviewed. Forty-two patients received computed tomography (CT) scans of the abdomen prior to initiation and at least twice after radiation therapy. Bone attenuation (in Hounsfield unit) (HU) measurements were collected for each vertebral level from T7 to L5 using sagittal CT images. Radiation point dose was obtained at each mid-vertebral body from the radiation treatment plan. Percent change in bone attenuation (Δ%HU) between baseline and post-radiation therapy were computed for each vertebral body. The Δ%HU was compared against radiation dose using Pearson's linear correlation. Abdominal radiotherapy caused significant reduction in vertebral BMD as measured by HU. Patients who received only chemotherapy did not show changes in their BMD in this study. The Δ%HU was significantly correlated with the radiation point dose to the vertebral body (R=-0.472, P<0.001) within 4-8 months following RT. The same relationship persisted in subsequent follow up scans 9 months following RT (R=-0.578, P<0.001). Based on the result of linear regression, 5 Gy, 15 Gy, 25 Gy, 35 Gy, and 45 Gy caused 21.7%, 31.1%, 40.5%, 49.9%, and 59.3% decrease in HU following RT, respectively. Our generalized linear model showed that pre-RT HU had a positive effect (β=0.830) on determining post-RT HU, while number of months post RT (β=-0.213) and radiation point dose (β=-1.475) had a negative effect. A comparison of the predicted versus actual HU showed significant correlation (R=0.883, P<0.001) with the slope of the best linear fit=0.81. Our model's predicted HU were within ±20 HU of the actual value in 53% of cases, 70% of the predictions were within ±30 HU, 81% were within ±40 HU, and 90% were within ±50 HU of the actual post-RT HU. Four of 42 patients were found to have vertebral body compression fractures in the field of radiation. Patients who receive abdominal chemoradiation develop significant BMD loss in the thoracic and lumbar vertebrae. Treatment-related BMD loss may contribute to the development of vertebral compression fractures. A predictive model for post-CRT BMD changes may inform bone protective strategies in patients planned for abdominal CRT. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model

PubMed Central

Mavridou, Eleftheria; Melchers, Ria J. B.; van Mil, Anita C. H. A. M.; Mangin, E.; Motyl, Mary R.

2014-01-01

MK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producing Pseudomonas aeruginosa and Klebsiella pneumoniae strains to determine its effect in vitro and in vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 106 CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits for T>MIC and area under the concentration-time curve (AUC)/MIC were comparable (R2 of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activity in vivo and results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans. PMID:25403667

Biological X-ray irradiator characterization for use with small animals and cells.

PubMed

Bruno, A Colello; Mazaro, S J; Amaral, L L; Rego, E M; Oliveira, H F; Pavoni, J F

2017-03-02

This study presents the characterization of an X-ray irradiator through dosimetric tests, which confirms the actual dose rate that small animals and cells will be exposed to during radiobiological experiments. We evaluated the linearity, consistency, repeatability, and dose distribution in the positions in which the animals or cells are placed during irradiation. In addition, we evaluated the performance of the X-ray tube (voltage and tube operating current), the radiometric survey (leakage radiation) and safety devices. The irradiator default setting was established as 160 kV and 25 mA. Tests showed that the dose rate was linear overtime (R2=1) and remained stable for long (constant) and short (repeatability) intervals between readings. The mean dose rate inside the animal cages was 1.27±0.06 Gy/min with a uniform beam of 95.40% (above the minimum threshold guaranteed by the manufacturer). The mean dose rate inside the cell plates was 0.92±0.19 Gy/min. The dose rate dependence with tube voltage and current presented a quadratic and linear relationship, respectively. There was no observed mechanical failure during evaluation of the irradiator safety devices and the radiometric survey obtained a maximum ambient equivalent dose rate of 0.26 mSv/h, which exempts it from the radiological protection requirements of the International Atomic Energy Agency. The irradiator characterization enables us to perform radiobiological experiments, and assists or even replaces traditional therapy equipment (e.g., linear accelerators) for cells and small animal irradiation, especially in early research stages.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.

PubMed

Girgis, I G; Patel, M R; Peters, G R; Moore, K T; Mahaffey, K W; Nessel, C C; Halperin, J L; Califf, R M; Fox, K A A; Becker, R C

2014-08-01

Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF. © 2014, The American College of Clinical Pharmacology.

Global Associations between UVR Exposure and Current Eczema Prevalence in Children from ISAAC Phase Three.

PubMed

Fuertes, Elaine; Flohr, Carsten; Silverberg, Jonathan I; Standl, Marie; Strachan, David P

2017-06-01

We sought to examine the relationship globally between UVR dose exposure and current eczema prevalences. ISAAC Phase Three provided data on eczema prevalence for 13- to 14-year-olds in 214 centers in 87 countries and for 6- to 7-year-olds in 132 centers in 57 countries. Linear and nonlinear associations between (natural log transformed) eczema prevalence and the mean, maximum, minimum, standard deviation, and range of monthly UV dose exposures were assessed using linear mixed-effects regression models. For the 13- to 14-year-olds, the country-level eczema prevalence was positively and linearly associated with country-level monthly mean (prevalence ratio = 1.31 [95% confidence interval = 1.05-1.63] per kJ/m 2 ) and minimum (1.25 [1.06-1.47] per kJ/m 2 ) UVR dose exposure. Linear and nonlinear associations were also observed for other metrics of UV. Results were similar in trend, but nonsignificant, for the fewer centers with 6- to 7-year-olds (e.g., 1.24 [0.96-1.59] per kJ/m 2 for country-level monthly mean UVR). No consistent within-country associations were observed (e.g., 1.05 [0.89-1.23] and 0.92 [0.71-1.18] per kJ/m 2 for center-level monthly mean UVR for the 13- to 14- and 6- to 7-year-olds, respectively). These ecological results support a role for UVR exposure in explaining some of the variation in global childhood eczema prevalence. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The feasibility assessment of radiation dose of movement 3D NIPAM gel by magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Hsieh, Chih-Ming; Leung, Joseph Hang; Ng, Yu-Bun; Cheng, Chih-Wu; Sun, Jung-Chang; Lin, Ping-Chin; Hsieh, Bor-Tsung

2015-11-01

NIPAM dosimeter is widely accepted and recommended for its 3D distribution and accuracy in dose absorption. Up to the moment, most research works on dose measurement are based on a fixed irradiation target without the consideration of the effect from physiological motion. We present a study to construct a respiratory motion simulating patient anatomical and dosimetry model for the study of dosimetic effect of organ motion. The dose on fixed and motion targets was measured by MRI after a dose adminstration of 1, 2, 5, 8, and 10 Gy from linear accelerator. Comparison of two situations is made. The average sensitivity of fixed NIPAM was 0.1356 s-1/Gy with linearity R2=0.998. The average sensitivity of movement NIPAM was 0.1366 s-1/Gy with linearity R2=0.998 both having only 0.001 of the sensitivity difference. The difference between the two based on dose rate dependency, position and depth was not significant. There was thus no apparent impact on NIPAM dosimeter from physiological motion. The high sensitivity, linearity and stability of NIPAM dosimeter proved to be an ideal apparatus in the dose measurement in these circumstances.

Using machine learning to model dose-response relationships.

PubMed

Linden, Ariel; Yarnold, Paul R; Nallamothu, Brahmajee K

2016-12-01

Establishing the relationship between various doses of an exposure and a response variable is integral to many studies in health care. Linear parametric models, widely used for estimating dose-response relationships, have several limitations. This paper employs the optimal discriminant analysis (ODA) machine-learning algorithm to determine the degree to which exposure dose can be distinguished based on the distribution of the response variable. By framing the dose-response relationship as a classification problem, machine learning can provide the same functionality as conventional models, but can additionally make individual-level predictions, which may be helpful in practical applications like establishing responsiveness to prescribed drug regimens. Using data from a study measuring the responses of blood flow in the forearm to the intra-arterial administration of isoproterenol (separately for 9 black and 13 white men, and pooled), we compare the results estimated from a generalized estimating equations (GEE) model with those estimated using ODA. Generalized estimating equations and ODA both identified many statistically significant dose-response relationships, separately by race and for pooled data. Post hoc comparisons between doses indicated ODA (based on exact P values) was consistently more conservative than GEE (based on estimated P values). Compared with ODA, GEE produced twice as many instances of paradoxical confounding (findings from analysis of pooled data that are inconsistent with findings from analyses stratified by race). Given its unique advantages and greater analytic flexibility, maximum-accuracy machine-learning methods like ODA should be considered as the primary analytic approach in dose-response applications. © 2016 John Wiley & Sons, Ltd.

Association between exposure to noise and risk of hypertension: a meta-analysis of observational epidemiological studies.

PubMed

Fu, Wenning; Wang, Chao; Zou, Li; Liu, Qiaoyan; Gan, Yong; Yan, Shijiao; Song, Fujian; Wang, Zhihong; Lu, Zuxun; Cao, Shiyi

2017-12-01

An increasing amount of original studies suggested that exposure to noise could be associated with the risk of hypertension, but the results remain inconsistent and inconclusive. We aimed to synthesize available epidemiological evidence about the relationship between various types of noise and hypertension, and to explore the potential dose-response relationship between them in an up-to-date meta-analysis. We conducted a literature search of PubMed and Embase from these databases' inception through December 2016 to identify observational epidemiological studies examining the association between noise and risk of hypertension. A random effects model was used to combine the results of included studies. Dose-response meta-analysis was conducted to examine the potential dose-response relationship. In total, 32 studies (five cohort studies, one case-control study, and 26 cross-section studies) involving 264 678 participants were eligible for inclusion. Pooled result showed that living or working in environment with noise exposure was significantly associated with increased risk of hypertension (odds ratio 1.62; 95% confidence interval: 1.40-1.88). We found no evidence of a curve linear association between noise and risk of hypertension. A dose-response analysis suggested that, for an increment of per 10 dB(A) of noise, the combined odds ratio of hypertension was 1.06 (95% confidence interval: 1.04-1.08). Integrated epidemiological evidence supports the hypothesis that exposure to noise may be a risk factor of hypertension, and there is a positive dose-response association between them.

Appropriate Use of Effective Dose in Radiation Protection and Risk Assessment.

PubMed

Fisher, Darrell R; Fahey, Frederic H

2017-08-01

Effective dose was introduced by the ICRP for the single, over-arching purpose of setting limits for radiation protection. Effective dose is a derived quantity or mathematical construct and not a physical, measurable quantity. The formula for calculating effective dose to a reference model incorporates terms to account for all radiation types, organ and tissue radiosensitivities, population groups, and multiple biological endpoints. The properties and appropriate applications of effective dose are not well understood by many within and outside the health physics profession; no other quantity in radiation protection has been more confusing or misunderstood. According to ICRP Publication 103, effective dose is to be used for "prospective dose assessment for planning and optimization in radiological protection, and retrospective demonstration of compliance for regulatory purposes." In practice, effective dose has been applied incorrectly to predict cancer risk among exposed persons. The concept of effective dose applies generally to reference models only and not to individual subjects. While conceived to represent a measure of cancer risk or heritable detrimental effects, effective dose is not predictive of future cancer risk. The formula for calculating effective dose incorporates committee-selected weighting factors for radiation quality and organ sensitivity; however, the organ weighting factors are averaged across all ages and both genders and thus do not apply to any specific individual or radiosensitive subpopulations such as children and young women. Further, it is not appropriate to apply effective dose to individual medical patients because patient-specific parameters may vary substantially from the assumptions used in generalized models. Also, effective dose is not applicable to therapeutic uses of radiation, as its mathematical underpinnings pertain only to observed late (stochastic) effects of radiation exposure and do not account for short-term adverse tissue reactions. The weighting factors incorporate substantial uncertainties, and linearity of the dose-response function at low dose is uncertain and highly disputed. Since effective dose is not predictive of future cancer incidence, it follows that effective dose should never be used to estimate future cancer risk from specific sources of radiation exposure. Instead, individual assessments of potential detriment should only be based on organ or tissue radiation absorbed dose, together with best scientific understanding of the corresponding dose-response relationships.

Investigating output and energy variations and their relationship to delivery QA results using Statistical Process Control for helical tomotherapy.

PubMed

Binny, Diana; Mezzenga, Emilio; Lancaster, Craig M; Trapp, Jamie V; Kairn, Tanya; Crowe, Scott B

2017-06-01

The aims of this study were to investigate machine beam parameters using the TomoTherapy quality assurance (TQA) tool, establish a correlation to patient delivery quality assurance results and to evaluate the relationship between energy variations detected using different TQA modules. TQA daily measurement results from two treatment machines for periods of up to 4years were acquired. Analyses of beam quality, helical and static output variations were made. Variations from planned dose were also analysed using Statistical Process Control (SPC) technique and their relationship to output trends were studied. Energy variations appeared to be one of the contributing factors to delivery output dose seen in the analysis. Ion chamber measurements were reliable indicators of energy and output variations and were linear with patient dose verifications. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

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

PubMed

Crump, K S

1996-10-01

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

Quality assurance of dynamic parameters in volumetric modulated arc therapy.

PubMed

Manikandan, A; Sarkar, B; Holla, R; Vivek, T R; Sujatha, N

2012-07-01

The purpose of this study was to demonstrate quality assurance checks for accuracy of gantry speed and position, dose rate and multileaf collimator (MLC) speed and position for a volumetric modulated arc treatment (VMAT) modality (Synergy S; Elekta, Stockholm, Sweden), and to check that all the necessary variables and parameters were synchronous. Three tests (for gantry position-dose delivery synchronisation, gantry speed-dose delivery synchronisation and MLC leaf speed and positions) were performed. The average error in gantry position was 0.5° and the average difference was 3 MU for a linear and a parabolic relationship between gantry position and delivered dose. In the third part of this test (sawtooth variation), the maximum difference was 9.3 MU, with a gantry position difference of 1.2°. In the sweeping field method test, a linear relationship was observed between recorded doses and distance from the central axis, as expected. In the open field method, errors were encountered at the beginning and at the end of the delivery arc, termed the "beginning" and "end" errors. For MLC position verification, the maximum error was -2.46 mm and the mean error was 0.0153 ±0.4668 mm, and 3.4% of leaves analysed showed errors of >±1 mm. This experiment demonstrates that the variables and parameters of the Synergy S are synchronous and that the system is suitable for delivering VMAT using a dynamic MLC.

Effect of ractopamine hydrochloride (Optaflexx) dose and duration on growth performance and carcass characteristics of finishing steers.

PubMed

Bittner, C J; Crawford, G I; Berger, L L; Holt, S; Pritchard, R R; Platter, W J; Van Koevering, M T; Pyatt, N A; Erickson, G E

2016-12-01

Three experiments evaluated the effects of ractopamine hydrochloride (RAC) dose and duration on growth performance and carcass characteristics of feedlot steers. In total, 1,509 crossbred steers (530 kg initial BW [SD 22]) were used in a randomized complete block design using a 3 × 3 factorial treatment structure. Treatments consisted of RAC dose (0, 100, or 200 mg/steer daily) and duration (28, 35, or 42 d) of RAC feeding prior to harvest. Initiation of RAC dose was staggered (7 d apart) based on RAC duration, which resulted in common days on feed among treatments. Data from the 3 experiments were combined for statistical analyses. There were no RAC dose × duration interactions ( ≥ 0.85) for growth performance. Live final BW was not different ( ≥ 0.24) as RAC dose increased. Dry matter intake linearly decreased ( < 0.01) as RAC dose increased. Live ADG and G:F linearly increased ( ≤ 0.01) as RAC dose increased. Carcass-adjusted ADG and G:F linearly increased ( ≤ 0.02) as RAC dose increased. Compared with steers fed 0 mg RAC/steer daily, G:F was improved by 5.0 and 13.0% when steers were fed 100 ( = 0.31) and 200 ( = 0.01) mg RAC/steer daily, respectively. Hot carcass weight tended ( = 0.10) to linearly increase as RAC dose increased, with carcasses from steers fed 100 ( = 0.38) and 200 ( = 0.10) mg RAC/steer daily being 2.2 and 4.1 kg heavier, respectively, than carcasses from steers fed 0 mg RAC/steer daily. Increasing RAC dose linearly ( < 0.01) increased LM area and linearly ( = 0.02) decreased marbling score. Live final BW was not different ( ≥ 0.60) among RAC durations. Carcass-adjusted final BW, ADG, and G:F were not different ( ≥ 0.41) as RAC duration increased. Carcass traits did not differ ( ≥ 0.18) among RAC duration. Feeding 200 mg RAC/steer daily improved ADG, feed efficiency, and HCW. Increasing the feeding duration of RAC had no effect of growth performance or carcass characteristics. These data indicate that feeding 200 mg RAC/steer daily for 28 d improves steer growth performance.

Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment.

PubMed

Woolley, Thomas E; Belmonte-Beitia, Juan; Calvo, Gabriel F; Hopewell, John W; Gaffney, Eamonn A; Jones, Bleddyn

2018-06-01

To estimate, from experimental data, the retreatment radiation 'tolerances' of the spinal cord at different times after initial treatment. A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated 'retreatment tolerance' BED value, denoted [Formula: see text] and [Formula: see text]. The primate data of Ang et al. ( 2001 ) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BED init ). The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted [Formula: see text] value into a formal BED value and then a practical dose fractionation schedule. Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment.

Room model based Monte Carlo simulation study of the relationship between the airborne dose rate and the surface-deposited radon progeny.

PubMed

Sun, Kainan; Field, R William; Steck, Daniel J

2010-01-01

The quantitative relationships between radon gas concentration, the surface-deposited activities of various radon progeny, the airborne radon progeny dose rate, and various residential environmental factors were investigated through a Monte Carlo simulation study based on the extended Jacobi room model. Airborne dose rates were calculated from the unattached and attached potential alpha-energy concentrations (PAECs) using two dosimetric models. Surface-deposited (218)Po and (214)Po were significantly correlated with radon concentration, PAECs, and airborne dose rate (p-values <0.0001) in both non-smoking and smoking environments. However, in non-smoking environments, the deposited radon progeny were not highly correlated to the attached PAEC. In multiple linear regression analysis, natural logarithm transformation was performed for airborne dose rate as a dependent variable, as well as for radon and deposited (218)Po and (214)Po as predictors. In non-smoking environments, after adjusting for the effect of radon, deposited (214)Po was a significant positive predictor for one dose model (RR 1.46, 95% CI 1.27-1.67), while deposited (218)Po was a negative predictor for the other dose model (RR 0.90, 95% CI 0.83-0.98). In smoking environments, after adjusting for radon and room size, deposited (218)Po was a significant positive predictor for one dose model (RR 1.10, 95% CI 1.02-1.19), while a significant negative predictor for the other model (RR 0.90, 95% CI 0.85-0.95). After adjusting for radon and deposited (218)Po, significant increases of 1.14 (95% CI 1.03-1.27) and 1.13 (95% CI 1.05-1.22) in the mean dose rates were found for large room sizes relative to small room sizes in the different dose models.

Solid Cancer Incidence in the Techa River Incidence Cohort: 1956-2007.

PubMed

Davis, F G; Yu, K L; Preston, D; Epifanova, S; Degteva, M; Akleyev, A V

2015-07-01

Previously reported studies of the Techa River Cohort have established associations between radiation dose and the occurrence of solid cancers and leukemia (non-CLL) that appear to be linear in dose response. These analyses include 17,435 cohort members alive and not known to have had cancer prior to January 1, 1956 who lived in areas near the river or Chelyabinsk City at some time between 1956 and the end of 2007, utilized individualized dose estimates computed using the Techa River Dosimetry System 2009 and included five more years of follow-up. The median and mean dose estimates based on these doses are consistently higher than those based on earlier Techa River Dosimetry System 2000 dose estimates. This article includes new site-specific cancer risk estimates and risk estimates adjusted for available information on smoking. There is a statistically significant (P = 0.02) linear trend in the smoking-adjusted all-solid cancer incidence risks with an excess relative risk (ERR) after exposure to 100 mGy of 0.077 with a 95% confidence interval of 0.013-0.15. Examination of site-specific risks revealed statistically significant radiation dose effects only for cancers of the esophagus and uterus with an ERR per 100 mGy estimates in excess of 0.10. Esophageal cancer risk estimates were modified by ethnicity and sex, but not smoking. While the solid cancer rates are attenuated when esophageal cancer is removed (ERR = 0.063 per 100 mGy), a dose-response relationship is present and it remains likely that radiation exposure has increased the risks for most solid cancers in the cohort despite the lack of power to detect statistically significant risks for specific sites.

Exercise and the heart--the harm of too little and too much.

PubMed

Lavie, Carl J; O'Keefe, James H; Sallis, Robert E

2015-01-01

Physical activity and exercise training are underutilized by much of Westernized society, and physical inactivity may be the greatest threat to health in the 21st century. Many studies have shown a linear relationship between one's activity level and heart health, leading to the conclusion that "if some exercise is good, more must be better." However, there is evolving evidence that high levels of exercise may produce similar or less overall cardiovascular (CV) benefits compared with those produced by lower doses of exercise. Very high doses of exercise may be associated with increased risk of atrial fibrillation, coronary artery disease, and malignant ventricular arrhythmias. These acute bouts of excessive exercise may lead to cardiac dilatation, cardiac dysfunction, and release of troponin and brain natriuretic peptide. The effects of too little and too much exercise on the heart are reviewed in this article, along with recommendations to optimize the dose of exercise to achieve heart health.

Cancer mortality among coke oven workers.

PubMed Central

Redmond, C K

1983-01-01

The OSHA standard for coke oven emissions, which went into effect in January 1977, sets a permissible exposure limit to coke oven emissions of 150 micrograms/m3 benzene-soluble fraction of total particulate matter (BSFTPM). Review of the epidemiologic evidence for the standard indicates an excess relative risk for lung cancer as high as 16-fold in topside coke oven workers with 15 years of exposure or more. There is also evidence for a consistent dose-response relationship in lung cancer mortality when duration and location of employment at the coke ovens are considered. Dose-response models fitted to these same data indicate that, while excess risks may still occur under the OSHA standard, the predicted levels of increased relative risk would be about 30-50% if a linear dose-response model is assumed and 3-7% if a quadratic model is assumed. Lung cancer mortality data for other steelworkers suggest the predicted excess risk has probably been somewhat overestimated, but lack of information on important confounding factors limits further dose-response analysis. PMID:6653539

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

PubMed

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

2016-12-01

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

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

PubMed

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

2015-08-01

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

Effects of a Multi-Ingredient Energy Supplement on Cognitive Performance and Cerebral-Cortical Activation.

PubMed

Daou, Marcos; Sassi, Julia Montagner; Miller, Matthew W; Gonzalez, Adam M

2018-03-13

This study assessed whether a multi-ingredient energy supplement (MIES) could enhance cerebral-cortical activation and cognitive performance during an attention-switching task. Cerebral-cortical activation was recorded in 24 young adults (12 males, 12 females; 22.8 ± 3.8 yrs) via electroencephalography (EEG) both at rest and during the attention-switching task before (pretest) and 30 min after (posttest) consumption of a single serving of a MIES (MIES-1), two servings of a MIES (MIES-2), or a placebo (PL) in a double-blinded, randomized crossover experimental design. EEG upper-alpha power was assessed at rest and during the task, wherein d' (Z[hit rate]-Z[false alarm rate]) and median reaction time (RT) for correct responses to targets on attention-hold and attention-switch trials were analyzed. For both d' and RT, the Session (MIES-1, MIES-2, PL) × Time (pretest, posttest) interaction approached statistical significance (p = .07, η 2 p = 0.106). Exploring these interactions with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (ps ≤.034), suggesting the pretest-to-posttest improvement in sensitivity to task target stimuli (d') and RT increased as a function of supplement dose. With respect to upper-alpha power, the Session × Time interaction was significant (p < .001, η 2 p = 0.422). Exploring this interaction with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (p < .001), suggesting pretest-to-posttest increases in cerebral-cortical activation were a function of supplement dose. In conclusion, our findings suggest that MIES can increase cerebral-cortical activation and RT during task performance while increasing sensitivity to target stimuli in a dose-dependent manner.

Longitudinal trends of total white blood cell and differential white blood cell counts of atomic bomb survivors.

PubMed

Hsu, Wan-Ling; Tatsukawa, Yoshimi; Neriishi, Kazuo; Yamada, Michiko; Cologne, John; Fujiwara, Saeko

2010-01-01

In studying the late health effects of atomic-bomb (A-bomb) survivors, earlier findings were that white blood cell (WBC) count increased with radiation dose in cross-sectional studies. However, a persistent effect of radiation on WBC count and other risk factors has yet to be confirmed. The objectives of the present study were 1) to examine the longitudinal relationship between A-bomb radiation dose and WBC and differential WBC counts among A-bomb survivors and 2) to investigate the potential confounding risk factors (such as age at exposure and smoking status) as well as modification of the radiation dose-response. A total of 7,562 A-bomb survivors in Hiroshima and Nagasaki were included in this study from 1964-2004. A linear mixed model was applied using the repeated WBC measurements. During the study period, a secular downward trend of WBC count was observed. Radiation exposure was a significant risk factor for elevated WBC and differential WBC counts over time. A significant increase of WBC counts among survivors with high radiation dose (> 2 Gy) was detected in men exposed below the age of 20 and in women regardless of age at exposure. Effects on WBC of low dose radiation remain unclear, however. Cigarette smoking produced the most pronounced effect on WBC counts and its impact was much larger than that of radiation exposure.

Controlled vaporized cannabis, with and without alcohol: subjective effects and oral fluid-blood cannabinoid relationships.

PubMed

Hartman, Rebecca L; Brown, Timothy L; Milavetz, Gary; Spurgin, Andrew; Gorelick, David A; Gaffney, Gary; Huestis, Marilyn A

2016-07-01

Vaporized cannabis and concurrent cannabis and alcohol intake are commonplace. We evaluated the subjective effects of cannabis, with and without alcohol, relative to blood and oral fluid (OF, advantageous for cannabis exposure screening) cannabinoid concentrations and OF/blood and OF/plasma vaporized-cannabinoid relationships. Healthy adult occasional-to-moderate cannabis smokers received a vaporized placebo or active cannabis (2.9% and 6.7% Δ(9) -tetrahydrocannabinol, THC) with or without oral low-dose alcohol (~0.065g/210L peak breath alcohol concentration [BrAC]) in a within-subjects design. Blood and OF were collected up to 8.3 h post-dose and subjective effects measured at matched time points with visual-analogue scales and 5-point Likert scales. Linear mixed models evaluated subjective effects by THC concentration, BrAC, and interactions. Effects by time point were evaluated by dose-wise analysis of variance (ANOVA). OF versus blood or plasma cannabinoid ratios and correlations were evaluated in paired-positive specimens. Nineteen participants (13 men) completed the study. Blood THC concentration or BrAC significantly associated with subjective effects including 'high', while OF contamination prevented significant OF concentration associations <1.4 h post-dose. Subjective effects persisted through 3.3-4.3 h, with alcohol potentiating the duration of the cannabis effects. Effect-versus-THC concentration and effect-versus-alcohol concentration hystereses were counterclockwise and clockwise, respectively. OF/blood and OF/plasma THC significantly correlated (all Spearman r≥0.71), but variability was high. Vaporized cannabis subjective effects were similar to those previously reported after smoking, with duration extended by concurrent alcohol. Cannabis intake was identified by OF testing, but OF concentration variability limited interpretation. Blood THC concentrations were more consistent across subjects and more accurate at predicting cannabis' subjective effects. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

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

PubMed

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

2002-12-01

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

The Healthy Worker Effect and Nuclear Industry Workers

PubMed Central

Fornalski, Krzysztof W.; Dobrzyński, Ludwik

2010-01-01

The linear no-threshold (LNT) dose-effect relationship has been consistently used by most radiation epidemiologists to estimate cancer mortality risk. The large scattering of data by International Agency for Research on Cancer, IARC (Vrijheid et al. 2007; Therry-Chef et al. 2007; Cardis et al. 2007), interpreted in accordance with LNT, has been previously demonstrated (Fornalski and Dobrzyński 2009). Using conventional and Bayesian methods the present paper demonstrates that the standard mortality ratios (SMRs), lower in the IARC cohort of exposed nuclear workers than in the non exposed group, should be considered as a hormetic effect, rather than a healthy worker effect (HWE) as claimed by the IARC group. PMID:20585442

The 10th anniversary of the publication of genes and environment: memoir of establishing the Japanese environmental mutagen society and a proposal for a new collaborative study on mutagenic hormesis.

PubMed

Sutou, Shizuyo

2017-01-01

The Japanese Environmental Mutagen Society (JEMS) was established in 1972 by 147 members, 11 of whom are still on the active list as of May 1, 2016. As one of them, I introduce some historic topics here. These include 1) establishment of JEMS, 2) the issue of 2-(2-furyl)-3-(3-nitro-2-furyl)acrylamide (AF-2), 3) the Mammalian Mutagenicity Study Group (MMS) and its achievements, and 4) the Collaborative Study Group of the Micronucleus Test (CSGMT) and its achievements. In addition to these historic matters, some of which are still ongoing, a new collaborative study is proposed on adaptive response or hormesis by mutagens. There is a close relationship between mutagens and carcinogens, the dose-response relationship of which has been thought to follow the linear no-threshold model (LNT). LNT was fabricated on the basis of Drosophila sperm experiments using high dose radiation delivered in a short period. The fallacious 60 years-old LNT is applied to cancer induction by radiation without solid data and then to cancer induction by carcinogens also without solid data. Therefore, even the smallest amount of carcinogens is postulated to be carcinogenic without thresholds now. Radiation hormesis is observed in a large variety of living organisms; radiation is beneficial at low doses, but hazardous at high doses. There is a threshold at the boundary between benefit and hazard. Hormesis denies LNT. Not a few papers report existence of chemical hormesis. If mutagens and carcinogens show hormesis, the linear dose-response relationship in mutagenesis and carcinogenesis is denied and thresholds can be introduced.

Pharmacokinetic-Pharmacodynamic Model for the Effect of l-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria

PubMed Central

Brussee, Janneke M.; Yeo, Tsin W.; Lampah, Daniel A.; Anstey, Nicholas M.

2015-01-01

Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of l-arginine, the substrate for endothelial cell NO synthase. We quantified the time course of the effects of adjunctive l-arginine treatment on endothelial function in 73 patients with moderately severe falciparum malaria derived from previous studies. Three groups of 10 different patients received 3 g, 6 g, or 12 g of l-arginine as a half-hour infusion. The remaining 43 received saline placebo. A pharmacokinetic-pharmacodynamic (PKPD) model was developed to describe the time course of changes in exhaled NO concentrations and reactive hyperemia-peripheral arterial tonometry (RH-PAT) index values describing endothelial function and then used to explore optimal dosing regimens for l-arginine. A PK model describing arginine concentrations in patients with moderately severe malaria was extended with two pharmacodynamic biomeasures, the intermediary biochemical step (NO production) and endothelial function (RH-PAT index). A linear model described the relationship between arginine concentrations and exhaled NO. NO concentrations were linearly related to RH-PAT index. Simulations of dosing schedules using this PKPD model predicted that the time within therapeutic range would increase with increasing arginine dose. However, simulations demonstrated that regimens of continuous infusion over longer periods would prolong the time within the therapeutic range even more. The optimal dosing regimen for l-arginine is likely to be administration schedule dependent. Further studies are necessary to characterize the effects of such continuous infusions of l-arginine on NO and microvascular reactivity in severe malaria. PMID:26482311

Low-Dose N,N-Dimethylformamide Exposure and Liver Injuries in a Cohort of Chinese Leather Industry Workers.

PubMed

Qi, Cong; Gu, Yiyang; Sun, Qing; Gu, Hongliang; Xu, Bo; Gu, Qing; Xiao, Jing; Lian, Yulong

2017-05-01

We assessed the risk of liver injuries following low doses of N,N-dimethylformamide (DMF) below threshold limit values (20 mg/m) among leather industry workers and comparison groups. A cohort of 429 workers from a leather factory and 466 non-exposed subjects in China were followed for 4 years. Poisson regression and piece-wise linear regression were used to examine the relationship between DMF and liver injury. Workers exposed to a cumulative dose of DMF were significantly more likely than non-exposed workers to develop liver injury. A nonlinear relationship between DMF and liver injury was observed, and a threshold of the cumulative DMF dose for liver injury was 7.30 (mg/m) year. The findings indicate the importance of taking action to reduce DMF occupational exposure limits for promoting worker health.

Dose rate effect of pulsed electron beam on micronucleus frequency in human peripheral blood lymphocytes.

PubMed

Acharya, Santhosh; Sanjeev, Ganesh; Bhat, Nagesh N; Narayana, Yerol

2010-03-01

The micronucleus assay in human peripheral blood lymphocytes is a sensitive indicator of radiation damage and could serve as a biological dosimeter in evaluating suspected overexposure to ionising radiation. Micronucleus (MN) frequency as a measure of chromosomal damage has also extensively been employed to quantify the effects of radiation dose rate on biological systems. Here we studied the effects of 8 MeV pulsed electron beam emitted by Microtron electron accelerator on MN induction at dose rates between 35 Gy min-1 and 352.5 Gy min-1. These dose rates were achieved by varying the pulse repetition rate (PRR). Fricke dosimeter was employed to measure the absorbed dose at different PRR and to ensure uniform dose distribution of the electron beam. To study the dose rate effect, blood samples were irradiated to an absorbed dose of (4.7+/-0.2) Gy at different rates and cytogenetic damage was quantified using the micronucleus assay. The obtained MN frequency showed no dose rate dependence within the studied dose rate range. Our earlier dose effect study using 8 MeV electrons revealed that the response of MN was linear-quadratic. Therefore, in the event of an accident, dose estimation can be made using linear-quadratic dose response parameters, without adding dose rate as a correction factor.

Lead in teeth from lead-dosed goats: Microdistribution and relationship to the cumulative lead dose

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

Bellis, David J.; Hetter, Katherine M.; Jones, Joseph

2008-01-15

Teeth are commonly used as a biomarker of long-term lead exposure. There appear to be few data, however, on the content or distribution of lead in teeth where data on specific lead intake (dose) are also available. This study describes the analysis of a convenience sample of teeth from animals that were dosed with lead for other purposes, i.e., a proficiency testing program for blood lead. Lead concentration of whole teeth obtained from 23 animals, as determined by atomic absorption spectrometry, varied from 0.6 to 80 {mu}g g{sup -1}. Linear regression of whole tooth lead ({mu}g g{sup -1}) on themore » cumulative lead dose received by the animal (g) yielded a slope of 1.2, with r{sup 2}=0.647 (p<0.0001). Laser ablation inductively coupled plasma mass spectrometry was employed to determine lead content at micrometer scale spatial resolution in the teeth of seven goats representing the dosing range. Highly localized concentrations of lead, ranging from about 10 to 2000 {mu}g g{sup -1}, were found in circumpulpal dentine. Linear regression of circumpulpal lead ({mu}g g{sup -1}) on cumulative lead dose (g) yielded a slope of 23 with r{sup 2}=0.961 (p=0.0001). The data indicated that whole tooth lead, and especially circumpulpal lead, of dosed goats increased linearly with cumulative lead exposure. These data suggest that circumpulpal dentine is a better biomarker of cumulative lead exposure than is whole tooth lead, at least for lead-dosed goats.« less

Gender Differences in the Effects of the Frequency of Physical Activity on the Incidence of Metabolic Syndrome: Results from a Middle-Aged Community Cohort in Taiwan.

PubMed

Chen, Sheng-Pyng; Chang, Huan-Cheng; Hsiao, Tien-Mu; Yeh, Chih-Jung; Yang, Hao-Jan

2018-06-01

Little is known about how the frequency of physical activity in adults influences the occurrence of metabolic syndrome (MetS), and whether there are gender differences within these effects. In this study, 3368 residents from the established "Landseed Cohort" underwent three waves of health examinations, and those who did not have MetS at baseline were selected and analyzed using a multiple Poisson regression model. By calculating the adjusted relative risk (ARR), the linear and nonlinear relationships between the frequency of physical activity and risk of developing MetS were examined for male and female participants. The prevalence of MetS was fairly stable across the three waves (ranging from 16.24% to 16.82%), but the incidence dropped from 7.11% to 4.52%. The risk of MetS in women was 10 times higher than that in men (ARR = 10.06; 95% CI = 6.60-15.33), and frequent exercise was shown to help prevent it. The frequency of exercise had a linear dose-response effect in females and an exponential protective effect in males on the occurrence of MetS. Exercising more than four times a week for females and twice or more a week for males effectively reduced the risk of developing MetS. The frequency of physical activity in adults was negatively related to the risk of developing MetS, and this relationship differed based on gender. The protective effect of physical activity on MetS was linear in females and exponential in males.

Pharmacokinetics, hemodynamic and metabolic effects of epinephrine to prevent post-operative low cardiac output syndrome in children

PubMed Central

2014-01-01

Introduction The response to exogenous epinephrine (Ep) is difficult to predict given the multitude of factors involved such as broad pharmacokinetic and pharmacodynamic between-subject variabilities, which may be more pronounced in children. We investigated the pharmacokinetics and pharmacodynamics of Ep, co-administered with milrinone, in children who underwent open heart surgical repair for congenital defects following cardiopulmonary bypass, including associated variability factors. Methods Thirty-nine children with a high risk of low cardiac output syndrome were prospectively enrolled. Ep pharmacokinetics, hemodynamic and metabolic effects were analyzed using the non-linear mixed effects modeling software MONOLIX. According to the final model, an Ep dosing simulation was suggested. Results Ep dosing infusions ranged from 0.01 to 0.23 μg.kg-1.min-1 in children whose weight ranged from 2.5 to 58 kg. A one-compartment open model with linear elimination adequately described the Ep concentration-time courses. Bodyweight (BW) was the main covariate influencing clearance (CL) and endogenous Ep production rate (q0) via an allometric relationship: CL(BWi) = θCL x (BWi)3/4 and q0(BWi) = θq0 x (BWi )3/4. The increase in heart rate (HR) and mean arterial pressure (MAP) as a function of Ep concentration were well described using an Emax model. The effect of age was significant on HR and MAP basal level parameters. Assuming that Ep stimulated the production rate of plasma glucose, the increases in plasma glucose and lactate levels were well described by turnover models without any significant effect of age, BW or exogenous glucose supply. Conclusions According to this population analysis, the developmental effects of BW and age explained a part of the pharmacokinetic and pharmacodynamics between-subject variabilities of Ep administration in critically ill children. This approach ultimately leads to a valuable Ep dosing simulation which should help clinicians to determine an appropriate a priori dosing regimen. PMID:24456639

Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers

PubMed Central

Ericsson, H; Fakt, C; Jolin-Mellgård, Å; Nordlander, M; Sohtell, L; Sunzel, M; Regårdh, C G

1999-01-01

Aims To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug. Methods Twenty-five subjects were enrolled in the study and twenty-one of them were included twice, resulting in a total of forty-six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 0.12 to 48 nmol min−1 kg−1. Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were evaluated by non-compartmental and compartmental analysis. An Emax model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine. Results Clevidipine was administered up to a target dose rate of 48 nmol min−1 kg−1, where a pre-determined escape criterion was reached (HR>120 beats min−1) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non-compartmental analysis was 0.125 l min−1 kg−1. Applying the population approach to the sparse data on clevidipine concentrations, an open two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.121 l min−1 kg−1, and the volume of distribution at steady state was 0.56 l kg−1. The initial half-life, contributing by more than 80% to the total area under the blood concentration-time curve following i.v. bolus administration, was 1.8 min, and the terminal half-life was 9.5 min. At the highest dose rates, MAP was reduced by approximately 10%, and the HR reached the pre-determined escape criterion for this study (>120 beats min−1). Conclusions Clevidipine is well tolerated and safe in healthy volunteers at dose rates up to at least 48 nmol min−1 kg−1. The pharmacokinetics are linear over a wide dose range. Clevidipine is a high clearance drug with extremely short half-lives. The effect of clevidipine on the blood pressure was marginal, probably due to a compensatory baroreflex activation in this population of healthy volunteers. A simple Emax model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blood concentrations of clevidipine. PMID:10336577

Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens

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. For noncancer effects the defaul...

SU-E-T-26: A Study On the Influence of Photonuclear Reactions On the Biological Effectiveness of Therapeutic High Energy X-Ray Beam

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

Wakita, A; National Cancer Center Hospital, Chuo-ku, Tokyo; Matsufuji, N

2014-06-01

Purpose: Photons from a modern high-energy therapeutic linear accelerator used in X-ray radiotherapy causes photonuclear reactions in an accelerator or patient's body. The aim of this study is to evaluate the biological effectiveness including these particles by Microdosimetric Kinetic Model (MKM) based on microdosimetry. Methods: A linear accelerator operating at 15 MV was used. CR-39 was used to obtain LET spectra of secondary ions selectively, as CR-39 is regarded insensitive to photons. CR-39 was put on the central axis of the X-ray beam at depths of 0, 5 and 10 cm in plastic phantom at a source to detector distancemore » of 100 cm. Pits formed by the traversal of ions were etched then analyzed to obtain restricted LET distribution. Frequency-mean and dose-mean lineal energy was evaluated from the relationship between the restricted LET and the lineal energy required to evaluate the biological effectiveness by MKM. The relationship was calculated by Monte Carlo simulations with GEANT4. Results: Restricted LET distributions of secondary particles showed broad distributions that decreases exponentially with increasing LET. Frequency-mean and dose-mean lineal energy were determined uniquely within the scope of the energies of secondary particles generated from photons of 15 MeV. The frequency-mean lineal energies at the depth of 0, 5 and 10 cm were 15.1, 16.0 and 19.7 keV/μm respectively, and the dose-mean lineal energies were 18.6, 20.5 and 19.6 keV/μm, respectively. RBE of secondary particles for HSG cell evaluated by MKM was about 2.0 at all depths, and RBE of all particles including photons was evaluated 1.0. Conclusion: We investigated the biological effectiveness of secondary particles by photonuclear reactions. The method to evaluate RBE by MKM was established with measurements and simulations. However, the influence of these secondary ions on RBE was found negligible in the entire biological effectiveness of the high-energy X-ray. This study has been supported by JSPS KAKENHI Grant Number 25861144.« less

SU-F-T-329: Characteristic Study of a Rado-Photoluminescenct Glass Dosimeter with Accumulated Dose

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

Kim, D; Chung, W; Chung, M

Purpose: This study investigated the effect of accumulated dose on radiophotoluminescent glass dosimeter in megavoltage photon. Methods: 45 commercially-available radio-photoluminescence glass dosimeters (RPLGD; GD-302M, Asahi Techno Glass Co., Shizuoka, JAPAN) were irradiated to 10 × 10 cm{sup 2} open-field with 6, 10 and 15 MV photon beams at 100 cm of source to surface distance and dose maximum depths. Each energy has consists of five groups which is consists of three detectors. A group #1 and #2 was irradiated about 1 Gy to 100 Gy, and estimated the integral dose response with and without annealing procedure. A group #3 wasmore » read the dose after irradiated 10 Gy of dose by 10 times repeatedly to estimate the fading effect of RPLGD. A group #4 and #5 was produced same ways with different irradiation dose such as 50 Gy for group #4 and 100 Gy for group #5. Results: From the results of group #1 and #2, an annealed detector shows linear response to integral dose but other detectors without the annealing process, has supra linearity for integral dose especially close to 100 Gy dose. For group #3, #4 and #5, the dose response of repeated irradiation, the dose response was decreased about 15%, 12% and 7% for 6 MV, 10 MV and 15MV. Conclusion: It was found that RPLGD response to accumulated dose was supra linear and this respond was altered with amount of accumulated dose to the RPLGD. In addition, the fading effect need to be concern with RPLGD.« less

Cannabis with high δ9-THC contents affects perception and visual selective attention acutely: an event-related potential study.

PubMed

Böcker, K B E; Gerritsen, J; Hunault, C C; Kruidenier, M; Mensinga, Tj T; Kenemans, J L

2010-07-01

Cannabis intake has been reported to affect cognitive functions such as selective attention. This study addressed the effects of exposure to cannabis with up to 69.4mg Delta(9)-tetrahydrocannabinol (THC) on Event-Related Potentials (ERPs) recorded during a visual selective attention task. Twenty-four participants smoked cannabis cigarettes with four doses of THC on four test days in a randomized, double blind, placebo-controlled, crossover study. Two hours after THC exposure the participants performed a visual selective attention task and concomitant ERPs were recorded. Accuracy decreased linearly and reaction times increased linearly with THC dose. However, performance measures and most of the ERP components related specifically to selective attention did not show significant dose effects. Only in relatively light cannabis users the Occipital Selection Negativity decreased linearly with dose. Furthermore, ERP components reflecting perceptual processing, as well as the P300 component, decreased in amplitude after THC exposure. Only the former effect showed a linear dose-response relation. The decrements in performance and ERP amplitudes induced by exposure to cannabis with high THC content resulted from a non-selective decrease in attentional or processing resources. Performance requiring attentional resources, such as vehicle control, may be compromised several hours after smoking cannabis cigarettes containing high doses of THC, as presently available in Europe and Northern America. Copyright 2010 Elsevier Inc. All rights reserved.

Azadirachtin effects on mating success, gametic abnormalities and progeny survival in Drosophila melanogaster (Diptera).

PubMed

Oulhaci, Chemseddine M; Denis, Béatrice; Kilani-Morakchi, Samira; Sandoz, Jean-Christophe; Kaiser, Laure; Joly, Dominique; Aribi, Nadia

2018-01-01

Azadirachtin is a prominent natural pesticide and represents an alternative to conventional insecticides. It has been successfully used against insect pests. However, its effects on reproduction require further analysis. Here we investigated lethal and sublethal effects of azadirachtin, on treated adults in a model insect, Drosophila melanogaster (Meigen). Dose-mortality relationships as well as several parameters of reproduction (mating, spermatogenesis, oogenesis and fertility) were examined. Neem-Azal, a commercial formulation of azadirachtin, applied topically on newly emerged adults, increased mortality with a positive dose-dependent relationship. The LD 50 (0.63 μg) was determined 24 h after treatment using a non-linear regression. Adults surviving this dose had a mating success that was divided by 3 and a progeny production reduced by half when males were treated, and even more when females were treated. When combining probability of survival, of mating and reduced progeny, it appeared that LD 50 induced a 98% reduction in reproductive rates. Reduced progeny was partially explained by the effect of adult treatment on gametes number and abnormalities. The number of cysts and the apical nuclei positions within the cysts decreased by 29.7% and 20%, respectively, in males. In females, the number of oocytes per ovary and the volume of basal oocytes also decreased by 16.1% and 32.4%, respectively. Azadirachtin causes significant toxic effects in both sexes and decreases the fecundity and fertility of D. melanogaster. Females are more sensitive to azadirachtin. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Use of iodine for water disinfection: iodine toxicity and maximum recommended dose.

PubMed Central

Backer, H; Hollowell, J

2000-01-01

Iodine is an effective, simple, and cost-efficient means of water disinfection for people who vacation, travel, or work in areas where municipal water treatment is not reliable. However, there is considerable controversy about the maximum safe iodine dose and duration of use when iodine is ingested in excess of the recommended daily dietary amount. The major health effect of concern with excess iodine ingestion is thyroid disorders, primarily hypothyroidism with or without iodine-induced goiter. A review of the human trials on the safety of iodine ingestion indicates that neither the maximum recommended dietary dose (2 mg/day) nor the maximum recommended duration of use (3 weeks) has a firm basis. Rather than a clear threshold response level or a linear and temporal dose-response relationship between iodine intake and thyroid function, there appears to be marked individual sensitivity, often resulting from unmasking of underlying thyroid disease. The use of iodine for water disinfection requires a risk-benefit decision based on iodine's benefit as a disinfectant and the changes it induces in thyroid physiology. By using appropriate disinfection techniques and monitoring thyroid function, most people can use iodine for water treatment over a prolonged period of time. PMID:10964787

Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MR finding of radiation-induced hepatic injury: relationship to absorbed dose and time course after irradiation.

PubMed

Okamoto, Daisuke; Nishie, Akihiro; Asayama, Yoshiki; Tajima, Tsuyoshi; Ishigami, Kousei; Kakihara, Daisuke; Nakayama, Tomohiro; Ohga, Saiji; Yoshitake, Tadamasa; Shioyama, Yoshiyuki; Honda, Hiroshi

2014-07-01

To evaluate if Gd-EOB-DTPA-enhanced MRI could identify liver tissue damage caused by radiation exposure in patients undergoing external beam radiation therapy. We enrolled 11 patients who underwent Gd-EOB-DTPA-enhanced MRI during or after radiotherapy in which the radiation field included the liver. External beam radiotherapy was delivered through multiple fields using a 10-MV linear accelerator. The hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI were qualitatively evaluated for the presence of a decreased uptake of Gd-EOB-DTPA in the irradiated area in the liver. Next, signal intensity (SI) ratio of the irradiated area to the non-irradiated liver parenchyma was also calculated. The absorbed dose of the irradiated area in the liver was standardized using equivalent dose in 2Gy fraction (EQD2) and biological effective dose (BED). The results of qualitative analysis were compared with EQD2 or BED, and linear regression analysis was performed between EQD2 or BED and SI ratio. Twenty-two irradiated areas were evaluated. Qualitative analysis revealed a decreased uptake of Gd-EOB-DTPA in 14 areas and no decreased uptake of Gd-EOB-DTPA in eight areas. The thresholds of EQD2 and BED causing a decreased uptake of Gd-EOB-DTPA were considered to be 24 to 29Gy and 29 to 35Gy, respectively. Quantitatively, SI ratio decreased as EQD2 or BED increased (r=0.89, p<0.001), and the inverse relationship between signal enhancement and the absorbed dose in the irradiated area was obtained. One area with EQD2 of 50Gy and BED of 60Gy showed a slightly decreased uptake of Gd-EOB-DTPA on the 40th day but a clearly decreased uptake of Gd-EOB-DTPA on the 123rd day from initiation of radiotherapy. Gd-EOB-DTPA-enhanced MRI described RLI as a decreased uptake of Gd-EOB-DTPA matching the irradiated area. The occurrence of this finding was significantly correlated with the absorbed dose of the irradiated area in the liver. Copyright © 2014 Elsevier Inc. All rights reserved.

Interplay effect on a 6-MV flattening-filter-free linear accelerator with high dose rate and fast multi-leaf collimator motion treating breast and lung phantoms.

PubMed

Netherton, Tucker; Li, Yuting; Nitsch, Paige; Shaitelman, Simona; Balter, Peter; Gao, Song; Klopp, Ann; Muruganandham, Manickam; Court, Laurence

2018-06-01

Using a new linear accelerator with high dose rate (800 MU/min), fast MLC motions (5.0 cm/s), fast gantry rotation (15 s/rotation), and 1 cm wide MLCs, we aimed to quantify the effects of complexity, arc number, and fractionation on interplay for breast and lung treatments under target motion. To study lung interplay, eight VMAT plans (1-6 arcs) and four-nine-field sliding-window IMRT plans varying in complexity were created. For the breast plans, four-four-field sliding-window IMRT plans were created. Using the Halcyon 1.0 linear accelerator, each plan was delivered five times each under sinusoidal breathing motion to a phantom with 20 implanted MOSFET detectors; MOSFET dose (cGy), delivery time, and MU/cGy values were recorded. Maximum and mean dose deviations were calculated from MOSFET data. The number of MOSFETs with at least 19 of 20 detectors agreeing with their expected dose within 5% per fraction was calculated across 10 6 iterations to model dose deviation as function of fraction number for all plan variants. To put interplay plans into clinical context, additional IMRT and VMAT plans were created and delivered for the sites of head and neck, prostate, whole brain, breast, pelvis, and lung. Average modulation and interplay effect were compared to those from conventional linear accelerators, as reported from previous studies. The mean beam modulation for plans created for the Halcyon 1.0 linear accelerator was 2.9 MU/cGy (two- to four-field IMRT breast plans), 6.2 MU/cGy (at least five-field IMRT), and 3.6 MU/cGy (four-arc VMAT). To achieve treatment plan objectives, Halcyon 1.0 VMAT plans require more arcs and modulation than VMAT on conventional linear accelerators. Maximum and mean dose deviations increased with increasing plan complexity under tumor motion for breast and lung treatments. Concerning VMAT plans under motion, maximum, and mean dose deviations were higher for one arc than for two arcs regardless of plan complexity. For plan variants with maximum dose deviations greater than 3.7%, dose deviation as a function of fraction number was protracted. For treatments on the Halcyon 1.0 linear accelerator, the convergence of dose deviation with fraction number happened more slowly than reported for conventional linear accelerators. However, if plan complexity is reduced for IMRT and if tumor motion is less than ~10-mm, interplay is greatly reduced. To minimize dose deviations across multiple fractions for dynamic targets, we recommend limiting treatment plan complexity and avoiding one-arc VMAT on the Halcyon 1.0 linear accelerator when interplay is a concern. © 2018 American Association of Physicists in Medicine.

Investigating the Implications of a Variable RBE on Proton Dose Fractionation Across a Clinical Pencil Beam Scanned Spread-Out Bragg Peak

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

Marshall, Thomas I.; Chaudhary, Pankaj; Michaelidesová, Anna

2016-05-01

Purpose: To investigate the clinical implications of a variable relative biological effectiveness (RBE) on proton dose fractionation. Using acute exposures, the current clinical adoption of a generic, constant cell killing RBE has been shown to underestimate the effect of the sharp increase in linear energy transfer (LET) in the distal regions of the spread-out Bragg peak (SOBP). However, experimental data for the impact of dose fractionation in such scenarios are still limited. Methods and Materials: Human fibroblasts (AG01522) at 4 key depth positions on a clinical SOBP of maximum energy 219.65 MeV were subjected to various fractionation regimens with an interfractionmore » period of 24 hours at Proton Therapy Center in Prague, Czech Republic. Cell killing RBE variations were measured using standard clonogenic assays and were further validated using Monte Carlo simulations and parameterized using a linear quadratic formalism. Results: Significant variations in the cell killing RBE for fractionated exposures along the proton dose profile were observed. RBE increased sharply toward the distal position, corresponding to a reduction in cell sparing effectiveness of fractionated proton exposures at higher LET. The effect was more pronounced at smaller doses per fraction. Experimental survival fractions were adequately predicted using a linear quadratic formalism assuming full repair between fractions. Data were also used to validate a parameterized variable RBE model based on linear α parameter response with LET that showed considerable deviations from clinically predicted isoeffective fractionation regimens. Conclusions: The RBE-weighted absorbed dose calculated using the clinically adopted generic RBE of 1.1 significantly underestimates the biological effective dose from variable RBE, particularly in fractionation regimens with low doses per fraction. Coupled with an increase in effective range in fractionated exposures, our study provides an RBE dataset that can be used by the modeling community for the optimization of fractionated proton therapy.« less

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

PubMed

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

2015-05-01

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

Quality assurance of dynamic parameters in volumetric modulated arc therapy

PubMed Central

Manikandan, A; Sarkar, B; Holla, R; Vivek, T R; Sujatha, N

2012-01-01

Objectives The purpose of this study was to demonstrate quality assurance checks for accuracy of gantry speed and position, dose rate and multileaf collimator (MLC) speed and position for a volumetric modulated arc treatment (VMAT) modality (Synergy® S; Elekta, Stockholm, Sweden), and to check that all the necessary variables and parameters were synchronous. Methods Three tests (for gantry position–dose delivery synchronisation, gantry speed–dose delivery synchronisation and MLC leaf speed and positions) were performed. Results The average error in gantry position was 0.5° and the average difference was 3 MU for a linear and a parabolic relationship between gantry position and delivered dose. In the third part of this test (sawtooth variation), the maximum difference was 9.3 MU, with a gantry position difference of 1.2°. In the sweeping field method test, a linear relationship was observed between recorded doses and distance from the central axis, as expected. In the open field method, errors were encountered at the beginning and at the end of the delivery arc, termed the “beginning” and “end” errors. For MLC position verification, the maximum error was −2.46 mm and the mean error was 0.0153 ±0.4668 mm, and 3.4% of leaves analysed showed errors of >±1 mm. Conclusion This experiment demonstrates that the variables and parameters of the Synergy® S are synchronous and that the system is suitable for delivering VMAT using a dynamic MLC. PMID:22745206

Development of a golden beam data set for the commissioning of a proton double-scattering system in a pencil-beam dose calculation algorithm

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

Slopsema, R. L., E-mail: rslopsema@floridaproton.org; Flampouri, S.; Yeung, D.

2014-09-15

Purpose: The purpose of this investigation is to determine if a single set of beam data, described by a minimal set of equations and fitting variables, can be used to commission different installations of a proton double-scattering system in a commercial pencil-beam dose calculation algorithm. Methods: The beam model parameters required to commission the pencil-beam dose calculation algorithm (virtual and effective SAD, effective source size, and pristine-peak energy spread) are determined for a commercial double-scattering system. These parameters are measured in a first room and parameterized as function of proton energy and nozzle settings by fitting four analytical equations tomore » the measured data. The combination of these equations and fitting values constitutes the golden beam data (GBD). To determine the variation in dose delivery between installations, the same dosimetric properties are measured in two additional rooms at the same facility, as well as in a single room at another facility. The difference between the room-specific measurements and the GBD is evaluated against tolerances that guarantee the 3D dose distribution in each of the rooms matches the GBD-based dose distribution within clinically reasonable limits. The pencil-beam treatment-planning algorithm is commissioned with the GBD. The three-dimensional dose distribution in water is evaluated in the four treatment rooms and compared to the treatment-planning calculated dose distribution. Results: The virtual and effective SAD measurements fall between 226 and 257 cm. The effective source size varies between 2.4 and 6.2 cm for the large-field options, and 1.0 and 2.0 cm for the small-field options. The pristine-peak energy spread decreases from 1.05% at the lowest range to 0.6% at the highest. The virtual SAD as well as the effective source size can be accurately described by a linear relationship as function of the inverse of the residual energy. An additional linear correction term as function of RM-step thickness is required for accurate parameterization of the effective SAD. The GBD energy spread is given by a linear function of the exponential of the beam energy. Except for a few outliers, the measured parameters match the GBD within the specified tolerances in all of the four rooms investigated. For a SOBP field with a range of 15 g/cm{sup 2} and an air gap of 25 cm, the maximum difference in the 80%–20% lateral penumbra between the GBD-commissioned treatment-planning system and measurements in any of the four rooms is 0.5 mm. Conclusions: The beam model parameters of the double-scattering system can be parameterized with a limited set of equations and parameters. This GBD closely matches the measured dosimetric properties in four different rooms.« less

Is patient size important in dose determination and optimization in cardiology?

NASA Astrophysics Data System (ADS)

Reay, J.; Chapple, C. L.; Kotre, C. J.

2003-12-01

Patient dose determination and optimization have become more topical in recent years with the implementation of the Medical Exposures Directive into national legislation, the Ionising Radiation (Medical Exposure) Regulations. This legislation incorporates a requirement for new equipment to provide a means of displaying a measure of patient exposure and introduces the concept of diagnostic reference levels. It is normally assumed that patient dose is governed largely by patient size; however, in cardiology, where procedures are often very complex, the significance of patient size is less well understood. This study considers over 9000 cardiology procedures, undertaken throughout the north of England, and investigates the relationship between patient size and dose. It uses simple linear regression to calculate both correlation coefficients and significance levels for data sorted by both room and individual clinician for the four most common examinations, left ventrical and/or coronary angiography, single vessel stent insertion and single vessel angioplasty. This paper concludes that the correlation between patient size and dose is weak for the procedures considered. It also illustrates the use of an existing method for removing the effect of patient size from dose survey data. This allows typical doses and, therefore, reference levels to be defined for the purposes of dose optimization.

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

PubMed

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

2014-12-01

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

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

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

DOE PAGES

Haley, Benjamin M.; Paunesku, Tatjana; Grdina, David J.; ...

2015-12-09

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

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

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

Haley, Benjamin M.; Paunesku, Tatjana; Grdina, David J.

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

Pharmacokinetics of isochlorgenic acid C in rats by HPLC-MS: Absolute bioavailability and dose proportionality.

PubMed

Huang, Li Hua; Xiong, Xiao Hong; Zhong, Yun Ming; Cen, Mei Feng; Cheng, Xuan Ge; Wang, Gui Xiang; Zang, Lin Quan; Wang, Su Jun

2016-06-05

Isochlorgenic acid C (IAC), one of the bioactive compounds of Lonicera japonica, exhibited diverse pharmacological effects. However, its pharmacokinetic properties and bioavailability remained unresolved. To determine the absolute bioavailability in rats and the dose proportionality on the pharmacokinetics of single oral dose of IAC. A validated HPLC-MS method was developed for the determination of IAC in rat plasma. Plasma concentration versus time data were generated following oral and intravenous dosing. The pharmacokinetic analysis was performed using DAS 3.0 software analysis. Absolute bioavailability in rats was determined by comparing pharmacokinetic data after administration of single oral (5, 10 and 25mgkg(-1)) and intravenous (5mgkg(-1)) doses of IAC. The dose proportionality of AUC(0-∞) and Cmax were analyzed by linear regression. Experimental data showed that absolute oral bioavailability of IAC in rats across the doses ranged between 14.4% and 16.9%. The regression analysis of AUC(0-∞) and Cmax at the three doses (5, 10 and 25mgkg(-1)) indicated that the equations were y=35.23x+117.20 (r=0.998) and y=121.03x+255.74 (r=0.995), respectively. A new HPLC-MS method was developed to determine the bioavailability and the dose proportionality of IAC. Bioavailability of IAC in rats was poor and both Cmax and AUC(0-∞) of IAC had a positive correlation with dose. Evaluation of the pharmacokinetics of IAC will be useful in assessing concentration-effect relationships for the potential therapeutic applications of IAC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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. © 2015 UICC.

A preliminary study of the thermal measurement with nMAG gel dosimeter by MRI

NASA Astrophysics Data System (ADS)

Chuang, Chun-Chao; Shao, Chia-Ho; Shih, Cheng-Ting; Yeh, Yu-Chen; Lu, Cheng-Chang; Chuang, Keh-Shih; Wu, Jay

2014-11-01

The methacrylic acid (nMAG) gel dosimeter is an effective tool for 3-dimensional quality assurance of radiation therapy. In addition to radiation induced polymerization effects, the nMAG gel also responds to temperature variation. In this study, we proposed a new method to evaluate the thermal response in thermal therapy using nMAG gel and magnetic resonance image (MRI) scans. Several properties of nMAG have been investigated including the R2 relaxation rate, temperature sensitivity, and temperature linearity of the thermal dose response. nMAG was heated by the double-boiling method in the range of 37-45 °C. MRI scans were performed with the head coil receiver. The temperature to R2 response curve was analyzed and simple linear regression was performed with an R-square value of 0.9835. The measured data showed a well inverse linear relationship between R2 and temperature. We conclude that the nMAG polymer gel dosimeter shows great potential as a technique to evaluate the temperature rise during thermal surgery.

Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors.

PubMed

Iwanaga, Masako; Hsu, Wan-Ling; Soda, Midori; Takasaki, Yumi; Tawara, Masayuki; Joh, Tatsuro; Amenomori, Tatsuhiko; Yamamura, Masaomi; Yoshida, Yoshiharu; Koba, Takashi; Miyazaki, Yasushi; Matsuo, Tatsuki; Preston, Dale L; Suyama, Akihiko; Kodama, Kazunori; Tomonaga, Masao

2011-02-01

The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb survivors. We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk. There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young. A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.

Characterization and implementation of OSL dosimeters for use in evaluating the efficacy of organ-based tube current modulation for CT scans of the face and orbits

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

Marsh, R. M.; Silosky, M., E-mail: michael.silosky@ucdenver.edu

Purpose: The purpose of this work was to characterize commercially available optically stimulated luminescent (OSL) dosimeters for general clinical applications and apply the results to the development of a method to evaluate the efficacy of a vendor-specific organ-based tube current modulation application for both phantom and clinical computed tomography (CT) scans of the face and orbits. Methods: This study consisted of three components: (1) thorough characterization of the dosimeters for CT scans in phantom, including evaluations of depletion, fading, angular dependence, and conversion from counts to absorbed dose; (2) evaluation of the efficacy of using plastic glasses to position themore » dosimeters over the eyes in both phantom and clinical studies; and (3) preliminary dosimetry measurements made using organ-based tube current modulation in computed tomography dose index (CTDI) and anthropomorphic phantom studies. Results: (1) Depletion effects were found to have a linear relationship with the output of the OSL dosimeters (R{sup 2} = 0.96). Fading was found to affect dosimeter readings during the first two hours following exposure but had no effect during the remaining 60-h period observed. No significant angular dependence was observed for the exposure conditions used in this study (with p-values ranging from 0.9 to 0.26 for all t-tests). Dosimeter counts varied linearly with absorbed dose when measured in the center and 12 o’clock positions of the CTDI phantoms. These linear models of counts versus absorbed dose had overlapping 95% confidence intervals for the intercepts but not for the slopes. (2) When dosimeters were positioned using safety glasses, there was no adverse effect on image quality, and there was no statistically significant difference between this placement and placement of the dosimeters directly on the eyes of the phantom (p = 0.24). (3) When using organ-based tube current modulation, the dose to the lens of the eye was reduced between 19% and 43%, depending on the scan protocol used and the positioning of the phantom. Furthermore, the amount of dose reduction was significantly affected by the vertical position of the phantom, with the largest reduction in dose seen when the phantom was centered in the gantry. Conclusions: (1) An appropriate correction factor, specific to CT scanning, was developed to account for depletion and fading characteristics of the dosimeters. Additionally, an equation to convert dosimeter counts to absorbed dose was established. (2) The use of plastic safety glasses was validated as an appropriate positioning device when measuring dose to the lens of the eye. (3) The use of organ-based tube current modulation can reduce dose to the lens of the eye during CT scanning. The amount of dose reduction, however, is largely influenced by the positioning of the anatomy in the gantry.« less

Characterization and implementation of OSL dosimeters for use in evaluating the efficacy of organ-based tube current modulation for CT scans of the face and orbits.

PubMed

Marsh, R M; Silosky, M

2015-04-01

The purpose of this work was to characterize commercially available optically stimulated luminescent (OSL) dosimeters for general clinical applications and apply the results to the development of a method to evaluate the efficacy of a vendor-specific organ-based tube current modulation application for both phantom and clinical computed tomography (CT) scans of the face and orbits. This study consisted of three components: (1) thorough characterization of the dosimeters for CT scans in phantom, including evaluations of depletion, fading, angular dependence, and conversion from counts to absorbed dose; (2) evaluation of the efficacy of using plastic glasses to position the dosimeters over the eyes in both phantom and clinical studies; and (3) preliminary dosimetry measurements made using organ-based tube current modulation in computed tomography dose index (CTDI) and anthropomorphic phantom studies. (1) Depletion effects were found to have a linear relationship with the output of the OSL dosimeters (R(2) = 0.96). Fading was found to affect dosimeter readings during the first two hours following exposure but had no effect during the remaining 60-h period observed. No significant angular dependence was observed for the exposure conditions used in this study (with p-values ranging from 0.9 to 0.26 for all t-tests). Dosimeter counts varied linearly with absorbed dose when measured in the center and 12 o'clock positions of the CTDI phantoms. These linear models of counts versus absorbed dose had overlapping 95% confidence intervals for the intercepts but not for the slopes. (2) When dosimeters were positioned using safety glasses, there was no adverse effect on image quality, and there was no statistically significant difference between this placement and placement of the dosimeters directly on the eyes of the phantom (p = 0.24). (3) When using organ-based tube current modulation, the dose to the lens of the eye was reduced between 19% and 43%, depending on the scan protocol used and the positioning of the phantom. Furthermore, the amount of dose reduction was significantly affected by the vertical position of the phantom, with the largest reduction in dose seen when the phantom was centered in the gantry. (1) An appropriate correction factor, specific to CT scanning, was developed to account for depletion and fading characteristics of the dosimeters. Additionally, an equation to convert dosimeter counts to absorbed dose was established. (2) The use of plastic safety glasses was validated as an appropriate positioning device when measuring dose to the lens of the eye. (3) The use of organ-based tube current modulation can reduce dose to the lens of the eye during CT scanning. The amount of dose reduction, however, is largely influenced by the positioning of the anatomy in the gantry.

Effects of ionizing radiation on extracellular matrix

NASA Astrophysics Data System (ADS)

Mohamed, F.; Bradley, D. A.; Winlove, C. P.

2007-09-01

The extracellular matrix is a ubiquitous and important component of tissues. We investigated the effects of ionizing radiation on the physical properties of its principal macromolecular components, pericardial collagen, ligament elastin and hyaluronan, a representative glycosaminoglycan. Samples were exposed to X-rays from an electron linear accelerator in the range of 10-100 Gy to cover the range of irradiation exposure during radiotherapy. A uniaxial mechanical testing protocol was used to characterize the fibrous proteins. For pericardial tissue the major change was an increase in the elastic modulus in the toe region of the curve (⩽20% strain), from 23±18 kPa for controls to 57±22 kPa at a dose of 10 Gy ( p=0.01, α=0.05). At larger strain (⩾20% strain), the elastic modulus in the linear region decreased from 1.92±0.70 MPa for control pericardium tissue to 1.31±0.56 MPa ( p=0.01, α=0.05) for 10 Gy X-irradiated sample. Similar observations have been made previously on tendon collagen at larger strains. For elastin, the stress-strain relationship was linear up to 30% strain, but the elastic modulus decreased significantly with irradiation (controls 626±65 kPa, irradiated 474±121 kPa ( p=0.02, α=0.05), at 10 Gy X-irradiation). The results suggest that for collagen the primary effect of irradiation is generation of additional cross-links, while for elastin chain scissions are important. The viscosity of HA (at 1.25% w/v and 0.125% w/v) was measured by both cone and plate and capillary viscometry, the former providing measurement at uniform shear rate and the latter providing a more sensitive indication of changes at low viscosity. Both techniques revealed a dose-dependent reduction in viscosity (from 3400±194 cP for controls to 1500±88 cP at a shear rate of 2 s -1 and dose of 75 Gy), again suggesting depolymerization.

Dietary fiber intake reduces risk of inflammatory bowel disease: result from a meta-analysis.

PubMed

Liu, Xiaoqin; Wu, Yili; Li, Fang; Zhang, Dongfeng

2015-09-01

Several epidemiological investigations have been conducted to evaluate the relationship between dietary fiber intake and inflammatory bowel diseases, but the results are inconsistent. This meta-analysis was performed to quantitatively summarize the evidence from observational studies. PubMed, Embase, and Web of Knowledge were searched for relevant articles published up to November 2014. The combined relative risks were calculated with the fixed- or random-effects model. Dose-response relationship was assessed using restricted cubic spline model. We hypothesized that the meta-analysis could yield a summary effect, which would indicate that dietary fiber intake could decrease the risk of ulcerative colitis and Crohn disease (CD). Overall, 8 articles involving 2 cohort studies, 1 nested case-control study, and 5 case-control studies were finally included in this study. The pooled relative risks with 95% confidence intervals of ulcerative colitis and CD for the highest vs lowest categories of dietary fiber intake were 0.80 (0.64-1.00) and 0.44 (0.29-0.69), respectively. A linear dose-response relationship was found between dietary fiber and CD risk, and the risk of CD decreased by 13% (P < .05) for every 10 g/d increment in fiber intake. The results from this meta-analysis indicated that the intake of dietary fiber was significantly associated with a decreased risk of inflammatory bowel disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients

PubMed Central

Hoermann, Rudolf; Midgley, John E. M.; Dietrich, Johannes W.; Larisch, Rolf

2017-01-01

Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion. Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships. Results: Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels. Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control. PMID:28794850

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

PubMed

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

2017-05-01

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

Induction of chromosomal aberrations at fluences of less than one HZE particle per cell nucleus.

PubMed

Hada, Megumi; Chappell, Lori J; Wang, Minli; George, Kerry A; Cucinotta, Francis A

2014-10-01

The assumption of a linear dose response used to describe the biological effects of high-LET radiation is fundamental in radiation protection methodologies. We investigated the dose response for chromosomal aberrations for exposures corresponding to less than one particle traversal per cell nucleus by high-energy charged (HZE) nuclei. Human fibroblast and lymphocyte cells were irradiated with several low doses of <0.1 Gy, and several higher doses of up to 1 Gy with oxygen (77 keV/μm), silicon (99 keV/μm) or Fe (175 keV/μm), Fe (195 keV/μm) or Fe (240 keV/μm) particles. Chromosomal aberrations at first mitosis were scored using fluorescence in situ hybridization (FISH) with chromosome specific paints for chromosomes 1, 2 and 4 and DAPI staining of background chromosomes. Nonlinear regression models were used to evaluate possible linear and nonlinear dose-response models based on these data. Dose responses for simple exchanges for human fibroblasts irradiated under confluent culture conditions were best fit by nonlinear models motivated by a nontargeted effect (NTE). The best fits for dose response data for human lymphocytes irradiated in blood tubes were a linear response model for all particles. Our results suggest that simple exchanges in normal human fibroblasts have an important NTE contribution at low-particle fluence. The current and prior experimental studies provide important evidence against the linear dose response assumption used in radiation protection for HZE particles and other high-LET radiation at the relevant range of low doses.

The relationship between peak velocity of saccadic eye movements and serum benzodiazepine concentration.

PubMed Central

Bittencourt, P R; Wade, P; Smith, A T; Richens, A

1981-01-01

1 Six healthy male volunteers received single oral doses of 10 mg diazepam, 20 mg temazepam, 15 mg flurazepam, 5 mg nitrazepam, 10 mg desmethyl-diazepam and placebo in a double-blind randomized fashion. 2 Peak velocity of saccadic eye movements, serum benzodiazepine concentration, and subjective ratings of wakefulness and co-ordination were measured at intervals up to 12 h after drug administration. 3 All active treatments produced a statistically significant decrease in peak saccadic velocity. The effect of temazepam and diazepam was generally more pronounced than that of flurazepam, nitrazepam and desmethyl-diazepam. 4 There were log-linear correlations between peak saccadic velocity and serum benzodiazepine concentration after ingestion of temazepam, diazepam and nitrazepam. 5 These results demonstrate a clear relationship between serum benzodiazepine concentration and its effect on a convenient measure of brainstem reticular formation function. PMID:6794587

Is time to peak effect of neuromuscular blocking agents dependent on dose? Testing the concept of buffered diffusion.

PubMed

Proost, J H; Houwertjes, M C; Wierda, J M K H

2008-07-01

For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic-pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect. Pigs (20-28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response. For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account. The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.

Pharmacokinetics and effect on the corrected QT interval of single-dose escitalopram in healthy elderly compared with younger adults.

PubMed

Chung, Hyewon; Kim, Anhye; Lim, Kyoung Soo; Park, Sang-In; Yu, Kyung-Sang; Yoon, Seo Hyun; Cho, Joo-Youn; Chung, Jae-Yong

2017-01-01

Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

PubMed

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B; George, Kerry A; Cucinotta, Francis A

2016-01-01

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictions of the charge number and energy dependence of RBE's using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE's are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE's against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Comparisons of the resulting model parameters to those used in the NASA radiation quality factor function are discussed.

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

DOE PAGES

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.; ...

2016-04-25

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints

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

Cacao, Eliedonna; Hada, Megumi; Saganti, Premkumar B.

The biological effects of high charge and energy (HZE) particle exposures are of interest in space radiation protection of astronauts and cosmonauts, and estimating secondary cancer risks for patients undergoing Hadron therapy for primary cancers. The large number of particles types and energies that makeup primary or secondary radiation in HZE particle exposures precludes tumor induction studies in animal models for all but a few particle types and energies, thus leading to the use of surrogate endpoints to investigate the details of the radiation quality dependence of relative biological effectiveness (RBE) factors. In this report we make detailed RBE predictionsmore » of the charge number and energy dependence of RBE’s using a parametric track structure model to represent experimental results for the low dose response for chromosomal exchanges in normal human lymphocyte and fibroblast cells with comparison to published data for neoplastic transformation and gene mutation. RBE’s are evaluated against acute doses of γ-rays for doses near 1 Gy. Models that assume linear or non-targeted effects at low dose are considered. Modest values of RBE (<10) are found for simple exchanges using a linear dose response model, however in the non-targeted effects model for fibroblast cells large RBE values (>10) are predicted at low doses <0.1 Gy. The radiation quality dependence of RBE’s against the effects of acute doses γ-rays found for neoplastic transformation and gene mutation studies are similar to those found for simple exchanges if a linear response is assumed at low HZE particle doses. Finally, we discuss comparisons of the resulting model parameters to those used in the NASA radiation quality factor function.« less

Measurement of additional shear during sludge conditioning and dewatering.

PubMed

Ormeci, Banu; Ahmad, Ayaz

2009-07-01

Optimum polymer dose is influenced both by the polymer demand of the sludge and the shear applied during conditioning. Sludge exposed to additional shear following conditioning will experience a decrease in cake solids concentration for the same polymer dose. Therefore, it is necessary to measure or quantify the additional shear in order to optimize the conditioning and dewatering. There is currently no direct or indirect method to achieve this. The main objective of this study was to develop a method based on torque rheology to measure the amount of shear that a sludge network experiences during conditioning and dewatering. Anaerobically digested sludge samples were exposed to increasing levels of mixing intensities and times, and rheological characteristics of samples were measured using a torque rheometer. Several rheological parameters were evaluated including the peak torque and totalized torque (area under the rheograms). The results of this study show that at the optimum polymer dose, a linear relationship exists between the applied shear and the area under the rheograms, and this relationship can be used to estimate an unknown amount of shear that the sludge was exposed to. The method is useful as a research tool to study the effect of shear on dewatering but also as an optimization tool in a dewatering automation system based on torque rheology.

Cataract production in mice by heavy charged particles

NASA Technical Reports Server (NTRS)

Ainsworth, E. J.; Jose, U.; Yang, V. V.; Barker, M. E.

1981-01-01

The cataractogenic effects of heavy charged particles are evaluated in mice in relation to dose and ionization density. The relative biological effectiveness in relation to linear energy transfer for various particles is considered. Results indicated that low single doses (5 to 20 rad) of Fe 56 or Ar 40 particles are cataractogenic at 11 to 18 months after irradiation; onset and density of the opacification are dose related and cataract density (grade) at 9, 11, 13, and 16 months after irradiation shows partial linear energy transfer dependence. The severity of cataracts is reduced significantly when 417 rad of Co 60 gamma radiation is given in 24 weekly 17 rad fractions compared to giving this radiation as a single dose, but cataract severity is not reduced by fractionation of C12 doses over 24 weeks.

Derivation of the expressions for γ50 and D50 for different individual TCP and NTCP models

NASA Astrophysics Data System (ADS)

Stavreva, N.; Stavrev, P.; Warkentin, B.; Fallone, B. G.

2002-10-01

This paper presents a complete set of formulae for the position (D50) and the normalized slope (γ50) of the dose-response relationship based on the most commonly used radiobiological models for tumours as well as for normal tissues. The functional subunit response models (critical element and critical volume) are used in the derivation of the formulae for the normal tissue. Binomial statistics are used to describe the tumour control probability, the functional subunit response as well as the normal tissue complication probability. The formulae are derived for the single hit and linear quadratic models of cell kill in terms of the number of fractions and dose per fraction. It is shown that the functional subunit models predict very steep, almost step-like, normal tissue individual dose-response relationships. Furthermore, the formulae for the normalized gradient depend on the cellular parameters α and β when written in terms of number of fractions, but not when written in terms of dose per fraction.

Arsenic in Drinking Water and Mortality for Cancer and Chronic Diseases in Central Italy, 1990-2010

PubMed Central

D’Ippoliti, Daniela; Santelli, Enrica; De Sario, Manuela; Scortichini, Matteo; Davoli, Marina; Michelozzi, Paola

2015-01-01

Background In several volcanic areas of Italy, arsenic levels exceed European regulatory limits (10 μg/L in drinking water). There is still uncertainty about health risks from arsenic at low-medium doses (<100 μg/L). Objectives A large population-based study using an administrative cohort of residents in the Viterbo province (Central Italy), chronically exposed to low-medium arsenic levels via drinking water, was investigated to evaluate the effects of a lifetime exposure to arsenic on mortality from cancers and chronic diseases. Methods The study population consisted of 165,609 residents of 17 municipalities, followed from 1990 until 2010. Average individual arsenic exposure at the first residence (AsI) was estimated through a space-time modeling approach using residential history and arsenic concentrations from water supply. A time-dependent Cumulative Arsenic dose Indicator (CAI) was calculated, accounting for daily water intake and exposure duration. Mortality Hazard Ratios (HR) were estimated by gender for different diseases using Cox proportional models, adjusting for individual and area-level confounders. A flexible non-parametric approach was used to investigate dose-response relationships. Results Mean AsI exposure was 19.3 μg/L, and average exposure duration was 39.5 years. Associations of AsI and CAI indicators with several diseases were found, with greatest risks found for lung cancer in both sexes (HR = 2.61 males; HR = 2.09 females), myocardial infarction, peripheral arterial disease and COPD in males (HR = 2.94; HR = 2.44; HR = 2.54 respectively) and diabetes in females (HR = 2.56). For lung cancer and cardiovascular diseases dose-response relationship is modelled by piecewise linear functions revealing effects even for doses lower than 10 μg/L, and no threshold dose value was identified as safe for health. Conclusions Results provide new evidence for risk assessment of low-medium concentrations of arsenic and contribute to the ongoing debate about the threshold-dose of effect, suggesting that even concentrations below 10 μg/L carry a mortality risk. Policy actions are urgently needed in areas exposed to arsenic like in the Viterbo province, to comply with current EU regulations. PMID:26383851

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

PubMed

Calderón, M A; Larenas, D; Kleine-Tebbe, J; Jacobsen, L; Passalacqua, G; Eng, P A; Varga, E M; Valovirta, E; Moreno, C; Malling, H J; Alvarez-Cuesta, E; Durham, S; Demoly, P

2011-10-01

For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. © 2011 John Wiley & Sons A/S.

Visible photoluminescence of color centers in LiF crystals for absorbed dose evaluation in clinical dosimetry

NASA Astrophysics Data System (ADS)

Villarreal-Barajas, J. E.; Piccinini, M.; Vincenti, M. A.; Bonfigli, F.; Khan, R. F.; Montereali, R. M.

2015-04-01

Among insulating materials, lithium fluoride (LiF) has been successfully used as ionizing radiation dosemeter for more than 60 years. Thermoluminescence (TL) has been the most commonly used reading technique to evaluate the absorbed dose. Lately, optically stimulated luminescence (OSL) of visible emitting color centers (CCs) has also been explored in pure and doped LiF. This work focuses on the experimental behaviour of nominally pure LiF crystals dosemeters for 6 MV x rays at low doses based on photoluminescence (PL) of radiation induced CCs. Polished LiF crystals were irradiated using 6 MV x rays produced by a clinical linear accelerator. The doses (absorbed dose to water) covered the 1-100 Gy range. Optical absorption spectra show stable formation of primary F defects up to a maximum concentration of 2×1016 cm-3, while no significant M absorption band at around 450 nm was detected. On the other hand, under Argon laser excitation at 458 nm, PL spectra of the irradiated LiF crystals clearly exhibited the characteristic F2 and F+3 visible broad emission bands. Their sum intensity is linearly proportional to the absorbed dose in the investigated range. PL integrated intensity was also measured using a conventional fluorescence optical microscope under blue lamp illumination. The relationship between the absorbed dose and the integrated F2 and F+3 PL intensities, represented by the net average pixel number in the optical fluorescence images, is also fairly linear. Even at the low point defect densities obtained at the investigated doses, these preliminary experimental results are encouraging for further investigation of CCs PL in LiF crystals for clinical dosimetry.

Population PKPD modelling of the long-term hypoglycaemic effect of gliclazide given as a once-a-day modified release (MR) formulation

PubMed Central

Frey, N; Laveille, C; Paraire, M; Francillard, M; Holford, N H G; Jochemsen, Roeline

2003-01-01

Aims To study the relationship between the pharmacokinetics (PK) of gliclazide and its long-term pharmacodynamic (PD) effect in a large population of Type 2 diabetic patients and to identify factors predicting intersubject variability. Methods A PKPD database of 634 Type 2 diabetic patients with a total of 5258 fasting plasma glucose (FPG) samples was built up from the data collected during the clinical development of a modified release formulation of gliclazide (gliclazide MR). The PKPD analysis used a nonlinear mixed effect modelling approach. A mixture model was used to identify patients with a FPG response to treatment. In patients identified as responders, the decrease in FPG was related to gliclazide exposure (AUC) by an Emax relationship. An effect compartment was used to describe the link between PK and PD. A linear disease-progression model was used to assess the glycaemic deterioration observable over several months of treatment. Simulations were performed to evaluate the predictive performance of the PKPD model and to illustrate the time course of the antidiabetic effect of gliclazide MR. Results Disease state was found to be the main explanatory factor for intersubject variability in response to gliclazide. The percentage of responders to gliclazide, used as monotherapy, increased inversely to the number of classes of antidiabetic agents received prior to entry in the studies. In responders, the initial dose (30 mg) of the gliclazide MR dosing regimen induced half of the maximum hypoglycaemic effect. The equilibration half-life between the PK and PD steady states was 3 weeks (intersubject variability of 84%). The rate of disease progression was 0.84 mmol l−1 year−1 (intersubject variability 143%). The PKPD model adequately predicted the FPG profiles of 234 patients who received the current formulation of gliclazide. Simulation of a 1-year parallel dose ranging clinical trial illustrated the influence of dose, time and type of previous antidiabetic treatment on the percentage of patients with clinically significant improvement of blood glucose control. Conclusions This population PKPD analysis has characterized the relationship between the exposure to gliclazide and its long-term hypoglycaemic effect, and has established that the intersubject variability in response is mostly related to disease state. These results underline the clinical interest of quickly increasing the dose of gliclazide MR according to the response to treatment in order to achieve effective blood glucose control. PMID:12580986

Dose-Effect Relationships for Individual Pelvic Floor Muscles and Anorectal Complaints After Prostate Radiotherapy

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

Smeenk, Robert Jan, E-mail: r.smeenk@rther.umcn.nl; Hoffmann, Aswin L.; Hopman, Wim P.M.

2012-06-01

Purpose: To delineate the individual pelvic floor muscles considered to be involved in anorectal toxicity and to investigate dose-effect relationships for fecal incontinence-related complaints after prostate radiotherapy (RT). Methods and Materials: In 48 patients treated for localized prostate cancer, the internal anal sphincter (IAS) muscle, the external anal sphincter (EAS) muscle, the puborectalis muscle (PRM), and the levator ani muscles (LAM) in addition to the anal wall (Awall) and rectal wall (Rwall) were retrospectively delineated on planning computed tomography scans. Dose parameters were obtained and compared between patients with and without fecal urgency, incontinence, and frequency. Dose-effect curves were constructed.more » Finally, the effect of an endorectal balloon, which was applied in 28 patients, was investigated. Results: The total volume of the pelvic floor muscles together was about three times that of the Awall. The PRM was exposed to the highest RT dose, whereas the EAS received the lowest dose. Several anal and rectal dose parameters, as well as doses to all separate pelvic floor muscles, were associated with urgency, while incontinence was associated mainly with doses to the EAS and PRM. Based on the dose-effect curves, the following constraints regarding mean doses could be deduced to reduce the risk of urgency: {<=}30 Gy to the IAS; {<=}10 Gy to the EAS; {<=}50 Gy to the PRM; and {<=}40 Gy to the LAM. No dose-effect relationships for frequency were observed. Patients treated with an endorectal balloon reported significantly less urgency and incontinence, while their treatment plans showed significantly lower doses to the Awall, Rwall, and all pelvic floor muscles. Conclusions: Incontinence-related complaints show specific dose-effect relationships to individual pelvic floor muscles. Dose constraints for each muscle can be identified for RT planning. When only the Awall is delineated, substantial components of the continence apparatus are excluded.« less

Dose-effect relationships for individual pelvic floor muscles and anorectal complaints after prostate radiotherapy.

PubMed

Smeenk, Robert Jan; Hoffmann, Aswin L; Hopman, Wim P M; van Lin, Emile N J Th; Kaanders, Johannes H A M

2012-06-01

To delineate the individual pelvic floor muscles considered to be involved in anorectal toxicity and to investigate dose-effect relationships for fecal incontinence-related complaints after prostate radiotherapy (RT). In 48 patients treated for localized prostate cancer, the internal anal sphincter (IAS) muscle, the external anal sphincter (EAS) muscle, the puborectalis muscle (PRM), and the levator ani muscles (LAM) in addition to the anal wall (Awall) and rectal wall (Rwall) were retrospectively delineated on planning computed tomography scans. Dose parameters were obtained and compared between patients with and without fecal urgency, incontinence, and frequency. Dose-effect curves were constructed. Finally, the effect of an endorectal balloon, which was applied in 28 patients, was investigated. The total volume of the pelvic floor muscles together was about three times that of the Awall. The PRM was exposed to the highest RT dose, whereas the EAS received the lowest dose. Several anal and rectal dose parameters, as well as doses to all separate pelvic floor muscles, were associated with urgency, while incontinence was associated mainly with doses to the EAS and PRM. Based on the dose-effect curves, the following constraints regarding mean doses could be deduced to reduce the risk of urgency: ≤ 30 Gy to the IAS; ≤ 10 Gy to the EAS; ≤ 50 Gy to the PRM; and ≤ 40 Gy to the LAM. No dose-effect relationships for frequency were observed. Patients treated with an endorectal balloon reported significantly less urgency and incontinence, while their treatment plans showed significantly lower doses to the Awall, Rwall, and all pelvic floor muscles. Incontinence-related complaints show specific dose-effect relationships to individual pelvic floor muscles. Dose constraints for each muscle can be identified for RT planning. When only the Awall is delineated, substantial components of the continence apparatus are excluded. Copyright © 2012 Elsevier Inc. All rights reserved.

The relationship between carbohydrate and the mealtime insulin dose in type 1 diabetes.

PubMed

Bell, Kirstine J; King, Bruce R; Shafat, Amir; Smart, Carmel E

2015-01-01

A primary focus of the nutritional management of type 1 diabetes has been on matching prandial insulin therapy with carbohydrate amount consumed. Different methods exist to quantify carbohydrate including counting in one gram increments, 10g portions or 15g exchanges. Clinicians have assumed that counting in one gram increments is necessary to precisely dose insulin and optimize postprandial control. Carbohydrate estimations in portions or exchanges have been thought of as inadequate because they may result in less precise matching of insulin dose to carbohydrate amount. However, studies examining the impact of errors in carbohydrate quantification on postprandial glycemia challenge this commonly held view. In addition it has been found that a single mealtime bolus of insulin can cover a range of carbohydrate intake without deterioration in postprandial control. Furthermore, limitations exist in the accuracy of the nutrition information panel on a food label. This article reviews the relationship between carbohydrate quantity and insulin dose, highlighting limitations in the evidence for a linear association. These insights have significant implications for patient education and mealtime insulin dose calculations. Copyright © 2015 Elsevier Inc. All rights reserved.

On the use of Lineal Energy Measurements to Estimate Linear Energy Transfer Spectra

NASA Technical Reports Server (NTRS)

Adams, David A.; Howell, Leonard W., Jr.; Adam, James H., Jr.

2007-01-01

This paper examines the error resulting from using a lineal energy spectrum to represent a linear energy transfer spectrum for applications in the space radiation environment. Lineal energy and linear energy transfer spectra are compared in three diverse but typical space radiation environments. Different detector geometries are also studied to determine how they affect the error. LET spectra are typically used to compute dose equivalent for radiation hazard estimation and single event effect rates to estimate radiation effects on electronics. The errors in the estimations of dose equivalent and single event rates that result from substituting lineal energy spectra for linear energy spectra are examined. It is found that this substitution has little effect on dose equivalent estimates in interplanetary quiet-time environment regardless of detector shape. The substitution has more of an effect when the environment is dominated by solar energetic particles or trapped radiation, but even then the errors are minor especially if a spherical detector is used. For single event estimation, the effect of the substitution can be large if the threshold for the single event effect is near where the linear energy spectrum drops suddenly. It is judged that single event rate estimates made from lineal energy spectra are unreliable and the use of lineal energy spectra for single event rate estimation should be avoided.

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

PubMed

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

2013-10-01

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

Alcohol outlet density and assault: a spatial analysis.

PubMed

Livingston, Michael

2008-04-01

A large number of studies have found links between alcohol outlet densities and assault rates in local areas. This study tests a variety of specifications of this link, focusing in particular on the possibility of a non-linear relationship. Cross-sectional data on police-recorded assaults during high alcohol hours, liquor outlets and socio-demographic characteristics were obtained for 223 postcodes in Melbourne, Australia. These data were used to construct a series of models testing the nature of the relationship between alcohol outlet density and assault, while controlling for socio-demographic factors and spatial auto-correlation. Four types of relationship were examined: a normal linear relationship between outlet density and assault, a non-linear relationship with potential threshold or saturation densities, a relationship mediated by the socio-economic status of the neighbourhood and a relationship which takes into account the effect of outlets in surrounding neighbourhoods. The model positing non-linear relationships between outlet density and assaults was found to fit the data most effectively. An increasing accelerating effect for the density of hotel (pub) licences was found, suggesting a plausible upper limit for these licences in Melbourne postcodes. The study finds positive relationships between outlet density and assault rates and provides evidence that this relationship is non-linear and thus has critical values at which licensing policy-makers can impose density limits.

Combined effects of radiation and caffeine on embryonic development in mice

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

Kusama, T.; Sugiura, N.; Kai, M.

1989-02-01

The combined effect of radiation and caffeine has been studied in mouse embryos. Radiation and/or caffeine were administered to ICR mice on Day 11 of gestation. Intrauterine death, gross malformation, and fetal body weight were selected as indicators of effects. Doses of whole-body gamma irradiation were 0.5 to 2.5 Gy and those of caffeine were 100 and 250 mg/kg maternal body wt. Intrauterine mortality increased with increasing radiation dose; this trend was more remarkable in combination with caffeine. Gross malformations such as cleft palate and defects of forelegs and hindlegs appeared frequently in the fetuses treated with both radiation andmore » caffeine. Decreased fetal weight was observed even in mice treated with 0.5 Gy of radiation or 100 mg/kg caffeine. There was a linear relationship between dose and reduction of fetal weight. The fetal weight was a sensitive, precise, and easy-to-handle indicator for the effects of growth retardation. Intrauterine mortality and frequencies of cleft palate and defects of forelegs and hindlegs were higher than the sum of those induced by radiation and by caffeine separately. The results indicated that the combined action of radiation and caffeine on intrauterine death and malformations was synergistic.« less

The prolonged gastrointestinal syndrome in rhesus macaques: the relationship between gastrointestinal, hematopoietic, and delayed multi-organ sequelae following acute, potentially lethal, partial-body irradiation.

PubMed

MacVittie, Thomas J; Bennett, Alexander; Booth, Catherine; Garofalo, Michael; Tudor, Gregory; Ward, Amanda; Shea-Donohue, Terez; Gelfond, Daniel; McFarland, Emylee; Jackson, William; Lu, Wei; Farese, Ann M

2012-10-01

The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min(-1) to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.

Antiresorptive effect of a cathepsin K inhibitor ONO-5334 and its relationship to BMD increase in a phase II trial for postmenopausal osteoporosis.

PubMed

Tanaka, Makoto; Hashimoto, Yoshitaka; Hasegawa, Chihiro; Deacon, Steve; Eastell, Richard

2017-06-19

ONO-5334 is a cathepsin K inhibitor that induced bone mineral density (BMD) gain in a phase II study in postmenopausal osteoporosis patients. Even though the antiresorptive effect could only be monitored in the morning during the study, simulation can allow the antiresorptive effect to be assessed over 24 h, with assessment of the relationship to BMD gain. Inhibition of the serum C-telopeptide of type I collagen (sCTX) level at doses of ONO-5334 of 100 mg once daily (QD), 300 mg QD, and 50 mg twice daily (BID) was simulated using plasma ONO-5334 pharmacokinetic (PK) data for repeated dose administration in a phase I study and corresponding sCTX inhibition from the PK-pharmacodynamic (PK/PD) relationship. sCTX was selected because it has a high signal-to-noise ratio compared to other telopeptides. A negative sigmoidal shape for the PK/PD relationship between plasma ONO-5334 and sCTX levels was obtained in our previous study. The simulated sCTX inhibition reached >99% of the maximal inhibitory effect (Emax) at 0.5 h in all treatment groups, and decreased to <80% Emax at 8 and 12 h at 50 mg BID and 100 mg QD, respectively. However, sCTX inhibition at 300 mg QD was maintained at ≥82% Emax over 24 h. The mean sCTX inhibition rates for 24 h at 100 mg QD, 300 mg QD and 50 mg BID were 63, 95 and 80% Emax, respectively. There was a positive linear relationship by treatment group between mean sCTX inhibition over 24 h and observed BMD gain in the phase II study. The dose response for BMD with ONO-5334 at 100 and 300 mg QD and higher BMD gain at 50 mg BID vs. 100 mg QD can be explained by sCTX inhibition over 24 h. The simulation gave the antiresorptive effect of ONO-5334 over 24 h and allowed prediction of BMD gain due to ONO-5334. The registration number in The European Union Clinical Trials Register is 2007-002417-39 . The date of registration was August 31, 2007.

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice

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

Porter, J.B.; Morgan, J.; Hoyes, K.P.

1990-12-01

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown bymore » a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).« less

Effect of americium-241 alpha-particles on the dose-response of chromosome aberrations in human lymphocytes analysed by fluorescence in situ hybridization.

PubMed

Barquinero, J F; Stephan, G; Schmid, E

2004-02-01

To evaluate by the fluorescent in-situ hybridization (FISH) technique the dose-response and intercellular distribution of alpha-particle-induced chromosome aberrations. In particular, the validity of using the yield of characteristic types of chromosome abnormalities in stable cells as quantitative indicators for retrospective dose reconstruction has been evaluated. Monolayers of human peripheral lymphocytes were exposed at doses from 0.02 to 1 Gy to alpha-particles emitted from a source of americium-241. The most probable energy of the alpha-particles entering the cells was 2.7 MeV. FISH painting was performed using DNA probes for chromosomes 2, 4 and 8 in combination with a pan-centromeric probe. In complete first-division cells, identified by harlequin staining, aberrations involving painted target chromosomal material were recorded as well as aberrations involving only unpainted chromosomal material. In total, the percentage of complex aberrations was about 35% and no dose dependence was observed. When complex-type exchanges were reduced to simple base types, the different cell distributions were clearly over-dispersed, and the linear coefficients of the dose-effect curves for translocations were significantly higher than for dicentrics. For past dose reconstruction, only a few complex aberrations were in stable cells. The linear coefficient obtained for transmissible aberrations in stable cells was more than seven times lower than that obtained in all analysed cells, i.e. including unstable cells. FISH-based analysis of complex rearrangements allows discrimination between partial-body exposures to low-linear energy transfer radiation and high-linear energy transfer exposures. In assessing past or chronic exposure to alpha-particles, the use of a dose-effect curve obtained by FISH-based translocation data, which had not excluded data determined in unstable cells, would underestimate the dose. Insertions are ineffective biomarkers because their frequency is too low.

Allopurinol, benzbromarone and risk of coronary heart disease in gout patients: A population-based study.

PubMed

Lin, Hsiu-Chen; Daimon, Masao; Wang, Ching-Hung; Ho, Yi; Uang, Yow-Shieng; Chiang, Shuo-Ju; Wang, Li-Hsuan

2017-04-15

The effect of gout on the risk of developing coronary artery disease (CAD) is uncertain. Some studies have found that gout is a risk factor for acute myocardial infarction. This study examined the changes in risk of CAD in gout patients taking allopurinol and/or benzbromarone, and analyzed the dose-response relationship of both drugs with CAD incidence. The medical records of one million subjects from 2000 to 2011 were provided by the Taiwan National Health Insurance Research Database. Cox proportional hazard ratio was used to compare the risk of CAD in gout patients taking allopurinol or/and benzbromarone with those taking neither drug. Hazard ratios (HR) were adjusted for possible confounding factors, including age, gender, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and relevant medications. Of 8047 gout patients, 1422 were treated with allopurinol (Group A), 4141 with benzbromarone (Group B), and 2484 with both drugs (Group A/B) during the follow-up period. Our results showed the incidence of CAD after adjusting for covariates for Group A, Group B, and Group A/B did not significantly differ from the comparison group. However, after adjustment for covariates in dose-response analyses, treatment with over 270 defined daily doses (DDDs) of allopurinol, and over 360 DDDs of benzbromarone, was associated with a significantly reduced risk of CAD. We found that the use of allopurinol and benzbromarone, whether alone or in combination, had a linear dose-response relationship between the numbers of defined daily doses and the risk of CAD, especially in higher DDDs. Copyright © 2017 Elsevier B.V. All rights reserved.

SU-E-T-91: Correction Method to Determine Surface Dose for OSL Detectors

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

Reynolds, T; Higgins, P

Purpose: OSL detectors are commonly used in clinic due to their numerous advantages, such as linear response, negligible energy, angle and temperature dependence in clinical range, for verification of the doses beyond the dmax. Although, due to the bulky shielding envelope, this type of detectors fails to measure skin dose, which is an important assessment of patient ability to finish the treatment on time and possibility of acute side effects. This study aims to optimize the methodology of determination of skin dose for conventional accelerators and a flattening filter free Tomotherapy. Methods: Measurements were done for x-ray beams: 6 MVmore » (Varian Clinac 2300, 10×10 cm{sup 2} open field, SSD = 100 cm) and for 5.5 MV (Tomotherapy, 15×40 cm{sup 2} field, SAD = 85 cm). The detectors were placed at the surface of the solid water phantom and at the reference depth (dref=1.7cm (Varian 2300), dref =1.0 cm (Tomotherapy)). The measurements for OSLs were related to the externally exposed OSLs measurements, and further were corrected to surface dose using an extrapolation method indexed to the baseline Attix ion chamber measurements. A consistent use of the extrapolation method involved: 1) irradiation of three OSLs stacked on top of each other on the surface of the phantom; 2) measurement of the relative dose value for each layer; and, 3) extrapolation of these values to zero thickness. Results: OSL measurements showed an overestimation of surface doses by the factor 2.31 for Varian 2300 and 2.65 for Tomotherapy. The relationships: SD{sup 2300} = 0.68 × M{sup 2300}-12.7 and SDτoμo = 0.73 × Mτoμo-13.1 were found to correct the single OSL measurements to surface doses in agreement with Attix measurements to within 0.1% for both machines. Conclusion: This work provides simple empirical relationships for surface dose measurements using single OSL detectors.« less

Sizing the association between lifestyle behaviours and fatness in a large, heterogeneous sample of youth of multiple ethnicities from 4 countries.

PubMed

Sluyter, John D; Scragg, Robert K R; Plank, Lindsay D; Waqa, Gade D; Fotu, Kalesita F; Swinburn, Boyd A

2013-10-12

The magnitude of the relationship between lifestyle risk factors for obesity and adiposity is not clear. The aim of this study was to clarify this in order to determine the level of importance of lifestyle factors in obesity aetiology. A cross-sectional analysis was carried out on data on youth who were not trying to change weight (n = 5714), aged 12 to 22 years and from 8 ethnic groups living in New Zealand, Australia, Fiji and Tonga. Demographic and lifestyle data were measured by questionnaires. Fatness was measured by body mass index (BMI), BMI z-score and bioimpedance analysis, which was used to estimate percent body fat and total fat mass (TFM). Associations between lifestyle and body composition variables were examined using linear regression and forest plots. TV watching was positively related to fatness in a dose-dependent manner. Strong, dose-dependent associations were observed between fatness and soft drink consumption (positive relationship), breakfast consumption (inverse relationship) and after-school physical activity (inverse relationship). Breakfast consumption-fatness associations varied in size across ethnic groups. Lifestyle risk factors for obesity were associated with percentage differences in body composition variables that were greatest for TFM and smallest for BMI. Lifestyle factors were most strongly related to TFM, which suggests that studies that use BMI alone to quantify fatness underestimate the full effect of lifestyle on adiposity. This study clarifies the size of lifestyle-fatness relationships observed in previous studies.

Transcranial Direct Current Stimulation Post-Stroke Upper Extremity Motor Recovery Studies Exhibit a Dose–Response Relationship

PubMed Central

Chhatbar, Pratik Y.; Ramakrishnan, Viswanathan; Kautz, Steven; George, Mark S.; Adams, Robert J.; Feng, Wuwei

2015-01-01

Background and purpose Transcranial direct current stimulation (tDCS) has shown mixed results in post-stroke motor recovery, possibly because of tDCS dose differences. The purpose of this meta-analysis was to explore whether the outcome has a dose–response relationship with various dose-related parameters. Methods The literature was searched for double-blind, randomized, sham-controlled clinical trials investigating the role of tDCS (≥5 sessions) in post-stroke motor recovery as measured by the Fugl-Meyer Upper Extremity (FM-UE) scale. Improvements in FM-UE scores were compared between active and sham groups by calculating standardized mean differences (Hedge’s g) to derive a summary effect size. Inverse-variance-weighted linear meta-regression across individual studies was performed between various tDCS parameters and Hedge’s g to test for dose–response relationships. Results Eight studies with total of 213 stroke subjects were included. Summary Hedge’s g was statistically significant in favor of the active group (Hedge’s g = 0.61, p = 0.02) suggesting moderate effect. Specifically, studies that used bihemispheric tDCS montage (Hedge’s g = 1.30, p = 0.08) or that recruited chronic stroke patients (Hedge’s g = 1.23, p = 0.02) showed large improvements in the active group. A positive dose–response relationship was found with current density (p = 0.017) and charge density (p = 0.004), but not with current amplitude. Moreover, a negative dose–response relationship was found with electrode size (p < 0.001, smaller electrodes were more effective). Conclusions Our meta-analysis and meta-regression results suggest superior motor recovery in the active group when compared to the sham group and dose–response relationships relating to electrode size, charge density and current density. These results need to be confirmed in future dedicated studies. PMID:26433609

Epidemiology of radiation-induced cancer.

PubMed Central

Radford, E P

1983-01-01

The epidemiology of radiation-induced cancer is important for theoretical and practical insights that these studies give to human cancer in general and because we have more evidence from radiation-exposed populations than for any other environmental carcinogen. On theoretical and experimental grounds, the linear no-threshold dose-response relationship is a reasonable basis for extrapolating effects to low doses. Leukemia is frequently the earliest observed radiogenic cancer but is now considered to be of minor importance, because the radiation effect dies out after 25 or 30 years, whereas solid tumors induced by radiation develop later and the increased cancer risk evidently persists for the remaining lifetime. Current estimates of the risk of particular cancers from radiation exposure cannot be fully evaluated until the population under study have been followed at least 40 or 50 years after exposure. Recent evidence indicates that for lung cancer induction, combination of cigarette smoking and radiation exposure leads to risks that are not multiplicative but rather nearly additive. PMID:6653538

Cell kill by megavoltage protons with high LET.

PubMed

Kuperman, Vadim Y

2016-07-21

The aim of the current study is to develop a radiobiological model which describes the effect of linear energy transfer (LET) on cell survival and relative biological effectiveness (RBE) of megavoltage protons. By assuming the existence of critical sites within a cell, analytical expression for cell survival S as a function of LET is derived. The obtained results indicate that in cases where dose per fraction is small, [Formula: see text] is a linear-quadratic (LQ) function of dose while both alpha and beta radio-sensitivities are non-linearly dependent on LET. In particular, in the current model alpha increases with increasing LET while beta decreases. Conversely, in the case of large dose per fraction, the LQ dependence of [Formula: see text] on dose is invalid. The proposed radiobiological model predicts cell survival probability and RBE which, in general, deviate from the results obtained by using conventional LQ formalism. The differences between the LQ model and that described in the current study are reflected in the calculated RBE of protons.

Estimating organ doses from tube current modulated CT examinations using a generalized linear model.

PubMed

Bostani, Maryam; McMillan, Kyle; Lu, Peiyun; Kim, Grace Hyun J; Cody, Dianna; Arbique, Gary; Greenberg, S Bruce; DeMarco, John J; Cagnon, Chris H; McNitt-Gray, Michael F

2017-04-01

Currently, available Computed Tomography dose metrics are mostly based on fixed tube current Monte Carlo (MC) simulations and/or physical measurements such as the size specific dose estimate (SSDE). In addition to not being able to account for Tube Current Modulation (TCM), these dose metrics do not represent actual patient dose. The purpose of this study was to generate and evaluate a dose estimation model based on the Generalized Linear Model (GLM), which extends the ability to estimate organ dose from tube current modulated examinations by incorporating regional descriptors of patient size, scanner output, and other scan-specific variables as needed. The collection of a total of 332 patient CT scans at four different institutions was approved by each institution's IRB and used to generate and test organ dose estimation models. The patient population consisted of pediatric and adult patients and included thoracic and abdomen/pelvis scans. The scans were performed on three different CT scanner systems. Manual segmentation of organs, depending on the examined anatomy, was performed on each patient's image series. In addition to the collected images, detailed TCM data were collected for all patients scanned on Siemens CT scanners, while for all GE and Toshiba patients, data representing z-axis-only TCM, extracted from the DICOM header of the images, were used for TCM simulations. A validated MC dosimetry package was used to perform detailed simulation of CT examinations on all 332 patient models to estimate dose to each segmented organ (lungs, breasts, liver, spleen, and kidneys), denoted as reference organ dose values. Approximately 60% of the data were used to train a dose estimation model, while the remaining 40% was used to evaluate performance. Two different methodologies were explored using GLM to generate a dose estimation model: (a) using the conventional exponential relationship between normalized organ dose and size with regional water equivalent diameter (WED) and regional CTDI vol as variables and (b) using the same exponential relationship with the addition of categorical variables such as scanner model and organ to provide a more complete estimate of factors that may affect organ dose. Finally, estimates from generated models were compared to those obtained from SSDE and ImPACT. The Generalized Linear Model yielded organ dose estimates that were significantly closer to the MC reference organ dose values than were organ doses estimated via SSDE or ImPACT. Moreover, the GLM estimates were better than those of SSDE or ImPACT irrespective of whether or not categorical variables were used in the model. While the improvement associated with a categorical variable was substantial in estimating breast dose, the improvement was minor for other organs. The GLM approach extends the current CT dose estimation methods by allowing the use of additional variables to more accurately estimate organ dose from TCM scans. Thus, this approach may be able to overcome the limitations of current CT dose metrics to provide more accurate estimates of patient dose, in particular, dose to organs with considerable variability across the population. © 2017 American Association of Physicists in Medicine.

Dose Titration Algorithm Tuning (DTAT) should supersede 'the' Maximum Tolerated Dose (MTD) in oncology dose-finding trials.

PubMed

Norris, David C

2017-01-01

Background . Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent 'confirmatory' Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational therapy. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of 'the' maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived, not as 'dose-finding', but as dose titration algorithm (DTA) -finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug's population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple DTA targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace 'the' MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible DTA capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. Although here illustrated specifically in relation to cytotoxic chemotherapy, the DTAT principle appears similarly applicable to Phase I studies of cancer immunotherapy and molecularly targeted agents.

Occupational radiation procedures and doses in South Korean dentists.

PubMed

Kim, Yoon-Ji; Cha, Eun Shil; Lee, Won Jin

2016-10-01

Dentistry is among the occupations involving chronic exposure to ionizing radiation. Although several cohort studies on medical radiation workers have been conducted in some countries, only a few epidemiological studies on dentists have been performed to examine occupational radiation exposure worldwide. The aim of this study was to investigate occupational characteristics and radiation exposures in South Korean dentists. A total of 658 dentists were surveyed from April 2012 to May 2013, and survey data were linked with dosimetry data from the National Dose Registry. Multiple linear regression analysis was used to identify the relationship between demographic or occupational factors and individual radiation doses. Of the dentists sampled, 78% were men, 51% were younger than age 40, and 61% began employment after 2000. The most frequent procedures performed by dentists were panoramic radiography, followed by intraoral and portable dental radiography. Male dentists were more frequently involved in radiation procedures, and a higher proportion of male than female dentists wore a lead apron for diagnostic radiology. The average annual effective dose was 0.18 mSv for male and 0.13 mSv for female dentists. Female dentists working in provincial areas had significantly higher average annual and cumulative effective doses than those in metropolitan areas. The cumulative effective doses were significantly greater for older dentists, those who entered the field in the 1990s, and those with longer employment duration. Our findings provided detailed information on work practices, number of procedures performed on a weekly basis, and occupational radiation doses, which enabled in-depth evaluation of occupational radiation exposure and work status among dentists. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacokinetic-pharmacodynamic modelling of the antihistaminic (H1) effect of bilastine.

PubMed

Jauregizar, Nerea; de la Fuente, Leire; Lucero, Maria Luisa; Sologuren, Ander; Leal, Nerea; Rodríguez, Mónica

2009-01-01

To model the pharmacokinetic and pharmacodynamic relationship of bilastine, a new histamine H(1) receptor antagonist, from single- and multiple-dose studies in healthy adult subjects. The pharmacokinetic model was developed from different single-dose and multiple-dose studies. In the single-dose studies, a total of 183 subjects received oral doses of bilastine 2.5, 5, 10, 20, 50, 100, 120, 160, 200 and 220 mg. In the multiple-dose studies, 127 healthy subjects received bilastine 10, 20, 40, 50, 80, 100, 140 or 200 mg/day as multiple doses during a 4-, 7- or 14-day period. The pharmacokinetic profile of bilastine was investigated using a simultaneous analysis of all concentration-time data by means of nonlinear mixed-effects modelling population pharmacokinetic software NONMEM version 6.1. Plasma concentrations were modelled according to a two-compartment open model with first-order absorption and elimination. For the pharmacodynamic analysis, the inhibitory effect of bilastine (inhibition of histamine-induced wheal and flare) was assessed on a preselected time schedule, and the predicted typical pharmacokinetic profile (based on the pharmacokinetic model previously developed) was used. An indirect response model was developed to describe the pharmacodynamic relationships between flare or wheal areas and bilastine plasma concentrations. Finally, once values of the concentration that produced 50% inhibition (IC(50)) had been estimated for wheal and flare effects, simulations were carried out to predict plasma concentrations for the doses of bilastine 5, 10 and 20 mg at steady state (72-96 hours). A non-compartmental analysis resulted in linear kinetics of bilastine in the dose range studied. Bilastine was characterized by two-compartmental kinetics with a rapid-absorption phase (first-order absorption rate constant = 1.50 h(-1)), plasma peak concentrations were observed at 1 hour following administration and the maximal response was observed at approximately 4 hours or later. Concerning the selected pharmacodynamic model to fit the data (type I indirect response model), this selection is attributable to the presence of inhibitory bilastine plasma concentrations that decrease the input response function, i.e. the production of the skin reaction. This model resulted in the best fit of wheal and flare data. The estimates (with relative standard errors expressed in percentages in parentheses) of the apparent zero-order rate constant for flare or wheal spontaneous appearance (k(in)), the first-order rate constant for flare or wheal disappearance (k(out)) and bilastine IC(50) values were 0.44 ng/mL/h (14.60%), 1.09 h(-1) (15.14%) and 5.15 ng/mL (16.16%), respectively, for wheal inhibition, and 11.10 ng/mL/h (8.48%), 1.03 h(-1) (8.35%) and 1.25 ng/mL (14.56%), respectively, for flare inhibition. The simulation results revealed that bilastine plasma concentrations do not remain over the IC(50) value throughout the inter-dose period for doses of 5 and 10 mg. However, with a dose of 20 mg of bilastine administered every 24 hours, plasma concentrations remained over the IC(50) value during the considered period for the flare effect, and up to 20 hours for the wheal effect. Pharmacokinetic and pharmacodynamic relationships of bilastine were reliably described with the use of an indirect response pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of bilastine.

Higher-Than-Conventional Radiation Doses in Localized Prostate Cancer Treatment: A Meta-analysis of Randomized, Controlled Trials

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

Viani, Gustavo Arruda; Stefano, Eduardo Jose; Afonso, Sergio Luis

2009-08-01

Purpose: To determine in a meta-analysis whether the outcomes in men with localized prostate cancer treated with high-dose radiotherapy (HDRT) are better than those in men treated with conventional-dose radiotherapy (CDRT), by quantifying the effect of the total dose of radiotherapy on biochemical control (BC). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as the proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing HDRT with CDRT for localized prostate cancer. To evaluate the dose-response relationship, we conducted a meta-regression analysis of BC ratios by means of weighted linear regression. Results:more » Seven RCTs with a total patient population of 2812 were identified that met the study criteria. Pooled results from these RCTs showed a significant reduction in the incidence of biochemical failure in those patients with prostate cancer treated with HDRT (p < 0.0001). However, there was no difference in the mortality rate (p = 0.38) and specific prostate cancer mortality rates (p = 0.45) between the groups receiving HDRT and CDRT. However, there were more cases of late Grade >2 gastrointestinal toxicity after HDRT than after CDRT. In the subgroup analysis, patients classified as being at low (p = 0.007), intermediate (p < 0.0001), and high risk (p < 0.0001) of biochemical failure all showed a benefit from HDRT. The meta-regression analysis also detected a linear correlation between the total dose of radiotherapy and biochemical failure (BC = -67.3 + [1.8 x radiotherapy total dose in Gy]; p = 0.04). Conclusions: Our meta-analysis showed that HDRT is superior to CDRT in preventing biochemical failure in low-, intermediate-, and high-risk prostate cancer patients, suggesting that this should be offered as a treatment for all patients, regardless of their risk status.« less

The Effects of Space Radiation on Linear Integrated Circuit

NASA Technical Reports Server (NTRS)

Johnston, A.

2000-01-01

Permanent and transient effects are discussed that are induced in linear integrated circuits by space radiation. Recent developments include enhanced damage at low dose rate, increased damage from protons due to displacement effects, and transients in digital comparators that can cause circuit malfunctions.

Space Radiation Effects and Hardness Assurance for Linear Integrated Circuits

NASA Technical Reports Server (NTRS)

Johnston, A. H.

2000-01-01

New effects that complicate the application of linear devices in space are discussed, including enhanced damage at low dose rate and proton damage, which cause permanent degradation. Transients produced by protons and heavy ions are also discussed.

Competitive inhibition can linearize dose-response and generate a linear rectifier

PubMed Central

Savir, Yonatan; Tu, Benjamin P.; Springer, Michael

2015-01-01

Summary Many biological responses require a dynamic range that is larger than standard bi-molecular interactions allow, yet the also ability to remain off at low input. Here we mathematically show that an enzyme reaction system involving a combination of competitive inhibition, conservation of the total level of substrate and inhibitor, and positive feedback can behave like a linear rectifier—that is, a network motif with an input-output relationship that is linearly sensitive to substrate above a threshold but unresponsive below the threshold. We propose that the evolutionarily conserved yeast SAGA histone acetylation complex may possess the proper physiological response characteristics and molecular interactions needed to perform as a linear rectifier, and we suggest potential experiments to test this hypothesis. One implication of this work is that linear responses and linear rectifiers might be easier to evolve or synthetically construct than is currently appreciated. PMID:26495436

Competitive inhibition can linearize dose-response and generate a linear rectifier.

PubMed

Savir, Yonatan; Tu, Benjamin P; Springer, Michael

2015-09-23

Many biological responses require a dynamic range that is larger than standard bi-molecular interactions allow, yet the also ability to remain off at low input. Here we mathematically show that an enzyme reaction system involving a combination of competitive inhibition, conservation of the total level of substrate and inhibitor, and positive feedback can behave like a linear rectifier-that is, a network motif with an input-output relationship that is linearly sensitive to substrate above a threshold but unresponsive below the threshold. We propose that the evolutionarily conserved yeast SAGA histone acetylation complex may possess the proper physiological response characteristics and molecular interactions needed to perform as a linear rectifier, and we suggest potential experiments to test this hypothesis. One implication of this work is that linear responses and linear rectifiers might be easier to evolve or synthetically construct than is currently appreciated.

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

PubMed

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

2011-02-01

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

Reversion of 6-thioguanine resistant Chinese hamster cell lines: agent specificity and evidence for the repair of promutagenic lesions.

PubMed

Hodgkiss, R J; Brennand, J; Fox, M

1980-02-01

The kinetics and mutagen specificity of reversion of an HGPRT(-)TG(R) line of Chinese hamster cells have been examined in detail by measuring the frequency of HAT(R) colonies. Alkylating agents which produce relatively high levels of O-atom reaction were effective in inducing reversion. MMS, DMS and u.v. were less efficient, and aflatoxin B1, acridine orange and N-acetoxy-AAF were completely ineffective. For agents which were effective, the relationship between HAT(R) colony frequency and dose of mutagen was linear at early expression times (6 h). HAT(R) colony frequency fell subsequently at all doses and the rate and extent of the fall was inversely related to dose. These observations suggest repair of a pro-mutagenic DNA lesion. Other TG(R) mutants isolated from the same wild-type cell line under different selective conditions were also tested for revertibility after exposure to the same mutagens. The majority did not revert, this suggests that they carry deletions within the structural gene for HGPRT. The infrequent revertible lines all arose spontaneously and our evidence suggests that they carry nonsense mutations.

Adaptive, dose-finding phase 2 trial evaluating the safety and efficacy of ABT-089 in mild to moderate Alzheimer disease.

PubMed

Lenz, Robert A; Pritchett, Yili L; Berry, Scott M; Llano, Daniel A; Han, Shu; Berry, Donald A; Sadowsky, Carl H; Abi-Saab, Walid M; Saltarelli, Mario D

2015-01-01

ABT-089, an α4β2 neuronal nicotinic receptor partial agonist, was evaluated for efficacy and safety in mild to moderate Alzheimer disease patients receiving stable doses of acetylcholinesterase inhibitors. This phase 2 double-blind, placebo-controlled, proof-of-concept, and dose-finding study adaptively randomized patients to receive ABT-089 (5, 10, 15, 20, 30, or 35 mg once daily) or placebo for 12 weeks. The primary efficacy endpoint was the Alzheimer's Disease Assessment Scale, cognition subscale (ADAS-Cog) total score. A Bayesian response-adaptive randomization algorithm dynamically assigned allocation probabilities based on interim ADAS-Cog total scores. A normal dynamic linear model for dose-response relationships and a longitudinal model for predicting final ADAS-cog score were employed in the algorithm. Stopping criteria for futility or success were defined. The futility stopping criterion was met, terminating the study with 337 patients randomized. No dose-response relationship was observed and no dose demonstrated statistically significant improvement over placebo on ADAS-Cog or any secondary endpoint. ABT-089 was well tolerated at all dose levels. When administered as adjunctive therapy to acetylcholinesterase inhibitors, ABT-089 was not efficacious in mild to moderate Alzheimer disease. The adaptive study design enabled the examination of a broad dose range, enabled rapid determination of futility, and reduced patient exposure to nonefficacious doses of the investigational compound.

Cytotoxicity of polycations: Relationship of molecular weight and the hydrolytic theory of the mechanism of toxicity.

PubMed

Monnery, Bryn D; Wright, Michael; Cavill, Rachel; Hoogenboom, Richard; Shaunak, Sunil; Steinke, Joachim H G; Thanou, Maya

2017-04-15

The mechanism of polycation cytotoxicity and the relationship to polymer molecular weight is poorly understood. To gain an insight into this important phenomenon a range of newly synthesised uniform (near monodisperse) linear polyethylenimines, commercially available poly(l-lysine)s and two commonly used PEI-based transfectants (broad 22kDa linear and 25kDa branched) were tested for their cytotoxicity against the A549 human lung carcinoma cell line. Cell membrane damage assays (LDH release) and cell viability assays (MTT) showed a strong relationship to dose and polymer molecular weight, and increasing incubation times revealed that even supposedly "non-toxic" low molecular weight polymers still damage cell membranes. The newly proposed mechanism of cell membrane damage is acid catalysed hydrolysis of lipidic phosphoester bonds, which was supported by observations of the hydrolysis of DOPC liposomes. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

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

PubMed

Dropkin, Greg

2016-11-24

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

Cumulative total effective whole-body radiation dose in critically ill patients.

PubMed

Rohner, Deborah J; Bennett, Suzanne; Samaratunga, Chandrasiri; Jewell, Elizabeth S; Smith, Jeffrey P; Gaskill-Shipley, Mary; Lisco, Steven J

2013-11-01

Uncertainty exists about a safe dose limit to minimize radiation-induced cancer. Maximum occupational exposure is 20 mSv/y averaged over 5 years with no more than 50 mSv in any single year. Radiation exposure to the general population is less, but the average dose in the United States has doubled in the past 30 years, largely from medical radiation exposure. We hypothesized that patients in a mixed-use surgical ICU (SICU) approach or exceed this limit and that trauma patients were more likely to exceed 50 mSv because of frequent diagnostic imaging. Patients admitted into 15 predesignated SICU beds in a level I trauma center during a 30-day consecutive period were prospectively observed. Effective dose was determined using Huda's method for all radiography, CT imaging, and fluoroscopic examinations. Univariate and multivariable linear regressions were used to analyze the relationships between observed values and outcomes. Five of 74 patients (6.8%) exceeded exposures of 50 mSv. Univariate analysis showed trauma designation, length of stay, number of CT scans, fluoroscopy minutes, and number of general radiographs were all associated with increased doses, leading to exceeding occupational exposure limits. In a multivariable analysis, only the number of CT scans and fluoroscopy minutes remained significantly associated with increased whole-body radiation dose. Radiation levels frequently exceeded occupational exposure standards. CT imaging contributed the most exposure. Health-care providers must practice efficient stewardship of radiologic imaging in all critically ill and injured patients. Diagnostic benefit must always be weighed against the risk of cumulative radiation dose.

Physics must join with biology in better assessing risk from low-dose irradiation.

PubMed

Feinendegen, L E; Neumann, R D

2005-01-01

This review summarises the complex response of mammalian cells and tissues to low doses of ionising radiation. This thesis encompasses induction of DNA damage, and adaptive protection against both renewed damage and against propagation of damage from the basic level of biological organisation to the clinical expression of detriment. The induction of DNA damage at low radiation doses apparently is proportional to absorbed dose at the physical/chemical level. However, any propagation of such damage to higher levels of biological organisation inherently follows a sigmoid function. Moreover, low-dose-induced inhibition of damage propagation is not linear, but instead follows a dose-effect function typical for adaptive protection, after an initial rapid rise it disappears at doses higher than approximately 0.1-0.2 Gy to cells. The particular biological response duality at low radiation doses precludes the validity of the linear-no-threshold hypothesis in the attempt to relate absorbed dose to cancer. In fact, theory and observation support not only a lower cancer incidence than expected from the linear-no-threshold hypothesis, but also a reduction of spontaneously occurring cancer, a hormetic response, in the healthy individual.

Predicted Risk of Radiation-Induced Cancers After Involved Field and Involved Node Radiotherapy With or Without Intensity Modulation for Early-Stage Hodgkin Lymphoma in Female Patients

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

Weber, Damien C., E-mail: damien.weber@unige.ch; Johanson, Safora; Peguret, Nicolas

2011-10-01

Purpose: To assess the excess relative risk (ERR) of radiation-induced cancers (RIC) in female patients with Hodgkin lymphoma (HL) female patients treated with conformal (3DCRT), intensity modulated (IMRT), or volumetric modulated arc (RA) radiation therapy. Methods and Materials: Plans for 10 early-stage HL female patients were computed for 3DCRT, IMRT, and RA with involved field RT (IFRT) and involvednode RT (INRT) radiation fields. Organs at risk dose--volume histograms were computed and inter-compared for IFRT vs. INRT and 3DCRT vs. IMRT/RA, respectively. The ERR for cancer induction in breasts, lungs, and thyroid was estimated using both linear and nonlinear models. Results:more » The mean estimated ERR for breast, lung, and thyroid were significantly lower (p < 0.01) with INRT than with IFRT planning, regardless of the radiation delivery technique used, assuming a linear dose-risk relationship. We found that using the nonlinear model, the mean ERR values were significantly (p < 0.01) increased with IMRT or RA compared to those with 3DCRT planning for the breast, lung, and thyroid, using an IFRT paradigm. After INRT planning, IMRT or RA increased the risk of RIC for lung and thyroid only. Conclusions: In this comparative planning study, using a nonlinear dose--risk model, IMRT or RA increased the estimated risk of RIC for breast, lung, and thyroid for HL female patients. This study also suggests that INRT planning, compared to IFRT planning, may reduce the ERR of RIC when risk is predicted using a linear model. Observing the opposite effect, with a nonlinear model, however, questions the validity of these biologically parameterized models.« less

Noninvasive monitoring of intraocular pharmacokinetics of daunorubicin using fluorophotometry.

PubMed

Kizhakkethara, I; Li, X; el-Sayed, S; Khoobehi, B; Moshfeghi, D M; Rahimy, M; Peyman, G A

Daunorubicin is a cytotoxic drug, which, in nontoxic doses, is effective in preventing cellular proliferation in experimental vitreoretinopathy. We studied dose and clearance of daunorubicin in various ocular tissues using fluorophotometry techniques. In vitro tests: The emission of fluorescence from the daunorubicin solution having a concentration range of 0.1 to 10 micrograms/mL in phosphate buffer was measured using an excitation wavelength range of 489 +/- 10 nm. The emission of fluorescence was measured at 514 nm; the linearity of the response was determined using linear regression analysis. There is a fluorescence peak of daunorubicin at 485 nm. The validity and reproducibility of the method were examined. In vivo tests: The rabbits were randomized into three groups and daunorubicin concentrations of 4, 6, or 8 micrograms/mL were injected into the vitreous. Fluorophotometry scanning from the retina to the anterior chamber was performed with a commercially available fluorophotometer at various times up to 48 hours after injection to quantify fluorescence emission of daunorubicin. The standard curve of fluorescence versus concentration of daunorubicin was linear in the range of 0.1 to 8 micrograms/mL. It was sensitive up to 0.1 microgram. The daunorubicin time concentration profile showed a dose response relationship over the 48-hour period studied. The half-life of daunorubicin in the vitreous was about 5 hours. We performed fluorophotometry using a fluorophotometer whose exciter emits light at 489 nm, which is very close to an absorption peak of daunorubicin. These two values are close enough to obviate the need for modifying the commercial fluorophotometer. Therefore the concentration of daunorubicin in the vitreous cavity can be measured noninvasively.

Single- and double-strand break formation in DNA irradiated in aqueous solution: dependence on dose and OH radical scavenger concentration

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

Siddiqi, M.A.; Bothe, E.

The yields of single- and double-strand breaks (SSB and DSB) in calf thymus DNA, after /sup 60/Co gamma irradiation in dilute aqueous solution, have been determined via molecular weight measurements using a low-angle laser light scattering technique. The irradiations were administered to N/sub 2/O-containing solutions of DNA in the absence and presence of oxygen and with different concentrations of the OH radical scavengers phenol, tertiary butanol, and methanol. OH radicals were found to produce SSB linearly with dose with a G value of 55 nmol J-1 and 54 nmol J-1 in deoxygenated and oxygenated solutions, respectively. DSB were formed accordingmore » to a linear-quadratic dose relationship and the G value of linearly formed DSB were GDSB alpha(r.t.) = 3.5 nmol J-1 in deoxygenated and 3.2 nmol J-1 in oxygenated solution. The ratio of GSSB/GDSB alpha(r.t.) = gamma of 19 +/- 6 was independent of the scavenger concentration in the case of tertiary butanol and methanol-containing solutions. GDSB alpha(r.t.) is interpreted to result from a radical site transferred from a sugar moiety of the cleaved strand to the complementary intact strand. This process of radical transfer and subsequent cleavage of the second strand occurs with a probability of about 6 +/- 2% in the presence of oxygen at all scavenger concentrations studied. These data on scavenging capacity on GDSB alpha(r.t.) suggest that the double-strand breakage produced via radical transfer remains higher than that resulting from direct effect, up to scavenging capacities of about 10(9) s-1.« less

Risk equivalent of exposure versus dose of radiation

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

Bond, V.P.

This report describes a risk analysis study of low-dose irradiation and the resulting biological effects on a cell. The author describes fundamental differences between the effects of high-level exposure (HLE) and low-level exposure (LLE). He stresses that the concept of absorbed dose to an organ is not a dose but a level of effect produced by a particular number of particles. He discusses the confusion between a linear-proportional representation of dose limits and a threshold-curvilinear representation, suggesting that a LLE is a composite of both systems. (TEM)

Linear energy transfer in water phantom within SHIELD-HIT transport code

NASA Astrophysics Data System (ADS)

Ergun, A.; Sobolevsky, N.; Botvina, A. S.; Buyukcizmeci, N.; Latysheva, L.; Ogul, R.

2017-02-01

The effect of irradiation in tissue is important in hadron therapy for the dose measurement and treatment planning. This biological effect is defined by an equivalent dose H which depends on the Linear Energy Transfer (LET). Usually, H can be expressed in terms of the absorbed dose D and the quality factor K of the radiation under consideration. In literature, various types of transport codes have been used for modeling and simulation of the interaction of the beams of protons and heavier ions with tissue-equivalent materials. In this presentation we used SHIELD-HIT code to simulate decomposition of the absorbed dose by LET in water for 16O beams. A more detailed description of capabilities of the SHIELD-HIT code can be found in the literature.

The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis

PubMed Central

Minneci, P. C.; Deans, K. J.; Eichacker, P. Q.; Natanson, C.

2012-01-01

A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p <0.001, I2 = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I2 = 14%, OR of death 1.39 (95% CI 1.04–1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I2 = 0%, OR of shock reversal 1.66 [95% CI 1.25–2.20), p <0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I2 = 25%, OR of death 0.64 (95% CI 0.45–0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis. PMID:19416302

Radiation health for a Mars mission

NASA Technical Reports Server (NTRS)

Robbins, Donald E.

1992-01-01

Uncertainties in risk assessments for exposure of a Mars mission crew to space radiation place limitations on mission design and operation. Large shielding penalties are imposed in order to obtain acceptable safety margins. Galactic cosmic rays (GCR) and solar particle events (SPE) are the major concern. A warning system and 'safe-haven' are needed to protect the crew from large SPE which produce lethal doses. A model developed at NASA Johnson Space Center (JSC) to describe solar modulation of GCR intensities reduces that uncertainty to less than 10 percent. Radiation transport models used to design spacecraft shielding have large uncertainties in nuclear fragmentation cross sections for GCR which interact with spacecraft materials. Planned space measurements of linear energy transfer (LET) spectra behind various shielding thicknesses will reduce uncertainties in dose-versus-shielding thickness relationships to 5-10 percent. The largest remaining uncertainty is in biological effects of space radiation. Data on effects of energetic ions in human are nonexistent. Experimental research on effects in animals and cell is needed to allow extrapolation to the risk of carcinogenesis in humans.

TH-AB-207A-06: The Use of Realistic Phantoms to Predict CT Dose to Pediatric Patients

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

Carver, D; Kost, S; Fraser, N

Purpose: To predict pediatric patient dose from diagnostic CT scans using Monte Carlo simulation of realistic reference phantoms of various ages, weights, and heights. Methods: A series of deformable pediatric reference phantoms using Non-Uniform Rational B-Splines (NURBS) was developed for a large range of ages, percentiles, and reference anatomy. Individual bones were modeled using age-dependent factors, and red marrow was modeled as functions of age and spatial distribution based on Cristy1. Organ and effective doses for the phantom series were calculated using Monte Carlo simulation of chest, abdominopelvic, and chest-abdomen-pelvis CT exams. Non-linear regression was performed to determine the relationshipmore » between dose-length-product (DLP)-normalized organ and effective doses and phantom diameter. Patient-specific voxel computational phantoms were also created by manual segmentation of previously acquired CT images for 40 pediatric patients (0.7 to 17 years). Organ and effective doses were determined by Monte Carlo simulation of these patient-specific phantoms. Each patient was matched to the closest pediatric reference phantom based primarily on age and diameter for all major organs within the torso. Results: A total of 80 NURBS phantoms were created ranging from newborn to 15 years with height/weight percentiles from 10 to 90%. Organ and effective dose normalized by DLP correlated strongly with exponentially decreasing average phantom diameter (R{sup 2} > 0.95 for most organs). A similar relationship was determined for the patient-specific voxel phantoms. Differences between patient-phantom matched organ-dose values ranged from 0.37 to 2.39 mGy (2.87% to 22.1%). Conclusion: Dose estimation using NURBS-based pediatric reference phantoms offers the ability to predict patient dose before and after CT examinations, and physicians and scientists can use this information in their analysis of dose prescriptions for particular subjects and study types. This may lead to practices that minimize radiation dose while still achieving high quality images and, ultimately, improved patient care. NIH/NCI 1 R01 CA155400-01A1.« less

Semiparametric methods for estimation of a nonlinear exposure-outcome relationship using instrumental variables with application to Mendelian randomization.

PubMed

Staley, James R; Burgess, Stephen

2017-05-01

Mendelian randomization, the use of genetic variants as instrumental variables (IV), can test for and estimate the causal effect of an exposure on an outcome. Most IV methods assume that the function relating the exposure to the expected value of the outcome (the exposure-outcome relationship) is linear. However, in practice, this assumption may not hold. Indeed, often the primary question of interest is to assess the shape of this relationship. We present two novel IV methods for investigating the shape of the exposure-outcome relationship: a fractional polynomial method and a piecewise linear method. We divide the population into strata using the exposure distribution, and estimate a causal effect, referred to as a localized average causal effect (LACE), in each stratum of population. The fractional polynomial method performs metaregression on these LACE estimates. The piecewise linear method estimates a continuous piecewise linear function, the gradient of which is the LACE estimate in each stratum. Both methods were demonstrated in a simulation study to estimate the true exposure-outcome relationship well, particularly when the relationship was a fractional polynomial (for the fractional polynomial method) or was piecewise linear (for the piecewise linear method). The methods were used to investigate the shape of relationship of body mass index with systolic blood pressure and diastolic blood pressure. © 2017 The Authors Genetic Epidemiology Published by Wiley Periodicals, Inc.

Semiparametric methods for estimation of a nonlinear exposure‐outcome relationship using instrumental variables with application to Mendelian randomization

PubMed Central

Staley, James R.

2017-01-01

ABSTRACT Mendelian randomization, the use of genetic variants as instrumental variables (IV), can test for and estimate the causal effect of an exposure on an outcome. Most IV methods assume that the function relating the exposure to the expected value of the outcome (the exposure‐outcome relationship) is linear. However, in practice, this assumption may not hold. Indeed, often the primary question of interest is to assess the shape of this relationship. We present two novel IV methods for investigating the shape of the exposure‐outcome relationship: a fractional polynomial method and a piecewise linear method. We divide the population into strata using the exposure distribution, and estimate a causal effect, referred to as a localized average causal effect (LACE), in each stratum of population. The fractional polynomial method performs metaregression on these LACE estimates. The piecewise linear method estimates a continuous piecewise linear function, the gradient of which is the LACE estimate in each stratum. Both methods were demonstrated in a simulation study to estimate the true exposure‐outcome relationship well, particularly when the relationship was a fractional polynomial (for the fractional polynomial method) or was piecewise linear (for the piecewise linear method). The methods were used to investigate the shape of relationship of body mass index with systolic blood pressure and diastolic blood pressure. PMID:28317167

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.

A CORRELATION BETWEEN RADIATION TOLERANCE AND NUCLEAR SURFACE AREA

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

Iversen, S.

1962-09-22

Sparrow and Miksche (Science, 134:282) determined the dose (r/day) required to produce severe growth inhibition in 23 species of plants and found a linear relationship between log nuclear volume and log dose. The following equations hold for 6 species: log nuclear volume - 4.42 -0.82 log dose and log nuclear volume = 1.66 + 0.66 log (DNA content). If all the nuclear DNA is distributed in two peripheral zones, the equations also hold: 2(log nuclear surface area) - 1.33(log nuclear volume) - 2.21 + 0.88 log(DNA content) and 5.88-- 1.09 log dose. For the 23 species, the equation was obtained:more » 2(log nuclear surface area) = 5.41 -- 0.97 log dose. All the slopes are close to the expected value of 1.00. (D.L.C.)« less

Dietary Magnesium Intake and Metabolic Syndrome in the Adult Population: Dose-Response Meta-Analysis and Meta-Regression

PubMed Central

Ju, Sang-Yhun; Choi, Whan-Seok; Ock, Sun-Myeong; Kim, Chul-Min; Kim, Do-Hoon

2014-01-01

Increasing evidence has suggested an association between dietary magnesium intake and metabolic syndrome. However, previous research examining dietary magnesium intake and metabolic syndrome has produced mixed results. Our objective was to determine the relationship between dietary magnesium intake and metabolic syndrome in the adult population using a dose-response meta-analysis. We searched the PubMed, Embase and the Cochrane Library databases from August, 1965, to May, 2014. Observational studies reporting risk ratios with 95% confidence intervals (CIs) for metabolic syndrome in ≥3 categories of dietary magnesium intake levels were selected. The data extraction was performed independently by two authors, and the quality of the studies was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS). Based on eight cross-sectional studies and two prospective cohort studies, the pooled relative risks of metabolic syndrome per 150 mg/day increment in magnesium intake was 0.88 (95% CI, 0.84–0.93; I2 = 36.3%). The meta-regression model showed a generally linear, inverse relationship between magnesium intake (mg/day) and metabolic syndrome. This dose-response meta-analysis indicates that dietary magnesium intake is significantly and inversely associated with the risk of metabolic syndrome. However, randomized clinical trials will be necessary to address the issue of causality and to determine whether magnesium supplementation is effective for the prevention of metabolic syndrome. PMID:25533010

Characterization and prediction of monomer-based dose rate effects in electron-beam polymerization

NASA Astrophysics Data System (ADS)

Schissel, Sage M.; Lapin, Stephen C.; Jessop, Julie L. P.

2017-12-01

Properties of some materials produced by electron-beam (EB) induced polymerization appear dependent upon the rate at which the initiating dose was delivered. However, the magnitude of these dose rate effects (DREs) can vary greatly with different monomer formulations, suggesting DREs are dependent on chemical structure. The relationship among dose, dose rate, conversion, and the glass transition temperature (Tg) of the cured material was explored for an acrylate monomer series. A strong correlation was determined between the DRE magnitude and monomer size, and this correlation may be attributed to chain transfer. Using the Tg shift caused by changes in dose, a preliminary predictive relationship was developed to estimate the magnitude of the Tg DRE, enabling scale-up of process variables for polymers prone to dose rate effects.

Search for the effect of E-beam irradiation on some steroids

NASA Astrophysics Data System (ADS)

Marciniec, B.; Ogrodowczyk, M.; Dettlaff, K.

2005-03-01

Seven steroid derivatives (hydrocortisone, hydrocortisone acetate, prednisolone, prednisolone acetate, methylprednisolone acetate, dexamethasone and fludrocortisone acetate) irradiated in the solid phase 10 MeV electrons, were studied by chromatographic methods (TLC and HPLC). Before the irradiation the derivatives contained different amounts of the following impurities: cortisone, cortisone acetate, prednisolone, prednisolone acetate and prednisone. After irradiation with a dose of upto 200 kGy radiolytic products were identified: cortisone, cortisone acetate, prednisone, prednisolone and methylprednisone acetate. All the identified radiolytic products were formed as a result of oxidation of the substituent at C 11, and in some cases the oxidation was accompanied by cleavage of the ester bond. The content of impurities before irradiation did not exceed 0.8%, while after the irradiation the content of the products of radiolysis depended on the kind of the derivative and the dose, and varied from 0.6% for a dose of 25 kGy to 4.03% for a dose of 200 kGy. For some derivatives, a linear relationship was found between the loss of a given steroid content and the dose. The studied steroid derivatives are characterised by high radiochemical stability and their sterilisation by irradiation does not lead to loss of the active substance below 97%, i.e. the lower limit admissible by the pharmacopoeias.

Neonatal outcomes following exposure in utero to fallout from Chernobyl.

PubMed

Hatch, Maureen; Little, Mark P; Brenner, Alina V; Cahoon, Elizabeth K; Tereshchenko, Valery; Chaikovska, Ludmyla; Pasteur, Igor; Likhtarov, Ilya; Bouville, Andre; Shpak, Victor; Bolshova, Olena; Zamotayeva, Galyna; Grantz, Katherine; Sun, Liping; Mabuchi, Kiyohiko; Albert, Paul; Tronko, Mykola

2017-12-01

Iodine 131 (I-131), the principal component of nuclear fallout from the Chernobyl accident, concentrates in the thyroid gland and may pose risks to fetal development. To evaluate this, neonatal outcomes following the accident in April of 1986 were investigated in a cohort of 2582 in utero-exposed individuals from northern Ukraine for whom estimates of fetal thyroid I-131 dose were available. We carried out a retrospective review of cohort members' prenatal, delivery and newborn records. The relationships of dose with neonatal anthropometrics and gestational length were modeled via linear regression with adjustment for potentially confounding variables. We found similar, statistically significant dose-dependent reductions in both head circumference (-1.0 cm/Gy, P = 0.005) and chest circumference (-0.9 cm/Gy, P = 0.023), as well as a similar but non-significant reduction in neonatal length (-0.6 cm/Gy, P = 0.169). Gestational length was significantly increased with increasing fetal dose (0.5 wks/Gy, P = 0.007). There was no significant (P > 0.1) effect of fetal dose on birth weight. The observed associations of radioiodine exposure with decreased head and chest circumference are consistent with those observed in the Japanese in utero-exposed atomic bomb survivors.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

PubMed

Flick, Burkhard; Schneider, Steffen; Melching-Kollmuss, Stephanie; Fussell, Karma C; Gröters, Sibylle; Buesen, Roland; Strauss, Volker; van Ravenzwaay, Bennard

2017-04-01

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Dose-response relationship of cardiorespiratory fitness adaptation to controlled endurance training in sedentary older adults.

PubMed

Huang, Guoyuan; Wang, Ru; Chen, Peijie; Huang, Sunny C; Donnelly, Joseph E; Mehlferber, Jon P

2016-03-01

The purpose of this investigation was to identify a quantitative dose-response relationship for enhancing maximal oxygen consumption (VO2max) in healthy sedentary older adults after controlled endurance training. This meta-analysis of controlled clinical trials included 1257 exercisers and 845 controls with a mean age of 67.45 ± 5.25 years. Effect sizes were calculated for training-induced VO2max changes. Different training regimens were analyzed and compared. The weighted net change of the mean VO2max values showed a significant increase of 3.78 ml/kg per min (95% confidence interval = 3.29 to 4.27; p < 0.0001) in response to aerobic training. Interstudy differences in VO2max changes were significantly related to exercise intensity, and explained approximately 11% of the variance of the VO2max responses. VO2max improved significantly at 35%-50% heart rate reserve (HRR) and continued improving at a greater rate with increasing "dose". The largest VO2max-improvement adaptation was achieved with a mean intensity of 66%-73% HRR. The magnitudes of the VO2max adaptation are identical to exercise at 57%-65% HRR and at 75%-80% HRR. Higher intensity doses more than 75-80% HRR did not lead to greater enhancement of VO2max improvements but, conversely, resulted in large declines. Our data provide quantitative insight into the magnitude of VO2max alterations as affected by exercise intensity, duration, frequency, and program length. The shapes of the dose-response curves are not simply linear, but with many similar trends and noteworthy characteristics. Aerobic training at a mean intensity of 66%-73% HRR with 40-50 min per session for 3-4 day/week for 30-40 weeks appears to be effective and optimal for maximum cardiorespiratory benefits in healthy sedentary older adults. © The European Society of Cardiology 2015.

Radiation dose and subsequent risk for stomach cancer in long-term survivors of cervical cancer

PubMed Central

Kleinerman, Ruth A.; Smith, Susan A.; Holowaty, Eric; Hall, Per; Pukkala, Eero; Vaalavirta, Leila; Stovall, Marilyn; Weathers, Rita; Gilbert, Ethel; Aleman, Berthe M.P.; Kaijser, Magnus; Andersson, Michael; Storm, Hans; Joensuu, Heikki; Lynch, Charles F.; Dores, Graça M.; Travis, Lois B.; Morton, Lindsay M.; Curtis, Rochelle E.

2013-01-01

Purpose To assess the dose-response relationship for stomach cancer following radiotherapy for cervical cancer. Methods and Materials We conducted a nested, matched case-control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943–1995, from five international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 gray [Gy], range 0.03–46.1 and following parallel opposed pelvic fields, 1.63 Gy, range 0.12–6.3). Results Over 90% of women received radiotherapy, mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was non-significantly increased (odds ratios [ORs] 1.27–2.28) for women receiving between 0.5–4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (OR=4.20, 95% confidence interval, 1.41–13.4, Ptrend=0.047) compared to non-irradiated women. A highly significant radiation dose-response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (Ptrend=0.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (Ptrend=0.23). Conclusions Our findings showed for the first time a significant linear dose-response relationship for risk of stomach cancer in long-term survivors of cervical cancer. PMID:23707149

Randomized controlled trial comparing impact on platelet reactivity of twice-daily with once-daily aspirin in people with Type 2 diabetes.

PubMed

Bethel, M A; Harrison, P; Sourij, H; Sun, Y; Tucker, L; Kennedy, I; White, S; Hill, L; Oulhaj, A; Coleman, R L; Holman, R R

2016-02-01

Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(™) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

Performance traits and metabolic responses in goats (Capra hircus) supplemented with inorganic trivalent chromium.

PubMed

Haldar, Sudipto; Mondal, Souvik; Samanta, Saikat; Ghosh, Tapan Kumar

2009-11-01

The effects of supplemental chromium (Cr) as chromic chloride hexahydrate in incremental dose levels (0, 0.5, 1.0, and 1.5 mg/day for 240 days) on metabolism of nutrients and trace elements were determined in dwarf Bengal goats (Capra hircus, castrated males, average age 3 months, n = 24, initial mean body weight 6.4 +/- 0.22 kg). Live weight increased linearly (p < 0.05) with the level of supplemental Cr. Organic matter and crude protein digestibility, intake of total digestible nutrients, and retention of N (g/g N intake) increased (p < 0.05) in a dose-dependent linear manner. Serum cholesterol and tryacylglycerol concentrations changed inversely with the dose of supplemental Cr (p < 0.01). Supplemental Cr positively influenced retention of copper and iron (p < 0.05) causing linear increase (p < 0.01) in their serum concentrations. It was concluded that Cr supplementation may improve utilization of nutrients including the trace elements and may also elicit a hypolidemic effect in goats. However, further study with regards to optimization of dose is warranted.

Use of aspartame-based sweetener tablets in emergency dosimetry using EPR.

PubMed

Maghraby, A; Salama, E

2010-06-01

Accident dosimetry aims to evaluate the unplanned radiation doses delivered to individuals through one of the objects exist in the area of the accident. The gamma dose response of free radicals generated in irradiated aspartame tablets and its usability for emergency dosimetry was studied. EPR spectra of unirradiated and irradiated aspartame-based sweetener were recorded. Two signals arise after irradiating, S(1) at g (S(1)) = 2.00229 +/- 0.00097 and S(2) at g (S(2)) = 2.00262 +/- 0.00088. Some EPR parameters were studied for radiation-induced radicals in aspartame sweeteners tablets, such as the microwave saturation behaviour, the effect of magnetic field modulation amplitude on the peak-to-peak height and peak-to-peak line width for both of S(1) and S(2). Responses of S(1) and S(2) to different radiation doses were studied and resulted in linear relationships, radicals persistence curves were plotted over a 49-d storage period. It was found that Aspartame sweeteners tablets are useful in the range from 0.96 to 39.96 Gy. Radiation-induced radicals possess reasonable stability.

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.

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...

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

PubMed

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

2017-08-17

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

Predicting terrestrial gamma dose rate based on geological and soil information: case study of Perak state, Malaysia.

PubMed

Ramli, A T; Apriantoro, N H; Heryansyah, A; Basri, N A; Sanusi, M S M; Abu Hanifah, N Z H

2016-03-01

An extensive terrestrial gamma radiation dose (TGRD) rate survey has been conducted in Perak State, Peninsular Malaysia. The survey has been carried out taking into account geological and soil information, involving 2930 in situ surveys. Based on geological and soil information collected during TGRD rate measurements, TGRD rates have been predicted in Perak State using a statistical regression analysis which would be helpful to focus surveys in areas that are difficult to access. An equation was formulated according to a linear relationship between TGRD rates, geological contexts and soil types. The comparison of in situ measurements and predicted TGRD dose rates was tabulated and showed good agreement with the linear regression equation. The TGRD rates in the study area ranged from 38 nGy h(-1) to 1039 nGy h(-1) with a mean value of 224  ±  138 nGy h(-1). This value is higher than the world average as reported in UNSCEAR 2000. The TGRD rates contribute an average dose rate of 1.37 mSv per year. An isodose map for the study area was developed using a Kriging method based on predicted and in situ TGRD rate values.

[Dose-Response Dependences for Frequency of RET/PTC Gene Rearrangements in Papillary Thyroid Carcinoma after Irradiation. Simple Pooling Analysis of Molecular Epidemiological Data].

PubMed

Koterov, A N; Ushenkova, L N; Biryukov, A P

2016-01-01

On the basis of all possible publications on the theme included in the previously formed base of sources on molecular epidemiology of RET/PTC rearrangements in thyroid papillary carcinoma a pooled analysis ("simple pooling data") on determination of the dose-effect dependences for RET/PTC frequency in radiogenic carcinomas of various irradiated groups was performed. (They are groups subjected to radiotherapeutic exposure, residents near the Chernobyl nuclear power plant (CNPP) and victims of nuclear bombing). The tendency to Pearson linear correlation (r = 0.746; p = 0.148) between the frequency of RET/PTC and the estimated dose on thyroid in the regions affected by the CNPP accident was revealed. But this tendency was recognized to be random owing to abnormally low values of the indicator for the most contaminated Gomel region. The method tentatively called "case-control" showed reliable differences in thyroid dose values for carcinomas with RET/PTC and without those. The versatility of changes was found: the lack of RET/PTC for radiotherapeutic impacts was associated with higher doses, whereas in case of the CNPP accident and for nuclear bombing victims it was the opposite. Probably, in the first case the "cellular cleaning" phenomenon after exposure to very high doses took place. Search of direct Pearson correlations between average/median thyroid doses on groups and RET/PTC frequency in carcinomas of these groups showed a high reliability for the dose-effect dependences- at the continuous dose scale (for RET/PTC in total and RET/PTC1 respectively: r = 0.830; p = 0.002 and r = 0.906; p = 0.0003); while there was no significant correlation received for RET/PTC3. When using the weighting least square regression analysis (proceeding from the number of carcinomas in samples), the specified regularities remained. Attempts to influence the strength of correlation by exception ofthe data of all the samples connected with the accident on the CNPP did not significantly reduce the strength of associations for RET/PTC in total. On the basis of ordinal scale doses (background, "low" (0.1 Gy), "middle" (0.1-1 Gy) and "large" (1-10 Gy) dose) also found was a significant correlation (Spearman) with the dose for the frequency RET/PTC in total (r = 0.736; p = 0.0098), but for certain types of rearrangements the results were reverse to the previous analysis (the effect was significant only for the RET/PTC3: r = 0.731; p = 0.024). The linear dose-response trends of the Cochrane-Armitage-test for the frequency of RET/PTC in total, RET/PTC1 and RET/PTC3 depending on the dose to the thyroid in the ordinal scale were registered (p, respectively: < 0.0001 < 0.0001 and 0.007). Thus; after more than 20 years of the molecular and epidemiological research of RET/PTC in thyroid radiogenic carcinomas the comprehensive evidence of the dose-effect dependence existence indicating a real relationship between the studied parameters and a radiation factor was obtained for the first time.

Dose and Effect Thresholds for Early Key Events in a Mode of ...

EPA Pesticide Factsheets

ABSTRACT Strategies for predicting adverse health outcomes of environmental chemicals are centered on early key events in toxicity pathways. However, quantitative relationships between early molecular changes in a given pathway and later health effects are often poorly defined. The goal of this study was to evaluate short-term key event indicators using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor-alpha (PPARα). Male B6C3F1 mice were exposed for 7 days to di(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), and n-butyl benzyl phthalate (BBP), which vary in PPARα activity and liver tumorigenicity. Each phthalate increased expression of select PPARα target genes at 7 days, while only DEHP significantly increased liver cell proliferation labeling index (LI). Transcriptional benchmark dose (BMDT) estimates for dose-related genomic markers stratified phthalates according to hypothetical tumorigenic potencies, unlike BMDs for non-genomic endpoints (liver weights or proliferation). The 7-day BMDT values for Acot1 as a surrogate measure for PPARα activation were 29, 370, and 676 mg/kg-d for DEHP, DNOP, and BBP, respectively, distinguishing DEHP (liver tumor BMD of 35 mg/kg-d) from non-tumorigenic DNOP and BBP. Effect thresholds were generated using linear regression of DEHP effects at 7 days and 2-year tumor incidence values to anchor early response molec

Isobio software: biological dose distribution and biological dose volume histogram from physical dose conversion using linear-quadratic-linear model.

PubMed

Jaikuna, Tanwiwat; Khadsiri, Phatchareewan; Chawapun, Nisa; Saekho, Suwit; Tharavichitkul, Ekkasit

2017-02-01

To develop an in-house software program that is able to calculate and generate the biological dose distribution and biological dose volume histogram by physical dose conversion using the linear-quadratic-linear (LQL) model. The Isobio software was developed using MATLAB version 2014b to calculate and generate the biological dose distribution and biological dose volume histograms. The physical dose from each voxel in treatment planning was extracted through Computational Environment for Radiotherapy Research (CERR), and the accuracy was verified by the differentiation between the dose volume histogram from CERR and the treatment planning system. An equivalent dose in 2 Gy fraction (EQD 2 ) was calculated using biological effective dose (BED) based on the LQL model. The software calculation and the manual calculation were compared for EQD 2 verification with pair t -test statistical analysis using IBM SPSS Statistics version 22 (64-bit). Two and three-dimensional biological dose distribution and biological dose volume histogram were displayed correctly by the Isobio software. Different physical doses were found between CERR and treatment planning system (TPS) in Oncentra, with 3.33% in high-risk clinical target volume (HR-CTV) determined by D 90% , 0.56% in the bladder, 1.74% in the rectum when determined by D 2cc , and less than 1% in Pinnacle. The difference in the EQD 2 between the software calculation and the manual calculation was not significantly different with 0.00% at p -values 0.820, 0.095, and 0.593 for external beam radiation therapy (EBRT) and 0.240, 0.320, and 0.849 for brachytherapy (BT) in HR-CTV, bladder, and rectum, respectively. The Isobio software is a feasible tool to generate the biological dose distribution and biological dose volume histogram for treatment plan evaluation in both EBRT and BT.

A new method for calculation of the chlorine demand of natural and treated waters.

PubMed

Warton, Ben; Heitz, Anna; Joll, Cynthia; Kagi, Robert

2006-08-01

Conventional methods of calculating chlorine demand are dose dependent, making intercomparison of samples difficult, especially in cases where the samples contain substantially different concentrations of dissolved organic carbon (DOC), or other chlorine-consuming species. Using the method presented here, the values obtained for chlorine demand are normalised, allowing valid comparison of chlorine demand between samples, independent of the chlorine dose. Since the method is not dose dependent, samples with substantially differing water quality characteristics can be reliably compared. In our method, we dosed separate aliquots of a water sample with different chlorine concentrations, and periodically measured the residual chlorine concentrations in these subsamples. The chlorine decay data obtained in this way were then fitted to first-order exponential decay functions, corresponding to short-term demand (0-4h) and long-term demand (4-168 h). From the derived decay functions, the residual concentrations at a given time within the experimental time window were calculated and plotted against the corresponding initial chlorine concentrations, giving a linear relationship. From this linear function, it was then possible to determine the residual chlorine concentration for any initial concentration (i.e. dose). Thus, using this method, the initial chlorine dose required to give any residual chlorine concentration can be calculated for any time within the experimental time window, from a single set of experimental data.

Cognitive function and dialysis adequacy: no clear relationship.

PubMed

Giang, Lena M; Weiner, Daniel E; Agganis, Brian T; Scott, Tammy; Sorensen, Eric P; Tighiouart, Hocine; Sarnak, Mark J

2011-01-01

Cognitive impairment is common in hemodialysis patients and may be impacted by multiple patient and treatment characteristics. The impact of dialysis dose on cognitive function remains uncertain, particularly in the current era of increased dialysis dose and flux. We explored the cross-sectional relationship between dialysis adequacy and cognitive function in a cohort of maintenance hemodialysis patients. Adequacy was defined as the average of the 3 most proximate single pool Kt/V assessments. A detailed neurocognitive battery was administered during the 1st hour of dialysis. Multivariable linear regression models were adjusted for age, sex, education, race and other clinical and demographic characteristics. Among 273 patients who underwent cognitive testing, the mean (SD) age was 63 (17) years and the median dialysis duration was 13 months, 47% were woman, 22% were African American, and 48% had diabetes. The mean (SD) Kt/V was 1.51 (0.24). In univariate, parsimonious and multivariable models, there were no significant relationships between decreased cognitive function and lower Kt/V. In contrast to several older studies, there is no association between lower Kt/V and worse cognitive performance in the current era of increased dialysis dose. Future studies should address the longitudinal relationship between adequacy of dialysis and cognitive function to confirm these findings. Copyright © 2010 S. Karger AG, Basel.

Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects.

PubMed

van Gerven, J M; Roncari, G; Schoemaker, R C; Massarella, J; Keesmaat, P; Kooyman, H; Heizmann, P; Zell, M; Cohen, A F; Dingemanse, J

1997-11-01

This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48-8684, compared with midazolam, in healthy subjects during first administration to man. The study was double-blind and five-way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48-8684 was infused in doses of 0.1-0.3-1 mg in the first group, and 1-3-10 mg in the second, with different infusion rates (expressed as mg min(-1)) among doses. Midazolam was infused at 0.1 mg(-1) kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. Ro 48-8684 caused dose-dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48-8684 were larger than of midazolam (337+/-114 vs 50+/-121 and 2.4+/-0.5 vs 0.47+/-0.11 l min(-1), resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48-8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48-8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48-8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration-effect-relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48-8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4-fold (range 1.6, 7.3 times), with doses of Ro 48-8684 increasing from 1 to 10 mg. The metabolite Ro 61-2466 had a longer half-life than the parent compound Ro 48-8684. The influence of this metabolite during prolonged administration should be further investigated. These results show that Ro 48-8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48-8684 with repeated administration of rising doses due to as yet undetermined factors.

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. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Pre- and postnatal bisphenol A treatment results in persistent deficits in the sexual behavior of male rats, but not female rats, in adulthood.

PubMed

Jones, Bryan A; Shimell, Jordan J; Watson, Neil V

2011-02-01

Perinatal administration of the endocrine disruptor bisphenol A (BPA) reportedly inhibits the sexual behavior of sexually naïve adult male rats. In order to evaluate the effects of BPA administration during early development on later reproductive behavior, we administered one of five doses of bisphenol A daily to pregnant female rats throughout gestation and lactation, and quantified the appetitive and consummatory sexual behaviors of the resultant male and female offspring over multiple sexual encounters in adulthood. Males receiving low dose perinatal BPA (50 μg/kg bw/day) showed persistent deficits in sexual behavior in adulthood. Males receiving the highest dose (5 mg/kg bw/day), however, were indistinguishable from controls with respect to consummatory sexual behaviors but showed decreased latencies to engage in those behaviors when sexually naïve, with significant non-linear, or U-shaped, dose-response relationships observed on the first and last day of testing. Adult female sexual behavior was not affected by early BPA administration at any dose tested. These results are consistent with previous reports that BPA exerts behavioral effects especially at low doses, and further indicates that BPA can cause lasting impairment of sexual behavior in males, but does not alter the normal development of female appetitive or consummatory sexual behaviors. To our knowledge, this is the first report indicating that adult sexual performance is impaired in sexually experienced animals following perinatal exposure to bisphenol A. Copyright © 2010 Elsevier Inc. All rights reserved.

Technical report. The application of probability-generating functions to linear-quadratic radiation survival curves.

PubMed

Kendal, W S

2000-04-01

To illustrate how probability-generating functions (PGFs) can be employed to derive a simple probabilistic model for clonogenic survival after exposure to ionizing irradiation. Both repairable and irreparable radiation damage to DNA were assumed to occur by independent (Poisson) processes, at intensities proportional to the irradiation dose. Also, repairable damage was assumed to be either repaired or further (lethally) injured according to a third (Bernoulli) process, with the probability of lethal conversion being directly proportional to dose. Using the algebra of PGFs, these three processes were combined to yield a composite PGF that described the distribution of lethal DNA lesions in irradiated cells. The composite PGF characterized a Poisson distribution with mean, chiD+betaD2, where D was dose and alpha and beta were radiobiological constants. This distribution yielded the conventional linear-quadratic survival equation. To test the composite model, the derived distribution was used to predict the frequencies of multiple chromosomal aberrations in irradiated human lymphocytes. The predictions agreed well with observation. This probabilistic model was consistent with single-hit mechanisms, but it was not consistent with binary misrepair mechanisms. A stochastic model for radiation survival has been constructed from elementary PGFs that exactly yields the linear-quadratic relationship. This approach can be used to investigate other simple probabilistic survival models.

Dietary cadmium and benzo(a)pyrene increased intestinal metallothionein expression in the fish Fundulus heteroclitus

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

Roesijadi, Guritno; Rezvankhah, Saeid; Perez-Matus, Alejandro

2008-10-17

To test the effect of dietary exposure to cadmium and benzo(a)pyrene on induction of metallothionein mRNA in the Fundulus heteroclitus, fish were individually fed a pelletized gel food containing cadmium, benzo(a)pyrene, or a combination of the two over a period of seven days, then analyzed for relative levels of metallothionein mRNA in the intestine, liver, and gill using real-time RT-qPCR. An initial experiment with only cadmium exposure showed an apparent 10-fold induction in the intestine, but no induction in liver or gill. Ingestion of contaminated pellets varied in individual fish, and because it was possible to monitor individual ingestion ratesmore » with our method, individual cadmium doses were estimated from the amount of ingested cadmium. When the levels of metallothionein mRNA were related to the dose to each fish, a linear dose-response relationship was observed for the intestine, but not the other organs, which showed no induction. In a second experiment, dose was controlled by placing the entire daily cadmium dose into a single contaminated pellet that was fed first (thereby, effectively controlling the effect of variable ingestion rates), and the interaction between cadmium and benzo(a)pyrene was also investigated. The intestine was again the primary organ for metallothionein induction by cadmium, with a 20-fold increase in metallothionein mRNA over control levels. When benzo(a)pyrene was administered together with cadmium, induction of metallothionein was potentiated by the presence of benzo(a)pyrene, with the main effect seen in the intestine, where already high levels of induction by cadmium alone increased by 1.74-fold when benzo(a)pyrene was present.« less

Caffeine Increases the Linearity of the Visual BOLD Response

PubMed Central

Liu, Thomas T.; Liau, Joy

2009-01-01

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

Statistical considerations in the analysis of data from replicated bioassays

USDA-ARS?s Scientific Manuscript database

Multiple-dose bioassay is generally the preferred method for characterizing virulence of insect pathogens. Linear regression of probit mortality on log dose enables estimation of LD50/LC50 and slope, the latter having substantial effect on LD90/95s (doses of considerable interest in pest management)...

Total Ionizing Dose Effects in Bipolar and BiCMOS Devices

NASA Technical Reports Server (NTRS)

Chavez, Rosa M.; Rax, Bernard G.; Scheick, Leif Z.; Johnston, Allan H.

2005-01-01

This paper describes total ionizing dose (TID) test results performed at JPL. Bipolar and BiCMOS device samples were tested exhibiting significant degradation and failures at different irradiation levels. Linear technology which is susceptible to low-dose dependency (ELDRS) exhibited greater damage for devices tested under zero bias condition.

A cut-off of daily sedentary time and all-cause mortality in adults: a meta-regression analysis involving more than 1 million participants.

PubMed

Ku, Po-Wen; Steptoe, Andrew; Liao, Yung; Hsueh, Ming-Chun; Chen, Li-Jung

2018-05-25

The appropriate limit to the amount of daily sedentary time (ST) required to minimize mortality is uncertain. This meta-analysis aimed to quantify the dose-response association between daily ST and all-cause mortality and to explore the cut-off point above which health is impaired in adults aged 18-64 years old. We also examined whether there are differences between studies using self-report ST and those with device-based ST. Prospective cohort studies providing effect estimates of daily ST (exposure) on all-cause mortality (outcome) were identified via MEDLINE, PubMed, Scopus, Web of Science, and Google Scholar databases until January 2018. Dose-response relationships between daily ST and all-cause mortality were examined using random-effects meta-regression models. Based on the pooled data for more than 1 million participants from 19 studies, the results showed a log-linear dose-response association between daily ST and all-cause mortality. Overall, more time spent in sedentary behaviors is associated with increased mortality risks. However, the method of measuring ST moderated the association between daily ST and mortality risk (p < 0.05). The cut-off of daily ST in studies with self-report ST was 7 h/day in comparison with 9 h/day for those with device-based ST. Higher amounts of daily ST are log-linearly associated with increased risk of all-cause mortality in adults. On the basis of a limited number of studies using device-based measures, the findings suggest that it may be appropriate to encourage adults to engage in less sedentary behaviors, with fewer than 9 h a day being relevant for all-cause mortality.

Age as a factor in the responsiveness of the organism to the disruption of cognitive performance by exposure to HZE particles differing in LET

USDA-ARS?s Scientific Manuscript database

INTRODUCTION Previous research has shown that the dose of 56Fe particles needed to disrupt cognitive performance decreases as the age at which the subject is irradiated increases. It remains to be established whether a similar relationship would be observed with lower Linear energy transfer (LET) ...

Cell killing mode of liblomycin (NK313), a novel dose-survival relationship different from bleomycins.

PubMed

Kuramochi-Motegi, A; Kuramochi, H; Takahashi, K; Takeuchi, T

1991-04-01

Liblomycin (NK313) is a novel derivative of bleomycin (BLM) and peplomycin (PEP). The cell kill kinetics of NK313 on rat ascites hepatoma AH66 were compared with those of PEP. NK313 induced intracellular DNA cleavage and arrested cell cycle progression at the G2 phase similarly to PEP. The cytocidal effect of NK313, however, was found to be different from that of PEP as described below: 1) The dose-survival curve for cells exposed to PEP for 1 hour was upward concave, whereas in case of NK313, the survival curve was linear. PEP was more effective to AH66 than NK313 at lower concentration, but at higher concentration, NK313 was much more effective. 2) The time-survival curve for cells treated with either NK313 or PEP was biphasic. NK313, however, did not induce temporary resistance of AH66 cells to NK313, while PEP induced resistance to PEP. 3) NK313 was effective against the cells which became temporarily resistant to PEP by the treatment of PEP. These differences suggest that NK313 might be of value to treat PEP-insensitive tumor cells.

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

NASA Technical Reports Server (NTRS)

Chappelli, Lori J.; Cucinotta, Francis A.

2010-01-01

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

Numerical evaluation of the skull for human neuromodulation with transcranial focused ultrasound

NASA Astrophysics Data System (ADS)

Mueller, Jerel K.; Ai, Leo; Bansal, Priya; Legon, Wynn

2017-12-01

Objective. Transcranial focused ultrasound is an emerging field for human non-invasive neuromodulation, but its dosing in humans is difficult to know due to the skull. The objective of the present study was to establish modeling methods based on medical images to assess skull differences between individuals on the wave propagation of ultrasound. Approach. Computational models of transcranial focused ultrasound were constructed using CT and MR scans to solve for intracranial pressure. We explored the effect of including the skull base in models, different transducer placements on the head, and differences between 250 kHz or 500 kHz acoustic frequency for both female and male models. We further tested these features using linear, nonlinear, and elastic simulations. To better understand inter-subject skull thickness and composition effects we evaluated the intracranial pressure maps between twelve individuals at two different skull sites. Main results. Nonlinear acoustic simulations resulted in virtually identical intracranial pressure maps with linear acoustic simulations. Elastic simulations showed a difference in max pressures and full width half maximum volumes of 15% at most. Ultrasound at an acoustic frequency of 250 kHz resulted in the creation of more prominent intracranial standing waves compared to 500 kHz. Finally, across twelve model human skulls, a significant linear relationship to characterize intracranial pressure maps was not found. Significance. Despite its appeal, an inherent problem with the use of a noninvasive transcranial ultrasound method is the difficulty of knowing intracranial effects because of the skull. Here we develop detailed computational models derived from medical images of individuals to simulate the propagation of neuromodulatory ultrasound across the skull and solve for intracranial pressure maps. These methods allow for a much better understanding of the intracranial effects of ultrasound for an individual in order to ensure proper targeting and more tightly control dosing.

Main clinical, therapeutic and technical factors related to patient's maximum skin dose in interventional cardiology procedures

PubMed Central

Journy, N; Sinno-Tellier, S; Maccia, C; Le Tertre, A; Pirard, P; Pagès, P; Eilstein, D; Donadieu, J; Bar, O

2012-01-01

Objective The study aimed to characterise the factors related to the X-ray dose delivered to the patient's skin during interventional cardiology procedures. Methods We studied 177 coronary angiographies (CAs) and/or percutaneous transluminal coronary angioplasties (PTCAs) carried out in a French clinic on the same radiography table. The clinical and therapeutic characteristics, and the technical parameters of the procedures, were collected. The dose area product (DAP) and the maximum skin dose (MSD) were measured by an ionisation chamber (Diamentor; Philips, Amsterdam, The Netherlands) and radiosensitive film (Gafchromic; International Specialty Products Advanced Materials Group, Wayne, NJ). Multivariate analyses were used to assess the effects of the factors of interest on dose. Results The mean MSD and DAP were respectively 389 mGy and 65 Gy cm−2 for CAs, and 916 mGy and 69 Gy cm−2 for PTCAs. For 8% of the procedures, the MSD exceeded 2 Gy. Although a linear relationship between the MSD and the DAP was observed for CAs (r=0.93), a simple extrapolation of such a model to PTCAs would lead to an inadequate assessment of the risk, especially for the highest dose values. For PTCAs, the body mass index, the therapeutic complexity, the fluoroscopy time and the number of cine frames were independent explanatory factors of the MSD, whoever the practitioner was. Moreover, the effect of technical factors such as collimation, cinematography settings and X-ray tube orientations on the DAP was shown. Conclusion Optimising the technical options for interventional procedures and training staff on radiation protection might notably reduce the dose and ultimately avoid patient skin lesions. PMID:22457404

The dose-effect relationship of baclofen in alcohol dependence: A 1-year cohort study.

PubMed

Pignon, Baptiste; Labreuche, Julien; Auffret, Marine; Gautier, Sophie; Deheul, Sylvie; Simioni, Nicolas; Cottencin, Olivier; Bordet, Régis; Duhamel, Alain; Rolland, Benjamin

2017-07-01

Our aim is to study the relationship between dose of baclofen and effectiveness in alcohol dependence. Two hundred two patients with alcohol dependence, who received baclofen treatment for drinking reduction, were followed up for 1 year. For each patient-month of treatment, the maximum daily dose of baclofen (DDB) and average weekly alcohol consumption (AWAC) were calculated. We defined a favorable drinking outcome as an AWAC under 200 g/w for at least 2 consecutive months. We divided the DDB of each patient-month into 3 categories (low dose: <90 mg/d, medium dose: 90-150 mg/d, and high dose: >150 mg/d) and investigated the relationship between reaching a favorable outcome and the concurrent DDB category in a time-varying Cox regression analysis. Hazard ratios (HRs) were adjusted based on age, sex, and initial AWAC. One hundred forty subjects were followed during at least 1 month. Of these patients, 58 (41%) had a favorable drinking outcome. In comparison to low dose, medium dose was associated with a decreased rate of favorable drinking outcome (HR = 0.42; 95% CI [0.20, 0.88]), whereas no difference was found with high dose (HR = 1.31; 95% CI [0.65, 2.64]). The relationship between dose of baclofen and favorable drinking outcome was U-shaped, that is, was increased at low and high doses compared to medium doses. Copyright © 2017 John Wiley & Sons, Ltd.

Analysis of linear energy transfers and quality factors of charged particles produced by spontaneous fission neutrons from 252Cf and 244Pu in the human body.

PubMed

Endo, Akira; Sato, Tatsuhiko

2013-04-01

Absorbed doses, linear energy transfers (LETs) and quality factors of secondary charged particles in organs and tissues, generated via the interactions of the spontaneous fission neutrons from (252)Cf and (244)Pu within the human body, were studied using the Particle and Heavy Ion Transport Code System (PHITS) coupled with the ICRP Reference Phantom. Both the absorbed doses and the quality factors in target organs generally decrease with increasing distance from the source organ. The analysis of LET distributions of secondary charged particles led to the identification of the relationship between LET spectra and target-source organ locations. A comparison between human body-averaged mean quality factors and fluence-averaged radiation weighting factors showed that the current numerical conventions for the radiation weighting factors of neutrons, updated in ICRP103, and the quality factors for internal exposure are valid.

Inhibition effects of perfluoroalkyl acids on progesterone production in mLTC-1.

PubMed

Zhao, Wei; Cui, Ruina; Wang, Jianshe; Dai, Jiayin

2017-06-01

Perfluoroalkyl substances (PFASs) are a class of fluorine substituted carboxylic acid, sulfonic acid and alcohol, structurally similar to their corresponding parent compounds. Previous study demonstrated the potential endocrine disruption and reproductive toxicity of perfluorooctane sulfonic acid and perfluorooctanoic acid, two dominant PFASs in animals and humans. We explored the relationship between eleven perfluoroalkyl acids (PFAAs) with different carbon chain length and their ability to inhibit progesterone production in mouse Leydig tumor cells (mLTC-1). We found an obvious dose-response relationship between progesterone inhibition rate and PFAA exposure concentration in mLTC-1. The relative inhibition rate of progesterone by PFAAs was linearly related to the carbon chain length and molar refractivity of PFAAs. Mitochondrial membrane potential (MMP) decreased after PFAA exposure at the half-maximal inhibitory effect concentration (IC 50 ) of progesterone production in mLTC-1, while the reactive oxygen species (ROS) content increased significantly. These results imply that the inhibition effect of PFAAs on progesterone production might be due, in part, to ROS damage and the decrease in MMP in mLTC-1. Copyright © 2016. Published by Elsevier B.V.

THE UKRAINIAN-AMERICAN STUDY OF LEUKEMIA AND RELATED DISORDERS AMONG CHORNOBYL CLEANUP WORKERS FROM UKRAINE: III. RADIATION RISKS

PubMed Central

Romanenko, A.Ye.; Finch, S.; Hatch, M.; Lubin, J.; Bebeshko, V.G.; Bazyka, D.A.; Gudzenko, N.; Dyagil, I.S.; Reiss, R.; Bouville, A.; Chumak, V.V.; Trotsiuk, N.K.; Babkina, N.G.; Belayev, Y.; Masnyk; Ron, E.; Howe, G.R.; Zablotska, L.B.

2010-01-01

Leukemia is one of the cancers most susceptible to induction by ionizing radiation, but the effects of lower doses delivered over time have not been adequately quantified. Following the Chornobyl (Chernobyl) accident in Ukraine in April 1986, several hundred thousand workers who were involved in cleaning up the site and its surroundings received fractionated exposure, primarily from external gamma radiation. To increase our understanding of the role of protracted low-dose radiation exposure in the etiology of leukemia, we conducted a nested case-control study of leukemia in a cohort of cleanup workers identified from the Chornobyl State Registry of Ukraine. The analysis is based on 71 cases of histologically confirmed leukemia diagnosed in 1986–2000 and 501 age- and residence-matched controls selected from the same cohort. Study subjects or their proxies were interviewed about their cleanup activities and other relevant factors. Individual bone marrow radiation doses were estimated by the RADRUE dose reconstruction method (mean dose=76.4 (SD=213.4) milligray (mGy)). We used conditional logistic regression to estimate leukemia risks. The excess relative risk of total leukemia was 3.44 per Gy (95% confidence interval 0.47–9.78, p<0.01). The dose-response was linear and did not significantly differ by calendar period of first work in the 30-km Chornobyl zone, duration or type of work. We found a similar dose-response relationship for chronic and non-chronic lymphocytic leukemia. PMID:19138038

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

NASA Technical Reports Server (NTRS)

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

2000-01-01

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

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

PubMed

Reichard, John F; Haber, Lynne T

2016-12-01

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

New stomatal flux-based critical levels for ozone effects on vegetation

NASA Astrophysics Data System (ADS)

Mills, Gina; Pleijel, Håkan; Braun, Sabine; Büker, Patrick; Bermejo, Victoria; Calvo, Esperanza; Danielsson, Helena; Emberson, Lisa; Fernández, Ignacio González; Grünhage, Ludger; Harmens, Harry; Hayes, Felicity; Karlsson, Per-Erik; Simpson, David

2011-09-01

The critical levels for ozone effects on vegetation have been reviewed and revised by the LRTAP Convention. Eight new or revised critical levels based on the accumulated stomatal flux of ozone (POD Y, the Phytotoxic Ozone Dose above a threshold flux of Y nmol m -2 PLA s -1, where PLA is the projected leaf area) have been agreed. For each receptor, data were combined from experiments conducted under naturally fluctuating environmental conditions in 2-4 countries, resulting in linear dose-response relationships with response variables specific to each receptor ( r2 = 0.49-0.87, p < 0.001 for all). For crops, critical levels were derived for effects on wheat (grain yield, grain mass, and protein yield), potato (tuber yield) and tomato (fruit yield). For forest trees, critical levels were derived for effects on changes in annual increment in whole tree biomass for beech and birch, and Norway spruce. For (semi-)natural vegetation, the critical level for effects on productive and high conservation value perennial grasslands was based on effects on important component species of the genus Trifolium (clover species). These critical levels can be used to assess protection against the damaging effects of ozone on food security, important ecosystem services provided by forest trees (roundwood production, C sequestration, soil stability and flood prevention) and the vitality of pasture.

Dose Titration Algorithm Tuning (DTAT) should supersede ‘the’ Maximum Tolerated Dose (MTD) in oncology dose-finding trials

PubMed Central

Norris, David C.

2017-01-01

Background. Absent adaptive, individualized dose-finding in early-phase oncology trials, subsequent ‘confirmatory’ Phase III trials risk suboptimal dosing, with resulting loss of statistical power and reduced probability of technical success for the investigational therapy. While progress has been made toward explicitly adaptive dose-finding and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of ‘the’ maximum tolerated dose (MTD). The purpose of this paper is to demonstrate concretely how the aim of early-phase trials might be conceived, not as ‘dose-finding’, but as dose titration algorithm (DTA)-finding. Methods. A Phase I dosing study is simulated, for a notional cytotoxic chemotherapy drug, with neutropenia constituting the critical dose-limiting toxicity. The drug’s population pharmacokinetics and myelosuppression dynamics are simulated using published parameter estimates for docetaxel. The amenability of this model to linearization is explored empirically. The properties of a simple DTA targeting neutrophil nadir of 500 cells/mm 3 using a Newton-Raphson heuristic are explored through simulation in 25 simulated study subjects. Results. Individual-level myelosuppression dynamics in the simulation model approximately linearize under simple transformations of neutrophil concentration and drug dose. The simulated dose titration exhibits largely satisfactory convergence, with great variance in individualized optimal dosing. Some titration courses exhibit overshooting. Conclusions. The large inter-individual variability in simulated optimal dosing underscores the need to replace ‘the’ MTD with an individualized concept of MTD i . To illustrate this principle, the simplest possible DTA capable of realizing such a concept is demonstrated. Qualitative phenomena observed in this demonstration support discussion of the notion of tuning such algorithms. Although here illustrated specifically in relation to cytotoxic chemotherapy, the DTAT principle appears similarly applicable to Phase I studies of cancer immunotherapy and molecularly targeted agents. PMID:28663782

Benzodiazepines impair smooth pursuit eye movements.

PubMed Central

Bittencourt, P R; Wade, P; Smith, A T; Richens, A

1983-01-01

Five healthy male volunteers received single oral doses of 10 mg diazepam, 20 mg temazepam and placebo, in a double-blind, randomised fashion. Smooth pursuit eye movement velocity and serum benzodiazepine concentration were measured before and after at 0.5,1,1.5,2,3,4,6,9 and 12 h after administration of the treatments. Significant decrease in smooth pursuit eye movement velocity as compared to placebo was observed between 0.5-2 h after temazepam, and between 1-2 h after diazepam. Smooth pursuit eye movement velocity was log-linearly correlated with serum temazepam and diazepam concentration. The results demonstrate the relationship between serum benzodiazepine concentration and its effect on an objective measure of oculomotor performance. PMID:6133544

The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 1. The Russell-Muller debate

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

Calabrese, Edward J., E-mail: edwardc@schoolph.uma

This paper assesses the discovery of the dose-rate effect in radiation genetics and how it challenged fundamental tenets of the linear non-threshold (LNT) dose response model, including the assumptions that all mutational damage is cumulative and irreversible and that the dose-response is linear at low doses. Newly uncovered historical information also describes how a key 1964 report by the International Commission for Radiological Protection (ICRP) addressed the effects of dose rate in the assessment of genetic risk. This unique story involves assessments by two leading radiation geneticists, Hermann J. Muller and William L. Russell, who independently argued that the report'smore » Genetic Summary Section on dose rate was incorrect while simultaneously offering vastly different views as to what the report's summary should have contained. This paper reveals occurrences of scientific disagreements, how conflicts were resolved, which view(s) prevailed and why. During this process the Nobel Laureate, Muller, provided incorrect information to the ICRP in what appears to have been an attempt to manipulate the decision-making process and to prevent the dose-rate concept from being adopted into risk assessment practices. - Highlights: • The discovery of radiation dose rate challenged the scientific basis of LNT. • Radiation dose rate occurred in males and females. • The dose rate concept supported a threshold dose-response for radiation.« less

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...

SU-G-BRB-14: Uncertainty of Radiochromic Film Based Relative Dose Measurements

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

Devic, S; Tomic, N; DeBlois, F

2016-06-15

Purpose: Due to inherently non-linear dose response, measurement of relative dose distribution with radiochromic film requires measurement of absolute dose using a calibration curve following previously established reference dosimetry protocol. On the other hand, a functional form that converts the inherently non-linear dose response curve of the radiochromic film dosimetry system into linear one has been proposed recently [Devic et al, Med. Phys. 39 4850–4857 (2012)]. However, there is a question what would be the uncertainty of such measured relative dose. Methods: If the relative dose distribution is determined going through the reference dosimetry system (conversion of the response bymore » using calibration curve into absolute dose) the total uncertainty of such determined relative dose will be calculated by summing in quadrature total uncertainties of doses measured at a given and at the reference point. On the other hand, if the relative dose is determined using linearization method, the new response variable is calculated as ζ=a(netOD)n/ln(netOD). In this case, the total uncertainty in relative dose will be calculated by summing in quadrature uncertainties for a new response function (σζ) for a given and the reference point. Results: Except at very low doses, where the measurement uncertainty dominates, the total relative dose uncertainty is less than 1% for the linear response method as compared to almost 2% uncertainty level for the reference dosimetry method. The result is not surprising having in mind that the total uncertainty of the reference dose method is dominated by the fitting uncertainty, which is mitigated in the case of linearization method. Conclusion: Linearization of the radiochromic film dose response provides a convenient and a more precise method for relative dose measurements as it does not require reference dosimetry and creation of calibration curve. However, the linearity of the newly introduced function must be verified. Dave Lewis is inventor and runs a consulting company for radiochromic films.« less

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

PubMed

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

2017-01-17

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

Simultaneous population pharmacokinetic modelling of plasma and intracellular PBMC miltefosine concentrations in New World cutaneous leishmaniasis and exploration of exposure-response relationships.

PubMed

Kip, Anke E; Castro, María Del Mar; Gomez, Maria Adelaida; Cossio, Alexandra; Schellens, Jan H M; Beijnen, Jos H; Saravia, Nancy Gore; Dorlo, Thomas P C

2018-05-10

Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days. A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

PubMed

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation. Food did not seem to have any clinically relevant impact on pharmacokinetic parameters. Bazedoxifene had an estimated oral bioavailability of ~6% and was safe and well tolerated in the range of doses evaluated. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

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

Rafat, M; Bazalova, M; Palma, B

Purpose: To characterize the effect of very rapid dose delivery as compared to conventional therapeutic irradiation times on clonogenic cell survival. Methods: We used a Varian Trilogy linear accelerator to deliver doses up to 10 Gy using a 6 MV SRS photon beam. We irradiated four cancer cell lines in times ranging from 30 sec to 30 min. We also used a Varian TrueBeam linear accelerator to deliver 9 MeV electrons at 10 Gy in 10 s to 30 min to determine the effect of irradiation time on cell survival. We then evaluated the effect of using 60 and 120more » MeV electrons on cell survival using the Next Linear Collider Test Accelerator (NLCTA) beam line at the SLAC National Accelerator Laboratory. During irradiation, adherent cells were maintained at 37oC with 20%O2/5%CO2. Clonogenic assays were completed following irradiation to determine changes in cell survival due to dose delivery time and beam quality, and the survival data were fitted with the linear-quadratic model. Results: Cell lines varied in radiosensitivity, ranging from two to four logs of cell kill at 10 Gy for both conventional and very rapid irradiation. Delivering radiation in shorter times decreased survival in all cell lines. Log differences in cell kill ranged from 0.2 to 0.7 at 10 Gy for the short compared to the long irradiation time. Cell kill differences between short and long irradiations were more pronounced as doses increased for all cell lines. Conclusion: Our findings suggest that shortening delivery of therapeutic radiation doses to less than 1 minute may improve tumor cell kill. This study demonstrates the potential advantage of technologies under development to deliver stereotactic ablative radiation doses very rapidly. Bill Loo and Peter Maxim have received Honoraria from Varian and Research Support from Varian and RaySearch.« less

Radiation induced chemical changes of phenolic compounds in strawberries

NASA Astrophysics Data System (ADS)

Breitfellner, F.; Solar, S.; Sontag, G.

2003-06-01

In unirradiated strawberries four phenolic acids (gallic acid, p-coumaric acid, caffeic acid and 4-hydroxybenzoic acid), the flavonoids (+)-catechin, (-)-epicatechin and glycosides from kaempferol and quercetin were determined by reversed phase chromatography with diode array detection. Characteristic linear dose/concentration relationships were found for 4-hydroxybenzoic acid and two unidentified compounds. One of them may be usable as marker to prove an irradiation treatment.

An approach to assessing stochastic radiogenic risk in medical imaging

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

Wolbarst, Anthony B.; Hendee, William R.; Department of Radiology, Mayo Clinic, Rochester, Minnesota 55901

2011-12-15

Purpose: This letter suggests a formalism, the medical effective dose (MED), that is suitable for assessing stochastic radiogenic risks in diagnostic medical procedures. Methods: The MED is derived from radiobiological and probabilistic first principals, including: (1) The independence of radiation-induced biological effects in neighboring voxels at low doses; (2) the linear no-threshold assumption for stochastic radiation injury (although other dose-response relationships could be incorporated, instead); (3) the best human radiation dose-response data currently available; and (4) the built-in possibility that the carcinogenic risk to an irradiated organ may depend on its volume. The MED involves a dose-risk summation over irradiatedmore » voxels at high spatial resolution; it reduces to the traditional effective dose when every organ is irradiated uniformly and when the dependence of risk on organ volumes is ignored. Standard relative-risk tissue weighting factors can be used with the MED approach until more refined data become available. Results: The MED is intended for clinical and phantom dosimetry, and it provides an estimate of overall relative radiogenic stochastic risk for any given dose distribution. A result of the MED derivation is that the stochastic risk may increase with the volume of tissue (i.e., the number of cells) irradiated, a feature that can be activated when forthcoming radiobiological research warrants it. In this regard, the MED resembles neither the standard effective dose (E) nor the CT dose index (CTDI), but it is somewhat like the CT dose-length product (DLP). Conclusions: The MED is a novel, probabilistically and biologically based means of estimating stochastic-risk-weighted doses associated with medical imaging. Built in, ab initio, is the ability to link radiogenic risk to organ volume and other clinical factors. It is straightforward to implement when medical dose distributions are available, provided that one is content, for the time being, to accept the relative tissue weighting factors published by the International Commission of Radiological Protection (ICRP). It requires no new radiobiological data and avoids major problems encountered by the E, CTDI, and CT-E formalisms. It makes possible relative inter-patient dosimetry, and also realistic intercomparisons of stochastic risks from different protocols that yield images of comparable quality.« less

Quantification of the Glycemic Response to Microdoses of Subcutaneous Glucagon at Varying Insulin Levels

PubMed Central

Castle, Jessica R.; Bakhtiani, Parkash A.; Haidar, Ahmad; Branigan, Deborah L.; Breen, Matthew; Ward, W. Kenneth

2014-01-01

OBJECTIVE Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. RESEARCH DESIGN AND METHODS Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. RESULTS At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P < 0.001). CONCLUSIONS EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas. PMID:25139882

Quantification of the glycemic response to microdoses of subcutaneous glucagon at varying insulin levels.

PubMed

El Youssef, Joseph; Castle, Jessica R; Bakhtiani, Parkash A; Haidar, Ahmad; Branigan, Deborah L; Breen, Matthew; Ward, W Kenneth

2014-11-01

Glucagon delivery in closed-loop control of type 1 diabetes is effective in minimizing hypoglycemia. However, high insulin concentration lowers the hyperglycemic effect of glucagon, and small doses of glucagon in this setting are ineffective. There are no studies clearly defining the relationship between insulin levels, subcutaneous glucagon, and blood glucose. Using a euglycemic clamp technique in 11 subjects with type 1 diabetes, we examined endogenous glucose production (EGP) of glucagon (25, 75, 125, and 175 μg) at three insulin infusion rates (0.016, 0.032, and 0.05 units/kg/h) in a randomized, crossover study. Infused 6,6-dideuterated glucose was measured every 10 min, and EGP was determined using a validated glucoregulatory model. Area under the curve (AUC) for glucose production was the primary outcome, estimated over 60 min. At low insulin levels, EGP rose proportionately with glucagon dose, from 5 ± 68 to 112 ± 152 mg/kg (P = 0.038 linear trend), whereas at high levels, there was no increase in glucose output (19 ± 53 to 26 ± 38 mg/kg, P = NS). Peak glucagon serum levels and AUC correlated well with dose (r2 = 0.63, P < 0.001), as did insulin levels with insulin infusion rates (r2 = 0.59, P < 0.001). EGP increases steeply with glucagon doses between 25 and 175 μg at lower insulin infusion rates. However, high insulin infusion rates prevent these doses of glucagon from significantly increasing glucose output and may reduce glucagon effectiveness in preventing hypoglycemia when used in the artificial pancreas. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

The infection rate of Daphnia magna by Pasteuria ramosa conforms with the mass-action principle.

PubMed

Regoes, R R; Hottinger, J W; Sygnarski, L; Ebert, D

2003-10-01

In simple epidemiological models that describe the interaction between hosts with their parasites, the infection process is commonly assumed to be governed by the law of mass action, i.e. it is assumed that the infection rate depends linearly on the densities of the host and the parasite. The mass-action assumption, however, can be problematic if certain aspects of the host-parasite interaction are very pronounced, such as spatial compartmentalization, host immunity which may protect from infection with low doses, or host heterogeneity with regard to susceptibility to infection. As deviations from a mass-action infection rate have consequences for the dynamics of the host-parasite system, it is important to test for the appropriateness of the mass-action assumption in a given host-parasite system. In this paper, we examine the relationship between the infection rate and the parasite inoculum for the water flee Daphnia magna and its bacterial parasite Pasteuria ramosa. We measured the fraction of infected hosts after exposure to 14 different doses of the parasite. We find that the observed relationship between the fraction of infected hosts and the parasite dose is largely consistent with an infection process governed by the mass-action principle. However, we have evidence for a subtle but significant deviation from a simple mass-action infection model, which can be explained either by some antagonistic effects of the parasite spores during the infection process, or by heterogeneity in the hosts' susceptibility with regard to infection.

Investigation of the response characteristics of OSL albedo neutron dosimeters in a 241AmBe reference neutron field

NASA Astrophysics Data System (ADS)

Liamsuwan, T.; Wonglee, S.; Channuie, J.; Esoa, J.; Monthonwattana, S.

2017-06-01

The objective of this work was to systematically investigate the response characteristics of optically stimulated luminescence Albedo neutron (OSLN) dosimeters to ensure reliable personal dosimetry service provided by Thailand Institute of Nuclear Technology (TINT). Several batches of InLight® OSLN dosimeters were irradiated in a reference neutron field generated by the in-house 241AmBe neutron irradiator. The OSL signals were typically measured 24 hours after irradiation using the InLight® Auto 200 Reader. Based on known values of delivered neutron dose equivalent, the reading correction factor to be used by the reader was evaluated. Subsequently, batch homogeneity, dose linearity, lower limit of detection and fading of the OSLN dosimeters were examined. Batch homogeneity was evaluated to be 0.12 ± 0.05. The neutron dose response exhibited a linear relationship (R2=0.9974) within the detectable neutron dose equivalent range under test (0.4-3 mSv). For this neutron field, the lower limit of detection was between 0.2 and 0.4 mSv. Over different post-irradiation storage times of up to 180 days, the readings fluctuated within ±5%. Personal dosimetry based on the investigated OSLN dosimeter is considered to be reliable under similar neutron exposure conditions, i.e. similar neutron energy spectra and dose equivalent values.

The comet moment as a measure of DNA damage in the comet assay.

PubMed

Kent, C R; Eady, J J; Ross, G M; Steel, G G

1995-06-01

The development of rapid assays of radiation-induced DNA damage requires the definition of reliable parameters for the evaluation of dose-response relationships to compare with cellular endpoints. We have used the single-cell gel electrophoresis (SCGE) or 'comet' assay to measure DNA damage in individual cells after irradiation. Both the alkaline and neutral protocols were used. In both cases, DNA was stained with ethidium bromide and viewed using a fluorescence microscope at 516-560 nm. Images of comets were stored as 512 x 512 pixel images using OPTIMAS, an image analysis software package. Using this software we tested various parameters for measuring DNA damage. We have developed a method of analysis that rigorously conforms to the mathematical definition of the moment of inertia of a plane figure. This parameter does not require the identification of separate head and tail regions, but rather calculates a moment of the whole comet image. We have termed this parameter 'comet moment'. This method is simple to calculate and can be performed using most image analysis software packages that support macro facilities. In experiments on CHO-K1 cells, tail length was found to increase linearly with dose, but plateaued at higher doses. Comet moment also increased linearly with dose, but over a larger dose range than tail length and had no tendency to plateau.

Total target volume is a better predictor of whole brain dose from gamma stereotactic radiosurgery than the number, shape, or location of the lesions

PubMed Central

Narayanasamy, Ganesh; Smith, Adam; Van Meter, Emily; McGarry, Ronald; Molloy, Janelle A.

2013-01-01

Purpose: To assess the hypothesis that the volume of whole brain that receives a certain dose level is primarily dependent on the treated volume rather than on the number, shape, or location of the lesions. This would help a physician validate the suitability of GammaKnife® based stereotactic radiosurgery (GKSR) prior to treatment. Methods: Simulation studies were performed to establish the hypothesis for both oblong and spherical shaped lesions of various numbers and sizes. Forty patients who underwent GKSR [mean age of 54 years (range 7–80), mean number of lesions of 2.5 (range 1–6), and mean lesion volume of 4.4 cm3 (range 0.02–22.2 cm3)] were also studied retrospectively. Following recommendations of QUANTEC, the volume of brain irradiated by the 12 Gy (VB12) isodose line was measured and a power-law based relation is proposed here for estimating VB12 from the known tumor volume and the prescription dose. Results: In the simulation study on oblong, spherical, and multiple lesions, the volume of brain irradiated by 50%, 10%, and 1% of maximum dose was found to have linear, linear, and exponentially increasing dependence on the volume of the treated region, respectively. In the retrospective study on 40 GKSR patients, a similar relationship was found to predict the brain dose with a Spearman correlation coefficient >0.9. In both the studies, the volume of brain irradiated by a certain dose level does not have a statistically significant relationship (p ≥ 0.05) with the number, shape, or position of the lesions. The measured VB12 agrees with calculation to within 1.7%. Conclusions: The results from the simulation and the retrospective clinical studies indicate that the volume of whole brain that receives a certain percentage of the maximum dose is primarily dependent on the treated volume and less on the number, shape, and location of the lesions. PMID:24007147

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

PubMed Central

Little, M.P.

2011-01-01

In this paper we review the evidence for departure from linearity for malignant and non-malignant disease and in the light of this assess likely mechanisms, and in particular the potential role for non-targeted effects. Excess cancer risks observed in the Japanese atomic bomb survivors and in many medically and occupationally exposed groups exposed at low or moderate doses are generally statistically compatible. For most cancer sites the dose–response in these groups is compatible with linearity over the range observed. The available data on biological mechanisms do not provide general support for the idea of a low dose threshold or hormesis. This large body of evidence does not suggest, indeed is not statistically compatible with, any very large threshold in dose for cancer, or with possible hormetic effects, and there is little evidence of the sorts of non-linearity in response implied by non-DNA-targeted effects. There are also excess risks of various types of non-malignant disease in the Japanese atomic bomb survivors and in other groups. In particular, elevated risks of cardiovascular disease, respiratory disease and digestive disease are observed in the A-bomb data. In contrast with cancer, there is much less consistency in the patterns of risk between the various exposed groups; for example, radiation-associated respiratory and digestive diseases have not been seen in these other (non-A-bomb) groups. Cardiovascular risks have been seen in many exposed populations, particularly in medically exposed groups, but in contrast with cancer there is much less consistency in risk between studies: risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well known (but unobserved) risk factors. In the absence of a convincing mechanistic explanation of epidemiological evidence that is, at present, less than persuasive, a cause-and-effect interpretation of the reported statistical associations for cardiovascular disease is unreliable but cannot be excluded. Inflammatory processes are the most likely mechanism by which radiation could modify the atherosclerotic disease process. If there is to be modification by low doses of ionizing radiation of cardiovascular disease through this mechanism, a role for non-DNA-targeted effects cannot be excluded. PMID:20105434

Bone cancer occurrence among beagles given 239Pu as young adults.

PubMed

Lloyd, R D; Taylor, G N; Angus, W; Bruenger, F W; Miller, S C

1993-01-01

The occurrence of skeletal malignancies has been documented among 234 young adult beagles given single intravenous injections of monomeric 239Pu citrate. Occurrence has also been documented among 132 comparable control group animals surviving the minimum latent time period of 2.79 y for radiation-induced bone cancer, who were maintained for lifespan observation. Injected amounts ranged from about 0.02-106 kBq kg-1 body mass with factors of 2 or 3 between dose levels. There were 84 radiographically apparent bone tumors in 76 plutonium-injected dogs and one tumor in a control group dog. Most of these were osteosarcomas except for seven chondrosarcomas, one liposarcoma, and one plasma cell myeloma of bone. The relationship between percent of dogs at any dose level with bone malignancy and average skeletal dose at the presumed time of tumor initiation of 1 y before death appeared to be linear below about 1.3 Gy average skeletal dose. The observed data can be approximated by the expression A = 0.76 + 75 D, where A = percent of dogs with bone cancer at any dose level, D = average skeletal dose in Gy (for doses up to 1.3 Gy) at tumor initiation, and 0.76 represents the percent tumor response in the control animals not given plutonium. Similar analysis of our corresponding data for beagles given 226Ra, excluding the two highest dose levels (approximately 100% occurrence), yielded the expression A = 0.76 + 4.7 D, where D = the average skeletal dose in Gy (for doses up to 20 Gy) at 1 y before death. The ratio of coefficients indicates the effectiveness for bone cancer induction of 239Pu relative to 226Ra, or [(75 +/- 22.5)(4.7 +/- 0.47)-1] = 16 +/- 5 for a single, brief intake of either nuclide into blood.

SU-F-T-130: [18F]-FDG Uptake Dose Response in Lung Correlates Linearly with Proton Therapy Dose

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

Kim, D; Titt, U; Mirkovic, D

2016-06-15

Purpose: Analysis of clinical outcomes in lung cancer patients treated with protons using 18F-FDG uptake in lung as a measure of dose response. Methods: A test case lung cancer patient was selected in an unbiased way. The test patient’s treatment planning and post treatment positron emission tomography (PET) were collected from picture archiving and communication system at the UT M.D. Anderson Cancer Center. Average computerized tomography scan was registered with post PET/CT through both rigid and deformable registrations for selected region of interest (ROI) via VelocityAI imaging informatics software. For the voxels in the ROI, a system that extracts themore » Standard Uptake Value (SUV) from PET was developed, and the corresponding relative biological effectiveness (RBE) weighted (both variable and constant) dose was computed using the Monte Carlo (MC) methods. The treatment planning system (TPS) dose was also obtained. Using histogram analysis, the voxel average normalized SUV vs. 3 different doses was obtained and linear regression fit was performed. Results: From the registration process, there were some regions that showed significant artifacts near the diaphragm and heart region, which yielded poor r-squared values when the linear regression fit was performed on normalized SUV vs. dose. Excluding these values, TPS fit yielded mean r-squared value of 0.79 (range 0.61–0.95), constant RBE fit yielded 0.79 (range 0.52–0.94), and variable RBE fit yielded 0.80 (range 0.52–0.94). Conclusion: A system that extracts SUV from PET to correlate between normalized SUV and various dose calculations was developed. A linear relation between normalized SUV and all three different doses was found.« less

Duloxetine Plasma Concentrations and Its Effectiveness in the Treatment of Nonorganic Chronic Pain in the Orofacial Region.

PubMed

Kobayashi, Yuka; Nagashima, Wataru; Tokura, Tatsuya; Yoshida, Keizo; Umemura, Eri; Miyauchi, Tomoya; Arao, Munetaka; Ito, Mikiko; Kimura, Hiroyuki; Kurita, Kenichi; Ozaki, Norio

The purpose of this study was to examine the relationship between the pain-relieving effects of duloxetine and its plasma concentrations in patients with burning mouth syndrome and atypical odontalgia characterized by chronic nonorganic pain in the orofacial region. We administered duloxetine to 77 patients diagnosed as having burning mouth syndrome or atypical odontalgia for 12 weeks. The initial dose of duloxetine was established as 20 mg/d and was increased to 40 mg/d after week 2. We evaluated pain using the visual analog scale and depressive symptoms using the Structured Interview Guide for the Hamilton Depression Rating Scale at weeks 0, 2, 4, 6, 8, 10, and 12 and measured plasma concentrations of duloxetine 12 weeks after the start of its administration. Visual analog scale scores were significantly lower 12 weeks after than at the start of the administration of duloxetine (paired t test, t = 6.65, P < 0.0001). We examined the relationship between the rate of decreases in visual analog scale scores and plasma concentrations of duloxetine. There was no significant linear regression or quadratic regression. Duloxetine significantly relieved pain in patients with chronic nonorganic pain in the orofacial region. However, no relationship was observed between its pain-relieving effects and plasma concentrations.

Effectiveness of sheltering in buildings and vehicles for plutonium

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

Engelmann, R.J.

1990-07-30

The purpose of this paper is to collect and present current knowledge relevant to the protection offered by sheltering against exposure to plutonium particles released to the atmosphere during accidents. For those many contaminants for which effects are linear with the airborne concentration, it is convenient to define a Dose Reduction Factor (DRF). In the past, the DRF has been defined as the ratio of the radiological dose that may be incurred within the shelter to that in the outdoors. As such, it includes the dose through shine from plumes aloft and from material deposited on the surface. For thismore » paper, which is concerned only with the inhalation pathway, the DRF is the ratio of the time-integrated concentration inside the shelter to that outdoors. It is important to note that the range over which effects are linear with concentration may be limited for many contaminants. Examples are when concentrations produce effects that are irreversible, or when concentrations are below effects threshold levels. 71 refs., 4 figs., 8 tabs.« less

Risk of a Second Malignant Neoplasm After Cancer in Childhood Treated With Radiotherapy: Correlation With the Integral Dose Restricted to the Irradiated Fields

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

Nguyen, France; Institut Gustave Roussy, Villejuif; Universite Paris XI, Villejuif

2008-03-01

Purpose: After successful treatment of cancers in childhood, the occurrence of second malignant neoplasm (SMN) came to the fore. Few studies have considered the relationship between the radiation dose received and the risk of developing an SMN. To take into account the heterogeneity of the dose distribution so as to evaluate the overall risk of an SMN after a childhood cancer, we therefore focused on the integral dose restricted to the irradiated fields. Methods and Materials: The study was performed in a cohort of 4,401 patients who were 3-year survivors of all types of childhood cancer treated between 1947 andmore » 1986 in France and Great Britain. For each patient, the integral dose was estimated for the volume inside the beam edges. Results: We found a significant dose-response relationship between the overall risk of an SMN and the estimated integral dose. The excess relative risk for each incremental unit of the integral dose was only 0.008 in a linear model and 0.017 when a negative exponential term was considered, when adjusted for chemotherapy. The risk of SMN occurrence was 2.6 times higher in the case of irradiation. However among patients who had received radiotherapy, only those who had received the highest integral dose actually had a higher risk. Conclusions: The integral dose in our study cannot be considered as a good predictor of later risks. However other studies with the same study design are obviously needed to evaluate the use of the integral dose as a tool for decision making concerning different radiotherapy techniques.« less

Lethal photosensitization of periodontal pathogens by a red-filtered Xenon lamp in vitro.

PubMed

Matevski, Donco; Weersink, Robert; Tenenbaum, Howard C; Wilson, Brian; Ellen, Richard P; Lépine, Guylaine

2003-08-01

The ability of Helium-Neon (He-Ne) laser irradiation of a photosensitizer to induce localized phototoxic effects that kill periodontal pathogens is well documented and is termed photodynamic therapy (PDT). We investigated the potential of a conventional light source (red-filtered Xenon lamp) to activate toluidine blue O (TBO) in vitro and determined in vitro model parameters that may be used in future in vivo trials. Porphyromonas gingivalis 381 was used as the primary test bacterium. Treatment with a 2.2 J/cm2 light dose and 50 micro g/ml TBO concentration resulted in a bacterial kill of 2.43 +/- 0.39 logs with the He-Ne laser control and 3.34 +/- 0.24 logs with the lamp, a near 10-fold increase (p = 0.028). Increases in light intensity produced significantly higher killing (p = 0.012) that plateaued at 25 mW/cm2. There was a linear relationship between light dose and bacterial killing (r2 = 0.916); as light dose was increased bacterial survival decreased. No such relationship was found for the drug concentrations tested. Addition of serum or blood at 50% v/v to the P. gingivalis suspension prior to irradiation diminished killing from approximately 5 logs to 3 logs at 10 J/cm2. When serum was washed off, killing returned to 5 logs for all species tested except Bacteroides forsythus (3.92 +/- 0.68 logs kill). The data indicate that PDT utilizing a conventional light source is at least as effective as laser-induced treatment in vitro. Furthermore, PDT achieves significant bactericidal activity in the presence of serum and blood when used with the set parameters of 10 J/cm2, 100 mW/cm2 and 12.5 micro g/ml TBO.

Coffee and caffeine intake and breast cancer risk: an updated dose-response meta-analysis of 37 published studies.

PubMed

Jiang, Wenjie; Wu, Yili; Jiang, Xiubo

2013-06-01

We conducted an updated meta-analysis to summarize the evidence from published studies regarding the association of coffee and caffeine intake with breast cancer risk. Pertinent studies were identified by a search of PubMed and by reviewing the reference lists of retrieved articles. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. 37 published articles, involving 59,018 breast cancer cases and 966,263 participants, were included in the meta-analysis. No significant association was found between breast cancer risk and coffee (RR=0.97, P=0.09), decaffeinated coffee (RR=0.98, P=0.55) and caffeine (RR=0.99, P=0.73), respectively. And the association was still not significant when combining coffee and caffeine (coffee/caffeine) (RR=0.97, P=0.09). However, an inverse association of coffee/caffeine with breast cancer risk was found for postmenopausal women (RR=0.94, P=0.02), and a strong and significant association of coffee with breast cancer risk was found for BRCA1 mutation carriers (RR=0.69, P<0.01). A linear dose-response relationship was found for breast cancer risk with coffee and caffeine, and the risk of breast cancer decreased by 2% (P=0.05) for every 2 cups/day increment in coffee intake, and 1% (P=0.52) for every 200mg/day increment in caffeine intake, respectively. Findings from this meta-analysis suggested that coffee/caffeine might be weakly associated with breast cancer risk for postmenopausal women, and the association for BRCA1 mutation carriers deserves further investigation. Copyright © 2013 Elsevier Inc. All rights reserved.

Investigation of electron beam irradiation effects on anti-nutritional factors, chemical composition and digestion kinetics of whole cottonseed, soybean and canola seeds

NASA Astrophysics Data System (ADS)

Ebrahimi-Mahmoudabad, S. R.; Taghinejad-Roudbaneh, M.

2011-12-01

This study was completed to determine effects of electron beam (EB) irradiation at doses of 15, 30 and 45 kGy on anti-nutritional factors, ruminal degradation and in vitro crude protein (CP) digestibility of whole cottonseed (WCS), soybean (SB) and canola seeds (CS). EB-irradiation eliminated completely ( P<0.001) phytic acid of WCS, SB and CS at a dose of 30 kGy. EB-irradiation decreased linearly ( P<0.001) the total glucosinolate content of CS. Trypsin inhibitor activity of 15, 30 and 45 kGy EB-irradiated SB was decreased by 19, 73 and 88%, respectively. Free gossypol content of WCS was reduced linearly ( P<0.001) by irradiation. EB-irradiation increased linearly ( P<0.001) CP digestibility of feeds. In conclusion, EB-irradiation was an effective processing method for improving the nutritive value of WCS, SB and CS.

Treatment of Amblyopia Using Personalized Dosing Strategies: Statistical Modelling and Clinical Implementation.

PubMed

Wallace, Michael P; Stewart, Catherine E; Moseley, Merrick J; Stephens, David A; Fielder, Alistair R

2016-12-01

To generate a statistical model for personalizing a patient's occlusion therapy regimen. Statistical modelling was undertaken on a combined data set of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS) and the Randomized Occlusion Treatment of Amblyopia Study (ROTAS). This exercise permits the calculation of future patients' total effective dose (TED)-that predicted to achieve their best attainable visual acuity. Daily patching regimens (hours/day) can be calculated from the TED. Occlusion data for 149 study participants with amblyopia (anisometropic in 50, strabismic in 43, and mixed in 56) were analyzed. Median time to best observed visual acuity was 63 days (25% and 75% quartiles; 28 and 91 days). Median visual acuity in the amblyopic eye at start of occlusion was 0.40 logMAR (quartiles 0.22 and 0.68 logMAR) and at end of occlusion was 0.12 (quartiles 0.025 and 0.32 logMAR). Median lower and upper estimates of TED were 120 hours (quartiles 34 and 242 hours), and 176 hours (quartiles 84 and 316 hours). The data suggest a piecewise linear relationship (P = 0.008) between patching dose-rate (hours/day) and TED with a single breakpoint estimated at 2.16 (standard error 0.51) hours/day, suggesting doses below 2.16 hours/day are less effective. We introduce the concept of TED of occlusion. Predictors for TED are visual acuity deficit, amblyopia type, and age at start of occlusion therapy. Dose-rates prescribed within the model range from 2.5 to 12 hours/day and can be revised dynamically throughout treatment in response to recorded patient compliance: a personalized dosing strategy.

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

PubMed

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

2018-03-19

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

Evaluating the relationship between leaf chlorophyll concentration and SPAD-502 chlorophyll meter readings.

PubMed

Uddling, J; Gelang-Alfredsson, J; Piikki, K; Pleijel, H

2007-01-01

Relationships between chlorophyll concentration ([chl]) and SPAD values were determined for birch, wheat, and potato. For all three species, the relationships were non-linear with an increasing slope with increasing SPAD. The relationships for birch and wheat were strong (r (2) approximately 0.9), while the potato relationship was comparatively weak (r (2) approximately 0.5). Birch and wheat had very similar relationships when the chlorophyll concentration was expressed per unit leaf area, but diverged when it was expressed per unit fresh weight. Furthermore, wheat showed similar SPAD-[chl] relationships for two different cultivars and during two different growing seasons. The curvilinear shape of the SPAD-[chl] relationships agreed well with the simulated effects of non-uniform chlorophyll distribution across the leaf surface and multiple scattering, causing deviations from linearity in the high and low SPAD range, respectively. The effect of non-uniformly distributed chlorophyll is likely to be more important in explaining the non-linearity in the empirical relationships, since the effect of scattering was predicted to be comparatively weak. The simulations were based on the algorithm for the calculation of SPAD-502 output values. We suggest that SPAD calibration curves should generally be parameterised as non-linear equations, and we hope that the relationships between [chl] and SPAD and the simulations of the present study can facilitate the interpretation of chlorophyll meter calibrations in relation to optical properties of leaves in future studies.

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

PubMed

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

2017-11-01

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

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

NASA Astrophysics Data System (ADS)

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

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

Improved delivery of fenoterol plus ipratropium bromide using Respimat compared with a conventional metered dose inhaler.

PubMed

Goldberg, J; Freund, E; Beckers, B; Hinzmann, R

2001-02-01

Asthma can be effectively treated by the use of bronchodilator therapies administered by inhalation. The objective of this study was to describe the dose-response relationship of combined doses of fenoterol hydrobromide (F) and ipratropium bromide (I) (F/I) delivered via Respimat, a soft mist inhaler, and to establish the Respimat dose which is as efficacious and as safe as the standard marketed dose of F/I (100/40 microg) which is delivered via a conventional metered dose inhaler (MDI). In a double-blind (within device) cross-over study with a balanced incomplete block design, 62 patients with stable bronchial asthma (mean forced expiratory volume in one second (FEV1) 63% predicted) were randomized at five study centres to receive five out of eight possible treatments: placebo, F/I 12.5/5, 25/10, 50/20, 100/40 or 200/80 microg delivered via Respimat; F/I 50/20 or 100/40 microg delivered via MDI. Pulmonary function results were based on the per-protocol dataset, comprising 47 patients. All F/I doses produced greater increases in FEV1 than placebo. A log-linear dose-response was obtained for the average increase in FEV1 up to 6 h (AUC0-6 h) and peak FEV1 across the dose range administered by Respimat. Statistically, therapeutic equivalence was not demonstrated between any F/I dose administered by Respimat compared with the MDI. However 12.5/5 and 25/10 microg F/I administered via Respimat were closest (slightly superior) to the F/I dose of 100/40 microg delivered via MDI. Pharmacokinetic data from 34 patients indicated a two-fold greater systemic availability of both drugs following inhalation by Respimat compared to MDI. In general, the active treatments were well tolerated and safe with regard to vital signs, electrocardiography, laboratory parameters and adverse events. In conclusion, combined administration of fenoterol hydrobromide and ipratropium bromide via Respimat, is as effective and as safe as higher doses given via a metered dose inhaler.

Radiation Dose-Response Relationships and Risk Assessment

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

Strom, Daniel J.

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 alsomore » the notion of dose rate. Usually, the dose is administered fairly acutely, in a single injection, pill, or swallow; a few puffs on a pipe; or a meal of eating or drinking. The same amount of intoxicants, medicine, or poisons administered over a week or month might have little or no observable effect. Thus, before the discovery of ionizing radiation in the late 19th century, toxicology ('the science of poisons') and pharmacology had deeply ingrained notions of dose-response relationships. This chapter demonstrates that the notion of a dose-response relationship for ionizing radiation is hopelessly simplistic from a scientific standpoint. While useful from a policy or regulatory standpoint, dose-response relationships cannot possibly convey enough information to describe the problem from a quantitative view of radiation biology, nor can they address societal values. Three sections of this chapter address the concepts, observations, and theories that contribute to the scientific input to the practice of managing risks from exposure to ionizing radiation. The presentation begins with irradiation regimes, followed by responses to high and low doses of ionizing radiation, and a discussion of how all of this can inform radiation risk management. The knowledge that is really needed for prediction of individual risk is presented. The chapter ends with conclusions and recommendations.« less

A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

PubMed Central

Stefani, Luciana Cadore; Muller, Suzana; Torres, Iraci L. S.; Razzolini, Bruna; Rozisky, Joanna R.; Fregni, Felipe; Markus, Regina; Caumo, Wolnei

2013-01-01

Background Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. Results Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 0.584 for PPTo). Conclusions The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre. PMID:25947930

Association Between Media Dose, Ad Tagging, and Changes in Web Traffic for a National Tobacco Education Campaign: A Market-Level Longitudinal Study.

PubMed

Shafer, Paul R; Davis, Kevin C; Patel, Deesha; Rodes, Robert; Beistle, Diane

2016-02-17

In 2012, the US Centers for Disease Control and Prevention (CDC) launched Tips From Former Smokers (Tips), the first federally funded national tobacco education campaign. In 2013, a follow-up Tips campaign aired on national cable television networks, radio, and other channels, with supporting digital advertising to drive traffic to the Tips campaign website. The objective of this study was to use geographic and temporal variability in 2013 Tips campaign television media doses and ad tagging to evaluate changes in traffic to the campaign website in response to specific doses of campaign media. Linear regression models were used to estimate the dose-response relationship between weekly market-level television gross rating points (GRPs) and weekly Web traffic to the Tips campaign website. This relationship was measured using unique visitors, total visits, and page views as outcomes. Ad GRP effects were estimated separately for ads tagged with the Tips campaign website URL and 1-800-QUIT-NOW. In the average media market, an increase of 100 television GRPs per week for ads tagged with the Tips campaign website URL was associated with an increase of 650 unique visitors (P<.001), 769 total visits (P<.001), and 1255 total page views (P<.001) per week. The associations between GRPs for ads tagged with 1-800-QUIT-NOW and each Web traffic measure were also statistically significant (P<.001), but smaller in magnitude. Based on these findings, we estimate that the 16-week 2013 Tips television campaign generated approximately 660,000 unique visitors, 900,000 total visits, and 1,390,000 page views for the Tips campaign website. These findings can help campaign planners forecast the likely impact of targeted advertising efforts on consumers' use of campaign-specific websites.

The relationship between the parenteral dose of fish oil supplementation and the variation of liver function tests in hospitalized adult patients.

PubMed

Badia-Tahull, Maria B; Leiva-Badosa, Elisabet; Jodar-Masanes, Ramon; Ramon-Torrell, Josep Maria; Llop-Talaveron, Josep

2015-07-02

Hepatic dysfunction is a complication associated with parenteral nutrition (PN). Our primary objective was to study the relationship between doses of intravenous fish oil (FO) emulsion in PN and the variation in the main liver function tests (LFTs) in hospitalized PN-treated adults. As a secondary objective, we studied the safety of FO administration. We conducted a retrospective study in adult patients receiving FO supplementation in PN. Demographic, nutritional and safety variables were collected. Variation of LFTs was defined as the difference between values just before the first administration of FO and values at the end of PN. A multiple linear regression was performed to study the association between PN-lipids (FO or vegetable) and the variation of each LFT; the following variables were used to adjust the effect of lipids: sepsis, length of stay in the intensive care unit and lipids dose. Student t-test was used to study safety variables. Data were analyzed using SPSS 19.0. Patients (53, median age 68 years (24-90); 62% men) with the principal diagnosis of digestive neoplasm (42%) received PN for a median of 19 (7-75) days. In the multivariate analysis, the amount of FO was related to a decrease in gamma-glutamyl transferase (GGT) (B = -2.23;CI95 % = -4.41/-0.05), a decrease in alkaline phosphatase (AP) (B = -1.23;CI95 % = -2.07/-0.37), and a decrease in alanine aminotransferase (ALT) (B = -0.82; CI95 % = -1.19/-0.44). No differences were found in safety variables. GGT, AP and ALT improved with FO PN-supplementation. Moreover, the improvement was greater when the doses of FO were higher. FO administration in PN is safe.

Assessing dose-response effects of national essential medicine policy in China: comparison of two methods for handling data with a stepped wedge-like design and hierarchical structure.

PubMed

Ren, Yan; Yang, Min; Li, Qian; Pan, Jay; Chen, Fei; Li, Xiaosong; Meng, Qun

2017-02-22

To introduce multilevel repeated measures (RM) models and compare them with multilevel difference-in-differences (DID) models in assessing the linear relationship between the length of the policy intervention period and healthcare outcomes (dose-response effect) for data from a stepped-wedge design with a hierarchical structure. The implementation of national essential medicine policy (NEMP) in China was a stepped-wedge-like design of five time points with a hierarchical structure. Using one key healthcare outcome from the national NEMP surveillance data as an example, we illustrate how a series of multilevel DID models and one multilevel RM model can be fitted to answer some research questions on policy effects. Routinely and annually collected national data on China from 2008 to 2012. 34 506 primary healthcare facilities in 2675 counties of 31 provinces. Agreement and differences in estimates of dose-response effect and variation in such effect between the two methods on the logarithm-transformed total number of outpatient visits per facility per year (LG-OPV). The estimated dose-response effect was approximately 0.015 according to four multilevel DID models and precisely 0.012 from one multilevel RM model. Both types of model estimated an increase in LG-OPV by 2.55 times from 2009 to 2012, but 2-4.3 times larger SEs of those estimates were found by the multilevel DID models. Similar estimates of mean effects of covariates and random effects of the average LG-OPV among all levels in the example dataset were obtained by both types of model. Significant variances in the dose-response among provinces, counties and facilities were estimated, and the 'lowest' or 'highest' units by their dose-response effects were pinpointed only by the multilevel RM model. For examining dose-response effect based on data from multiple time points with hierarchical structure and the stepped wedge-like designs, multilevel RM models are more efficient, convenient and informative than the multilevel DID models. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Modeling the dose effects of soybean oil in salad dressing on carotenoid and fat-soluble vitamin bioavailability in salad vegetables.

PubMed

White, Wendy S; Zhou, Yang; Crane, Agatha; Dixon, Philip; Quadt, Frits; Flendrig, Leonard M

2017-10-01

Background: Previously, we showed that vegetable oil is necessary for carotenoid absorption from salad vegetables. Research is needed to better define the dose effect and its interindividual variation for carotenoids and fat-soluble vitamins. Objective: The objective was to model the dose-response relation between the amount of soybean oil in salad dressing and the absorption of 1 ) carotenoids, phylloquinone, and tocopherols in salad vegetables and 2 ) retinyl palmitate formed from the provitamin A carotenoids. Design: Women ( n = 12) each consumed 5 vegetable salads with salad dressings containing 0, 2, 4, 8, or 32 g soybean oil. Blood was collected at selected time points. The outcome variables were the chylomicron carotenoid and fat-soluble vitamin area under the curve (AUC) and maximum content in the plasma chylomicron fraction ( C max ). The individual-specific and group-average dose-response relations were investigated by fitting linear mixed-effects random coefficient models. Results: Across the entire 0-32-g range, soybean oil was linearly related to the chylomicron AUC and C max values for α-carotene, lycopene, phylloquinone, and retinyl palmitate. Across 0-8 g of soybean oil, there was a linear increase in the chylomicron AUC and C max values for β-carotene. Across a more limited 0-4-g range of soybean oil, there were minor linear increases in the chylomicron AUC for lutein and α- and total tocopherol. Absorption of all carotenoids and fat-soluble vitamins was highest with 32 g oil ( P < 0.002). For 32 g oil, the interindividual rank order of the chylomicron AUCs was consistent across the carotenoids and fat-soluble vitamins ( P < 0.0001). Conclusions: Within the linear range, the average absorption of carotenoids and fat-soluble vitamins could be largely predicted by the soybean oil effect. However, the effect varied widely, and some individuals showed a negligible response. There was a global soybean oil effect such that those who absorbed more of one carotenoid and fat-soluble vitamin also tended to absorb more of the others. This trial was registered at clinicaltrials.gov as NCT02867488. © 2017 American Society for Nutrition.

A computational approach to the relationship between radiation induced double strand breaks and translocations

NASA Technical Reports Server (NTRS)

Holley, W. R.; Chatterjee, A.

1994-01-01

A theoretical framework is presented which provides a quantitative analysis of radiation induced translocations between the ab1 oncogene on CH9q34 and a breakpoint cluster region, bcr, on CH 22q11. Such translocations are associated frequently with chronic myelogenous leukemia. The theory is based on the assumption that incorrect or unfaithful rejoining of initial double strand breaks produced concurrently within the 200 kbp intron region upstream of the second abl exon, and the 16.5 kbp region between bcr exon 2 and exon 6 interact with each other, resulting in a fusion gene. for an x-ray dose of 100 Gy, there is good agreement between the theoretical estimate and the one available experimental result. The theory has been extended to provide dose response curves for these types of translocations. These curves are quadratic at low doses and become linear at high doses.

Cilazapril stability in the presence of hydrochlorothiazide in model mixtures and fixed dose combination.

PubMed

Paszun, Sylwia K; Stanisz, Beata J; Gradowska, Agnieszka

2013-01-01

The presented study aimed at the evaluation of hydrochlorothiazide influence on cilazapril stability in model mixture and fixed dose tablet formulation. The degradation of cilazapril in the presence of hydrochlorothiazide took place according to autocatalytic reaction kinetic mechanism, described mathematically by Prout-Tompkins equation. Hydrochlorothiazide coexistence with cilazapril in model mixture and fixed dose tablet without blister package accelerated cilazapril degradation in comparison with degradation of cilazapril substance. Values of reaction induction time shortened, while those of observed reaction rate constant increased. Increasing values of relative humidity and temperature have negative impact on cilazapril stability. Determined semi-logarithmic relationships: In k = f(RH) and Arrhenius ln k = f(1/T) are linear and are cilazapril stability predictive. The blister (OPA/Alu/PVC//Alu) package of fixed dose tablets, constitutes absolute moisture protection and prevent cilazapril--hydrochlorothiazide interaction occurrence.

Preliminary investigation of PAGAT polymer gel radionuclide dosimetry of Tc-99m

NASA Astrophysics Data System (ADS)

Braun, Kelly; Bailey, Dale; Hill, Brendan; Baldock, Clive

2009-05-01

PAGAT polymer gel was investigated as a suitable dosimeter materials for measuring absorbed dose from the unsealed source radionuclide Tc-99m. Differing amounts of Tc-99m over the range of 25-5000 MBq were introduced into a normoxic polymer gel mixture (PAGAT) in sealed nitrogen-filled P6 glass vials. After irradiation the gels were evaluated using MRI more than 48 hours after preparation to allow for radioactive decay. The dose delivered to the vial was also calculated empirically. R2 versus total activity curves were obtained over a number of experiments and these were used to evaluate the relationship between the amount of gel polymerization and the dose deposited by the radionuclide. A linear response up to 1000 MBq (corresponding to 20Gy) was displayed and was still behaving monotonically at 5000 MBq. Polymer gels offer the potential to measure radiation dose three-dimensionally using MRI.

Dynamics of Cellular Responses to Radiation

PubMed Central

Wodarz, Dominik; Sorace, Ron; Komarova, Natalia L.

2014-01-01

Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed. PMID:24722167

SU-F-T-115: Uncertainty in the Esophagus Dose in Retrospective Epidemiological Study of Breast Cancer Radiotherapy Patients

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

Mosher, E; Kim, S; Lee, C

Purpose: Epidemiological studies of second cancer risks in breast cancer radiotherapy patients often use generic patient anatomy to reconstruct normal tissue doses when CT images of patients are not available. To evaluate the uncertainty involved in the dosimetry approach, we evaluated the esophagus dose in five sample patients by simulating breast cancer treatments. Methods: We obtained the diagnostic CT images of five anonymized adult female patients in different Body Mass Index (BMI) categories (16– 36kg/m2) from National Institutes of Health Clinical Center. We contoured the esophagus on the CT images and imported them into a Treatment Planning System (TPS) tomore » create treatment plans and calculate esophagus doses. Esophagus dose was calculated once again via experimentally-validated Monte Carlo (MC) transport code, XVMC under the same geometries. We compared the esophagus doses from TPS and the MC method. We also investigated the degree of variation in the esophagus dose across the five patients and also the relationship between the patient characteristics and the esophagus doses. Results: Eclipse TPS using Analytical Anisotropic Algorithm (AAA) significantly underestimates the esophagus dose in breast cancer radiotherapy compared to MC. In the worst case, the esophagus dose from AAA was only 40% of the MC dose. The Coefficient of Variation across the patients was 48%. We found that the maximum esophagus dose was up to 2.7 times greater than the minimum. We finally observed linear relationship (Dose = 0.0218 × BMI – 0.1, R2=0.54) between patient’s BMI and the esophagus doses. Conclusion: We quantified the degree of uncertainty in the esophagus dose in five sample breast radiotherapy patients. The results of the study underscore the importance of individualized dose reconstruction for the study cohort to avoid misclassification in the risk analysis of second cancer. We are currently extending the number of patients up to 30.« less

The Effects of Multiple Linked Representations on Students' Learning of Linear Relationships

ERIC Educational Resources Information Center

Ozgun-Koca, S. Asli

2004-01-01

The focus of this study was on comparing three groups of Algebra I 9th-year students: one group using linked representation software, the second group using similar software but with semi-linked representations, and the control group in order to examine the effects on students' understanding of linear relationships. Data collection methods…

Visualization of risk of radiogenic second cancer in the organs and tissues of the human body.

PubMed

Zhang, Rui; Mirkovic, Dragan; Newhauser, Wayne D

2015-04-28

Radiogenic second cancer is a common late effect in long term cancer survivors. Currently there are few methods or tools available to visually evaluate the spatial distribution of risks of radiogenic late effects in the human body. We developed a risk visualization method and demonstrated it for radiogenic second cancers in tissues and organs of one patient treated with photon volumetric modulated arc therapy and one patient treated with proton craniospinal irradiation. Treatment plans were generated using radiotherapy treatment planning systems (TPS) and dose information was obtained from TPS. Linear non-threshold risk coefficients for organs at risk of second cancer incidence were taken from the Biological Effects of Ionization Radiation VII report. Alternative risk models including linear exponential model and linear plateau model were also examined. The predicted absolute lifetime risk distributions were visualized together with images of the patient anatomy. The risk distributions of second cancer for the two patients were visually presented. The risk distributions varied with tissue, dose, dose-risk model used, and the risk distribution could be similar to or very different from the dose distribution. Our method provides a convenient way to directly visualize and evaluate the risks of radiogenic second cancer in organs and tissues of the human body. In the future, visual assessment of risk distribution could be an influential determinant for treatment plan scoring.

Studies on the mechanism of endogenous pyrogen production. III. Human blood monocytes.

PubMed

Bodel, P

1974-10-01

The characteristics of pyrogen production and release by human blood monocytes were investigated. A dose-response assay of monocyte pyrogen in rabbits indicated a linear relationship of temperature elevation to dose of pyrogen at lower doses. Monocytes did not contain pyrogen when first obtained, nor did they release it spontaneously even after 5 days of incubation in vitro. Pyrogen production was apparent 4 h after stimulation by endotoxin or phagocytosis, and continued for 24 h or more. Puromycin, an inhibitor of protein synthesis, prevented both initiation and continuation of pyrogen production and release. Pyrogen-containing supernates retained most pyrogenic activity during overnight incubation even in the presence of activated cells. Lymphocytes appeared to play no role in either initiation or continuation of pyrogen production in these studies.

Dose-Response Analysis of the Effect of Carbidopa-Levodopa Extended-Release Capsules (IPX066) in Levodopa-Naive Patients With Parkinson Disease.

PubMed

Mao, Zhongping Lily; Modi, Nishit B

2016-08-01

Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Potassium measurements and risk of type 2 diabetes: a dose-response meta-analysis of prospective cohort studies

PubMed Central

Peng, Yang; Zhong, Guo-Chao; Mi, Qiao; Li, Kejia; Wang, Ao; Li, Ling; Liu, Hua; Yang, Gangyi

2017-01-01

Objective To clarify the relationship between serum, dietary, and urinary potassium and the risk of type 2 diabetes mellitus (T2DM). Materials and Methods We searched PubMed and EMBASE through January 6, 2017 for studies reporting risk estimates on the association of potassium measurements and the risk of T2DM. The summary risk estimates were obtained through a random-effects model. Dose-response analysis was conducted. Results Eight studies involving 5,053 cases and 119,993 individuals were included. A trend toward significance was found in the highest versus lowest meta-analysis on serum potassium and T2DM risk (RR = 0.79; 95% CI 0.60–1.04); moreover, the RR per 1 mmol/L increase in serum potassium was 0.83 (95% CI 0.73–0.95). A non-significant association of dietary potassium and T2DM risk was detected (RR for the highest versus lowest category: 0.93; 95% CI 0.81–1.06; RR for every 1000mg increase per day: 1.00, 95% CI 0.96–1.05). A similar non-significant association was found for urinary potassium and T2DM risk (RR for the highest versus lowest category: 0.83; 95% CI 0.39–1.75; RR per 10 mmol increase: 1.00; 95% CI 0.95–1.05). Evidence of a linear association between serum, dietary, and urinary potassium and the risk of T2DM was found (all Pnon-linearity > 0.05). Conclusions Low serum potassium increases the risk of T2DM in a linear dose-response manner; nevertheless, neither dietary potassium nor urinary potassium shows any association with the risk of T2DM. However, these findings should be interpreted with caution due to limited studies. PMID:29246005

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

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

Appelt, Ane L., E-mail: ane.lindegaard.appelt@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

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 themore » 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.« less

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

2016-07-08

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

SU-F-T-124: Radiation Biological Equivalent Presentations OfLEM-1 and MKM Approaches in the Carbon-Ion Radiotherapy

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

Hsi, W; Jiang, G; Sheng, Y

Purpose: To study the correlations of the radiation biological equivalent doses (BED) along depth and lateral distance between LEM-1 and MKM approaches. Methods: In NIRS-MKM (Microdosimetric Kinetic Model) approach, the prescribed BED, referred as C-Eq, doses aims to present the relative biological effectiveness (RBE) for different energies of carbon-ions on a fixed 10% survival value of HCG cell with respect to convention X-ray. Instead of a fixed 10% survival, the BED doses of LEM-1 (Local Effect Model) approach, referred as X-Eq, aims to present the RBE over the whole survival curve of chordoma-like cell with alpha/beta ratio of 2.0. Themore » relationship of physical doses as a function of C-Eq and X-Eq doses were investigated along depth and lateral distance for various sizes of cubic targets in water irradiated by carbon-ions. Results: At the center of each cubic target, the trends between physical and C-Eq or X-Eq doses can be described by a linear and 2nd order polynomial functions, respectively. Using fit functions can then calculate a scaling factor between C-Eq and X-Eq doses to have similar physical doses. With equalized C-Eq and X-Eq doses at the depth of target center, over- and under-estimated X-Eq to C-Eq are seen for depths before and after the target center, respectively. Near the distal edge along depth, sharp rising of RBE value is observed for X-Eq, but sharp dropping of RBE value is observed for C-Eq. For lateral locations near and just outside 50% dose level, sharp raising of RBE value is also seen for X-Eq, while only minor increasing with fast dropping for C-Eq. Conclusion: An analytical function to model the differences between the CEq and X-Eq doses along depth and lateral distance need to further investigated to explain varied clinic outcome of specific cancers using two different approaches to calculated BED doses.« less

Compendium of Current Total Ionizing Dose and Displacement Damage Results from NASA Goddard Space Flight Center and NASA Electronic Parts and Packaging Program

NASA Technical Reports Server (NTRS)

Topper, Alyson D.; Campola, Michael J.; Chen, Dakai; Casey, Megan C.; Yau, Ka-Yen; Cochran, Donna J.; Label, Kenneth A.; Ladbury, Raymond L.; Mondy, Timothy K.; O'Bryan, Martha V.;

The pharmacokinetics of oxypurinol in people with gout

PubMed Central

Stocker, Sophie L; McLachlan, Andrew J; Savic, Radojka M; Kirkpatrick, Carl M; Graham, Garry G; Williams, Kenneth M; Day, Richard O

2012-01-01

AIMS Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations. METHODS Non-linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information. RESULTS A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/Fm) from 65% to 29%. CL/Fm for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h−1, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines. CONCLUSIONS In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment. PMID:22300439

BENCHMARK DOSE TECHNICAL GUIDANCE DOCUMENT ...

EPA Pesticide Factsheets

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

Method for simulating dose reduction in digital mammography using the Anscombe transformation.

PubMed

Borges, Lucas R; Oliveira, Helder C R de; Nunes, Polyana F; Bakic, Predrag R; Maidment, Andrew D A; Vieira, Marcelo A C

2016-06-01

This work proposes an accurate method for simulating dose reduction in digital mammography starting from a clinical image acquired with a standard dose. The method developed in this work consists of scaling a mammogram acquired at the standard radiation dose and adding signal-dependent noise. The algorithm accounts for specific issues relevant in digital mammography images, such as anisotropic noise, spatial variations in pixel gain, and the effect of dose reduction on the detective quantum efficiency. The scaling process takes into account the linearity of the system and the offset of the detector elements. The inserted noise is obtained by acquiring images of a flat-field phantom at the standard radiation dose and at the simulated dose. Using the Anscombe transformation, a relationship is created between the calculated noise mask and the scaled image, resulting in a clinical mammogram with the same noise and gray level characteristics as an image acquired at the lower-radiation dose. The performance of the proposed algorithm was validated using real images acquired with an anthropomorphic breast phantom at four different doses, with five exposures for each dose and 256 nonoverlapping ROIs extracted from each image and with uniform images. The authors simulated lower-dose images and compared these with the real images. The authors evaluated the similarity between the normalized noise power spectrum (NNPS) and power spectrum (PS) of simulated images and real images acquired with the same dose. The maximum relative error was less than 2.5% for every ROI. The added noise was also evaluated by measuring the local variance in the real and simulated images. The relative average error for the local variance was smaller than 1%. A new method is proposed for simulating dose reduction in clinical mammograms. In this method, the dependency between image noise and image signal is addressed using a novel application of the Anscombe transformation. NNPS, PS, and local noise metrics confirm that this method is capable of precisely simulating various dose reductions.

Inhaled corticosteroids in children with persistent asthma: effects on growth.

PubMed

Zhang, Linjie; Prietsch, Sílvio O M; Ducharme, Francine M

2014-07-17

Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014. Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

PubMed

Murphy, Patricia J; Yasuda, Sanae; Nakai, Kenya; Yoshinaga, Takashi; Hall, Nancy; Zhou, Meijian; Aluri, Jagadeesh; Rege, Bhaskar; Moline, Margaret; Ferry, Jim; Darpo, Borje

2017-01-01

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed C max was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies. © 2016, The American College of Clinical Pharmacology.

Low-dose computed tomography scans with automatic exposure control for patients of different ages undergoing cardiac PET/CT and SPECT/CT.

PubMed

Yang, Ching-Ching; Yang, Bang-Hung; Tu, Chun-Yuan; Wu, Tung-Hsin; Liu, Shu-Hsin

2017-06-01

This study aimed to evaluate the efficacy of automatic exposure control (AEC) in order to optimize low-dose computed tomography (CT) protocols for patients of different ages undergoing cardiac PET/CT and single-photon emission computed tomography/computed tomography (SPECT/CT). One PET/CT and one SPECT/CT were used to acquire CT images for four anthropomorphic phantoms representative of 1-year-old, 5-year-old and 10-year-old children and an adult. For the hybrid systems investigated in this study, the radiation dose and image quality of cardiac CT scans performed with AEC activated depend mainly on the selection of a predefined image quality index. Multiple linear regression methods were used to analyse image data from anthropomorphic phantom studies to investigate the effects of body size and predefined image quality index on CT radiation dose in cardiac PET/CT and SPECT/CT scans. The regression relationships have a coefficient of determination larger than 0.9, indicating a good fit to the data. According to the regression models, low-dose protocols using the AEC technique were optimized for patients of different ages. In comparison with the standard protocol with AEC activated for adult cardiac examinations used in our clinical routine practice, the optimized paediatric protocols in PET/CT allow 32.2, 63.7 and 79.2% CT dose reductions for anthropomorphic phantoms simulating 10-year-old, 5-year-old and 1-year-old children, respectively. The corresponding results for cardiac SPECT/CT are 8.4, 51.5 and 72.7%. AEC is a practical way to reduce CT radiation dose in cardiac PET/CT and SPECT/CT, but the AEC settings should be determined properly for optimal effect. Our results show that AEC does not eliminate the need for paediatric protocols and CT examinations using the AEC technique should be optimized for paediatric patients to reduce the radiation dose as low as reasonably achievable.

Effect of radiation protraction on BED in the case of large fraction dose

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

Kuperman, V. Y.

2013-08-15

Purpose: To investigate the effect of radiation protraction on biologically effective dose (BED) in the case when dose per fraction is significantly greater than the standard dose of 2 Gy.Methods: By using the modified linear-quadratic model with monoexponential repair, the authors investigate the effect of long treatment times combined with dose escalation.Results: The dependences of the protraction factor and the corresponding BED on fraction time were determined for different doses per fraction typical for stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). In the calculations, the authors consider changes in the BED to the normal tissue under the conditionmore » of fixed BED to the target.Conclusion: The obtained results demonstrate that simultaneous increase in fraction time and dose per fraction can be beneficial for SRS and SBRT because of the related decrease in BED to normal structures while BED to the target is fixed.« less

The Influence of Assay Design, Blinding, and Gymnema sylvestre on Sucrose Detection by Humans.

PubMed

Aleman, Max G; Marconi, Lauren J; Nguyen, Nam H; Park, Jae M; Patino, Maria M; Wang, Yuchi; Watkins, Celeste S; Shelley, Chris

2016-01-01

The detection and grading of tastes corresponding to different taste modalities can be tested in engaging laboratory sessions using students themselves as test subjects. This article describes a series of experiments in which data pertaining to the detection of salty and sweet tastes are obtained, and the ability of the herb Gymnema sylvestre to disrupt the detection of sucrose is quantified. The effects of blinding and different assay designs on EC50 estimation are also investigated. The data obtained allow for substantial data analysis, including non-linear regression using fixed and free parameters to quantify dose-response relationships, and the use of often under-utilized permutation tests to determine significant differences when the underlying data display heteroscedasticity.

The Influence of Assay Design, Blinding, and Gymnema sylvestre on Sucrose Detection by Humans

PubMed Central

Aleman, Max G.; Marconi, Lauren J.; Nguyen, Nam H.; Park, Jae M.; Patino, Maria M.; Wang, Yuchi; Watkins, Celeste S.; Shelley, Chris

2016-01-01

The detection and grading of tastes corresponding to different taste modalities can be tested in engaging laboratory sessions using students themselves as test subjects. This article describes a series of experiments in which data pertaining to the detection of salty and sweet tastes are obtained, and the ability of the herb Gymnema sylvestre to disrupt the detection of sucrose is quantified. The effects of blinding and different assay designs on EC50 estimation are also investigated. The data obtained allow for substantial data analysis, including non-linear regression using fixed and free parameters to quantify dose-response relationships, and the use of often under-utilized permutation tests to determine significant differences when the underlying data display heteroscedasticity. PMID:27980466

The influence of air humidity on an unsealed ionization chamber in a linear accelerator.

PubMed

Blad, B; Nilsson, P; Knöös, T

1996-11-01

The safe and accurate delivery of the prescribed absorbed dose is the central function of the dose monitoring and beam stabilization system in a medical linear accelerator. The absorbed dose delivered to the patient during radiotherapy is often monitored by a transmission ionization chamber. Therefore it is of utmost importance that the chamber behaves correctly. We have noticed that the sensitivity of an unsealed chamber in a Philips SL linear accelerator changes significantly, especially during and after the summer season. The reason for this is probably a corrosion effect of the conductive plates in the chamber due to the increased relative humidity during hot periods. We have found that the responses of the different ion chamber plates change with variations in air humidity and that they do not return to their original values when the air humidity is returned to ambient conditions.

Relationship between anthropometric factors, radiation exposure, and colon cancer incidence in the Life Span Study cohort of atomic bomb survivors.

PubMed

Semmens, Erin O; Kopecky, Kenneth J; Grant, Eric; Mathes, Robert W; Nishi, Nobuo; Sugiyama, Hiromi; Moriwaki, Hiroko; Sakata, Ritsu; Soda, Midori; Kasagi, Fumiyoshi; Yamada, Michiko; Fujiwara, Saeko; Akahoshi, Masazumi; Davis, Scott; Kodama, Kazunori; Li, Christopher I

2013-01-01

We examined colon cancer risk in atomic bomb survivors to investigate whether excess body weight after the bombings alters sensitivity to radiation effects. Of the 56,064 Japanese atomic bomb survivors with follow-up through 2002 with self-reported anthropometric data obtained from periodic mail surveys, 1,142 were diagnosed with colon cancer. We evaluated the influence of body mass index (BMI) and height on radiation-associated colon cancer risk using Poisson regression. We observed a similar linear dose-response relationship for the 56,064 subjects included in our analysis and the entire cohort of Japanese atomic bomb survivors [excess relative risk (ERR) per Gray (Gy) = 0.53, 95 % confidence interval (CI) 0.25-0.86]. Elevation in earliest reported BMI, BMI reported closest to colon cancer diagnosis, and time-varying BMI were associated with an elevated risk of colon cancer [relative risk (RR) per 5 kg/m(2) increase in BMI = 1.14, 95 % CI 1.03-1.26; RR = 1.16, 95 % CI 1.05-1.27; and RR = 1.15, 95 % CI 1.04-1.27, respectively]. Height was not significantly related to colon cancer risk. Inclusion of anthropometric variables in models had little impact on radiation risk estimates, and there was no evidence that sensitivity to the effect of radiation on colon cancer risk depended on BMI. Radiation exposure and BMI are both risk factors for colon cancer. BMI at various times after exposure to the atomic bombings does not significantly influence the relationship between radiation dose and colon cancer risk, suggesting that BMI and radiation impact colon cancer risk independently of each other.

Evaluation of systemic markers of inflammation in atomic-bomb survivors with special reference to radiation and age effects.

PubMed

Hayashi, Tomonori; Morishita, Yukari; Khattree, Ravindra; Misumi, Munechika; Sasaki, Keiko; Hayashi, Ikue; Yoshida, Kengo; Kajimura, Junko; Kyoizumi, Seishi; Imai, Kazue; Kusunoki, Yoichiro; Nakachi, Kei

2012-11-01

Past exposure to atomic bomb (A-bomb) radiation has exerted various long-lasting deleterious effects on the health of survivors. Some of these effects are seen even after >60 yr. In this study, we evaluated the subclinical inflammatory status of 442 A-bomb survivors, in terms of 8 inflammation-related cytokines or markers, comprised of plasma levels of reactive oxygen species (ROS), interleukin (IL)-6, tumor necrosis factor α (TNF-α), C-reactive protein (CRP), IL-4, IL-10, and immunoglobulins, and erythrocyte sedimentation rate (ESR). The effects of past radiation exposure and natural aging on these markers were individually assessed and compared. Next, to assess the biologically significant relationship between inflammation and radiation exposure or aging, which was masked by the interrelationship of those cytokines/markers, we used multivariate statistical analyses and evaluated the systemic markers of inflammation as scores being calculated by linear combinations of selected cytokines and markers. Our results indicate that a linear combination of ROS, IL-6, CRP, and ESR generated a score that was the most indicative of inflammation and revealed clear dependences on radiation dose and aging that were found to be statistically significant. The results suggest that collectively, radiation exposure, in conjunction with natural aging, may enhance the persistent inflammatory status of A-bomb survivors.

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

PubMed

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

2014-06-01

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

New pharmacokinetic methods. III. Two simple test for deep pool effect

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

Browne, T.R.; Greenblatt, D.J.; Schumacher, G.E.

1990-08-01

If a portion of administered drug is distributed into a deep peripheral compartment, the drug's actual elimination half-life during the terminal exponential phase of elimination may be longer than determined by a single dose study or a tracer dose study (deep pool effect). Two simple methods of testing for deep pool effect applicable to drugs with either linear or nonlinear pharmacokinetic properties are described. The methods are illustrated with stable isotope labeled (13C15N2) tracer dose studies of phenytoin. No significant (P less than .05) deep pool effect was detected.

Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone.

PubMed

Thygesen, Peter; Andersen, Henrik Sune; Behrens, Carsten; Fels, Johannes Josef; Nørskov-Lauritsen, Leif; Rischel, Christian; Johansen, Nils Langeland

2017-08-01

Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys. Pharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production. Pharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5-6h in rats, 10-12h in minipigs, and 17-20h in monkeys. Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3-4days in each dosing interval (p<0.001). The nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species. Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3-4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dosimetry investigation of MOSFET for clinical IMRT dose verification.

PubMed

Deshpande, Sudesh; Kumar, Rajesh; Ghadi, Yogesh; Neharu, R M; Kannan, V

2013-06-01

In IMRT, patient-specific dose verification is followed regularly at each centre. Simple and efficient dosimetry techniques play a very important role in routine clinical dosimetry QA. The MOSFET dosimeter offers several advantages over the conventional dosimeters such as its small detector size, immediate readout, immediate reuse, multiple point dose measurements. To use the MOSFET as routine clinical dosimetry system for pre-treatment dose verification in IMRT, a comprehensive set of experiments has been conducted, to investigate its linearity, reproducibility, dose rate effect and angular dependence for 6 MV x-ray beam. The MOSFETs shows a linear response with linearity coefficient of 0.992 for a dose range of 35 cGy to 427 cGy. The reproducibility of the MOSFET was measured by irradiating the MOSFET for ten consecutive irradiations in the dose range of 35 cGy to 427 cGy. The measured reproducibility of MOSFET was found to be within 4% up to 70 cGy and within 1.4% above 70 cGy. The dose rate effect on the MOSFET was investigated in the dose rate range 100 MU/min to 600 MU/min. The response of the MOSFET varies from -1.7% to 2.1%. The angular responses of the MOSFETs were measured at 10 degrees intervals from 90 to 270 degrees in an anticlockwise direction and normalized at gantry angle zero and it was found to be in the range of 0.98 ± 0.014 to 1.01 ± 0.014. The MOSFETs were calibrated in a phantom which was later used for IMRT verification. The measured calibration coefficients were found to be 1 mV/cGy and 2.995 mV/cGy in standard and high sensitivity mode respectively. The MOSFETs were used for pre-treatment dose verification in IMRT. Nine dosimeters were used for each patient to measure the dose in different plane. The average variation between calculated and measured dose at any location was within 3%. Dose verification using MOSFET and IMRT phantom was found to quick and efficient and well suited for a busy radiotherapy department.

Comparative dosimetric characterization for different types of detectors in high-energy electron beams

NASA Astrophysics Data System (ADS)

Lee, Chang Yeol; Kim, Woo Chul; Kim, Hun Jeong; Huh, Hyun Do; Park, Seungwoo; Choi, Sang Hyoun; Kim, Kum Bae; Min, Chul Kee; Kim, Seong Hoon; Shin, Dong Oh

2017-02-01

The purpose of this study is to perform a comparison and on analysis of measured dose factor values by using various commercially available high-energy electron beam detectors to measure dose profiles and energy property data. By analyzing the high-energy electron beam data from each detector, we determined the optimal detector for measuring electron beams in clinical applications. The dose linearity, dose-rate dependence, percentage depth dose, and dose profile of each detector were measured to evaluate the dosimetry characteristics of high-energy electron beams. The dose profile and the energy characteristics of high-energy electron beams were found to be different when measured by different detectors. Through comparison with other detectors based on the analyzed data, the microdiamond detector was found to have outstanding dose linearity, a low dose-rate dependency, and a small effective volume. Thus, this detector has outstanding spatial resolution and is the optimal detector for measuring electron beams. Radiation therapy results can be improved and related medical accidents can be prevented by using the procedure developed in this research in clinical practice for all beam detectors when measuring the electron beam dose.

Dose response relationship in anti-stress gene regulatory networks.

PubMed

Zhang, Qiang; Andersen, Melvin E

2007-03-02

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

The mechanism of dioxin toxicity: relationship to risk assessment.

PubMed Central

Birnbaum, L S

1994-01-01

Risk characterization involves hazard identification, determination of dose-response relationships, and exposure assessment. Improvement of the risk assessment process requires inclusion of the best available science. Recent findings in the area of dioxin toxicity have led to a major effort to reassess its risk. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as "dioxin," is the most toxic member of a class of related chemicals including the polyhalogenated dibenzo-p-dioxins, dibenzofurans, biphenyls, naphthalenes, azo- and azoxy-benzenes, whose toxicities can be expressed as fractional equivalencies of TCDD. These chemicals exert their effects through interaction with a specific intracellular protein, the Ah receptor. While binding to the receptor is necessary, it is not sufficient to bring about a chain of events leading to various responses including enzyme induction, immunotoxicity, reproductive and endocrine effects, developmental toxicity, chloracne, tumor promotion, etc. Some of these responses appear to be linear at low doses. Immunotoxicity and effects on the reproductive system appear to be among the most sensitive responses. The Ah receptor functions as a transcriptional enhancer, interacting with a number of other regulatory proteins (heat shock proteins, kinases, translocases, DNA binding species). Interaction with specific base sequences in the DNA appear to be modulated by the presence of other growth factors, hormones and their receptors as well as other regulatory proteins. Thus, dioxin appears to function as a hormone, initiating a cascade of events that is dependent upon the environment of each cell and tissue. While Ah receptor variants exist, all vertebrates examined have demonstrated such a protein with similar numbers of receptors and binding affinity for TCDD. Most species respond similarly to dioxin and related compounds. While a given species may be an outlier for a given response, it will behave like other animals for other responses. For both in vivo and in vitro end points where animal and human data exist, such as enzyme induction, chloracne, immunotoxicity, developmental toxicity, and cancer, the sensitivity of humans appears similar to that of experimental animals. Current levels of environmental exposure to this class of chemicals may be resulting in subtle responses in populations at special risk such as subsistence fisherman and the developing infant, as well as in the general population. Increased understanding of the mechanism of dioxin's effects as well as elucidation of exposure-dose relationships is leading to the development of a biologically based dose-response model in the ongoing process of incorporating the best science into the risk assessment of TCDD and related compounds. PMID:7698077

Evaluation of Biologic Effective Dose and Schedule of Fractionation for Preoperative Radiotherapy for Rectal Cancer: Meta-Analyses and Meta-Regression;Rectal cancer; Preoperative radiotherapy; Biologic effective dose; Meta-analysis

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

Arruda Viani, Gustavo, E-mail: gusviani@gmail.com; Stefano, Eduardo Jose; Vendito Soares, Francisco

2011-07-15

Purpose: To evaluate whether the risk of local recurrence depends on the biologic effective dose (BED) or fractionation dose in patients with resectable rectal cancer undergoing preoperative radiotherapy (RT) compared with surgery alone. Methods and Materials: A meta-analysis of randomized controlled trials (RCTs) was performed. The MEDLINE, Embase, CancerLit, and Cochrane Library databases were systematically searched for evidence. To evaluate the dose-response relationship, we conducted a meta-regression analysis. Four subgroups were created: Group 1, RCTs with a BED >30 Gy{sub 10} and a short RT schedule; Group 2, RCTs with BED >30 Gy{sub 10} and a long RT schedule; Groupmore » 3, RCTs with BED {<=}30 Gy{sub 10} and a short RT schedule; and Group 4, RCTs with BED {<=}30 Gy{sub 10} and a long RT schedule. Results: Our review identified 21 RCTs, yielding 9,097 patients. The pooled results from these 21 randomized trials of preoperative RT showed a significant reduction in mortality for groups 1 (p = .004) and 2 (p = .03). For local recurrence, the results were also significant in groups 1 (p = .00001) and 2 (p = .00001).The only subgroup that showed a greater sphincter preservation (SP) rate than surgery was group 2 (p = .03). The dose-response curve was linear (p = .006), and RT decreased the risk of local recurrence by about 1.7% for each Gy{sub 10} of BED. Conclusion: Our data have shown that RT with a BED of >30 Gy{sub 10} is more efficient in reducing local recurrence and mortality rates than a BED of {<=}30 Gy{sub 10}, independent of the schedule of fractionation used. A long RT schedule with a BED of >30 Gy{sub 10} should be recommended for sphincter preservation.« less

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

PubMed Central

Vaiserman, Alexander M.

2010-01-01

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

Effects of relationship motivation, partner familiarity, and alcohol on women's risky sexual decision making.

PubMed

Zawacki, Tina; Norris, Jeanette; Hessler, Danielle M; Morrison, Diane M; Stoner, Susan A; George, William H; Davis, Kelly Cue; Abdallah, Devon A

2009-06-01

This experiment examined the effects of women's relationship motivation, partner familiarity, and alcohol consumption on sexual decision making. Women completed an individual difference measure of relationship motivation and then were randomly assigned to partner familiarity condition (low, high) and to alcohol consumption condition (high dose, low dose, no alcohol, placebo). Then women read and projected themselves into a scenario of a sexual encounter. Relationship motivation and partner familiarity interacted with intoxication to influence primary appraisals of relationship potential. Participants' primary and secondary relationship appraisals mediated the effects of women's relationship motivation, partner familiarity, and intoxication on condom negotiation, sexual decision abdication, and unprotected sex intentions. These findings support a cognitive mediation model of women's sexual decision making and identify how individual and situational factors interact to shape alcohol's influences on cognitive appraisals that lead to risky sexual decisions. This knowledge can inform empirically based risky sex interventions.

SU-C-BRD-05: Non-Invasive in Vivo Biodosimetry in Radiotherapy Patients Using Electron Paramagnetic Resonance (EPR) Spectroscopy

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

Bahar, N; Roberts, K; Stabile, F

Purpose: Medical intervention following a major, unplanned radiation event can elevate the human whole body exposure LD50 from 3 to 7 Gy. On a large scale, intervention cannot be achieved effectively without accurate and efficient triage. Current methods of retrospective biodosimetry are restricted in capability and applicability; published human data is limited. We aim to further develop, validate, and optimize an automated field-deployable in vivo electron paramagnetic resonance (EPR) instrument that can fill this need. Methods: Ionizing radiation creates highly-stable, carbonate-based free radicals within tooth enamel. Using a process similar to nuclear magnetic resonance, EPR directly measures the presence ofmore » radiation-induced free radicals. We performed baseline EPR measurements on one of the upper central incisors of total body irradiation (TBI) and head and neck (H&N) radiotherapy patients before their first treatment. Additional measurements were performed between subsequent fractions to examine the EPR response with increasing radiation dose. Independent dosimetry measurements were performed with optically-stimulated luminescent dosimeters (OSLDs) and diodes to more accurately establish the relationship between EPR signal and delivered radiation dose. Results: 36 EPR measurements were performed over the course of four months on two TBI and four H & N radiotherapy patients. We observe a linear increase in EPR signal with increasing dose across the entirety of the tested range. A linear least squares-weighted fit of delivered dose versus measured signal amplitude yields an adjusted R-square of 0.966. The standard error of inverse prediction (SEIP) is 1.77 Gy. For doses up to 7 Gy, the range most relevant to triage, we calculate an SEIP of 1.29 Gy. Conclusion: EPR spectroscopy provides a promising method of retrospective, non-invasive, in vivo biodosimetry. Our preliminary data show an excellent correlation between predicted signal amplitude and delivered dose. With further development, a robust means of predicting delivered radiation dose from EPR measurements is expected. This project was funded by the Biomedical Advanced Research and Development Authority (BARDA) within the U.S. Department of Health and Human Services subcontracted through the Geisel School of Medicine at Dartmouth and by the Dartmouth Physically-Based Biodosimetry Center for Medical Countermeasures Against Radiation (Dart-Dose CMCR) Pilot Program.« less

Methadone and Metabolites in Hair of Methadone-Assisted Pregnant Women and Their Infants

PubMed Central

Himes, Sarah K; Goodwin, Robert S; Rock, Colleen M; Jones, Hendrée E; Johnson, Rolley E; Wilkins, Diana G; Huestis, Marilyn A

2012-01-01

Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes. Materials and Methods Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3cm), washed (maternal hair only) and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP) by liquid chromatography tandem mass spectrometry. Results There was large inter-subject variability and no dose-concentration relationship for cumulative methadone dose and methadone, EDDP, EMDP or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone’s induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference or amount of neonatal morphine pharmacotherapy. Maternal cumulative 3rd trimester methadone dose was positively correlated with infant birth weight. Conclusion Methadone and EDDP in pregnant women’s hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure. PMID:22495425

Environmentally relevant pyrethroid mixtures: A study on the correlation of blood and brain concentrations of a mixture of pyrethroid insecticides to motor activity in the rat.

PubMed

Hughes, Michael F; Ross, David G; Starr, James M; Scollon, Edward J; Wolansky, Marcelo J; Crofton, Kevin M; DeVito, Michael J

2016-06-01

Human exposure to multiple pyrethroid insecticides may occur because of their broad use on crops and for residential pest control. To address the potential health risk from co-exposure to pyrethroids, it is important to understand their disposition and toxicity in target organs such as the brain, and surrogates such as the blood when administered as a mixture. The objective of this study was to assess the correlation between blood and brain concentrations of pyrethroids and neurobehavioral effects in the rat following an acute oral administration of the pyrethroids as a mixture. Male Long-Evans rats were administered a mixture of β-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate and cis- and trans-permethrin in corn oil at seven dose levels. The pyrethroid with the highest percentage in the dosing solution was trans-permethrin (31% of total mixture dose) while deltamethrin and esfenvalerate had the lowest percentage (3%). Motor activity of the rats was then monitored for 1h. At 3.5h post-dosing, the animals were euthanized and blood and brain were collected. These tissues were extracted and analyzed for parent pyrethroid using HPLC-tandem mass spectrometry. Cypermethrin and cis-permethrin were the predominate pyrethroids detected in blood and brain, respectively, at all dosage levels. The relationship of total pyrethroid concentration between blood and brain was linear (r=0.93). The pyrethroids with the lowest fraction in blood were trans-permethrin and β-cyfluthrin and in brain were deltamethrin and esfenvalerate. The relationship between motor activity of the treated rats and summed pyrethroid blood and brain concentration was described using a sigmoidal Emax model with the Effective Concentration50 being more sensitive for brain than blood. The data suggests summed pyrethroid rat blood concentration could be used as a surrogate for brain concentration as an aid to study the neurotoxic effects of pyrethroids administered as a mixture under the conditions used in this study. Published by Elsevier Ireland Ltd.

Expanding the occupational health methodology: A concatenated artificial neural network approach to model the burnout process in Chinese nurses.

PubMed

Ladstätter, Felix; Garrosa, Eva; Moreno-Jiménez, Bernardo; Ponsoda, Vicente; Reales Aviles, José Manuel; Dai, Junming

2016-01-01

Artificial neural networks are sophisticated modelling and prediction tools capable of extracting complex, non-linear relationships between predictor (input) and predicted (output) variables. This study explores this capacity by modelling non-linearities in the hardiness-modulated burnout process with a neural network. Specifically, two multi-layer feed-forward artificial neural networks are concatenated in an attempt to model the composite non-linear burnout process. Sensitivity analysis, a Monte Carlo-based global simulation technique, is then utilised to examine the first-order effects of the predictor variables on the burnout sub-dimensions and consequences. Results show that (1) this concatenated artificial neural network approach is feasible to model the burnout process, (2) sensitivity analysis is a prolific method to study the relative importance of predictor variables and (3) the relationships among variables involved in the development of burnout and its consequences are to different degrees non-linear. Many relationships among variables (e.g., stressors and strains) are not linear, yet researchers use linear methods such as Pearson correlation or linear regression to analyse these relationships. Artificial neural network analysis is an innovative method to analyse non-linear relationships and in combination with sensitivity analysis superior to linear methods.

Fluence-to-dose conversion coefficients for heavy ions calculated using the PHITS code and the ICRP/ICRU adult reference computational phantoms.

PubMed

Sato, Tatsuhiko; Endo, Akira; Niita, Koji

2010-04-21

The fluence to organ-absorbed-dose and effective-dose conversion coefficients for heavy ions with atomic numbers up to 28 and energies from 1 MeV/nucleon to 100 GeV/nucleon were calculated using the PHITS code coupled to the ICRP/ICRU adult reference computational phantoms, following the instruction given in ICRP Publication 103 (2007 (Oxford: Pergamon)). The conversion coefficients for effective dose equivalents derived using the radiation quality factors of both Q(L) and Q(y) relationships were also estimated, utilizing the functions for calculating the probability densities of absorbed dose in terms of LET (L) and lineal energy (y), respectively, implemented in PHITS. The calculation results indicate that the effective dose can generally give a conservative estimation of the effective dose equivalent for heavy-ion exposure, although it is occasionally too conservative especially for high-energy lighter-ion irradiations. It is also found from the calculation that the conversion coefficients for the Q(y)-based effective dose equivalents are generally smaller than the corresponding Q(L)-based values because of the conceptual difference between LET and y as well as the numerical incompatibility between the Q(L) and Q(y) relationships. The calculated data of these dose conversion coefficients are very useful for the dose estimation of astronauts due to cosmic-ray exposure.

Pharmacokinetics of temozolomide given three times a day in pediatric and adult patients.

PubMed

Riccardi, Anna; Mazzarella, Giorgio; Cefalo, Graziella; Garrè, Maria Luisa; Massimino, Maura; Barone, Carlo; Sandri, Alessandro; Ridola, Vita; Ruggiero, Antonio; Mastrangelo, Stefano; Lazzareschi, Ilaria; Caldarelli, Massimo; Maira, Giulio; Madon, Enrico; Riccardi, Riccardo

2003-12-01

To characterize and compare pharmacokinetic parameters in children and adults treated with temozolomide (TMZ) administered for 5 days in three doses daily, and to evaluate the possible relationship between AUC values and hematologic toxicity. TMZ pharmacokinetic parameters were characterized in pediatric and adult patients with primary central nervous system tumors treated with doses ranging from 120 to 200 mg/m2 per day, divided into three doses daily for 5 days. Plasma levels were measured over 8 h following oral administration in a fasting state. A total of 40 courses were studied in 22 children (mean age 10 years, range 3-16 years) and in 8 adults (mean age 30 years, range 19-54 years). In all patients, a linear relationship was found between systemic exposure (AUC) and increasing doses of TMZ. Time to peak concentration, elimination half-life, apparent clearance and volume of distribution were not related to TMZ dose. No differences were seen among TMZ C(max), t(1/2), V(d) or CL/F in children compared with adults. Intra- and interpatient variability of systemic exposure were limited in both children and adults. No statistically significant differences were found between the AUCs of children who experienced grade 4 hematologic toxicity and children who did not. No difference appears to exist between pharmacokinetic parameters in adults and children when TMZ is administered in three doses daily. Hematologic toxicity was not related to TMZ AUC. AUC measurement does not appear to be of any use in optimizing TMZ treatment.

The characterization of oxotremorine-induced hypothermic response in the rat.

PubMed

Ryan, P M; Kelly, J P; Chambers, P L; Leonard, B E

1996-11-01

Oxotremorine is a muscarinic receptor agonist that induces a variety of physiological and behavioural effects including hypothermia in mice. These effects are antagonized dose-dependently by classical anticholinergic compounds such as atropine. Although the oxotremorine-induced hypothermic response has been demonstrated in mice, few studies of the effects of this muscarinic agonist have been made in the rat. The following studies were made in male Sprague Dawley rats: 1. an investigation of the dose-response relationship between oxotremorine and hypothermia; 2. an examination of the effect of housing on the oxotremorine-induced hypothermic response, and 3, an investigation of the acute administration of various doses of atropine sulphate on the hypothermia caused by oxotremorine. The results indicate that the dose-response relationship between oxotremorine and the antagonism of hypothermia is similar in rat as it is in mice. The results also showed that this effect did not occur in group-housed animals.

Comparison of fluence-to-dose conversion coefficients for deuterons, tritons and helions.

PubMed

Copeland, Kyle; Friedberg, Wallace; Sato, Tatsuhiko; Niita, Koji

2012-02-01

Secondary radiation in aircraft and spacecraft includes deuterons, tritons and helions. Two sets of fluence-to-effective dose conversion coefficients for isotropic exposure to these particles were compared: one used the particle and heavy ion transport code system (PHITS) radiation transport code coupled with the International Commission on Radiological Protection (ICRP) reference phantoms (PHITS-ICRP) and the other the Monte Carlo N-Particle eXtended (MCNPX) radiation transport code coupled with modified BodyBuilder™ phantoms (MCNPX-BB). Also, two sets of fluence-to-effective dose equivalent conversion coefficients calculated using the PHITS-ICRP combination were compared: one used quality factors based on linear energy transfer; the other used quality factors based on lineal energy (y). Finally, PHITS-ICRP effective dose coefficients were compared with PHITS-ICRP effective dose equivalent coefficients. The PHITS-ICRP and MCNPX-BB effective dose coefficients were similar, except at high energies, where MCNPX-BB coefficients were higher. For helions, at most energies effective dose coefficients were much greater than effective dose equivalent coefficients. For deuterons and tritons, coefficients were similar when their radiation weighting factor was set to 2.

78 FR 46274 - Pyroxasulfone; Pesticide Tolerances

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-31

... following a 4-week dermal exposure producing local inflammation and systemic effects of minimal to mild...- linear approach (i.e., Reference dose (RfD)) will adequately account for all chronic toxicity, including... and other relevant data. Cancer risk is quantified using a linear or nonlinear approach. If sufficient...

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

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

Scott, Bobby, R., Ph.D.

2003-06-27

OAK - B135 This project final report summarizes modeling research conducted in the U.S. Department of Energy (DOE), Low Dose Radiation Research Program at the Lovelace Respiratory Research Institute from October 1998 through June 2003. The modeling research described involves critically evaluating the validity of the linear nonthreshold (LNT) risk model as it relates to stochastic effects induced in cells by low doses of ionizing radiation and genotoxic chemicals. The LNT model plays a central role in low-dose risk assessment for humans. With the LNT model, any radiation (or genotoxic chemical) exposure is assumed to increase one¡¯s risk of cancer.more » Based on the LNT model, others have predicted tens of thousands of cancer deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Our research has focused on developing biologically based models that explain the shape of dose-response curves for low-dose radiation and genotoxic chemical-induced stochastic effects in cells. Understanding the shape of the dose-response curve for radiation and genotoxic chemical-induced stochastic effects in cells helps to better understand the shape of the dose-response curve for cancer induction in humans. We have used a modeling approach that facilitated model revisions over time, allowing for timely incorporation of new knowledge gained related to the biological basis for low-dose-induced stochastic effects in cells. Both deleterious (e.g., genomic instability, mutations, and neoplastic transformation) and protective (e.g., DNA repair and apoptosis) effects have been included in our modeling. Our most advanced model, NEOTRANS2, involves differing levels of genomic instability. Persistent genomic instability is presumed to be associated with nonspecific, nonlethal mutations and to increase both the risk for neoplastic transformation and for cancer occurrence. Our research results, based on applications of NEOTRANS2, indicate that nonlinear threshold-type, dose-response relationships for excess stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected after exposure to low linear energy transfer (LET) gamma rays or gamma rays in combination with high-LET alpha radiation. Similar thresholds are expected for low-dose-rate low-LET beta irradiation. We attribute the thresholds to low-dose, low-LET radiation induced protection against spontaneous mutations and neoplastic transformations. The protection is presumed mainly to involve selective elimination of problematic cells via apoptosis. Low-dose, low-LET radiation is presumed to trigger wide-area cell signaling, which in turn leads to problematic bystander cells (e.g., mutants, neoplastically transformed cells) selectively undergoing apoptosis. Thus, this protective bystander effect leads to selective elimination of problematic cells (a tissue cleansing process in vivo). However, this protective bystander effects is a different process from low-dose stimulation of the immune system. Low-dose, low-LET radiation stimulation of the immune system may explain why thresholds for inducing excess cancer appear much larger (possibly more than 100-fold larger) than thresholds for inducing excess mutations and neoplastic transformations, when the dose rate is low. For ionizing radiation, the current risk assessment paradigm is such that the relative risk (RR) is always ¡Ý 1, no matter how small the dose. Our research results indicate that for low-dose or low-dose-rate, low-LET irradiation, RR < 1 may be more the rule than the exception. Directly tied to the current RR paradigm are the billion-dollar cleanup costs for radionuclide-contaminated DOE sites. Our research results suggest that continued use of the current RR paradigm for which RR ¡Ý 1 could cause more harm than benefit to society (e.g., by spreading unwarranted fear about phantom excess risks associated with low-dose low-LET radiation). Such phantom risks also may arise from risk assessments conducted for combined exposure to low- and high-LET radiations when based on the LNT or other models that exclude RR < 1. Our results for high-LET radiation are consistent with the LNT hypothesis but only where there is no additional low-LET contribution (e.g., gamma rays) to the total dose. For high-LET neutron sources, gamma rays arise (especially in vivo) for large mammals such as humans from neutron interactions with tissue. The gamma rays might provide some protection from low-dose-related stochastic effects via inducing the protective bystander apoptosis effect that is considered to contribute to tissue cleansing via removal of problematic cells.« less

Adequacy in dialysis: intermittent versus continuous therapies.

PubMed

Misra, M; Nolph, K D

2000-01-01

A vital conceptual difference between intermittent and continuous dialysis therapies is the difference in the relationship between Kt/V urea and dietary protein intake. For a given level of protein intake the intermittent therapies require a higher Kt/V urea due to the reasons mentioned above. The recently released adequacy guidelines by DOQI for intermittent and continuous therapies are based on these assumptions. The link between adequacy targets and patient survival is well documented for an intermittent therapy like HD. For a continuous therapy like CAPD however, the evidence linking improved peritoneal clearance to better survival is not as direct. However, present consensus allows one to extrapolate results based on HD. The concept of earlier and healthier initiation of dialysis is gaining hold and incremental dialysis forms an integral aspect of the whole concept. Tools like urea kinetic modeling give us valuable insight in making mathematical projections about the timing as well as dosing of dialysis. Daily home hemodialysis is still an underutilized modality despite offering best survival figures. Hopefully, with increasing availability of better and simpler machines its use will increase. Still several questions remain unanswered. Despite availability of data in hemodialysis patients suggesting that an increased dialysis prescription leads to a better survival, optimal dialysis dose is yet to be defined. Concerns regarding methodology of such studies and conclusions thereof has been raised. Other issues relating to design of the studies, variation in dialysis delivery, use of uncontrolled historical standards and lack of patient randomization etc also need to be considered when designing such trials. Hopefully an ongoing prospective randomized trial, namely the HEMO study, looking at two precisely defined and carefully maintained dialysis prescriptions will provide some insight into adequacy of dialysis dose and survival. In diabetic patients, the relationship between outcome and dialysis dose needs to be better defined. Data relating adequacy of dialysis to outcome in a pediatric population is not available. In dialysis therapy, the Risk/Dose (R/D) function does not bear a linear relationship. This together with a lack of proof equating peritoneal to renal clearance lends some uncertainty to the validity of the recommendation that there is a linear and constant decrease in RR for std (Kt/V) [equivalent standardized Kt/V calculated from average predialysis BUN for any frequency and/or combination of intermittent and continuous dialysis ref] up to 2.3 as reported in the CANUSA study. Due to the complex nature of this problem it may be prudent to undertake a multi-center trial with std (Kt/V) prospectively randomized to either 2.0 or 2.4. This would provide a reliable database to evaluate the R/D function over this critical range of normalized peritoneal urea clearance. Likewise in PD, the postulated linearity between dialysis dose and outcome needs to be studied in a prospective randomized manner. The amount of dialysis dose required for malnourished patients, diabetic and pediatric patients needs to be better defined. The role of aggressive dialysis in reversing malnutrition needs to be studied and studies need to be done to identify the most scientific use of V in malnourished patients. Justification of a healthy start/incremental dialysis based on outcome measures needs to be established and it's cost effectiveness validated by clinical trials. Again, a prospective randomized controlled trial comparing incremental dialysis with dietary protein restriction in patients with GFR < or = 10.5 ml/min/1.73 m2 with properly defined outcome measures like morbidity, mortality, decline of GFR and quality of life needs to be conducted. Comparisons of incremental hemodialysis and incremental peritoneal dialysis need to be made especially with regard to technique survival and preservation of residual renal function (RRF). (ABSTR

A 3-year study of addiction mutual-help group participation following intensive outpatient treatment.

PubMed

Kelly, John F; Stout, Robert; Zywiak, William; Schneider, Robert

2006-08-01

Addiction-focused mutual-help group participation is associated with better substance use disorder (SUD) treatment outcomes. However, little has been documented regarding which types of mutual-help organizations patients attend, what levels of participation may be beneficial, and which patients, in particular, are more or less likely to participate. Furthermore, much of the evidence supporting the use of these organizations comes from studies examining participation and outcomes concurrently, raising doubts about cause-effect connections, and little is known about influences that may moderate the degree of any general benefit. Alcohol-dependent outpatients (N=227; 27% female; M age=42) enrolled in a randomized-controlled telephone case monitoring trial were assessed at treatment intake and at 1, 2, and 3 years postdischarge. Lagged-panel, hierarchical linear models tested whether mutual-help group participation in the first and second year following treatment predicted subsequent outcomes and whether these effects were moderated by gender, concurrent axis I diagnosis, religious preference, and prior mutual-help experience. Robust regression curve analysis was used to examine dose-response relationships between mutual-help and outcomes. Mutual-help participation was associated with both greater abstinence and fewer drinks per drinking day and this relationship was not found to be influenced by gender, Axis I diagnosis, religious preference, or prior mutual-help participation. Mutual-help participants attended predominantly Alcoholics Anonymous and tended to be Caucasian, be more educated, have prior mutual-help experience, and have more severe alcohol involvement. Dose-response curve analyses suggested that even small amounts of participation may be helpful in increasing abstinence, whereas higher doses may be needed to reduce relapse intensity. Use of mutual-help groups following intensive outpatient SUD treatment appears to be beneficial for many different types of patients and even modest levels of participation may be helpful. Future emphasis should be placed on ways to engage individuals with these cost-effective resources over time and to gather and disseminate evidence regarding additional mutual-help organizations.

Treating primary dysmenorrhoea with acupuncture: a narrative review of the relationship between acupuncture 'dose' and menstrual pain outcomes.

PubMed

Armour, Mike; Smith, Caroline A

2016-12-01

A number of randomised controlled trials have been performed to determine the effectiveness or efficacy of acupuncture in primary dysmenorrhoea. The objective of this review was to explore the relationship between the 'dose' of the acupuncture intervention and menstrual pain outcomes. Eight databases were systematically searched for trials examining penetrating body acupuncture for primary dysmenorrhoea published in English up to September 2015. Dose components for each trial were extracted, assessed by the two authors and categorised by neurophysiological dose (number of needles, retention time and mode of stimulation), cumulative dose (total number and frequency of treatments), needle location and treatment timing. Eleven trials were included. Components of acupuncture dose were well reported across all trials. The relationship between needle location and menstrual pain demonstrated conflicting results. Treatment before the menses appeared to produce greater reductions in pain than treatment starting at the onset of menses. A single needle during menses may provide greater pain reduction compared to multiple needles. Conversely, multiple needles before menses were superior to a single needle. Electroacupuncture may provide more rapid pain reduction compared to manual acupuncture but may not have a significantly different effect on overall menstrual pain. There appear to be relationships between treatment timing and mode of needle stimulation, and menstrual pain outcomes. Needle location, number of needles used and frequency of treatment show clear dose-response relationships with menstrual pain outcomes. Current research is insufficient to make definitive clinical recommendations regarding optimum dose parameters for treating primary dysmenorrhoea. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

[Study on effect of aqueous extracts from aconite on "dose-time-toxicity" relationships in mice hearts].

PubMed

Feng, Qun; Li, Xiao-yu; Luan, Yong-fu; Sun, Sai-nan; Sun, Rong

2015-03-01

To study the effect of single administration of aqueous extracts from aconite on "dose-toxicity" relationship and "time-toxicity" relationship of mice hearts, through changes in electrocardiogram (ECG) and serum biochemical indexes. Mice were grouped according to different drug doses and time points, and orally administered with water extracts from aconite for once to observe the changes of mice ECG before and after the administration, calculate visceral indexes heart, liver and kidney, and detect levels of CK, LDH, BNP and CTn-I in serum. According to the "time-toxicity" relationship study, at 5 min after oral administration with aqueous extracts from aconite in mice, the heart rate of mice began rising, reached peak at 60 min and then slowly reduced; QRS, R amplitude, T duration and amplitude and QT interval declined at 5 min, reduced to the bottom at 60 min and then gradually elevated. The levels of CK, LDH, BNP and CTn-I in serum elevated at 5 min and reached the peak at 60 min, with no significant change in ratios of organs to body at different time points. On the basis of the "dose-toxicity" relationship, with the increase in single dose of aqueous extracts from aconite, the heart rate of mice. QRS, T duration and amplitude and QT interval declined gradually, and levels of CK, LDH, BNP and CTn-I in serum slowly elevated, with a certain dose dependence and no significant change in ratios of organs to body in mice. Single oral administration of different doses of aqueous extracts from aconite could cause different degrees of heart injury at different time points, with a certain dose dependence. Its peak time of toxicity is at 60 min after the administration of aqueous extracts from aconite.

Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships.

PubMed

Mégarbane, Bruno; Declèves, Xavier; Bloch, Vanessa; Bardin, Christophe; Chast, François; Baud, Frédéric J

2007-01-01

Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations. We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay. Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R-methadone concentrations fitted well a sigmoidal Emax model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects. After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.

Incorporating nonlinearity into mediation analyses.

PubMed

Knafl, George J; Knafl, Kathleen A; Grey, Margaret; Dixon, Jane; Deatrick, Janet A; Gallo, Agatha M

2017-03-21

Mediation is an important issue considered in the behavioral, medical, and social sciences. It addresses situations where the effect of a predictor variable X on an outcome variable Y is explained to some extent by an intervening, mediator variable M. Methods for addressing mediation have been available for some time. While these methods continue to undergo refinement, the relationships underlying mediation are commonly treated as linear in the outcome Y, the predictor X, and the mediator M. These relationships, however, can be nonlinear. Methods are needed for assessing when mediation relationships can be treated as linear and for estimating them when they are nonlinear. Existing adaptive regression methods based on fractional polynomials are extended here to address nonlinearity in mediation relationships, but assuming those relationships are monotonic as would be consistent with theories about directionality of such relationships. Example monotonic mediation analyses are provided assessing linear and monotonic mediation of the effect of family functioning (X) on a child's adaptation (Y) to a chronic condition by the difficulty (M) for the family in managing the child's condition. Example moderated monotonic mediation and simulation analyses are also presented. Adaptive methods provide an effective way to incorporate possibly nonlinear monotonicity into mediation relationships.

Low dose radiation interactions with the transformation growth factor (TFG)-beta pathway

NASA Astrophysics Data System (ADS)

Maslowski, Amy Jesse

A major limiting factor for long-term, deep-space missions is the radiation dose to astronauts. Because the dose to the astronauts is a mixed field of low- and high-LET radiation, there is a need to understand the effects of both radiation types on whole tissue; however, there are limited published data on the effects of high-LET (linear-energy-transfer) radiation on tissue. Thus, we designed a perfusion chamber system for rat trachea in order to mimic in vivo respiratory tissue. We successfully maintained the perfused tracheal tissue ex vivo in a healthy and viable condition for up to three days. In addition, this project studied the effects of high-LET Fe particles on the overall transformation growth factor (TGF)-beta response after TGF-beta inactivation and compared the results to the TGF-beta response post x-ray irradiation. It was found that a TGF-beta response could be measured in the perfused tracheal tissue, for x-ray and Fe particle irradiations, despite the high autofluorescent background intrinsic to tissue. However, after comparing the TGF-beta response of x-ray irradiation to High-Z-High-energy (HZE) irradiation, there was not a significant difference in radiation types. The TGF-beta response in x-ray and HZE irradiated perfusion chambers was also measured over time post irradiation. It was found that for 6 hour and 8 hour post irradiation, the TGF-beta response was higher for lower doses of radiation than for higher doses. This is in contrast to the 0 hour fixation which found the TGF-beta response to increase with increased dose. The inverse relationship found for 6 hour and 8 hour fixation times may indicate a threshold response for TGF-beta response; i.e., for low doses, a threshold of dose must be reached for an immediate TGF-beta response, otherwise the tissue responds more slowly to the irradiation damage. This result was unexpected and will require further investigation to determine if the threshold can be determined for the 250 kVp x-rays and 1 Gev Fe particles.

Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies.

PubMed

Petit, Caroline; Samson, Adeline; Morita, Satoshi; Ursino, Moreno; Guedj, Jérémie; Jullien, Vincent; Comets, Emmanuelle; Zohar, Sarah

2018-06-01

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose-toxicity and dose-efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children.

Guaifenesin Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years

PubMed Central

Thompson, Gary A.; Solomon, Gail; Albrecht, Helmut H.; Reitberg, Donald P.

2016-01-01

Abstract This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age‐based doses of 100‐400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo) and terminal volume of distribution (Vz/F) increased with age. Due to a larger increase in Vz/F than CLo, an increase in terminal exponential half‐life was also observed. Allometric scaling indicated no maturation‐related changes in CLo and Vz/F. PMID:26632082

Neutron dose estimation via LET spectrometry using CR-39 detector for the reaction 9Be (p, n)

PubMed Central

Sahoo, G. S.; Tripathy, S. P.; Paul, S.; Sharma, S. D.; Sharma, S. C.; Joshi, D. S.; Bandyopadhyay, T.

2014-01-01

CR-39 detectors, widely used for neutron dosimetry in accelerator radiation environment, have also been applied in tissue microdosimetry by generating the linear energy transfer (LET) spectrum. In this work, the neutron dose has been estimated via LET spectrometry for 9Be (p, n) reaction which is useful for personnel monitoring around particle accelerators and accelerator based therapy facilities. Neutrons were generated by the interaction of protons of 6 different energies from 4–24 MeV with a thick Be target. The LET spectra were obtained from the major and minor radii of each track and the thickness of removed surface. From the LET spectra, the absorbed dose (DLET) and the dose equivalent (HLET) were estimated using Q-L relationship as given by International Commission on Radiological Protection (ICRP) 60. The track density in CR-39 detector and hence the neutron yield was found to be increasing with the increase in projectile (proton) energy. Similar observations were also obtained for absorbed dose (DLET) and dose equivalents (HLET). PMID:25525310

SU-E-T-09: A Dosimetric Analysis of Various Clinically Used Bolus Materials

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

Stowe, M; Yeager, C; Zhou, F

Purpose: To evaluate the dosimetric effect of various clinically used bolus materials. Methods: Materials investigated include solid water, superflab, wet gauze, wet sheets, Play-Doh{sup ™}, and gauze embedded with petroleum jelly. Each bolusing material was scanned in a Philips CT to determine the Hounsfield unit (HU) and to verify uniformity throughout the material. Using the corresponding HU, boluses of 0.5 cm and 1.0 cm thicknesses were created in the Eclipse treatment planning system (TPS) on a solid water phantom. Dose was calculated at various depths for beam energies 6 MV, 6 MeV, 9 MeV, and 12 MeV to determine themore » effects of each material on deposition of dose. In addition, linac-based measurements at these energies were made using a farmer chamber in solid water. Wet sheets and wet gauze were measured with various water content to quantify the effects on dose. Results: Preliminary CT scans find a range in HU of bolus materials from −120 to almost 300. There is a trend in the dose at depth based on the HU of the material; however inconsistencies are found when the bolus materials have a negative HU value. The measured data indicates that there is a linear relationship between the mass of water in a material and the dose reading, the slope of which is material dependent. Conclusion: Due to the variation in HU of the bolus materials studied, it is recommended that any new bolus be evaluated before clinical use to determine physical and dosimetric properties. If possible, patients should have bolus included in their CT scans; or if the bolus is created in the TPS, the HU should correspond to the material used. For water-soaked materials, once the bolus material is selected (gauze or sheet), the bolusing effect is only dependent on the amount of water applied to the material.« less

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

PubMed

Chen, D G; Pounds, J G

1998-12-01

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

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

PubMed Central

Chen, D G; Pounds, J G

1998-01-01

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

Human responses to bright light of different durations.

PubMed

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

2012-07-01

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

The Risk of Cataract among Survivors of Childhood and Adolescent Cancer: A Report from the Childhood Cancer Survivor Study

PubMed Central

Chodick, Gabriel; Sigurdson, Alice J.; Kleinerman, Ruth A.; Sklar, Charles A.; Leisenring, Wendy; Mertens, Ann C.; Stovall, Marilyn; Smith, Susan A.; Weathers, Rita E.; Veiga, Lene H. S.; Robison, Leslie L.; Inskip, Peter D.

2016-01-01

With therapeutic successes and improved survival after a cancer diagnosis in childhood, increasing numbers of cancer survivors are at risk of subsequent treatment-related morbidities, including cataracts. While it is well known that the lens of the eye is one of the most radiosensitive tissues in the human body, the risks associated with radiation doses less than 2 Gy are less understood, as are the long- and short-term cataract risks from exposure to ionizing radiation at a young age. In this study, we followed 13,902 five-year survivors of childhood cancer in the Childhood Cancer Survivor Study cohort an average of 21.4 years from the date of first cancer diagnosis. For patients receiving radiotherapy, lens dose (mean: 2.2 Gy; range: 0–66 Gy) was estimated based on radiotherapy records. We used unconditional multivariable logistic regression models to evaluate prevalence of self-reported cataract in relationship to cumulative radiation dose both at five years after the initial cancer diagnosis and at the end of follow-up. We modeled the radiation effect in terms of the excess odds ratio (EOR) per Gy. We also analyzed cataract incidence starting from five years after initial cancer diagnosis to the end of follow-up using Cox regression. A total of 483 (3.5%) cataract cases were identified, including 200 (1.4%) diagnosed during the first five years of follow-up. In a multivariable logistic regression model, cataract prevalence at the end of follow-up was positively associated with lens dose in a manner consistent with a linear dose-response relationship (EOR per Gy = 0.92; 95% CI: 0.65–1.20). The odds ratio for doses between 0.5 and 1.5 Gy was elevated significantly relative to doses <0.5 Gy (OR = 2.2; 95% CI: 1.3–3.7). The results from this study indicate a strong association between ocular exposure to ionizing radiation and long-term risk of pre-senile cataract. The risk of cataract increased with increasing exposure, beginning at lens doses as low as 0.5 Gy. Our findings are in agreement with a growing body of evidence of an elevated risk for lens opacities in populations exposed to doses of ionizing radiation below the previously suggested threshold level of 2 Gy. PMID:27023263

Genetic susceptibility: radiation effects relevant to space travel.

PubMed

Peng, Yuanlin; Nagasawa, Hatsumi; Warner, Christy; Bedford, Joel S

2012-11-01

Genetic variation in the capacity to repair radiation damage is an important factor influencing both cellular and tissue radiosensitivity variation among individuals as well as dose rate effects associated with such damage. This paper consists of two parts. The first part reviews some of the available data relating to genetic components governing such variability among individuals in susceptibility to radiation damage relevant for radiation protection and discusses the possibility and extent to which these may also apply for space radiations. The second part focuses on the importance of dose rate effects and genetic-based variations that influence them. Very few dose rate effect studies have been carried out for the kinds of radiations encountered in space. The authors present here new data on the production of chromosomal aberrations in noncycling low passage human ATM+/+ or ATM+/- cells following irradiations with protons (50 MeV or 1 GeV), 1 GeV(-1) n iron ions and gamma rays, where doses were delivered at a high dose rate of 700 mGy(-1) min, or a lower dose rate of 5 mGy min(-1). Dose responses were essentially linear over the dose ranges tested and not significantly different for the two cell strains. Values of the dose rate effectiveness factor (DREF) were expressed as the ratio of the slopes of the dose-response curves for the high versus the lower (5 mGy min(-1)) dose rate exposures. The authors refer to this as the DREF5. For the gamma ray standard, DREF5 values of approximately two were observed. Similar dose rate effects were seen for both energies of protons (DREF5 ≈ 2.2 in both cases). For 1 GeV(-1) n iron ions [linear energy transfer (LET) ≈ 150 keV μ(-1)], the DREF5 was not 1 as might have been expected on the basis of LET alone but was approximately 1.3. From these results and conditions, the authors estimate that the relative biological effectiveness for 1 GeV(-1) n iron ions for high and low dose rates, respectively, were about 10 and 15 rather than around 20 for low dose rates, as has been assumed by most recommendations from radiation protection organizations for charged particles of this LET. The authors suggest that similar studies using appropriate animal models of carcinogenesis would be valuable.

Differential pencil beam dose computation model for photons.

PubMed

Mohan, R; Chui, C; Lidofsky, L

1986-01-01

Differential pencil beam (DPB) is defined as the dose distribution relative to the position of the first collision, per unit collision density, for a monoenergetic pencil beam of photons in an infinite homogeneous medium of unit density. We have generated DPB dose distribution tables for a number of photon energies in water using the Monte Carlo method. The three-dimensional (3D) nature of the transport of photons and electrons is automatically incorporated in DPB dose distributions. Dose is computed by evaluating 3D integrals of DPB dose. The DPB dose computation model has been applied to calculate dose distributions for 60Co and accelerator beams. Calculations for the latter are performed using energy spectra generated with the Monte Carlo program. To predict dose distributions near the beam boundaries defined by the collimation system as well as blocks, we utilize the angular distribution of incident photons. Inhomogeneities are taken into account by attenuating the primary photon fluence exponentially utilizing the average total linear attenuation coefficient of intervening tissue, by multiplying photon fluence by the linear attenuation coefficient to yield the number of collisions in the scattering volume, and by scaling the path between the scattering volume element and the computation point by an effective density.

A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling—The importance of homeostatic control for an essential metal

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

Gentry, P. Robinan, E-mail: rgentry@ramboll.com

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposuresmore » into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. > 10 μg/m{sup 3}) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to “convert” an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls. - Highlights: • Manganese is an essential nutrient, adding complexity to its risk assessment. • Nonlinearities in biological processes are important for manganese risk assessment. • A PBPK model was used to estimate target tissue concentrations of manganese. • An MOS approach also considered target tissue concentrations for ambient exposures. • Relationships between ambient Mn exposures and dose-to-target tissue are not linear.« less

Time-to-Seizure Modeling of Lacosamide Used in Monotherapy in Patients with Newly Diagnosed Epilepsy.

PubMed

Lindauer, Andreas; Laveille, Christian; Stockis, Armel

2017-11-01

To quantify the relationship between exposure to lacosamide monotherapy and seizure probability, and to simulate the effect of changing the dose regimen. Structural time-to-event models for dropouts (not because of a lack of efficacy) and seizures were developed using data from 883 adult patients newly diagnosed with epilepsy and experiencing focal or generalized tonic-clonic seizures, participating in a trial (SP0993; ClinicalTrials.gov identifier: NCT01243177) comparing the efficacy of lacosamide and carbamazepine controlled-release monotherapy. Lacosamide dropout and seizure models were used for simulating the effect of changing the initial target dose on seizure freedom. Repeated time-to-seizure data were described by a Weibull distribution with parameters estimated separately for the first and subsequent seizures. Daily area under the plasma concentration-time curve was related linearly to the log-hazard. Disease severity, expressed as the number of seizures during the 3 months before the trial (baseline), was a strong predictor of seizure probability: patients with 7-50 seizures at baseline had a 2.6-fold (90% confidence interval 2.01-3.31) higher risk of seizures compared with the reference two to six seizures. Simulations suggested that a 400-mg/day, rather than a 200-mg/day initial target dose for patients with seven or more seizures at baseline could potentially result in an additional 8% of seizure-free patients for 6 months at the last evaluated dose level. Patients receiving lacosamide had a slightly lower dropout risk compared with those receiving carbamazepine. Baseline disease severity was the most important predictor of seizure probability. Simulations suggest that an initial target dose >200 mg/day could potentially benefit patients with greater disease severity.

Effectiveness of respiratory-gated radiotherapy with audio-visual biofeedback for synchrotron-based scanned heavy-ion beam delivery

NASA Astrophysics Data System (ADS)

He, Pengbo; Li, Qiang; Zhao, Ting; Liu, Xinguo; Dai, Zhongying; Ma, Yuanyuan

2016-12-01

A synchrotron-based heavy-ion accelerator operates in pulse mode at a low repetition rate that is comparable to a patient’s breathing rate. To overcome inefficiencies and interplay effects between the residual motion of the target and the scanned heavy-ion beam delivery process for conventional free breathing (FB)-based gating therapy, a novel respiratory guidance method was developed to help patients synchronize their breathing patterns with the synchrotron excitation patterns by performing short breath holds with the aid of personalized audio-visual biofeedback (BFB) system. The purpose of this study was to evaluate the treatment precision, efficiency and reproducibility of the respiratory guidance method in scanned heavy-ion beam delivery mode. Using 96 breathing traces from eight healthy volunteers who were asked to breathe freely and guided to perform short breath holds with the aid of BFB, a series of dedicated four-dimensional dose calculations (4DDC) were performed on a geometric model which was developed assuming a linear relationship between external surrogate and internal tumor motions. The outcome of the 4DDCs was quantified in terms of the treatment time, dose-volume histograms (DVH) and dose homogeneity index. Our results show that with the respiratory guidance method the treatment efficiency increased by a factor of 2.23-3.94 compared with FB gating, depending on the duty cycle settings. The magnitude of dose inhomogeneity for the respiratory guidance methods was 7.5 times less than that of the non-gated irradiation, and good reproducibility of breathing guidance among different fractions was achieved. Thus, our study indicates that the respiratory guidance method not only improved the overall treatment efficiency of respiratory-gated scanned heavy-ion beam delivery, but also had the advantages of lower dose uncertainty and better reproducibility among fractions.

Melanogenesis stimulation in murine b16 melanoma cells by umberiferae plant extracts and their coumarin constituents.

PubMed

Matsuda, Hideaki; Hirata, Noriko; Kawaguchi, Yoshiko; Yamazaki, Miho; Naruto, Shunsuke; Shibano, Makio; Taniguchi, Masahiko; Baba, Kimiye; Kubo, Michinori

2005-07-01

Melanogenesis stimulation activities of seven ethanolic extracts obtained from Umbelliferae plants used as Chinese crude drugs, namely the roots of Angelica dahurica BENTH. et HOOK., A. biserrata SHEN et YUAN, Notopterygium incisum TING, Heracleum lanatum MICHX., and H. candicans WALL., and the fruits of Cinidium monnieri (L.) CUSSON and C. formosanum YABE, were examined by using cultured murine B16 melanoma cells. Among them, the extract (5, 25 microg/ml) of H. lanatum showed a potent stimulatory effect on melanogenesis with significant enhancement of cell proliferation in a dose-dependent manner. The melanogenesis stimulatory effects of sixteen coumarins (1-16) isolated from the seven Umbelliferae crude drugs were also examined. Among them, linear-furocoumarins [psoralen (1), xanthotoxin (2), bergapten (3), and isopimpinellin (4)] and angular-furocoumarin [sphondin (13)] exhibited potent melanogenesis stimulation activity. From the view point of structure-activity relationships, it may be assumed that a linear-furocoumarin ring having a hydrogen and/or methoxyl group at 5 and 8 positions such as 1, 2, 3 and 4 was preferable for the melanogenesis stimulation activity. The introduction of a prenyl group into the furocoumarin ring was disadvantageous. Coumarin derivatives having a simple coumarin ring were inactive.

Pharmacokinetic–pharmacodynamic relationships of central nervous system effects of scopolamine in healthy subjects

PubMed Central

Liem-Moolenaar, Marieke; de Boer, Peter; Timmers, Maarten; Schoemaker, Rik C; van Hasselt, J G Coen; Schmidt, Stephan; van Gerven, Joop M A

2011-01-01

AIM(S) Although scopolamine is a frequently used memory impairment model, the relationships between exposure and corresponding central nervous system (CNS) effects are mostly unknown. The aim of our study was to characterize these using pharmacokinetic–pharmacodynamic (PK–PD) modelling. METHODS In two double-blind, placebo-controlled, four-way crossover studies, 0.5-mg scopolamine was administered i.v. to 90 healthy male subjects. PK and PD/safety measures were monitored pre-dose and up to 8.5 h after administration. PK–PD relationships were modelled using non-linear mixed-effect modelling. RESULTS Most PD responses following scopolamine administration in 85 subjects differed significantly from placebo. As PD measures lagged behind the plasma PK profile, PK–PD relationships were modelled using an effect compartment and arbitrarily categorized according to their equilibration half-lives (t1/2keo; hysteresis measure). t1/2keo for heart rate was 17 min, saccadic eye movements and adaptive tracking 1–1.5 h, body sway, smooth pursuit, visual analogue scales alertness and psychedelic 2.5–3.5 h, pupil size, finger tapping and visual analogue scales feeling high more than 8 h. CONCLUSIONS Scopolamine affected different CNS functions in a concentration-dependent manner, which based on their distinct PK–PD characteristics seemed to reflect multiple distinct functional pathways of the cholinergic system. All PD effects showed considerable albeit variable delays compared with plasma concentrations. The t1/2keo of the central effects was longer than of the peripheral effects on heart rate, which at least partly reflects the long CNS retention of scopolamine, but possibly also the triggering of independent secondary mechanisms. PK–PD analysis can optimize scopolamine administration regimens for future research and give insight into the physiology and pharmacology of human cholinergic systems. PMID:21306419

Electron irradiation response on Ge and Al-doped SiO 2 optical fibres

NASA Astrophysics Data System (ADS)

Yaakob, N. H.; Wagiran, H.; Hossain, I.; Ramli, A. T.; Bradley, D. A.; Hashim, S.; Ali, H.

2011-05-01

This paper describes the thermoluminescence response, sensitivity, stability and reproducibility of SiO 2 optical fibres with various electron energies and doses. The TL materials that comprise Al- and Ge-doped silica fibres were used in this experiment. The TL results are compared with those of the commercially available TLD-100. The doped SiO 2 optical fibres and TLD-100 are placed in a solid phantom and irradiated with 6, 9 and 12 MeV electron beams at doses ranging from 0.2 to 4.0 Gy using the LINAC at Hospital Sultan Ismail, Johor Bahru, Malaysia. It was found that the commercially available Al- and Ge-doped optical fibres have a linear dose-TL signal relationship. The intensity of TL response of Ge-doped fibre is markedly greater than that of the Al-doped fibre.

SU-F-T-554: Dark Current Effect On CyberKnife Beam Dosimetry

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

Kim, H; Chang, A

Purpose: All RF linear accelerators produce dark current to varying degrees when an accelerating voltage and RF input is applied in the absence of electron gun injection. This study is to evaluate how dark current from the linear accelerator of CyberKnife affect the dose in the reference dosimetry. Methods: The G4 CyberKnife system with 6MV photon beam was used in this study. Using the ion chamber and the diode detector, the dose was measured in water with varying time delay between acquiring charges and staring beam-on after applying high-voltage into the linear accelerator. The dose was measured after the timemore » delay with over the range of 0 to 120 seconds in the accelerating high-voltage mode without beam-on, applying 0, 10, 50, 100, and 200 MUs. For the measurements, the collimator of 60 mm was used and the detectors were placed at the depths of 10 cm with the source-to-surface distance of 80 cm. Results: The dark current was constant over time regardless of MU. The dose due to the dark current increased over time linearly with the R-squared value of 0.9983 up to 4.4 cGy for the time 120 seconds. In the dose rate setting of 720 MU/min, the relative dose when applying the accelerating voltage without beam-on was increased over time up to 0.6% but it was less than the leakage radiation resulted from the accelerated head. As the reference dosimetry condition, when 100 MU was delivered after 10 seconds time delay, the relative dose increased by 0.7% but 6.7% for the low MU (10 MU). Conclusion: In the dosimetry using CyberKnife system, the constant dark current affected to the dose. Although the time delay in the accelerating high-voltage mode without beam-on is within 10 seconds, the dose less than 100 cGy can be overestimated more than 1%.« less

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

PubMed Central

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

2014-01-01

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

Dependence of pentobarbital kinetics upon the dose of the drug and its pharmacodynamic effects.

PubMed

Kozlowski, K H; Szaykowski, A; Danysz, A

1977-01-01

Pentobarbital (PB), at dose range of 20--50 mg/kg, displays in rabbits non-linear, dose-dependent kinetics. Pharmacokinetics parameters of drug elimination depend largely upon the dose, while the distribution phase is dose-independent. The rate of disappearance of PB from the central compartment (plasma) decreases with the increase of the dose. The analysis of pharmacodynamic parameters has shown that this dose-dependent retardation of PB elimination is probably caused by an impairment of metabolic processes, resulting from disturbance of the circulatory system. A close correlation has been found between the hypotensive effect of PB and the elimination constant, k13, and also between the hypotensive effect and beta.Vd(extrap), a coefficient proportional to the rate of metabolism of PB [23, 29]. The results indicate the necessity of considering the changes in the functional state of the organism, related to the action of a drug, in pharmacokinetic studies.

A flexible-dose dispenser for immediate and extended release 3D printed tablets.

PubMed

Pietrzak, Katarzyna; Isreb, Abdullah; Alhnan, Mohamed A

2015-10-01

The advances in personalised medicine increased the demand for a fast, accurate and reliable production method of tablets that can be digitally controlled by healthcare staff. A flexible dose tablet system is presented in this study that proved to be suitable for immediate and extended release tablets with a realistic drug loading and an easy-to-swallow tablet design. The method bridges the affordable and digitally controlled Fused Deposition Modelling (FDM) 3D printing with a standard pharmaceutical manufacturing process, Hot Melt Extrusion (HME). The reported method was compatible with three methacrylic polymers (Eudragit RL, RS and E) as well as a cellulose-based one (hydroxypropyl cellulose, HPC SSL). The use of a HME based pharmaceutical filament preserved the linear relationship between the mass and printed volume and was utilized to digitally control the dose via an input from computer software with dose accuracy in the range of 91-95%. Higher resolution printing quality doubled the printing time, but showed a little effect on in vitro release pattern of theophylline and weight accuracy. Physical characterization studies indicated that the majority of the model drug (theophylline) in the 3D printed tablet exists in a crystal form. Owing to the small size, ease of use and the highly adjustable nature of FDM 3D printers, the method holds promise for future individualised treatment. Copyright © 2015. Published by Elsevier B.V.

Parent health literacy and adherence-related outcomes in children with epilepsy.

PubMed

Paschal, Angelia M; Mitchell, Qshequilla P; Wilroy, Jereme D; Hawley, Suzanne R; Mitchell, Jermaine B

2016-03-01

The relationship between parent health literacy and adherence to treatment in children with epilepsy has not been fully explored. The purpose of this study was to determine whether parent health literacy and other variables predicted factors associated with adherence, such as missed medication doses, missed medical appointments, and seizure frequency, in children with epilepsy between 1 and 12 years old. It was hypothesized that parents with adequate parent health literacy would report fewer missed doses, missed appointments, and seizure occurrences. Using a nonexperimental, cross-sectional study design, interviews were conducted with 146 parents and guardians of children with epilepsy who resided in rural communities. Univariate analyses, including ANOVA, and multiple linear regressions were conducted. Results indicated that parent health literacy was the strongest predictor of two of the adherence-related factors. Higher health literacy scores were associated with fewer missed medication doses and seizure occurrences. However, health literacy was not associated with missed medical appointments. Among other study variables, higher household income was also predictive of fewer missed doses. The study findings suggest that inadequate health literacy among parents may serve as an independent risk factor for adherence-related outcomes among children with epilepsy. Further research, as well as effective, targeted parent health literacy strategies used to improve epilepsy management and care in children, is recommended. Copyright © 2015 Elsevier Inc. All rights reserved.

Accuracy and efficiency of published film dosimetry techniques using a flat-bed scanner and EBT3 film.

PubMed

Spelleken, E; Crowe, S B; Sutherland, B; Challens, C; Kairn, T

2018-03-01

Gafchromic EBT3 film is widely used for patient specific quality assurance of complex treatment plans. Film dosimetry techniques commonly involve the use of transmission scanning to produce TIFF files, which are analysed using a non-linear calibration relationship between the dose and red channel net optical density (netOD). Numerous film calibration techniques featured in the literature have not been independently verified or evaluated. A range of previously published film dosimetry techniques were re-evaluated, to identify whether these methods produce better results than the commonly-used non-linear, netOD method. EBT3 film was irradiated at calibration doses between 0 and 4000 cGy and 25 pieces of film were irradiated at 200 cGy to evaluate uniformity. The film was scanned using two different scanners: The Epson Perfection V800 and the Epson Expression 10000XL. Calibration curves, uncertainty in the fit of the curve, overall uncertainty and uniformity were calculated following the methods described by the different calibration techniques. It was found that protocols based on a conventional film dosimetry technique produced results that were accurate and uniform to within 1%, while some of the unconventional techniques produced much higher uncertainties (> 25% for some techniques). Some of the uncommon methods produced reliable results when irradiated to the standard treatment doses (< 400 cGy), however none could be recommended as an efficient or accurate replacement for a common film analysis technique which uses transmission scanning, red colour channel analysis, netOD and a non-linear calibration curve for measuring doses up to 4000 cGy when using EBT3 film.

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.

Radiation Dose and Subsequent Risk for Stomach Cancer in Long-term Survivors of Cervical Cancer

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

Kleinerman, Ruth A., E-mail: kleinerr@mail.nih.gov; Smith, Susan A.; Holowaty, Eric

2013-08-01

Purpose: To assess the dose–response relationship for stomach cancer after radiation therapy for cervical cancer. Methods and Materials: We conducted a nested, matched case–control study of 201 cases and 378 controls among 53,547 5-year survivors of cervical cancer diagnosed from 1943 to 1995, from 5 international, population-based cancer registries. We estimated individual radiation doses to the site of the stomach cancer for all cases and to corresponding sites for the matched controls (overall mean stomach tumor dose, 2.56 Gy, range 0.03-46.1 and after parallel opposed pelvic fields, 1.63 Gy, range 0.12-6.3). Results: More than 90% of women received radiation therapy,more » mostly with external beam therapy in combination with brachytherapy. Stomach cancer risk was nonsignificantly increased (odds ratio 1.27-2.28) for women receiving between 0.5 and 4.9 Gy to the stomach cancer site and significantly increased at doses ≥5 Gy (odds ratio 4.20, 95% confidence interval 1.41-13.4, P{sub trend}=.047) compared with nonirradiated women. A highly significant radiation dose–response relationship was evident when analyses were restricted to the 131 cases (251 controls) whose stomach cancer was located in the middle and lower portions of the stomach (P{sub trend}=.003), whereas there was no indication of increasing risk with increasing dose for 30 cases (57 controls) whose cancer was located in the upper stomach (P{sub trend}=.23). Conclusions: Our findings show for the first time a significant linear dose–response relationship for risk of stomach cancer in long-term survivors of cervical cancer.« less

The link between tissue elasticity and thermal dose in vivo

NASA Astrophysics Data System (ADS)

Sapin-de Brosses, Emilie; Pernot, Mathieu; Tanter, Mickaël

2011-12-01

The objective of this study was to investigate in vivo the relationship between stiffness and thermal dose. For this purpose, shear wave elastography (SWE)—a novel ultrasound-based technique for real-time mapping of the stiffness of biological soft tissues—is performed in temperature-controlled experiments. Experiments were conducted on nine anesthetized rats. Their right leg was put in a thermo-regulated waterbath. The right leg of each animal was heated at one particular temperature between 38 °C and 48.5 °C for 15 min to 3 h. Shear waves were generated in the muscle using the acoustic radiation force induced by a linear ultrasonic probe. The shear wave propagation was imaged in real time by the probe using an ultrafast scanner prototype (10 000 frames s-1). The local tissue stiffness was derived from the shear wave speed. Two optical fiber sensors were inserted into the muscle to measure in situ the temperature. Stiffness was found to increase strongly during the experiments. When expressed as a function of the thermal dose, the stiffness curves were found to be the same for all experiments. A thermal dose threshold was found at 202 min for an eightfold stiffness increase. Finally, the time-temperature relationship was established for different stiffness ratios. The slope of the time-temperature relationship based on stiffness measurements was found identical to the one obtained for cell death in the seminal paper on the thermal dose by Sapareto and Dewey in 1984 (Int. J. Radiat. Oncol. Biol. Phys. 10 787-800). The present results highlight the stiffness increase as a good indicator of thermal necrosis. SWE imaging can be used in vivo for necrosis threshold determination in thermal therapy.

Dose-Effect Relationships for Adverse Events After Cranial Radiation Therapy in Long-term Childhood Cancer Survivors

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

Dijk, Irma W.E.M. van, E-mail: i.w.vandijk@amc.uva.nl; Cardous-Ubbink, Mathilde C.; Pal, Helena J.H. van der

Purpose: To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. Methods and Materials: The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD{sub 2}). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 yearsmore » after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD{sub 2} in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. Results: There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD{sub 2}, we found significant dose-effect relationships for these and other AEs. Conclusion: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD{sub 2} instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.« less

High Relative Biologic Effectiveness of Carbon Ion Radiation on Induction of Rat Mammary Carcinoma and its Lack of H-ras and Tp53 Mutations

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

Imaoka, Tatsuhiko; Nishimura, Mayumi; Kakinuma, Shizuko

2007-09-01

Purpose: The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon ion radiation and molecular changes that occur in the rat mammary cancer model. Methods and Materials: We observed 7-8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiation (0.05-2 Gy) with either 290 MeV/u carbon ions with a spread out Bragg peak (LET 40-90 keV/{mu}m) generated from the Heavy-Ion Medical Acceleratormore » in Chiba or {sup 137}Cs {gamma}-rays. Results: Carbon ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose-effect relationship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction. In contrast, {approx}10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor {alpha}. All carcinomas examined were free of common H-ras and Tp53 mutations. Importantly, lung metastasis (7%) was characteristic of carbon ion-irradiated rats. Conclusions: We found clear genetic variability in the susceptibility to carbon ion-induced mammary carcinomas. The high RBE for carbon ion radiation further supports the importance of precise dose localization in radiotherapy. Common point mutations in H-ras and Tp53 were not involved in carbon ion induction of rat mammary carcinomas.« less

High relative biologic effectiveness of carbon ion radiation on induction of rat mammary carcinoma and its lack of H-ras and Tp53 mutations.

PubMed

Imaoka, Tatsuhiko; Nishimura, Mayumi; Kakinuma, Shizuko; Hatano, Yukiko; Ohmachi, Yasushi; Yoshinaga, Shinji; Kawano, Akihiro; Maekawa, Akihiko; Shimada, Yoshiya

2007-09-01

The high relative biologic effectiveness (RBE) of high-linear energy transfer (LET) heavy-ion radiation has enabled powerful radiotherapy. The potential risk of later onset of secondary cancers, however, has not been adequately studied. We undertook the present study to clarify the RBE of therapeutic carbon ion radiation and molecular changes that occur in the rat mammary cancer model. We observed 7-8-week-old rats (ACI, F344, Wistar, and Sprague-Dawley) until 1 year of age after irradiation (0.05-2 Gy) with either 290 MeV/u carbon ions with a spread out Bragg peak (LET 40-90 keV/mum) generated from the Heavy-Ion Medical Accelerator in Chiba or (137)Cs gamma-rays. Carbon ions significantly induced mammary carcinomas in Sprague-Dawley rats but less so in other strains. The dose-effect relationship for carcinoma incidence in the Sprague-Dawley rats was concave downward, providing an RBE of 2 at a typical therapeutic dose per fraction. In contrast, approximately 10 should be considered for radiation protection at low doses. Immunohistochemically, 14 of 18 carcinomas were positive for estrogen receptor alpha. All carcinomas examined were free of common H-ras and Tp53 mutations. Importantly, lung metastasis (7%) was characteristic of carbon ion-irradiated rats. We found clear genetic variability in the susceptibility to carbon ion-induced mammary carcinomas. The high RBE for carbon ion radiation further supports the importance of precise dose localization in radiotherapy. Common point mutations in H-ras and Tp53 were not involved in carbon ion induction of rat mammary carcinomas.

A composite microdose Adaptive Response (AR) and Bystander Effect (BE) model-application to low LET and high LET AR and BE data.

PubMed

Leonard, Bobby E

2008-08-01

It has been suggested that Adaptive Response (AR) may reduce risk of adverse health effects due to ionizing radiation. But very low dose Bystander Effects (BE) may impose dominant deleterious human risks. These conflicting behaviors have stimulated controversy regarding the Linear No-Threshold human risk model. A dose and dose rate-dependent microdose model, to examine AR behavior, was developed in prior work. In the prior work a number of in vitro and in vivo dose response data were examined with the model. Recent new data show AR behavior with some evidence of very low dose BE. The purpose of this work is to supplement the microdose model to encompass the Brenner and colleagues BaD (Bystander and Direct Damage) model and apply this composite model to obtain new knowledge regarding AR and BE and illustrate the use of the model to plan radio-biology experiments. The biophysical composite AR and BE Microdose Model quantifies the accumulation of hits (Poisson distributed, microdose specific energy depositions) to cell nucleus volumes. This new composite AR and BE model provides predictions of dose response at very low dose BE levels, higher dose AR levels and even higher dose Direct (linear-quadratic) Damage radiation levels. We find good fits of the model to both BE data from the Columbia University microbeam facility and combined AR and BE data for low Linear Energy Transfer (LET) and high LET data. A Bystander Factor of about 27,000 and an AR protection factor of 0.61 are obtained for the low LET in vivo mouse spleen exposures. A Bystander Factor of 317 and an AR protection factor of 0.53 are obtained for high LET radon alpha particles in human lymphocytes. In both cases the AR is activated at most by one or two radiation induced charged particle traversals through the cell nucleus. The results of the model analysis is consistent with a premise that both Bystander damage and Adaptive Response radioprotection can occur in the same cell type, derived from the same cell species. The model provides an analytical tool to biophysically study the combined effects of BE and AR.

A network model of successive partitioning-limited solute diffusion through the stratum corneum.

PubMed

Schumm, Phillip; Scoglio, Caterina M; van der Merwe, Deon

2010-02-07

As the most exposed point of contact with the external environment, the skin is an important barrier to many chemical exposures, including medications, potentially toxic chemicals and cosmetics. Traditional dermal absorption models treat the stratum corneum lipids as a homogenous medium through which solutes diffuse according to Fick's first law of diffusion. This approach does not explain non-linear absorption and irregular distribution patterns within the stratum corneum lipids as observed in experimental data. A network model, based on successive partitioning-limited solute diffusion through the stratum corneum, where the lipid structure is represented by a large, sparse, and regular network where nodes have variable characteristics, offers an alternative, efficient, and flexible approach to dermal absorption modeling that simulates non-linear absorption data patterns. Four model versions are presented: two linear models, which have unlimited node capacities, and two non-linear models, which have limited node capacities. The non-linear model outputs produce absorption to dose relationships that can be best characterized quantitatively by using power equations, similar to the equations used to describe non-linear experimental data.

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.

Effects of Alcohol on Performance on a Distraction Task During Simulated Driving

PubMed Central

Allen, Allyssa J.; Meda, Shashwath A.; Skudlarski, Pawel; Calhoun, Vince; Astur, Robert; Ruopp, Kathryn C.; Pearlson, Godfrey D.

2009-01-01

Background Prior studies report that accidents involving intoxicated drivers are more likely to occur during performance of secondary tasks. We studied this phenomenon, using a dual-task paradigm, involving performance of a visual oddball (VO) task while driving in an alcohol challenge paradigm. Previous functional MRI (fMRI) studies of the VO task have shown activation in the anterior cingulate, hippocampus, and prefrontal cortex. Thus, we predicted dose-dependent decreases in activation of these areas during VO performance. Methods Forty healthy social drinkers were administered 3 different doses of alcohol, individually tailored to their gender and weight. Participants performed a VO task while operating a virtual reality driving simulator in a 3T fMRI scanner. Results Analysis showed a dose-dependent linear decrease in Blood Oxygen Level Dependent activation during task performance, primarily in hippocampus, anterior cingulate, and dorsolateral prefrontal areas, with the least activation occurring during the high dose. Behavioral analysis showed a dose-dependent linear increase in reaction time, with no effects associated with either correct hits or false alarms. In all dose conditions, driving speed decreased significantly after a VO stimulus. However, at the high dose this decrease was significantly less. Passenger-side line crossings significantly increased at the high dose. Conclusions These results suggest that driving impairment during secondary task performance may be associated with alcohol-related effects on the above brain regions, which are involved with attentional processing/decision-making. Drivers with high blood alcohol concentrations may be less able to orient or detect novel or sudden stimuli during driving. PMID:19183133

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients.

PubMed

Zafar, M Urooj; Farkouh, Michael E; Osende, Julio; Shimbo, Daichi; Palencia, Stella; Crook, Julia; Leadley, Robert; Fuster, Valentin; Chesebro, James H

2007-03-01

It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrombosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with clopidogrel, but none with heparin. Coronary patients (n = 18, 59 +/- 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor- Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [EoI], and four hours and eight hours after EoI, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to EoI were 29%, 34% and 68%, respectively (p < 0.001), and at 8-h post EoI were 11%, 19% and 27%, respectively (p < 0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson's r = 0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein IIbIIIa inhibition.

Joint nonparametric correction estimator for excess relative risk regression in survival analysis with exposure measurement error

PubMed Central

Wang, Ching-Yun; Cullings, Harry; Song, Xiao; Kopecky, Kenneth J.

2017-01-01

SUMMARY Observational epidemiological studies often confront the problem of estimating exposure-disease relationships when the exposure is not measured exactly. In the paper, we investigate exposure measurement error in excess relative risk regression, which is a widely used model in radiation exposure effect research. In the study cohort, a surrogate variable is available for the true unobserved exposure variable. The surrogate variable satisfies a generalized version of the classical additive measurement error model, but it may or may not have repeated measurements. In addition, an instrumental variable is available for individuals in a subset of the whole cohort. We develop a nonparametric correction (NPC) estimator using data from the subcohort, and further propose a joint nonparametric correction (JNPC) estimator using all observed data to adjust for exposure measurement error. An optimal linear combination estimator of JNPC and NPC is further developed. The proposed estimators are nonparametric, which are consistent without imposing a covariate or error distribution, and are robust to heteroscedastic errors. Finite sample performance is examined via a simulation study. We apply the developed methods to data from the Radiation Effects Research Foundation, in which chromosome aberration is used to adjust for the effects of radiation dose measurement error on the estimation of radiation dose responses. PMID:29354018

Non-linear effects of the built environment on automobile-involved pedestrian crash frequency: A machine learning approach.

PubMed

Ding, Chuan; Chen, Peng; Jiao, Junfeng

2018-03-01

Although a growing body of literature focuses on the relationship between the built environment and pedestrian crashes, limited evidence is provided about the relative importance of many built environment attributes by accounting for their mutual interaction effects and their non-linear effects on automobile-involved pedestrian crashes. This study adopts the approach of Multiple Additive Poisson Regression Trees (MAPRT) to fill such gaps using pedestrian collision data collected from Seattle, Washington. Traffic analysis zones are chosen as the analytical unit. The effects of various factors on pedestrian crash frequency investigated include characteristics the of road network, street elements, land use patterns, and traffic demand. Density and the degree of mixed land use have major effects on pedestrian crash frequency, accounting for approximately 66% of the effects in total. More importantly, some factors show clear non-linear relationships with pedestrian crash frequency, challenging the linearity assumption commonly used in existing studies which employ statistical models. With various accurately identified non-linear relationships between the built environment and pedestrian crashes, this study suggests local agencies to adopt geo-spatial differentiated policies to establish a safe walking environment. These findings, especially the effective ranges of the built environment, provide evidence to support for transport and land use planning, policy recommendations, and road safety programs. Copyright © 2018 Elsevier Ltd. All rights reserved.

Dose requirements of alfentanil to eliminate autonomic responses during rapid-sequence induction with thiopental 4 mg/kg and rocuronium 0.6 mg/kg.

PubMed

Abou-Arab, Mohammad H; Rostrup, Morten; Heier, Tom

2016-12-01

Opioids are integral part of anesthesia induction, but information on optimal dosing is limited. We aimed to determine doses of alfentanil needed to eliminate increases in 5 autonomic response variables (plasma concentrations of epinephrine, norepinephrine and vasopressin, arterial blood pressure [ABP], and heart rate) during rapid-sequence induction of anesthesia with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Prospective, randomized, observer-blinded, interventional clinical study. Large academic institution. Eighty-four healthy patients, aged 18 to 55 years, received 1 of 7 assessor-blinded doses of alfentanil (0, 10, 20, 30, 40, 50, and 60 μg/kg) together with thiopental 4 mg/kg and rocuronium 0.6 mg/kg, administered in rapid succession (15 seconds). Laryngoscopy was initiated 40 seconds after rocuronium, and tracheal intubation was concluded within 15 seconds thereafter. An indwelling radial artery catheter was used for hemodynamic monitoring and blood sampling. Relationships between alfentanil dose and response variables were tested with linear regression, and the influence of covariates (sex, body weight, and age) was determined. Alfentanil dose needed to prevent increases in ABP >10% above baseline with 95% probability was estimated with logistic regression. Significant relationships were determined between alfentanil dose and response variables. Clinically interesting influence of covariates was not found. Alfentanil 55 μg/kg was needed to prevent increases in ABP postintubation >10% above baseline with 95% probability. One individual needed a bolus of vasopressor postintubation. Optimal control of autonomic responses during rapid-sequence induction was achieved with clinically relevant doses of alfentanil in healthy patients anesthetized with thiopental 4 mg/kg and rocuronium 0.6 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

Estimation of the initial slope of the cell survival curve after irradiation from micronucleus frequency in cytokinesis-blocked cells

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

Ono, K.; Masunaga, S.; Akaboshi, M.

1994-04-01

We have already reported that the {alpha}/{beta} ratio of the cell survival curve could be estimated from the micronucleus frequency in cytokinesis-blocked cells treated with cytochalasin-B after irradiation. In this paper, we investigate the direct relationship between the {alpha} value and the appearance of micronuclei. Cells of the SCCVII, RIF-1, EMT6, V-79, CHO, HeLa and human esophageal cancer cell lines were used for the study. Low-dose-rate irradiation was used to determine the {alpha} component of the relationship between dose and micronucleus frequency according to the linear-quadratic (LQ) model. A reduction of the dose rate from 3.09 to 0.0142 Gy/min correspondinglymore » decreased the micronucleus frequency; however, the fraction of binucleate cells without micronuclei was not affected in SCCVII and RIF-1 cells. When this fraction was defined as the normal nuclear division fraction, it decreased exponentially as a function of radiation dose. Then dose vs normal nuclear division fraction (NNDF) was fitted as follows: -In NNDF = aD + C, where D is radiation dose in grays and C is constant. The slope of the dose vs normal nuclear division fraction was not affected by dose rate. The correlation was also explored between the slope (a) and the {alpha} value of the cell survival curve determined by the colony formation assay in cells of eight cell lines. These two values showed extremely high agreement: {alpha} = 1.01a + 0.00795 (r = 0.99, P < 0.01). This assay was applied to estimate the {alpha} value of the cell survival curve of human esophageal cancer cell lines established from surgical specimens. 13 refs., 5 figs.« less

Co-occurrence of psychotic experiences and common mental health conditions across four racially and ethnically diverse population samples.

PubMed

DeVylder, J E; Burnette, D; Yang, L H

2014-12-01

Prior research with racially/ethnically homogeneous samples has demonstrated widespread co-occurrence of psychotic experiences (PEs) and common mental health conditions, particularly multi-morbidity, suggesting that psychosis may be related to the overall severity of psychiatric disorder rather than any specific subtype. In this study we aimed to examine whether PEs are associated with the presence of specific disorders or multi-morbidity of co-occurring disorders across four large racially/ethnically diverse samples of adults in the USA. Data were drawn from the National Comorbidity Survey Replication (NCS-R), the National Survey of American Life (NSAL) and separately from the Asian and Latino subsamples of the National Latino and Asian American Study (NLAAS). Logistic regression models were used to examine the relationship between PEs and individual subtypes of DSM-IV disorder, and to test for a linear dose-response relationship between the number of subtypes and PEs. Prevalence of PEs was moderately greater among individuals with each subtype of disorder in each data set [odds ratios (ORs) 1.8-3.8], although associations were only variably significant when controlling for clinical and demographic variables. However, the sum of disorder subtypes was related to odds for PEs in a linear dose-response fashion across all four samples. PEs are related primarily to the extent or severity of psychiatric illness, as indicated by the presence of multiple psychiatric disorders, rather than to any particular subtype of disorder in these data. This relationship applies to the general population and across diverse racial/ethnic groups.

The relationship of body mass index and abdominal fat on the radiation dose received during routine computed tomographic imaging of the abdomen and pelvis.

PubMed

Chan, Victoria O; McDermott, Shaunagh; Buckley, Orla; Allen, Sonya; Casey, Michael; O'Laoide, Risteard; Torreggiani, William C

2012-11-01

To determine the relationship of increasing body mass index (BMI) and abdominal fat on the effective dose acquired from computed tomography (CT) abdomen and pelvis scans. Over 6 months, dose-length product and total milliamp-seconds (mAs) from routine CT abdomen and pelvis scans of 100 patients were recorded. The scans were performed on a 64-slice CT scanner by using an automatic exposure control system. Effective dose (mSv) based on dose-length product, BMI, periumbilical fat thickness, and intra-abdominal fat were documented for each patient. BMI, periumbilical fat thickness, and intra-abdominal fat were compared with effective dose. Thirty-nine men and 61 women were included in the study (mean age, 56.3 years). The mean BMI was 26.2 kg/m(2). The mean effective dose was 10.3 mSv. The mean periumbilical fat thickness was 2.4 cm. Sixty-five patients had a small amount of intra-abdominal fat, and 35 had a large amount of intra-abdominal fat. The effective dose increased with increasing BMI (P < .001) and increasing amounts of intra-abdominal fat (P < .001). For every kilogram of weight, there is a 0.13 mSv increase in effective dose, which is equal to 6.5 chest radiographs per CT examination. For an increase in BMI by 5 kg/m(2), there is a 1.95 mSv increase in effective dose, which is equal to 97.5 chest radiographs per CT examination. Increasing BMI and abdominal fat significantly increases the effective dose received from CT abdomen and pelvis scans. Copyright © 2012 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

Experimental evaluation of a GPU-based Monte Carlo dose calculation algorithm in the Monaco treatment planning system.

PubMed

Paudel, Moti R; Kim, Anthony; Sarfehnia, Arman; Ahmad, Sayed B; Beachey, David J; Sahgal, Arjun; Keller, Brian M

2016-11-08

A new GPU-based Monte Carlo dose calculation algorithm (GPUMCD), devel-oped by the vendor Elekta for the Monaco treatment planning system (TPS), is capable of modeling dose for both a standard linear accelerator and an Elekta MRI linear accelerator. We have experimentally evaluated this algorithm for a standard Elekta Agility linear accelerator. A beam model was developed in the Monaco TPS (research version 5.09.06) using the commissioned beam data for a 6 MV Agility linac. A heterogeneous phantom representing several scenarios - tumor-in-lung, lung, and bone-in-tissue - was designed and built. Dose calculations in Monaco were done using both the current clinical Monte Carlo algorithm, XVMC, and the new GPUMCD algorithm. Dose calculations in a Pinnacle TPS were also produced using the collapsed cone convolution (CCC) algorithm with heterogeneity correc-tion. Calculations were compared with the measured doses using an ionization chamber (A1SL) and Gafchromic EBT3 films for 2 × 2 cm2, 5 × 5 cm2, and 10 × 10 cm2 field sizes. The percentage depth doses (PDDs) calculated by XVMC and GPUMCD in a homogeneous solid water phantom were within 2%/2 mm of film measurements and within 1% of ion chamber measurements. For the tumor-in-lung phantom, the calculated doses were within 2.5%/2.5 mm of film measurements for GPUMCD. For the lung phantom, doses calculated by all of the algorithms were within 3%/3 mm of film measurements, except for the 2 × 2 cm2 field size where the CCC algorithm underestimated the depth dose by ~ 5% in a larger extent of the lung region. For the bone phantom, all of the algorithms were equivalent and calculated dose to within 2%/2 mm of film measurements, except at the interfaces. Both GPUMCD and XVMC showed interface effects, which were more pronounced for GPUMCD and were comparable to film measurements, whereas the CCC algorithm showed these effects poorly. © 2016 The Authors.

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

Sugano, Yasutaka; Mizuta, Masahiro; Takao, Seishin

Purpose: Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose–volume histograms for tumor and normal tissues of organs around the tumor. Methods: Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of themore » tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose–volume histogram. Results: It was found that the optimization of fractionation scheme incorporating the dose–volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8–32 fractions with a daily dose of 2.2–6.3 Gy. Conclusions: It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose–volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.« less

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

Paudel, M R; Beachey, D J; Sarfehnia, A

Purpose: A new commercial GPU-based Monte Carlo dose calculation algorithm (GPUMCD) developed by the vendor Elekta™ to be used in the Monaco Treatment Planning System (TPS) is capable of modeling dose for both a standard linear accelerator and for an Elekta MRI-Linear accelerator (modeling magnetic field effects). We are evaluating this algorithm in two parts: commissioning the algorithm for an Elekta Agility linear accelerator (the focus of this work) and evaluating the algorithm’s ability to model magnetic field effects for an MRI-linear accelerator. Methods: A beam model was developed in the Monaco TPS (v.5.09.06) using the commissioned beam data formore » a 6MV Agility linac. A heterogeneous phantom representing tumor-in-lung, lung, bone-in-tissue, and prosthetic was designed/built. Dose calculations in Monaco were done using the current clinical algorithm (XVMC) and the new GPUMCD algorithm (1 mm3 voxel size, 0.5% statistical uncertainty) and in the Pinnacle TPS using the collapsed cone convolution (CCC) algorithm. These were compared with the measured doses using an ionization chamber (A1SL) and Gafchromic EBT3 films for 2×2 cm{sup 2}, 5×5 cm{sup 2}, and 10×10 cm{sup 2} field sizes. Results: The calculated central axis percentage depth doses (PDDs) in homogeneous solid water were within 2% compared to measurements for XVMC and GPUMCD. For tumor-in-lung and lung phantoms, doses calculated by all of the algorithms were within the experimental uncertainty of the measurements (±2% in the homogeneous phantom and ±3% for the tumor-in-lung or lung phantoms), except for 2×2 cm{sup 2} field size where only the CCC algorithm differs from film by 5% in the lung region. The analysis for bone-in-tissue and the prosthetic phantoms are ongoing. Conclusion: The new GPUMCD algorithm calculated dose comparable to both the XVMC algorithm and to measurements in both a homogeneous solid water medium and the heterogeneous phantom representing lung or tumor-in-lung for 2×2 cm{sup 2}-10×10 cm{sup 2} field sizes. Funding support was obtained from Elekta.« less

The relationship between sleep disorders and testosterone in men

PubMed Central

Wittert, Gary

2014-01-01

Plasma testosterone levels display circadian variation, peaking during sleep, and reaching a nadir in the late afternoon, with a superimposed ultradian rhythm with pulses every 90 min reflecting the underlying rhythm of pulsatile luteinizing hormone (LH) secretion. The increase in testosterone is sleep, rather than circadian rhythm, dependent and requires at least 3 h of sleep with a normal architecture. Various disorders of sleep including abnormalities of sleep quality, duration, circadian rhythm disruption, and sleep-disordered breathing may result in a reduction in testosterone levels. The evidence, to support a direct effect of sleep restriction or circadian rhythm disruption on testosterone independent of an effect on sex hormone binding globulin (SHBG), or the presence of comorbid conditions, is equivocal and on balance seems tenuous. Obstructive sleep apnea (OSA) appears to have no direct effect on testosterone, after adjusting for age and obesity. However, a possible indirect causal process may exist mediated by the effect of OSA on obesity. Treatment of moderate to severe OSA with continuous positive airway pressure (CPAP) does not reliably increase testosterone levels in most studies. In contrast, a reduction in weight does so predictably and linearly in proportion to the amount of weight lost. Apart from a very transient deleterious effect, testosterone treatment does not adversely affect OSA. The data on the effect of sleep quality on testosterone may depend on whether testosterone is given as replacement, in supratherapeutic doses, or in the context abuse. Experimental data suggest that testosterone may modulate individual vulnerability to subjective symptoms of sleep restriction. Low testosterone may affect overall sleep quality which is improved by replacement doses. Large doses of exogenous testosterone and anabolic/androgenic steroid abuse are associated with abnormalities of sleep duration and architecture. PMID:24435056

Errors introduced by dose scaling for relative dosimetry

PubMed Central

Watanabe, Yoichi; Hayashi, Naoki

2012-01-01

Some dosimeters require a relationship between detector signal and delivered dose. The relationship (characteristic curve or calibration equation) usually depends on the environment under which the dosimeters are manufactured or stored. To compensate for the difference in radiation response among different batches of dosimeters, the measured dose can be scaled by normalizing the measured dose to a specific dose. Such a procedure, often called “relative dosimetry”, allows us to skip the time‐consuming production of a calibration curve for each irradiation. In this study, the magnitudes of errors due to the dose scaling procedure were evaluated by using the characteristic curves of BANG3 polymer gel dosimeter, radiographic EDR2 films, and GAFCHROMIC EBT2 films. Several sets of calibration data were obtained for each type of dosimeters, and a calibration equation of one set of data was used to estimate doses of the other dosimeters from different batches. The scaled doses were then compared with expected doses, which were obtained by using the true calibration equation specific to each batch. In general, the magnitude of errors increased with increasing deviation of the dose scaling factor from unity. Also, the errors strongly depended on the difference in the shape of the true and reference calibration curves. For example, for the BANG3 polymer gel, of which the characteristic curve can be approximated with a linear equation, the error for a batch requiring a dose scaling factor of 0.87 was larger than the errors for other batches requiring smaller magnitudes of dose scaling, or scaling factors of 0.93 or 1.02. The characteristic curves of EDR2 and EBT2 films required nonlinear equations. With those dosimeters, errors larger than 5% were commonly observed in the dose ranges of below 50% and above 150% of the normalization dose. In conclusion, the dose scaling for relative dosimetry introduces large errors in the measured doses when a large dose scaling is applied, and this procedure should be applied with special care. PACS numbers: 87.56.Da, 06.20.Dk, 06.20.fb PMID:22955658

Dosimetric evaluation of a new OneDose MOSFET for Ir-192 energy.

PubMed

Kinhikar, Rajesh A; Sharma, Pramod K; Tambe, Chandrashekhar M; Deshpande, Deepak D

2006-03-07

The purpose of this study was to investigate dosimetry (reproducibility, energy correction, relative response with distance from source, linearity with threshold dose, rate of fading, temperature and angular dependence) of a newly designed OneDosetrade mark MOSFET patient dosimetry system for use in HDR brachytherapy with Ir-192 energy. All measurements were performed with a MicroSelectron HDR unit and OneDose MOSFET detectors. All dosimeters were normalized to 3 min post-irradiation to minimize fading effects. All dosimeters gave reproducible readings with mean deviation of 1.8% (SD 0.4) and 2.4% (SD 0.6) for 0 degrees and 180 degrees incidences, respectively. The mean energy correction factor was found to be 1.1 (range 1.06-1.12). Overall, there was 60% and 40% mean response of the MOSFET at 2 and 3 cm, respectively, from the source. MOSFET results showed good agreement with TLD and parallel plate ion chamber. Linear dose response with threshold voltage shift was observed with applied doses of 0.3 Gy-5 Gy with Ir-192 energy. Linearity (R2 = 1) was observed in the MOSFET signal with the applied dose range of 0.3 Gy-5 Gy with Ir-192 energy. Fading effects were less than 1% after 10 min and the MOSFET detectors stayed stable (within 5%) over a period of 1 month. The MOSFET response was found to be decreased by approximately 1.5% at 37 degrees C compared to 20 degrees C. The isotropic response of the MOSFET was found to be within +/-6%. A maximum deviation of 5.5% was obtained between 0 degrees and 180 degrees for both the axes and this should be considered in clinical applications. The small size, cable-less, instant readout, permanent storage of dose and ease of use make the MOSFET a novel dosimeter and beneficial to patients for skin dose measurements with HDRBT using an Ir-192 source compared to the labour demanding and time-consuming TLDs.

Radiation protocols determine acute graft-versus-host disease incidence after allogeneic bone marrow transplantation in murine models.

PubMed

Schwarte, Sebastian; Bremer, Michael; Fruehauf, Joerg; Sorge, Yanina; Skubich, Susanne; Hoffmann, Matthias W

2007-09-01

Effects of radiation sources used for total body irradiation (TBI) on Graft-versus-Host Disease (GvHD) induction were examined. In a T cell receptor (TCR) transgenic mouse model, single fraction TBI was performed with different radiation devices ((60)Cobalt; (137)Cesium; 6 MV linear accelerator), dose rates (0.85; 1.5; 2.9; 5 Gy/min) and total doses before allogeneic bone marrow transplantation (BMT). Recipients were observed for 120 days. Different tissues were examined histologically. Acute GvHD was induced by a dose rate of 0.85 Gy/min ((60)Cobalt) and a total dose of 9 Gy and injection of 5 x 10(5) lymph node cells plus 5 x 10(6) bone marrow cells. Similar results were obtained using 6 MV linear accelerator- (linac-) photons with a dose rate of 1.5 Gy/min and 0.85 Gy/min, a total dose of 9.5 Gy and injection of same cell numbers. TBI with (137)Cesium (dose rate: 2.5 Gy/min) did not lead reproducibly to lethal acute GvHD. Experimental TBI in murine models may induce different immunological responses, depending on total energy, total single dose and dose rate. GvHD might also be induced by TBI with low dose rates.

Characterization of ferrous-methylthymol blue-polyvinyl alcohol gel dosimeters using nuclear magnetic resonance and optical techniques

NASA Astrophysics Data System (ADS)

Rabaeh, Khalid A.; Eyadeh, Molham M.; Hailat, Tariq F.; Aldweri, Feras M.; Alheet, Samer M.; Eid, Rania M.

2018-07-01

A new composition of Ferrous sulphate-Metheylthymol blue (MTB)-Polyvinyl alcohol (PVA) dosimeter is introduced in this work and evaluated using nuclear magnetic resonance (NMR) and absorbance spectrophotometry techniques. The Fricke-MTB-PVA dosimeters were irradiated using a medical linear accelerator in a cubic water phantom. The dose response of the dosimeters was investigated using NMR in terms of spin-spin relaxation rate (R2), and ultraviolet and visible regions (UV-Vis) spectrophotometry in terms of absorbance. The dosimeter presents a linear dose response for doses up to 20 Gy with UV-Vis and 40 Gy with NMR method. The sample with 0.1 mM MTB, 5% PVA by weight showed highest dose sensitivity for both techniques. The Fricke-MTB-PVA dosimeter developed in this work has a significant advance over the Fricke-MTB-gelatin system: the NMR sensitivity was remarkably improved; the auto-oxidation rate was seven times lower, and no significant dose rate or photon energy effects were observed.

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. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Ward, W.F.; Kim, Y.T.; Molteni, A.

The ability of the angiotensin converting enzyme (ACE) inhibitor Captopril to modify radiation-induced pulmonary endothelial dysfunction was determined in male rats sacrificed 2 months after a single dose of 10-30 Gy of /sup 60/Co gamma rays to the right hemithorax. Half of each dose group consumed feed containing 0.12% w/w Captopril (60 mg/kg/day) continuously after irradiation, and half consumed control feed. Four markers of endothelial function were monitored: ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. All data were plotted as dose-response curves, and subjected to linear regression analysis. The Captopril modifying effect was expressedmore » as the ratio of isoeffective doses at a common intermediate response (DRF), or as the ratio of the response curve slopes. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. Captopril exhibited DRF values of 1.4-2.1, and slope ratios of 1.4-5.1 for all four functional markers (p less than 0.05). Thus, the ACE inhibitor Captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats sacrificed 2 months postirradiation. Although the mechanism of Captopril action is not clear at present, these data suggest a novel application for this class of compounds as injury-modifying agents in irradiated lung.« less

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

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

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

1995-11-01

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

The Relationship Between Caffeine Intake and Immunological and Virological Markers of HIV Disease Progression in Miami Adult Studies on HIV Cohort.

PubMed

Ramamoorthy, Venkataraghavan; Campa, Adriana; Rubens, Muni; Martinez, Sabrina S; Fleetwood, Christina; Stewart, Tiffanie; Liuzzi, Juan P; George, Florence; Khan, Hafiz; Li, Yinghui; Baum, Marianna K

2017-05-01

Although there are many studies on adverse health effects of substance use and HIV disease progression, similar studies about caffeine consumption are few. In this study, we investigated the effects of caffeine on immunological and virological markers of HIV disease progression. A convenience sample of 130 clinically stable people living with HIV/AIDS on antiretroviral therapy (65 consuming ≤250 mg/day and 65 consuming >250 mg/day of caffeine) were recruited from the Miami Adult Studies on HIV (MASH) cohort. This study included a baseline and 3-month follow-up visit. Demographics, body composition measures, substance use, Modified Caffeine Consumption Questionnaire (MCCQ), and CD4 count and HIV viral load were obtained for all participants. Multivariable linear regression and Linear Mixed Models (LMMs) were used to understand the effect of caffeine consumption on CD4 count and HIV viral load. The mean age of the cohort was 47.9 ± 6.4 years, 60.8% were men and 75.4% were African Americans. All participants were on ART during both the visits. Mean caffeine intake at baseline was 337.6 ± 305.0 mg/day and did not change significantly at the 3-month follow-up visit. Multivariable linear regressions after adjustment for covariates showed significant association between caffeine consumption and higher CD4 count (β = 1.532, p = 0.049) and lower HIV viral load (β = -1.067, p = 0.048). LMM after adjustment for covariates showed that the relationship between caffeine and CD4 count (β = 1.720, p = 0.042) and HIV viral load (β = -1.389, p = 0.033) continued over time in a dose-response manner. Higher caffeine consumption was associated with higher CD4 cell counts and lower HIV viral loads indicating beneficial effects on HIV disease progression. Further studies examining biochemical effects of caffeine on CD4 cell counts and viral replication need to be done in the future.

SU-F-E-19: A Novel Method for TrueBeam Jaw Calibration

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

Corns, R; Zhao, Y; Huang, V

2016-06-15

Purpose: A simple jaw calibration method is proposed for Varian TrueBeam using an EPID-Encoder combination that gives accurate fields sizes and a homogeneous junction dose. This benefits clinical applications such as mono-isocentric half-beam block breast cancer or head and neck cancer treatment with junction/field matching. Methods: We use EPID imager with pixel size 0.392 mm × 0.392 mm to determine the radiation jaw position as measured from radio-opaque markers aligned with the crosshair. We acquire two images with different symmetric field sizes and record each individual jaw encoder values. A linear relationship between each jaw’s position and its encoder valuemore » is established, from which we predict the encoder values that produce the jaw positions required by TrueBeam’s calibration procedure. During TrueBeam’s jaw calibration procedure, we move the jaw with the pendant to set the jaw into position using the predicted encoder value. The overall accuracy is under 0.1 mm. Results: Our in-house software analyses images and provides sub-pixel accuracy to determine field centre and radiation edges (50% dose of the profile). We verified the TrueBeam encoder provides a reliable linear relationship for each individual jaw position (R{sup 2}>0.9999) from which the encoder values necessary to set jaw calibration points (1 cm and 19 cm) are predicted. Junction matching dose inhomogeneities were improved from >±20% to <±6% using this new calibration protocol. However, one technical challenge exists for junction matching, if the collimator walkout is large. Conclusion: Our new TrueBeam jaw calibration method can systematically calibrate the jaws to crosshair within sub-pixel accuracy and provides both good junction doses and field sizes. This method does not compensate for a larger collimator walkout, but can be used as the underlying foundation for addressing the walkout issue.« less

Breast cancer cell targeted MR molecular imaging probe: Anti-MUC1 antibody-based magnetic nanoparticles

NASA Astrophysics Data System (ADS)

Moradi Khaniabadi, P.; S. A Majid, A. M.; Asif, M.; Moradi Khaniabadi, B.; Shahbazi-Gahrouei, D.; Jaafar, M. S.

2017-05-01

Effective and specific diagnostic imaging techniques are important in early-stage breast cancer treatment. The objective of this study was to develop a specific breast cancer contrast agent for magnetic resonance imaging (MRI). In so doing, superparamagnetic iron oxide nanoparticles (SPIONs) were conjugated to C595 monoclonal antibody using EDC chemistry to produce nanoprobe with high relaxivity and narrow size (87.4±0.7 nm). To test the developed nanoprobe in vitro, assessments including Cell toxicity, targeting efficacy, cellular binding, and MR imaging were carried out. The results indicated that after 6 hrs incubation with MCF-7 cells at 200 to 25 µg Fe/ml doses, 76% to 16% T2 reduction was obtained. The presence of iron localised in MCF-7 cells measured by atomic absorption spectroscopy (AAS) was about 9.95±0.09 ppm iron/cell at higher doses of nanoprobe. Moreover, a linear relationship between iron concentration of nontoxic SPION-C595 and T2 relaxation times was observed. This study also revealed that developed nanoprobe might be used as a specific negative contrast agent for detecting breast cancer.

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

PubMed Central

Maziak, Wasim; Ward, Kenneth D; Rastam, Samer; Mzayek, Fawaz; Eissenberg, Thomas

2005-01-01

Background There is a dearth of standardized studies examining exposure to environmental tobacco smoke (ETS) and its relationship to respiratory health among adults in developing countries. Methods In 2004, the Syrian Center for Tobacco Studies (SCTS) conducted a population-based survey using stratified cluster sampling to look at issues related to environmental health of adults aged 18–65 years in Aleppo (2,500,000 inhabitants). Exposure to ETS was assessed from multiple self-reported indices combined into a composite score (maximum 22), while outcomes included both self-report (symptoms/diagnosis of asthma, bronchitis, and hay fever), and objective indices (spirometric assessment of FEV1 and FVC). Logistic and linear regression analyses were conducted to study the relation between ETS score and studied outcomes, whereby categorical (tertiles) and continuous scores were used respectively, to evaluate the association between ETS exposure and respiratory health, and explore the dose-response relationship of the association. Results Of 2038 participants, 1118 were current non-smokers with breath CO levels ≤ 10 ppm (27.1% men, mean age 34.7 years) and were included in the current analysis. The vast majority of study participants were exposed to ETS, whereby only 3.6% had ETS score levels ≤ 2. In general, there was a significant dose-response pattern in the relationship of ETS score with symptoms of asthma, hay fever, and bronchitis, but not with diagnoses of these outcomes. The magnitude of the effect was in the range of twofold increases in the frequency of symptoms reported in the high exposure group compared to the low exposure group. Severity of specific respiratory problems, as indicated by frequency of symptoms and health care utilization for respiratory problems, was not associated with ETS exposure. Exposure to ETS was associated with impaired lung function, indicative of airflow limitation, among women only. Conclusions This study provides evidence for the alarming extent of exposure to ETS among adult non-smokers in Syria, and its dose-response relationship with respiratory symptoms of infectious and non-infectious nature. It calls for concerted efforts to increase awareness of this public health problem and to enforce regulations aimed at protecting non-smokers. PMID:15701169

Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly.

PubMed

Evans, M V; Chiu, W A; Okino, M S; Caldwell, J C

2009-05-01

Trichloroethylene (TCE) is a lipophilic solvent rapidly absorbed and metabolized via oxidation and conjugation to a variety of metabolites that cause toxicity to several internal targets. Increases in liver weight (hepatomegaly) have been reported to occur quickly in rodents after TCE exposure, with liver tumor induction reported in mice after long-term exposure. An integrated dataset for gavage and inhalation TCE exposure and oral data for exposure to two of its oxidative metabolites (TCA and DCA) was used, in combination with an updated and more accurate physiologically-based pharmacokinetic (PBPK) model, to examine the question as to whether the presence of TCA in the liver is responsible for TCE-induced hepatomegaly in mice. The updated PBPK model was used to help discern the quantitative contribution of metabolites to this effect. The update of the model was based on a detailed evaluation of predictions from previously published models and additional preliminary analyses based on gas uptake inhalation data in mice. The parameters of the updated model were calibrated using Bayesian methods with an expanded pharmacokinetic database consisting of oral, inhalation, and iv studies of TCE administration as well as studies of TCE metabolites in mice. The dose-response relationships for hepatomegaly derived from the multi-study database showed that the proportionality of dose to response for TCE- and DCA-induced hepatomegaly is not observed for administered doses of TCA in the studied range. The updated PBPK model was used to make a quantitative comparison of internal dose of metabolized and administered TCA. While the internal dose of TCA predicted by modeling of TCE exposure (i.e., mg TCA/kg-d) showed a linear relationship with hepatomegaly, the slope of the relationship was much greater than that for directly administered TCA. Thus, the degree of hepatomegaly induced per unit of TCA produced through TCE oxidation is greater than that expected per unit of TCA administered directly, which is inconsistent with the hypothesis that TCA alone accounts for TCE-induced hepatomegaly. In addition, TCE-induced hepatomegaly showed a much more consistent relationship with PBPK model predictions of total oxidative metabolism than with predictions of TCE area-under-the-curve in blood, consistent with toxicity being induced by oxidative metabolites rather than the parent compound. Therefore, these results strongly suggest that oxidative metabolites in addition to TCA are necessary contributors to TCE-induced liver weight changes in mice.

Risk of breast cancer following low-dose radiation exposure

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

Boice, J.D. Jr.; Land, C.E.; Shore, R.E.

1979-06-01

Risk of breast cancer following radiation exposure was studied, based on surveys of tuberculosis patients who had multiple fluoroscopic examinations of the chest, mastitis patients given radiotherapy, and atomic bomb survivors. Analysis suggests that the risk is greatest for persons exposed as adolescents, although exposure at all ages carries some risk. The dose-response relationship was consistent with linearity in all studies. Direct evidence of radiation risk at doses under 0.5 Gy (50 rad) is apparent among A-bomb survivors. Fractionation does not appear to diminish risk, nor does time since exposure (even after 45 years of observation). The interval between exposuremore » and the clinical appearance of radiogenic breast cancer may be mediated by hormonal or other age-related factors but is unrelated to dose. Age-specific absolute risk estimtes for all studies are remarkably similar. The best estimate of risk among American women exposed after age 20 is 6.6 excess cancers/10/sup 4/ WY-Gy (10/sup 6/ WY-rad).« less

Risk Factors and Dose-Effect Relationship for Mandibular Osteoradionecrosis in Oral and Oropharyngeal Cancer Patients

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

Lee, Ik Jae; Koom, Woong Sub; Lee, Chang Geol, E-mail: cglee1023@yuhs.a

2009-11-15

Purpose: To analyze risk factors and the dose-effect relationship for osteoradionecrosis (ORN) of the mandible after radiotherapy of oral and oropharyngeal cancers. Materials and Methods: One-hundred ninety-eight patients with oral (45%) and oropharyngeal cancer (55%) who had received external radiotherapy between 1990 and 2000 were retrospectively reviewed. All patients had a dental evaluation before radiotherapy. The median radiation dose was 60 Gy (range, 16-75 Gy), and the median biologically effective dose for late effects (BED{sub late}) in bone was 114 Gy{sub 2} (range, 30-167 Gy{sub 2}). Results: The frequency of ORN was 13 patients (6.6%). Among patients with mandibular surgery,more » eight had ORN at the surgical site. Among patients without mandibular surgery, five patients had ORN on the molar area of the mandible. The median time to ORN was 22 months (range, 1-69 months). Univariate analysis revealed that mandibular surgery and Co-60 were significant risk factors for ORN (p = 0.01 and 0.04, respectively). In multivariate analysis, mandibular surgery was the most important factor (p = 0.001). High radiation doses over BED 102.6 Gy{sub 2} (conventional dose of 54 Gy at 1.8 Gy/fraction) were also a significant factor for ORN (p = 0.008) and showed a positive dose-effect relationship in logistic regression (p = 0.04) for patients who had undergone mandibular surgery. Conclusions: Mandibular surgery was the most significant risk factor for ORN of mandible in oral and oropharyngeal cancers patients. A BED of 102.6 Gy{sub 2} or higher to the mandible also significantly increases the risk of ORN.« less

SEMICONDUCTOR TECHNOLOGY: An efficient dose-compensation method for proximity effect correction

NASA Astrophysics Data System (ADS)

Ying, Wang; Weihua, Han; Xiang, Yang; Renping, Zhang; Yang, Zhang; Fuhua, Yang

2010-08-01

A novel simple dose-compensation method is developed for proximity effect correction in electron-beam lithography. The sizes of exposed patterns depend on dose factors while other exposure parameters (including accelerate voltage, resist thickness, exposing step size, substrate material, and so on) remain constant. This method is based on two reasonable assumptions in the evaluation of the compensated dose factor: one is that the relation between dose factors and circle-diameters is linear in the range under consideration; the other is that the compensated dose factor is only affected by the nearest neighbors for simplicity. Four-layer-hexagon photonic crystal structures were fabricated as test patterns to demonstrate this method. Compared to the uncorrected structures, the homogeneity of the corrected hole-size in photonic crystal structures was clearly improved.

THE EFFECT OF BACKGROUND SIGNAL AND ITS REPRESENTATION IN DECONVOLUTION OF EPR SPECTRA ON ACCURACY OF EPR DOSIMETRY IN BONE.

PubMed

Ciesielski, Bartlomiej; Marciniak, Agnieszka; Zientek, Agnieszka; Krefft, Karolina; Cieszyński, Mateusz; Boguś, Piotr; Prawdzik-Dampc, Anita

2016-12-01

This study is about the accuracy of EPR dosimetry in bones based on deconvolution of the experimental spectra into the background (BG) and the radiation-induced signal (RIS) components. The model RIS's were represented by EPR spectra from irradiated enamel or bone powder; the model BG signals by EPR spectra of unirradiated bone samples or by simulated spectra. Samples of compact and trabecular bones were irradiated in the 30-270 Gy range and the intensities of their RIS's were calculated using various combinations of those benchmark spectra. The relationships between the dose and the RIS were linear (R 2  > 0.995), with practically no difference between results obtained when using signals from irradiated enamel or bone as the model RIS. Use of different experimental spectra for the model BG resulted in variations in intercepts of the dose-RIS calibration lines, leading to systematic errors in reconstructed doses, in particular for high- BG samples of trabecular bone. These errors were reduced when simulated spectra instead of the experimental ones were used as the benchmark BG signal in the applied deconvolution procedures. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Coffee Consumption and Risk of Biliary Tract Cancers and Liver Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

PubMed

Godos, Justyna; Micek, Agnieszka; Marranzano, Marina; Salomone, Federico; Rio, Daniele Del; Ray, Sumantra

2017-08-28

A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose-response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC.

The effects of pig manure application on the spread of tetracycline resistance in bulk and cucumber rhizosphere soils: a greenhouse experiment.

PubMed

Kang, Yijun; Hao, Yangyang; Xia, Dan; Shen, Min; Li, Qing; Hu, Jian

2017-07-01

It is important to understand the dynamics of tetracycline-resistant bacteria (TRB) and tetracycline resistance genes (TRGs) in bulk and rhizosphere soils for evaluating the spread of TRGs from pig manure to human. In this work, a greenhouse experiment was conducted to investigate the difference in abundance of TRB, tetracycline-resistant Escherichia coli (TRE), tetracycline-resistant Pseudomonas spp. (TRP), and TRGs between bulk and cucumber rhizosphere soils. The application of pig manure resulted in the long-term persistence of TRB, TRE, TRP, and TRGs in bulk soil and rhizosphere of cucumber for at least 65 days. Pig manure application dose was the major driving force in altering the abundances of TRB and TRE, whereas TRP was disturbed mainly by compartment (bulk soil or rhizosphere). Both TRE and the percentage of TRE in bulk and rhizosphere soils increased linearly with an increase in dose of pig manure. The exponential relationships between pig manure dose and TRP along with TRP percentage were also noted. There were significant differences in the relative abundances of TRGs between bulk and cucumber rhizosphere soils, suggesting the use of pig manure exerted a more lasting impact on the spread of TRGs in the rhizosphere than in the bulk soil.

Impairment related to blood amphetamine and/or methamphetamine concentrations in suspected drugged drivers.

PubMed

Gustavsen, Ingebjørg; Mørland, Jørg; Bramness, Jørgen G

2006-05-01

Experimental studies have investigated effects of low oral doses of amphetamine and methamphetamine on psychomotor functions, while less work has been done on effects of high doses taken by abusers in real-life settings. There are indications that intake of high doses may impair traffic related skills, and that abuse of amphetamines may cause hypersomnolence at the end-of-binge. The present study aimed at investigating the concentration-effect relationship between blood amphetamines concentrations and impairment in a population of real-life users. Eight hundred and seventy-eight cases with amphetamine or methamphetamine as the only drugs present in the blood samples were selected from the impaired driver registry at The Norwegian Institute of Public Health. In each case the police physician had concluded on whether the driver was impaired or not. 27% of the drivers were judged as not impaired, while 73% were judged as impaired. There was a positive relationship between blood amphetamines concentrations and impairment. The relationship reached a ceiling at blood amphetamines concentrations of 0.27-0.53 mg/l. Younger drivers were more often judged impaired than older drivers at similar concentrations. Despite the performance enhancing qualities of amphetamines demonstrated in some low dose laboratory experiments; this study revealed a positive relationship between blood amphetamines concentration and traffic related impairment.

NOTE: Investigating the potential of polymer gel dosimetry for interventional radiology: first results

NASA Astrophysics Data System (ADS)

Antoniou, P. E.; Bousbouras, P.; Sandaltzopoulos, R.; Kaldoudi, E.

2008-04-01

Complex interventional radiology (IR) procedures contribute an increasing percentage of the overall medical radiation exposure of the population making accurate dosimetry a challenge. Magnetic resonance (MR) based polymer gel dosimetry has been widely employed in complex dosimetric problems in radiotherapy. The aim of this note is to investigate the feasibility of normoxic gel dosimetry in IR. Dose response, energy dependence and dose rate dependence were investigated in irradiation set-ups relevant to IR for a particular normoxic gel, based on methacrylic acid (MAA) as the monomer and including tetrakis-hydroxy-methyl-phosphonium chloride (THPC) as antioxidant. The gel presents a linear dose response beyond a 25 cGy threshold. No significant energy dependence was observed in the useful range of interventional radiology (80-110 kVp). A linear correlation between the gel response and dose rate was observed in the range of dose rates relevant to IR (5-8 cGy min-1). These results demonstrate a reduction of gel sensitivity at very low dose rate levels. A possible explanation of this effect is suggested.

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

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

Krmar, M.; Kuzmanović, A.; Nikolić, D.

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 themore » 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.« less

Comparison of two indices of exposure to polycyclic aromatic hydrocarbons in a retrospective aluminium smelter cohort.

PubMed

Friesen, Melissa C; Demers, Paul A; Spinelli, John J; Lorenzi, Maria F; Le, Nhu D

2007-04-01

The association between coal tar-derived substances, a complex mixture of polycyclic aromatic hydrocarbons, and cancer is well established. However, the specific aetiological agents are unknown. To compare the dose-response relationships for two common measures of coal tar-derived substances, benzene-soluble material (BSM) and benzo(a)pyrene (BaP), and to evaluate which among these is more strongly related to the health outcomes. The study population consisted of 6423 men with > or =3 years of work experience at an aluminium smelter (1954-97). Three health outcomes identified from national mortality and cancer databases were evaluated: incidence of bladder cancer (n = 90), incidence of lung cancer (n = 147) and mortality due to acute myocardial infarction (AMI, n = 184). The shape, magnitude and precision of the dose-response relationships and cumulative exposure levels for BSM and BaP were evaluated. Two model structures were assessed, where 1n(relative risk) increased with cumulative exposure (log-linear model) or with log-transformed cumulative exposure (log-log model). The BaP and BSM cumulative exposure metrics were highly correlated (r = 0.94). The increase in model precision using BaP over BSM was 14% for bladder cancer and 5% for lung cancer; no difference was observed for AMI. The log-linear BaP model provided the best fit for bladder cancer. The log-log dose-response models, where risk of disease plateaus at high exposure levels, were the best-fitting models for lung cancer and AMI. BaP and BSM were both strongly associated with bladder and lung cancer and modestly associated with AMI. Similar conclusions regarding the associations could be made regardless of the exposure metric.

Radiation dose and cataract surgery incidence in atomic bomb survivors, 1986-2005.

PubMed

Neriishi, Kazuo; Nakashima, Eiji; Akahoshi, Masazumi; Hida, Ayumi; Grant, Eric J; Masunari, Naomi; Funamoto, Sachiyo; Minamoto, Atsushi; Fujiwara, Saeko; Shore, Roy E

2012-10-01

To examine the incidence of clinically important cataracts in relation to lens radiation doses between 0 and approximately 3 Gy to address risks at relatively low brief doses. Informed consent was obtained, and human subjects procedures were approved by the ethical committee at the Radiation Effects Research Foundation. Cataract surgery incidence was documented for 6066 atomic bomb survivors during 1986-2005. Sixteen risk factors for cataract, such as smoking, hypertension, and corticosteroid use, were not confounders of the radiation effect on the basis of Cox regression analysis. Radiation dose-response analyses were performed for cataract surgery incidence by using Poisson regression analysis, adjusting for demographic variables and diabetes mellitus, and results were expressed as the excess relative risk (ERR) and the excess absolute risk (EAR) (ie, measures of how much radiation multiplies [ERR] or adds to [EAR] the risk in the unexposed group). Of 6066 atomic bomb survivors, 1028 underwent a first cataract surgery during 1986-2005. The estimated threshold dose was 0.50 Gy (95% confidence interval [CI]: 0.10 Gy, 0.95 Gy) for the ERR model and 0.45 Gy (95% CI: 0.10 Gy, 1.05 Gy) for the EAR model. A linear-quadratic test for upward curvature did not show a significant quadratic effect for either the ERR or EAR model. The linear ERR model for a 70-year-old individual, exposed at age 20 years, showed a 0.32 (95% CI: 0.09, 0.53) [corrected] excess risk at 1 Gy. The ERR was highest for those who were young at exposure. These data indicate a radiation effect for vision-impairing cataracts at doses less than 1 Gy. The evidence suggests that dose standards for protection of the eye from brief radiation exposures should be 0.5 Gy or less. © RSNA, 2012.

Coffee and caffeine consumption and depression: A meta-analysis of observational studies.

PubMed

Wang, Longfei; Shen, Xiaoli; Wu, Yili; Zhang, Dongfeng

2016-03-01

The results from observation studies on the relationship between coffee intake and risk of depression and the relationship between caffeine consumption and depression remain controversial. We conducted a meta-analysis with a dose-response analysis to quantitatively summarize the evidence about the association between coffee and caffeine intakes and risk of depression. Relevant articles were identified by researching PubMed, Web of Science, China National Knowledge Infrastructure and WANFANG DATA in English or Chinese from 1 January 1980 to 1 May 2015. Case-control, cohort or cross-sectional studies evaluating coffee or caffeine consumption and depression were included. A random-effects model was used to combine study-specific relative risk and 95% confidence interval. Dose-response relationship was assessed by restricted cubic spline functions. Data were obtained from 11 observation articles; 330,677 participants from seven studies in seven articles were included in the coffee-depression analysis, while 38,223 participants from eight studies in seven articles were involved in the caffeine-depression analysis. Compared with the lowest level consumption, the pooled relative risk (95% confidence interval) for coffee-depression and caffeine-depression was 0.757 [0.624, 0.917] and 0.721 [0.522, 0.997], respectively. For dose-response analysis, evidence of a linear association was found between coffee consumption and depression, and the risk of depression decreased by 8% (relative risk = 0.92, 95% confidence interval = [0.87, 0.97], p = 0.002) for each cup/day increment in coffee intake; a nonlinear association was found between caffeine consumption and depression, the risk of depression decreased faster and the association became significant when the caffeine consumption was above 68 mg/day and below 509 mg/day. Coffee and caffeine consumption were significantly associated with decreased risk of depression. © The Royal Australian and New Zealand College of Psychiatrists 2015.

Quantitative structure property relationships for the adsorption of pharmaceuticals onto activated carbon.

PubMed

Dickenson, E R V; Drewes, J E

2010-01-01

Isotherms were determined for the adsorption of five pharmaceutical residues, primidone, carbamazepine, ibuprofen, naproxen and diclofenac, to Calgon Filtrasorb 300 powdered activated carbon (PAC). The sorption behavior was examined in ultra-pure and wastewater effluent organic matter (EfOM) matrices, where more sorption was observed in the ultra-pure water for PAC doses greater than 10 mg/L suggesting the presence of EfOM hinders the sorption of the pharmaceuticals to the PAC. Adsorption behaviors were described by the Freundlich isotherm model. Quantitative structure property relationships (QSPRs) in the form of polyparameter linear solvation energy relationships were developed for simulating the Freundlich adsorption capacity in both ultra-pure and EfOM matrices. The significant 3D-based descriptors for the QSPRs were the molar volume, polarizability and hydrogen-bond donor parameters.

Brain uptake of a non-radioactive pseudo-carrier and its effect on the biodistribution of [(18)F]AV-133 in mouse brain.

PubMed

Wu, Xianying; Zhou, Xue; Zhang, Shuxian; Zhang, Yan; Deng, Aifang; Han, Jie; Zhu, Lin; Kung, Hank F; Qiao, Jinping

2015-07-01

9-[(18)F]Fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) is a new PET imaging agent targeting vesicular monoamine transporter type II (VMAT2). To shorten the preparation of [(18)F]AV-133 and to make it more widely available, a simple and rapid purification method using solid-phase extraction (SPE) instead of high-pressure liquid chromatography (HPLC) was developed. The SPE method produced doses containing the non-radioactive pseudo-carrier 9-hydroxypropyl-(+)-dihydrotetrabenazine (AV-149). The objectives of this study were to evaluate the brain uptake of AV-149 by UPLC-MS/MS and its effect on the biodistribution of [(18)F]AV-133 in the brains of mice. The mice were injected with a bolus including [(18)F]AV-133 and different doses of AV-149. Brain tissue and blood samples were harvested. The effect of different amounts of AV-149 on [(18)F]AV-133 was evaluated by quantifying the brain distribution of radiolabelled tracer [(18)F]AV-133. The concentrations of AV-149 in the brain and plasma were analyzed using a UPLC-MS/MS method. The concentrations of AV-149 in the brain and plasma exhibited a good linear relationship with the doses. The receptor occupancy curve was fit, and the calculated ED50 value was 8.165mg/kg. The brain biodistribution and regional selectivity of [(18)F]AV-133 had no obvious differences at AV-149 doses lower than 0.1mg/kg. With increasing doses of AV-149, the brain biodistribution of [(18)F]AV-133 changed significantly. The results are important to further support that the improved radiolabelling procedure of [(18)F]AV-133 using an SPE method may be suitable for routine clinical application. Copyright © 2015 Elsevier Inc. All rights reserved.

[Antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives and their nootropic action in alloxan diabetes].

PubMed

Volchegorskiĭ, I A; Rassokhina, L M; Miroshnichenko, I Iu

2011-01-01

Relationship between the antihypoxic effect of 3-hydroxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) and their effect on conditional learning, glycemia, and lipidemia was studied in rats with alloxan-induced diabetes. In parallel, the analogous relationship was investigated for alpha-lipoic acid that is regarded as a "gold standard" in treatment of diabetic neuropathy. It was established that single administration of emoxipine and mexidol in mice in doses equivalent to therapeutic-range doses in humans produces antihypoxic effect manifested by increased resistance to acute hypoxic hypoxia in test animals. Alpha-lipoic acid is inferior to emoxipin and mexidol in the degree of antihypoxic action. Reamberin does not exhibit this effect. The introduction of emoxipin, reamberin, mexidol, and alpha-lipoic acid in rats with alloxan diabetes during 7 or 14 days in doses equivalent to therapeutic-range doses in humans corrects conditional learning disorders in direct relationship with the antihypoxic activity of these drugs. The development of the nootropic effect of emoxipin, mexidol, and alpha-lipoic acid is related to a decrease in hyperglycemia and hyperlipidemia in rats with alloxan diabetes. The nootropic action of reamberin is accompanied by a transient hypoglycemizing effect and aggravation of dyslipidemic disorders. The antihypoxic activity of investigated drugs determines the direction and expression of their lipidemic effect, but is not correlated with the hypoglycemizing action these drugs on test animals with alloxan diabetes.

Commentary 2 to Cox and Little: radiation-induced oncogenic transformation: the interplay between dose, dose protraction, and radiation quality

NASA Technical Reports Server (NTRS)

Brenner, D. J.; Hall, E. J.

1992-01-01

There is now a substantial body of evidence for end points such as oncogenic transformation in vitro, and carcinogenesis and life shortening in vivo, suggesting that dose protraction leads to an increase in effectiveness relative to a single, acute exposure--at least for radiations of medium linear energy transfer (LET) such as neutrons. Table I contains a summary of the pertinent data from studies in which the effect is seen. [table: see text] This phenomenon has come to be known as the "inverse dose rate effect," because it is in marked contrast to the situation at low LET, where protraction in delivery of a dose of radiation, either by fractionation or low dose rate, results in a decreased biological effect; additionally, at medium and high LET, for radiobiological end points such as clonogenic survival, the biological effectiveness is independent of protraction. The quantity and quality of the published reports on the "inverse dose rate effect" leaves little doubt that the effect is real, but the available evidence indicates that the magnitude of the effect is due to a complex interplay between dose, dose rate, and radiation quality. Here, we first summarize the available data on the inverse dose rate effect and suggest that it follows a consistent pattern in regard to dose, dose rate, and radiation quality; second, we describe a model that predicts these features; and, finally, we describe the significance of the effect for radiation protection.