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

ERIC Educational Resources Information Center

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

2012-01-01

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

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

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

Levy, R.P.

1991-01-01

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

Dose-response approaches for nuclear receptor-mediated ...

EPA Pesticide Factsheets

A public workshop, organized by a Steering Committee of scientists from government, industry, universities, and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose-response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose-response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of subthreshold doses for a number of receptor-mediated MOPs. The workshop explored the development of dose-response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance framework (HRF). Case studies addressed activation of the AHR; the CAR/PXR, and the PPARa. This paper describes the workshop process, key issues discussed, and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose-response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the

The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

PubMed

Simon, Ted W; Simons, S Stoney; Preston, R Julian; Boobis, Alan R; Cohen, Samuel M; Doerrer, Nancy G; Fenner-Crisp, Penelope A; McMullin, Tami S; McQueen, Charlene A; Rowlands, J Craig

2014-08-01

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.

Dose-response characteristics of an amorphous silicon EPID.

PubMed

Winkler, Peter; Hefner, Alfred; Georg, Dietmar

2005-10-01

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

Clinical application of Chamomilla recutita in phlebitis: dose response curve study.

PubMed

Reis, Paula Elaine Diniz Dos; Carvalho, Emilia Campos de; Bueno, Paula Carolina Pires; Bastos, Jairo Kenupp

2011-01-01

This experimental and dose-response curve study aimed to carry out the quality control of the Chamomilla recutita sample, as well as to estimate the ideal dose, for anti-inflammatory effect, of the extract of its capitula, in patients with phlebitis due to peripheral intravenous infusion of antineoplastic chemotherapy and to evaluate the toxicity of this extract in human beings. The therapeutic efficacy, concerning the anti-inflammatory potential, of different doses of Chamomilla recutita extract were analyzed and compared in 25 patients. The time of regression of phlebitis was shorter for groups with 2.5% concentration (mean=29.2h, standard deviation = 8.98) and 5% concentration (mean = 38.8h, standard deviation = 17.47). Local toxicity was almost not observed. This research contributes to the innovation of the nursing clinical practice, since it suggests an alternative for the treatment of phlebitis through the clinical use of phytotherapeutic drugs.

Development of noise dose/visitor response relationships for the national parks overflight rule : Bryce Canyon National Park Study

DOT National Transportation Integrated Search

1998-07-01

This research was conducted in support of the National Parks Overflight Rule (National Rule). The foundation of the research program for the National Rule is the performance of noise dose/visitor response (dose-response) studies in several National P...

Progesterone in experimental permanent stroke: a dose-response and therapeutic time-window study

PubMed Central

Wali, Bushra; Ishrat, Tauheed; Won, Soonmi; Stein, Donald G.

2014-01-01

Currently, the only approved treatment for ischaemic stroke is tissue plasminogen activator, a clot-buster. This treatment can have dangerous consequences if not given within the first 4 h after stroke. Our group and others have shown progesterone to be beneficial in preclinical studies of stroke, but a progesterone dose-response and time-window study is lacking. We tested male Sprague-Dawley rats (12 months old) with permanent middle cerebral artery occlusion or sham operations on multiple measures of sensory, motor and cognitive performance. For the dose-response study, animals received intraperitoneal injections of progesterone (8, 16 or 32 mg/kg) at 1 h post-occlusion, and subcutaneous injections at 6 h and then once every 24 h for 7 days. For the time-window study, the optimal dose of progesterone was given starting at 3, 6 or 24 h post-stroke. Behavioural recovery was evaluated at repeated intervals. Rats were killed at 22 days post-stroke and brains extracted for evaluation of infarct volume. Both 8 and 16 mg/kg doses of progesterone produced attenuation of infarct volume compared with the placebo, and improved functional outcomes up to 3 weeks after stroke on locomotor activity, grip strength, sensory neglect, gait impairment, motor coordination and spatial navigation tests. In the time-window study, the progesterone group exhibited substantial neuroprotection as late as 6 h after stroke onset. Compared with placebo, progesterone showed a significant reduction in infarct size with 3- and 6-h delays. Moderate doses (8 and 16 mg/kg) of progesterone reduced infarct size and improved functional deficits in our clinically relevant model of stroke. The 8 mg/kg dose was optimal in improving motor, sensory and memory function, and this effect was observed over a large therapeutic time window. Progesterone shows promise as a potential therapeutic agent and should be examined for safety and efficacy in a clinical trial for ischaemic stroke. PMID:24374329

Dose-response relationships for carcinogens: a review.

PubMed Central

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

1987-01-01

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

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

Animal and human dose-response models for Brucella species.

PubMed

Teske, Sondra S; Huang, Yin; Tamrakar, Sushil B; Bartrand, Timothy A; Weir, Mark H; Haas, Charles N

2011-10-01

Human Brucellosis is one of the most common zoonotic diseases worldwide. Disease transmission often occurs through the handling of domestic livestock, as well as ingestion of unpasteurized milk and cheese, but can have enhanced infectivity if aerosolized. Because there is no human vaccine available, rising concerns about the threat of Brucellosis to human health and its inclusion in the Center for Disease Control's Category B Bioterrorism/Select Agent List make a better understanding of the dose-response relationship of this microbe necessary. Through an extensive peer-reviewed literature search, candidate dose-response data were appraised so as to surpass certain standards for quality. The statistical programming language, "R," was used to compute the maximum likelihood estimation to fit two models, the exponential and the approximate beta-Poisson (widely used for quantitative risk assessment) to dose-response data. Dose-response models were generated for prevalent species of Brucella: Br. suis, Br. melitensis, and Br. abortus. Dose-response models were created for aerosolized Br. suis exposure to guinea pigs from pooled studies. A parallel model for guinea pigs inoculated through both aerosol and subcutaneous routes with Br. melitensis showed that the median infectious dose corresponded to a 30 colony-forming units (CFU) dose of Br. suis, much less than the N(50) dose of about 94 CFU for Br. melitensis organisms. When Br. melitensis was tested subcutaneously on mice, the N(50) dose was higher, 1,840 CFU. A dose-response model was constructed from pooled data for mice, rhesus macaques, and humans inoculated through three routes (subcutaneously/aerosol/intradermally) with Br. melitensis. © 2011 Society for Risk Analysis.

Probabilistic assessment method of the non-monotonic dose-responses-Part I: Methodological approach.

PubMed

Chevillotte, Grégoire; Bernard, Audrey; Varret, Clémence; Ballet, Pascal; Bodin, Laurent; Roudot, Alain-Claude

2017-08-01

More and more studies aim to characterize non-monotonic dose response curves (NMDRCs). The greatest difficulty is to assess the statistical plausibility of NMDRCs from previously conducted dose response studies. This difficulty is linked to the fact that these studies present (i) few doses tested, (ii) a low sample size per dose, and (iii) the absence of any raw data. In this study, we propose a new methodological approach to probabilistically characterize NMDRCs. The methodology is composed of three main steps: (i) sampling from summary data to cover all the possibilities that may be presented by the responses measured by dose and to obtain a new raw database, (ii) statistical analysis of each sampled dose-response curve to characterize the slopes and their signs, and (iii) characterization of these dose-response curves according to the variation of the sign in the slope. This method allows characterizing all types of dose-response curves and can be applied both to continuous data and to discrete data. The aim of this study is to present the general principle of this probabilistic method which allows to assess the non-monotonic dose responses curves, and to present some results. Copyright © 2017 Elsevier Ltd. All rights reserved.

THYROID INSUFFICIENCY AND GENE EXPRESSION IN DEVELOPING RAT BRAIN: A DOSE RESPONSE STUDY.

EPA Science Inventory

Thyroid Insufficiency and Gene Expression in Developing Rat Brain: A Dose Response Study. JE Royland and ME Gilbert, Neurotox. Div., U.S. EPA, RTP, NC, USA. Endocrine disruption is an area of major concern in environmental neurotoxicity. Deficits in thyroid hormone (TH) levels h...

Education and Risk of Dementia: Dose-Response Meta-Analysis of Prospective Cohort Studies.

PubMed

Xu, Wei; Tan, Lan; Wang, Hui-Fu; Tan, Meng-Shan; Tan, Lin; Li, Jie-Qiong; Zhao, Qing-Fei; Yu, Jin-Tai

2016-07-01

Educational level has been regarded as one of the most widely accepted risk factors in the epidemiological studies for dementia, despite with discordant qualitative results. However, the dose-response relation between education and incident dementia was still unknown. To quantitatively evaluate the association between exposure level to high and low education and risk of dementia, we searched PubMed, EMBASE, and the Cochrane Library up to November 2014 and references of retrieved literatures. Specific prospective cohort studies, in which educational attainment was categorized into at least three levels, were included. Newcastle-Ottawa scale was used to assess the quality of included studies. Fifteen prospective cohort studies with 55655 for low education and eight prospective cohort studies with 20172 for high education were included. In the qualitative analysis, both low and high education showed a dose-response trend with risk of dementia and Alzheimer's disease (AD). In the quantitative analysis, the dementia risk was reduced by 7 % for per year increase in education (RR, 0.93; 95 % CI, 0.92-0.94; p for overall trend = 0.000; p for nonlinearity = 0.0643). Nonetheless, we did not find statistically significant association between per year decrease in education and dementia (RR, 1.03; 95 % CI, 0.96-1.10; p for overall trend = 0.283; p for nonlinearity = 0.0041) or AD (RR, 1.03; 95 % CI, 0.97-1.10; p for overall trend = 0.357; p for nonlinearity = 0.0022). Both low and high education showed a trend of dose-response relation with risk of dementia and AD. The dementia risk was reduced by 7 % for per year increase in education.

Toward a unified approach to dose-response modeling in ecotoxicology.

PubMed

Ritz, Christian

2010-01-01

This study reviews dose-response models that are used in ecotoxicology. The focus lies on clarification of differences and similarities between models, and as a side effect, their different guises in ecotoxicology are unravelled. A look at frequently used dose-response models reveals major discrepancies, among other things in naming conventions. Therefore, there is a need for a unified view on dose-response modeling in order to improve the understanding of it and to facilitate communication and comparison of findings across studies, thus realizing its full potential. This study attempts to establish a general framework that encompasses most dose-response models that are of interest to ecotoxicologists in practice. The framework includes commonly used models such as the log-logistic and Weibull models, but also features entire suites of models as found in various guidance documents. An outline on how the proposed framework can be implemented in statistical software systems is also provided.

A Generalized QMRA Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2016-10-01

Quantitative microbial risk assessment (QMRA) is widely accepted for characterizing the microbial risks associated with food, water, and wastewater. Single-hit dose-response models are the most commonly used dose-response models in QMRA. Denoting PI(d) as the probability of infection at a given mean dose d, a three-parameter generalized QMRA beta-Poisson dose-response model, PI(d|α,β,r*), is proposed in which the minimum number of organisms required for causing infection, K min , is not fixed, but a random variable following a geometric distribution with parameter 0dose-response mechanism. Since a maximum likelihood solution is not easily available, a likelihood-free approximate Bayesian computation (ABC) algorithm is employed for parameter estimation. By fitting the generalized model to four experimental data sets from the literature, this study reveals that the posterior median r* estimates produced fall short of meeting the required condition of r* = 1 for single-hit assumption. However, three out of four data sets fitted by the generalized models could not achieve an improvement in goodness of fit. These combined results imply that, at least in some cases, a single-hit assumption for characterizing the dose-response process may not be appropriate, but that the more complex models may be difficult to support especially if the sample size is small. The three-parameter generalized model provides a possibility to investigate the mechanism of a dose-response process in greater detail than is possible under a single-hit model. © 2016 Society for Risk Analysis.

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.

Transcriptomic Dose-Response Analysis for Mode of Action ...

EPA Pesticide Factsheets

Microarray and RNA-seq technologies can play an important role in assessing the health risks associated with environmental exposures. The utility of gene expression data to predict hazard has been well documented. Early toxicogenomics studies used relatively high, single doses with minimal replication. Thus, they were not useful in understanding health risks at environmentally-relevant doses. Until the past decade, application of toxicogenomics in dose response assessment and determination of chemical mode of action has been limited. New transcriptomic biomarkers have evolved to detect chemical hazards in multiple tissues together with pathway methods to study biological effects across the full dose response range and critical time course. Comprehensive low dose datasets are now available and with the use of transcriptomic benchmark dose estimation techniques within a mode of action framework, the ability to incorporate informative genomic data into human health risk assessment has substantially improved. The key advantage to applying transcriptomic technology to risk assessment is both the sensitivity and comprehensive examination of direct and indirect molecular changes that lead to adverse outcomes. Book Chapter with topic on future application of toxicogenomics technologies for MoA and risk assessment

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

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

Physiological and performance effects of pyridostigmine bromide in healthy volunteers: a dose-response study.

PubMed

Cook, Mary R; Graham, Charles; Sastre, Antonio; Gerkovich, Mary M

2002-07-01

Questions have been raised about the role pyridostigmine bromide (PB) plays in the etiology of Gulf War veterans' illnesses. There is a need to understand better the physiological and behavioral effects of this drug, particularly at the 30-mg/8-h regimen recommended by the US Military. OBJECTIVE. To perform a double-blind, cross-over, dose-response study of PB in 67 healthy, young volunteers (31 women, 36 men). Volunteers were initially trained on a standardized test battery. Supervised administration of placebo (PL) and PB (every 8 h/5 days) occurred in each of two dosing weeks, separated by a non-dosing week. One group received 30 mg PB and PL, and the other 60 mg PB and PL. In each dosing week, the battery was performed after the first pill and again when steady-state plasma PB levels were achieved. PB was associated with an overall improvement in reaction time on tests of memory and attention, and with a reduction in RMS error on a tracking task. PB slowed heart rate and decreased the high frequency component of heart rate variability (HF HRV). Dose-response effects were found only for HF HRV, and RMS error. The extent of cholinesterase inhibition was directly related to the magnitude of the HF HRV decrease, and was predicted by the weight-normalized PB dose. Cholinesterase inhibition was not related to the extent or severity of reported drug side effects. PB does not appear to have detrimental physiological or performance consequences at the recommended 30-mg dose, or at twice that dose, when evaluated under non-stressful laboratory conditions.

Inhalation Anthrax: Dose Response and Risk Analysis

PubMed Central

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

2008-01-01

The notion that inhalation of a single Bacillus anthracis spore is fatal has become entrenched nearly to the point of urban legend, in part because of incomplete articulation of the scientific basis for microbial risk assessment, particularly dose-response assessment. Risk analysis (ie, risk assessment, risk communication, risk management) necessitates transparency: distinguishing scientific facts, hypotheses, judgments, biases in interpretations, and potential misinformation. The difficulty in achieving transparency for biothreat risk is magnified by misinformation and poor characterization of both dose-response relationships and the driving mechanisms that cause susceptibility or resistance to disease progression. Regrettably, this entrenchment unnecessarily restricts preparedness planning to a single response scenario: decontaminate until no spores are detectable in air, water, or on surfaces—essentially forcing a zero-tolerance policy inconsistent with the biology of anthrax. We present evidence about inhalation anthrax dose-response relationships, including reports from multiple studies documenting exposures insufficient to cause inhalation anthrax in laboratory animals and humans. The emphasis of the article is clarification about what is known from objective scientific evidence for doses of anthrax spores associated with survival and mortality. From this knowledge base, we discuss the need for future applications of more formal risk analysis processes to guide development of alternative non-zero criteria or standards based on science to inform preparedness planning and other risk management activities. PMID:18582166

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.

Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects.

PubMed

Strassman, R J; Qualls, C R

1994-02-01

To begin applying basic neuropharmacological hypotheses of hallucinogenic drug actions to humans, we generated dose-response data for intravenously administered dimethyltryptamine fumarate's (DMT) neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users. Dimethyltryptamine, an endogenous mammalian hallucinogen and drug of abuse, was administered intravenously at 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users, in a double-blind, saline placebo-controlled, randomized design. Treatments were separated by at least 1 week. Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration, and were negligible at 30 minutes. Dimethyltryptamine dose dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Threshold doses for significant effects relative to placebo were also hallucinogenic (0.2 mg/kg and higher). Subjects with five or more exposures to 3,4-methylenedioxymethamphetamine demonstrated less robust pupil diameter effects than those with two or fewer exposures. Dimethyltryptamine can be administered safely to experienced hallucinogen users and dose-response data generated for several measures hypothesized under serotonergic modulatory control. Additional studies characterizing the specific mechanisms mediating DMT's biological effects may prove useful in psychopharmacological investigations of drug-induced and endogenous alterations in brain function.

The dose-response of Harshaw TLD-700H.

PubMed

Velbeck, K J; Luo, L Z; Ramlo, M J; Rotunda, J E

2006-01-01

Harshaw TLD-700H (7LiF:Mg,Cu,P) was previously characterised for low- to high-dose ranges from 1 microGy to 20 Gy. This paper describes the studies and results of dose-response and linearity at much higher doses. TLD-700H is a near perfect dosimetric material with near tissue equivalence, flat energy response, and the ability to measure beta, gamma and X rays. These new results extend the applicability of Harshaw TLD-700H into more dosimetric measurement environments. The simple glow curve structure provides insignificant fade, eliminating special oven preparation methods experienced by other materials. The work presented in this paper quantifies the performance of Harshaw TLD-700H in extended ranges.

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

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

PubMed Central

Hyun, Seung Won; Wong, Weng Kee

2016-01-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

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

PubMed

Hyun, Seung Won; Wong, Weng Kee

2015-11-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.

Dose-Response Relation Between Work Hours and Cardiovascular Disease Risk: Findings From the Panel Study of Income Dynamics.

PubMed

Conway, Sadie H; Pompeii, Lisa A; Roberts, Robert E; Follis, Jack L; Gimeno, David

2016-03-01

The aim of this study was to examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. A retrospective cohort study of 1926 individuals from the Panel Study of Income Dynamics (1986 to 2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with an increased risk of CVD. Compared with working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD.

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

PubMed

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

2009-07-01

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

Dose-Response Relation between Work Hours and Cardiovascular Disease Risk: Findings from the Panel Study of Income Dynamics

PubMed Central

Conway, Sadie H.; Pompeii, Lisa A.; Roberts, Robert E.; Follis, Jack L.; Gimeno, David

2015-01-01

Objectives To examine the presence of a dose-response relationship between work hours and incident cardiovascular disease (CVD) in a representative sample of U.S. workers. Methods Retrospective cohort study of 1,926 individuals from the Panel Study of Income Dynamics (1986–2011) employed for at least 10 years. Restricted cubic spline regression was used to estimate the dose-response relationship of work hours with CVD. Results A dose-response relationship was observed in which an average workweek of 46 hours or more for at least 10 years was associated with increased risk of CVD. Compared to working 45 hours per week, working an additional 10 hours per week or more for at least 10 years increased CVD risk by at least 16%. Conclusions Working more than 45 work hours per week for at least 10 years may be an independent risk factor for CVD. PMID:26949870

Fenoterol delivery by Respimat soft mist inhaler versus CFC metered dose inhaler: cumulative dose-response study in asthma patients.

PubMed

Vincken, Walter; Dewberry, Helen; Moonen, Diane

2003-09-01

Respimat (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 microg/actuation, RMT50; or 100 microg/actuation. RMT100) and MDI (100 microg/actuation; MDI100). A total of 41 asthma patients received cumulative doses of fenoterol 600 microg (RMT50) or 1200 microg (RMT100 and MDI100) on 3 test days. The bronchodilator response (forced expiratory volume in 1 second [FEV1]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of +/- 0.15L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. CONCLUSIONS; The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI.

Occupational Exposure to Diesel Motor Exhaust and Lung Cancer: A Dose-Response Relationship Hidden by Asbestos Exposure Adjustment? The ICARE Study

PubMed Central

Matrat, Mireille; Guida, Florence; Cénée, Sylvie; Févotte, Joelle; Carton, Matthieu; Cyr, Diane; Menvielle, Gwenn; Paget-Bailly, Sophie; Radoï, Loredana; Schmaus, Annie; Bara, Simona; Velten, Michel; Luce, Danièle; Stücker, Isabelle; The Icare Study Group

2015-01-01

Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent. PMID:26425123

Duration of post-vaccination immunity to yellow fever in volunteers eight years after a dose-response study.

PubMed

de Menezes Martins, Reinaldo; Maia, Maria de Lourdes S; de Lima, Sheila Maria Barbosa; de Noronha, Tatiana Guimarães; Xavier, Janaina Reis; Camacho, Luiz Antonio Bastos; de Albuquerque, Elizabeth Maciel; Farias, Roberto Henrique Guedes; da Matta de Castro, Thalita; Homma, Akira

2018-06-27

In 2009, Bio-Manguinhos conducted a dose-response study with the yellow fever vaccine, administering the vaccine in the usual mean dose of 27,476 IU (full dose, reference) and in tapered doses (10,447 IU, 3013 IU, 587 IU, 158 IU, and 31 IU) by the usual subcutaneous route and usual volume (0.5 mL). Tapered doses were obtained by dilution in the manufacturer's laboratory, and the test batches presented industrial quality. Doses down to 587 IU showed similar immunogenicity to the full dose (27,476, reference), while the 158 IU and 31 IU doses displayed lower immunogenicity. Seropositivity was maintained at 10 months, except in the group that received the 31 IU dose. The current study aims to determine whether yellow fever seropositivity was maintained eight years after YF vaccination in non-revaccinated individuals. According to the current study's results, seropositivity was maintained in 85% of 318 participants and was similar across groups. The findings support the use of the yellow fever vaccine in fractional doses during outbreaks, but each fractional dose should have at least 587 IU. This study also supports the minimum dose required by WHO, 1000 IU. Clinicaltrials.gov NCT 03338231. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

Dose-response studies and 'no-effect-levels' of N-nitroso compounds: some general aspects.

PubMed

Preussmann, R

1980-01-01

One major problem in the evaluation of potential carcinogenic food additives and contaminants is that of thresholds or, better, of 'no-adverse-effect-levels'. Arguments in favor of the postulated 'irreversibility' of carcinogenic effects are based on dose-response studies, single dose and multigeneration experiments as well as on the concept of somatic mutation as the first step in carcinogenesis with subsequent transmittance of induced defects during cell replication. The problem of extrapolation of results of animal experiments using high doses to low exposure and low incidences in man is not yet solved satisfactorily. Possible practical consequences include zero tolerance, acceptable thresholds at low risk and safety factors. Acceptable intakes should never be considered constants but should be changeable as soon as new facts in regard to the safety evaluation are available.

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

Classification and Dose-Response Characterization of ...

EPA Pesticide Factsheets

Thirty years and over a billion of today’s dollars worth of pesticide registration toxicity studies, historically stored as hardcopy and scanned documents, have been digitized into highly standardized and structured toxicity data, within the U.S. Environmental Protection Agency’s (EPA) Toxicity Reference Database (ToxRefDB). The source toxicity data in ToxRefDB covers multiple study types, including subchronic, developmental, reproductive, chronic, and cancer studies, resulting in a diverse set of endpoints and toxicities. Novel approaches to chemical classification are performed as a model application of ToxRefDB and as an essential need for highly detailed chemical classifications within the EPA’s ToxCast™ research program. In order to develop predictive models and biological signatures utilizing high-throughput screening (HTS) and in vitro genomic data, endpoints and toxicities must first be identified and globally characterized for ToxCast Phase I chemicals. Secondarily, dose-response characterization within and across toxicity endpoints provide insight into key precursor toxicity events and overall endpoint relevance. Toxicity-based chemical classification and dose-response characterization utilizing ToxRefDB prioritized toxicity endpoints and differentiated toxicity outcomes across a large chemical set.

Response to low-dose herbicide selection in self-pollinated Avena fatua.

PubMed

Busi, Roberto; Girotto, Marcelo; Powles, Stephen B

2016-03-01

When applied at the correct plant stage and dose, herbicides are highly toxic to plants. At reduced, low herbicide doses (below the recommended dose) plants can survive and display continuous and quantitative variation in dose-survival responses. Recurrent (directional) selection studies can reveal whether such a phenotypic variation in plant survival response to low herbicide dose is heritable and leads to herbicide resistance. In a common experimental garden study, we have subjected a susceptible population of self-pollinated hexaploid Avena fatua to low-dose recurrent selection with the ACCase-inhibiting herbicide diclofop-methyl for three consecutive generations. Significant differences in response to low-dose diclofop-methyl selection were observed between the selected progenies and parent plants, with a twofold diclofop-methyl resistance and cross-resistance to ALS-inhibiting herbicides. Thus, the capacity of self-pollinated A. fatua to respond to low-dose herbicide selection is marginal, and it is much lower than in cross-pollinated L. rigidum. Lolium rigidum in the same experiment evolved 40-fold diclofop-methyl resistance by progressive enrichment of quantitative resistance-endowing traits. Cross-pollination rate, genetic variation and ploidy levels are identified as possible drivers affecting the contrasting capacity of Avena versus Lolium plants to respond to herbicide selection and the subsequent likelihood of resistance evolution at low herbicide dose usage. © 2015 Society of Chemical Industry.

Fruit and vegetables consumption and incident hypertension: dose-response meta-analysis of prospective cohort studies.

PubMed

Wu, L; Sun, D; He, Y

2016-10-01

The role of dietary factors on chronic diseases seems essential in the potentially adverse or preventive effects. However, no evidence of dose-response meta-analysis of prospective cohort studies has verified the association between the intake of fruit and/or vegetables and the risk of developing hypertension. The PubMed and Embase were searched for prospective cohort studies. A generic inverse-variance method with random effects model was used to calculate the pooled relative risks (RRs) and 95% confidence intervals (CIs). Generalized least squares trend estimation model was used to calculate the study-specific slopes for the dose-response analyses. Seven articles comprised nine cohorts involving 185 676 participants were assessed. The highest intake of fruit or vegetables separately, and total fruit and vegetables were inversely associated with the incident risk of hypertension compared with the lowest level, and the pooled RRs and 95% CIs were 0.87 (0.79, 0.95), 0.88 (0.79, 0.99) and 0.90 (0.84, 0.98), respectively. We also found an inverse dose-response relation between the risk of developing hypertension and fruit intake, and total fruit and vegetables consumption. The incident risk of hypertension was decreased by 1.9% for each serving per day of fruit consumption, and decreased by 1.2% for each serving per day of total fruit and vegetables consumption. Our results support the recommendation to increase the consumption of fruit and vegetables with respect to preventing the risk of developing hypertension. However, further large prospective studies and long-term high-quality randomized controlled trials are still needed to confirm the observed association.

Augmentation index (AI) in a dose-response relationship with smoking habits in males: The Tanushimaru study.

PubMed

Tsuru, Tomoko; Adachi, Hisashi; Enomoto, Mika; Fukami, Ako; Kumagai, Eita; Nakamura, Sachiko; Nohara, Yume; Kono, Shoko; Nakao, Erika; Sakaue, Akiko; Morikawa, Nagisa; Fukumoto, Yoshihiro

2016-12-01

We investigated the relationship between augmentation index (AI) and smoking habits in community-dwelling Japanese.This cross-sectional study enrolled 1926 subjects (769 males and 1157 females) aged 40 to 95 years who underwent a health check-up in a Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town in Kyushu Island in 2009. The subjects' medical history, alcohol intake, smoking habit, and current medications for hypertension, dyslipidemia, and diabetes were ascertained by questionnaire. Radial arterial pressure wave analysis was used to obtain AI. We analyzed the data stratified by gender.Age-adjusted means of AI in males showed a clear dose-response relationship in 4 categories of smoking habits (P = 0.010). There was no significant relationship between AI and smoking habits in females (P = 0.127). The significant dose-response relationship (P = 0.036) in males between AI and 4 categories of smoking habits still remained even after adjustment for age, body mass index, systolic blood pressure, estimated glomerular filtration rate, glucose, hypertensive medication, and alcohol intake.The present study demonstrated that AI values were significantly associated with smoking habits in a dose-dependent manner in Japanese males.

Shared dosimetry error in epidemiological dose-response analyses

DOE PAGES

Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail; ...

2015-03-23

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

Shared Dosimetry Error in Epidemiological Dose-Response Analyses

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

Stram, Daniel O.; Preston, Dale L.; Sokolnikov, Mikhail

2015-03-23

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

Liposomal bupivacaine as a single-injection peripheral nerve block: a dose-response study.

PubMed

Ilfeld, Brian M; Malhotra, Nisha; Furnish, Timothy J; Donohue, Michael C; Madison, Sarah J

2013-11-01

Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration of <24 hours. A liposomal bupivacaine formulation (EXPAREL, Pacira Pharmaceuticals, Inc., San Diego, CA), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration but not peripheral nerve blocks. Bilateral single-injection femoral nerve blocks were administered in healthy volunteers (n = 14). For each block, liposomal bupivacaine (0-80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received 2 different doses, 1 on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally. There were statistically significant dose responses in MVIC (0.09%/mg, SE = 0.03, 95% confidence interval [CI], 0.04-0.14, P = 0.002) and tolerance to cutaneous current (-0.03 mA/mg, SE = 0.01, 95% CI, -0.04 to -0.02, P < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI, 43%-93%), block duration usually lasted much longer: for bupivacaine doses >40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 hours in 100% of subjects (95% CI, 56%-100%). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI, 54%-100%). Motor block duration was not correlated with bupivacaine dose (0.06 hour/mg, SE = 0

Liposomal Bupivacaine as a Single-Injection Peripheral Nerve Block: A Dose-Response Study

PubMed Central

Ilfeld, Brian M.; Malhotra, Nisha; Furnish, Timothy J.; Donohue, Michael C.; Madison, Sarah J.

2013-01-01

Background Currently available local anesthetics approved for single-injection peripheral nerve blocks have a maximum duration less than 24 hours. A liposomal bupivacaine formulation (EXPAREL®, Pacira Pharmaceuticals, Inc., San Diego, California), releasing bupivacaine over 96 hours, recently gained Food and Drug Administration approval exclusively for wound infiltration, but not peripheral nerve blocks. Methods Bilateral single-injection femoral nerve blocks were administered in healthy volunteers (n=14). For each block, liposomal bupivacaine (0–80 mg) was mixed with normal saline to produce 30 mL of study fluid. Each subject received two different doses, one on each side, applied randomly in a double-masked fashion. The end points included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current in the femoral nerve distribution. Measurements were performed from baseline until quadriceps MVIC returned to 80% of baseline bilaterally. Results There were statistically significant dose responses in MVIC (0.09% / mg, SE = 0.03, 95% CI 0.04 to 0.14, p = 0.002) and tolerance to cutaneous current (−0.03 mA / mg, SE = 0.01, 95% CI −0.04 to 0.02, p < 0.001), however, in the opposite direction than expected (the higher the dose, the lower the observed effect). This inverse relationship is biologically implausible, and most likely due to the limited sample size and the subjective nature of the measurement instruments. While peak effects occurred within 24 hours after block administration in 75% of cases (95% CI 43 to 93%), block duration usually lasted much longer: for bupivacaine doses above 40 mg, tolerance to cutaneous current did not return to within 20% above baseline until after 24 h in 100% of subjects (95% CI 56 to 100). MVIC did not consistently return to within 20% of baseline until after 24 hours in 90% of subjects (95% CI 54 to 100%). Motor block duration was not correlated with

Regulation of operant oral ethanol self-administration: a dose-response curve study in rats.

PubMed

Carnicella, Sebastien; Yowell, Quinn V; Ron, Dorit

2011-01-01

Oral ethanol self-administration procedures in rats are useful preclinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation into the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose-response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored because of the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In this study, we set out to determine whether a meaningful dose-response curve for oral ethanol self-administration can be obtained in rats. Long-Evans rats were trained to self-administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self-administration, the concentration of the solution was varied from 2.5 to 60% (v/v), and operant and drinking behaviors, as well as blood ethanol concentration (BEC), were evaluated following the self-administration of a 20, 40, and 60% ethanol solution. Varying the concentration of ethanol from 2.5 to 60% after the development of excessive ethanol consumption led to a typical inverted U-shaped dose-response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders. Copyright © 2010 by the Research Society on Alcoholism.

The hormesis database: the occurrence of hormetic dose responses in the toxicological literature.

PubMed

Calabrese, Edward J; Blain, Robyn B

2011-10-01

In 2005 we published an assessment of dose responses that satisfied a priori evaluative criteria for inclusion within the relational retrieval hormesis database (Calabrese and Blain, 2005). The database included information on study characteristics (e.g., biological model, gender, age and other relevant aspects, number of doses, dose distribution/range, quantitative features of the dose response, temporal features/repeat measures, and physical/chemical properties of the agents). The 2005 article covered information for about 5000 dose responses; the present article has been expanded to cover approximately 9000 dose responses. This assessment extends and strengthens the conclusion of the 2005 paper that the hormesis concept is broadly generalizable, being independent of biological model, endpoint measured and chemical class/physical agent. It also confirmed the definable quantitative features of hormetic dose responses in which the strong majority of dose responses display maximum stimulation less than twice that of the control group and a stimulatory width that is within approximately 10-20-fold of the estimated toxicological or pharmacological threshold. The remarkable consistency of the quantitative features of the hormetic dose response suggests that hormesis may provide an estimate of biological plasticity that is broadly generalized across plant, microbial and animal (invertebrate and vertebrate) models. Copyright © 2011 Elsevier Inc. All rights reserved.

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

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

Calabrese, Edward J.; Blain, Robyn

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

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

PubMed

Calabrese, Edward J; Blain, Robyn

2005-02-01

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

Characterization of a developmental toxicity dose-response model.

PubMed Central

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

1989-01-01

The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose. PMID:2707204

Red and processed meat consumption and the risk of lung cancer: a dose-response meta-analysis of 33 published studies

PubMed Central

Xue, Xiu-Juan; Gao, Qing; Qiao, Jian-Hong; Zhang, Jie; Xu, Cui-Ping; Liu, Ju

2014-01-01

This meta-analysis was to summarize the published studies about the association between red/processed meat consumption and the risk of lung cancer. 5 databases were systematically reviewed, and random-effect model was used to pool the study results and to assess dose-response relationships. Results shown that six cohort studies and twenty eight case-control studies were included in this meat-analysis. The pooled Risk Radios (RR) for total red meat and processed meat were 1.44 (95% CI, 1.29-1.61) and 1.23 (95% CI, 1.10-1.37), respectively. Dose-response analysis revealed that for every increment of 120 grams red meat per day the risk of lung cancer increases 35% and for every increment of 50 grams red meat per day the risk of lung cancer increases 20%. The present dose-response meta-analysis suggested that both red and processed meat consumption showed a positive effect on lung cancer risk. PMID:25035778

Analysis of Transcriptomic Dose Response Data in the ...

EPA Pesticide Factsheets

Slide presentation at the HESI-HEALTH Canada-McGill Workshop on Transcriptomic Dose Response Data in the Context of Chemical Risk Assessment Slide presentation at the HESI-HEALTH Canada-McGill Workshop on Transcriptomic Dose Response Data in the Context of Chemical Risk Assessment

Intracoronary Adenosine: Dose-Response Relationship With Hyperemia.

PubMed

Adjedj, Julien; Toth, Gabor G; Johnson, Nils P; Pellicano, Mariano; Ferrara, Angela; Floré, Vincent; Di Gioia, Giuseppe; Barbato, Emanuele; Muller, Olivier; De Bruyne, Bernard

2015-09-01

The present study sought to establish the dosage of intracoronary (IC) adenosine associated with minimal side effects and above which no further increase in flow can be expected. Despite the widespread adoption of IC adenosine in clinical practice, no wide-ranging, dose-response study has been conducted. A recurring debate still exists regarding its optimal dose. In 30 patients, Doppler-derived flow velocity measurements were obtained in 10 right coronary arteries (RCAs) and 20 left coronary arteries (LCAs) free of stenoses >20% in diameter. Flow velocity was measured at baseline and after 8 ml bolus administrations of arterial blood, saline, contrast medium, and 9 escalating doses of adenosine (4 to 500 μg). The hyperemic value was expressed in percent of the maximum flow velocity reached in a given artery (Q/Qmax, %). Q/Qmax did not increase significantly beyond dosages of 60 μg for the RCA and 160 μg for LCA. Heart rate did not change, whereas mean arterial blood pressure decreased by a maximum of 7% (p < 0.05) after bolus injections of IC adenosine. The incidence of transient A-V blocks was 40% after injection of 100 μg in the RCA and was 15% after injection of 200 μg in the LCA. The duration of the plateau reached 12 ± 13 s after injection of 100 μg in the RCA and 21 ± 6 s after the injection of 200 μg in the LCA. A progressive prolongation of the time needed to return to baseline was observed. Hyperemic response after injection of 8 ml of contrast medium reached 65 ± 36% of that achieved after injection of 200 μg of adenosine. This wide-ranging, dose-response study indicates that an IC adenosine bolus injection of 100 μg in the RCA and 200 μg in the LCA induces maximum hyperemia while being associated with minimal side effects. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Immune Response And Anamnestic Immune Response In Children After A 3-Dose Primary Hepatitis B Vaccination.

PubMed

Afzal, Muhammad Faheem; Sultan, Muhammad Ashraf; Saleemi, Ahmad Imran

2016-01-01

Diseases caused by Hepatitis B virus (HBV) have a worldwide distribution. Pakistan adopted the recommendations of World Health Organization (WHO) for routine universal infant vaccination against hepatitis B in 2002, currently being administered at 6, 10, and 14 weeks of age in a combination vaccine. This study was conducted to determine the immune response & anamnestic immune response in children, 9 months-10 years of age, after a 3dose primary Hepatitis B vaccination. This cross sectional study was conducted in the Department of Paediatrics, King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from January to June, 2014. A total of 200 children of either sex between the ages of 9 months to 10 years, documented to have received 3 doses of hepatitis B vaccines according to Expanded Program of Immunization (6,10,14 weeks) schedule in infancy, were recruited by consecutive sampling. The level of serum antiHBsAb by ELIZA was measured. Children with antiHBs titers ≥10 mIU/mL were considered to be immune. Those with anti HBsAb levels <10 mIU/mL were offered a booster dose of infant recombinant hepatitis B vaccine. The second serum sample was obtained 21-28 days following the administration of the booster dose and the anamnestic immune response was measured. Data was analysed using SPSS 17 to determine the relation between time interval since last vaccination and antibody titer. Chi square test was applied. Of the 200 children, protective antibody response was found in 58%. Median serological response was 18.60 (range 2.82 - 65.15). Antibody levels were found to have a statistically significant ( pvalue 0.019) negative correlation with the time since last administration of vaccine. A booster dose of Hepatitis B vacci ne was administered to all nonresponders, with each registering a statistically significant (pvalue 0.00) anamnestic response. The vaccination schedule with short dosage interval was unable to provide protection to 42% of the study population

Dose-response plasma appearance of coffee chlorogenic and phenolic acids in adults.

PubMed

Renouf, Mathieu; Marmet, Cynthia; Giuffrida, Francesca; Lepage, Mélissa; Barron, Denis; Beaumont, Maurice; Williamson, Gary; Dionisi, Fabiola

2014-02-01

Coffee contains phenolic compounds, mainly chlorogenic acids (CGAs). Even though coffee intake has been associated with some health benefits in epidemiological studies, the bioavailability of coffee phenolics is not fully understood. We performed a dose-response study measuring plasma bioavailability of phenolics after drinking three increasing, but still nutritionally relevant doses of instant pure soluble coffee. The study design was a one treatment (coffee) three-dose randomized cross-over design, with a washout period of 2 wks between visits. CGAs, phenolic acids, and late-appearing metabolites all increased with increasing ingested dose. Hence, the sum of area under the curve was significantly higher for the medium to low dose, and high to medium dose, by 2.23- and 2.38-fold, respectively. CGAs were not well absorbed in their intact form, regardless of the dose. CGA and phenolic acids appeared rapidly in plasma, indicating an early absorption in the gastrointestinal tract. Late-appearing metabolites were the most abundant, regardless of the dose. This study confirmed previous findings about coffee bioavailability but also showed that coffee phenolics appear in a positive dose-response manner in plasma when drank at nutritionally relevant doses. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

MedlinePlus

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

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

EPA Science Inventory

DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY. LE Gray Jr, C Wolf, J Furr, M Price, C Lambright, VS Wilson and J Ostby. USEPA, ORD, NHEERL, EB, RTD, RTP, NC, USA.
Dose-response behavior of a...

Influence of DNA repair on nonlinear dose-responses for mutation.

PubMed

Thomas, Adam D; Jenkins, Gareth J S; Kaina, Bernd; Bodger, Owen G; Tomaszowski, Karl-Heinz; Lewis, Paul D; Doak, Shareen H; Johnson, George E

2013-03-01

Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O(6)-methylguanine (O(6)MeG) by the suicide enzyme O(6)MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis.

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

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

PubMed

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

2017-05-01

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

A dose-response study in animals to evaluate the anticoagulant effect of the stage 2 unfractionated heparin USP monograph change.

PubMed

Honchel, R; Carraway, J; Gopee, N; Callicott, R; Chen, J; Patton, R; Xu, Q; Zalkkar, J; Laniyonu, A; Krefting, I; Cato, M; Robie-Suh, K; Rieves, R

2011-08-01

The United States Pharmacopeia (USP) monograph for unfractionated heparin (UFH) was revised in October 2009. This revision was anticipated, based upon in vitro tests, to reduce UFH potency by approximately 10%. To study the potential in vivo consequences of the monograph change, we evaluated activated partial thromboplastin time (aPTT) and activated clotting time (ACT) responses in animals. Female mini-pigs and monkeys (n=8/species) were administered intravenously 60, 54, 48, or 42 U/kg and 50, 45, 40, or 35 U/kg "old" (pre-USP revision) UFH, respectively, in a Williams 4×4 crossover design. Blood samples for aPTT and ACT were collected at 15 min after dosing. The same study design was then repeated using "new" (post-USP revision) UFH. Mean "new" UFH aPTT and ACT values were generally lower than those for "old" UFH although individual animal responses varied considerably. The aPTT and ACT response was generally dose-proportional for both "old" and "new" UFH. These studies indicate that the USP monograph alteration for UFH may result in a modest reduction in the anticoagulant response across a population, but the variability in animal responses underscores the importance of individualization of clinical UFH dosing and the importance of anticoagulant test monitoring. Published by Elsevier Inc.

Dose-response relationship in the treatment of gastrointestinal disorders.

PubMed

Weihrauch, T R; Demol, P

1989-08-01

Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

Dose/Exposure‐Response Modeling to Support Dosing Recommendation for Phase III Development of Baricitinib in Patients with Rheumatoid Arthritis

PubMed Central

Chua, Laiyi; Ernest, Charles; Macias, William; Rooney, Terence; Tham, Lai San

2017-01-01

Baricitinib is an oral inhibitor of Janus kinases (JAKs), selective for JAK1 and 2. It demonstrated dose‐dependent efficacy in patients with moderate‐to‐severe rheumatoid arthritis (RA) in a phase IIb study up to 24 weeks. Population pharmacokinetic/pharmacodynamic (PopPK/PD) models were developed to characterize concentration‐time profiles and dose/exposure‐response (D/E‐R) relationships for the key efficacy (proportion of patients achieving American College of Rheumatology 20%, 50%, or 70% response rate) and safety endpoints (incidence of anemia) for the phase IIb study. The modeling suggested that 4 mg q.d. was likely to offer the optimum risk/benefit balance, whereas 2 mg q.d. had the potential for adequate efficacy. In addition, at the same total daily dose, a twice‐daily regimen is not expected to provide an advantage over q.d. dosing for the efficacy or safety endpoints. The model‐based simulations formed the rationale for key aspects of dosing, such as dose levels and dosing frequency for phase III development. PMID:28891251

The Model Averaging for Dichotomous Response Benchmark Dose (MADr-BMD) Tool

EPA Pesticide Factsheets

Providing quantal response models, which are also used in the U.S. EPA benchmark dose software suite, and generates a model-averaged dose response model to generate benchmark dose and benchmark dose lower bound estimates.

Influence of DNA Repair on Nonlinear Dose-Responses for Mutation

PubMed Central

Johnson, George E.

2013-01-01

Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O6-methylguanine (O6MeG) by the suicide enzyme O6MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis. PMID:23288051

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.

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

NASA Technical Reports Server (NTRS)

Chappell, Lori J.; Cucinotta, Francis A.

2010-01-01

There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies.

Dose-Response Analysis of RNA-Seq Profiles in Archival ...

EPA Pesticide Factsheets

Use of archival resources has been limited to date by inconsistent methods for genomic profiling of degraded RNA from formalin-fixed paraffin-embedded (FFPE) samples. RNA-sequencing offers a promising way to address this problem. Here we evaluated transcriptomic dose responses using RNA-sequencing in paired FFPE and frozen (FROZ) samples from two archival studies in mice, one 20 years old. Experimental treatments included 3 different doses of di(2-ethylhexyl)phthalate or dichloroacetic acid for the recently archived and older studies, respectively. Total RNA was ribo-depleted and sequenced using the Illumina HiSeq platform. In the recently archived study, FFPE samples had 35% lower total counts compared to FROZ samples but high concordance in fold-change values of differentially expressed genes (DEGs) (r2 = 0.99), highly enriched pathways (90% overlap with FROZ), and benchmark dose estimates for preselected target genes (2% difference vs FROZ). In contrast, older FFPE samples had markedly lower total counts (3% of FROZ) and poor concordance in global DEGs and pathways. However, counts from FFPE and FROZ samples still positively correlated (r2 = 0.84 across all transcripts) and showed comparable dose responses for more highly expressed target genes. These findings highlight potential applications and issues in using RNA-sequencing data from FFPE samples. Recently archived FFPE samples were highly similar to FROZ samples in sequencing q

The dose-response of salvage radiotherapy following radical prostatectomy: A systematic review and meta-analysis.

PubMed

King, Christopher R

2016-11-01

To date neither the optimal radiotherapy dose nor the existence of a dose-response has been established for salvage RT (SRT). A systematic review from 1996 to 2015 and meta-analysis was performed to identify the pathologic, clinical and treatment factors associated with relapse-free survival (RFS) after SRT (uniformly defined as a PSA>0.2ng/mL or rising above post-SRT nadir). A sigmoidal dose-response curve was objectively fitted and a non-parametric statistical test used to determine significance. 71 studies (10,034 patients) satisfied the meta-analysis criteria. SRT dose (p=0.0001), PSA prior to SRT (p=0.0009), ECE+ (p=0.039) and SV+ (p=0.046) had significant associations with RFS. Statistical analyses confirmed the independence of SRT dose-response. Omission of series with ADT did not alter results. Dose-response is well fit by a sigmoidal curve (p=0.0001) with a TCD 50 of 65.8Gy, with a dose of 70Gy achieving 58.4% RFS vs. 38.5% for 60Gy. A 2.0% [95% CI 1.1-3.2] improvement in RFS is achieved for each Gy. The SRT dose-response remarkably parallels that for definitive RT of localized disease. This study provides level 2a evidence for dose-escalated SRT>70Gy. The presence of an SRT dose-response for microscopic disease supports the hypothesis that prostate cancer is inherently radio-resistant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Key Events Dose-Response Framework: a cross-disciplinary mode-of-action based approach to examining dose-response and thresholds.

PubMed

Julien, Elizabeth; Boobis, Alan R; Olin, Stephen S

2009-09-01

The ILSI Research Foundation convened a cross-disciplinary working group to examine current approaches for assessing dose-response and identifying safe levels of intake or exposure for four categories of bioactive agents-food allergens, nutrients, pathogenic microorganisms, and environmental chemicals. This effort generated a common analytical framework-the Key Events Dose-Response Framework (KEDRF)-for systematically examining key events that occur between the initial dose of a bioactive agent and the effect of concern. Individual key events are considered with regard to factors that influence the dose-response relationship and factors that underlie variability in that relationship. This approach illuminates the connection between the processes occurring at the level of fundamental biology and the outcomes observed at the individual and population levels. Thus, it promotes an evidence-based approach for using mechanistic data to reduce reliance on default assumptions, to quantify variability, and to better characterize biological thresholds. This paper provides an overview of the KEDRF and introduces a series of four companion papers that illustrate initial application of the approach to a range of bioactive agents.

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

EPA Science Inventory

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

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.

A randomized study of rotigotine dose response on 'off' time in advanced Parkinson's disease.

PubMed

Nicholas, Anthony P; Borgohain, Rupam; Chaná, Pedro; Surmann, Erwin; Thompson, Emily L; Bauer, Lars; Whitesides, John; Elmer, Lawrence W

2014-01-01

Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

Dose-response relation between physical activity and cognitive function: guangzhou biobank cohort study.

PubMed

Xu, Lin; Jiang, Chao Qiang; Lam, Tai Hing; Zhang, Wei Sen; Thomas, G Neil; Cheng, Kar Keung

2011-11-01

To examine, via cross-sectional analysis, the dose-response association between physical activity and cognitive function in Chinese subjects. A total of 27,651 participants aged 50 to 85 years were recruited from 2003 to 2008. Information on potential confounders, including demographic and anthropometric characteristics, socioeconomic position, lifestyle, and disease history, was collected by standardized interview and procedures. Cognitive function was assessed by the delayed 10-word recall test (DWRT). When the International Physical Activity Questionnaire was used, we found that most of the participants were classified as physically active (53.1%), with 42.4% moderately active and 4.5% physically inactive. Significant dose-response relations across quintiles of metabolic equivalent value (METs) with DWRT score in participants with or without good self-rated health were found (all p for trend <.001). In participants with poor self-rated heath, compared with the first quintile of METs, those in the fifth quintile (highest METs) had a significantly reduced risk for mild cognitive impairment by 28% (adjusted odds ratio, 0.72; 95% confidence interval, 0.58-0.89, p < .01; p for trend = .006). After additional adjustment for depression, we found that the association between physical activity and DWRT score remained significant. A significant dose-response relationship between physical activity and cognitive function was found, and the association was more pronounced in participants with poor self-rated health. Copyright © 2011 Elsevier Inc. All rights reserved.

Bayesian Dose-Response Modeling in Sparse Data

NASA Astrophysics Data System (ADS)

Kim, Steven B.

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

Dose response of alanine detectors irradiated with carbon ion beams

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

Herrmann, Rochus; Jaekel, Oliver; Palmans, Hugo

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

Coffee consumption is not associated with ovarian cancer risk: a dose-response meta-analysis of prospective cohort studies.

PubMed

Berretta, Massimiliano; Micek, Agnieszka; Lafranconi, Alessandra; Rossetti, Sabrina; Di Francia, Raffaele; De Paoli, Paolo; Rossi, Paola; Facchini, Gaetano

2018-04-17

Coffee consumption has been associated with numerous cancers, but evidence on ovarian cancer risk is controversial. Therefore, we performed a meta-analysis on prospective cohort studies in order to review the evidence on coffee consumption and risk of ovarian cancer. Studies were identified through searching the PubMed and MEDLINE databases up to March 2017. Risk estimates were retrieved from the studies, and dose-response analysis was modelled by using restricted cubic splines. Additionally, a stratified analysis by menopausal status was performed. A total of 8 studies were eligible for the dose-response meta-analysis. Studies included in the analysis comprised 787,076 participants and 3,541 ovarian cancer cases. The results showed that coffee intake was not associated with ovarian cancer risk (RR = 1.06, 95% CI: 0.89, 1.26). Stratified and subgroup analysis showed consisted results. This comprehensive meta-analysis did not find evidence of an association between the consumption of coffee and risk of ovarian cancer.

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.

Microbiota and Dose Response: Evolving Paradigm of Health Triangle.

PubMed

Coleman, Margaret; Elkins, Christopher; Gutting, Bradford; Mongodin, Emmanuel; Solano-Aguilar, Gloria; Walls, Isabel

2018-06-13

SRA Dose-Response and Microbial Risk Analysis Specialty Groups jointly sponsored symposia that addressed the intersections between the "microbiome revolution" and dose response. Invited speakers presented on innovations and advances in gut and nasal microbiota (normal microbial communities) in the first decade after the Human Microbiome Project began. The microbiota and their metabolites are now known to influence health and disease directly and indirectly, through modulation of innate and adaptive immune systems and barrier function. Disruption of healthy microbiota is often associated with changes in abundance and diversity of core microbial species (dysbiosis), caused by stressors including antibiotics, chemotherapy, and disease. Nucleic-acid-based metagenomic methods demonstrated that the dysbiotic host microbiota no longer provide normal colonization resistance to pathogens, a critical component of innate immunity of the superorganism. Diverse pathogens, probiotics, and prebiotics were considered in human and animal models (in vivo and in vitro). Discussion included approaches for design of future microbial dose-response studies to account for the presence of the indigenous microbiota that provide normal colonization resistance, and the absence of the protective microbiota in dysbiosis. As NextGen risk analysis methodology advances with the "microbiome revolution," a proposed new framework, the Health Triangle, may replace the old paradigm based on the Disease Triangle (focused on host, pathogen, and environment) and germophobia. Collaborative experimental designs are needed for testing hypotheses about causality in dose-response relationships for pathogens present in our environments that clearly compete in complex ecosystems with thousands of bacterial species dominating the healthy superorganism. © 2018 Society for Risk Analysis.

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

PubMed

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

2007-07-01

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

Dose-response of an extrafine dry powder inhaler formulation of glycopyrronium bromide: randomized, double-blind, placebo-controlled, dose-ranging study (GlycoNEXT).

PubMed

Beeh, Kai M; Emirova, Aida; Prunier, Hélène; Santoro, Debora; Nandeuil, Marie Anna

2018-01-01

An extrafine formulation of the long-acting muscarinic antagonist, glycopyrronium bromide (GB), has been developed for delivery via the NEXThaler dry powder inhaler (DPI). This study assessed the bronchodilator efficacy and safety of different doses of this formulation in patients with COPD to identify the optimal dose for further development. This was a multicenter, randomized, double-blind, placebo-controlled, incomplete block, three-way crossover study, including three 28-day treatment periods, each separated by a 21-day washout period. Eligible patients had a diagnosis of COPD and post-bronchodilator forced expiratory volume in 1 s (FEV 1 ) 40%-70% predicted. Treatments administered were GB 6.25, 12.5, 25 and 50 μg or matched placebo; all were given twice daily (BID) via DPI, with spirometry assessed on Days 1 and 28 of each treatment period. The primary end point was FEV 1 area under the curve from 0 to 12 h (AUC 0-12 h ) on Day 28. A total of 202 patients were randomized (61% male, mean age 62.6 years), with 178 (88%) completing all the three treatment periods. For the primary end point, all the four GB doses were superior to placebo ( p <0.001) with mean differences (95% CI) of 114 (74, 154), 125 (85, 166), 143 (104, 183) and 187 (147, 228) mL for GB 6.25, 12.5, 25 and 50 μg BID, respectively. All four GB doses were also statistically superior to placebo for all secondary efficacy end points, showing clear dose-response relationships for most of the endpoints. Accordingly, GB 25 μg BID met the criteria for the minimally acceptable dose. Adverse events were reported by 15.5, 16.2, 10.9 and 14.3% of patients receiving GB 6.25, 12.5, 25 and 50 μg BID, respectively, and 14.8% receiving placebo. This study supports the selection of GB 25 μg BID as the minimal effective dose for patients with COPD when delivered with this extrafine DPI formulation.

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

PubMed

Calabrese, Edward J

2013-11-01

The most common quantitative feature of the hormetic-biphasic dose response is its modest stimulatory response which at maximum is only 30-60% greater than control values, an observation that is consistently independent of biological model, level of organization (i.e., cell, organ or individual), endpoint measured, chemical/physical agent studied, or mechanism. This quantitative feature suggests an underlying "upstream" mechanism common across biological systems, therefore basic and general. Hormetic dose response relationships represent an estimate of the peak performance of integrative biological processes that are allometrically based. Hormetic responses reflect both direct stimulatory or overcompensation responses to damage induced by relatively low doses of chemical or physical agents. The integration of the hormetic dose response within an allometric framework provides, for the first time, an explanation for both the generality and the quantitative features of the hormetic dose response. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

Comparative study of nuclear magnetic resonance and UV-visible spectroscopy dose-response of polymer gel based on N-(Isobutoxymethyl) acrylamide

NASA Astrophysics Data System (ADS)

Lotfy, S.; Basfar, A. A.; Moftah, B.; Al-Moussa, A. A.

2017-12-01

A comparative study of nuclear magnetic resonance and UV-visible spectroscopy of dose-response for polymer gel dosimeters was performed. Dosimeters were prepared using N-(Isobutoxymethyl) acrylamide (NIBMA) as a new monomer via radiation induced polymerization for use in radiotherapy planning. The prepared dosimeters were irradiated with doses up to 30 Gy at a constant dose rate of 600 MU/min. Using a medical linear accelerator at irradiation energies of 6, 10 and 18 MV photon beam. The nuclear magnetic resonance (NMR), via spin-spin relaxation rate (R2) for water proton surrounding the polymer formulation and UV-Visible spectroscopy, via the optical absorbance measurements of irradiated dosimeters at selected wavelengths of 500 nm, was used to investigate the dose response of NIBMAGAT gel dosimeters. Scavenge of oxygen was done using tetrakis (hydroxymethyl) phosphonium chloride (THPC). The THPC optimum concentration in the dosimeters formulations were 5 and 10 mM for the NMR and optical absorbance measurements respectively. The quantitative investigation of the dosimeters components reveals the selective formulations based on 4% w/w gelatin, 1% w/w NIBMA, 3% w/w BisAAm, 5 or 10 mM THPC and 17% w/w glycerol which significantly increase the dosimeters dose response. The prepared dosimeters were found to be dose rate and photon beam irradiation energy independent. The stability study shows no change in the relaxation rate or in the optical absorbance of the gel dosimeters up to 8 days post-irradiation. The prepared polymer gel dosimeters at the energies of 6, 10 and 18 MV photon beam irradiation in the range of 1-30 Gy have the linearity of the dose response function in the case of R2 is better than in the case of absorbance measurements; correlation coefficient (r2) equals 0.995 and 0.991, respectively. Dose sensitivity, R2 of NIBMAGAT dosimeters (0.0775 s-1 Gy-1). The absorption band intensity increases linearly with a dose sensitivity of 0.016 cm-1 Gy-1. The

Depressive disorder, coronary heart disease, and stroke: dose-response and reverse causation effects in the Whitehall II cohort study.

PubMed

Brunner, Eric J; Shipley, Martin J; Britton, Annie R; Stansfeld, Stephen A; Heuschmann, Peter U; Rudd, Anthony G; Wolfe, Charles D A; Singh-Manoux, Archana; Kivimaki, Mika

2014-03-01

Systematic reviews examining associations of depressive disorder with coronary heart disease and stroke produce mixed results. Failure to consider reverse causation and dose-response patterns may have caused inconsistencies in evidence. This prospective cohort study on depressive disorder, coronary heart disease, and stroke analysed reverse causation and dose-response effects using four 5-year and three 10-year observation cycles (total follow up 24 years) based on multiple repeat measures of exposure. Participants in the Whitehall II study (n = 10,036, 31,395 person-observations, age at start 44.4 years) provided up to six repeat measures of depressive symptoms via the 30-item General Health Questionnaire (GHQ-30) and one measure via Center for Epidemiologic Studies Depression Scale (CES-D). The cohort was followed up for major coronary events (coronary death/nonfatal myocardial infarction) and stroke (stroke death/morbidity) through the national mortality register Hospital Episode Statistics, ECG-screening, medical records, and self-report questionnaires. GHQ-30 caseness predicted stroke over 0-5 years (age-, sex- and ethnicity-adjusted HR 1.60, 95% CI 1.1-2.3) but not over 5-10 years (HR 0.94, 95% CI 0.6-1.4). Using the last 5-year observation cycle, cumulative GHQ-30 caseness was associated with incident coronary heart disease in a dose-response manner (1-2 times a case: HR 1.12, 95% CI 0.7-1.7; 3-4 times: HR 2.06, 95% CI 1.2-3.7), and CES-D caseness predicted coronary heart disease (HR 1.81, 95% CI 1.1-3.1). There was evidence of a dose-response effect of depressive symptoms on risk of coronary heart disease. In contrast, prospective associations of depressive symptoms with stroke appeared to arise wholly or partly through reverse causation.

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

PubMed

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

2016-03-01

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

Hematopoietic responses under protracted exposures to low daily dose gamma irradiation

NASA Astrophysics Data System (ADS)

Seed, T. M.; Fritz, T. E.; Tolle, D. V.; Jackson, W. E.

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d -1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d -1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (> 1yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d -1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d -1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation.

Hematopoietic responses under protracted exposures to low daily dose gamma irradiation.

PubMed

Seed, T M; Fritz, T E; Tolle, D V; Jackson, W E

2002-01-01

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation. Published by Elsevier Science Ltd on behalf of COSPAR.

Identifying the most successful dose (MSD) in dose-finding studies in cancer.

PubMed

Zohar, Sarah; O'Quigley, John

2006-01-01

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not

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

PubMed

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

2016-11-19

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

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

PubMed Central

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

2016-01-01

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

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

PubMed

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

2018-03-01

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

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

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

An Exploratory Study of Responses to Low-Dose Lithium in African Americans and Hispanics

PubMed Central

Arnold, Jodi Gonzalez; Salcedo, Stephanie; Ketter, Terrence A.; Calabrese, Joseph R.; Rabideau, Dustin J.; Nierenberg, Andrew A.; Bazan, Melissa; Leon, Andrew C.; Friedman, Edward S.; Iosifescu, Dan; Sylvia, Louisa G.; Ostacher, Michael; Thase, Michael; Reilly-Harrington, Noreen A.; Bowden, Charles L.

2015-01-01

Objectives Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic Whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS). Methods LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) versus OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes. Results African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups. Conclusions African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group. PMID:25827507

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

PubMed

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

2015-04-01

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

An adaptive two-stage dose-response design method for establishing proof of concept.

PubMed

Franchetti, Yoko; Anderson, Stewart J; Sampson, Allan R

2013-01-01

We propose an adaptive two-stage dose-response design where a prespecified adaptation rule is used to add and/or drop treatment arms between the stages. We extend the multiple comparison procedures-modeling (MCP-Mod) approach into a two-stage design. In each stage, we use the same set of candidate dose-response models and test for a dose-response relationship or proof of concept (PoC) via model-associated statistics. The stage-wise test results are then combined to establish "global" PoC using a conditional error function. Our simulation studies showed good and more robust power in our design method compared to conventional and fixed designs.

Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats

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

Laham, S.; Szabo, J.; Long, G.

The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0more » g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.« less

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

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

EPA Science Inventory

Effects of Prenatal Testosterone Propionate on Sexual Development of Male and Female Rats: A Dose-Response Study
Cynthia Wolf1,2, Joe Ostby1*, Andrew Hotchkiss3, Gerald LeBlanc2, and L. Earl Gray, Jr.1
1USEPA, NHEERL, Reproductive Toxicology Division, RTP, NC; 2Dept. of To...

Time and dose-response effects of honokiol on UVB-induced skin cancer development.

PubMed

Guillermo, Ruth F; Chilampalli, Chandeshwari; Zhang, Xiaoying; Zeman, David; Fahmy, Hesham; Dwivedi, Chandradhar

2012-06-01

Honokiol has shown chemopreventive effects in chemically-induced and UVB-induced skin cancer in mice. In this investigation, we assessed the time-effects of a topical low dose of honokiol (30 μg), and then the effects of different honokiol doses (30, 45, and 60 μg) on a UVB-induced skin cancer model to find an optimal dose and time for desirable chemopreventive effects. UVB radiation (30 mJ/cm(2), 5 days/week for 25 or 27 weeks) was used to induce skin carcinogenesis in SKH-1 mice. For the time-response experiment 30 μg honokiol in acetone was applied topically to the animals before the UVB exposure (30 min, 1 h, and 2 h) and after the UVB exposure (immediately, 30 min, and 1 h). Control groups were treated with acetone. For the dose-response study, animals were treated topically with acetone or honokiol (30, 45, and 60 μg) one hour before the UVB exposure. In the time-response experiment, honokiol inhibited skin tumor multiplicity by 49-58% while reducing tumor volumes by 70-89%. In the dose-response study, honokiol (30, 45, and 60 μg) significantly decreased skin tumor multiplicity by 36-78% in a dose-dependent manner, while tumor area was reduced by 76-94%. Honokiol (60 μg) significantly reduced tumor incidence by 40% as compared to control group. Honokiol applied in very low doses (30 μg) either before or after UVB radiation shows chemopreventive effects. Honokiol (30, 45, and 60 μg) prevents UVB-induced skin cancer in a dose-dependent manner. Honokiol can be an effective chemopreventive agent against skin cancer.

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

PubMed Central

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

2015-01-01

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

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.

U-SHAPED DOSE-RESPONSE CURVES: THEIR OCCURRENCE AND IMPLICATIONS FOR RISK ASSESSMENT

EPA Science Inventory

A class of curvilinear dose-response relationships in toxicological and epidemiological studies may be roughly described by "U-shaped curves. uch curves reflect an apparent reversal or inversion in the effect of an otherwise toxic agent at a low or intermediate region of the dose...

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

ERIC Educational Resources Information Center

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

2011-01-01

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

Changes in post-traumatic symptom pattern during and after exposure to extreme war stress: an uncontrolled, preliminary study supporting the dose-response model.

PubMed

Ben-Ezra, Menachem; Palgi, Yuval; Shrira, Amit; Sternberg, Dina; Essar, Nir

2010-01-01

Exposure to prolonged war stress is understudied. While there is debate regarding the empirical data of the dose-response model for posttraumatic stress disorder (PTSD), little is known about how weekly changes in external stress influences the level of PTSD symptoms. The purpose of this study was to measure the relation between objective external stress and PTSD symptoms across time, and thus, gain a deeper understating of the dose-response model. The study hypothesis postulates that the more severe the external stressor, the more severe the exhibition of traumatic symptoms. Thirteen special army administrative staff (SAAS) members from the Rambam Medical Center in Haifa attended seven intervention meetings during the war. These personnel answered a battery of questionnaires regarding demographics and PTSD symptoms during each session. A non-parametric test was used in order to measure the changes in PTSD symptoms between sessions. Pearson correlations were used in order to study the relationship between the magnitude of external stressors and the severity of PTSD symptoms. The results suggested that there was a significant relationship between the magnitude of external stressors and the severity of PTSD symptoms. These results are in line with the dose-response model. The results suggest that a pattern of decline in PTSD symptoms confirm the dose-response model for PTSD.

Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

PubMed

Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

2017-07-01

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

Different responses of tumor and normal cells to low-dose radiation

PubMed Central

Liu, Ning; Wang, Hao; Shang, Qingjun; Jiang, Peng; Zhang, Yuanmei

2013-01-01

Aim of the study We demonstrated stimulation of both erythrocyte immune function and superoxide dismutase activity in tumor-bearing mice in response to whole-body 75 mGy X-rays. In addition, we enhanced the chemotherapeutic effect by exposing tumor-bearing mice to low-dose radiation (LDR). This study aims to investigate the different responses of tumor cells and normal cells to LDR. Material and methods Survival fraction, micronucleus frequency, and cell cycle of Lewis cells and primary human fibroblast AG01522 cells were measured. S180 sarcoma cells were implanted in mice, and tumor sizes were measured in vivo. Results In response to LDR exposure in vitro, a stimulating effect was observed in AG01522 cells but not in Lewis cells. Low-dose radiation did not cause an adaptive response in the Lewis cell cycle. Lack of an LDR-induced radioadaptive response in tumor cells was observed in tumor-bearing mouse models. Furthermore, a higher apoptotic effect and lower expression of the anti-apoptosis gene Bcl-2 were found in tumor cells of tumor-bearing mice exposed to D1 + D2 than those in tumor cells of tumor-bearing mice exposed to D2 alone. Conclusions Different responses of tumor cells and normal cells to LDR were found. Low-dose radiation was found to stimulate the growth of normal cells but not of tumor cells in vitro and in vivo, which is a very important and clinically relevant phenomenon. PMID:24592123

Biphasic Dose Response in Low Level Light Therapy – An Update

PubMed Central

Huang, Ying-Ying; Sharma, Sulbha K; Carroll, James; Hamblin, Michael R

2011-01-01

Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments. PMID:22461763

ENDOCRINE ACTIVE SUBSTANCES AND DOSE-RESPONSE FOR INDIVIDUALS AND POPULATIONS

EPA Science Inventory

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

Abstract for IUPAC-SCOPE article

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

EVALUATING QUANTITATIVE FORMULAS FOR DOSE-RESPONSE ASSESSMENT OF CHEMICAL MIXTURES

EPA Science Inventory

Risk assessment formulas are often distinguished from dose-response models by being rough but necessary. The evaluation of these rough formulas is described here, using the example of mixture risk assessment. Two conditions make the dose-response part of mixture risk assessment d...

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...

Pseudomonas aeruginosa dose response and bathing water infection.

PubMed

Roser, D J; van den Akker, B; Boase, S; Haas, C N; Ashbolt, N J; Rice, S A

2014-03-01

Pseudomonas aeruginosa is the opportunistic pathogen mostly implicated in folliculitis and acute otitis externa in pools and hot tubs. Nevertheless, infection risks remain poorly quantified. This paper reviews disease aetiologies and bacterial skin colonization science to advance dose-response theory development. Three model forms are identified for predicting disease likelihood from pathogen density. Two are based on Furumoto & Mickey's exponential 'single-hit' model and predict infection likelihood and severity (lesions/m2), respectively. 'Third-generation', mechanistic, dose-response algorithm development is additionally scoped. The proposed formulation integrates dispersion, epidermal interaction, and follicle invasion. The review also details uncertainties needing consideration which pertain to water quality, outbreaks, exposure time, infection sites, biofilms, cerumen, environmental factors (e.g. skin saturation, hydrodynamics), and whether P. aeruginosa is endogenous or exogenous. The review's findings are used to propose a conceptual infection model and identify research priorities including pool dose-response modelling, epidermis ecology and infection likelihood-based hygiene management.

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

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

PubMed

Rothenberg, Stephen J; Rothenberg, Jesse C

2005-09-01

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

Potential uncertainty reduction in model-averaged benchmark dose estimates informed by an additional dose study.

PubMed

Shao, Kan; Small, Mitchell J

2011-10-01

A methodology is presented for assessing the information value of an additional dosage experiment in existing bioassay studies. The analysis demonstrates the potential reduction in the uncertainty of toxicity metrics derived from expanded studies, providing insights for future studies. Bayesian methods are used to fit alternative dose-response models using Markov chain Monte Carlo (MCMC) simulation for parameter estimation and Bayesian model averaging (BMA) is used to compare and combine the alternative models. BMA predictions for benchmark dose (BMD) are developed, with uncertainty in these predictions used to derive the lower bound BMDL. The MCMC and BMA results provide a basis for a subsequent Monte Carlo analysis that backcasts the dosage where an additional test group would have been most beneficial in reducing the uncertainty in the BMD prediction, along with the magnitude of the expected uncertainty reduction. Uncertainty reductions are measured in terms of reduced interval widths of predicted BMD values and increases in BMDL values that occur as a result of this reduced uncertainty. The methodology is illustrated using two existing data sets for TCDD carcinogenicity, fitted with two alternative dose-response models (logistic and quantal-linear). The example shows that an additional dose at a relatively high value would have been most effective for reducing the uncertainty in BMA BMD estimates, with predicted reductions in the widths of uncertainty intervals of approximately 30%, and expected increases in BMDL values of 5-10%. The results demonstrate that dose selection for studies that subsequently inform dose-response models can benefit from consideration of how these models will be fit, combined, and interpreted. © 2011 Society for Risk Analysis.

Fractional poisson--a simple dose-response model for human norovirus.

PubMed

Messner, Michael J; Berger, Philip; Nappier, Sharon P

2014-10-01

This study utilizes old and new Norovirus (NoV) human challenge data to model the dose-response relationship for human NoV infection. The combined data set is used to update estimates from a previously published beta-Poisson dose-response model that includes parameters for virus aggregation and for a beta-distribution that describes variable susceptibility among hosts. The quality of the beta-Poisson model is examined and a simpler model is proposed. The new model (fractional Poisson) characterizes hosts as either perfectly susceptible or perfectly immune, requiring a single parameter (the fraction of perfectly susceptible hosts) in place of the two-parameter beta-distribution. A second parameter is included to account for virus aggregation in the same fashion as it is added to the beta-Poisson model. Infection probability is simply the product of the probability of nonzero exposure (at least one virus or aggregate is ingested) and the fraction of susceptible hosts. The model is computationally simple and appears to be well suited to the data from the NoV human challenge studies. The model's deviance is similar to that of the beta-Poisson, but with one parameter, rather than two. As a result, the Akaike information criterion favors the fractional Poisson over the beta-Poisson model. At low, environmentally relevant exposure levels (<100), estimation error is small for the fractional Poisson model; however, caution is advised because no subjects were challenged at such a low dose. New low-dose data would be of great value to further clarify the NoV dose-response relationship and to support improved risk assessment for environmentally relevant exposures. © 2014 Society for Risk Analysis Published 2014. This article is a U.S. Government work and is in the public domain for the U.S.A.

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

EPA Science Inventory

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

A Review: Development of a Microdose Model for Analysis of Adaptive Response and Bystander Dose Response Behavior

PubMed Central

Leonard, Bobby E.

2008-01-01

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type 125I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

A review: Development of a microdose model for analysis of adaptive response and bystander dose response behavior.

PubMed

Leonard, Bobby E

2008-02-27

Prior work has provided incremental phases to a microdosimetry modeling program to describe the dose response behavior of the radio-protective adaptive response effect. We have here consolidated these prior works (Leonard 2000, 2005, 2007a, 2007b, 2007c) to provide a composite, comprehensive Microdose Model that is also herein modified to include the bystander effect. The nomenclature for the model is also standardized for the benefit of the experimental cellular radio-biologist. It extends the prior work to explicitly encompass separately the analysis of experimental data that is 1.) only dose dependent and reflecting only adaptive response radio-protection, 2.) both dose and dose-rate dependent data and reflecting only adaptive response radio-protection for spontaneous and challenge dose damage, 3.) only dose dependent data and reflecting both bystander deleterious damage and adaptive response radio-protection (AR-BE model). The Appendix cites the various applications of the model. Here we have used the Microdose Model to analyze the, much more human risk significant, Elmore et al (2006) data for the dose and dose rate influence on the adaptive response radio-protective behavior of HeLa x Skin cells for naturally occurring, spontaneous chromosome damage from a Brachytherapy type (125)I photon radiation source. We have also applied the AR-BE Microdose Model to the Chromosome inversion data of Hooker et al (2004) reflecting both low LET bystander and adaptive response effects. The micro-beam facility data of Miller et al (1999), Nagasawa and Little (1999) and Zhou et al (2003) is also examined. For the Zhou et al (2003) data, we use the AR-BE model to estimate the threshold for adaptive response reduction of the bystander effect. The mammogram and diagnostic X-ray induction of AR and protective BE are observed. We show that bystander damage is reduced in the similar manner as spontaneous and challenge dose damage as shown by the Azzam et al (1996) data. We cite

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

PubMed

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

2016-01-01

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

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

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

Levy, R.P.

1991-12-01

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

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

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

Levy, Richard P.

1991-12-01

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

An effective dose of ketamine for eliminating pain during injection of propofol: a dose response study.

PubMed

Wang, M; Wang, Q; Yu, Y Y; Wang, W S

2013-09-01

Ketamine can completely eliminate pain associated with propofol injection. However, the effective dose of ketamine to eliminate propofol injection pain has not been determined. The purpose of this study was to determine the effective dose of ketamine needed to eliminate pain in 50% and 95% of patients (ED50 and ED95, respectively) during propofol injections. This study was conducted in a double-blinded fashion and included 50 patients scheduled for elective gynecological laparoscopy under general anesthesia. The initial dose of ketamine used in the first patient was 0.25mg/kg. The dosing modifications were in increments or decrements of 0.025 mg/kg. Ketamine was administered 15 seconds before injecting propofol (2.5mg/kg), which was injected at a rate of 1mL/s. Patients were asked to rate their pain during propofol injection every 5s econds using a 0-3 pain scale. The highest pain score was recorded. The ED50, ED95 and 95% confidence intervals (CI) were determined by probit analyses. The dose of ketamine ranged from 0.175 to 0.275 mg/kg. The ED50 and ED95 of ketamine for eliminating pain during propofol injection were 0.227 mg/kg and 0.283 mg/kg, respectively (95%CI: 0.211-0.243 mg/kg and 0.26-0.364 mg/kg, respectively). Ketamine at an approximate dose of 0.3mg/kg was effective in eliminating pain during propofol injection. Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

Time-dependent dose-response relation for absence of vaginal elasticity after gynecological radiation therapy.

PubMed

Alevronta, Eleftheria; Åvall-Lundqvist, Elisabeth; Al-Abany, Massoud; Nyberg, Tommy; Lind, Helena; Waldenström, Ann-Charlotte; Olsson, Caroline; Dunberger, Gail; Bergmark, Karin; Steineck, Gunnar; Lind, Bengt K

2016-09-01

To investigate the dose-response relation between the dose to the vagina and the patient-reported symptom 'absence of vaginal elasticity' and how time to follow-up influences this relation. The study included 78 long-term gynecological cancer survivors treated between 1991 and 2003 with external beam radiation therapy. Of those, 24 experienced absence of vaginal elasticity. A normal tissue complication model is introduced that takes into account the influence of time to follow-up on the dose-response relation and the patient's age. The best estimates of the dose-response parameters were calculated using Probit, Probit-Relative Seriality (RS) and Probit-time models. Log likelihood (LL) values and the Akaike Information Criterion (AIC) were used to evaluate the model fit. The dose-response parameters for 'absence of vaginal elasticity' according to the Probit and Probit-time models with the 68% Confidence Intervals (CI) were: LL=-39.8, D 50 =49.7 (47.2-52.4) Gy, γ 50 =1.40 (1.12-1.70) and LL=-37.4, D 50 =46.9 (43.5-50.9) Gy, γ 50 =1.81 (1.17-2.51) respectively. The proposed model, which describes the influence of time to follow-up on the dose-response relation, fits our data best. Our data indicate that the steepness of the dose-response curve of the dose to the vagina and the symptom 'absence of vaginal elasticity' increases with time to follow-up, while D 50 decreases. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

USE OF MECHANISTIC DATA TO HELP DEFINE DOSE-RESPONSE CURVES

EPA Science Inventory

Use of Mechanistic Data to Help Define Dose-Response Curves

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

Processing of facial affect in social drinkers: a dose-response study of alcohol using dynamic emotion expressions.

PubMed

Kamboj, Sunjeev K; Joye, Alyssa; Bisby, James A; Das, Ravi K; Platt, Bradley; Curran, H Valerie

2013-05-01

Studies of affect recognition can inform our understanding of the interpersonal effects of alcohol and help develop a more complete neuropsychological profile of this drug. The objective of the study was to examine affect recognition in social drinkers using a novel dynamic affect-recognition task, sampling performance across a range of evolutionarily significant target emotions and neutral expressions. Participants received 0, 0.4 or 0.8 g/kg alcohol in a double-blind, independent groups design. Relatively naturalistic changes in facial expression-from neutral (mouth open) to increasing intensities of target emotions, as well as neutral (mouth closed)-were simulated using computer-generated dynamic morphs. Accuracy and reaction time were measured and a two-high-threshold model applied to hits and false-alarm data to determine sensitivity and response bias. While there was no effect on the principal emotion expressions (happiness, sadness, fear, anger and disgust), compared to those receiving 0.8 g/kg of alcohol and placebo, participants administered with 0.4 g/kg alcohol tended to show an enhanced response bias to neutral expressions. Exploration of this effect suggested an accompanying tendency to misattribute neutrality to sad expressions following the 0.4-g/kg dose. The 0.4-g/kg alcohol-but not 0.8 g/kg-produced a limited and specific modification in affect recognition evidenced by a neutral response bias and possibly an accompanying tendency to misclassify sad expressions as neutral. In light of previous findings on involuntary negative memory following the 0.4-g/kg dose, we suggest that moderate-but not high-doses of alcohol have a special relevance to emotional processing in social drinkers.

Randomised controlled trials define shape of dose-response for Pollinex Quattro Birch allergoid immunotherapy.

PubMed

Worm, Margitta; Higenbottam, Tim; Pfaar, Oliver; Mösges, Ralph; Aberer, Werner; Gunawardena, Kulasiri; Wessiepe, Dorothea; Lee, Denise; Kramer, Matthias F; Skinner, Murray; Lees, Bev; Zielen, Stefan

2018-05-19

The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX ® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed two phase II studies to determine its optimal cumulative dose. The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction of Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modelling analysis was used to test for the dose-response, shape of the curve, and estimation of the median effective dose (ED 50 ), a measure of potency. Statistically significant dose-responses (p<0.01 & 0.001) were seen respectively. The highest cumulative dose in PQBirch204 (27300 standardised units [SU]) approached a plateau. Potency of the PQ Birch was demonstrated by an ED 50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. Increasing the cumulative dose of PQ Birch 5.5-fold from 5100 to 27300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase of efficacy of 50%, without compromising safety. The cumulative dose-response was confirmed to be curvilinear in shape. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Dose response evaluation of a low-density normoxic polymer gel dosimeter using MRI

NASA Astrophysics Data System (ADS)

Haraldsson, P.; Karlsson, A.; Wieslander, E.; Gustavsson, H.; Bäck, S. Å. J.

2006-02-01

A low-density (~0.6 g cm-3) normoxic polymer gel, containing the antioxidant tetrakis (hydroxymethyl) phosponium (THP), has been investigated with respect to basic absorbed dose response characteristics. The low density was obtained by mixing the gel with expanded polystyrene spheres. The depth dose data for 6 and 18 MV photons were compared with Monte Carlo calculations. A large volume phantom was irradiated in order to study the 3D dose distribution from a 6 MV field. Evaluation of the gel was carried out using magnetic resonance imaging. An approximately linear response was obtained for 1/T2 versus dose in the dose range of 2 to 8 Gy. A small decrease in the dose response was observed for increasing concentrations of THP. A good agreement between measured and Monte Carlo calculated data was obained, both for test tubes and the larger 3D phantom. It was shown that a normoxic polymer gel with a reduced density could be obtained by adding expanded polystyrene spheres. In order to get reliable results, it is very important to have a uniform distribution of the gel and expanded polystyrene spheres in the phantom volume.

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia.

PubMed

Yadav, Manisha C; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L; Whyte, Michael P; Crine, Philippe; Millán, José Luis

2011-08-01

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD(10), renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2(-/-)) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2(-/-) mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2mg/kg for 43days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED(80) (the dose that prevents bone defects in 80% of mice) was 3.2, 2.8 and 2.9mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PP(i) concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP in patients, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP to mice. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. Copyright © 2011 Elsevier Inc. All rights reserved.

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

PubMed Central

Yadav, Manisha C.; Lemire, Isabelle; Leonard, Pierre; Boileau, Guy; Blond, Laurent; Beliveau, Martin; Cory, Esther; Sah, Robert L.; Whyte, Michael P.; Crine, Philippe; Millán, José Luis

2011-01-01

Hypophosphatasia (HPP) features rickets or osteomalacia from tissue-nonspecific alkaline phosphatase (TNSALP) deficiency due to deactivating mutations within the ALPL gene. Enzyme replacement therapy with a bone-targeted, recombinant TNSALP (sALP-FcD10, renamed ENB-0040) prevents manifestations of HPP when initiated at birth in TNSALP knockout (Akp2−/−) mice. Here, we evaluated the dose-response relationship of ENB-0040 to various phenotypic traits of Akp2−/− mice receiving daily subcutaneous (SC) injections of ENB-0040 from birth at 0.5, 2.0, or 8.2 mg/kg for 43 days. Radiographs, μCT, and histomorphometric analyses documented better bone mineralization with increasing doses of ENB-0040. We found a clear, positive correlation between ENB-0040 dose and prevention of mineralization defects of the feet, rib cage, lower limbs, and jaw bones. According to a dose-response model, the ED80 (the dose prevents the bone defects in 80% of mice) was 3.2, 2.8 and 2.9 mg/kg/day for these sites, respectively. Long bones seemed to respond to lower daily doses of ENB-0040. There was also a positive relationship between ENB-0040 dose and survival. Median survival, body weight, and bone length all improved with increasing doses of ENB-0040. Urinary PPi concentrations remained elevated in all treatment groups, indicating that while this parameter is a good biochemical marker for diagnosing HPP, it may not be a good follow up marker for evaluating response to treatment when administering bone-targeted TNSALP. These dose-response relationships strongly support the pharmacological efficacy of ENB-0040 for HPP, and provide the experimental basis for the therapeutic range of ENB-0040 chosen for clinical trials. PMID:21458605

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

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

Landry, Greg M., E-mail: Landry.Greg@mayo.edu; Dunning, Cody L., E-mail: cdunni@lsuhsc.edu; Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu

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

AS03-Adjuvanted, Very-Low-Dose Influenza Vaccines Induce Distinctive Immune Responses Compared to Unadjuvanted High-Dose Vaccines in BALB/c Mice

PubMed Central

Yam, Karen K.; Gupta, Jyotsana; Winter, Kaitlin; Allen, Elizabeth; Brewer, Angela; Beaulieu, Édith; Mallett, Corey P.; Burt, David S.; Ward, Brian J.

2015-01-01

During the 2009–2010 influenza pandemic, an adjuvanted, dose-sparing vaccine was recommended for most Canadians. We hypothesize that differences exist in the responses to AS03-adjuvanted, low antigen (Ag) dose versus unadjuvanted, full-dose vaccines. We investigated the relationship between Ag dose and the oil-in-water emulsion Adjuvant System AS03. BALB/c mice received two IM doses of AS03A or AS03B with exaggerated dilutions of A/Uruguay/716/2007 H3N2 split virion vaccine Ag. Immune responses were assessed 3 weeks after the booster. Unadjuvanted “high” (3 μg) and low-dose (0.03–0.003 μg) vaccines generated similar serum antibody titers and cytokine secretion patterns in restimulated splenocytes. Compared to unadjuvanted “high-dose” vaccination, both AS03A and AS03B-adjuvanted low-dose vaccines tended to elicit higher serum antibody titers, broader induction of cytokine secretion and generated more influenza-specific antibody secreting cells and cytokine-secreting CD4 and CD8 T cells in splenocytes. We show that varying Ag and/or AS03 dose in this influenza vaccination mouse model can strongly influence both the magnitude and pattern of the immune response elicited. These findings are highly relevant given the likelihood of expanded use of adjuvanted, dose-sparing vaccines and raise questions about the use of “standard” doses of vaccines in pre-clinical vaccine studies. PMID:25972874

Soy food intake and risk of gastric cancer: A dose-response meta-analysis of prospective studies.

PubMed

Weng, Ke-Gui; Yuan, Ya-Ling

2017-08-01

Epidemiological studies were inconsistent on the association between soy food intake and risk of gastric cancer (GC). This study aimed to determine the role of soy food intake in the development of GC.A systematic search was conducted in PubMed and Web of Science to identify all relevant studies. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model, and the dose-response relationship between soy food intake and GC risk was also assessed.Thirteen prospective studies were identified with a total of 517,106 participants and 5800 cases. Among 11 types of soy food, high intake of total soy food (the highest vs the lowest category: RR: 0.78, 95% CI: 0.62-0.98) and nonfermented soy food (RR: 0.63, 95% CI: 0.50-0.79) were inversely associated with GC risk, while high intake of miso soup was associated with the risk in male (RR: 1.17, 95% CI: 1.02-1.36). In dose-response meta-analysis, total soy food intake (0-150 g/day) showed no significant association with GC risk, while high intake of nonfermented soy food was inversely related, especially an intake of more than 100 g/day. In male, miso soup intake (1-5 cups/day) was significantly associated with GC risk.High intake of nonfermented soy food might reduce the risk of GC, while miso soup intake might increase the risk in male.

Physical activity and cancer risk: dose-response and cancer, all sites and site-specific.

PubMed

Thune, I; Furberg, A S

2001-06-01

The association between physical activity and overall and site-specific cancer risk is elaborated in relation to whether any observed dose-response association between physical activity and cancer can be interpreted in terms of how much physical activity (type, intensity, duration, frequency) is needed to influence site- and gender-specific cancer risk. Observational studies were reviewed that have examined the independent effect of the volume of occupational physical activity (OPA) and/or leisure time physical activity (LPA) on overall and site-specific cancer risk. The evidence of cohort and case-control studies suggests that both leisure time and occupational physical activity protect against overall cancer risk, with a graded dose-response association suggested in both sexes. Confounding effects such as diet, body weight, and parity are often included as a covariate in the analyses, with little influence on the observed associations. A crude graded inverse dose-response association was observed between physical activity and colon cancer in 48 studies including 40,674 colon/colorectal cancer cases for both sexes. A dose-response effect of physical activity on colon cancer risk was especially observed, when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed as MET-hours per week. An observed inverse association with a dose-response relationship between physical activity and breast cancer was also identified in the majority of the 41 studies including 108,031 breast cancer cases. The dose-response relationship was in particular observed in case-control studies and supported by observations in cohort studies when participation in activities of at least moderate activity (>4.5 MET) and demonstrated by activities expressed by MET-hours per week. This association between physical activity and breast cancer risk is possibly dependent on age at exposure, age at diagnosis, menopausal status and other effect

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

EPA Science Inventory

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

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

Dose-response association between leisure time physical activity and work ability: Cross-sectional study among 3000 workers.

PubMed

Calatayud, Joaquin; Jakobsen, Markus D; Sundstrup, Emil; Casaña, Jose; Andersen, Lars L

2015-12-01

Regular physical activity is important for longevity and health, but knowledge about the optimal dose of physical activity for maintaining good work ability is unknown. This study investigates the association between intensity and duration of physical activity during leisure time and work ability in relation to physical demands of the job. From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners with physically demanding work (n = 2952) replied to questions about work, lifestyle and health. Excellent (100 points), very good (75 points), good (50 points), fair (25 points) and poor (0 points) work ability in relation to the physical demands of the job was experienced by 18%, 40%, 30%, 10% and 2% of the respondents, respectively. General linear models that controlled for gender, age, physical and psychosocial work factors, lifestyle and chronic disease showed that the duration of high-intensity physical activity during leisure was positively associated with work ability, in a dose-response fashion (p < 0.001). Those performing ⩾ 5 hours of high-intensity physical activity per week had on average 8 points higher work ability than those not performing such activities. The duration of low-intensity leisure-time physical activity was not associated with work ability (p = 0.5668). The duration of high-intensity physical activity during leisure time is associated in a dose-response fashion with work ability, in workers with physically demanding jobs. © 2015 the Nordic Societies of Public Health.

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

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

Diez, Patricia; Vogelius, Ivan S.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792

2010-07-15

Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, {gamma}{sub 50}, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies.more » Results: Nonrandomized studies produced a statistically significantly higher {gamma}{sub 50} than randomized studies for intermediate- to high-risk patients ({gamma}{sub 50} = 1.63 vs. {gamma}{sub 50} = 0.93, p = 0.03) and a borderline significantly higher ({gamma}{sub 50} = 1.78 vs. {gamma}{sub 50} = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in {gamma}{sub 50} was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of {gamma}{sub 50} = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.« less

Dose-response effects of corneal anesthetics.

PubMed

Polse, K A; Keener, R J; Jauregui, M J

1978-01-01

With double-masking procedures, the dose-response curves for 0.1, 0.2, and 0.4% benoxinate and 0.125, 0.25, and 0.50% proparacaine hydrochloride were determined by monitoring changes in corneal touch threshold after applying each anesthetic. The level of corneal anesthesia necessary for applanation tonometry was also determined. The maximum increase in threshold that could be measured following instillation of 50 microliter of the drug was 200 mg/mm2 All 6 anesthetic solutions produced this amount of decreased corneal sensitivity. Recovery from the anesthetic was exponential for all concentrations; however, the lower doses had the shortest duration. For applanation tonometry, the corneal threshold for touch must be 75 mg/mm2 or higher. We conclude that a quarter to a half of the commonly used anesthetic dose is sufficient for routine tonometric evaluation.

Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

PubMed

Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh

2017-01-01

Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

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

PubMed

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

2016-07-01

The in vivo low-dose responses of zebrafish (Danio rerio) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead. © The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

A randomized, double-blind, placebo-controlled, dose-ranging study of lisdexamfetamine dimesylate augmentation for major depressive disorder in adults with inadequate response to antidepressant therapy

PubMed Central

Richards, Cynthia; Iosifescu, Dan V; Mago, Rajnish; Sarkis, Elias; Reynolds, James; Geibel, Brooke; Dauphin, Matthew

2017-01-01

Background: This randomized, double-blind, placebo-controlled study evaluated dose-response relationships of lisdexamfetamine dimesylate when used as augmentation for major depressive disorder in individuals exhibiting inadequate responses to antidepressant monotherapy. Methods: Eligible adults (18–65 years) were assigned to antidepressant monotherapy (escitalopram or venlafaxine extended-release) plus lisdexamfetamine dimesylate-matching placebo during an eight-week single-blind lead-in phase. Participants meeting randomization criteria were randomized (1:1:1:1:1) to eight weeks of lisdexamfetamine dimesylate (10, 30, 50, or 70 mg) or placebo while maintaining antidepressant therapy. Dose-responses for changes from augmentation baseline to week 16/early termination for Montgomery-Åsberg Depression Rating Scale total score (primary efficacy endpoint) and vital signs (systolic and diastolic blood pressure and pulse) were assessed using multiple comparisons procedures with modeling. Results: For Montgomery-Åsberg Depression Rating Scale total score change, no significant dose-responses were observed for any candidate dose-response curve (all p>0.10). In the dose-response evaluable population, least squares mean (90% confidence interval) treatment differences versus placebo for Montgomery-Åsberg Depression Rating Scale total score change at week 16 were −1.4 (−3.9, 1.2), 0.1 (−2.5, 2.7), −0.7 (−3.4, 2.0), and −0.9 (−3.5, 1.6) with 10, 30, 50, and 70 mg lisdexamfetamine dimesylate, respectively. For all vital sign parameters, lisdexamfetamine dimesylate exhibited significant dose-responses for all candidate dose-response curves (all p<0.10), with increases observed as lisdexamfetamine dimesylate dose increased; a linear relationship provided the best fit. Mean±standard deviation changes from augmentation baseline for systolic and diastolic blood pressure and pulse at week 16/early termination were −0.7±9.90 and −0.3±7.24 mm Hg and 0.2±10

The Prevalence and Clinical Features of Non-responsive Gastroesophageal Reflux Disease to Practical Proton Pump Inhibitor Dose in Korea: A Multicenter Study.

PubMed

Park, Hong Jun; Park, Soo Heon; Shim, Ki Nam; Kim, Yong Sung; Kim, Hyun Jin; Han, Jae Pil; Kim, Yong Sik; Bang, Byoung Wook; Kim, Gwang Ha; Baik, Gwang Ho; Kim, Hyung Hun; Park, Seon Young; Kim, Sung Soo

2016-07-25

In Korea, there are no available multicenter data concerning the prevalence of or diagnostic approaches for non-responsive gastroesophageal reflux disease (GERD) which does not respond to practical dose of proton pump inhibitor (PPI) in Korea. The purpose of this study is to evaluate the prevalence and the symptom pattern of non-responsive GERD. A total of 12 hospitals who were members of a Korean GERD research group joined this study. We used the composite score (CS) as a reflux symptom scale which is a standardized questionnaire based on the frequency and severity of typical symptoms of GERD. We defined "non-responsive GERD" as follows: a subject with the erosive reflux disease (ERD) whose CS was not decreased by at least 50% after standard-dose PPIs for 8 weeks or a subject with non-erosive reflux disease (NERD) whose CS was not decreased by at least 50% after half-dose PPIs for 4 weeks. A total of 234 subjects were analyzed. Among them, 87 and 147 were confirmed to have ERD and NERD, respectively. The prevalence of non-responsive GERD was 26.9% (63/234). The rates of non-responsive GERD were not different between the ERD and NERD groups (25.3% vs. 27.9%, respectively, p=0.664). There were no differences between the non-responsive GERD and responsive GERD groups for sex (p=0.659), age (p=0.134), or BMI (p=0.209). However, the initial CS for epigastric pain and fullness were higher in the non-responsive GERD group (p=0.044, p=0.014, respectively). In conclusion, this multicenter Korean study showed that the rate of non-responsive GERD was substantially high up to 26%. In addition, the patients with the non-responsive GERD frequently showed dyspeptic symptoms such as epigastric pain and fullness.

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Dose-response relationship between hand-transmitted vibration and hand-arm vibration syndrome in a tropical environment.

PubMed

Su, Anselm Ting; Maeda, Setsuo; Fukumoto, Jin; Darus, Azlan; Hoe, Victor C W; Miyai, Nobuyuki; Isahak, Marzuki; Takemura, Shigeki; Bulgiba, Awang; Yoshimasu, Kouichi; Miyashita, Kazuhisa

2013-07-01

The dose-response relationship for hand-transmitted vibration has been investigated extensively in temperate environments. Since the clinical features of hand-arm vibration syndrome (HAVS) differ between the temperate and tropical environment, we conducted this study to investigate the dose-response relationship of HAVS in a tropical environment. A total of 173 male construction, forestry and automobile manufacturing plant workers in Malaysia were recruited into this study between August 2011 and 2012. The participants were interviewed for history of vibration exposure and HAVS symptoms, followed by hand functions evaluation and vibration measurement. Three types of vibration doses-lifetime vibration dose (LVD), total operating time (TOT) and cumulative exposure index (CEI)-were calculated and its log values were regressed against the symptoms of HAVS. The correlation between each vibration exposure dose and the hand function evaluation results was obtained. The adjusted prevalence ratio for finger tingling and numbness was 3.34 (95% CI 1.27 to 8.98) for subjects with lnLVD≥20 ln m(2) s(-4) against those <16 ln m(2) s(-4). Similar dose-response pattern was found for CEI but not for TOT. No subject reported white finger. The prevalence of finger coldness did not increase with any of the vibration doses. Vibrotactile perception thresholds correlated moderately with lnLVD and lnCEI. The dose-response relationship of HAVS in a tropical environment is valid for finger tingling and numbness. The LVD and CEI are more useful than TOT when evaluating the dose-response pattern of a heterogeneous group of vibratory tools workers.

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

EPA Science Inventory

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

Different dose rate-dependent responses of human melanoma cells and fibroblasts to low dose fast neutrons.

PubMed

Dionet, Claude; Müller-Barthélémy, Melanie; Marceau, Geoffroy; Denis, Jean-Marc; Averbeck, Dietrich; Gueulette, John; Sapin, Vincent; Pereira, Bruno; Tchirkov, Andrei; Chautard, Emmanuel; Verrelle, Pierre

2016-09-01

To analyze the dose rate influence in hyper-radiosensitivity (HRS) of human melanoma cells to very low doses of fast neutrons and to compare to the behaviour of normal human skin fibroblasts. We explored different neutron dose rates as well as possible implication of DNA double-strand breaks (DSB), apoptosis, and energy-provider adenosine-triphosphate (ATP) levels during HRS. HRS in melanoma cells appears only at a very low dose rate (VLDR), while a high dose rate (HDR) induces an initial cell-radioresistance (ICRR). HRS does not seem to be due either to DSB or to apoptosis. Both phenomena (HRS and ICRR) appear to be related to ATP availability for triggering cell repair. Fibroblast survival after neutron irradiation is also dose rate-dependent but without HRS. Melanoma cells or fibroblasts exert their own survival behaviour at very low doses of neutrons, suggesting that in some cases there is a differential between cancer and normal cells radiation responses. Only the survival of fibroblasts at HDR fits the linear no-threshold model. This new insight into human cell responses to very low doses of neutrons, concerns natural radiations, surroundings of accelerators, proton-therapy devices, flights at high altitude. Furthermore, ATP inhibitors could increase HRS during high-linear energy transfer (high-LET) irradiation.

Salmonella Fecal Shedding and Immune Responses are Dose- and Serotype- Dependent in Pigs

PubMed Central

Ivanek, Renata; Österberg, Julia; Gautam, Raju; Sternberg Lewerin, Susanna

2012-01-01

Despite the public health importance of Salmonella infection in pigs, little is known about the associated dynamics of fecal shedding and immunity. In this study, we investigated the transitions of pigs through the states of Salmonella fecal shedding and immune response post-Salmonella inoculation as affected by the challenge dose and serotype. Continuous-time multistate Markov models were developed using published experimental data. The model for shedding had four transient states, of which two were shedding (continuous and intermittent shedding) and two non-shedding (latency and intermittent non-shedding), and one absorbing state representing permanent cessation of shedding. The immune response model had two transient states representing responses below and above the seroconversion level. The effects of two doses [low (0.65×106 CFU/pig) and high (0.65×109 CFU/pig)] and four serotypes (Salmonella Yoruba, Salmonella Cubana, Salmonella Typhimurium, and Salmonella Derby) on the models' transition intensities were evaluated using a proportional intensities model. Results indicated statistically significant effects of the challenge dose and serotype on the dynamics of shedding and immune response. The time spent in the specific states was also estimated. Continuous shedding was on average 10–26 days longer, while intermittent non-shedding was 2–4 days shorter, in pigs challenged with the high compared to low dose. Interestingly, among pigs challenged with the high dose, the continuous and intermittent shedding states were on average up to 10–17 and 3–4 days longer, respectively, in pigs infected with S. Cubana compared to the other three serotypes. Pigs challenged with the high dose of S. Typhimurium or S. Derby seroconverted on average up to 8–11 days faster compared to the low dose. These findings highlight that Salmonella fecal shedding and immune response following Salmonella challenge are dose- and serotype-dependent and that the detection of specific

A dose-responsive model of smoke inhalation injury. Severity-related alteration in cardiopulmonary function.

PubMed Central

Shimazu, T; Yukioka, T; Hubbard, G B; Langlinais, P C; Mason, A D; Pruitt, B A

1987-01-01

The dose responsiveness of selected physiologic indices was studied in a sheep model of smoke inhalation injury. In this model, graded severity of injury was achieved by changing the contact time with smoke (defined by "unit"), whereas other variables were kept constant. Blood gas and cardiopulmonary indices were measured in 70 sheep, including 12 controls, either 24 or 72 hours after exposure to 3, 6, 9, 12, 15, or 18 units of smoke. A 12-unit dose of smoke was fatal within 72 hours and an 18-unit dose was fatal within 24 hours. The best correlation between smoke dose and response was observed in arterial oxygen tension 24 hours after exposure. At 24 hours, most of the cardiopulmonary indices showed significant change only after a 12-unit exposure. Although the exact shape of the dose-response curve could not be defined, sigmoid or curved linear shape was suggested, reflecting the progressive deterioration. Images Fig. 3. Fig. 4A. Fig. 4B. PMID:3606236

Dose-time-response association between occupational asbestos exposure and pleural mesothelioma.

PubMed

Lacourt, Aude; Lévêque, Emilie; Guichard, Elie; Gilg Soit Ilg, Anabelle; Sylvestre, Marie-Pierre; Leffondré, Karen

2017-09-01

Early occupational exposure to asbestos has been shown to be associated with an increased risk of pleural mesothelioma (PM), which suggests that the timing of exposure might play a role in the dose-response relationship. However, none studies has evaluated the relative impact of increasing the annual intensity of occupational exposure to asbestos at each time of the whole exposure history. Yet such evaluation would allow the comparison of the risks of PM associated with different longitudinal profiles of occupational exposure to asbestos. Our objective was to estimate the time-dependent relative impact of asbestos exposure intensity over the whole occupational history and to compare the resulting estimated risks of PM associated with different profiles of exposure, using data from a large French case-control study. This study included 1196 male cases recruited in 1987-2006 and 2369 matched controls on birth year. Occupational exposure to asbestos was assessed using a job exposure matrix and represented in logistic regression models using a flexible weighted cumulative index of exposure. Due to much stronger weights of early doses of asbestos exposure, subjects who accumulated 20 fibres/mL over their entire job history with high doses during the first years and low doses thereafter were at higher risk of PM than those who accumulated most of the doses later (OR=2.37 (95% CI 2.01 to 2.87)). This study provides new insights on the dose-time-response relationship between occupational asbestos and PM and illustrates the importance of considering timing of exposure in its association with cancer risk. © 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.

Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases

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

Balajee, A.S.; Meador, J.A.; Su, Y.

differences in cellular defense mechanisms between low and high doses of low LET radiation and to define the radiation doses where the cellular DNA damage signaling and repair mechanisms tend to shift. This information is critically important to address and advance some of the low dose research program objectives of DOE. The results of this proposed study will lead to a better understanding of the mechanisms for the cellular responses to low and high doses of low LET radiation. Further, systematic analysis of the role of PIKK signaling pathways as a function of radiation dose in tissue microenvironment will provide useful mechanistic information for improving the accuracy of radiation risk assessment for low doses. Knowledge of radiation responses in tissue microenvironment is important for the accurate prediction of ionizing radiation risks associated with cancer and tissue degeneration in humans.« less

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

NASA Astrophysics Data System (ADS)

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

2009-01-01

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

Coffee intake and the incident risk of cognitive disorders: A dose-response meta-analysis of nine prospective cohort studies.

PubMed

Wu, Lei; Sun, Dali; He, Yao

2017-06-01

Previous epidemiological studies have provided inconsistent conclusions on the impact of coffee consumption in the developing of cognitive disorders. However, no previous meta-analysis has pooled the evidence from the prospective cohort studies to assess the influence of coffee drinking and its potential dose-response patterns on the risk of developing cognitive disorders specifically. Two databases (PubMed and Embase) were searched for evidence of cohort studies from inception to February 2016. We used a generic inverse-variance method with a random-effects model to pool the fully adjusted relative risks (RRs) and the corresponding 95% confidence intervals (CIs). In the dose-response analyses, a generalized least-squares trend estimation model was applied to computing the study-specific slopes. Nine prospective cohort studies involving 34,282 participants were included in our study. The duration of follow-up years ranged from 1.3 to 28. Compared with <1 cup, daily drinking of 1-2 cups of coffee was inversely linked with the occurrence of cognitive disorders (i.e., Alzheimer's disease, dementia, cognitive decline, and cognitive impairment), and the pooled RR (95% CI) was 0.82 (0.71, 0.94) with evidence of non-significant heterogeneity (I 2  = 25%). Non-significant differences were presented for the association between coffee consumption (>3 vs. <1 cup/d) and incident cognitive disorders. The dose-response analysis showed a "J-shaped" curve relationship of the risk of developing cognitive disorders with coffee consumption. A "J-shaped" association was presented between coffee intake and incident cognitive disorders, with the lowest risk of incident cognitive disorders at a daily consumption level of 1-2 cups of coffee. Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

'Omics analysis of low dose acetaminophen intake demonstrates novel response pathways in humans

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

Jetten, Marlon J.A.; Gaj, Stan; Ruiz-Aracama, Ainhoa

2012-03-15

Acetaminophen is the primary cause of acute liver toxicity in Europe/USA, which led the FDA to reconsider recommendations concerning safe acetaminophen dosage/use. Unfortunately, the current tests for liver toxicity are no ideal predictive markers for liver injury, i.e. they only measure acetaminophen exposure after profound liver toxicity has already occurred. Furthermore, these tests do not provide mechanistic information. Here, 'omics techniques (global analysis of metabolomic/gene-expression responses) may provide additional insight. To better understand acetaminophen-induced responses at low doses, we evaluated the effects of (sub-)therapeutic acetaminophen doses on metabolite formation and global gene-expression changes (including, for the first time, full-genome humanmore » miRNA expression changes) in blood/urine samples from healthy human volunteers. Many known and several new acetaminophen-metabolites were detected, in particular in relation to hepatotoxicity-linked, oxidative metabolism of acetaminophen. Transcriptomic changes indicated immune-modulating effects (2 g dose) and oxidative stress responses (4 g dose). For the first time, effects of acetaminophen on full-genome human miRNA expression have been considered and confirmed the findings on mRNA level. 'Omics techniques outperformed clinical chemistry tests and revealed novel response pathways to acetaminophen in humans. Although no definitive conclusion about potential immunotoxic effects of acetaminophen can be drawn from this study, there are clear indications that the immune system is triggered even after intake of low doses of acetaminophen. Also, oxidative stress-related gene responses, similar to those seen after high dose acetaminophen exposure, suggest the occurrence of possible pre-toxic effects of therapeutic acetaminophen doses. Possibly, these effects are related to dose-dependent increases in levels of hepatotoxicity-related metabolites. -- Highlights: ► 'Omics techniques

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.

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

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

Munira A Kadhim

2010-03-05

To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry andmore » risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies

Diabetogenic action of streptozotocin: relationship of dose to metabolic response

PubMed Central

Junod, Alain; Lambert, André E.; Stauffacher, Werner; Renold, Albert E.

1969-01-01

The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections. PMID:4241908

Dose-Response of Sodium Bicarbonate Ingestion Highlights Individuality in Time Course of Blood Analyte Responses.

PubMed

Jones, Rebecca Louise; Stellingwerff, Trent; Artioli, Guilherme Giannini; Saunders, Bryan; Cooper, Simon; Sale, Craig

2016-10-01

To defend against hydrogen cation accumulation and muscle fatigue during exercise, sodium bicarbonate (NaHCO 3 ) ingestion is commonplace. The individualized dose-response relationship between NaHCO 3 ingestion and blood biochemistry is unclear. The present study investigated the bicarbonate, pH, base excess and sodium responses to NaHCO 3 ingestion. Sixteen healthy males (23 ± 2 years; 78.6 ± 15.1 kg) attended three randomized order-balanced, nonblinded sessions, ingesting a single dose of either 0.1, 0.2 or 0.3 g·kg -1 BM of NaHCO 3 (Intralabs, UK). Fingertip capillary blood was obtained at baseline and every 10 min for 1 hr, then every 15 min for a further 2 hr. There was a significant main effect of both time and condition for all assessed blood analytes (p ≤ .001). Blood analyte responses were significantly lower following 0.1 g·kg -1 BM compared with 0.2 g·kg -1 BM; bicarbonate concentrations and base excess were highest following ingestion of 0.3 g·kg -1 BM (p ≤ .01). Bicarbonate concentrations and pH significantly increased from baseline following all doses; the higher the dose the greater the increase. Large interindividual variability was shown in the magnitude of the increase in bicarbonate concentrations following each dose (+2.0-5; +5.1-8.1; and +6.0-12.3 mmol·L -1 for 0.1, 0.2 and 0.3 g·kg -1 BM) and in the range of time to peak concentrations (30-150; 40-165; and 75-180 min for 0.1, 0.2 and 0.3 g·kg -1 BM). The variability in bicarbonate responses was not affected by normalization to body mass. These results challenge current practices relating to NaHCO 3 supplementation and clearly show the need for athletes to individualize their ingestion protocol and trial varying dosages before competition.

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

EPA Science Inventory

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

ABSTRACT
Testosterone plays a major role in ...

Radiation dose-response curves: cell repair mechanisms vs. ion track overlapping

NASA Astrophysics Data System (ADS)

Kowalska, Agata; Czerski, Konrad; Nasonova, Elena; Kutsalo, Polina; Krasavin, Eugen

2017-12-01

Chromosome aberrations in human lymphocytes exposed to different doses of particle radiation: 150 MeV and spread out Bragg peak proton beams, 22 MeV/u boron beam and 199 V/u carbon beam were studied. For comparison, an experiment with 60Co γ-rays was also performed. We investigated distributions of aberration frequency and the shape of dose-response curves for the total aberration yield as well as for exchange and non-exchange aberrations, separately. Applying the linear-quadratic model, we could derive a relation between the fitted parameters and the ion track radius which could explain experimentally observed curvature of the dose-response curves. The results compared with physical expectations clearly show that the biological effects of cell repair are much more important than the ion track overlapping. Contribution to the Topical Issue "Dynamics of Systems at the Nanoscale", edited by Andrey Solov'yov and Andrei Korol.

Effectiveness of one dose of oral cholera vaccine in response to an outbreak: a case-cohort study.

PubMed

Azman, Andrew S; Parker, Lucy A; Rumunu, John; Tadesse, Fisseha; Grandesso, Francesco; Deng, Lul L; Lino, Richard Laku; Bior, Bior K; Lasuba, Michael; Page, Anne-Laure; Ontweka, Lameck; Llosa, Augusto E; Cohuet, Sandra; Pezzoli, Lorenzo; Sodjinou, Dossou Vincent; Abubakar, Abdinasir; Debes, Amanda K; Mpairwe, Allan M; Wamala, Joseph F; Jamet, Christine; Lessler, Justin; Sack, David A; Quilici, Marie-Laure; Ciglenecki, Iza; Luquero, Francisco J

2016-11-01

Oral cholera vaccines represent a new effective tool to fight cholera and are licensed as two-dose regimens with 2-4 weeks between doses. Evidence from previous studies suggests that a single dose of oral cholera vaccine might provide substantial direct protection against cholera. During a cholera outbreak in May, 2015, in Juba, South Sudan, the Ministry of Health, Médecins Sans Frontières, and partners engaged in the first field deployment of a single dose of oral cholera vaccine to enhance the outbreak response. We did a vaccine effectiveness study in conjunction with this large public health intervention. We did a case-cohort study, combining information on the vaccination status and disease outcomes from a random cohort recruited from throughout the city of Juba with that from all the cases detected. Eligible cases were those aged 1 year or older on the first day of the vaccination campaign who sought care for diarrhoea at all three cholera treatment centres and seven rehydration posts throughout Juba. Confirmed cases were suspected cases who tested positive to PCR for Vibrio cholerae O1. We estimated the short-term protection (direct and indirect) conferred by one dose of cholera vaccine (Shanchol, Shantha Biotechnics, Hyderabad, India). Between Aug 9, 2015, and Sept 29, 2015, we enrolled 87 individuals with suspected cholera, and an 898-person cohort from throughout Juba. Of the 87 individuals with suspected cholera, 34 were classified as cholera positive, 52 as cholera negative, and one had indeterminate results. Of the 858 cohort members who completed a follow-up visit, none developed clinical cholera during follow-up. The unadjusted single-dose vaccine effectiveness was 80·2% (95% CI 61·5-100·0) and after adjusting for potential confounders was 87·3% (70·2-100·0). One dose of Shanchol was effective in preventing medically attended cholera in this study. These results support the use of a single-dose strategy in outbreaks in similar epidemiological

Species- and dose-specific pancreatic responses and progression in single- and repeat-dose studies with GI181771X: a novel cholecystokinin 1 receptor agonist in mice, rats, and monkeys.

PubMed

Myer, James R; Romach, Elizabeth H; Elangbam, Chandikumar S

2014-01-01

Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate–Dependent Manner

PubMed Central

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR. PMID:29531508

Gamma Low-Dose-Rate Ionizing Radiation Stimulates Adaptive Functional and Molecular Response in Human Aortic Endothelial Cells in a Threshold-, Dose-, and Dose Rate-Dependent Manner.

PubMed

Vieira Dias, Juliana; Gloaguen, Celine; Kereselidze, Dimitri; Manens, Line; Tack, Karine; Ebrahimian, Teni G

2018-01-01

A central question in radiation protection research is whether low-dose and low-dose-rate (LDR) exposures to ionizing radiation play a role in progression of cardiovascular disease. The response of endothelial cells to different LDR exposures may help estimate risk of cardiovascular disease by providing the biological mechanism involved. We investigated the effect of chronic LDR radiation on functional and molecular responses of human aorta endothelial cells (HAoECs). Human aorta endothelial cells were continuously irradiated at LDR (6 mGy/h) for 15 days and analyzed at time points when the cumulative dose reached 0.05, 0.5, 1.0, and 2.0 Gy. The same doses were administered acutely at high-dose rate (HDR; 1 Gy/min). The threshold for the loss of angiogenic capacity for both LDR and HDR radiations was between 0.5 and 1.0 Gy. At 2.0 Gy, angiogenic capacity returned to normal only for HAoEC exposed to LDR radiation, associated with increased expression of antioxidant and anti-inflammatory genes. Pre-LDR, but not pre-HDR, radiation, followed by a single acute 2.0 Gy challenge dose sustained the expression of antioxidant and anti-inflammatory genes and stimulated angiogenesis. Our results suggest that dose rate is important in cellular response and that a radioadaptive response is involved for a 2.0 Gy dose at LDR.

2,3,7,8-Tetrachlorodibenzo-P-Dioxin (TCDD) Dose-Response Studies: Preliminary Literature Search Results and Request for Additional Studies

EPA Science Inventory

EPA invited the public to comment on the preliminary list of in vivo mammalian dose-response citations for 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). This list was compiled as a first step in the development of EPA’s response to the National Academy of Sciences comments (NAS, 2...

Guidelines for Use of the Approximate Beta-Poisson Dose-Response Model.

PubMed

Xie, Gang; Roiko, Anne; Stratton, Helen; Lemckert, Charles; Dunn, Peter K; Mengersen, Kerrie

2017-07-01

For dose-response analysis in quantitative microbial risk assessment (QMRA), the exact beta-Poisson model is a two-parameter mechanistic dose-response model with parameters α>0 and β>0, which involves the Kummer confluent hypergeometric function. Evaluation of a hypergeometric function is a computational challenge. Denoting PI(d) as the probability of infection at a given mean dose d, the widely used dose-response model PI(d)=1-(1+dβ)-α is an approximate formula for the exact beta-Poisson model. Notwithstanding the required conditions α<β and β>1, issues related to the validity and approximation accuracy of this approximate formula have remained largely ignored in practice, partly because these conditions are too general to provide clear guidance. Consequently, this study proposes a probability measure Pr(0 < r < 1 | α̂, β̂) as a validity measure (r is a random variable that follows a gamma distribution; α̂ and β̂ are the maximum likelihood estimates of α and β in the approximate model); and the constraint conditions β̂>(22α̂)0.50 for 0.02<α̂<2 as a rule of thumb to ensure an accurate approximation (e.g., Pr(0 < r < 1 | α̂, β̂) >0.99) . This validity measure and rule of thumb were validated by application to all the completed beta-Poisson models (related to 85 data sets) from the QMRA community portal (QMRA Wiki). The results showed that the higher the probability Pr(0 < r < 1 | α̂, β̂), the better the approximation. The results further showed that, among the total 85 models examined, 68 models were identified as valid approximate model applications, which all had a near perfect match to the corresponding exact beta-Poisson model dose-response curve. © 2016 Society for Risk Analysis.

Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

PubMed

Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

2015-01-01

We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.

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

Putrescine as indicator of manganese neurotoxicity: Dose-response study in human SH-SY5Y cells.

PubMed

Fernandes, Jolyn; Chandler, Joshua D; Liu, Ken H; Uppal, Karan; Go, Young-Mi; Jones, Dean P

2018-06-01

Disrupted polyamine metabolism with elevated putrescine is associated with neuronal dysfunction. Manganese (Mn) is an essential nutrient that causes neurotoxicity in excess, but methods to evaluate biochemical responses to high Mn are limited. No information is available on dose-response effects of Mn on putrescine abundance and related polyamine metabolism. The present research was to test the hypothesis that Mn causes putrescine accumulation over a physiologically adequate to toxic concentration range in a neuronal cell line. We used human SH-SY5Y neuroblastoma cells treated with MnCl 2 under conditions that resulted in cell death or no cell death after 48 h. Putrescine and other metabolites were analyzed by liquid chromatography-ultra high-resolution mass spectrometry. Putrescine-related pathway changes were identified with metabolome-wide association study (MWAS). Results show that Mn caused a dose-dependent increase in putrescine over a non-toxic to toxic concentration range. MWAS of putrescine showed positive correlations with the polyamine metabolite N8-acetylspermidine, methionine-related precursors, and arginine-associated urea cycle metabolites, while putrescine was negatively correlated with γ-aminobutyric acid (GABA)-related and succinate-related metabolites (P < 0.001, FDR < 0.01). These data suggest that measurement of putrescine and correlated metabolites may be useful to study effects of Mn intake in the high adequate to UL range. Copyright © 2018. Published by Elsevier Ltd.

RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R828035)

EPA Science Inventory

Three dose_¯response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID₅₀) using a simple cumulative perce...

TH-CD-202-10: Tumor Metabolic Control Probability & Dose Response Mapping for Adaptive Dose Painting by Number

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

Chen, S; Wilson, G; Krauss, D

Purpose: Adaptive dose-painting-by-number (DPbN) requires a dose-response-mapping (DRM) obtained early in the treatment course. To obtain DRM, voxel-by-voxel tumor dose response needs to be quantified. Our recent study has demonstrated that voxel-by-voxel radio-sensitivity of patient tumor can be determined using tumor-metabolic-ratio measured early during the treatment using FDG-PET images. In this study, the measurements were utilized to construct tumor metabolic control probability (TMCP) and DRM for DPbN. Methods: FDG-PET/CT images of 18 HN cancer patients obtained pre- and weekly during the treatment were used. Spatial parametric images of tumor-metabolic-ratio (dSUV) were constructed following voxel-by-voxel deformable image registration. Each voxel valuemore » in dSUV was a function of baseline SUV and delivered dose. Utilizing all values of dSUV in the controlled tumor group at the last treatment week, a cut-off function between the baseline SUV and dSUV was formed, and applied in early treatment days on dSUV of all tumors to model the TMCP. At the treatment week k, TMCP was constructed with respect to the tumor voxel dSUV appeared at the week using the maximum likelihood estimation for all dose levels, and used for DRM construction. Results: TMCPs estimated in the week 2 & 3 have D{sub 50}=11.1∼47.6Gy; γ{sub 50}=0.55∼0.92 respectively with respect to dSUV=0.3∼1.2. The corresponding DRM between tumor voxel dSUV and the expected treatment dose has sigmoid shape. The expected treatment dose are 26∼40Gy (for 95% TMCP) for high sensitive tumor voxels with dSUV=0.3∼0.5; and 65∼110Gy for low sensitive tumor voxels with the dSUV>1.0 depending on the time of the estimation. Conclusion: TMCP can be constructed voxel-by-voxel in human tumor using multiple FDG-PET imaging obtained in early treatment days. TMCP provides a potential quantitative objective of tumor DRM for DPbN to plan the best dose, escalate or de-escalate, in tumor adaptively based on

Sustained Antibody Responses 6 Years Following 1, 2, or 3 Doses of Quadrivalent Human Papillomavirus (HPV) Vaccine in Adolescent Fijian Girls, and Subsequent Responses to a Single Dose of Bivalent HPV Vaccine: A Prospective Cohort Study.

PubMed

Toh, Zheng Quan; Russell, Fiona M; Reyburn, Rita; Fong, James; Tuivaga, Evelyn; Ratu, Tupou; Nguyen, Cattram D; Devi, Rachel; Kama, Mike; Matanitobua, Silivia; Tabrizi, Sepehr N; Garland, Suzanne M; Sinha, Rohit; Frazer, Ian; Tikoduadua, Lisi; Kado, Joseph; Rafai, Eric; Mulholland, Edward K; Licciardi, Paul V

2017-04-01

The duration of antibody response following reduced human papillomavirus (HPV) vaccine doses has not been determined. We compared the antibody responses in girls previously vaccinated with zero, 1, 2, or 3 doses of quadrivalent HPV vaccine (4vHPV; Gardasil, Merck) 6 years previously. A prospective cohort study was undertaken in 200 Fijian girls 15-19 years of age. Approximately equal numbers of girls from 2 main ethnic groups (Fijians of Indian descent [FID] and Indigenous Fijians [iTaukei]) in Fiji were recruited for each dosage groups. Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine (2vHPV; Cervarix, GlaxoSmithKline). We measured neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 using the pseudovirion-based neutralization assay. After 6 years (before a dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216 [95% confidence interval {CI},1695-2896]; 2D: 1476 [95% CI, 1019-2137]; P = .07), HPV-11 (3D: 4431 [95% CI, 3396-5783]; 2D: 2951 [95% CI, 1984-4390]; P = .09), HPV-16 (3D: 3373 [95% CI, 2511-4530]; 2D: 3275 [95% CI, 2452-4373]; P = .89); HPV-18 (3D: 628 [95% CI: 445-888]; 2D: 606 [95% CI, 462-862]; P = .89), and were higher in FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls. Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1, 2, or 3 doses of 4vHPV previously. Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years, although the clinical significance is unknown. A single dose of 4vHPV elicits antibodies that persisted for at least 6 years, and induced immune memory, suggesting possible protection against HPV vaccine types after a single dose of 4vHPV. © The Author 2016. Published by Oxford University

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

EPA Science Inventory

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

Optimal design of clinical trials with biologics using dose-time-response models.

PubMed

Lange, Markus R; Schmidli, Heinz

2014-12-30

Biologics, in particular monoclonal antibodies, are important therapies in serious diseases such as cancer, psoriasis, multiple sclerosis, or rheumatoid arthritis. While most conventional drugs are given daily, the effect of monoclonal antibodies often lasts for months, and hence, these biologics require less frequent dosing. A good understanding of the time-changing effect of the biologic for different doses is needed to determine both an adequate dose and an appropriate time-interval between doses. Clinical trials provide data to estimate the dose-time-response relationship with semi-mechanistic nonlinear regression models. We investigate how to best choose the doses and corresponding sample size allocations in such clinical trials, so that the nonlinear dose-time-response model can be precisely estimated. We consider both local and conservative Bayesian D-optimality criteria for the design of clinical trials with biologics. For determining the optimal designs, computer-intensive numerical methods are needed, and we focus here on the particle swarm optimization algorithm. This metaheuristic optimizer has been successfully used in various areas but has only recently been applied in the optimal design context. The equivalence theorem is used to verify the optimality of the designs. The methodology is illustrated based on results from a clinical study in patients with gout, treated by a monoclonal antibody. Copyright © 2014 John Wiley & Sons, Ltd.

Duration of Exposure and the Dose-Response Model of PTSD

ERIC Educational Resources Information Center

Kaysen, Debra; Rosen, Gerald; Bowman, Marilyn; Resick, Patricia A.

2010-01-01

A dose-response model underlies posttraumatic stress disorder (PTSD) and posits a relationship between event magnitude and clinical outcome. The present study examines whether one index of event magnitude--duration of exposure--contributes to risk of PTSD among female victims of sexual assault. Findings support a small but significant contribution…

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

PubMed Central

Upton, A C

1983-01-01

The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell. PMID:6653536

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

PubMed

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

2016-01-01

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

Single visit rabies pre-exposure priming induces a robust anamnestic antibody response after simulated post-exposure vaccination: results of a dose-finding study.

PubMed

Jonker, Emile F F; Visser, Leonardus G

2017-09-01

The current standard 3-dose intramuscular rabies PrEP schedule suffers from a number of disadvantages that severely limit accessibility and availability. The cost of is often prohibitive, it requires 3 visits to the clinic, and there are regular vaccine shortages. Volunteers ( N  = 30) were randomly assigned to 4 study arms: 1 standard dose intramuscular (IM) dose of PVRV (purified Vero cell rabies vaccine, Verorab), and 1/5th, 2/5th or 3/5th- fractional intradermal (ID) dose of PVRV in a single visit. All subjects received a simulated rabies post-exposure prophylaxis (D0, D3) 1 year later. Rabies virus neutralizing antibodies (RVNA) were determined by virus neutralization microtest (FAVN) on D0, D7, D28, Y1 and Y1 + D7. 28 out of 30 subjects (93%) seroconverted 1 month after primary vaccination; 1 subject in the 1-dose IM arm and 1 in the 1/5th-fractional dose ID arm did not. After 1 year, 22 out of 30 subjects (73%) no longer had RVNA above 0.5 IU/ml, with no discernible difference between study groups. After 1 year, all 30 subjects mounted a booster response within 7 days after simulated PEP, with the highest titers found in the single dose IM group ( P  < 0.03). This dose finding study demonstrates that priming with a single dose of rabies vaccine was sufficient to induce an adequate anamnestic antibody response to rabies PEP in all subjects 1 year later, even in those in whom the RVNA threshold of 0.5 IU/ml was not reached after priming. © International Society of Travel Medicine, 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.

PubMed

Jakubovski, Ewgeni; Varigonda, Anjali L; Freemantle, Nicholas; Taylor, Matthew J; Bloch, Michael H

2016-02-01

Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder. The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder. Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54). Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

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.

Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults.

PubMed

Levin, Myron J; Schmader, Kenneth E; Pang, Lei; Williams-Diaz, Angela; Zerbe, Gary; Canniff, Jennifer; Johnson, Michael J; Caldas, Yupanqui; Cho, Alice; Lang, Nancy; Su, Shu-Chih; Parrino, Janie; Popmihajlov, Zoran; Weinberg, Adriana

2016-01-01

Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥ 70 years old who had received a dose of ZV ≥ 10 years previously (NCT01245751). Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥ 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50-59 years, 100 aged 60-69 years, and 200 aged ≥ 70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥ 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥ 10 years and was enhanced by the booster dose. These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. NCT01245751. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

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.

Low dose intranasal oxytocin delivered with Breath Powered device dampens amygdala response to emotional stimuli: A peripheral effect-controlled within-subjects randomized dose-response fMRI trial.

PubMed

Quintana, Daniel S; Westlye, Lars T; Alnæs, Dag; Rustan, Øyvind G; Kaufmann, Tobias; Smerud, Knut T; Mahmoud, Ramy A; Djupesland, Per G; Andreassen, Ole A

2016-07-01

It is unclear if and how exogenous oxytocin (OT) reaches the brain to improve social behavior and cognition and what is the optimal dose for OT response. To better understand the delivery routes of intranasal OT administration to the brain and the dose-response, we compared amygdala response to facial stimuli by means of functional magnetic resonance imaging (fMRI) in four treatment conditions, including two different doses of intranasal OT using a novel Breath Powered device, intravenous (IV) OT, which provided similar concentrations of blood plasma OT, and placebo. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli, with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo. These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT. This trial is registered at the U.S. National Institutes of Health clinical trial registry (www.clinicaltrials.gov; NCT01983514) and as EudraCT no. 2013-001608-12. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of dose-response relationship between smoking load and cardiopulmonary fitness in adult smokers: A cross-sectional study.

PubMed

Lauria, V T; Sperandio, E F; de Sousa, T L W; de Oliveira Vieira, W; Romiti, M; de Toledo Gagliardi, A R; Arantes, R L; Dourado, V Z

To evaluate the dose-response relationship between smoking load and cardiopulmonary fitness, as measured with cardiopulmonary exercise testing (CPET), in adult smokers free of respiratory diseases. After a complete clinical evaluation and spirometry, 95 adult smokers (35 men and 60 women) underwent CPET on a treadmill. The physiological responses during CPET showed lower cardiorespiratory fitness levels, regardless of smoking load, with a peak [Formula: see text] lower than 100% of the expected value and a lower maximum heart rate. We observed a significant moderate negative correlation between smoking load and peak [Formula: see text] . The smoking load also presented a significant negative correlation with maximum heart rate(r=-0.36; p<0.05), lactate threshold(r=-0.45; p<0.05), and peak ventilation(r=-0.43; p<0.05). However, a dose-response relationship between smoking load quartiles and cardiopulmonary fitness was not found comparing quartiles of smoking loads after adjustment for age, sex and cardiovascular risk. There appears to be no dose-response relationship between SL and cardiopulmonary fitness in adult smokers with preserved pulmonary function, after adjusting the analysis for age and cardiovascular risk. Our results suggest that smoking cessation might be useful as the primary strategy to prevent cardiopulmonary fitness decline in smokers, regardless of smoking load. Thus, even a very low dose of tobacco use must be avoided in preventive strategies focusing on becoming people more physically active and fit. Copyright © 2016 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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

2006-07-01

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

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

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

Daila S. Gridley, PhD

2012-03-30

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

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

Low-Active Male Adolescents: A Dose Response to High-Intensity Interval Training.

PubMed

Logan, Greig Robert Melrose; Harris, Nigel; Duncan, Scott; Plank, Lindsay D; Merien, Fabrice; Schofield, Grant

2016-03-01

High-intensity interval training (HIIT) is a potential alternative to traditionally recommended steady state exercise for providing health benefits in adolescents, yet its dose-response relationship in this cohort remains unclear, as does its translatability to real-world, nonclinical settings. The present study adopts a novel dose-response design to investigate the effects of undertaking 8 wk of HIIT on the cardiometabolic health of low-active male adolescents. Twenty-six male adolescents (age 16 ± 1 yr), identified as low active by nonparticipation in structured sport and physical education classes, were randomly assigned to one of five treatment groups. Corresponding with their group numbers (1-5), participants completed a number of HIIT "sets," which consisted of 4 repeated bouts of 20-s near-maximal exertion interspersed with 10-s passive recovery. Participants performed two HIIT sessions and one resistance training session each week for 8 wk. Baseline and follow-up health measures consisted of peak oxygen uptake (V˙O2peak) with an incremental ramp test to volitional exhaustion; body composition (including visceral fat mass, body fat, and lean tissue mass) with dual-energy x-ray absorptiometry; and lipid profile, glucose, insulin, and interleukin-6 from blood analysis. All health outcomes were analyzed as percentage changes, and data were modeled using a quadratic function to explore dose-response relationships. Significant improvements were observed for V˙O2peak (∼6%), body fat percentage (∼4%), visceral fat mass (∼10%), and waist circumference-to-height ratio (∼3%), but there was no clear effect of dose across groups. Low-active adolescent males performing a single HIIT set twice weekly, in addition to one resistance training session, gained meaningful improvements in fitness and body composition. Performing additional HIIT sets provided no additional improvements to those of the lowest dose in this study.

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

EPA Science Inventory

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

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

EPA Science Inventory

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

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

Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes.

PubMed

Strange, P; Schwartz, S L; Graf, R J; Polvino, W; Weston, I; Marbury, T C; Huang, W C; Goldberg, R B

1999-01-01

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose (MTD) in Future Studies.

PubMed

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2015-07-01

High doses in Tg.rasH2 carcinogenicity studies are usually set at the maximum tolerated dose (MTD), although this dose selection strategy has not been critically evaluated. We analyzed the body weight gains (BWGs), mortality, and tumor response in control and treated groups of 29 Tg.rasH2 studies conducted at BioReliance. Based on our analysis, it is evident that the MTD was exceeded at the high and/or mid-doses in several studies. The incidence of tumors in high doses was lower when compared to the low and mid-doses of both sexes. Thus, we recommend that the high dose in male mice should not exceed one-half of the estimated MTD (EMTD), as it is currently chosen, and the next dose should be one-fourth of the EMTD. Because females were less sensitive to decrements in BWG, the high dose in female mice should not exceed two-third of EMTD and the next dose group should be one-third of EMTD. If needed, a third dose group should be set at one-eighth EMTD in males and one-sixth EMTD in females. In addition, for compounds that do not show toxicity in the range finding studies, a limit dose should be applied for the 26-week carcinogenicity studies. © 2014 by The Author(s).

Ultra Low-Dose Radiation: Stress Responses and Impacts Using Rice as a Grass Model

PubMed Central

Rakwal, Randeep; Agrawal, Ganesh Kumar; Shibato, Junko; Imanaka, Tetsuji; Fukutani, Satoshi; Tamogami, Shigeru; Endo, Satoru; Sahoo, Sarata Kumar; Masuo, Yoshinori; Kimura, Shinzo

2009-01-01

We report molecular changes in leaves of rice plants (Oryza sativa L. - reference crop plant and grass model) exposed to ultra low-dose ionizing radiation, first using contaminated soil from the exclusion zone around Chernobyl reactor site. Results revealed induction of stress-related marker genes (Northern blot) and secondary metabolites (LC-MS/MS) in irradiated leaf segments over appropriate control. Second, employing the same in vitro model system, we replicated results of the first experiment using in-house fabricated sources of ultra low-dose gamma (γ) rays and selected marker genes by RT-PCR. Results suggest the usefulness of the rice model in studying ultra low-dose radiation response/s. PMID:19399245

TU-D-201-07: Severity Indication in High Dose Rate Brachytherapy Emergency Response Procedure

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

Li, K; Rustad, F

Purpose: Understanding the corresponding dose to different staff during the High Dose Rate (HDR) Brachytherapy emergency response procedure could help to develop a strategy in efficiency and effective action. In this study, the variation and risk analysis methodology was developed to simulation the HDR emergency response procedure based on severity indicator. Methods: A GammaMedplus iX HDR unit from Varian Medical System was used for this simulation. The emergency response procedure was decomposed based on risk management methods. Severity indexes were used to identify the impact of a risk occurrence on the step including dose to patient and dose to operationmore » staff by varying the time, HDR source activity, distance from the source to patient and staff and the actions. These actions in 7 steps were to press the interrupt button, press emergency shutoff switch, press emergency button on the afterloader keypad, turn emergency hand-crank, remove applicator from the patient, disconnect transfer tube and move afterloader from the patient, and execute emergency surgical recovery. Results: Given the accumulated time in second at the assumed 7 steps were 15, 5, 30, 15, 180, 120, 1800, and the dose rate of HDR source is 10 Ci, the accumulated dose in cGy to patient at 1cm distance were 188, 250, 625, 813, 3063, 4563 and 27063, and the accumulated exposure in rem to operator at outside the vault, 1m and 10cm distance were 0.0, 0.0, 0.1, 0.1, 22.6, 37.6 and 262.6. The variation was determined by the operators in action at different time and distance from the HDR source. Conclusion: The time and dose were estimated for a HDR unit emergency response procedure. It provided information in making optimal decision during the emergency procedure. Further investigation would be to optimize and standardize the responses for other emergency procedure by time-spatial-dose severity function.« less

Poster — Thur Eve — 27: Flattening Filter Free VMAT Quality Assurance: Dose Rate Considerations for Detector Response

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

Viel, Francis; Duzenli, Cheryl; British Columbia Cancer Agency, Department of Medical Physics, Vancouver Centre

2014-08-15

Introduction: Radiation detector responses can be affected by dose rate. Due to higher dose per pulse and wider range of mu rates in FFF beams, detector responses should be characterized prior to implementation of QA protocols for FFF beams. During VMAT delivery, the MU rate may also vary dramatically within a treatment fraction. This study looks at the dose per pulse variation throughout a 3D volume for typical VMAT plans and the response characteristics for a variety of detectors, and makes recommendations on the design of QA protocols for FFF VMAT QA. Materials and Methods: Linac log file data andmore » a simplified dose calculation algorithm are used to calculate dose per pulse for a variety of clinical VMAT plans, on a voxel by voxel basis, as a function of time in a cylindrical phantom. Diode and ion chamber array responses are characterized over the relevant range of dose per pulse and dose rate. Results: Dose per pulse ranges from <0.1 mGy/pulse to 1.5 mGy/pulse in a typical VMAT treatment delivery using the 10XFFF beam. Diode detector arrays demonstrate increased sensitivity to dose (+./− 3%) with increasing dose per pulse over this range. Ion chamber arrays demonstrate decreased sensitivity to dose (+/− 1%) with increasing dose rate over this range. Conclusions: QA protocols should be designed taking into consideration inherent changes in detector sensitivity with dose rate. Neglecting to account for changes in detector response with dose per pulse can lead to skewed QA results.« less

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

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

Abstract Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

Chernobyl Doses. Volume 1. Analysis of Forest Canopy Radiation Response from Multispectral Imagery and the Relationship to Doses

DTIC Science & Technology

1994-09-01

AD-A284 746 Defense Nuclear Agency Alexandria, VA 22310-3398 DNA-TR-92-37-V1 Chernobyl Doses Volume 1-Analysis of Forest Canopy Radiation Response...REPORT DATE 3. REPORT TYPE AND DATES COVERED 940901 Technical 870929- 930930 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Chernobyl Doses Volume 1-Analysis of...volume of the report Chernobyl Doses presents details of a new, quantitative method for remotely sensing ionizing radiation dose to vegetation

Hierarchical dose response of E. coli O157:H7 from human outbreaks incorporating heterogeneity in exposure.

PubMed

Teunis, P F M; Ogden, I D; Strachan, N J C

2008-06-01

The infectivity of pathogenic microorganisms is a key factor in the transmission of an infectious disease in a susceptible population. Microbial infectivity is generally estimated from dose-response studies in human volunteers. This can only be done with mildly pathogenic organisms. Here a hierarchical Beta-Poisson dose-response model is developed utilizing data from human outbreaks. On the lowest level each outbreak is modelled separately and these are then combined at a second level to produce a group dose-response relation. The distribution of foodborne pathogens often shows strong heterogeneity and this is incorporated by introducing an additional parameter to the dose-response model, accounting for the degree of overdispersion relative to Poisson distribution. It was found that heterogeneity considerably influences the shape of the dose-response relationship and increases uncertainty in predicted risk. This uncertainty is greater than previously reported surrogate and outbreak models using a single level of analysis. Monte Carlo parameter samples (alpha, beta of the Beta-Poisson model) can be readily incorporated in risk assessment models built using tools such as S-plus and @ Risk.

Does beer, wine or liquor consumption correlate with the risk of renal cell carcinoma? A dose-response meta-analysis of prospective cohort studies

PubMed Central

Xu, Xin; Zhu, Yi; Zheng, Xiangyi; Xie, Liping

2015-01-01

Despite plenty of evidence supports an inverse association between alcohol drinking and risk of renal cell carcinoma (RCC), sex-specific and beverage-specific dose-response relationships have not been well established. We examined this association by performing a systematic review and meta-analysis of prospective studies. Studies were identified by comprehensively searching PubMed and EMBASE databases through February 21, 2015. Categorical and dose-response meta-analyses were conducted to identify the effects of alcohol on RCC. A total of eight publications (including seven cohort studies and one pooled analysis of 12 cohort studies) were eligible for this meta-analysis. Dose-response analysis showed that each 5 g/day increment of alcohol intake corresponded to a 5% decrease in risk of RCC for males and 9% for females. Alcohol intakes from wine, beer, and liquor were each associated with a reduced risk of RCC. When these associations were examined separately by gender, statistically significant inverse associations were restricted to alcohol from wine among females (RR = 0.82, 95% CI 0.73–0.91) and to alcohol from beer and from liquor among males (RR = 0.87, 95% CI 0.83–0.91 and RR = 0.95, 95% CI 0.92–0.99, respectively). In conclusion, there exist gender-specific and beverage-specific differences in the association between alcohol intake and RCC risk. PMID:25965820

Phosphoprotein profiles of candidate markers for early cellular responses to low-dose γ-radiation in normal human fibroblast cells

PubMed Central

Yim, Ji-Hye; Yun, Jung Mi; Kim, Ji Young; Lee, In Kyung; Nam, Seon Young

2017-01-01

Abstract Ionizing radiation causes biological damage that leads to severe health effects. However, the effects and subsequent health implications caused by exposure to low-dose radiation are unclear. The objective of this study was to determine phosphoprotein profiles in normal human fibroblast cell lines in response to low-dose and high-dose γ-radiation. We examined the cellular response in MRC-5 cells 0.5 h after exposure to 0.05 or 2 Gy. Using 1318 antibodies by antibody array, we observed ≥1.3-fold increases in a number of identified phosphoproteins in cells subjected to low-dose (0.05 Gy) and high-dose (2 Gy) radiation, suggesting that both radiation levels stimulate distinct signaling pathways. Low-dose radiation induced nucleic acid–binding transcription factor activity, developmental processes, and multicellular organismal processes. By contrast, high-dose radiation stimulated apoptotic processes, cell adhesion and regulation, and cellular organization and biogenesis. We found that phospho-BTK (Tyr550) and phospho-Gab2 (Tyr643) protein levels at 0.5 h after treatment were higher in cells subjected to low-dose radiation than in cells treated with high-dose radiation. We also determined that the phosphorylation of BTK and Gab2 in response to ionizing radiation was regulated in a dose-dependent manner in MRC-5 and NHDF cells. Our study provides new insights into the biological responses to low-dose γ-radiation and identifies potential candidate markers for monitoring exposure to low-dose ionizing radiation. PMID:28122968

Erythrocyte Omega-3 Fatty Acid Content in Elite Athletes in Response to Omega-3 Supplementation: A Dose-Response Pilot Study

PubMed Central

Rueda, Félix; Pons, Victoria; Banquells, Montserrat; Cordobilla, Begoña; Domingo, Joan Carles

2017-01-01

Introduction Supplementation of Omega-3 fatty acids (n-3FA) in athletes is related to the anti-inflammatory and/or antioxidant effect and consequently its action on all the processes of tissue restoration and adaptation to physical stress. Objective Evaluate the Omega-3 Index (O3Ix) response, in red blood cells, to supplemental EPA + DHA intake in the form of high purity and stable composition gums (G), in elite summer athletes. Method Twenty-four summer sport athletes of both sexes, pertaining to the Olympic Training Center in Spain, were randomized to two groups (2G = 760 or 3G = 1140 mg of n-3 FA in Omegafort OKids, Ferrer Intl.) for 4 months. Five athletes and four training staff volunteers were control group. Results The O3Ix was lower than 8% in 93.1% of all the athletes. The supplementation worked in a dose-dependent manner: 144% for the 3G dose and 135% for the 2G, both p < 0.001, with a 3% significant decrease of Omega-6 FAs. No changes were observed for the control group. Conclusions Supplementation with n-3FA increases the content of EPA DHA in the red blood cells at 4 months in a dose-dependent manner. Athletes with lower basal O3Ix were more prone to increment their levels. The study is registered with Protocol Registration and Results System (ClinicalTrials.gov) number NCT02610270. PMID:28656110

Thyroid nodules in the population living around Semipalatinsk nuclear test site: possible implications for dose-response relationships study.

PubMed

Zhumadilov, Zhaxybay

2006-02-01

The risk of radiation-induced nodules is higher than the risk for radiation-induced cancer. Risk factors and specific modifiers of the dose-response relationship may vary among different populations and not be well recognized. Many thyroid studies have considered thyroid nodularity itself, but not specific morphological types of thyroid nodules. There are many specific types of thyroid nodules which follow a morphological classification of thyroid lesions, including some congenital and tumor-like conditions. Modern equipment and technique can help us to identify particular specific types of thyroid nodules. In this study we report some results of a clinically applicable approach to materials derived from three studies. From 1999 through 2002, we have screened 571 current residents from 4 exposed and 1 control village near the Semipalatinsk Nuclear Test Site area, who were of similar ages (<20) at the time of major radiation fallout events at the SNTS. Prevalent nodules were identified by ultrasound and fine-needle aspiration biopsy, cytopathology results. Analysis of ultrasound images and cytopathology of thyroid lesions among exposed and non-exposed population allowed us to distinguish some interesting ultrasound features for specific types of thyroid nodules. We believe that it would be interesting and possibly more informative for thyroid dosimetry studies to consider specific morphological types of thyroid nodules. We need more detailed research to clarify the feasibility of applying these findings for study of the dose-response relationship.

SU-F-J-59: Assessment of Dose Response Distribution in Individual Human Tumor

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

Yan, D; Chen, S; Krauss, D

Purpose: To fulfill precision radiotherapy via adaptive dose painting by number, voxel-by-voxel dose response or radio-sensitivity in individual human tumor needs to be determined in early treatment to guide treatment adaptation. In this study, multiple FDG PET images obtained pre- and weekly during the treatment course were utilized to determine the distribution/spectrum of dose response parameters in individual human tumors. Methods: FDG PET/CT images of 18 HN cancer patients were used in the study. Spatial parametric image of tumor metabolic ratio (dSUV) was created following voxel by voxel deformable image registration. Each voxel value in dSUV was a function ofmore » pre-treatment baseline SUV and treatment delivered dose, and used as a surrogate of tumor survival fraction (SF). Regression fitting with break points was performed using the LQ-model with tumor proliferation for the control and failure group of tumors separately. The distribution and spectrum of radiation sensitivity and growth in individual tumors were determined and evaluated. Results: Spectrum of tumor dose-sensitivity and proliferation in the controlled group was broad with α in tumor survival LQ-model from 0.17 to 0.8. It was proportional to the baseline SUV. Tlag was about 21∼25 days, and Tpot about 0.56∼1.67 days respectively. Commonly tumor voxels with high radio-sensitivity or larger α had small Tlag and Tpot. For the failure group, the radio-sensitivity α was low within 0.05 to 0.3, but did not show clear Tlag. In addition, tumor voxel radio-sensitivity could be estimated during the early treatment weeks. Conclusion: Dose response distribution with respect to radio-sensitivity and growth in individual human tumor can be determined using FDG PET imaging based tumor metabolic ratio measured in early treatment course. The discover is critical and provides a potential quantitative objective to implement tumor specific precision radiotherapy via adaptive dose painting by number.« less

The effect of low dose rate on metabolomic response to radiation in mice

PubMed Central

Goudarzi, Maryam; Mak, Tytus D.; Chen, Congju; Smilenov, Lubomir B.; Brenner, David J.

2014-01-01

Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level. Our study took advantage of a modern mass spectrometry approach in exploring the effects of dose rate on the urinary excretion levels of metabolites 2 days after IR in mice. A wide variety of statistical tools were employed to further focus on metabolites, which showed responses to LDR IR exposure (0.00309 Gy/min) distinguishable from those of HDR. From a total of 709 detected spectral features, more than 100 were determined to be statistically significant when comparing urine from mice irradiated with 1.1 or 4.45 Gy to that of sham-irradiated mice 2 days post-exposure. The results of this study show that LDR and HDR exposures perturb many of the same pathways such as TCA cycle and fatty acid metabolism, which also have been implicated in our previous IR studies. However, it is important to note that dose rate did affect the levels of particular metabolites. Differences in urinary excretion levels of such metabolites could potentially be used to assess an individual's exposure in a radiobiological event and thus would have utility for both triage and injury assessment. PMID:25047638

Proof of concept and dose estimation with binary responses under model uncertainty.

PubMed

Klingenberg, B

2009-01-30

This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.

PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

EPA Science Inventory

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking infor...

Dose-response meta-analysis of poultry intake and colorectal cancer incidence and mortality.

PubMed

Shi, Yan; Yu, Pei-Wu; Zeng, Dong-Zhu

2015-03-01

Poultry intake has been inconsistently associated with incidence or mortality of colorectal cancer (CRC) in epidemiologic studies. The purpose of this study was to assess their relationships by performing a dose-response meta-analysis. We conducted a search of PubMed database between January 1966 and July 2013 for prospective studies that reported relative risks (RRs) with 95 % confidence interval (CIs) of CRC for at least three categories of poultry intake. Dose-response relationships were examined with the generalized least-squares trend estimation. Study-specific results were pooled with a random-effects model. Subgroup, sensitivity, and meta-regression analyses were also conducted to explore heterogeneity. Sixteen studies on poultry intake and CRC incidence, and four studies regarding poultry intake and CRC mortality were identified. These studies involved a total of 13,949 incident CRC cases and 983 CRC deaths. The RRs of CRC for higher compared with lower intake of poultry were reported in these studies, and the reported levels of poultry intake varied substantially. Results of the dose-response meta-analysis conferred a RR of 0.89 (95 % CI 0.81-0.97) for an increase in poultry intake of 50 g/day. The results were not sensitive to any individual studies and were similar for colon and rectal cancer. Poultry intake was not associated with CRC mortality (RR for 50 g/day = 0.97, 95 % CI 0.79-1.20). This meta-analysis indicates that poultry intake may be moderately associated with reduced incidence of CRC.

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

NASA Technical Reports Server (NTRS)

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

2011-01-01

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

Individual human cell responses to low doses of chemicals studied by synchrotron infrared spectromicroscopy

NASA Astrophysics Data System (ADS)

Holman, Hoi-Ying N.; Goth-Goldstein, Regine; Blakely, Elanor A.; Bjornstad, Kathy; Martin, Michael C.; McKinney, Wayne R.

2000-05-01

Vibrational spectroscopy, when combined with synchrotron radiation-based (SR) microscopy, is a powerful new analytical tool with high spatial resolution for detecting biochemical changes in the individual living cells. In contrast to other microscopy methods that require fixing, drying, staining or labeling, SR-FTIR microscopy probes intact living cells providing a composite view of all of the molecular response and the ability to monitor the response over time in the same cell. Observed spectral changes include all types of lesions induced in that cell as well as cellular responses to external and internal stresses. These spectral changes combined with other analytical tools may provide a fundamental understanding of the key molecular mechanisms induced in response to stresses created by low- doses of chemicals. In this study we used the high spatial - resolution SR-FTIR vibrational spectromicroscopy as a sensitive analytical tool to detect chemical- and radiation- induced changes in individual human cells. Our preliminary spectral measurements indicate that this technique is sensitive enough to detect changes in nucleic acids and proteins of cells treated with environmentally relevant concentrations of dioxin. This technique has the potential to distinguish changes from exogenous or endogenous oxidative processes. Future development of this technique will allow rapid monitoring of cellular processes such as drug metabolism, early detection of disease, bio- compatibility of implant materials, cellular repair mechanisms, self assembly of cellular apparatus, cell differentiation and fetal development.

Dose response of surfactants to attenuate gas embolism related platelet aggregation

NASA Astrophysics Data System (ADS)

Eckmann, David M.; Eckmann, Yonaton Y.; Tomczyk, Nancy

2014-03-01

Intravascular gas embolism promotes blood clot formation, cellular activation, and adhesion events, particularly with platelets. Populating the interface with surfactants is a chemical-based intervention to reduce injury from gas embolism. We studied platelet activation and platelet aggregation, prominent adverse responses to blood contact with bubbles. We examined dose-response relationships for two chemically distinct surfactants to attenuate the rise in platelet function stimulated by exposure to microbubbles. Significant reduction in platelet aggregation and platelet activation occurred with increasing concentration of the surfactants, indicating presence of a saturable system. A population balance model for platelet aggregation in the presence of embolism bubbles and surfactants was developed. Monte Carlo simulations for platelet aggregation were performed. Results agree qualitatively with experimental findings. Surfactant dose-dependent reductions in platelet activation and aggregation indicate inhibition of the gas/liquid interface's ability to stimulate cellular activation mechanically.

Investigation of vacuum pumping on the dose response of the MAGAS normoxic polymer gel dosimeter.

PubMed

Venning, A J; Mather, M L; Baldock, C

2005-06-01

The effect of vacuum pumping on the dose response of the MAGAS polymer gel dosimeter has been investigated. A delay of several days post-manufacture before irradiation was previously necessary due to the slow oxygen scavenging of ascorbic acid. The MAGAS polymer gel dosimeter was vacuum pumped before gelation to remove dissolved oxygen. The MAGAS polymer gel dosimeter was poured into glass screw-top vials, which were irradiated at various times, post-manufacture to a range of doses. Magnetic resonance imaging techniques were used to determine the R2-dose response and R2-dose sensitivity of the MAGAS polymer gel. The results were compared with a control batch of MAGAS polymer gel that was not vacuum pumped. It was shown that vacuum pumping on the MAGAS polymer gel solution immediately prior to sealing in glass screw-top vials initially increases the R2-dose response and R2-dose sensitivity of the dosimeter. An increase in the R2-dose response and R2-dose sensitivity was observed with increasing time between manufacture and irradiation. Over the range of post-manufacture irradiation times investigated, the greatest R2-dose response and R2-dose sensitivity occurred at 96 hours.

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

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

Chung, Eugene; Corbett, James R.; Moran, Jean M.

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

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

EPA Science Inventory

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

Magnetic field influences on the lateral dose response functions of photon-beam detectors: MC study of wall-less water-filled detectors with various densities.

PubMed

Looe, Hui Khee; Delfs, Björn; Poppinga, Daniela; Harder, Dietrich; Poppe, Björn

2017-06-21

The distortion of detector reading profiles across photon beams in the presence of magnetic fields is a developing subject of clinical photon-beam dosimetry. The underlying modification by the Lorentz force of a detector's lateral dose response function-the convolution kernel transforming the true cross-beam dose profile in water into the detector reading profile-is here studied for the first time. The three basic convolution kernels, the photon fluence response function, the dose deposition kernel, and the lateral dose response function, of wall-less cylindrical detectors filled with water of low, normal and enhanced density are shown by Monte Carlo simulation to be distorted in the prevailing direction of the Lorentz force. The asymmetric shape changes of these convolution kernels in a water medium and in magnetic fields of up to 1.5 T are confined to the lower millimetre range, and they depend on the photon beam quality, the magnetic flux density and the detector's density. The impact of this distortion on detector reading profiles is demonstrated using a narrow photon beam profile. For clinical applications it appears as favourable that the magnetic flux density dependent distortion of the lateral dose response function, as far as secondary electron transport is concerned, vanishes in the case of water-equivalent detectors of normal water density. By means of secondary electron history backtracing, the spatial distribution of the photon interactions giving rise either directly to secondary electrons or to scattered photons further downstream producing secondary electrons which contribute to the detector's signal, and their lateral shift due to the Lorentz force is elucidated. Electron history backtracing also serves to illustrate the correct treatment of the influences of the Lorentz force in the EGSnrc Monte Carlo code applied in this study.

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

Dose-response model of Rocky Mountain spotted fever (RMSF) for human.

PubMed

Tamrakar, Sushil B; Haas, Charles N

2011-10-01

Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever (RMSF) and is the prototype bacterium in the spotted fever group of rickettsiae, which is found in North, Central, and South America. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through tick bites; however, some cases of aerosol transmission also have been reported. The disease can be difficult to diagnose in the early stages, and without prompt and appropriate treatment, it can be fatal. This article develops dose-response models of different routes of exposure for RMSF in primates and humans. The beta-Poisson model provided the best fit to the dose-response data of aerosol-exposed rhesus monkeys, and intradermally inoculated humans (morbidity as end point of response). The average 50% infectious dose among (ID₅₀) exposed human population, N₅₀, is 23 organisms with 95% confidence limits of 1 to 89 organisms. Similarly, ID₁₀ and ID₂₀ are 2.2 and 5.0, respectively. Moreover, the data of aerosol-exposed rhesus monkeys and intradermally inoculated humans could be pooled. This indicates that the dose-response models fitted to different data sets are not significantly different and can be described by the same relationship. © 2011 Society for Risk Analysis.

A distributed lag approach to fitting non-linear dose-response models in particulate matter air pollution time series investigations.

PubMed

Roberts, Steven; Martin, Michael A

2007-06-01

The majority of studies that have investigated the relationship between particulate matter (PM) air pollution and mortality have assumed a linear dose-response relationship and have used either a single-day's PM or a 2- or 3-day moving average of PM as the measure of PM exposure. Both of these modeling choices have come under scrutiny in the literature, the linear assumption because it does not allow for non-linearities in the dose-response relationship, and the use of the single- or multi-day moving average PM measure because it does not allow for differential PM-mortality effects spread over time. These two problems have been dealt with on a piecemeal basis with non-linear dose-response models used in some studies and distributed lag models (DLMs) used in others. In this paper, we propose a method for investigating the shape of the PM-mortality dose-response relationship that combines a non-linear dose-response model with a DLM. This combined model will be shown to produce satisfactory estimates of the PM-mortality dose-response relationship in situations where non-linear dose response models and DLMs alone do not; that is, the combined model did not systemically underestimate or overestimate the effect of PM on mortality. The combined model is applied to ten cities in the US and a pooled dose-response model formed. When fitted with a change-point value of 60 microg/m(3), the pooled model provides evidence for a positive association between PM and mortality. The combined model produced larger estimates for the effect of PM on mortality than when using a non-linear dose-response model or a DLM in isolation. For the combined model, the estimated percentage increase in mortality for PM concentrations of 25 and 75 microg/m(3) were 3.3% and 5.4%, respectively. In contrast, the corresponding values from a DLM used in isolation were 1.2% and 3.5%, respectively.

Comparison of dose response functions for EBT3 model GafChromic™ film dosimetry system.

PubMed

Aldelaijan, Saad; Devic, Slobodan

2018-05-01

Different dose response functions of EBT3 model GafChromic™ film dosimetry system have been compared in terms of sensitivity as well as uncertainty vs. error analysis. We also made an assessment of the necessity of scanning film pieces before and after irradiation. Pieces of EBT3 film model were irradiated to different dose values in Solid Water (SW) phantom. Based on images scanned in both reflection and transmission mode before and after irradiation, twelve different response functions were calculated. For every response function, a reference radiochromic film dosimetry system was established by generating calibration curve and by performing the error vs. uncertainty analysis. Response functions using pixel values from the green channel demonstrated the highest sensitivity in both transmission and reflection mode. All functions were successfully fitted with rational functional form, and provided an overall one-sigma uncertainty of better than 2% for doses above 2 Gy. Use of pre-scanned images to calculate response functions resulted in negligible improvement in dose measurement accuracy. Although reflection scanning mode provides higher sensitivity and could lead to a more widespread use of radiochromic film dosimetry, it has fairly limited dose range and slightly increased uncertainty when compared to transmission scan based response functions. Double-scanning technique, either in transmission or reflection mode, shows negligible improvement in dose accuracy as well as a negligible increase in dose uncertainty. Normalized pixel value of the images scanned in transmission mode shows linear response in a dose range of up to 11 Gy. Copyright © 2018 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

WE-D-BRE-06: Quantification of Dose-Response for High Grade Esophagtis Patients Using a Novel Voxel-To-Voxel Method

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

Niedzielski, J; Martel, M; Tucker, S

2014-06-15

Purpose: Radiation induces an inflammatory response in the esophagus, discernible on CT studies. This work objectively quantifies the voxel esophageal radiation-response for patients with acute esophagitis. This knowledge is an important first-step towards predicting the effect of complex dose distributions on patient esophagitis symptoms. Methods: A previously validated voxel-based methodology of quantifying radiation esophagitis severity was used to identify the voxel dose-response for 18 NSCLC patients with severe esophagitis (CTCAE grading criteria, grade2 or higher). The response is quantified as percent voxel volume change for a given dose. During treatment (6–8 weeks), patients had weekly 4DCT studies and esophagitis scoring.more » Planning CT esophageal contours were deformed to each weekly CT using a demons DIR algorithm. An algorithm using the Jacobian Map from the DIR of the planning CT to all weekly CTs was used to quantify voxel-volume change, along with corresponding delivered voxel dose, to the planning voxel. Dose for each voxel for each time-point was calculated on each previous weekly CT image, and accumulated using DIR. Thus, for each voxel, the volume-change and delivered dose was calculated for each time-point. The data was binned according to when the volume-change first increased by a threshold volume (10%–100%, in 10% increments), and the average delivered dose calculated for each bin. Results: The average dose resulting in a voxel volume increase of 10–100% was 21.6 to 45.9Gy, respectively. The mean population dose to give a 50% volume increase was 36.3±4.4Gy, (range:29.8 to 43.5Gy). The average week of 50% response was 4.1 (range:4.9 to 2.8 weeks). All 18 patients showed similar dose to first response curves, showing a common trend in the initial inflammatoryresponse. Conclusion: We extracted the dose-response curve of the esophagus on a voxel-to-voxel level. This may be useful for estimating the esophagus response (and patient

Spatial Prediction of Coxiella burnetii Outbreak Exposure via Notified Case Counts in a Dose-Response Model.

PubMed

Brooke, Russell J; Kretzschmar, Mirjam E E; Hackert, Volker; Hoebe, Christian J P A; Teunis, Peter F M; Waller, Lance A

2017-01-01

We develop a novel approach to study an outbreak of Q fever in 2009 in the Netherlands by combining a human dose-response model with geostatistics prediction to relate probability of infection and associated probability of illness to an effective dose of Coxiella burnetii. The spatial distribution of the 220 notified cases in the at-risk population are translated into a smooth spatial field of dose. Based on these symptomatic cases, the dose-response model predicts a median of 611 asymptomatic infections (95% range: 410, 1,084) for the 220 reported symptomatic cases in the at-risk population; 2.78 (95% range: 1.86, 4.93) asymptomatic infections for each reported case. The low attack rates observed during the outbreak range from (Equation is included in full-text article.)to (Equation is included in full-text article.). The estimated peak levels of exposure extend to the north-east from the point source with an increasing proportion of asymptomatic infections further from the source. Our work combines established methodology from model-based geostatistics and dose-response modeling allowing for a novel approach to study outbreaks. Unobserved infections and the spatially varying effective dose can be predicted using the flexible framework without assuming any underlying spatial structure of the outbreak process. Such predictions are important for targeting interventions during an outbreak, estimating future disease burden, and determining acceptable risk levels.

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.

Beta-cell response during a meal test: a comparative study of incremental doses of repaglinide in type 2 diabetic patients.

PubMed

Cozma, Lawrence S; Luzio, Stephen D; Dunseath, Gareth J; Underwood, Paul M; Owens, David R

2005-05-01

To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal. Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart. The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses. Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.

Spline-based procedures for dose-finding studies with active control

PubMed Central

Helms, Hans-Joachim; Benda, Norbert; Zinserling, Jörg; Kneib, Thomas; Friede, Tim

2015-01-01

In a dose-finding study with an active control, several doses of a new drug are compared with an established drug (the so-called active control). One goal of such studies is to characterize the dose–response relationship and to find the smallest target dose concentration d*, which leads to the same efficacy as the active control. For this purpose, the intersection point of the mean dose–response function with the expected efficacy of the active control has to be estimated. The focus of this paper is a cubic spline-based method for deriving an estimator of the target dose without assuming a specific dose–response function. Furthermore, the construction of a spline-based bootstrap CI is described. Estimator and CI are compared with other flexible and parametric methods such as linear spline interpolation as well as maximum likelihood regression in simulation studies motivated by a real clinical trial. Also, design considerations for the cubic spline approach with focus on bias minimization are presented. Although the spline-based point estimator can be biased, designs can be chosen to minimize and reasonably limit the maximum absolute bias. Furthermore, the coverage probability of the cubic spline approach is satisfactory, especially for bias minimal designs. © 2014 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:25319931

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

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

Little, Mark P., E-mail: mark.little@nih.gov; Kleinerman, Ruth A.; Stovall, Marilyn

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

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

PubMed

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

2017-11-01

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

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

USDA-ARS?s Scientific Manuscript database

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

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

PubMed

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

2010-12-01

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

Dose-response effects for disease management programs on hospital utilization in Illinois Medicaid.

PubMed

Berg, Gregory D; Donnelly, Shawn; Miller, Mary; Medina, Wendie; Warnick, Kathleen

2012-12-01

The objective of this study is to estimate a dose-response impact of disease management contacts on inpatient admissions. Multivariate regression analysis of panel data was used to test the hypothesis that increased disease management contacts lower the odds of an inpatient admission. Subjects were 40,452 members of Illinois' noninstitutionalized Medicaid-only aged, blind, or disabled population diagnosed with asthma, coronary artery disease, chronic obstructive pulmonary disease, diabetes, and/or heart failure. All members are also in the state's Illinois Health Connect program, a medical home strategy in place for most of the 2.4 million Illinois Medicaid beneficiaries. The statistical measure is the odds ratio, which is a measure of association between the monthly inpatient admission indicator and the number of contacts (doses) a member has had for each particular disease management intervention. Statistically significant contacts are between 8 and 12 for heart failure, between 4 and 12 contacts for diabetes, and between 8 and 13 contacts for asthma. Total inpatient savings during the study period is estimated to be $12.4 million. This study shows the dose-response pattern of inpatient utilization improvements through the number of disease management contacts.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

PubMed Central

San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

2015-01-01

Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

Discerning strain effects in microbial dose-response data.

PubMed

Coleman, Margaret E; Marks, Harry M; Golden, Neal J; Latimer, Heejeong K

In order to estimate the risk or probability of adverse events in risk assessment, it is necessary to identify the important variables that contribute to the risk and provide descriptions of distributions of these variables for well-defined populations. One component of modeling dose response that can create uncertainty is the inherent genetic variability among pathogenic bacteria. For many microbial risk assessments, the "default" assumption used for dose response does not account for strain or serotype variability in pathogenicity and virulence, other than perhaps, recognizing the existence of avirulent strains. However, an examination of data sets from human clinical trials in which Salmonella spp. and Campylobacter jejuni strains were administered reveals significant strain differences. This article discusses the evidence for strain variability and concludes that more biologically based alternatives are necessary to replace the default assumptions commonly used in microbial risk assessment, specifically regarding strain variability.

A dose related response of 6-OHDA on chicken spectral sensitivity and oscillatory potentials of recording electroretinograms.

PubMed

Li, X; Schaeffel, F; Konrad, K; Eberhart, Z

1996-10-01

To further study the contribution of dopamine system to the local growth controlling mechanisms, a dose related response of 6-hydroxydopamine (6-OHDA) was studied by recording electroretinograms (ERGs). The spectral sensitivity of the b-waves and spectral efficiency function of oscillatory potentials (OPs) including OP1, OP2 and OP3 in 4 different doses group were measured. The effect of ascorbate that must be contained in solution of 6-OHDA was first tested with the spectral sensitivity of the b-waves and a correlation between response of the OPs and age, as well as a difference in both own eyes was analyzed for determining an intra-subject and inter-subject variance. An enhanced response was found in OP1, OP2 with doses of 175 micrograms and OP3 with dose of 150 micrograms, and the effect of OPs was mainly in wavelength from 620 nm to 480 nm. No significant increase was found in the spectral sensitivity of the b-waves. The dose 200 micrograms seemed to be toxic to the retina estimated by both spectral sensitivity of the b-waves and spectral efficiency function of the OPs. The dose 175 micrograms and 150 micrograms of 6-OHDA yielded an effect on the chicken retina.

Sodium phenylbutyrate in Huntington's disease: a dose-finding study.

PubMed

Hogarth, Penelope; Lovrecic, Luca; Krainc, Dimitri

2007-10-15

Transcriptional dysregulation in Huntington's disease (HD) is mediated in part by aberrant patterns of histone acetylation. We performed a dose-finding study in human HD of sodium phenylbutyrate (SPB), a histone deacetylase inhibitor that ameliorates the HD phenotype in animal models. We used a dose-escalation/de-escalation design, using prespecified toxicity criteria and standard clinical and laboratory safety measures. The maximum tolerated dose was 15 g/day. At higher doses, toxicity included vomiting, lightheadedness, confusion, and gait instability. We saw no significant laboratory or electrocardiographic abnormalities. Gene expression changes in blood suggested an inverse dose-response. In conclusion, SPB at 12 to 15 g/day appears to be safe and well-tolerated in human HD. 2007 Movement Disorder Society

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.

High-dose alcohol intoxication differentially modulates cognitive subprocesses involved in response inhibition.

PubMed

Stock, Ann-Kathrin; Schulz, Tom; Lenhardt, Martin; Blaszkewicz, Meinolf; Beste, Christian

2016-01-01

Aside from well-known physiological effects, high-dose alcohol intoxication (a.k.a. binge drinking) can lead to aversive social and legal consequences because response inhibition is usually compromised under the influence of alcohol. Although the behavioral aspects of this phenomenon were reported on extensively, the underlying neurophysiological mechanisms mediating this disinhibition are unclear. To close this gap, we used both behavioral and neurophysiological measures (event-related potentials, ERPs) to investigate which subprocesses of response inhibition are altered under the influence of high-dose alcohol intoxication. Using a within-subject design, we asked young healthy participants (n = 27) to complete a GO/NOGO task once sober and once intoxicated (approximately 1.2‰). During intoxication, high-dose alcohol effects were highest in a condition where the participants could not rely on automated stimulus-response mapping processes during response inhibition. In this context, the NOGO-P3 (ERP), that likely depends on dopaminergic signaling within mesocorticolimbic pathways and is thought to reflect motor inhibition and/or the evaluation of inhibitory processes, was altered in the intoxicated state. In contrast to this, the N2 component, which largely depends on nigrostriatal dopamine pathways and is thought to reflect inhibition on a pre-motor level, was not altered. Based on these results, we demonstrate that alcohol-induced changes of dopaminergic neurotransmission do not exert a global effect on response inhibition. Instead, changes are highly subprocess-specific and seem to mainly target mesocorticolimbic pathways that contribute to motor inhibition and the evaluation of such. © 2014 Society for the Study of Addiction.

The energy dependence of the lateral dose response functions of detectors with various densities in photon-beam dosimetry.

PubMed

Looe, Hui Khee; Harder, Dietrich; Poppe, Björn

2017-02-07

The lateral dose response function is a general characteristic of the volume effect of a detector used for photon dosimetry in a water phantom. It serves as the convolution kernel transforming the true absorbed dose to water profile, which would be produced within the undisturbed water phantom, into the detector-measured signal profile. The shape of the lateral dose response function characterizes (i) the volume averaging attributable to the detector's size and (ii) the disturbance of the secondary electron field associated with the deviation of the electron density of the detector material from the surrounding water. In previous work, the characteristic dependence of the shape of the lateral dose response function upon the electron density of the detector material was studied for 6 MV photons by Monte Carlo simulation of a wall-less voxel-sized detector (Looe et al 2015 Phys. Med. Biol. 60 6585-07). This study is here continued for 60 Co gamma rays and 15 MV photons in comparison with 6 MV photons. It is found (1) that throughout these photon spectra the shapes of the lateral dose response functions are retaining their characteristic dependence on the detector's electron density, and (2) that their energy-dependent changes are only moderate. This appears as a practical advantage because the lateral dose response function can then be treated as practically invariant across a clinical photon beam in spite of the known changes of the photon spectrum with increasing distance from the beam axis.

Analyzing the dose-dependence of the Saccharomyces cerevisiae global transcriptional response to methyl methanesulfonate and ionizing radiation.

PubMed

Benton, Michael G; Somasundaram, Swetha; Glasner, Jeremy D; Palecek, Sean P

2006-12-01

One of the most crucial tasks for a cell to ensure its long term survival is preserving the integrity of its genetic heritage via maintenance of DNA structure and sequence. While the DNA damage response in the yeast Saccharomyces cerevisiae, a model eukaryotic organism, has been extensively studied, much remains to be elucidated about how the organism senses and responds to different types and doses of DNA damage. We have measured the global transcriptional response of S. cerevisiae to multiple doses of two representative DNA damaging agents, methyl methanesulfonate (MMS) and gamma radiation. Hierarchical clustering of genes with a statistically significant change in transcription illustrated the differences in the cellular responses to MMS and gamma radiation. Overall, MMS produced a larger transcriptional response than gamma radiation, and many of the genes modulated in response to MMS are involved in protein and translational regulation. Several clusters of coregulated genes whose responses varied with DNA damaging agent dose were identified. Perhaps the most interesting cluster contained four genes exhibiting biphasic induction in response to MMS dose. All of the genes (DUN1, RNR2, RNR4, and HUG1) are involved in the Mec1p kinase pathway known to respond to MMS, presumably due to stalled DNA replication forks. The biphasic responses of these genes suggest that the pathway is induced at lower levels as MMS dose increases. The genes in this cluster with a threefold or greater transcriptional response to gamma radiation all showed an increased induction with increasing gamma radiation dosage. Analyzing genome-wide transcriptional changes to multiple doses of external stresses enabled the identification of cellular responses that are modulated by magnitude of the stress, providing insights into how a cell deals with genotoxicity.

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

PubMed Central

Simon, Nicholas W.; Moghaddam, Bita

2016-01-01

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

Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

PubMed

Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

2017-08-15

The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

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

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

Olson, J.J.; Friedman, R.; Orr, K.

1990-05-01

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

The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

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

Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.

Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, weremore » significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.« less

Threshold-type dose response for induction of neoplastic transformation by 1 GeV/nucleon iron ions.

PubMed

Elmore, E; Lao, X-Y; Kapadia, R; Redpath, J L

2009-06-01

Neoplastic transformation of HeLa x skin fibroblast human hybrid cells by doses of 1 GeV/nucleon iron ions in the range 1 cGy to 1 Gy to exposed cultures has been examined. The data indicate a threshold-type dose-response curve with no increase in transformation frequency until doses above 20 cGy. At doses <10 cGy, not all exposed cells receive a direct traversal of an iron-ion track core, but all exposed cells receive up to several mGy of low-LET radiation associated with the delta-ray penumbra. It is proposed that the threshold-type response seen is a consequence of an adaptive response associated with the delta-ray exposure. For comparison purposes, the dose response for (137)Cs gamma rays over the same dose range was examined using the same experimental procedure. As we have shown previously, the dose response for (137)Cs gamma radiation was J-shaped. The iron ions were 1.5 to 1.7 times more biologically effective than the gamma radiation over the dose range examined.

Empirical evaluation of meta-analytic approaches for nutrient and health outcome dose-response data

USDA-ARS?s Scientific Manuscript database

The objective of this study is to empirically compare alternative meta-analytic methods for combining dose-response data from epidemiological studies. We identified meta-analyses of epidemiological studies that analyzed the association between a single nutrient and a dichotomous outcome. For each to...

Mode of Action (MOA) and Dose-Response Approaches for Nuclear Receptors

EPA Science Inventory

Abstract: The presence of sub-threshold doses for non-cancer and (in appropriate cases) cancer has been the dominant paradigm for the practice of risk assessment, but the application of dose-response modeling approaches that include a threshold have been questioned in a 2009 NRC ...

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

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

Schmitz, T., E-mail: schmito@uni-mainz.de; Bassler, N.; Blaickner, M.

Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particlemore » spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields

Prenatal low-dose bisphenol A enhances behavioral responses induced by a predator odor.

PubMed

Fujimoto, Tetsuya; Kubo, Kazuhiko; Nishikawa, Yasuo; Aou, Shuji

2015-01-01

Bisphenol A (BPA) is an environmental endocrine disrupter (EED). Previous studies by our group showed that pre- and postnatal administration of low-level BPA induced depression-like behavior in rats. In this study, we evaluated the effects of prenatal BPA on behavioral responses to a predator odor by using a novel cross-form apparatus consisting of 4 plastic chambers. On the first day, nothing was placed into the chambers (Session 1). On the second day, a predator odor (fox odor) was located in separate chambers at 2 opposite corners of the apparatus (Session 2). Pregnant Wistar rats were exposed to low-dose BPA (less than the reference dose) during the 7 days just before birth, and the offspring of the treated rats were evaluated as adults. The locomotor activity and avoidance response of each rat on both test days were compared. The control and BPA groups showed reduced locomotor activity in the presence of the predator odor, but the odor-avoidance response was significant only in the BPA rats. The BPA-exposed rats were obviously sensitive to the predator odor. These results suggest that prenatal BPA exposure has an amplifying effect on avoidance responses to predator odor stress.

Evaluation of the Emergency Response Dose Assessment System(ERDAS)

NASA Technical Reports Server (NTRS)

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

1996-01-01

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

Quantitative dose-response assessment of inhalation exposures to toxic air pollutants

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

Jarabek, A.M.; Foureman, G.L.; Gift, J.S.

1997-12-31

Implementation of the 1990 Clean Air Act Amendments, including evaluation of residual risks. requires accurate human health risk estimates of both acute and chronic inhalation exposures to toxic air pollutants. The U.S. Environmental Protection Agency`s National Center for Environmental Assessment, Research Triangle Park, NC, has a research program that addresses several key issues for development of improved quantitative approaches for dose-response assessment. This paper describes three projects underway in the program. Project A describes a Bayesian approach that was developed to base dose-response estimates on combined data sets and that expresses these estimates as probability density functions. A categorical regressionmore » model has been developed that allows for the combination of all available acute data, with toxicity expressed as severity categories (e.g., mild, moderate, severe), and with both duration and concentration as governing factors. Project C encompasses two refinements to uncertainty factors (UFs) often applied to extrapolate dose-response estimates from laboratory animal data to human equivalent concentrations. Traditional UFs have been based on analyses of oral administration and may not be appropriate for extrapolation of inhalation exposures. Refinement of the UF applied to account for the use of subchronic rather than chronic data was based on an analysis of data from inhalation exposures (Project C-1). Mathematical modeling using the BMD approach was used to calculate the dose-response estimates for comparison between the subchronic and chronic data so that the estimates were not subject to dose-spacing or sample size variability. The second UF that was refined for extrapolation of inhalation data was the adjustment for the use of a LOAEL rather than a NOAEL (Project C-2).« less

Dose responses for adaption to low doses of (60)Co gamma rays and (3)H beta particles in normal human fibroblasts.

PubMed

Broome, E J; Brown, D L; Mitchel, R E J

2002-08-01

The dose response for adaption to radiation at low doses was compared in normal human fibroblasts (AG1522) exposed to either (60)Co gamma rays or (3)H beta particles. Cells were grown in culture to confluence and exposed at either 37 degrees C or 0 degrees C to (3)H beta-particle or (60)Co gamma-ray adapting doses ranging from 0.1 mGy to 500 mGy. These cells, and unexposed control cells, were allowed to adapt during a fixed 3-h, 37 degrees C incubation prior to a 4-Gy challenge dose of (60)Co gamma rays. Adaption was assessed by measuring micronucleus frequency in cytokinesis-blocked, binucleate cells. No adaption was detected in cells exposed to (60)Co gamma radiation at 37 degrees C after a dose of 0.1 mGy given at a low dose rate or to 500 mGy given at a high dose rate. However, low-dose-rate exposure (1-3 mGy/min) to any dose between 1 and 500 mGy from either radiation, delivered at either temperature, caused cells to adapt and reduced the micronucleus frequency that resulted from the subsequent 4-Gy exposure. Within this dose range, the magnitude of the reduction was the same, regardless of the dose or radiation type. These results demonstrate that doses as low as (on average) about one track per cell (1 mGy) produce the same maximum adaptive response as do doses that deposit many tracks per cell, and that the two radiations were not different in this regard. Exposure at a temperature where metabolic processes, including DNA repair, were inactive (0 degrees C) did not alter the result, indicating that the adaptive response is not sensitive to changes in the accumulation of DNA damage within this range. The results also show that the RBE for low doses of tritium beta-particle radiation is 1, using adaption as the end point.

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.

Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

PubMed

Salerno, Francesco; Navickis, Roberta J; Wilkes, Mahlon M

2015-11-25

Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of

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

PubMed

Simon, Nicholas W; Moghaddam, Bita

2017-01-01

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

Mathematical modeling improves EC50 estimations from classical dose-response curves.

PubMed

Nyman, Elin; Lindgren, Isa; Lövfors, William; Lundengård, Karin; Cervin, Ida; Sjöström, Theresia Arbring; Altimiras, Jordi; Cedersund, Gunnar

2015-03-01

The β-adrenergic response is impaired in failing hearts. When studying β-adrenergic function in vitro, the half-maximal effective concentration (EC50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations. The classical interpretation of such data is to assume a maximal response before the decrease, and to fit a sigmoid curve to the remaining data to determine EC50 . Instead, we have applied a mathematical modeling approach to interpret the full dose-response curve in a new way. The developed model predicts a non-steady-state caused by a short resting time between increased concentrations of agonist, which affect the dose-response characterization. Therefore, an improved estimate of EC50 may be calculated using steady-state simulations of the model. The model-based estimation of EC50 is further refined using additional time-resolved data to decrease the uncertainty of the prediction. The resulting model-based EC50 (180-525 nm) is higher than the classically interpreted EC50 (46-191 nm). Mathematical modeling thus makes it possible to re-interpret previously obtained datasets, and to make accurate estimates of EC50 even when steady-state measurements are not experimentally feasible. The mathematical models described here have been submitted to the JWS Online Cellular Systems Modelling Database, and may be accessed at http://jjj.bio.vu.nl/database/nyman. © 2015 FEBS.

Herpes Zoster Vaccine Response in Inflammatory Bowel Disease Patients on Low-dose Immunosuppression.

PubMed

Wasan, Sharmeel K; Zullow, Samantha; Berg, Adam; Cheifetz, Adam S; Ganley-Leal, Lisa; Farraye, Francis A

2016-06-01

Inflammatory Bowel Disease (IBD) patients are at an increased risk of developing herpes zoster (HZ), especially when immunosuppressed. HZ may be preventable with the herpes zoster vaccine (HZV), but many patients are not offered vaccination over concern regarding efficacy and fear of adverse events. Although the Center for Disease Control and Prevention recommends that low-dose immunosuppression is not a contraindication, few IBD patients on these medications are receiving HZV. This study was a prospective clinical trial to assess the safety and immunogenicity of HZV among 2 groups of IBD patients. Group A consisted of 14 patients on low-dose immunomodulators and group B consisted of 25 patients either on 5-aminosalicylic acid or no IBD therapy. Blood samples were obtained to measure immune responses. HZ specific immunoglobulin G rose significantly in both groups but the response was lower in the immunosuppressed group (P = 0.0002). Peripheral blood mononuclear cell secretion of Tumor necrosis factor-α in response to HZ antigen increased after HZV in group B, but not in group A. Interleukin-8 secretion increased in both groups, but the response was much higher in group B. There were no significant differences in adverse events between groups. No patients developed a HZ-like rash within 1 year after vaccination. IBD patients on low-dose immunosuppressive therapy have a blunted immune response to HZV as compared with nonimmunosuppressed subjects. Despite this, immunosuppressed IBD patients are able to mount a statistically significant immune response. There were no serious adverse events to HZV.

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

PubMed Central

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

2015-01-01

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

On the origin of the visible light responsible for proton dose measurement using plastic optical fibers

NASA Astrophysics Data System (ADS)

Darafsheh, Arash; Taleei, Reza; Kassaee, Alireza; Finlay, Jarod C.

2017-03-01

We experimentally and by means of Monte Carlo simulations investigated the origin of the visible signal responsible for proton therapy dose measurement using bare plastic optical fibers. Experimentally, the fiber optic probe, embedded in tissue-mimicking plastics, was irradiated with a proton beam produced by a proton therapy cyclotron and the luminescence spectroscopy was performed by a CCD-coupled spectrograph to analyze the emission spectrum of the fiber tip. Monte Carlo simulations were performed using FLUKA Monte Carlo code to stochastically simulate radiation transport, ionizing radiation dose deposition, and optical emission of Čerenkov radiation. The spectroscopic study of proton-irradiated plastic fibers showed a continuous spectrum with shape different from that of Čerenkov radiation. The Monte Carlo simulations confirmed that the amount of the generated Čerenkov light does not follow the radiation absorbed dose in a medium. Our results show that the origin of the optical signal responsible for the proton dose measurement using bare optical fibers is not Čerenkov radiation. Our results point toward a connection between the scintillation of the plastic material of the fiber and the origin of the signal responsible for dose measurement.

Dose-response effects of water supplementation on cognitive performance and mood in children and adults.

PubMed

Edmonds, Caroline J; Crosbie, Laura; Fatima, Fareeha; Hussain, Maryam; Jacob, Nicole; Gardner, Mark

2017-01-01

Water supplementation has been found to facilitate visual attention and short-term memory, but the dose required to improve performance is not yet known. We assessed the dose response effect of water on thirst, mood and cognitive performance in both adults and children. Participants were offered either no water, 25 ml or 300 ml water to drink. Study 1 assessed 96 adults and in Study 2, data are presented from 60 children aged 7-9 years. In both studies, performance was assessed at baseline and 20 min after drinking (or no drink); on thirst and mood scales, letter cancellation and a digit span test. For both children and adults, a large drink (300 ml) was necessary to reduce thirst, while a small drink (25 ml) was sufficient to improve visual attention (letter cancellation). In adults, a large drink improved digit span, but there was no such effect in children. In children, but not adults, a small drink resulted in increased thirst ratings. Both children and adults show dose-response effects of drinking on visual attention. Visual attention is enhanced by small amounts of fluid and appears not to be contingent on thirst reduction. Memory performance may be related to thirst, but differently for children and adults. These contrasting dose-response characteristics could imply cognitive enhancement by different mechanisms for these two domains. Copyright © 2016 Elsevier Ltd. All rights reserved.

DOSE-DEPENDENT TRANSITIONS IN MECHANISMS OF TOXICITY: CASE STUDIES

EPA Science Inventory

Experience with dose response and mechanisms of toxicity has shown that multiple mechanisms may exist for a single agent along the continuum of the full dose-response curve. It is highly likely that critical, limiting steps in any given mechanistic pathway may become overwhelmed ...

Low-Dose Carcinogenicity Studies

EPA Science Inventory

One of the major deficiencies of cancer risk assessments is the lack of low-dose carcinogenicity data. Most assessments require extrapolation from high to low doses, which is subject to various uncertainties. Only 4 low-dose carcinogenicity studies and 5 low-dose biomarker/pre-n...

Contrasting effects of low versus high ascorbate doses on blood pressure responses to oral nitrite in L-NAME-induced hypertension.

PubMed

Pinheiro, Lucas C; Ferreira, Graziele C; Vilalva, Kelvin H; Toledo, José C; Tanus-Santos, Jose E

2018-04-01

Nitrite reduces blood pressure (BP) in both clinical and experimental hypertension. This effect is attributable to the formation of nitric oxide (NO) and other NO-related species, which may be improved by ascorbate or other antioxidants. However, the BP responses to oral nitrite result, at least in part, of increased gastric S-nitrosothiol formation. This study tested the hypothesis that ascorbate may destroy S-nitrosothiols and therefore not all doses of ascorbate enhance the BP responses to oral nitrite. We assessed the BP responses to oral sodim nitrite (0.2 mmol/kg) in L-NAME hypertensive rats pretreated with ascorbate (0, 0.02, 0.2, or 2 mmol/kg). Plasma and gastric wall concentrations of nitrite and nitroso compounds concentrations were determined using an ozone-based reductive chemiluminescence assay. Nitrate concentrations were determined using the Griess reaction. Free thiol concentrations were determined by a colorimetric assay. The BP responses to nitrite exhibited a bell-shape profile as they were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated BP responses. In parallel with BP responses, nitrite-induced increases in plasma nitrite and RSNO species were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated them. Similar experiments were carried out with an equimolar dose of S-nitrosogluthathione. Ascorbate dose-dependently impaired the BP responses to S-nitrosogluthathione, and the corresponding increases in plasma RSNO, but not in plasma nitrite concentrations. This is the first study to show that while ascorbate dose-dependently impairs the BP responses to oral S-nitrosogluthathione, there are contrasting effects when low versus high ascorbate doses are compared with respect to its effects on the blood pressure responses to oral nitrite administration. Our findings may have special implications to patients taking

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

Treatment of aplastic anaemia with lower-dose anti-thymocyte globulin produces similar response rates and survival as per standard dose anti-thymocyte globulin schedules.

PubMed

Scott, A; Morris, K; Butler, J; Mills, A K; Kennedy, G A

2016-10-01

Aplastic anaemia (AA) is a rare acquired bone marrow failure syndrome resulting from the immune-mediated destruction of haemopoietic stem cells. For adults in whom first-line haemopoietic progenitor cell transplantation is not feasible, combination anti-thymocyte globulin (ATGAM) plus cyclosporine A is standard therapy; however, there are minimal data available regarding the optimal ATGAM dosage in terms of efficacy and survival. Our institutions have historically used different dosing protocols of ATGAM in the treatment of AA. We aimed to review the outcome of AA patients treated with these protocols and compare them to the published literature. We conducted a retrospective study of 31 adults who received first-line ATGAM for AA and compared response rates and survival between cohorts who received standard (40 mg/kg/day D1-4) versus lower-dose (15 mg/kg/day D1-5) ATGAM schedules. There were similar rates of response (64 vs 71%, P = 1.0), relapse (33 vs 33%, P = 1.0), transformation (14 vs 24%, P = 0.66) or infection (43 vs 47%, P = 1.0), respectively, between standard and lower-dose cohorts. At a median follow up of 24 months, there was no statistical difference between standard and lower-dose cohorts in either event-free (42.2 vs 64.7%, P = 0.91) or overall survival (73.1 vs 88.2%, P = 0.75). Our experience suggests that lower-dose ATGAM at 15 mg/kg/day D1-5 as treatment of AA produces similar responses and outcomes as per standard-dose ATGAM schedules. Prospective trials comparing ATGAM dose schedules in AA are warranted. © 2016 Royal Australasian College of Physicians.

Hepatitis B vaccine booster dose: low-dose recombinant hepatitis B vaccines as a booster dose.

PubMed

Bryan, J P; MacArthy, P; Rudock, A; Fogarty, J P; Dowd, H; Legters, L J; Perine, P L

1997-06-01

The timing and best regimen for a booster dose of hepatitis B vaccine have not been determined. Two studies were conducted to determine the response to a booster dose of 5 micrograms recombinant hepatitis B vaccine. In the first study, a 5 micrograms (0.5 ml) dose of Recombivax HB was administered intramuscularly 38 months after the initial dose to 71 volunteers. In a second study, we offered a 5 micrograms dose recombinant hepatitis B vaccine, either Recombivax HB (0.5 ml) or Engerix B (0.25 ml), to students who had previously been immunized with three doses of vaccine. In the first study, among the 44 persons for whom postbooster sera were available, the geometric mean concentration of anti-hepatitis B surface antigens increased from 42 to 2090 mIU/ml after the 5 micrograms (0.5 ml) dose of Recombivax. In the second study, after a 5 micrograms (0.5 ml) dose of Recombivax, the geometric mean concentration increased from 43 to 990 mIU/ml (n = 48), and in the group that received a 5 micrograms (0.25 ml) dose of Engerix B, the concentration increased from 83 to 2337 mIU/ml (n = 45) (p = 0.18 for postdose concentrations). A 5 micrograms dose of recombinant vaccine results in an excellent booster response at a cost one fourth to one half that of a full 1 ml dose of vaccine.

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

PubMed

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

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

Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

PubMed

Gentry, P R; Yager, J W; Clewell, R A; Clewell, H J

2014-10-01

In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies. Copyright © 2014 Elsevier Ltd. All rights reserved.

SU-F-J-86: Method to Include Tissue Dose Response Effect in Deformable Image Registration

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

Zhu, J; Liang, J; Chen, S

Purpose: Organ changes shape and size during radiation treatment due to both mechanical stress and radiation dose response. However, the dose response induced deformation has not been considered in conventional deformable image registration (DIR). A novel DIR approach is proposed to include both tissue elasticity and radiation dose induced organ deformation. Methods: Assuming that organ sub-volume shrinkage was proportional to the radiation dose induced cell killing/absorption, the dose induced organ volume change was simulated applying virtual temperature on each sub-volume. Hence, both stress and heterogeneity temperature induced organ deformation. Thermal stress finite element method with organ surface boundary condition wasmore » used to solve deformation. Initial boundary correspondence on organ surface was created from conventional DIR. Boundary condition was updated by an iterative optimization scheme to minimize elastic deformation energy. The registration was validated on a numerical phantom. Treatment dose was constructed applying both the conventional DIR and the proposed method using daily CBCT image obtained from HN treatment. Results: Phantom study showed 2.7% maximal discrepancy with respect to the actual displacement. Compared with conventional DIR, subvolume displacement difference in a right parotid had the mean±SD (Min, Max) to be 1.1±0.9(−0.4∼4.8), −0.1±0.9(−2.9∼2.4) and −0.1±0.9(−3.4∼1.9)mm in RL/PA/SI directions respectively. Mean parotid dose and V30 constructed including the dose response induced shrinkage were 6.3% and 12.0% higher than those from the conventional DIR. Conclusion: Heterogeneous dose distribution in normal organ causes non-uniform sub-volume shrinkage. Sub-volume in high dose region has a larger shrinkage than the one in low dose region, therefore causing more sub-volumes to move into the high dose area during the treatment course. This leads to an unfavorable dose-volume relationship for the normal

Effect of egg ingestion on trimethylamine-N-oxide production in humans: a randomized, controlled, dose-response study1234

PubMed Central

Miller, Carolyn A; Corbin, Karen D; da Costa, Kerry-Ann; Zhang, Shucha; Zhao, Xueqing; Galanko, Joseph A; Blevins, Tondra; Bennett, Brian J; O'Connor, Annalouise; Zeisel, Steven H

2014-01-01

Background: It is important to understand whether eating eggs, which are a major source of dietary choline, results in increased exposure to trimethylamine-N-oxide (TMAO), which is purported to be a risk factor for developing heart disease. Objective: We determined whether humans eating eggs generate TMAO and, if so, whether there is an associated increase in a marker for inflammation [ie, high-sensitivity C-reactive protein (hsCRP)] or increased oxidation of low-density lipoprotein (LDL). Design: In a longitudinal, double-blind, randomized dietary intervention, 6 volunteers were fed breakfast doses of 0, 1, 2, 4, or 6 egg yolks. Diets were otherwise controlled on the day before and day of each egg dose with a standardized low-choline menu. Plasma TMAO at timed intervals (immediately before and 1, 2, 4, 8, and 24 h after each dose), 24-h urine TMAO, predose and 24-h postdose serum hsCRP, and plasma oxidized LDL were measured. Volunteers received all 5 doses with each dose separated by >2-wk washout periods. Results: The consumption of eggs was associated with increased plasma and urine TMAO concentrations (P < 0.01), with ∼14% of the total choline in eggs having been converted to TMAO. There was considerable variation between individuals in the TMAO response. There was no difference in hsCRP or oxidized LDL concentrations after egg doses. Conclusions: The consumption of ≥2 eggs results in an increased formation of TMAO. Choline is an essential nutrient that is required for normal human liver and muscle functions and important for normal fetal development. Additional study is needed to both confirm the association between TMAO and atherosclerosis and identify factors, microbiota and genetic, that influence the generation of TMAO before policy and medical recommendations are made that suggest reduced dietary choline intake. This trial was registered at clinicaltrials.gov as NCT01906554. PMID:24944063

Dramatic response to high-dose icotinib in a lung adenocarcinoma patient after erlotinib failure.

PubMed

Guan, Yin; Zhao, Hong; Meng, Jing; Yan, Xiang; Jiao, ShunChang

2014-02-01

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) retreatment is rarely administered for non-small cell lung cancer (NSCLC) patients who did not respond to previous TKI treatment. A high dose of TKI may overcome resistance to the standard dose of TKI and have different effectiveness toward cancer compared with the standard dose of TKI. This manuscript describes a dramatic and durable response to high-dose icotinib in a NSCLC patient who did not respond to a previous standard dose of erlotinib. The treatment extended the life of the patient for one additional year. A higher dose of icotinib deserves further study not only for patients whose therapy failed with the standard dose of TKI but also for newly diagnosed NSCLC patients with a sensitive mutation. Serial mutation testing during disease development is necessary for analysis and evaluation of EGFR TKI treatment. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

No regional difference in cisatracurium dose-response and time-course-of-action between patients in China and Bosnia.

PubMed

Dahaba, A A; Suljevic, I; Bornemann, H; Wu, X-M; Metzler, H

2011-03-01

Variability in drug response could result from a variety of genetic and environmental factors that are often hard to define or quantify. A number of studies demonstrated regional geographic variations in potency of neuromuscular blocking agents (NMBAs). The aim of our study was to compare dose-response and time-course-of-action of cisatracurium besylate, an NMBA eliminated via the Hoffman degradation, in two countries with different life habits, diet, and ambient conditions; being Han Chinese in China and Caucasians in Bosnia. Neuromuscular block of cisatracurium 20 µg kg(-1), followed by four incremental 10 µg kg(-1) doses, and the remainder of 100 µg kg(-1) was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, The Netherlands). Dose-response curves were created using log-dose-probit-response transformation. There were no significant differences in cisatracurium mean (95% confidence intervals) ED(50), ED(90), and ED(95) (effective doses for 50%, 90%, and 95% first twitch depression) in Caucasian [39.1 (35.7-42.3), 50.6 (45.5-54.3), and 54.4 (49.8-58.9) µg kg(-1)] compared with Chinese patients [39.2 (35.1-43.1), 52.4 (47.9-56.8), and 56.9 (52.8-61.9) µg kg(-1)], respectively. There were no significant differences in mean (sd) Dur(25) and Dur(0.9) (time until 25% first twitch and 0.9 train-of-four ratio recoveries) in Caucasian [47.1 (6.4) and 77.5 (9.1) min)] compared with Chinese patients [(45.9 (4.7) and 72.3 (9.1) min)], respectively. Cisatracurium dose-response relationship and time-course-of-action were not influenced by geographic location. Thus, cisatracurium would not require dose adjustments between patients living in the two geographic locations.

Protein adducts of malondialdehyde and 4-hydroxynonenal contribute to trichloroethene-mediated autoimmunity via activating Th17 cells: Dose- and time-response studies in female MRL+/+ mice

PubMed Central

Wang, Gangduo; Wang, Jianling; Fan, Xiuzhen; Ansari, G. A. S.; Khan, M. Firoze

2011-01-01

Trichloroethene (TCE), a common occupational and environmental toxicant, is known to induce autoimmunity. Previous studies in our laboratory showed increased oxidative stress in TCE-mediated autoimmunity. To further establish the role of oxidative stress and to investigate the mechanisms of TCE-mediated autoimmunity, dose- and time- response studies were conducted in MRL+/+ mice by treating them with TCE via drinking water at doses of 0.5, 1.0 or 2.0 mg/ml for 12, 24 or 36 weeks. TCE exposure led to dose-related increases in malondialdehyde (MDA)-/hydroxynonenal (HNE)-protein adducts and their corresponding antibodies in the sera and decreases in GSH and GSH/GSSG ratio in the kidneys at 24 and 36 weeks, with greater changes at 36 weeks. The increases in these protein adducts and decreases in GSH/GSSG ratio were associated with significant elevation in serum anti-nuclear- and anti-ssDNA-antibodies, suggesting an association between TCE-induced oxidative stress and autoimmune response. Interestingly, splenocytes from mice treated with TCE for 24 weeks secreted significantly higher levels of IL-17 and IL-21 than did splenocytes from controls after stimulation with MDA-mouse serum albumin (MSA) or HNE-MSA adducts. The increased release of these cytokines showed a dose-related response and was more pronounced in mice treated with TCE for 36 weeks. These studies provide evidence that MDA- and or HNE-protein adducts contribute to TCE-mediated autoimmunity, which may be via activation of Th17 cells. PMID:22178267

Effect of contrast water therapy duration on recovery of cycling performance: a dose-response study.

PubMed

Versey, Nathan; Halson, Shona; Dawson, Brian

2011-01-01

This study investigated whether contrast water therapy (CWT) has a dose-response effect on recovery from high-intensity cycling. Eleven trained male cyclists completed four trials, each commencing with a 75-min cycling protocol containing six sets of five 15-s sprints and three 5-min time-trials in thermoneutral conditions. Ten minutes post-exercise, participants performed one of four recovery protocols: CWT for 6 min (CWT6), 12 min (CWT12), or 18 min (CWT18) duration, or a seated rest control trial. The CWT commenced in hot water (38.4 ± 0.6°C) and alternated between hot and cold water (14.6 ± 0.3°C) every minute with a 5-s changeover. The cycling protocol was repeated 2 h after completion of exercise bout one. Prior to exercise bout two, core temperature was lower in CWT12 (-0.19 ± 0.14°C, mean ± 90% CL) and CWT18 (-0.21 ± 0.10°C) than control. Compared with control, CWT6 substantially improved time-trial (1.5 ± 2.1%) and sprint performance (3.0 ± 3.1%), and CWT12 substantially improved sprint total work (4.3 ± 3.4%) and peak power (2.7 ± 3.8%) in exercise bout two. All CWT conditions generally improved thermal sensation, whole body fatigue and muscle soreness compared with control, but no differences existed between conditions in heart rate or rating of perceived exertion. In conclusion, CWT duration did not have a dose-response effect on recovery from high-intensity cycling; however, CWT for up to 12 min assisted recovery of cycling performance.

Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.

PubMed

Cervantes, Francisco; Correa, Juan-Gonzalo; Pérez, Isabel; García-Gutiérrez, Valentín; Redondo, Sara; Colomer, Dolors; Jiménez-Velasco, Antonio; Steegmann, Juan-Luis; Sánchez-Guijo, Fermín; Ferrer-Marín, Francisca; Pereira, Arturo; Osorio, Santiago

2017-01-01

To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR 4 , MR 4.5 , and MR 5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR 3 . At the last follow-up, response was MR 3 , MR 4 , MR 4.5 , and MR 5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

A Framework for "Fit for Purpose" Dose Response Assessment

EPA Science Inventory

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

A Dose-Response Study of Inactivated Low Pathogenic Avian Influenza H9N2 Virus in Specific-Pathogen-Free and Commercial Broiler Chickens.

PubMed

Kilany, Walid H; Ali, Ahmed; Bazid, Abdel-Hamid I; El-Deeb, Ayman H; El-Abideen, Mohamed A Zain; Sayed, Magdy El; El-Kady, Magdy F

2016-05-01

Since the first report of low pathogenic avian influenza (LPAI) H9N2 virus in Egypt in 2011, the Egyptian poultry industry has suffered from unexpected economic losses as a result of the wide spread of LPAI H9N2. Hence, inactivated H9N2 vaccines have been included in the vaccination programs of different poultry production sectors. The optimal antigen content of avian influenza virus vaccines is essential to reach protective antibody titers. In this study, the correlation between antigen content (based on hemagglutinating units [HAU]) and postvaccination (PV) antibody response of H9N2 inactivated vaccine was studied. Five different vaccine antigen loads (128, 200, 250, 300, and 350 HAU formulas/dose) were investigated in commercial broiler and specific-pathogen-free (SPF) chickens. Vaccine safety and PV antibody responses were monitored. At the fourth week PV only SPF vaccinated groups (128, 200, 250, and 300 HAU/dose) were challenged using LPAI H9N2 (A/Ck/EG/114940v/NLQP/11) virus with 10(6) EID50/bird. Oropharyngeal swabs were used to monitor virus shedding at 2, 4, 6, and 10 days postchallenge. Results showed that all vaccine formulations were well tolerated, and the highest antibody titers were observed in birds vaccinated with higher HAU. Vaccines containing 128 and 200 HAU/dose did not induce the required protective HI titers by 3 wk PV. Meanwhile, the challenge experiment in SPF chickens showed that 250 and 300 HAU vaccine doses were required to reduce the level and duration of virus shedding. Study results thus suggest that inactivated H9N2 vaccines containing at least 250 HAU/dose will induce the optimal protective titers and minimize virus shedding in SPF chickens.

Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

PubMed

Land, Charles E; Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M; Simon, Steven L

2015-02-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population

Accounting for Shared and Unshared Dosimetric Uncertainties in the Dose Response for Ultrasound-Detected Thyroid Nodules after Exposure to Radioactive Fallout

PubMed Central

Hoffman, F. Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M.; Simon, Steven L.

2015-01-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semi-palatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point “best estimates”. In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5

Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins

PubMed Central

Feng, Xuan; Han, Diana; Kilaru, Bharat K.; Franek, Beverly S.; Niewold, Timothy B.; Reder, Anthony T.

2014-01-01

Objective To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease. PMID:22801747

On use of the multistage dose-response model for assessing laboratory animal carcinogenicity

PubMed Central

Nitcheva, Daniella; Piegorsch, Walter W.; West, R. Webster

2007-01-01

We explore how well a statistical multistage model describes dose-response patterns in laboratory animal carcinogenicity experiments from a large database of quantal response data. The data are collected from the U.S. EPA’s publicly available IRIS data warehouse and examined statistically to determine how often higher-order values in the multistage predictor yield significant improvements in explanatory power over lower-order values. Our results suggest that the addition of a second-order parameter to the model only improves the fit about 20% of the time, while adding even higher-order terms apparently does not contribute to the fit at all, at least with the study designs we captured in the IRIS database. Also included is an examination of statistical tests for assessing significance of higher-order terms in a multistage dose-response model. It is noted that bootstrap testing methodology appears to offer greater stability for performing the hypothesis tests than a more-common, but possibly unstable, “Wald” test. PMID:17490794

A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

PubMed

Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

2015-07-31

Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

Platelet response to increased aspirin dose in patients with persistent platelet aggregation while treated with aspirin 81 mg.

PubMed

Gengo, Fran; Westphal, Erica S; Rainka, Michelle M; Janda, Maria; Robson, Matthew J; Hourihane, J Maurice; Bates, Vernice

2016-04-01

This study demonstrates that patients who are taking 81 mg of aspirin and are nonresponsive benefit from a dose of 162 mg or greater vs a different antiplatelet therapy. We identified 100 patients who were nonresponsive to aspirin 81 mg via whole blood aggregometry and observed how many patients became responsive at a dose of 162 mg or greater. Platelet nonresponsiveness was defined as >10 Ω of resistance to collagen 1 µg/mL and/or an ohms ratio of collagen 1 µg/mL to collagen 5 µg/mL >0.5 and/or >6 Ω to arachidonate. Borderline response was defined as an improvement in 1 but not both of the above criteria. Of the initial 100 patients who were nonresponsive to an aspirin dose of 81 mg, 79% became responsive at a dose of 162 mg or >162 mg. Only 6% did not respond to any increase in dose. We believe that patients treated with low-dose aspirin who have significant risk for secondary vascular events should be individually assessed to determine their antiplatelet response. Those found to have persistent platelet aggregation despite treatment with 81 mg of aspirin have a higher likelihood of obtaining an adequate antiplatelet response at a higher aspirin dose. © 2015, The American College of Clinical Pharmacology.

Adjunctive aripiprazole in the treatment of risperidone-induced hyperprolactinemia: A randomized, double-blind, placebo-controlled, dose-response study.

PubMed

Chen, Jing-Xu; Su, Yun-Ai; Bian, Qing-Tao; Wei, Li-He; Zhang, Rong-Zhen; Liu, Yan-Hong; Correll, Christoph; Soares, Jair C; Yang, Fu-De; Wang, Shao-Li; Zhang, Xiang-Yang

2015-08-01

Hyperprolactinemia is an unwanted adverse effect associated with several antipsychotics. The addition of partial dopamine receptor agonist aripiprazole may attenuate antipsychotic-induced hyperprolactinemia effectively. However, the ideal dosing regimen for this purpose is unknown. We aimed to evaluate the dose effects of adjunctive treatment with aripiprazole on prolactin levels and hyperprolactinemia in schizophrenia patients. Stable subjects 18-45 years old with schizophrenia and hyperprolactinemia (i.e., >24 ng/ml for females and >20 ng/ml for males) were randomly assigned to receive 8 weeks of placebo (n=30) or oral aripiprazole 5mg/day (n=30), 10mg/day (n=29), or 20mg/day (n=30) added on to fixed dose risperidone treatment. Serum prolactin levels were measured at baseline and after 2, 4 and 8 weeks; clinical symptoms and side effects were assessed at baseline and week 8 using the Positive and Negative Syndrome Scale, Clinical Global Impressions Severity scale, Barnes Akathisia Scale, Simpson-Angus Scale and UKU Side Effects Rating Scale. Of 119 randomized patients, 107 (89.9%) completed the 8-week study. At study end, all three aripiprazole doses resulted in significantly lower prolactin levels (beginning at week 2), higher response rates (≥30% prolactin reduction) and higher prolactin normalization rates than placebo. Effects were significantly greater in the 10 and 20mg/day groups than the 5mg/day group. No significant changes were observed in any treatment groups regarding psychopathology and adverse effect ratings. Adjunctive aripiprazole treatment was effective and safe for resolving risperidone-induced hyperprolactinemia, producing significant and almost maximal improvements by week 2 without significant effects on psychopathology and side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Study of the Genes and Mechanism Involved in the Radioadaptive Response

NASA Technical Reports Server (NTRS)

Dasgupta, Pushan R.

2009-01-01

The radioadaptive response is a phenomenon where exposure to a prior low dose of radiation reduces the level of damage induced by a subsequent high radiation dose. The molecular mechanism behind this is still not well understood. Learning more about the radioadaptive response is critical for long duration spaceflight since astronauts are exposed to low levels of cosmic radiation. The micronucleus assay was used to measure the level of damage caused by radiation. Although cells which were not washed with phosphate buffered saline (PBS) after a low priming dose of 5cGy did not show adaptation to the challenge dose, washing the cells with PBS and giving the cells fresh media after the low dose did allow radioadaptation to occur. This is consistent with the results of a previous publication by another research group. In the present study, genes involved in DNA damage signaling and the oxidative stress response were studied using RT PCR techniques in order to look at changes in expression level after the low dose with or without washing. Our preliminary results indicate that upregulation of oxidative stress response genes ANGPTL7, NCF2, TTN, and SRXN1 may be involved in the radioadaptive response. The low dose of radiation alone was found to activate the oxidative stress response genes GPR156 and MTL5, whereas, washing the cells alone caused relatively robust upregulation of the oxidative stress response genes DUSP1 and PTGS2. Washing after the priming dose showed some changes in the expression level of several DNA damage signaling genes. In addition, we studied whether washing the cells after the priming dose has an effect on the level of nitric oxide in both the media and cells, since nitric oxide levels are known to increase in the media of the cells after a high dose of radiation only if the cells were already exposed to a low priming dose. Based on this preliminary study, we propose that washing the cells after priming exposure actually eliminates some factor

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

Dose-response studies of Ropivacaine in blood flow of upper extremity after supraclavicular block: a double-blind randomized controlled study.

PubMed

Li, Ting; Ye, Qiguang; Wu, Daozhu; Li, Jun; Yu, Jingui

2017-12-02

The sympathetic block of upper limb leading to increased blood flow has important clinical implication in microvascular surgery. However, little is known regarding the relationship between concentration of local anesthetic and blood flow of upper limb. The aim of this dose-response study was to determine the ED 50 and ED 95 of ropivacaine in blood flow after supraclavicular block (SB). Patients undergoing upper limb surgery and supraclavicular block were randomly assigned to receive 30ml ropivacaine in concentrations of 0.125%(A Group), 0.2%(B Group), 0.25%(C Group), 0.375%(D Group), 0.5%(E Group), or 0.75%(F Group) (n=13 per group). All patients received supraclavicular block (SB). Time average maximum velocity (TAMAX), cross-sectional area (CSA) of brachial artery and skin temperatures (T s ) were measured repeatedly at the same marked points, they were taken at baseline (before block, t 0 ) and at 30min after SB (t 1 ). Blood flow(BF) = TAMAX× CSA×60 sec.. Relative blood flow (ΔBF) = BF t1 / BF t0 . Success of SB was assessed simultaneously. Supplementary anesthesia and other adverse events (AE) were recorded. Significant increase in TAMAX, CSA, BF and T s were seen in all concentration groups at t 1 comparing with t 0 (P<0.001). There was an upward trend of TAMAX, CSA, BF with the increasing concentration of ropivacaine except T s . There was no significant different of T s at t 1 among different concentration group. The dose-response formula of ropivacaine on ΔBF was Y=1+3.188/(1+10^((-2.451-X) × 1.730)) and ED 50 /ED 95 (95%CI) were 0.35/1.94%(0.25-0.45/0.83-4.52), and R 2 (coefficient of determination) =0.85. ED 50 /ED 95 (95%CI) values of sensory block were 0.18/0.33% (0.15-0.21/0.27-0.51), R 2 =0.904. The dose-response curve between SB ropivacaine and the changes of BF was determined. The ED 50 /ED 95 of ropivacaine of ΔBF are 0.35/1.94% (0.25-0.45/0.83-4.52). TAMAX, CSA and BF consistently increased with ropivacaine concentration. The maximal

Alectinib Dose Escalation Reinduces Central Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib.

PubMed

Gainor, Justin F; Chi, Andrew S; Logan, Jennifer; Hu, Ranliang; Oh, Kevin S; Brastianos, Priscilla K; Shih, Helen A; Shaw, Alice T

2016-02-01

The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in anaplastic lymphoma kinase (ALK)-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard dose alectinib (600 mg twice daily), but who subsequently experienced recurrences with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis. Copyright © 2015 International Association for the Study of Lung Cancer. 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.

A dose error evaluation study for 4D dose calculations

NASA Astrophysics Data System (ADS)

Milz, Stefan; Wilkens, Jan J.; Ullrich, Wolfgang

2014-10-01

Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms. The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms. The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex

A dose error evaluation study for 4D dose calculations.

PubMed

Milz, Stefan; Wilkens, Jan J; Ullrich, Wolfgang

2014-11-07

Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms.The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms.The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm; 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex programming

Risk of solid cancer in low dose-rate radiation epidemiological studies and the dose-rate effectiveness factor.

PubMed

Shore, Roy; Walsh, Linda; Azizova, Tamara; Rühm, Werner

2017-10-01

Estimated radiation risks used for radiation protection purposes have been based primarily on the Life Span Study (LSS) of atomic bomb survivors who received brief exposures at high dose rates, many with high doses. Information is needed regarding radiation risks from low dose-rate (LDR) exposures to low linear-energy-transfer (low-LET) radiation. We conducted a meta-analysis of LDR epidemiologic studies that provide dose-response estimates of total solid cancer risk in adulthood in comparison to corresponding LSS risks, in order to estimate a dose rate effectiveness factor (DREF). We identified 22 LDR studies with dose-response risk estimates for solid cancer after minimizing information overlap. For each study, a parallel risk estimate was derived from the LSS risk model using matching values for sex, mean ages at first exposure and attained age, targeted cancer types, and accounting for type of dosimetric assessment. For each LDR study, a ratio of the excess relative risk per Gy (ERR Gy -1 ) to the matching LSS ERR risk estimate (LDR/LSS) was calculated, and a meta-analysis of the risk ratios was conducted. The reciprocal of the resultant risk ratio provided an estimate of the DREF. The meta-analysis showed a LDR/LSS risk ratio of 0.36 (95% confidence interval [CI] 0.14, 0.57) for the 19 studies of solid cancer mortality and 0.33 (95% CI 0.13, 0.54) when three cohorts with only incidence data also were added, implying a DREF with values around 3, but statistically compatible with 2. However, the analyses were highly dominated by the Mayak worker study. When the Mayak study was excluded the LDR/LSS risk ratios increased: 1.12 (95% CI 0.40, 1.84) for mortality and 0.54 (95% CI 0.09, 0.99) for mortality + incidence, implying a lower DREF in the range of 1-2. Meta-analyses that included only cohorts in which the mean dose was <100 mGy yielded a risk ratio of 1.06 (95% CI 0.30, 1.83) for solid cancer mortality and 0.58 (95% CI 0.10, 1.06) for mortality�

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

Empirical Evaluation of Meta-Analytic Approaches for Nutrient and Health Outcome Dose-Response Data

ERIC Educational Resources Information Center

Yu, Winifred W.; Schmid, Christopher H.; Lichtenstein, Alice H.; Lau, Joseph; Trikalinos, Thomas A.

2013-01-01

The objective of this study is to empirically compare alternative meta-analytic methods for combining dose-response data from epidemiological studies. We identified meta-analyses of epidemiological studies that analyzed the association between a single nutrient and a dichotomous outcome. For each topic, we performed meta-analyses of odds ratios…

Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines.

PubMed

Huebner, Robin E; Nicol, Mark; Mothupi, Rosalia; Käyhty, Helena; Mbelle, Nontombi; Khomo, Esther; Klugman, Keith P

2004-12-21

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 microg) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of > or =1.25 microg of HibCRM197 vaccine produced mean anti-PRP responses at 18 weeks of > or =5.72 microg/ml and > or =0.15 microg/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of > or =1.0 microg/ml. Concentrations of > or =1.25 microg of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of > or =8.63 microg/ml and > or =0.15 microg/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of > or =1.0 microg/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of > or =0.15 microg/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses > or =1.25 microg of HibCRM197 and Hib-tetanus to mean concentrations > or =37.71 and 16.07 microg/ml, respectively. There were no differences in antibody responses for vaccine doses > or =1.25 microg of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of > or =1.25 microg may be sufficient to

No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

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

Sheehan, Daniel M.

2006-01-15

We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated onmore » a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.« less

The Effect of Ongoing Exposure Dynamics in Dose Response Relationships

PubMed Central

Pujol, Josep M.; Eisenberg, Joseph E.; Haas, Charles N.; Koopman, James S.

2009-01-01

Characterizing infectivity as a function of pathogen dose is integral to microbial risk assessment. Dose-response experiments usually administer doses to subjects at one time. Phenomenological models of the resulting data, such as the exponential and the Beta-Poisson models, ignore dose timing and assume independent risks from each pathogen. Real world exposure to pathogens, however, is a sequence of discrete events where concurrent or prior pathogen arrival affects the capacity of immune effectors to engage and kill newly arriving pathogens. We model immune effector and pathogen interactions during the period before infection becomes established in order to capture the dynamics generating dose timing effects. Model analysis reveals an inverse relationship between the time over which exposures accumulate and the risk of infection. Data from one time dose experiments will thus overestimate per pathogen infection risks of real world exposures. For instance, fitting our model to one time dosing data reveals a risk of 0.66 from 313 Cryptosporidium parvum pathogens. When the temporal exposure window is increased 100-fold using the same parameters fitted by our model to the one time dose data, the risk of infection is reduced to 0.09. Confirmation of this risk prediction requires data from experiments administering doses with different timings. Our model demonstrates that dose timing could markedly alter the risks generated by airborne versus fomite transmitted pathogens. PMID:19503605

Mathematical Modeling of Allelopathy. III. A Model for Curve-Fitting Allelochemical Dose Responses

PubMed Central

Liu, De Li; An, Min; Johnson, Ian R.; Lovett, John V.

2003-01-01

Bioassay techniques are often used to study the effects of allelochemicals on plant processes, and it is generally observed that the processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. A simple empirical model is presented to analyze this type of response. The stimulation-inhibition properties of allelochemical-dose responses can be described by the parameters in the model. The indices, p% reductions, are calculated to assess the allelochemical effects. The model is compared with experimental data for the response of lettuce seedling growth to Centaurepensin, the olfactory response of weevil larvae to α-terpineol, and the responses of annual ryegrass (Lolium multiflorum Lam.), creeping red fescue (Festuca rubra L., cv. Ensylva), Kentucky bluegrass (Poa pratensis L., cv. Kenblue), perennial ryegrass (L. perenne L., cv. Manhattan), and Rebel tall fescue (F. arundinacea Schreb) seedling growth to leachates of Rebel and Kentucky 31 tall fescue. The results show that the model gives a good description to observations and can be used to fit a wide range of dose responses. Assessments of the effects of leachates of Rebel and Kentucky 31 tall fescue clearly differentiate the properties of the allelopathic sources and the relative sensitivities of indicators such as the length of root and leaf. PMID:19330111

Estimating adolescent sleep need using dose-response modeling.

PubMed

Short, Michelle A; Weber, Nathan; Reynolds, Chelsea; Coussens, Scott; Carskadon, Mary A

2018-04-01

This study will (1) estimate the nightly sleep need of human adolescents, (2) determine the time course and severity of sleep-related deficits when sleep is reduced below this optimal quantity, and (3) determine whether sleep restriction perturbs the circadian system as well as the sleep homeostat. Thirty-four adolescents aged 15 to 17 years spent 10 days and nine nights in the sleep laboratory. Between two baseline nights and two recovery nights with 10 hours' time in bed (TIB) per night, participants experienced either severe sleep restriction (5-hour TIB), moderate sleep restriction (7.5-hour TIB), or no sleep restriction (10-hour TIB) for five nights. A 10-minute psychomotor vigilance task (PVT; lapse = response after 500 ms) and the Karolinska Sleepiness Scale were administered every 3 hours during wake. Salivary dim-light melatonin onset was calculated at baseline and after four nights of each sleep dose to estimate circadian phase. Dose-dependent deficits to sleep duration, circadian phase timing, lapses of attention, and subjective sleepiness occurred. Less TIB resulted in less sleep, more lapses of attention, greater subjective sleepiness, and larger circadian phase delays. Sleep need estimated from 10-hour TIB sleep opportunities was approximately 9 hours, while modeling PVT lapse data suggested that 9.35 hours of sleep is needed to maintain optimal sustained attention performance. Sleep restriction perturbs homeostatic and circadian systems, leading to dose-dependent deficits to sustained attention and sleepiness. Adolescents require more sleep for optimal functioning than typically obtained.

Neuroprotective Dose Response in RCS Rats Implanted with Microphotodiode Arrays

PubMed Central

Pardue, Machelle T.; Kim, Moon K.; Walker, Tiffany A.; Faulkner, Amanda E.; Chow, Alan Y.; Ciavatta, Vincent T.

2012-01-01

Purpose Neuropreservation of retinal function and structure in RCS rats following implantation of a microphotodiode array (MPA) has been shown in previous studies(Pardue et al. 2005a; Pardue et al. 2005b). Since microphotodiodes produce electrical currents in proportion to the intensity of incident light, increased light exposure may result in greater neuroprotective effects. Our previous studies suggested that the frequency of light exposure to electroretinogram (ERG) flash stimuli might provide increased neuroprotection. Thus, in this study, we examined the dose response of subretinal electrical stimulation by exposing RCS rats implanted with MPAs to variable durations and combinations of two different lighting regimens: pulsing incandescent bulbs and xenon stimuli from an ERG Ganzfeld. While incandescent light regimens did not produce any significant differences in ERG function, we found significantly greater dark-adapted ERG b-wave amplitudes in RCS rats that received weekly versus biweekly ERGs over the course of 8 weeks of follow-up. These results suggest that subretinal electrical stimulation may be optimized to produce greater neuroprotective effects by dosing with periodic higher current. PMID:22183323

Radiation dose response of N channel MOSFET submitted to filtered X-ray photon beam

NASA Astrophysics Data System (ADS)

Gonçalves Filho, Luiz C.; Monte, David S.; Barros, Fabio R.; Santos, Luiz A. P.

2018-01-01

MOSFET can operate as a radiation detector mainly in high-energy photon beams, which are normally used in cancer treatments. In general, such an electronic device can work as a dosimeter from threshold voltage shift measurements. The purpose of this article is to show a new way for measuring the dose-response of MOSFETs when they are under X-ray beams generated from 100kV potential range, which is normally used in diagnostic radiology. Basically, the method consists of measuring the MOSFET drain current as a function of the radiation dose. For this the type of device, it has to be biased with a high value resistor aiming to see a substantial change in the drain current after it has been irradiated with an amount of radiation dose. Two types of N channel device were used in the experiment: a signal transistor and a power transistor. The delivered dose to the device was varied and the electrical curves were plotted. Also, a sensitivity analysis of the power MOSFET response was made, by varying the tube potential of about 20%. The results show that both types of devices have responses very similar, the shift in the electrical curve is proportional to the radiation dose. Unlike the power MOSFET, the signal transistor does not provide a linear function between the dose rate and its drain current. We also have observed that the variation in the tube potential of the X-ray equipment produces a very similar dose-response.

Typical doses and dose rates in studies pertinent to radiation risk inference at low doses and low dose rates

PubMed Central

Rühm, Werner; Azizova, Tamara; Bouffler, Simon; Cullings, Harry M; Grosche, Bernd; Little, Mark P; Shore, Roy S; Walsh, Linda; Woloschak, Gayle E

2018-01-01

Abstract In order to quantify radiation risks at exposure scenarios relevant for radiation protection, often extrapolation of data obtained at high doses and high dose rates down to low doses and low dose rates is needed. Task Group TG91 on ‘Radiation Risk Inference at Low-dose and Low-dose Rate Exposure for Radiological Protection Purposes’ of the International Commission on Radiological Protection is currently reviewing the relevant cellular, animal and human studies that could be used for that purpose. This paper provides an overview of dose rates and doses typically used or present in those studies, and compares them with doses and dose rates typical of those received by the A-bomb survivors in Japan. PMID:29432579

DOSE-RESPONSE ASSESSMENT FOR DEVELOPMENTAL TOXICITY III. STATISTICAL MODELS

EPA Science Inventory

Although quantitative modeling has been central to cancer risk assessment for years, the concept of do@e-response modeling for developmental effects is relatively new. he benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpo...

A Randomized Phase II Dose-Response Exercise Trial among Colon Cancer Survivors: Purpose, Study Design, Methods, and Recruitment Results

PubMed Central

Brown, Justin C.; Troxel, Andrea B.; Ky, Bonnie; Damjanov, Nevena; Zemel, Babette S.; Rickels, Michael R.; Rhim, Andrew D.; Rustgi, Anil K.; Courneya, Kerry S.; Schmitz, Kathryn H.

2016-01-01

Background Observational studies indicate that higher volumes of physical activity are associated with improved disease outcomes among colon cancer survivors. The aim of this report is to describe the purpose, study design, methods, and recruitment results of the COURAGE trial, a National Cancer Institute (NCI) sponsored, phase II, randomized, dose-response exercise trial among colon cancer survivors. Methods/Results The primary objective of the COURAGE trial is to quantify the feasibility, safety, and physiologic effects of low-dose (150 min·wk−1) and high-dose (300 min·wk−1) moderate-intensity aerobic exercise compared to usual-care control group over six months. The exercise groups are provided with in-home treadmills and heart rate monitors. Between January and July 2015, 1,433 letters were mailed using a population-based state cancer registry; 126 colon cancer survivors inquired about participation, and 39 were randomized onto the study protocol. Age was associated with inquiry about study participation (P<0.001) and randomization onto the study protocol (P<0.001). No other demographic, clinical, or geographic characteristics were associated with study inquiry or randomization. The final trial participant was randomized in August 2015. Six month endpoint data collection was completed in February 2016. Discussion The recruitment of colon cancer survivors into an exercise trial is feasible. The findings from this trial will inform key design aspects for future phase 2 and phase 3 randomized controlled trials to examine the efficacy of exercise to improve clinical outcomes among colon cancer survivors. PMID:26970181

Systematic review with dose-response meta-analyses between vitamin B-12 intake and European Micronutrient Recommendations Aligned's prioritized biomarkers of vitamin B-12 including randomized controlled trials and observational studies in adults and elderly persons.

PubMed

Dullemeijer, Carla; Souverein, Olga W; Doets, Esmée L; van der Voet, Hilko; van Wijngaarden, Janneke P; de Boer, Waldo J; Plada, Maria; Dhonukshe-Rutten, Rosalie A M; In 't Veld, Paulette H; Cavelaars, Adrienne E J M; de Groot, Lisette C P G M; van 't Veer, Pieter

2013-02-01

Many randomized controlled trials (RCTs) and observational studies have provided information on the association between vitamin B-12 intake and biomarkers. The use of these data to estimate dose-response relations provides a useful means to summarize the body of evidence. We systematically reviewed studies that investigated vitamin B-12 intake and biomarkers of vitamin B-12 status and estimated dose-response relations with the use of a meta-analysis. This systematic review included all RCTs, prospective cohort studies, nested case-control studies, and cross-sectional studies in healthy adult populations published through January 2010 that supplied or measured dietary vitamin B-12 intake and measured vitamin B-12 status as serum or plasma vitamin B-12, methylmalonic acid (MMA), or holotranscobalamin. We calculated an intake-status regression coefficient ( ) for each individual study and calculated the overall pooled and SE ( ) by using random-effects meta-analysis on a double-log scale. The meta-analysis of observational studies showed a weaker slope of dose-response relations than the meta-analysis of RCTs. The pooled dose-response relation of all studies between vitamin B-12 intake and status indicated that a doubling of the vitamin B-12 intake increased vitamin B-12 concentrations by 11% (95% CI: 9.4%, 12.5%). This increase was larger for studies in elderly persons (13%) than in studies in adults (8%). The dose-response relation between vitamin B-12 intake and MMA concentrations indicated a decrease in MMA of 7% (95% CI: -10%, -4%) for every doubling of the vitamin B-12 intake. The assessment of risk of bias within individual studies and across studies indicated risk that was unlikely to seriously alter these results. The obtained dose-response estimate between vitamin B-12 intake and status provides complementary evidence to underpin recommendations for a vitamin B-12 intake of populations.

Regulatory Forum Opinion Piece*: Retrospective Evaluation of Doses in the 26-week Tg.rasH2 Mice Carcinogenicity Studies: Recommendation to Eliminate High Doses at Maximum Tolerated Dose in Future Studies. A Response to the Counterpoints.

PubMed

Paranjpe, Madhav G; Denton, Melissa D; Vidmar, Tom J; Elbekai, Reem H

2016-01-01

We recently conducted a retrospective analysis of data collected from 29 Tg.rasH2 carcinogenicity studies conducted at our facility to determine how successful was the strategy of choosing the high dose of the 26-week studies based on an estimated maximum tolerated dose (MTD). As a result of our publication, 2 counterviews were expressed. Both counterviews illustrate very valid points in their interpretation of our data. In this article, we would like to highlight clarifications based on several points and issues they have raised in their papers, namely, the dose-level selection, determining if MTD was exceeded in 26-week studies, and a discussion on the number of dose groups to be used in the studies. © The Author(s) 2015.

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

PubMed Central

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-01-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID:26038704

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa.

PubMed

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-03-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.

Assessment of Ablative Therapies in Swine: Response of Respiratory Diaphragm to Varying Doses.

PubMed

Singal, Ashish; Mattison, Lars M; Soule, Charles L; Ballard, John R; Rudie, Eric N; Cressman, Erik N K; Iaizzo, Paul A

2018-03-28

Ablation is a common procedure for treating patients with cancer, cardiac arrhythmia, and other conditions, yet it can cause collateral injury to the respiratory diaphragm. Collateral injury can alter the diaphragm's properties and/or lead to respiratory dysfunction. Thus, it is important to understand the diaphragm's physiologic and biomechanical properties in response to ablation therapies, in order to better understand ablative modalities, minimize complications, and maximize the safety and efficacy of ablative procedures. In this study, we analyzed physiologic and biomechanical properties of swine respiratory diaphragm muscle bundles when exposed to 5 ablative modalities. To assess physiologic properties, we performed in vitro tissue bath studies and measured changes in peak force and baseline force. To assess biomechanical properties, we performed uniaxial stress tests, measuring force-displacement responses, stress-strain characteristics, and avulsion forces. After treating the muscle bundles with all 5 ablative modalities, we observed dose-dependent sustained reductions in peak force and transient increases in baseline force-but no consistent dose-dependent biomechanical responses. These data provide novel insights into the effects of various ablative modalities on the respiratory diaphragm, insights that could enable improvements in ablative techniques and therapies.

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

PubMed

Cox, Louis Anthony Tony

2018-06-19

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

RISK ASSESSMENT FOR CRYPTOSPORIDIUM: A HIERARCHICAL BAYESIAN ANALYSIS OF HUMAN DOSE-RESPONSE DATA. (R829180)

EPA Science Inventory

Three dose–response studies were conducted with healthy volunteers using different Cryptosporidium parvum isolates (IOWA, TAMU, and UCP). The study data were previously analyzed for median infectious dose (ID₅₀) using a simple cumulative percent endpoi...

Dose-response studies of intracerebroventricular infusion of aldosterone in sensitized and non-sensitized rats.

PubMed

Gomez Sanchez, E P

1988-06-01

We have shown previously that the intracerebroventricular (icvt) infusion of 5 ng/h aldosterone (ALD) in the sensitized rat (one kidney removed, 1% NaCl plus 0.15% KCl solution to drink) produced hypertension similar in amplitude and time of onset to a 100-fold dose administered subcutaneously (s.c.), while a 5-ng/h subcutaneous infusion had no effect on blood pressure (BP). Dose-response studies on the icvt infusion of ALD were carried out in sensitized and non-sensitized (intact, with tap water to drink) male Sprague-Dawley rats (SDR). In both studies, a control group received the diluent, artificial cerebrospinal fluid (CSF), icvt. In sensitized rats, the pressures became significantly (P less than 0.05) elevated at day 7 in those receiving 15 ng/h icvt, day 11 in those receiving 5 ng/h icvt and 500 ng/h s.c. and day 18 in those receiving 1.5 ng/h icvt. The indirect systolic BPs at day 20 of infusion were 119 +/- 0.8 (s.e.) mmHg for controls, 182 +/- 5 for 15 ng/h icvt, 140 +/- 2 mmHg for 5 ng/h icvt, 131 +/- 1 mmHg for 1.5 ng/h icvt, 125 +/- 1 mmHg for 0.5 ng/h, and 159 +/- 5 mmHg for 500 ng/h s.c. Recovery (removal of pumps and return to water to drink) for 18 days resulted in the return of normal pressures in all groups except the 15 ng/h, icvt group in which pressures remained slightly, but significantly elevated at 127 +/- 3 mmHg. In non-sensitized rats, the pressures became significantly elevated in animals receiving 45 ng/h icvt and 1 microgram/h s.c. by day 14.(ABSTRACT TRUNCATED AT 250 WORDS)

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...

Dosing study of massage for chronic neck pain: protocol for the dose response evaluation and analysis of massage [DREAM] trial

PubMed Central

2012-01-01

Background Despite the growing popularity of massage, its effectiveness for treating neck pain remains unclear, largely because of the poor quality of research. A major deficiency of previous studies has been their use of low “doses” of massage that massage therapists consider inadequate. Unfortunately, the number of minutes per massage session, sessions per week, or weeks of treatment necessary for massage to have beneficial or optimal effects are not known. This study is designed to address these gaps in our knowledge by determining, for persons with chronic neck pain: 1) the optimal combination of number of treatments per week and length of individual treatment session, and 2) the optimal number of weeks of treatment. Methods/design In this study, 228 persons with chronic non-specific neck pain will be recruited from primary health care clinics in a large health care system in the Seattle area. Participants will be randomized to a wait list control group or 4 weeks of treatment with one of 5 different dosing combinations (2 or 3 30-min treatments per week or 1, 2, or 3 60-min treatments per week). At the end of this 4-week primary treatment period, participants initially receiving each of the 5 dosing combinations will be randomized to a secondary treatment period of either no additional treatment or 6 weekly 60-min massages. The primary outcomes, neck-related dysfunction and pain, will be assessed by blinded telephone interviewers 5, 12, and 26 weeks post-randomization. To better characterize the trajectory of treatment effects, these interview data will be supplemented with outcomes data collected by internet questionnaire at 10, 16, 20 and 39 weeks. Comparisons of outcomes for the 6 groups during the primary treatment period will identify the optimal weekly dose, while comparisons of outcomes during the secondary treatment period will determine if 10 weeks of treatment is superior to 4 weeks. Discussion A broad dosing schedule was included in this trial

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.

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.

Poor Immune Responses to a Birth Dose of Diphtheria, Tetanus, and Acellular Pertussis Vaccine

PubMed Central

Halasa, Natasha B.; O’Shea, Alice; Shi, Jian R.; Lafleur, Bonnie J.; Edwards, Kathryn M.

2013-01-01

Objectives To evaluate the safety and immunogenicity of an additional birth dose of diphtheria, tetanus, and acellular pertussis vaccine (DTaP). Study design Fifty infants between 2 to 14 days of age were randomly assigned to receive either DTaP and hepatitis B vaccines (experimental) or hepatitis B alone (control) at birth. At 2, 4, 6, and 17 months of age, DTaP and routine vaccines were administered to both groups. Safety data were collected after each dose, and sera were obtained at birth, 6, 7, 17, and 18 months. Immune responses to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae were measured by enzyme-linked immunosorbent assay; responses to other vaccines were assessed. Results No differences were seen between the 2 groups in either local or systemic reactions; all vaccines were well tolerated. Compared with the control group, infants in the experimental group demonstrated significantly lower geometric mean antibody concentrations for pertussis toxin and pertactin 6, 7, and 18 months, for fimbrae at 6, 7, 17, and 18 months, and for FHA at 18 months, and lower geometric mean antibody concentrations for diphtheria at 7 months. Immune responses to all other vaccine antigens were comparable. Conclusion Administration of an additional dose of DTaP at birth was safe but was associated with a significantly lower response to diphtheria and 3 of 4 pertussis antigens compared with controls. PMID:18534242

A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

NASA Astrophysics Data System (ADS)

Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

2016-02-01

Purpose: Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a ;priming; dose of protons on the cardiac cellular and molecular response to a ;challenge; dose of 56Fe in a mouse model. Methods: Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results: Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions: This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions.

A priming dose of protons alters the early cardiac cellular and molecular response to (56)Fe irradiation.

PubMed

Ramadan, Samy S; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R; Hauer-Jensen, Martin; Nelson, Gregory A; Boerma, Marjan

2016-02-01

Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a "priming" dose of protons on the cardiac cellular and molecular response to a "challenge" dose of (56)Fe in a mouse model. Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of (56)Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of (56)Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Exposure to (56)Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before (56)Fe prevented all of the responses to (56)Fe. This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. Copyright © 2015 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

A priming dose of protons alters the early cardiac cellular and molecular response to 56Fe irradiation

PubMed Central

Ramadan, Samy S.; Sridharan, Vijayalakshmi; Koturbash, Igor; Miousse, Isabelle R.; Hauer-Jensen, Martin; Nelson, Gregory A.; Boerma, Marjan

2015-01-01

Purpose Recent evidence suggests that the heart may be injured by ionizing radiation at lower doses than was previously thought. This raises concerns about the cardiovascular risks from exposure to radiation during space travel. Since space travel is associated with exposure to both protons from solar particle events and heavy ions from galactic cosmic rays, we here examined the effects of a “priming” dose of protons on the cardiac cellular and molecular response to a “challenge” dose of 56Fe in a mouse model. Methods Male C57BL/6 mice at 10 weeks of age were exposed to sham-irradiation, 0.1 Gy of protons (150 MeV), 0.5 Gy of 56Fe (600 MeV/n), or 0.1 Gy of protons 24 hours prior to 0.5 Gy of 56Fe. Hearts were obtained at 7 days post-irradiation and western-blots were used to determine protein markers of cardiac remodeling, inflammatory infiltration, and cell death. Results Exposure to 56Fe caused an increase in expression of α-smooth muscle cell actin, collagen type III, the inflammatory cell markers mast cell tryptase, CD2 and CD68, the endothelial glycoprotein thrombomodulin, and cleaved caspase 3. Of all proteins investigated, protons at a dose of 0.1 Gy induced a small increase only in cleaved caspase 3 levels. On the other hand, exposure to protons 24 hours before 56Fe prevented all of the responses to 56Fe. Conclusions This study shows that a low dose of protons may prime the heart to respond differently to a subsequent challenge dose of heavy ions. Further investigation is required to identify responses at additional time points, consequences for cardiac function, threshold dose levels, and mechanisms by which a proton priming dose may alter the response to heavy ions. PMID:26948008

Feasibility study on inverse four-dimensional dose reconstruction using the continuous dose-image of EPID

PubMed Central

Yeo, Inhwan Jason; Jung, Jae Won; Yi, Byong Yong; Kim, Jong Oh

2013-01-01

Purpose: When an intensity-modulated radiation beam is delivered to a moving target, the interplay effect between dynamic beam delivery and the target motion due to miss-synchronization can cause unpredictable dose delivery. The portal dose image in electronic portal imaging device (EPID) represents radiation attenuated and scattered through target media. Thus, it may possess information about delivered radiation to the target. Using a continuous scan (cine) mode of EPID, which provides temporal dose images related to target and beam movements, the authors’ goal is to perform four-dimensional (4D) dose reconstruction. Methods: To evaluate this hypothesis, first, the authors have derived and subsequently validated a fast method of dose reconstruction based on virtual beamlet calculations of dose responses using a test intensity-modulated beam. This method was necessary for processing a large number of EPID images pertinent for four-dimensional reconstruction. Second, cine mode acquisition after summation over all images was validated through comparison with integration mode acquisition on EPID (IAS3 and aS1000) for the test beam. This was to confirm the agreement of the cine mode with the integrated mode, specifically for the test beam, which is an accepted mode of image acquisition for dosimetry with EPID. Third, in-phantom film and exit EPID dosimetry was performed on a moving platform using the same beam. Heterogeneous as well as homogeneous phantoms were used. The cine images were temporally sorted at 10% interval. The authors have performed dose reconstruction to the in-phantom plane from the sorted cine images using the above validated method of dose reconstruction. The reconstructed dose from each cine image was summed to compose a total reconstructed dose from the test beam delivery, and was compared with film measurements. Results: The new method of dose reconstruction was validated showing greater than 95.3% pass rates of the gamma test with the criteria

A dose-response study of dexmedetomidine administered as the primary sedative in infants following open heart surgery.

PubMed

Su, Felice; Nicolson, Susan C; Zuppa, Athena F

2013-06-01

To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease postoperative from open heart surgery. Prospective open-label dose-escalation pharmacokinetic-pharmacodynamic study. Tertiary pediatric cardiac ICU. Thirty-six evaluable infants, 1-24 months old, postoperative from open heart surgery requiring mechanical ventilation. Cohorts of 12 infants were enrolled sequentially to one of the three IV loading doses of dexmedetomidine (0.35, 0.7, and 1 mcg/kg) over 10 minutes followed by respective continuous infusions (0.25, 0.5, and 0.75 mcg/kg/hr) for up to 24 hours. Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function, and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs 1) despite requiring minimal supplemental sedation (0 unit doses/hr) and fewer analgesic medications (0.07 vs 0.15 unit doses/hr) while receiving dexmedetomidine compared with the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion. Only one patient remained intubated due to oversedation during the infusion. While receiving dexmedetomidine, there was a decrease in heart rate compared with baseline, 132 versus 161 bpm, but there was an increase in heart rate compared with postinfusion values, 132 versus 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure. Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements, leading to successful extubation while receiving a continuous infusion. The postoperative hemodynamic changes that occur in

Dose-specific transcriptional responses in thyroid tissue in mice after (131)I administration.

PubMed

Rudqvist, Nils; Schüler, Emil; Parris, Toshima Z; Langen, Britta; Helou, Khalil; Forssell-Aronsson, Eva

2015-03-01

In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after (131)I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with (131)I exposure in normal mouse thyroid tissue and 2) propose biomarkers for (131)I exposure of the thyroid. Adult BALB/c nude mice were i.v. injected with 13, 130 or 260 kBq of (131)I and killed 24h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17 Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. In total, 497, 546, and 90 transcripts were regulated (fold change ≥1.5) in the thyroid after 0.85, 8.5, and 17 Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9, Plau, Prf1, and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9, Plau, Prf1, and S100a8 genes might be novel potential absorbed dose-related biomarkers to (131)I exposure of thyroid. During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low, intermediate, and high absorbed doses from (131)I exposure in vivo

Antipsychotic dose modulates behavioral and neural responses to feedback during reinforcement learning in schizophrenia.

PubMed

Insel, Catherine; Reinen, Jenna; Weber, Jochen; Wager, Tor D; Jarskog, L Fredrik; Shohamy, Daphna; Smith, Edward E

2014-03-01

Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.

Enhanced stereotyped response to amphetamine after pretreatment with small doses of molindone.

PubMed

Conway, P; Uretsky, N J

1983-05-01

Pretreatment of rats with small doses of the antipsychotic drug, molindone, enhanced the stereotyped behavioral response to amphetamine. In order to determine whether molindone enhanced amphetamine-induced stereotypy by the same mechanism as chronic administration of amphetamine or drugs that inhibit central noradrenergic transmission, the effect of these drugs on the stereotyped behavior produced by beta-phenethylamine (PEA) was compared. Following the administration of phenoxybenzamine, reserpine and diethyldithiocarbamate, the stereotyped response produced by beta-phenethylamine was intensified. In contrast, neither molindone nor chronic pretreatment with amphetamine altered beta-phenethylamine-induced stereotypy. As shown previously with chronic amphetamine pretreatment, molindone also failed to enhance the stereotyped response produced by apomorphine. However, in contrast to the effects of chronic administration of amphetamine, molindone both increased the striatal concentration of dihydroxyphenylacetic acid (DOPAC) and blocked the ability of small doses of apomorphine to decrease this dopamine (DA) metabolite. The doses of molindone that blocked the apomorphine-induced reduction in the concentration of DOPAC in the striatum correlated with the doses that enhanced amphetamine-induced stereotypy. Since the decrease in DOPAC in the striatum produced by apomorphine is thought to be mediated through the stimulation of striatal DA autoreceptors, these results suggest that molindone enhances amphetamine-induced stereotypy by selectively inhibiting DA autoreceptors.

Persistence of antibody to hepatitis B surface antigen after low-dose, intradermal hepatitis B immunization and response to a booster dose.

PubMed

Bryan, J P; Sjogren, M H; Macarthy, P; Cox, E; Legters, L J; Perine, P L

1992-01-01

To determine the duration of antibody after low-dose, intradermal (i.d.), plasma-derived hepatitis B vaccination and the response to a booster dose, we studied two classes of medical students who were immunized with 2 micrograms doses i.d. In one class, 73/88 (85%) who had been immunized by skilled personnel at 0, 1 and 6 months, had protective concentrations (greater than or equal to 10 mIU ml-1) of anti-HBs at 20 months after the first dose. Twelve (92%) out of 13 students who received only two doses at 0 and 1 months also had protective concentrations at month 20. At month 27, 11/16 (69%) with antibody less than or equal to 10 mIU ml-1 responded to a fourth dose of 2 micrograms i.d. with protective concentrations of anti-HBs. In the second class, after three doses of vaccine at 0, 1, and 6 months, protective concentrations of anti-HBs were present in 90/93 (97%) at 14 months and in 71/80 (89%) at 25 months. In those who received only two doses, protective concentrations were found in 24/31 (74%) at 14 months and 9/16 (56%) at 25 months. After a booster dose of 2 micrograms i.d. at month 25, anti-HBs concentrations rose from a geometric mean of 78 to 1198 mIU ml-1 in 60 subjects previously immunized with three doses and from 18 to 1054 mIU ml-1 in 16 students previously immunized with only two doses. Overall, 73/76 (96%) of students in the second group had protective concentrations of antibody after the booster dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: a dose escalation and pharmacologic study.

PubMed

Phuphanich, Surasak; Baker, Sharyn D; Grossman, Stuart A; Carson, Kathryn A; Gilbert, Mark R; Fisher, Joy D; Carducci, Michael A

2005-04-01

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 muM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

Response-adapted treatment with upfront high-dose chemotherapy followed by autologous stem-cell transplantation rescue or consolidation phase high-dose methotrexate for primary central nervous system lymphoma: a long-term mono-center study.

PubMed

Nakasu, Yoko; Mitsuya, Koichi; Hayashi, Nakamasa; Okamura, Ikue; Mori, Keita; Enami, Terukazu; Tatara, Raine; Nakasu, Satoshi; Ikeda, Takashi

2016-01-01

Treatment regimens for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based chemotherapy, with or without radiotherapy and are based on studies of selected patient groups. This retrospective study assessed a consistent strategy of response-adapted protocol applied for patients including age >65 years in a cancer center for 10 years longitudinally. Case notes were studied of 61 consecutively treated patients with PCNSL histologically diagnosed between 2003 and 2013. Clinical follow-up during and after treatment included neurologic examination and magnetic resonance imaging. Of the patients studied, 14.8 % (9/61) were clinically unfit for chemotherapy; the remaining 85.2 % (52/61) of patients were treated with HD-MTX. Of these patients, 58 % (30/52) achieved an initial complete response, with a median survival of 100.1 months. Of these response-adapted patients, 33 % (10/30) were <65 years and were treated with upfront high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT). The remaining response-adapted patients included 53 % (16/30) who were ≥65 years underwent consolidation with HD-MTX, and 14 % (4/30) who chose radiotherapy. The median survival of patients with HDC-ASCT had not yet been reached compared with 67.6 months for patients with HD-MTX consolidation treatment (p = 0.26). At the end of the study, 75 % (39/52) of patients had died mainly owing to progression or relapse of PCNSL. Multivariate analysis showed that age younger than 65 years (p = 0.02) and complete response for up-front HD-MTX (p = 0.001) were independent prognostic indicators of overall survival. In conclusion, this single-center retrospective clinical study has shown that treatment of PCNSL with upfront HDC-ASCT and consolidation phase HD-MTX monotherapy may be feasible, even for elderly patients in a routine clinical setting, using the three-step selection by eligibility and response to initial HD-MTX, and

QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single-Hit Dose-Response Models.

PubMed

Nilsen, Vegard; Wyller, John

2016-01-01

Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson-distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional "single-hit" dose-response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose-response models in terms of probability generating functions. It is shown formally that the theoretical single-hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single-hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single-hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose-response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose-response assessment as well as practical risk characterization are discussed. © 2016 Society for Risk Analysis.

Dose- and Time-Dependent Transcriptional Response of Ishikawa Cells Exposed to Genistein

PubMed Central

Naciff, Jorge M.; Khambatta, Zubin S.; Carr, Gregory J.; Tiesman, Jay P.; Singleton, David W.; Khan, Sohaib A.; Daston, George P.

2016-01-01

To further define the utility of the Ishikawa cells as a reliable in vitro model to determine the potential estrogenic activity of chemicals of interest, transcriptional changes induced by genistein (GES) in Ishikawa cells at various doses (10 pM, 1 nM, 100 nM, and 10 μM) and time points (8, 24, and 48 h) were identified using a comprehensive microarray approach. Trend analysis indicated that the expression of 5342 unique genes was modified by GES in a dose- and time-dependent manner (P ≤ 0.0001). However, the majority of gene expression changes induced in Ishikawa cells were elicited by the highest dose of GES evaluated (10 μM). The GES’ estrogenic activity was identified by comparing the Ishikawa cells’ response to GES versus 17 α-ethynyl estradiol (EE, at equipotent doses, ie, 10 μM vs 1 μM, respectively) and was defined by changes in the expression of 284 unique genes elicited by GES and EE in the same direction, although the magnitude of the change for some genes was different. Further, comparing the response of the Ishikawa cells exposed to high doses of GES and EE versus the response of the juvenile rat uterus exposed to EE, we identified 66 unique genes which were up- or down regulated in a similar manner in vivo as well as in vitro. Genistein elicits changes in multiple molecular pathways affecting various biological processes particularly associated with cell organization and biogenesis, regulation of translation, cell proliferation, and intracellular transport; processes also affected by estrogen exposure in the uterus of the rat. These results indicate that Ishikawa cells are capable of generating a biologically relevant estrogenic response and offer an in vitro model to assess this mode of action. PMID:26865667

Effect of increased CRM₁₉₇ carrier protein dose on meningococcal C bactericidal antibody response.

PubMed

Lee, Lucia H; Blake, Milan S

2012-04-01

New multivalent CRM(197)-based conjugate vaccines are available for childhood immunization. Clinical studies were reviewed to assess meningococcal group C (MenC) antibody responses following MenC-CRM(197) coadministration with CRM(197)-based pneumococcal or Haemophilus influenzae type b conjugate vaccines. Infants receiving a total CRM(197) carrier protein dose of ∼50 μg and concomitant diphtheria-tetanus-acellular pertussis (DTaP)-containing vaccine tended to have lower MenC geometric mean antibody titers and continued to have low titers after the toddler dose. Nevertheless, at least 95% of children in the reported studies achieved a MenC serum bactericidal antibody (SBA) titer of ≥ 1:8 after the last infant or toddler dose. SBA was measured using an assay with a baby rabbit or human complement source. Additional studies are needed to assess long-term antibody persistence and MenC CRM(197) conjugate vaccine immunogenicity using alternative dosing schedules.

Dose-response relationships using brain–computer interface technology impact stroke rehabilitation

PubMed Central

Young, Brittany M.; Nigogosyan, Zack; Walton, Léo M.; Remsik, Alexander; Song, Jie; Nair, Veena A.; Tyler, Mitchell E.; Edwards, Dorothy F.; Caldera, Kristin; Sattin, Justin A.; Williams, Justin C.; Prabhakaran, Vivek

2015-01-01

Brain–computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 < p < 0.1) negative correlations with LI changes, while therapy frequency did not affect LI. Reductions in LI were then correlated (p ≤ 0.05) with increased SIS Activities of Daily Living scores and improved 9-HPT performance. Therefore, some behavioral changes may be reflected by brain changes sensitive to differences in BCI therapy administration, while others such as SIS Strength may be directly responsive to BCI therapy administration. Data preliminarily suggest that when using BCI in stroke rehabilitation, therapy frequency may be less important than dose

SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

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

Dean, J; Welsh, L; Gulliford, S

Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receivingmore » radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% – 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for

[Occlusion treatment for amblyopia. Age dependence and dose-response relationship].

PubMed

Fronius, M

2016-04-01

Based on clinical experience and studies on animal models the age of 6-7 years was regarded as the limit for treatment of amblyopia, although functional improvement was also occasionally reported in older patients. New technical developments as well as insights from clinical studies and the neurosciences have attracted considerable attention to this topic. Various aspects of the age dependence of amblyopia treatment are discussed in this article, e. g. prescription, electronic monitoring of occlusion dosage, calculation of indicators for age-dependent plasticity of the visual system, and novel, alternative treatment approaches. Besides a discussion of the recent literature, results of studies by our "Child Vision Research Unit" in Frankfurt are presented: results of a questionnaire about prescription habits concerning age limits of patching, electronic recording of occlusion in patients beyond the conventional treatment age, calculation of dose-response function and efficiency of patching and their age dependence. The results of the questionnaire illustrate the uncertainty about age limits of prescription with significant deviations from the guideline of the German Ophthalmological Society (DOG). Electronic recording of occlusion allowed the quantification of declining dose-response function and treatment efficiency between 5 and 16 years of age. Reports about successful treatment with conventional and novel methods in adults are at variance with the notion of a rigid adult visual system lacking plasticity. Electronic recording of patching allowed new insights into the age-dependent susceptibility of the visual system and contributes to a more evidence-based treatment of amblyopia. Alternative approaches for adults challenge established notions about age limits of amblyopia therapy. Further studies comparing different treatment options are urgently needed.

Dose-Response Issues Concerning the Relations between Regular Physical Activity and Health.

ERIC Educational Resources Information Center

Rankinen, Tuomo; Bouchard, Claude

2002-01-01

This paper categorizes the many benefits of physical activity, offering information concerning the type of dose necessary to get that benefit. In 2000, Health Canada and the United States Centers for Disease Control and Prevention, along with other agencies, sponsored a symposium to determine whether there was a dose-response relationship between…

Uncertainty of fast biological radiation dose assessment for emergency response scenarios.

PubMed

Ainsbury, Elizabeth A; Higueras, Manuel; Puig, Pedro; Einbeck, Jochen; Samaga, Daniel; Barquinero, Joan Francesc; Barrios, Lleonard; Brzozowska, Beata; Fattibene, Paola; Gregoire, Eric; Jaworska, Alicja; Lloyd, David; Oestreicher, Ursula; Romm, Horst; Rothkamm, Kai; Roy, Laurence; Sommer, Sylwester; Terzoudi, Georgia; Thierens, Hubert; Trompier, Francois; Vral, Anne; Woda, Clemens

2017-01-01

Reliable dose estimation is an important factor in appropriate dosimetric triage categorization of exposed individuals to support radiation emergency response. Following work done under the EU FP7 MULTIBIODOSE and RENEB projects, formal methods for defining uncertainties on biological dose estimates are compared using simulated and real data from recent exercises. The results demonstrate that a Bayesian method of uncertainty assessment is the most appropriate, even in the absence of detailed prior information. The relative accuracy and relevance of techniques for calculating uncertainty and combining assay results to produce single dose and uncertainty estimates is further discussed. Finally, it is demonstrated that whatever uncertainty estimation method is employed, ignoring the uncertainty on fast dose assessments can have an important impact on rapid biodosimetric categorization.

Maternal dietary nitrate intake and risk of neural tube defects: A systematic review and dose-response meta-analysis.

PubMed

Kakavandi, Nader Rahimi; Hasanvand, Amin; Ghazi-Khansari, Mahmoud; Sezavar, Ahmad Habibian; Nabizadeh, Hassan; Parohan, Mohammad

2018-05-12

Despite growing evidence for the potential teratogenicity of nitrate, knowledge about the dose-response relationship of dietary nitrate intake and risk of specific birth defects such as neural tube defects (NTDs) is limited. Therefore, the aim of this meta-analysis was to synthesize the knowledge about the dose-response relation between maternal dietary nitrate intake and the risk of NTDs. We conducted a systematic search in PubMed, ISI Web of Science and Scopus up to February 2018 for observational studies. Risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated using a random-effects model for highest versus lowest intake categories. The linear and non-linear relationships between nitrate intake and risk of NTDs were also investigated. Overall, 5 studies were included in the meta-analyses. No association was observed between nitrate intake and NTDs risk in high versus low intake (RR: 1.33; 95% CI: 0.89-1.99, p = 0.158) and linear dose-response (RR: 1.03; 95% CI: 0.99-1.07, p = 0.141) meta-analysis. However, there were positive relationships between nitrate intake and risk of NTDs in non-linear (p non-linearity <0.05) model. Findings from this dose-response meta-analysis indicate that maternal nitrate intake higher than ∼3 mg/day is positively associated with NTDs risk. Copyright © 2018 Elsevier Ltd. All rights reserved.

Dose-Response Relationship between Radiation Dose and Loco-regional Control in Patients with Stage II-III Esophageal Cancer Treated with Definitive Chemoradiotherapy.

PubMed

Kim, Hyun Ju; Suh, Yang-Gun; Lee, Yong Chan; Lee, Sang Kil; Shin, Sung Kwan; Cho, Byung Chul; Lee, Chang Geol

2017-07-01

The correlation between radiation dose and loco-regional control (LRC) was evaluated in patients with stage II-III esophageal cancer treated with definitive concurrent chemoradiotherapy (CRT). Medical records of 236 stage II-III esophageal cancer patients treated with definitive CRT at Yonsei Cancer Center between 1994 and 2013 were retrospectively reviewed. Among these, 120 received a radiation dose of < 60 Gy (standard-dose group), while 116 received ≥ 60 Gy (high-dose group). The median doses of radiation in the standard- and high-dose groups were 50.4 and 63 Gy, respectively. Concurrent 5-fluorouracil/cisplatin chemotherapy was administered to most patients. There were no differences in patient characteristics between the two groups except for high Karnofsky performance status and lower-thoracic lesions being more prevalent in the standard-dose group. The median progression-free survival (PFS) and overall survival (OS) times were 13.2 months and 26.2 months, respectively. Patients in the high-dose group had significantly better 2-year LRC (69.1% vs. 50.3%, p=0.002), median PFS (16.7 months vs. 11.7 months, p=0.029), and median OS (35.1 months vs. 22.3 months, p=0.043). Additionally, LRC exhibited a dose-response relationship and the complete response rate was significantly higher in the high-dose group (p=0.006). There were no significant differences in treatment-related toxicities between the groups. A higher radiation dose (> 60 Gy) is associated with increased LRC, PFS, and OS in patients with stage II-III esophageal cancer treated with definitive CRT.

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

EPA Science Inventory

Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? Leon Earl Gray Jr, USEPA, ORD, NHEERL, TAD, RTB. RTP, NC, USA The shape of the dose response curve in the low dose region has been debated since th...

Dose-dependent response of Trichoderma harzianum in improving drought tolerance in rice genotypes.

PubMed

Pandey, Veena; Ansari, Mohammad W; Tula, Suresh; Yadav, Sandep; Sahoo, Ranjan K; Shukla, Nandini; Bains, Gurdeep; Badal, Shail; Chandra, Subhash; Gaur, A K; Kumar, Atul; Shukla, Alok; Kumar, J; Tuteja, Narendra

2016-05-01

This study demonstrates a dose-dependent response of Trichoderma harzianum Th-56 in improving drought tolerance in rice by modulating proline, SOD, lipid peroxidation product and DHN / AQU transcript level, and the growth attributes. In the present study, the effect of colonization of different doses of T. harzianum Th-56 strain in rice genotypes were evaluated under drought stress. The rice genotypes treated with increasing dose of T. harzianum strain Th-56 showed better drought tolerance as compared with untreated control plant. There was significant change in malondialdehyde, proline, higher superoxide dismutase level, plant height, total dry matter, relative chlorophyll content, leaf rolling, leaf tip burn, and the number of scorched/senesced leaves in T. harzianum Th-56 treated rice genotypes under drought stress. This was corroborated with altered expression of aquaporin and dehydrin genes in T. harzianum Th-56 treated rice genotypes. The present findings suggest that a dose of 30 g/L was the most effective in improving drought tolerance in rice, and its potential exploitation will contribute to the advancement of rice genotypes to sustain crop productivity under drought stress. Interaction studies of T. harzianum with three aromatic rice genotypes suggested that PSD-17 was highly benefitted from T. harzianum colonization under drought stress.

Bayesian dose selection design for a binary outcome using restricted response adaptive randomization.

PubMed

Meinzer, Caitlyn; Martin, Renee; Suarez, Jose I

2017-09-08

In phase II trials, the most efficacious dose is usually not known. Moreover, given limited resources, it is difficult to robustly identify a dose while also testing for a signal of efficacy that would support a phase III trial. Recent designs have sought to be more efficient by exploring multiple doses through the use of adaptive strategies. However, the added flexibility may potentially increase the risk of making incorrect assumptions and reduce the total amount of information available across the dose range as a function of imbalanced sample size. To balance these challenges, a novel placebo-controlled design is presented in which a restricted Bayesian response adaptive randomization (RAR) is used to allocate a majority of subjects to the optimal dose of active drug, defined as the dose with the lowest probability of poor outcome. However, the allocation between subjects who receive active drug or placebo is held constant to retain the maximum possible power for a hypothesis test of overall efficacy comparing the optimal dose to placebo. The design properties and optimization of the design are presented in the context of a phase II trial for subarachnoid hemorrhage. For a fixed total sample size, a trade-off exists between the ability to select the optimal dose and the probability of rejecting the null hypothesis. This relationship is modified by the allocation ratio between active and control subjects, the choice of RAR algorithm, and the number of subjects allocated to an initial fixed allocation period. While a responsive RAR algorithm improves the ability to select the correct dose, there is an increased risk of assigning more subjects to a worse arm as a function of ephemeral trends in the data. A subarachnoid treatment trial is used to illustrate how this design can be customized for specific objectives and available data. Bayesian adaptive designs are a flexible approach to addressing multiple questions surrounding the optimal dose for treatment efficacy