dose-response relation exist: Topics by Science.gov

Sample records for dose-response relation exist

The question of nonlinearity in the dose-response relation between particulate matter air pollution and mortality: can Akaike's Information Criterion be trusted to take the right turn?

PubMed

Roberts, Steven; Martin, Michael A

2006-12-15

The shape of the dose-response relation between particulate matter air pollution and mortality is crucial for public health assessment, and departures of this relation from linearity could have important regulatory consequences. A number of investigators have studied the shape of the particulate matter-mortality dose-response relation and concluded that the relation could be adequately described by a linear model. Some of these researchers examined the hypothesis of linearity by comparing Akaike's Information Criterion (AIC) values obtained under linear, piecewise linear, and spline alternative models. However, at the current time, the efficacy of the AIC in this context has not been assessed. The authors investigated AIC as a means of comparing competing dose-response models, using data from Cook County, Illinois, for the period 1987-2000. They found that if nonlinearities exist, the AIC is not always successful in detecting them. In a number of the scenarios considered, AIC was equivocal, picking the correct simulated dose-response model about half of the time. These findings suggest that further research into the shape of the dose-response relation using alternative model selection criteria may be warranted.
Evaluation and comparison of absorbed dose for electron beams by LiF and diamond dosimeters

NASA Astrophysics Data System (ADS)

Mosia, G. J.; Chamberlain, A. C.

2007-09-01

The absorbed dose response of LiF and diamond thermoluminescent dosimeters (TLDs), calibrated in 60Co γ-rays, has been determined using the MCNP4B Monte Carlo code system in mono-energetic megavoltage electron beams from 5 to 20 MeV. Evaluation of the dose responses was done against the dose responses of published works by other investigators. Dose responses of both dosimeters were compared to establish if any relation exists between them. The dosimeters were irradiated in a water phantom with the centre of their top surfaces (0.32×0.32 cm 2), placed at dmax perpendicular to the radiation beam on the central axis. For LiF TLD, dose responses ranged from 0.945±0.017 to 0.997±0.011. For the diamond TLD, the dose response ranged from 0.940±0.017 to 1.018±0.011. To correct for dose responses by both dosimeters, energy correction factors were generated from dose response results of both TLDs. For LiF TLD, these correction factors ranged from 1.003 up to 1.058 and for diamond TLD the factors ranged from 0.982 up to 1.064. The results show that diamond TLDs can be used in the place of the well-established LiF TLDs and that Monte Carlo code systems can be used in dose determinations for radiotherapy treatment planning.
Harderian Gland Tumorigenesis: Low-Dose and LET Response.

PubMed

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

2016-05-01

Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.
Harderian Gland Tumorigenesis: Low-Dose and LET Response

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

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

Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSvmore » are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ~70 keV/μm) and 1,000 MeV/u titanium (LET ~100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.« less
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.
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.
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 ...
A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

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

Houweling, Antonetta C., E-mail: A.Houweling@umcutrecht.n; Philippens, Marielle E.P.; Dijkema, Tim

2010-03-15

Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulatedmore » salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.« less
Dynamics of Cellular Responses to Radiation

PubMed Central

Wodarz, Dominik; Sorace, Ron; Komarova, Natalia L.

2014-01-01

Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed. PMID:24722167
Evaluation of a toxicogenomic approach to the local lymph node assay (LLNA).

PubMed

Boverhof, Darrell R; Gollapudi, B Bhaskar; Hotchkiss, Jon A; Osterloh-Quiroz, Mandy; Woolhiser, Michael R

2009-02-01

Genomic technologies have the potential to enhance and complement existing toxicology endpoints; however, assessment of these approaches requires a systematic evaluation including a robust experimental design with genomic endpoints anchored to traditional toxicology endpoints. The present study was conducted to assess the sensitivity of genomic responses when compared with the traditional local lymph node assay (LLNA) endpoint of lymph node cell proliferation and to evaluate the responses for their ability to provide insights into mode of action. Female BALB/c mice were treated with the sensitizer trimellitic anhydride (TMA), following the standard LLNA dosing regimen, at doses of 0.1, 1, or 10% and traditional tritiated thymidine ((3)HTdR) incorporation and gene expression responses were monitored in the auricular lymph nodes. Additional mice dosed with either vehicle or 10% TMA and sacrificed on day 4 or 10, were also included to examine temporal effects on gene expression. Analysis of (3)HTdR incorporation revealed TMA-induced stimulation indices of 2.8, 22.9, and 61.0 relative to vehicle with an EC(3) of 0.11%. Examination of the dose-response gene expression responses identified 9, 833, and 2122 differentially expressed genes relative to vehicle for the 0.1, 1, and 10% TMA dose groups, respectively. Calculation of EC(3) values for differentially expressed genes did not identify a response that was more sensitive than the (3)HTdR value, although a number of genes displayed comparable sensitivity. Examination of temporal responses revealed 1760, 1870, and 953 differentially expressed genes at the 4-, 6-, and 10-day time points respectively. Functional analysis revealed many responses displayed dose- and time-specific induction patterns within the functional categories of cellular proliferation and immune response, including numerous immunoglobin genes which were highly induced at the day 10 time point. Overall, these experiments have systematically illustrated the potential utility of genomic endpoints to enhance the LLNA and support further exploration of this approach through examination of a more diverse array of chemicals.
The Use of Mode of Action Information in Risk Assessment: Quantitative Key Events/Dose-Response Framework for Modeling the Dose-Response for Key Events

EPA Science Inventory

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Act...
Hazard identification, dose-response and environmental characteristics of stachybotryotoxins and other health-related products from Stachybotrys.

PubMed

Lai, K M

2006-03-01

An extensive growth of Stachybotrys in water-damaged buildings is of great public health concern. It is inconclusive whether Stachybotrys is responsible for the reported health effects on the occupants in these contaminated environments. However, based on the veterinary, occupational and laboratory toxicity studies, it is reasonable to project that Stachybotrys can cause adverse health responses once the toxic level of the corresponding agents reached the target systems. In order to assess the risk to occupants in contaminated buildings, it is essential to outline and collect information for risk assessment. This review paper presents the current information in the format of hazard identification, dose-response and environmental characteristics and aims to discuss existing information with researchers and risk assessors and help to conduct risk characterization under different indoor conditions.
WE-AB-207B-10: On Spinal Nerve Toxicity from Single-Session SAbR in Pigs and the Translation of Small Animal NTCP Models

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

Hrycushko, B; Medin, P

Purpose: The incidence of peripheral neuropathy has risen with increased utilization of SAbR. There is no consensus regarding the dose-tolerance of the peripheral nervous system. In 2015, we commenced an investigation to test the hypotheses that single-session irradiation to the pig spinal nerves exhibit a similar dose-tolerance as that of the spinal cord and that a dose-length effect exists. This work evaluates the direct application of small animal NTCP models to both large animal spinal cord and preliminary peripheral nerve data. Methods: To date, 16 of 25 Yucatan minipigs have received single-session SAbR to a 1.5cm length and 4 ofmore » 25 have received irradiation to a 0.5cm length of left-sided C6-C8 spinal nerves. Toxicity related gait change has been observed in 13 animals (9 from the long length group and 4 from the short). This preliminary data is overlaid on several dose-response models which have been fit to rodent spinal cord tolerance experiments. Model parameters define a toxicity profile between a completely serial or parallel behaving organ. Adequacy of model application, including how length effects are handled, to published minipig spinal cord dose-response data and to preliminary peripheral nerve response data was evaluated through residual analysis. Results: No rodent-derived dose-response models were directly applicable to all pig data for the different lengths irradiated. Several models fit the long-length irradiated spinal cord data well, with the more serial-like models fitting best. Preliminary data on the short-length irradiation suggests no length effect exists, disproving our hypothesis. Conclusion: Direct application of small-animal NTCP models to pig data suggests dose-length effect predictions from small animal data may not translate clinically. However, the small animal models used have not considered dose heterogeneity and it is expected that including the low-to-mid dose levels in the penumbral region will improve this match. This work was funded by the Cancer Prevention Research Institute of Texas (CPRIT).« less
DOE Office of Scientific and Technical Information (OSTI.GOV)

Walton, B.T.

A chemical impurity isolated from commercially purchased acridine causes cricket embryos to develop extra compound eyes, branched antennae, extra antennae, and extra heads. Purified acridine does not produce similar duplications of cricket heads or head structures nor do the substituted acridines proflavine, acriflavine, or acridine orange. A dose-response relation exists such that the number and severity of abnormalities increase with increasing concentration of the teratogen.
Effects of crystallization interfaces on irradiated ferroelectric thin films

NASA Astrophysics Data System (ADS)

Brewer, S. J.; Williams, S. C.; Cress, C. D.; Bassiri-Gharb, N.

2017-11-01

This work investigates the role of crystallization interfaces and chemical heterogeneity in the radiation tolerance of chemical solution-deposited lead zirconate titanate (PZT) thin films. Two sets of PZT thin films were fabricated with crystallization performed at (i) every deposited layer or (ii) every three layers. The films were exposed to a range of 60Co gamma radiation doses, between 0.2 and 20 Mrad, and their functional response was compared before and after irradiation. The observed trends indicate enhancements of dielectric, ferroelectric, and piezoelectric responses at low radiation doses and degradation of the same at higher doses. Response enhancements are expected to result from low-dose (≤2 Mrad), ionizing radiation-induced charging of internal interfaces—an effect that results in neutralization of pre-existing internal bias in the samples. At higher radiation doses (>2 Mrad), accumulation and self-ordering of radiation-modified, mobile, oxygen vacancy-related defects contribute to degradation of dielectric, ferroelectric, and piezoelectric properties, exacerbated in the samples with more crystallization layers, potentially due to increased defect accumulation at these internal interfaces. These results suggest that the interaction between radiation and crystallization interfaces is multifaceted—the effects of ionization, domain wall motion, point defect mobility, and microstructure are considered.
GENE EXPRESSION CHANGES IN MOUSE BLADDER TISSUE IN RESPONSE TO INORGANIC ARSENIC

EPA Science Inventory

Chronic human exposures to high arsenic concentrations are associated with lung, skin, and bladder cancer. Considerable controversy exists concerning arsenic mode of action and low dose extrapolation. This investigation was designed to identify dose-response changes in gene expre...
SU-G-BRB-14: Uncertainty of Radiochromic Film Based Relative Dose Measurements

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

Devic, S; Tomic, N; DeBlois, F

2016-06-15

Purpose: Due to inherently non-linear dose response, measurement of relative dose distribution with radiochromic film requires measurement of absolute dose using a calibration curve following previously established reference dosimetry protocol. On the other hand, a functional form that converts the inherently non-linear dose response curve of the radiochromic film dosimetry system into linear one has been proposed recently [Devic et al, Med. Phys. 39 4850–4857 (2012)]. However, there is a question what would be the uncertainty of such measured relative dose. Methods: If the relative dose distribution is determined going through the reference dosimetry system (conversion of the response bymore » using calibration curve into absolute dose) the total uncertainty of such determined relative dose will be calculated by summing in quadrature total uncertainties of doses measured at a given and at the reference point. On the other hand, if the relative dose is determined using linearization method, the new response variable is calculated as ζ=a(netOD)n/ln(netOD). In this case, the total uncertainty in relative dose will be calculated by summing in quadrature uncertainties for a new response function (σζ) for a given and the reference point. Results: Except at very low doses, where the measurement uncertainty dominates, the total relative dose uncertainty is less than 1% for the linear response method as compared to almost 2% uncertainty level for the reference dosimetry method. The result is not surprising having in mind that the total uncertainty of the reference dose method is dominated by the fitting uncertainty, which is mitigated in the case of linearization method. Conclusion: Linearization of the radiochromic film dose response provides a convenient and a more precise method for relative dose measurements as it does not require reference dosimetry and creation of calibration curve. However, the linearity of the newly introduced function must be verified. Dave Lewis is inventor and runs a consulting company for radiochromic films.« less
The mechanism of dioxin toxicity: relationship to risk assessment.

PubMed Central

Birnbaum, L S

1994-01-01

Risk characterization involves hazard identification, determination of dose-response relationships, and exposure assessment. Improvement of the risk assessment process requires inclusion of the best available science. Recent findings in the area of dioxin toxicity have led to a major effort to reassess its risk. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly referred to as "dioxin," is the most toxic member of a class of related chemicals including the polyhalogenated dibenzo-p-dioxins, dibenzofurans, biphenyls, naphthalenes, azo- and azoxy-benzenes, whose toxicities can be expressed as fractional equivalencies of TCDD. These chemicals exert their effects through interaction with a specific intracellular protein, the Ah receptor. While binding to the receptor is necessary, it is not sufficient to bring about a chain of events leading to various responses including enzyme induction, immunotoxicity, reproductive and endocrine effects, developmental toxicity, chloracne, tumor promotion, etc. Some of these responses appear to be linear at low doses. Immunotoxicity and effects on the reproductive system appear to be among the most sensitive responses. The Ah receptor functions as a transcriptional enhancer, interacting with a number of other regulatory proteins (heat shock proteins, kinases, translocases, DNA binding species). Interaction with specific base sequences in the DNA appear to be modulated by the presence of other growth factors, hormones and their receptors as well as other regulatory proteins. Thus, dioxin appears to function as a hormone, initiating a cascade of events that is dependent upon the environment of each cell and tissue. While Ah receptor variants exist, all vertebrates examined have demonstrated such a protein with similar numbers of receptors and binding affinity for TCDD. Most species respond similarly to dioxin and related compounds. While a given species may be an outlier for a given response, it will behave like other animals for other responses. For both in vivo and in vitro end points where animal and human data exist, such as enzyme induction, chloracne, immunotoxicity, developmental toxicity, and cancer, the sensitivity of humans appears similar to that of experimental animals. Current levels of environmental exposure to this class of chemicals may be resulting in subtle responses in populations at special risk such as subsistence fisherman and the developing infant, as well as in the general population. Increased understanding of the mechanism of dioxin's effects as well as elucidation of exposure-dose relationships is leading to the development of a biologically based dose-response model in the ongoing process of incorporating the best science into the risk assessment of TCDD and related compounds. PMID:7698077
Surgical Responses of Medial Rectus Muscle Recession in Thyroid Eye Disease-Related Esotropia

PubMed Central

Lyu, In Jeong; Lee, Ju-Yeun; Kong, Mingui; Park, Kyung-Ah; Oh, Sei Yeul

2016-01-01

We evaluate the surgical outcomes and surgical responses of medial rectus muscle (MR) recession patients with thyroid eye disease (TED)-related esotropia (ET). The surgical dose-response curves 1 week postoperatively and at the final visit were analyzed. Univariable and multivariable linear regression analyses were applied to investigate factors influencing surgical dose-response. A total of 43 patients with TED-related ET that underwent MR recession were included. The final success rate was 86.0% and the rate of undercorrection was 14.0%. The surgical dose-response curves of TED-related ET showed a gentle slope compared with those of standard surgical tables. In the univariable model, simultaneous vertical rectus muscle recession was the only significant factor influencing surgical dose-response of MR recession in TED-related ET (β = -0.397, P = 0.044). In a model adjusted for age, sex, type of surgery, and preoperative horizontal angle of deviation, simultaneous vertical rectus muscle recession showed marginal significance (β = -0.389, P = 0.064). The surgical dose-response curve of TED-related ET was unique. Simultaneous vertical rectus muscle recession was associated with increased surgical dose-response in TED-related ET. PMID:26796354
Cumulative Training Dose's Effects on Interrelationships Between Common Training-Load Models During Basketball Activity.

PubMed

Scanlan, Aaron T; Fox, Jordan L; Borges, Nattai R; Dascombe, Ben J; Dalbo, Vincent J

2017-02-01

The influence of various factors on training-load (TL) responses in basketball has received limited attention. This study aimed to examine the temporal changes and influence of cumulative training dose on TL responses and interrelationships during basketball activity. Ten state-level Australian male junior basketball players completed 4 × 10-min standardized bouts of simulated basketball activity using a circuit-based protocol. Internal TL was quantified using the session rating of perceived exertion (sRPE), summated heart-rate zones (SHRZ), Banister training impulse (TRIMP), and Lucia TRIMP models. External TL was assessed via measurement of mean sprint and circuit speeds. Temporal TL comparisons were performed between 10-min bouts, while Pearson correlation analyses were conducted across cumulative training doses (0-10, 0-20, 0-30, and 0-40 min). sRPE TL increased (P < .05) after the first 10-min bout of basketball activity. sRPE TL was only significantly related to Lucia TRIMP (r = .66-.69; P < .05) across 0-10 and 0-20 min. Similarly, mean sprint and circuit speed were significantly correlated across 0-20 min (r = .67; P < .05). In contrast, SHRZ and Banister TRIMP were significantly related across all training doses (r = .84-.89; P < .05). Limited convergence exists between common TL approaches across basketball training doses lasting beyond 20 min. Thus, the interchangeability of commonly used internal and external TL approaches appears dose-dependent during basketball activity, with various psychophysiological mediators likely underpinning temporal changes.

Nitrogen Dioxide Exposure and Airway Responsiveness in ...

EPA Pesticide Factsheets

Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction, 70% of individuals with asthma exposed to NO2 at rest, experience increases in airway responsiveness following 30-minute exposures to NO2 in the range of 200 to 300 ppb and following 60-minute exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise. A variety of fa
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.
Response of TLD-100 in mixed fields of photons and electrons

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

Lawless, Michael J.; Junell, Stephanie; Hammer, Cliff

Purpose: Thermoluminescent dosimeters (TLDs) are routinely used for dosimetric measurements of high energy photon and electron fields. However, TLD response in combined fields of photon and electron beam qualities has not been characterized. This work investigates the response of TLD-100 (LiF:Mg,Ti) to sequential irradiation by high-energy photon and electron beam qualities. Methods: TLDs were irradiated to a known dose by a linear accelerator with a 6 MV photon beam, a 6 MeV electron beam, and a NIST-traceable {sup 60}Co beam. TLDs were also irradiated in a mixed field of the 6 MeV electron beam and the 6 MV photon beam.more » The average TLD response per unit dose of the TLDs for each linac beam quality was normalized to the average response per unit dose of the TLDs irradiated by the {sup 60}Co beam. Irradiations were performed in water and in a Virtual Water Trade-Mark-Sign phantom. The 6 MV photon beam and 6 MeV electron beam were used to create dose calibration curves relating TLD response to absorbed dose to water, which were applied to the TLDs irradiated in the mixed field. Results: TLD relative response per unit dose in the mixed field was less sensitive than the relative response in the photon field and more sensitive than the relative response in the electron field. Application of the photon dose calibration curve to the TLDs irradiated in a mixed field resulted in an underestimation of the delivered dose, while application of the electron dose calibration curve resulted in an overestimation of the dose. Conclusions: The relative response of TLD-100 in mixed fields fell between the relative response in the photon-only and electron-only fields. TLD-100 dosimetry of mixed fields must account for this intermediate response to minimize the estimation errors associated with calibration factors obtained from a single beam quality.« less
Response of TLD-100 in mixed fields of photons and electrons.

PubMed

Lawless, Michael J; Junell, Stephanie; Hammer, Cliff; DeWerd, Larry A

2013-01-01

Thermoluminescent dosimeters (TLDs) are routinely used for dosimetric measurements of high energy photon and electron fields. However, TLD response in combined fields of photon and electron beam qualities has not been characterized. This work investigates the response of TLD-100 (LiF:Mg,Ti) to sequential irradiation by high-energy photon and electron beam qualities. TLDs were irradiated to a known dose by a linear accelerator with a 6 MV photon beam, a 6 MeV electron beam, and a NIST-traceable (60)Co beam. TLDs were also irradiated in a mixed field of the 6 MeV electron beam and the 6 MV photon beam. The average TLD response per unit dose of the TLDs for each linac beam quality was normalized to the average response per unit dose of the TLDs irradiated by the (60)Co beam. Irradiations were performed in water and in a Virtual Water™ phantom. The 6 MV photon beam and 6 MeV electron beam were used to create dose calibration curves relating TLD response to absorbed dose to water, which were applied to the TLDs irradiated in the mixed field. TLD relative response per unit dose in the mixed field was less sensitive than the relative response in the photon field and more sensitive than the relative response in the electron field. Application of the photon dose calibration curve to the TLDs irradiated in a mixed field resulted in an underestimation of the delivered dose, while application of the electron dose calibration curve resulted in an overestimation of the dose. The relative response of TLD-100 in mixed fields fell between the relative response in the photon-only and electron-only fields. TLD-100 dosimetry of mixed fields must account for this intermediate response to minimize the estimation errors associated with calibration factors obtained from a single beam quality.
PREDICTING THE RISKS OF NEUROTOXIC VOLATILE ORGANIC COMPOUNDS BASED ON TARGET TISSUE DOSE.

EPA Science Inventory

Quantitative exposure-dose-response models relate the external exposure of a substance to the dose in the target tissue, and then relate the target tissue dose to production of adverse outcomes. We developed exposure-dose-response models to describe the affects of acute exposure...
MODELING THE INTERACTION THRESHOLD: THE BREAK-POINT BETWEEN ADDITIVITY AND NON-ADDITIVITY

EPA Science Inventory

Dose-dependent changes in toxicity mechanisms of single chemicals may take place along the full dose-response spectrum. At high doses, the possibility exists for some steps in the principle mechanism of toxicity to shift to other mechanisms. The possibility of mechanism shifts fo...
Chronic naltrindole administration does not modify the inhibitory effect of morphine on vocalization responses in the tail electric stimulation test in rats.

PubMed

Fernández, B; Alberti, I; Kitchen, I; Paz Viveros, M

1999-01-29

To address the existence of possible functional interactions between delta- and mu- receptors in relation to the affective component of pain, we have studied the effects of functional blockade of delta-receptors by a chronic treatment with naltrindole (1 mg/kg, 8 consecutive days) on antinociceptive responses to morphine (2 and 5 mg/kg) in the tail electric stimulation test, in adult male rats. The thresholds for the motor response (tail withdrawal), vocalization during stimulus and vocalization afterdischarge were assessed. These responses are considered to be integrated at spinal, medulla oblongata and diencephalon-rhinencephalon levels, respectively. The results show that the vocalization during stimulus and the vocalization afterdischarge were significantly affected by morphine in a dose dependent manner, the latter response being the most sensitive to the effects of the mu-opioid agonist. However, no significant effect was observed on motor responses at the doses used in this study. Chronic naltrindole treatment did not modify the inhibitory effect of morphine on the vocalization responses. Since the vocalization afterdischarge is related to the affective component of pain, the data suggest that the delta-opioid receptor is not involved in the supraspinal mechanisms at which these responses are organized and that there is not a mu-delta interaction in the modulation of the affective responses to noxious electrical stimulation.
Sparsely Ionizing Diagnostic and Natural Background Radiations are Likely Preventing Cancer and Other Genomic-Instability-Associated Diseases

PubMed Central

Scott, Bobby R.; Di Palma, Jennifer

2007-01-01

Routine diagnostic X-rays (e.g., chest X-rays, mammograms, computed tomography scans) and routine diagnostic nuclear medicine procedures using sparsely ionizing radiation forms (e.g., beta and gamma radiations) stimulate the removal of precancerous neo-plastically transformed and other genomically unstable cells from the body (medical radiation hormesis). The indicated radiation hormesis arises because radiation doses above an individual-specific stochastic threshold activate a system of cooperative protective processes that include high-fidelity DNA repair/apoptosis (presumed p53 related), an auxiliary apoptosis process (PAM process) that is presumed p53-independent, and stimulated immunity. These forms of induced protection are called adapted protection because they are associated with the radiation adaptive response. Diagnostic X-ray sources, other sources of sparsely ionizing radiation used in nuclear medicine diagnostic procedures, as well as radioisotope-labeled immunoglobulins could be used in conjunction with apopto-sis-sensitizing agents (e.g., the natural phenolic compound resveratrol) in curing existing cancer via low-dose fractionated or low-dose, low-dose-rate therapy (therapeutic radiation hormesis). Evidence is provided to support the existence of both therapeutic (curing existing cancer) and medical (cancer prevention) radiation hormesis. Evidence is also provided demonstrating that exposure to environmental sparsely ionizing radiations, such as gamma rays, protect from cancer occurrence and the occurrence of other diseases via inducing adapted protection (environmental radiation hormesis). PMID:18648608
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.
Mechanisms of carcinogensis: dose response

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

Gehring, P.J.; Blau, G.E.

There is great controversy whether the carcinogenicity of chemicals is dose-dependent and whether a threshold dose exists below which cancer will not be induced by exposure. Evidence for dose-dependency exists and is believed to be accepted generally if extricated as it should be from the threshold concept. The threshold concept conflict is not likely to be resolved in the foreseeable future; proponents and opponents argue their case in a manner similar to those arguing religion. In this paper the various arguments are reviewed. Subsequently, a chemical process model for carcinogenesis is developed based on the generally accepted evidence that themore » carcinogenic activity of many chemicals can be related to electrophilic alkylation of DNA. Using this model, some incidence of cancer, albeit negligible, will be predicted regardless how low the dose. However, the model revelas that the incidence of cancer induced by real-life exposures is likely to be greatly overestimated by currently used stochastic statistical extrapolations. Even more important, modeling of the chemical processes involved in the fate of a carcinogenic chemical in the body reveals experimental approaches to elucidating the mechanism(s) of carcinogenesis and ultimately a more scientifically sound basis for assessing the hazard of low-level exposure to a chemical carcinogen.« less
Oral desmopressin in central diabetes insipidus.

PubMed Central

Westgren, U; Wittström, C; Harris, A S

1986-01-01

Seven paediatric patients with central diabetes insipidus were studied in an open dose ranging study in hospital followed by a six month study on an outpatient basis to assess the efficacy and safety of peroral administration of DDAVP (desmopressin) tablets. In the dose ranging study a dose dependent antidiuretic response was observed. The response to 12.5-50 mcg was, however, less effective in correcting baseline polyuria than were doses of 100 mcg and above. Patients were discharged from hospital on a preliminary dosage regimen ranging from 100 to 400 mcg three times daily. After an initial adjustment in dosage in three patients at one week follow up, all patients were stabilised on treatment with tablets and reported an adequate water turnover at six months. As with the intranasal route of administration dosage requirements varied from patient to patient, and a dose range rather than standard doses were required. A significant correlation, however, was found for the relation between previous intranasal and present oral daily dosage. No adverse reactions were reported. No clinically significant changes were noted in blood chemistry and urinalysis. All patients expressed a preference for the oral over existing intranasal treatment. Treatment with tablets offers a beneficial alternative to the intranasal route, particularly in patients with chronic rhinitis or impaired vision. PMID:3963868
Mathematical modelling and quantitative methods.

PubMed

Edler, L; Poirier, K; Dourson, M; Kleiner, J; Mileson, B; Nordmann, H; Renwick, A; Slob, W; Walton, K; Würtzen, G

2002-01-01

The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible. It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output.
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.
Technical Note: On GAFChromic EBT-XD film and the lateral response artifact.

PubMed

Lewis, David F; Chan, Maria F

2016-02-01

The new radiochromic film, GAFChromic EBT-XD, contains the same active material, lithium-10,12-pentacosadiynoate, as GAFChromic EBT3, but the crystalline form is different. This work investigates the effect of this change on the well-known lateral response artifact when EBT-XD film is digitized on a flatbed scanner. The dose response of a single production lot of EBT-XD was characterized by scanning an unexposed film plus a set of films exposed to doses between 2.5 and 50 Gy using 6 MV photons. To characterize the lateral response artifact, the authors used the unexposed film plus a subset of samples exposed to doses between 20 and 50 Gy. Digital images of these films were acquired at seven discrete lateral locations perpendicular to the scan direction on three Epson 10000XL scanners. Using measurements at the discrete lateral positions, the scanner responses were determined as a function of the lateral position of the film. From the data for each scanner, a set of coefficients were derived whereby measured response values could be corrected to remove the effects of the lateral response artifact. The EBT-XD data were analyzed as in their previous work and compared to results reported for EBT3 in that paper. For films scanned in the same orientation and having equal responses, the authors found that the lateral response artifact for EBT-XD and EBT3 films was remarkably similar. For both films, the artifact increases with increased net response. However, as EBT-XD is less sensitive than EBT3, a greater exposure dose is required to reach the same net response. On this basis, the lower sensitivity of EBT-XD relative to EBT3 results in less net response change for equal exposure and a reduction in the impact of the lateral response artifact. The shape of the crystalline active component in EBT-XD and EBT3 does not affect the fundamental existence of the lateral response artifact when the films are digitized on flatbed scanners. Owing its lower sensitivity, EBT-XD film requires higher dose to reach the same response as EBT3, resulting in lesser impact of the lateral response artifact. For doses >10 Gy, the slopes of the EBT-XD red and green channel dose response curves are greater than the corresponding ones for EBT3. For these two reasons, the authors prefer EBT-XD for doses exceeding about 10 Gy.
Technical Note: On GAFChromic EBT-XD film and the lateral response artifact

PubMed Central

Lewis, David F.

2016-01-01

Purpose: The new radiochromic film, GAFChromic EBT-XD, contains the same active material, lithium-10,12-pentacosadiynoate, as GAFChromic EBT3, but the crystalline form is different. This work investigates the effect of this change on the well-known lateral response artifact when EBT-XD film is digitized on a flatbed scanner. Methods: The dose response of a single production lot of EBT-XD was characterized by scanning an unexposed film plus a set of films exposed to doses between 2.5 and 50 Gy using 6 MV photons. To characterize the lateral response artifact, the authors used the unexposed film plus a subset of samples exposed to doses between 20 and 50 Gy. Digital images of these films were acquired at seven discrete lateral locations perpendicular to the scan direction on three Epson 10000XL scanners. Using measurements at the discrete lateral positions, the scanner responses were determined as a function of the lateral position of the film. From the data for each scanner, a set of coefficients were derived whereby measured response values could be corrected to remove the effects of the lateral response artifact. The EBT-XD data were analyzed as in their previous work and compared to results reported for EBT3 in that paper. Results: For films scanned in the same orientation and having equal responses, the authors found that the lateral response artifact for EBT-XD and EBT3 films was remarkably similar. For both films, the artifact increases with increased net response. However, as EBT-XD is less sensitive than EBT3, a greater exposure dose is required to reach the same net response. On this basis, the lower sensitivity of EBT-XD relative to EBT3 results in less net response change for equal exposure and a reduction in the impact of the lateral response artifact. Conclusions: The shape of the crystalline active component in EBT-XD and EBT3 does not affect the fundamental existence of the lateral response artifact when the films are digitized on flatbed scanners. Owing its lower sensitivity, EBT-XD film requires higher dose to reach the same response as EBT3, resulting in lesser impact of the lateral response artifact. For doses >10 Gy, the slopes of the EBT-XD red and green channel dose response curves are greater than the corresponding ones for EBT3. For these two reasons, the authors prefer EBT-XD for doses exceeding about 10 Gy. PMID:26843228
Persistent effects of chronic Δ9-THC exposure on motor impulsivity in rats.

PubMed

Irimia, Cristina; Polis, Ilham Y; Stouffer, David; Parsons, Loren H

2015-08-01

In humans, long-term marijuana use is associated with impaired impulse control and attentional capacity, though it has been difficult to distinguish pre-existing cognitive deficits from possible consequences of prolonged marijuana exposure. To evaluate the effects of long-term exposure to Δ9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent in marijuana, on indices of impulse control and attentional capacity using the rat 5-Choice Serial Reaction Time Task (5-CSRTT). Ten 14-day cycles of Δ9-THC dosing and 5-CSRTT testing were employed, each comprised of 5-day Δ9-THC dosing (0.3 or 3 mg/kg b.i.d.) and 5-CSRTT testing during the 9 days of drug abstinence. Subsequent 5-CSRTT testing continued during 5 weeks of protracted abstinence. Dose-dependent increases in motor impulsivity (premature responses) and behavioral disinhibition (perseverative responses) emerged following 5 cycles of Δ9-THC exposure that persisted for the remaining dosing and testing cycles. Δ9-THC-related disruptions in motor impulsivity and behavioral inhibition were most pronounced during cognitively challenging 5-CSRTT sessions incorporating varying novel inter-trial intervals (ITIs), and these disruptions persisted for at least 5 weeks of Δ9-THC abstinence. Δ9-THC-related impairments in attentional capacity (response accuracy) were also evident during variable ITI challenge tests, though these attentional disruptions abated within 3 weeks of Δ9-THC abstinence. These observations demonstrate that long-term intermittent exposure to clinically meaningful Δ9-THC doses induces persistent impairments in impulse control and attentional function. If present in humans, these disruptions may impact academic and professional performance.
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
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. Introduction of birth dose of Hepatitis B vaccine to the existing schedule is recommended.
An Adaptive Staggered Dose Design for a Normal Endpoint.

PubMed

Wu, Joseph; Menon, Sandeep; Chang, Mark

2015-01-01

In a clinical trial where several doses are compared to a control, a multi-stage design that combines both the selection of the best dose and the confirmation of this selected dose is desirable. An example is the two-stage drop-the-losers or pick-the-winner design, where inferior doses are dropped after interim analysis. Selection of target dose(s) can be based on ranking of observed effects, hypothesis testing with adjustment for multiplicity, or other criteria at interim stages. A number of methods have been proposed and have made significant gains in trial efficiency. However, many of these designs started off with all doses with equal allocation and did not consider prioritizing the doses using existing dose-response information. We propose an adaptive staggered dose procedure that allows explicit prioritization of doses and applies error spending scheme that favors doses with assumed better responses. This design starts off with only a subset of the doses and adaptively adds new doses depending on interim results. Using simulation, we have shown that this design performs better in terms of increased statistical power than the drop-the-losers design given strong prior information of dose response.
Acute effects of THC on time perception in frequent and infrequent cannabis users.

PubMed

Sewell, R Andrew; Schnakenberg, Ashley; Elander, Jacqueline; Radhakrishnan, Rajiv; Williams, Ashley; Skosnik, Patrick D; Pittman, Brian; Ranganathan, Mohini; D'Souza, D Cyril

2013-03-01

Cannabinoids have been shown to alter time perception, but existing literature has several limitations. Few studies have included both time estimation and production tasks, few control for subvocal counting, most had small sample sizes, some did not record subjects' cannabis use, many tested only one dose, and used either oral or inhaled administration of Δ⁹-tetrahydrocannabinol (THC), leading to variable pharmacokinetics, and some used whole-plant cannabis containing cannabinoids other than THC. Our study attempted to address these limitations. This study aims to characterize the acute effects of THC and frequent cannabis use on seconds-range time perception. THC was hypothesized to produce transient, dose-related time overestimation and underproduction. Frequent cannabis smokers were hypothesized to show blunted responses to these alterations. IV THC was administered at doses from 0.015 to 0.05 mg/kg to 44 subjects who participated in several double-blind, randomized, counterbalanced, crossover, placebo-controlled studies. Visual time estimation and production tasks in the seconds range were presented to subjects three times on each test day. All doses induced time overestimation and underproduction. Chronic cannabis use had no effect on baseline time perception. While infrequent/nonsmokers showed temporal overestimation at medium and high doses and temporal underproduction at all doses, frequent cannabis users showed no differences. THC effects on time perception were not dose related. A psychoactive dose of THC increases internal clock speed as indicated by time overestimation and underproduction. This effect is not dose related and is blunted in chronic cannabis smokers who did not otherwise have altered baseline time perception.

A comparative dose-effect study with cardiac glycosides assessing cardiac and extracardiac responses in normal subjects.

PubMed

Alken, R G; Belz, G G

1984-01-01

We tested the hypothesis that differences exist in the pharmacodynamic pattern of different cardiac glycosides. We conducted a randomized, placebo-controlled study in normal volunteers and evaluated the effects of weekly increased oral dosing of digoxin (n = 10; from 0.25 to 1.0 mg/day), meproscillarin (n = 10; from 0.5 to 2.0 mg/day), and placebo (n = 5). To determine the glycoside effects, corrected electromechanical systole (QS2c) was used to measure inotropy and the PQ interval to test dromotropy. Red-green discrimination and critical flicker fusion (CFF) assessed visual functions. Subjective complaints were collected using rating lists. Both glycosides dose dependently shortened QS2c and prolonged PQ interval. PQ prolongations over +20 ms occurred in seven of 10 digoxin subjects, in two of 10 meproscillarin, and in one of five placebo. Equi-inotropic response, identified at 12 ms mean QS2c shortening, revealed the relative potency of digoxin to be 2.4 times higher than meproscillarin; this ratio increased to sevenfold for equi-effective negative dromotropic effects at 12 ms mean PQ prolongation. Each drug was associated with a dominant subjective complaint: digoxin with anergy and meproscillarin with diarrhea. Red-green discrimination was better under meproscillarin and CFF was depressed by digoxin. The results indicate that pharmacodynamic differences exist between cardiac glycosides. A differential use of various glycosides should be considered and tested clinically.
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 Â© 2016 Elsevier Ireland Ltd. All rights reserved.
Evaluation of the protein quality of wheat grains (Grizza 155) and eight related products by the dose-response bioassay.

PubMed

Hussein, L; Abbassy, M; Arafa, A; Morcos, S R

1979-12-01

The amino acid analysis revealed that wheat grains, white and dark flour, baladi bread prepared from white or dark flour, bread prepared from formulae enriched with gluten and biscuits are poor in lysine with chemical scores ranging between 20 and 49. The assessment of the protein quality of wheat and related products was done by slope ratio bioassay. Results based on slopes relative to those of reference casein + methionine ranked bread prepared from dark flour and cooked wheat (belila) as the highest in their protein quality, followed by their parent; wheat (RNV = 44). Dietetic bread with gluten had RNV = 20-24; owing to its high protein content (38%), its utilizable protein approached that of good proteins (8%). Very high significant correlation existed between the two measures of response; gain in weight and net increase in body water as response of nitrogen intake.
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
Response of LiF:Mg,Ti thermoluminescent dosimeters at photon energies relevant to the dosimetry of brachytherapy (<1 MeV).

PubMed

Tedgren, Asa Carlsson; Hedman, Angelica; Grindborg, Jan-Erik; Carlsson, Gudrun Alm

2011-10-01

High energy photon beams are used in calibrating dosimeters for use in brachytherapy since absorbed dose to water can be determined accurately and with traceability to primary standards in such beams, using calibrated ion chambers and standard dosimetry protocols. For use in brachytherapy, beam quality correction factors are needed, which include corrections for differences in mass energy absorption properties between water and detector as well as variations in detector response (intrinsic efficiency) with radiation quality, caused by variations in the density of ionization (linear energy transfer (LET) -distributions) along the secondary electron tracks. The aim of this work was to investigate experimentally the detector response of LiF:Mg,Ti thermoluminescent dosimeters (TLD) for photon energies below 1 MeV relative to (60)Co and to address discrepancies between the results found in recent publications of detector response. LiF:Mg,Ti dosimeters of formulation MTS-N Poland were irradiated to known values of air kerma free-in-air in x-ray beams at tube voltages 25-250 kV, in (137)Cs- and (60)Co-beams at the Swedish Secondary Standards Dosimetry Laboratory. Conversions from air kerma free-in-air into values of mean absorbed dose in the dosimeters in the actual irradiation geometries were made using EGSnrc Monte Carlo simulations. X-ray energy spectra were measured or calculated for the actual beams. Detector response relative to that for (60)Co was determined at each beam quality. An increase in relative response was seen for all beam qualities ranging from 8% at tube voltage 25 kV (effective energy 13 keV) to 3%-4% at 250 kV (122 keV effective energy) and (137)Cs with a minimum at 80 keV effective energy (tube voltage 180 kV). The variation with effective energy was similar to that reported by Davis et al. [Radiat. Prot. Dosim. 106, 33-43 (2003)] with our values being systematically lower by 2%-4%. Compared to the results by Nunn et al. [Med. Phys. 35, 1861-1869 (2008)], the relative detector response as a function of effective energy differed in both shape and magnitude. This could be explained by the higher maximum read-out temperature (350 °C) used by Nunn et al. [Med. Phys. 35, 1861-1869 (2008)], allowing light emitted from high-temperature peaks with a strong LET dependence to be registered. Use of TLD-100 by Davis et al. [Radiat. Prot. Dosim. 106, 33-43 (2003)] with a stronger super-linear dose response compared to MTS-N was identified as causing the lower relative detector response in this work. Both careful dosimetry and strict protocols for handling the TLDs are required to reach solid experimental data on relative detector response. This work confirms older findings that an over-response relative to (60)Co exists for photon energies below 200-300 keV. Comparison with the results from the literature indicates that using similar protocols for annealing and read-out, dosimeters of different makes (TLD-100, MTS-N) differ in relative detector response. Though universality of the results has not been proven and further investigation is needed, it is anticipated that with the use of strict protocols for annealing and read-out, it will be possible to determine correction factors that can be used to reduce uncertainties in dose measurements around brachytherapy sources at photon energies where primary standards for absorbed dose to water are not available.
Phase I/II adaptive design for drug combination oncology trials

PubMed Central

Wages, Nolan A.; Conaway, Mark R.

2014-01-01

Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose–toxicity and dose–efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID:24470329
DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, David F., E-mail: rcfilmconsulting@gmail.com; Chan, Maria F.

Purpose: The new radiochromic film, GAFChromic EBT-XD, contains the same active material, lithium-10,12-pentacosadiynoate, as GAFChromic EBT3, but the crystalline form is different. This work investigates the effect of this change on the well-known lateral response artifact when EBT-XD film is digitized on a flatbed scanner. Methods: The dose response of a single production lot of EBT-XD was characterized by scanning an unexposed film plus a set of films exposed to doses between 2.5 and 50 Gy using 6 MV photons. To characterize the lateral response artifact, the authors used the unexposed film plus a subset of samples exposed to dosesmore » between 20 and 50 Gy. Digital images of these films were acquired at seven discrete lateral locations perpendicular to the scan direction on three Epson 10000XL scanners. Using measurements at the discrete lateral positions, the scanner responses were determined as a function of the lateral position of the film. From the data for each scanner, a set of coefficients were derived whereby measured response values could be corrected to remove the effects of the lateral response artifact. The EBT-XD data were analyzed as in their previous work and compared to results reported for EBT3 in that paper. Results: For films scanned in the same orientation and having equal responses, the authors found that the lateral response artifact for EBT-XD and EBT3 films was remarkably similar. For both films, the artifact increases with increased net response. However, as EBT-XD is less sensitive than EBT3, a greater exposure dose is required to reach the same net response. On this basis, the lower sensitivity of EBT-XD relative to EBT3 results in less net response change for equal exposure and a reduction in the impact of the lateral response artifact. Conclusions: The shape of the crystalline active component in EBT-XD and EBT3 does not affect the fundamental existence of the lateral response artifact when the films are digitized on flatbed scanners. Owing its lower sensitivity, EBT-XD film requires higher dose to reach the same response as EBT3, resulting in lesser impact of the lateral response artifact. For doses >10 Gy, the slopes of the EBT-XD red and green channel dose response curves are greater than the corresponding ones for EBT3. For these two reasons, the authors prefer EBT-XD for doses exceeding about 10 Gy.« less
Low doses of ionizing radiation to mammalian cells may rather control than cause DNA damage

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

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

This report examines the origin of tissue effects that may follow from different cellular responses to low-dose irradiation, using published data. Two principal categories of cellular responses are considered. One response category relates to the probability of radiation-induced DNA damage. The other category consists of low-dose induced metabolic changes that induce mechanisms of DNA damage mitigation, which do not operate at high levels of exposure. Modeled in this way, tissue is treated as a complex adaptive system. The interaction of the various cellular responses results in a net tissue dose-effect relation that is likely to deviate from linearity in themore » low-dose region. This suggests that the LNT hypothesis should be reexamined. This paper aims at demonstrating tissue effects as an expression of cellular responses, both damaging and defensive, in relation to the energy deposited in cell mass, by use of microdosimetric concepts.« less
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...
Configuration of automatic exposure control on mammography units for computed radiography to match patient dose of screen film systems

NASA Astrophysics Data System (ADS)

Yang, Chang-Ying Joseph; Huang, Weidong

2009-02-01

Computed radiography (CR) is considered a drop-in addition or replacement for traditional screen-film (SF) systems in digital mammography. Unlike other technologies, CR has the advantage of being compatible with existing mammography units. One of the challenges, however, is to properly configure the automatic exposure control (AEC) on existing mammography units for CR use. Unlike analogue systems, the capture and display of digital CR images is decoupled. The function of AEC is changed from ensuring proper and consistent optical density of the captured image on film to balancing image quality with patient dose needed for CR. One of the preferences when acquiring CR images under AEC is to use the same patient dose as SF systems. The challenge is whether the existing AEC design and calibration process-most of them proprietary from the X-ray systems manufacturers and tailored specifically for SF response properties-can be adapted for CR cassettes, in order to compensate for their response and attenuation differences. This paper describes the methods for configuring the AEC of three different mammography units models to match the patient dose used for CR with those that are used for a KODAK MIN-R 2000 SF System. Based on phantom test results, these methods provide the dose level under AEC for the CR systems to match with the dose of SF systems. These methods can be used in clinical environments that require the acquisition of CR images under AEC at the same dose levels as those used for SF systems.
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...
EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ...

EPA Pesticide Factsheets

While the effect that TCDD has on humoral immunity in the mouse has been well documented, it has not been for the rat. n this study, the effect that TCDD has on the antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBC) in adult female B6C3F1 mice and F344 rats was compared. ice or rats were given a single intraperitoneal injection of TCDD at doses ranging from 0.1 to 30 ug/kg, 7 days prior to intravenous immunization with SRBC. our days later the PFC response to SRBC was determined. ice showed a dose related suppression of the PFC response, with an ED50 of 0.71 ug/kg TCDD. n contrast, TCDD failed to suppress and in fact enhanced the PFC response to SRBC in rats at doses as high as 30 ug/kg. he inability of TCDD to suppress the PFC response in rats was unrelated to hepatic CYP1A1 and CYP1A2 induction which was detectable at doses of 1 and 0.3 ug/kg TCDD, respectively. here was no shift in the time to peak PFC response in rats dosed with TCDD, nor was the failure of TCDD to suppress the PFC response in rats related to gender or strain. henotypic analysis of thymocytes and splenic lymphocytes from TCDD-dosed (i.e., 3, 10 or 30 ug/kg) and SREC-immunized mice and rats revealed that CD4-CD8+ splenocytes were reduced in a dose related manner in rats only and that this reduction in CD4-CD8+ was accompanied by a dose related increase in IgM+ splenocytes. hese results demonstrate species differences in the effect of TCDD on the PFC response to SRBC w
Implications of the implementation of the revised dose limit to the lens of the eye: the view of IRPA professionals.

PubMed

Broughton, J; Cantone, M C; Ginjaume, M; Shah, B; Czarwinski, R

2015-06-01

In April 2011, the International Commission on Radiological Protection issued a statement on reduction of the equivalent dose limits for the lens of the eye, and strongly recommended its consideration in the revision of the International Atomic Energy Agency's International Basic Safety Standards on Radiation Protection. The reduced dose limit was incorporated in the final version of the Basic Safety Standards. As significant concern was expressed by radiation protection professionals worldwide, the International Radiation Protection Association (IRPA) established a task group to assess the impact of implementation of the revised dose limit for the lens of the eye for occupational exposure. IRPA Associate Societies (ASs) were asked for their views using a questionnaire addressing three topics: implications for dosimetry, implications for methods of protection, and wider implications. The responses received indicate various methods of approach and express different points of view, reflecting nuances of particular ASs or specific professional groups. Topic experts nominated by ASs were selected to assist with collation of responses, and a report was produced by the task group. Conclusions were drawn on the three issues, including potential cost implications. A number of recommendations were drawn from the responses received including: the request for more understanding about the relationship between exposure of the lens of the eye and cataract formation, and further guidance to assist implementation; the importance of economic and social considerations when introducing the limits into national regulations; the need to propose or define procedures related to employment of people with existing or pre-cataract conditions; and the practical aspects relating to dosimetry and protective equipment. © The International Society for Prosthetics and Orthotics Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

PubMed

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

2017-04-01

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

EPA Science Inventory

There has been a long-running debate over the existence of thresholds for adverse effects. The difficulty stems from two fundamental challenges: (i) statistical analysis by itself cannot prove the existence of a threshold, i.e., a dose below which there is no effect; and (ii) the...
Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC

EPA Science Inventory

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

PubMed Central

Lipton, J. M.; Ticknor, C. B.

1979-01-01

1. Intravenous injections of leucocytic pyrogen in doses of 15, 30 and 60 μl./kg caused febrile reactions in male rabbits that were related to age of the animal: rabbits under 2 yr of age developed fevers that were related to dose of pyrogen, while rabbits 2-3 yr old showed large febrile responses which were not dose-related. 2. Female rabbits of comparable ages generally showed smaller febrile reactions to I.V. leucocytic pyrogen, and still older females (3-5 yr) developed fever only after the largest dose. 3. Dose-related febrile responses to 2·5, 5 and 10 μl. leucocytic pyrogen given intracerebroventricularly (I.C.V.) were greater in male rabbits 1-3 yr old than in females of comparable age. Female rabbits 3-5 yr old showed dose-related fevers that were smaller than those of younger animals of both sexes. 4. There were no major differences in response to 125, 250 and 500 ng PGE2, given I.C.V., between male and female rabbits under 2 yr of age. Females 2-3 yr of age had greater responses to PGE2 than males of comparable age whilst the oldest females showed smaller responses. 5. It is concluded that the febrile response of the rabbit to peripheral and central leucocytic pyrogen varies with both age and sex. Differences in sensitivity of central fever controls to endogenous pyrogen in animals of different ages and sexes may account for the different responses to peripheral pyrogen. PMID:521933
Influence of sex and age on febrile responses to peripheral and central administration of pyrogens in the rabbit.

PubMed

Lipton, J M; Ticknor, C B

1979-10-01

1. Intravenous injections of leucocytic pyrogen in doses of 15, 30 and 60 mul./kg caused febrile reactions in male rabbits that were related to age of the animal: rabbits under 2 yr of age developed fevers that were related to dose of pyrogen, while rabbits 2-3 yr old showed large febrile responses which were not dose-related.2. Female rabbits of comparable ages generally showed smaller febrile reactions to I.V. leucocytic pyrogen, and still older females (3-5 yr) developed fever only after the largest dose.3. Dose-related febrile responses to 2.5, 5 and 10 mul. leucocytic pyrogen given intracerebroventricularly (I.C.V.) were greater in male rabbits 1-3 yr old than in females of comparable age. Female rabbits 3-5 yr old showed dose-related fevers that were smaller than those of younger animals of both sexes.4. There were no major differences in response to 125, 250 and 500 ng PGE(2), given I.C.V., between male and female rabbits under 2 yr of age. Females 2-3 yr of age had greater responses to PGE(2) than males of comparable age whilst the oldest females showed smaller responses.5. It is concluded that the febrile response of the rabbit to peripheral and central leucocytic pyrogen varies with both age and sex. Differences in sensitivity of central fever controls to endogenous pyrogen in animals of different ages and sexes may account for the different responses to peripheral pyrogen.
Effect of aerosol fenoterol on the severity of bronchial hyperreactivity in patients with asthma.

PubMed Central

Salome, C M; Schoeffel, R E; Yan, K; Woolcock, A J

1983-01-01

Beta adrenergic agents given by aerosol decrease the responsiveness of the airways to histamine and methacholine in subjects with asthma, causing a shift of the dose response curve to the right. To find out whether the shift is related to the dose of beta adrenergic agent given and to determine the duration of the reduced responsiveness, eight subjects with asthma were given histamine inhalation tests after inhaled saline and after increasing doses of inhaled fenoterol on different days. The histamine inhalation tests were repeated at hourly intervals for five hours after a selected dose of fenoterol. Fenoterol caused a dose related shift to the right of the histamine dose response curve in each subject and in some the dose response relationship reached the "non-symptomatic range." The shift in the dose response curve was short lived and had returned towards the control position within three hours in all subjects. There was no change in shape of the curves at the time of maximal shift. The results show that inhaled fenoterol greatly reduces the airway responsiveness to histamine, but up to 400 micrograms of fenoterol every four to five hours may be needed to keep the responsiveness of the airways in the non-symptomatic range. PMID:6648868
Physical activity in ovarian cancer survivors: associations with fatigue, sleep, and psychosocial functioning.

PubMed

Stevinson, Clare; Steed, Helen; Faught, Wylam; Tonkin, Katia; Vallance, Jeffrey K; Ladha, Aliya B; Schepansky, Alexandra; Capstick, Valerie; Courneya, Kerry S

2009-01-01

Physical activity has been associated with better health-related outcomes in several cancer survivor groups but very few data exist for women with ovarian cancer. The purpose of this study was to investigate the associations between physical activity and health-related outcomes in ovarian cancer survivors and to examine any dose-response relationship. A cross-sectional postal survey of ovarian cancer survivors on and off treatment identified through the Alberta Cancer Registry was performed. Participants completed self-report measures of physical activity, cancer-related fatigue, peripheral neuropathy, depression, anxiety, and happiness, as well as demographic and medical variables. A total of 359 ovarian cancer survivors participated (51.4% response rate) of whom 31.1% were meeting the public health physical activity guidelines of the Centers for Disease Control and Prevention. Those meeting guidelines reported significantly lower fatigue than those not meeting guidelines (mean difference, 7.1; 95% confidence interval, 5.5-8.8; d = 0.87; P < 0.001). Meeting guidelines was also significantly inversely associated with peripheral neuropathy, depression, anxiety, sleep latency, use of sleep medication, and daytime dysfunction and was positively associated with happiness, sleep quality, and sleep efficiency. There was no evidence of a dose-response relationship beyond meeting or not meeting the guidelines for any variables. Ovarian cancer survivors who were meeting physical activity guidelines reported more favorable outcomes of fatigue, peripheral neuropathy, sleep, and psychosocial functioning.

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

PubMed

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

2011-02-01

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

PubMed

Robar, V; Zankowski, C; Olivares Pla, M; Podgorsak, E B

1996-05-01

The response of thermoluminescent dosimeters to electron irradiations depends on the radiation dose, mean electron energy at the position of the dosimeter in phantom, and the size of the dosimeter. In this paper the semi-empirical expression proposed by Holt et al. [Phys. Med. Biol. 20, 559-570 (1975)] is combined with the calculated electron dose fraction to determine the thermoluminescent dosimetry (TLD) response as a function of the mean electron energy and the dosimeter size. The electron and photon dose fractions, defined as the relative contributions of electrons and bremsstrahlung photons to the total dose for a clinical electron beam, are calculated with Monte Carlo techniques using EGS4. Agreement between the calculated and measured TLD response is very good. We show that the considerable reduction in TLD response per unit dose at low electron energies, i.e., at large depths in phantom, is offset by an ever-increasing relative contribution of bremsstrahlung photons to the total dose of clinical electron beams. This renders the TLD sufficiently reliable for dose measurements over the entire electron depth dose distribution despite the dependence of the TLD response on electron beam energy.
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...
Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

PubMed

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

2016-05-01

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

PubMed

Smith, Jordan Ned; Hinderliter, Paul M; Timchalk, Charles; Bartels, Michael J; Poet, Torka S

2014-08-01

Sensitivity to some chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to predict disposition of chlorpyrifos and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, previously measured age-dependent metabolism of chlorpyrifos and chlorpyrifos-oxon were integrated into age-related descriptions of human anatomy and physiology. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ⩾0.6mg/kg of chlorpyrifos (100- to 1000-fold higher than environmental exposure levels), 6months old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent doses. At lower doses more relevant to environmental exposures, simulations predict that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict chlorpyrifos disposition and biological response over various postnatal life stages. Copyright © 2013 Elsevier Inc. All rights reserved.
Electroantennogram and behavioral responses of the imported fire ant, Solenopsis invicta Buren, to an alarm pheromone component and its analogues.

PubMed

Guan, Di; Lu, Yong-Yue; Liao, Xiao-Lan; Wang, Lei; Chen, Li

2014-12-10

A characteristic behavior in ants is to move rapidly to emission sources of alarm pheromones. The addition of ant alarm pheromones to bait is expected to enhance its attractiveness. To search for candidate compounds for bait enhancement in fire ant control, 13 related alkylpyrazine analogues in addition to synthetic alarm pheromone component were evaluated for electroantennogram (EAG) and behavioral activities in Solenopsis invicta. Most compounds elicited dose-dependent EAG and behavioral responses. There exists a correlation between the EAG and behavioral responses. Among the 14 tested alkylpyrazines, three compounds, 2-ethyl-3,6(5)-dimethyl pyrazine (1), 2,3,5-trimethylpyrazine (7), and 2,3-diethyl-5-methylpyrazine (12), elicited significant alarm responses at a dose range of 0.1-1000 ng. Further bait discovery bioassay with the three most active alkylpyrazines demonstrated that food bait accompanied by sample-treated filter paper disk attracted significantly more fire ant workers in the first 15 min period. EAG and behavioral bioassays with pure pheromone isomers accumulated by semi-preparative high-performance liquid chromatography demonstrated that 2-ethyl-3,6-dimethylpyrazine was significantly more active than 2-ethyl-3,5-dimethylpyrazine.
Analysis of sheltering and evacuation strategies for an urban nuclear detonation scenario.

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

Yoshimura, Ann S.; Brandt, Larry D.

2009-05-01

Development of an effective strategy for shelter and evacuation is among the most important planning tasks in preparation for response to a low yield, nuclear detonation in an urban area. This study examines shelter-evacuate policies and effectiveness focusing on a 10 kt scenario in Los Angeles. The goal is to provide technical insights that can support development of urban response plans. Results indicate that extended shelter-in-place can offer the most robust protection when high quality shelter exists. Where less effective shelter is available and the fallout radiation intensity level is high, informed evacuation at the appropriate time can substantially reducemore » the overall dose to personnel. However, uncertainties in the characteristics of the fallout region and in the exit route can make evacuation a risky strategy. Analyses indicate that only a relatively small fraction of the total urban population may experience significant dose reduction benefits from even a well-informed evacuation plan.« less
SU-E-T-137: The Response of TLD-100 in Mixed Fields of Photons and Electrons.

PubMed

Lawless, M; Junell, S; Hammer, C; DeWerd, L

2012-06-01

Thermoluminescent dosimeters are used routinely for dosimetric measurements of photon and electron fields. However, no work has been published characterizing TLDs for use in combined photon and electron fields. This work investigates the response of TLD-100 (LiF:Mg,Ti) in mixed fields of photon and electron beam qualities. TLDs were irradiated in a 6 MV photon beam, 6 MeV electron beam, and a NIST traceable cobalt-60 beam. TLDs were also irradiated in a mixed field of the electron and photon beams. All irradiations were normalized to absorbed dose to water as defined in the AAPM TG-51 report. The average response per dose (nC/Gy) for each linac beam quality was normalized to the average response per dose of the TLDs irradiated by the cobalt-60 standard.Irradiations were performed in a water tank and a Virtual Water™ phantom. Two TLD dose calibration curves for determining absorbed dose to water were generated using photon and electron field TLD response data. These individual beam quality dose calibration curves were applied to the TLDs irradiated in the mixed field. The TLD response in the mixed field was less sensitive than the response in the photon field and more sensitive than the response in the electron field. TLD determination of dose in the mixed field using the dose calibration curve generated by TLDs irradiated by photons resulted in an underestimation of the delivered dose, while the use of a dose calibration curve generated using electrons resulted in an overestimation of the delivered dose. The relative response of TLD-100 in mixed fields fell consistently between the photon nd electron relative responses. When using TLD-100 in mixed fields, the user must account for this intermediate response to avoid an over- or underestimation of the dose due to calibration in a single photon or electron field. © 2012 American Association of Physicists in Medicine.
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.
A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

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

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

Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy{sup -1} of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018,more » 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.« less
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
Dose-response-a challenge for allelopathy?

PubMed

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

2005-04-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.
'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 outperformed classic clinical chemistry tests. ► Metabolomic analyses led to the detection of five new acetaminophen metabolites. ► Low dose APAP changed immune and oxidative stress related gene expression in blood. ► APAP-induced full-genome human blood miRNA profiles were assessed for the first time.« less
Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation.

PubMed

Holden, J E; Wang, E; Moes, J R; Wagner, M; Maduko, A; Jeong, Y

2014-06-13

Lateral hypothalamic (LH) stimulation produces antinociception in female rats in acute, nociceptive pain. Whether this effect occurs in neuropathic pain or whether male-female sex differences exist is unknown. We examined the effect of LH stimulation in male and female rats using conditions of nociceptive and neuropathic pain. Neuropathic groups received chronic constriction injury (CCI) to induce thermal hyperalgesia, a sign of neuropathic pain. Nociceptive rats were naive for CCI, but received the same thermal stimulus following LH stimulation. To demonstrate that CCI ligation produced thermal hyperalgesia, males and females received either ligation or sham surgery for control. Both males and females demonstrated significant thermal hyperalgesia following CCI ligation (p<0.05), but male sham surgery rats also showed a significant left-right difference not present in female sham rats. In the second experiment, rats randomly assigned to CCI or nociceptive groups were given one of three doses of the cholinergic agonist carbachol (125, 250, or 500 nmol) or normal saline for control, microinjected into the left LH. Paw withdrawal from a thermal stimulus (paw withdrawal latency; PWL) was measured every 5 min for 45 min. Linear mixed models analysis showed that males and females in both pain conditions demonstrated significant antinociception, with the 500-nmol dose producing the greatest effect across groups compared with controls for the left paw (p<0.05). Female CCI rats showed equivalent responses to the three doses, while male CCI rats showed more variability for dose. However, nociceptive females responded only to the 500-nmol dose, while nociceptive males responded to all doses (p<0.05). For right PWL, only nociceptive males showed a significant carbachol dose response. These findings are suggestive that LH stimulation produces antinociception in male and female rats in both nociceptive and neuropathic pain, but dose response differences exist based on sex and pain condition. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
The effects of cannabinoids on serum cortisol and prolactin in humans

PubMed Central

Ranganathan, Mohini; Braley, Gabriel; Pittman, Brian; Cooper, Thomas; Perry, Edward; Krystal, John; D’Souza, Deepak Cyril

2010-01-01

Background Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids. While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Furthermore, the existing literature on the neuroendocrine effects of cannabinoids is limited by small sample sizes (n=6–22), heterogeneous samples with regard to cannabis exposure (lumping users and nonusers), lack of controlling for chronic cannabis exposure, differing methodologies, and limited dose–response data. Delta-9-tetrahydrocannabinol (Δ-9-THC) was hypothesized to produce dose-related increases in plasma cortisol levels and decreases in plasma prolactin levels. Furthermore, relative to controls, frequent users of cannabis were hypothesized to show altered baseline levels of these hormones and blunted Δ-9-THC-induced changes of these hormones. Materials and methods Pooled data from a series of laboratory studies with multiple doses of intravenous Δ-9-THC in healthy control subjects (n=36) and frequent users of cannabis (n=40) was examined to characterize the acute, chronic, and acute on chronic effects of cannabinoids on plasma cortisol and prolactin levels. Hormone levels were measured before (baseline) and 70 min after administration of each dose of Δ-9-THC. Data were analyzed using linear mixed models with +70 min hormonal levels as the dependant variable and baseline hormonal level as the covariate. Results At socially relevant doses, Δ-9-THC raised plasma cortisol levels in a dose-dependent manner but frequent users showed blunted increases relative to healthy controls. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. Conclusions These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences in neuroendocrine function in frequent users of cannabis and not a consequence of cannabis use. PMID:19083209
Response of LiF:Mg,Ti thermoluminescent dosimeters at photon energies relevant to the dosimetry of brachytherapy (<1 MeV)

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

Tedgren, Aasa Carlsson; Hedman, Angelica; Grindborg, Jan-Erik

2011-10-15

Purpose: High energy photon beams are used in calibrating dosimeters for use in brachytherapy since absorbed dose to water can be determined accurately and with traceability to primary standards in such beams, using calibrated ion chambers and standard dosimetry protocols. For use in brachytherapy, beam quality correction factors are needed, which include corrections for differences in mass energy absorption properties between water and detector as well as variations in detector response (intrinsic efficiency) with radiation quality, caused by variations in the density of ionization (linear energy transfer (LET) -distributions) along the secondary electron tracks. The aim of this work wasmore » to investigate experimentally the detector response of LiF:Mg,Ti thermoluminescent dosimeters (TLD) for photon energies below 1 MeV relative to {sup 60}Co and to address discrepancies between the results found in recent publications of detector response. Methods: LiF:Mg,Ti dosimeters of formulation MTS-N Poland were irradiated to known values of air kerma free-in-air in x-ray beams at tube voltages 25-250 kV, in {sup 137}Cs- and {sup 60}Co-beams at the Swedish Secondary Standards Dosimetry Laboratory. Conversions from air kerma free-in-air into values of mean absorbed dose in the dosimeters in the actual irradiation geometries were made using EGSnrc Monte Carlo simulations. X-ray energy spectra were measured or calculated for the actual beams. Detector response relative to that for {sup 60}Co was determined at each beam quality. Results: An increase in relative response was seen for all beam qualities ranging from 8% at tube voltage 25 kV (effective energy 13 keV) to 3%-4% at 250 kV (122 keV effective energy) and {sup 137}Cs with a minimum at 80 keV effective energy (tube voltage 180 kV). The variation with effective energy was similar to that reported by Davis et al.[Radiat. Prot. Dosim. 106, 33-43 (2003)] with our values being systematically lower by 2%-4%. Compared to the results by Nunn et al.[Med. Phys. 35, 1861-1869 (2008)], the relative detector response as a function of effective energy differed in both shape and magnitude. This could be explained by the higher maximum read-out temperature (350 deg. C) used by Nunn et al.[Med. Phys. 35, 1861-1869 (2008)], allowing light emitted from high-temperature peaks with a strong LET dependence to be registered. Use of TLD-100 by Davis et al.[Radiat. Prot. Dosim. 106, 33-43 (2003)] with a stronger super-linear dose response compared to MTS-N was identified as causing the lower relative detector response in this work. Conclusions: Both careful dosimetry and strict protocols for handling the TLDs are required to reach solid experimental data on relative detector response. This work confirms older findings that an over-response relative to {sup 60}Co exists for photon energies below 200-300 keV. Comparison with the results from the literature indicates that using similar protocols for annealing and read-out, dosimeters of different makes (TLD-100, MTS-N) differ in relative detector response. Though universality of the results has not been proven and further investigation is needed, it is anticipated that with the use of strict protocols for annealing and read-out, it will be possible to determine correction factors that can be used to reduce uncertainties in dose measurements around brachytherapy sources at photon energies where primary standards for absorbed dose to water are not available.« 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
Evaluating the evidence for non-monotonic dose-response relationships: A systematic literature review and (re-)analysis of in vivo toxicity data in the area of food safety.

PubMed

Varret, C; Beronius, A; Bodin, L; Bokkers, B G H; Boon, P E; Burger, M; De Wit-Bos, L; Fischer, A; Hanberg, A; Litens-Karlsson, S; Slob, W; Wolterink, G; Zilliacus, J; Beausoleil, C; Rousselle, C

2018-01-15

This study aims to evaluate the evidence for the existence of non-monotonic dose-responses (NMDRs) of substances in the area of food safety. This review was performed following the systematic review methodology with the aim to identify in vivo studies published between January 2002 and February 2015 containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. A set of six checkpoints was developed to establish the likelihood that the data retrieved contained evidence for NMDR. In this review, 49 in vivo studies were identified as relevant and reliable, of which 42 were used for dose-response analysis. These studies contained 179 in vivo dose-response datasets with at least five dose groups (and a control group) as fewer doses cannot provide evidence for NMDR. These datasets were extracted and analyzed using the PROAST software package. The resulting dose-response relationships were evaluated for possible evidence of NMDRs by applying the six checkpoints. In total, 10 out of the 179 in vivo datasets fulfilled all six checkpoints. While these datasets could be considered as providing evidence for NMDR, replicated studies would still be needed to check if the results can be reproduced to rule out that the non-monotonicity was caused by incidental anomalies in that specific study. This approach, combining a systematic review with a set of checkpoints, is new and appears useful for future evaluations of the dose response datasets regarding evidence of non-monotonicity. Published by Elsevier Inc.
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.
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.

Comparison of bone cancer risks in beagle dogs for inhaled plutonium-238 dioxide, inhaled strontium-90 chloride, and injected strontium-90

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

Griffith, W.C.; Muggenburg, B.A.; Hahn, F.F.

1995-12-01

There is a continuing need to understand dose-response relationships for ionizing radiation in order to protect the health of the public and nuclear workers from undue exposures. However, relatively few human populations have been exposed to doses of radiation high enough to cause observable, long-term health effects from which to derive dose-response relationships. This is particularly true for internally deposited radionuclides, although much effort has been devoted to epidemiological studies of the few types of exposures available, including lung cancers in uranium miners form the inhalation of the radioactive decay products of Ra, liver cancers in patients injected with Thorotrastmore » X-ray contrast medium containing Th, bone cancers in radium dial painters who ingested Ra, and bone cancers in patients who received therapeutic doses of Ra. These four types of exposures to internally deposited radionuclides provide a basis for understanding the health effects of many other radionuclides for which a potential for exposure exists. However, potential exposures to internally deposited radionuclides may differ in many modifying factors, such as route of exposure, population differences, and physical, chemical, and elemental forms of radionuclides. The only means available to study many of these modifying factors has been in laboratory animals, and to then extrapolate the results to humans. Three conclusions can be drawn from this example.« less
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.
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. Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.« less
The effects of a selective 5-HT2 receptor antagonist (ICI 170,809) on platelet aggregation and pupillary responses in healthy volunteers.

PubMed Central

Millson, D S; Jessup, C L; Swaisland, A; Haworth, S; Rushton, A; Harry, J D

1992-01-01

1. ICI 170,809 (2-(2-dimethylamino-2-methylpropylthio)-3-phenylquinoline hydrochloride) is a potent 5-hydroxytryptamine (5-HT) type 2 postsynaptic receptor antagonist. 2. Effects of ICI 170,809 as single oral doses (3, 7, 15 and 30 mg) or placebo were studied on the duration of antagonism for the ex vivo platelet aggregatory response to 5-HT and to the pupillary light constrictor response in eight healthy male volunteers. 3. Pupillary dark adapted responses to a 0.5 s light stimulus were measured using a portable infrared pupillometer, for up to 24 h after dosing. 4. The in vitro platelet 5-HT aggregation response was reduced by ICI 170,809, with depression of the dose-response curve to 5-HT at all concentrations of 5-HT and with no evidence for a parallel shift. 5. The ex vivo platelet 5-HT response demonstrated a dose related significant (P less than 0.02) decrease in aggregation reaching a maximum at 2 h after dosing with the effect persisting for at least 8 h after dosing with the 7 and 15 mg doses. 6. Resting pupil diameter (RPD), and light induced pupillary responses in the dark adapted pupil, showed a significant (P less than 0.01) dose related reduction with significant (P less than 0.05) effects still present with the 15 and 30 mg doses at 8 h after dosing. 7. We conclude that, changes in both ex vivo platelet aggregation to 5-HT and dark adapted pupil size, are significantly correlated (P less than 0.0001) with log plasma concentrations (ng ml-1) of ICI 170,809, enabling the assessment of 5-HT2-receptor antagonism in man. PMID:1576048
Tolvaptan for the treatment of liver cirrhosis oedema.

PubMed

Sakaida, Isao

2014-07-01

No alternative therapeutic option exists if liver cirrhosis patients have insufficient response to conventional diuretics and/or experience conventional diuretic-related adverse events. In 2013, tolvaptan (7.5 mg/day), an arginine vasopressin V2 receptor antagonist, was approved in Japan for the treatment of liver cirrhosis with oedema. Short-term use of tolvaptan produced decreases in body weight, reduction in ascites volume and increases in urine volume when compared to placebo, despite the use of conventional diuretics. Additionally, approximately 60% of patients with oedema-related symptoms improved. Low-dose tolvaptan, 3.75 mg, was also efficacious. Even in patients with low serum albumin (<2.5 g/dL), decrease in body weight was greater with tolvaptan than with placebo. For future research, the efficacy and safety of lower tolvaptan doses for the treatment of liver cirrhosis patients with oedema should be confirmed in Japan. The results of this research could be used as an indicator or a guideline for physicians around the world.
Recent advances in mathematical modeling of developmental abnormalities using mechanistic information.

PubMed

Kavlock, R J

1997-01-01

During the last several years, significant changes in the risk assessment process for developmental toxicity of environmental contaminants have begun to emerge. The first of these changes is the development and beginning use of statistically based dose-response models [the benchmark dose (BMD) approach] that better utilize data derived from existing testing approaches. Accompanying this change is the greater emphasis placed on understanding and using mechanistic information to yield more accurate, reliable, and less uncertain risk assessments. The next stage in the evolution of risk assessment will be the use of biologically based dose-response (BBDR) models that begin to build into the statistically based models factors related to the underlying kinetic, biochemical, and/or physiologic processes perturbed by a toxicant. Such models are now emerging from several research laboratories. The introduction of quantitative models and the incorporation of biologic information into them has pointed to the need for even more sophisticated modifications for which we offer the term embryologically based dose-response (EBDR) models. Because these models would be based upon the understanding of normal morphogenesis, they represent a quantum leap in our thinking, but their complexity presents daunting challenges both to the developmental biologist and the developmental toxicologist. Implementation of these models will require extensive communication between developmental toxicologists, molecular embryologists, and biomathematicians. The remarkable progress in the understanding of mammalian embryonic development at the molecular level that has occurred over the last decade combined with advances in computing power and computational models should eventually enable these as yet hypothetical models to be brought into use.
The dose response relation for rat spinal cord paralysis analyzed in terms of the effective size of the functional subunit

NASA Astrophysics Data System (ADS)

Adamus-Górka, Magdalena; Mavroidis, Panayiotis; Brahme, Anders; Lind, Bengt K.

2008-11-01

Radiobiological models for estimating normal tissue complication probability (NTCP) are increasingly used in order to quantify or optimize the clinical outcome of radiation therapy. A good NTCP model should fulfill at least the following two requirements: (a) it should predict the sigmoid shape of the corresponding dose-response curve and (b) it should accurately describe the probability of a specified response for arbitrary non-uniform dose delivery for a given endpoint as accurately as possible, i.e. predict the volume dependence. In recent studies of the volume effect of a rat spinal cord after irradiation with narrow and broad proton beams the authors claim that none of the existing NTCP models is able to describe their results. Published experimental data have been used here to try to quantify the change in the effective dose (D50) causing 50% response for different field sizes. The present study was initiated to describe the induction of white matter necrosis in a rat spinal cord after irradiation with narrow proton beams in terms of the mean dose to the effective volume of the functional subunit (FSU). The physically delivered dose distribution was convolved with a function describing the effective size or, more accurately, the sensitivity distribution of the FSU to obtain the effective mean dose deposited in it. This procedure allows the determination of the mean D50 value of the FSUs of a certain size which is of interest for example if the cell nucleus of the oligodendrocyte is the sensitive target. Using the least-squares method to compare the effective doses for different sizes of the functional subunits with the experimental data the best fit was obtained with a length of about 9 mm. For the non-uniform dose distributions an effective FSU length of 8 mm gave the optimal fit with the probit dose-response model. The method could also be used to interpret the so-called bath and shower experiments where the heterogeneous dose delivery was used in the convolution process. The assumption of an effective FSU size is consistent with most of the effects seen when different portions of the rat spinal cord are irradiated to different doses. The effective FSU length from these experiments is about 8.5 ± 0.5 mm. This length could be interpreted as an effective size of the functional subunits in a rat spinal cord, where multiple myelin sheaths are connected by a single oligodendrocyte and repair is limited by the range of oligodendrocyte progenitor cell diffusion. It was even possible to suggest a more likely than uniform effective FSU sensitivity distribution from the experimental data.
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.
Alcohol consumption impairs stimulus- and error-related processing during a Go/No-Go Task.

PubMed

Easdon, Craig; Izenberg, Aaron; Armilio, Maria L; Yu, He; Alain, Claude

2005-12-01

Alcohol consumption has been shown to increase the number of errors in tasks that require a high degree of cognitive control, such as a go/no-go task. The alcohol-related decline in performance may be related to difficulties in maintaining attention on the task at hand and/or deficits in inhibiting a prepotent response. To test these two accounts, we investigated the effects of alcohol on stimulus- and response-locked evoked potentials recorded during a go/no-go task that involved the withholding of key presses to rare targets. All participants performed the task prior to drinking and were then assigned randomly to either a control, low-dose, or moderate-dose treatment. Both doses of alcohol increased the number of errors relative to alcohol-free performance. Success in withholding a prepotent response was associated with an early-enhanced stimulus-locked negativity at inferior parietal sites, which was delayed when participants failed to inhibit the motor command. Moreover, low and moderate doses of alcohol reduced N170 and P3 amplitudes during go, no-go, and error trials. In comparison with the correct responses, errors generated large response-locked negative (Ne) and positive (Pe) waves at central sites. Both doses of alcohol reduced the Ne amplitude whereas the Pe amplitude decreased only after moderate doses of alcohol. These results are consistent with the interpretation that behavioral disinhibition following alcohol consumption involved alcohol-induced deficits in maintaining and allocating attention thereby affecting the processing of incoming stimuli and the recognition that an errant response has been made.
Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

PubMed Central

Despotovic, Jenny M.; Mortier, Nicole A.; Flanagan, Jonathan M.; He, Jin; Smeltzer, Matthew P.; Kimble, Amy C.; Aygun, Banu; Wu, Song; Howard, Thad; Sparreboom, Alex

2011-01-01

Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal. PMID:21876119
Dose-dependent increase in subjective symptoms among toluene-exposed workers

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

Ukai, Hirohiko; Watanabe, Takao; Nakatsuka, Haruo

1993-02-01

A factory survey on dose-response relationship in toluene toxicity was conducted in 1985-1989 in four cities in China. The examination items consisted of personal diffusive sampling for TWA exposure measurement, questionnaires on subjective symptoms, hematology and serum biochemistry, and clinical examination including simple neurology tests. Hippuric acid was also determined in urine samples collected at the end of the shift. With selection criteria that (1) complete results were available on all study items and (2) valid toluene exposure data (i.e., toluene shared 90% or more of the exposure) were obtained for the exposed, 452 toluene-exposed workers (206 men and 246more » women; toluene exposure at 24.7 ppm as GM) and 517 nonexposed controls (246 men and 271 women) were selected. The subjective symptoms increased in close association with the intensity of exposure to toluene; the threshold concentration appeared to exist at 100 ppm in the case of symptoms during work, and it might be at 50-100 ppm when symptoms off work were evaluated. During the work with exposure at higher concentrations, various symptoms possibly related to CNS or local effects (e.g., eyes, nose, and throat) were complained, and dizziness and floating sensations were identified as typical symptoms with significant dose-response relationship. Several symptoms persisted off work, most of which were apparently related but not necessarily limited to CNS effects. Hematology and serum biochemistry were essentially negative. 46 refs., 4 figs., 6 tabs.« less
EXPOSURE RELATED DOSE ESTIMATING MODEL ( ERDEM ) A PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC ( PBPK/PD ) MODEL FOR ASSESSING HUMAN EXPOSURE AND RISK

EPA Science Inventory

The Exposure Related Dose Estimating Model (ERDEM) is a PBPK/PD modeling system that was developed by EPA's National Exposure Research Laboratory (NERL). The ERDEM framework provides the flexibility either to use existing models and to build new PBPK and PBPK/PD models to address...
Marginal iodide deficiency and thyroid function: dose-response analysis for quantitative pharmacokinetic modeling.

PubMed

Gilbert, M E; McLanahan, E D; Hedge, J; Crofton, K M; Fisher, J W; Valentín-Blasini, L; Blount, B C

2011-04-28

Severe iodine deficiency (ID) results in adverse health outcomes and remains a benchmark for understanding the effects of developmental hypothyroidism. The implications of marginal ID, however, remain less well known. The current study examined the relationship between graded levels of ID in rats and serum thyroid hormones, thyroid iodine content, and urinary iodide excretion. The goals of this study were to provide parametric and dose-response information for development of a quantitative model of the thyroid axis. Female Long Evans rats were fed casein-based diets containing varying iodine (I) concentrations for 8 weeks. Diets were created by adding 975, 200, 125, 25, or 0 μg/kg I to the base diet (~25 μg I/kg chow) to produce 5 nominal I levels, ranging from excess (basal+added I, Treatment 1: 1000 μg I/kg chow) to deficient (Treatment 5: 25 μg I/kg chow). Food intake and body weight were monitored throughout and on 2 consecutive days each week over the 8-week exposure period, animals were placed in metabolism cages to capture urine. Food, water intake, and body weight gain did not differ among treatment groups. Serum T4 was dose-dependently reduced relative to Treatment 1 with significant declines (19 and 48%) at the two lowest I groups, and no significant changes in serum T3 or TSH were detected. Increases in thyroid weight and decreases in thyroidal and urinary iodide content were observed as a function of decreasing I in the diet. Data were compared with predictions from a recently published biologically based dose-response (BBDR) model for ID. Relative to model predictions, female Long Evans rats under the conditions of this study appeared more resilient to low I intake. These results challenge existing models and provide essential information for development of quantitative BBDR models for ID during pregnancy and lactation. Published by Elsevier Ireland Ltd.
Influence of phantom materials on the energy dependence of LiF:Mg,Ti thermoluminescent dosimeters exposed to 20-300 kV narrow x-ray spectra, 137Cs and 60Co photons.

PubMed

Massillon-J L, G; Cabrera-Santiago, A; Minniti, R; O'Brien, M; Soares, C G

2014-08-07

LiF:Mg,Ti, are widely used to estimate absorbed-dose received by patients during diagnostic or medical treatment. Conveniently, measurements are usually made in plastic phantoms. However, experimental conditions vary from one group to another and consequently, a lack of consensus data exists for the energy dependence of thermoluminescent (TL) response. This work investigated the energy dependence of TLD-100 TL-response and the effect of irradiating the dosimeters in different phantom materials for a broad range of energy photons in an attempt to understand the parameters that affect the discrepancies reported by various research groups. TLD-100s were exposed to 20-300 kV narrow x-ray spectra, (137)Cs and (60)Co photons. Measurements were performed in air, PMMA, wt1, polystyrene and TLDS as surrounding material. Total air-kerma values delivered were between 50 and 150 mGy for x-rays and 50 mGy for (137)Cs and (60)Co beams; each dosimeter was irradiated individually. Relative response, R, defined as the TL-response per air-kerma and relative efficiency, RE, described as the TL-response per absorbed-dose (obtained through Monte Carlo (MC) and analytically) were used to describe the TL-response. Both R and RE are normalized to the responses in a (60)Co beam. The results indicate that the use of different phantom materials affects the TL-response and this response varies with energy and material type. MC simulations reproduced qualitatively the experimental data: a) R increases, reaches a maximum at ~25 keV and decreases; b) RE decreases, down to a minimum at ~60 keV, increases to a maximum at ~150 keV and after decreases. Independent of the phantom materials, RE strongly depends on how the absorbed dose is evaluated and the discrepancies between RE evaluated analytically and by MC simulation are around 4% and 18%, dependent on the photon energy. The comparison between our results and that reported in the literature suggests that the discrepancy observed between different research groups appears to be most likely related to supralinearity effect, phantom materials, difference on the energy-spectra and geometry conditions during each experiment rather than parameters such as heating-rate or annealing procedure, which was supported by MC simulation. From the results obtained in this work and the strict analysis performed, we can conclude that for clinical applications of TLD-100, special attention must be taken when published data are used to convert TL calibration curve from (60)Co to low-energy photons. Otherwise, this can lead to incorrect results when later used to measure absorbed dose in human tissue.
Dose-Response—A Challenge for Allelopathy?

PubMed Central

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

2005-01-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions. PMID:19330161
Considering the cumulative risk of mixtures of chemicals – A challenge for policy makers

PubMed Central

2012-01-01

Background The current paradigm for the assessment of the health risk of chemical substances focuses primarily on the effects of individual substances for determining the doses of toxicological concern in order to inform appropriately the regulatory process. These policy instruments place varying requirements on health and safety data of chemicals in the environment. REACH focuses on safety of individual substances; yet all the other facets of public health policy that relate to chemical stressors put emphasis on the effects of combined exposure to mixtures of chemical and physical agents. This emphasis brings about methodological problems linked to the complexity of the respective exposure pathways; the effect (more complex than simple additivity) of mixtures (the so-called 'cocktail effect'); dose extrapolation, i.e. the extrapolation of the validity of dose-response data to dose ranges that extend beyond the levels used for the derivation of the original dose-response relationship; the integrated use of toxicity data across species (including human clinical, epidemiological and biomonitoring data); and variation in inter-individual susceptibility associated with both genetic and environmental factors. Methods In this paper we give an overview of the main methodologies available today to estimate the human health risk of environmental chemical mixtures, ranging from dose addition to independent action, and from ignoring interactions among the mixture constituents to modelling their biological fate taking into account the biochemical interactions affecting both internal exposure and the toxic potency of the mixture. Results We discuss their applicability, possible options available to policy makers and the difficulties and potential pitfalls in implementing these methodologies in the frame of the currently existing policy framework in the European Union. Finally, we suggest a pragmatic solution for policy/regulatory action that would facilitate the evaluation of the health effects of chemical mixtures in the environment and consumer products. Conclusions One universally applicable methodology does not yet exist. Therefore, a pragmatic, tiered approach to regulatory risk assessment of chemical mixtures is suggested, encompassing (a) the use of dose addition to calculate a hazard index that takes into account interactions among mixture components; and (b) the use of the connectivity approach in data-rich situations to integrate mechanistic knowledge at different scales of biological organization. PMID:22759500
Modern dosimetric tools for 60Co irradiation at high containment laboratories

PubMed Central

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

2011-01-01

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

PubMed

Lentz, Thomas J; Rice, Carol H; Succop, Paul A; Lockey, James E; Dement, John M; LeMasters, Grace K

2003-04-01

Increasing production of refractory ceramic fiber (RCF), a synthetic vitreous material with industrial applications (e.g., kiln insulation), has created interest in potential respiratory effects of exposure to airborne fibers during manufacturing. An ongoing study of RCF manufacturing workers in the United States has indicated an association between cumulative fiber exposure and pleural plaques. Fiber sizing data, obtained from electron microscopy analyses of 118 air samples collected in three independent studies over a 20-year period (1976-1995), were used with a computer deposition model to estimate pulmonary dose of fibers of specified dimensions for 652 former and current RCF production workers. Separate dose correction factors reflecting differences in fiber dimensions in six uniform job title groups were used with data on airborne fiber concentration and employment duration to calculate cumulative dose estimates for each worker. From review of the literature, critical dimensions (diameter <0.4 microm, length <10 microm) were defined for fibers that may translocate to the parietal pleura. Each of three continuous exposure/dose metrics analyzed in separate logistic regression models was significantly related to plaques, even after adjusting for possible past asbestos exposure: cumulative fiber exposure, chi(2) = 15.2 (p < 0.01); cumulative pulmonary dose (all fibers), chi(2) = 14.6 (p < 0.01); cumulative pulmonary dose (critical dimension fibers), chi(2) = 12.4 (p < 0.01). Odds ratios (ORs) were calculated for levels of each metric. Increasing ORs were statistically significant for the two highest dose levels of critical dimension fibers (level three, OR = 11, 95%CI = [1.4, 98]; level four, OR = 25, 95%CI = [3.2, 190]). Similar associations existed for all metrics after adjustment for possible asbestos exposure. It was concluded that development of pleural plaques follows exposure- and dose-response patterns, and that airborne fibers in RCF manufacturing facilities include those with critical dimensions associated with pleural plaque formation. Analysis of additional air samples may improve estimates of the dose-response relationship.
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.
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.

Skull counting in late stages after internal contamination by actinides.

PubMed

Tani, Kotaro; Shutt, Arron; Kurihara, Osamu; Kosako, Toshiso

2015-02-01

Monitoring preparation for internal contamination with actinides (e.g. Pu and Am) is required to assess internal doses at nuclear fuel cycle-related facilities. In this paper, the authors focus on skull counting in case of single-incident inhalation of (241)Am and propose an effective procedure for skull counting with an existing system, taking into account the biokinetic behaviour of (241)Am in the human body. The predicted response of the system to skull counting under a certain counting geometry was found to be only ∼1.0 × 10(-5) cps Bq(-1) 1y after intake. However, this disadvantage could be remedied by repeated measurements of the skull during the late stage of the intake due to the predicted response reaching a plateau at about the 1000th day after exposure and exceeding that in the lung counting. Further studies are needed for the development of a new detection system with higher sensitivity to perform reliable internal dose estimations based on direct measurements. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Comparison of the relative airways and systemic potencies of inhaled fenoterol and salbutamol in asthmatic patients.

PubMed Central

Lipworth, B. J.; Newnham, D. M.; Clark, R. A.; Dhillon, D. P.; Winter, J. H.; McDevitt, D. G.

1995-01-01

BACKGROUND--There is controversy as to the relative safety of fenoterol and salbutamol. No differences have been found in the relative cardiac beta 1/beta 2 receptor activity of inhaled fenoterol and salbutamol in normal subjects. These initial findings have been extended by comparing the respective potencies of equivalent doses by weight of fenoterol and salbutamol in asthmatic subjects, in terms of airways and systemic responses. METHODS--Eighteen asthmatic patients of mean (SD) age 40 (14) years and a forced expiratory volume in one second (FEV1)% predicted of 56 (14)% (1.97 (0.66)1) were randomised to inhale fenoterol (100 micrograms/puff or 200 micrograms/puff), salbutamol, or placebo (100 micrograms/puff or 200 micrograms/puff) on three separate days. Dose-response curves were constructed using cumulative doses of 100 micrograms, 200 micrograms, 400 micrograms, 1000 micrograms, 2000 micrograms, and 4000 micrograms, and airways and systemic responses were measured 20 minutes after each dose with 40 minute increments. Dose ratios for the relative potency of fenoterol versus salbutamol were calculated from the dose-response curves using regression analysis of parallel slopes. RESULTS--There was no difference in bronchodilator potency between fenoterol and salbutamol (as median dose ratio): FEV1 1.1 (95% CI 0.4 to 4.6). In contrast, dose ratios for systemic responses showed that fenoterol was more potent than salbutamol: serum potassium 3.7 (95% CI 2.0 to 6.0), tremor 5.7 (95% CI 1.4 to 10.2), heart rate 1.6 (95% CI 1.0 to 2.3). At a conventional dose of 200 micrograms the only difference in response between the two drugs was observed for tremor (as mean difference): 0.23 log units (95% CI 0.06 to 0.41 log units). CONCLUSIONS--There was no difference in the bronchodilator potency between fenoterol and salbutamol on a microgram equivalent basis. In contrast, systemic potency was greater with fenoterol, although this difference was not clinically relevant at conventional dosages up to 200 micrograms. PMID:7886650
Age-related respiratory responses to substance P in normal sheep.

PubMed

Corcoran, B M; Haigh, A L

1993-01-01

The in vivo effects of substance P (SP) on respiratory parameters in four different age groups of sheep were examined. Intravenous SP (10(-8) to 5 x 10(-6) mol kg-1 bodyweight) caused a dose-dependent reduction in dynamic compliance and increase in respiratory resistance in all four groups. The bronchoconstrictor response was age-related, with the greatest response occurring in the youngest age group (four to six months). In the oldest group (over four years) there was minimal bronchomotor response to SP, but a dose-dependent apnoea was present. These findings indicate that there is an age-related alteration in the respiratory response to SP in sheep.
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:…
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.
Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

PubMed Central

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

2016-01-01

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

PubMed

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

2016-01-01

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

PubMed

Roch-Lefèvre, Sandrine; Grégoire, Eric; Martin-Bodiot, Cécile; Flegal, Matthew; Fréneau, Amélie; Blimkie, Melinda; Bannister, Laura; Wyatt, Heather; Barquinero, Joan-Francesc; Roy, Laurence; Benadjaoud, Mohamed; Priest, Nick; Jourdain, Jean-René; Klokov, Dmitry

2018-06-08

The aim of this study was to carry out a comprehensive examination of potential genotoxic effects of low doses of tritium delivered chronically to mice and to compare these effects to the ones resulting from equivalent doses of gamma-irradiation. Mice were chronically exposed for one or eight months to either tritiated water (HTO) or organically bound tritium (OBT) in drinking water at concentrations of 10 kBq/L, 1 MBq/L or 20 MBq/L. Dose rates of internal β-particle resulting from such tritium treatments were calculated and matching external gamma-exposures were carried out. We measured cytogenetic damage in bone marrow and in peripheral blood lymphocytes (PBLs) and the cumulative tritium doses (0.009 - 181 mGy) were used to evaluate the dose-response of OBT in PBLs, as well as its relative biological effectiveness (RBE). Neither tritium, nor gamma exposures produced genotoxic effects in bone marrow. However, significant increases in chromosome damage rates in PBLs were found as a result of chronic OBT exposures at 1 and 20 M Bq/L, but not at 10 kBq/L. When compared to an external acute gamma-exposure ex vivo , the RBE of OBT for chromosome aberrations induction was evaluated to be significantly higher than 1 at cumulative tritium doses below 10 mGy. Although found non-existent at 10 kBq/L (the WHO limit), the genotoxic potential of low doses of tritium (>10 kBq/L), mainly OBT, may be higher than currently assumed.
Dose Response Data for Hormonally Active Chemicals ...

EPA Pesticide Factsheets

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

PubMed

Visser, R; Godart, J; Wauben, D J L; Langendijk, J A; Van't Veld, A A; Korevaar, E W

2016-05-21

The objective of this study was to introduce a new iterative method to reconstruct multi leaf collimator (MLC) positions based on low resolution ionization detector array measurements and to evaluate its error detection performance. The iterative reconstruction method consists of a fluence model, a detector model and an optimizer. Expected detector response was calculated using a radiotherapy treatment plan in combination with the fluence model and detector model. MLC leaf positions were reconstructed by minimizing differences between expected and measured detector response. The iterative reconstruction method was evaluated for an Elekta SLi with 10.0 mm MLC leafs in combination with the COMPASS system and the MatriXX Evolution (IBA Dosimetry) detector with a spacing of 7.62 mm. The detector was positioned in such a way that each leaf pair of the MLC was aligned with one row of ionization chambers. Known leaf displacements were introduced in various field geometries ranging from -10.0 mm to 10.0 mm. Error detection performance was tested for MLC leaf position dependency relative to the detector position, gantry angle dependency, monitor unit dependency, and for ten clinical intensity modulated radiotherapy (IMRT) treatment beams. For one clinical head and neck IMRT treatment beam, influence of the iterative reconstruction method on existing 3D dose reconstruction artifacts was evaluated. The described iterative reconstruction method was capable of individual MLC leaf position reconstruction with millimeter accuracy, independent of the relative detector position within the range of clinically applied MU's for IMRT. Dose reconstruction artifacts in a clinical IMRT treatment beam were considerably reduced as compared to the current dose verification procedure. The iterative reconstruction method allows high accuracy 3D dose verification by including actual MLC leaf positions reconstructed from low resolution 2D measurements.
Investigating a Potential Auxin-Related Mode of Hormetic/Inhibitory Action of the Phytotoxin Parthenin.

PubMed

Belz, Regina G

2016-01-01

Parthenin is a metabolite of Parthenium hysterophorus and is believed to contribute to the weed's invasiveness via allelopathy. Despite the potential of parthenin to suppress competitors, low doses stimulate plant growth. This biphasic action was hypothesized to be auxin-like and, therefore, an auxin-related mode of parthenin action was investigated using two approaches: joint action experiments with Lactuca sativa, and dose-response experiments with auxin/antiauxin-resistant Arabidopsis thaliana genotypes. The joint action approach comprised binary mixtures of subinhibitory doses of the auxin 3-indoleacetic acid (IAA) mixed with parthenin or one of three reference compounds [indole-3-butyric acid (IBA), 2,3,5-triiodobenzoic acid (TIBA), 2-(p-chlorophenoxy)-2-methylpropionic acid (PCIB)]. The reference compounds significantly interacted with IAA at all doses, but parthenin interacted only at low doses indicating that parthenin hormesis may be auxin-related, in contrast to its inhibitory action. The genetic approach investigated the response of four auxin/antiauxin-resistant mutants and a wildtype to parthenin or two reference compounds (IAA, PCIB). The responses of mutant plants to the reference compounds confirmed previous reports, but differed from the responses observed for parthenin. Parthenin stimulated and inhibited all mutants independent of resistance. This provided no indication for an auxin-related action of parthenin. Therefore, the hypothesis of an auxin-related inhibitory action of parthenin was rejected in two independent experimental approaches, while the hypothesis of an auxin-related stimulatory effect could not be rejected.
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 dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.
Hyperuricemia and the risk for coronary heart disease morbidity and mortality a systematic review and dose-response meta-analysis

NASA Astrophysics Data System (ADS)

Li, Min; Hu, Xiaolan; Fan, Yingli; Li, Kun; Zhang, Xiaowei; Hou, Wenshang; Tang, Zhenyu

2016-01-01

Considerable controversy exists regarding the association between hyperuricemia and coronary heart disease (CHD). Therefore, we performed a systematic review and dose-response meta-analysis of prospective studies to examine the controversy. Prospective cohort studies with relative risks (RRs) and 95% confidence intervals (CIs) for CHD according to serum uric acid levels in adults were eligible. A random-effects model was used to compute the pooled risk estimate. The search yielded 29 prospective cohort studies (n = 958410 participants). Hyperuricemia was associated with increased risk of CHD morbidity (adjusted RR 1.13; 95% CI 1.05 to 1.21) and mortality (adjusted RR 1.27; 95% CI 1.16 to 1.39). For each increase of 1 mg/dl in uric acid level, the pooled multivariate RR of CHD mortality was 1.13 (95% CI 1.06 to 1.20). Dose-response analysis indicated that the combined RR of CHD mortality for an increase of 1 mg uric acid level per dl was 1.02 (95% CI 0.84 to 1.24) without heterogeneity among males (P = 0.879, I2 = 0%) and 2.44 (95% CI 1.69 to 3.54) without heterogeneity among females (P = 0.526, I2 = 0%). The increased risk of CHD associated with hyperuricemia was consistent across most subgroups. Hyperuricemia may increase the risk of CHD events, particularly CHD mortality in females.
Discrimination and common mental disorders of undergraduate students of the Universidade Federal de Santa Catarina.

PubMed

de Souza, Maria Vitória Cordeiro; Lemkuhl, Isabel; Bastos, João Luiz

2015-01-01

The pathogenic and consistent effect of discrimination on mental health has been largely documented in the literature. However, there are few studies measuring multiple types of discrimination, evaluating the existence of a dose-response relationship or investigating possible effect modifiers of such an association. To investigate the association between experiences of discrimination attributed to multiple reasons and common mental disorders, including the adjustment for potential confounders, assessment of dose-response relations, and examination of effect modifiers in undergraduate students from southern Brazil. In the first semester of 2012, 1,023 students from the Universidade Federal de Santa Catarina answered a self-administered questionnaire on socio-demographic characteristics, undergraduate course, experiences of discrimination and common mental disorders. Associations were analyzed through logistic regression models, estimation of Odds Ratios and 95% confidence intervals (95%CI). The study results showed that students reporting discrimination at high frequency and intensity were 4.4 (95%CI 1.6 - 12.4) times more likely to present common mental disorders. However, the relationship between discrimination and common mental disorders was protective among Electrical Engineering students, when compared to Accounting Sciences students who did not report discrimination. The findings suggest that the dose-response relationship between experiences of discrimination and common mental disorders reinforces the hypothetical causal nature of this association. Nevertheless, the modification of effect caused by the undergraduate course should be considered in future studies for a better understanding and measurement of both phenomena.
An evaluation of some pertinent parameters that influence the dosimetric performance of synthetic diamond detectors

NASA Astrophysics Data System (ADS)

Ade, N.; Nam, T. L.; Mhlanga, S. H.

2013-05-01

Although the near-tissue equivalence of diamond allows the direct measurement of dose for clinical applications without the need for energy-corrections, it is often cited that diamond detectors require pre-irradiation, a procedure necessary to stabilize the response or sensitivity of a diamond detector before dose measurements. In addition it has been pointed out that the relative dose measured with a diamond detector requires dose rate dependence correction and that the angular dependence of a detector could be due to its mechanical design or to the intrinsic angular sensitivity of the detection process. While the cause of instability of response has not been meticulously investigated, the issue of dose rate dependence correction is uncertain as some studies ignored it but reported good results. The aims of this study were therefore to investigate, in particular (1) the major cause of the unstable response of diamond detectors requiring pre-irradiation; (2) the influence of dose rate dependence correction in relative dose measurements; and (3) the angular dependence of the diamond detectors. The study was conducted with low-energy X-rays and electron therapy beams on HPHT and CVD synthesized diamonds. Ionization chambers were used for comparative measurements. Through systematic investigations, the major cause of the unstable response of diamond detectors requiring the recommended pre-irradiation step was isolated and attributed to the presence and effects of ambient light. The variation in detector's response between measurements in light and dark conditions could be as high as 63% for a CVD diamond. Dose rate dependence parameters (Δ values) of 0.950 and 1.035 were found for the HPHT and CVD diamond detectors, respectively. Without corrections based on dose rate dependence, the relative differences between depth-doses measured with the diamond detectors and a Markus chamber for exposures to 7 and 14 MeV electron beams were within 2.5%. A dose rate dependence correction using the Δ values obtained seemed to worsen the performance of the HPHT sample (up to about 3.3%) but it had a marginal effect on the performance of the CVD sample. In addition, the angular response of the CVD diamond detector was shown to be comparable with that of a cylindrical chamber. This study concludes that once the responses of the diamond detectors have been stabilised and they are properly shielded from ambient light, pre-irradiation prior to each measurement is not required. Also, the relative dose measured with the diamond detectors do not require dose rate dependence corrections as the required correction is only marginal and could have no dosimetric significance.
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…
Verapamil Blocks Scopolamine Enhancement Effect on Memory Consolidation in Passive Avoidance Task in Rats

PubMed Central

Giménez De Béjar, Verónica; Caballero Bleda, María; Popović, Natalija; Popović, Miroljub

2017-01-01

Our recent data have indicated that scopolamine, a non-selective muscarinic receptor antagonist, improves memory consolidation, in a passive avoidance task, tested in rats. It has been found that verapamil, a phenylalkylamine class of the L-type voltage-dependent calcium channel antagonist, inhibits [3H] N-methyl scopolamine binding to M1 muscarinic receptors. However, there are no data about the effect of verapamil on memory consolidation in the passive avoidance task, in rats. The purpose of the present study was to examine the effects of verapamil (0.5, 1.0, 2.5, 5.0, 10, or 20 mg/kg i.p.) as well as the interaction between scopolamine and verapamil on memory consolidation in the step-through passive avoidance task, in Wistar rats. Our results showed that verapamil (1.0 and 2.5 mg/kg) administered immediately after the acquisition task significantly increased the latency of the passive avoidance response, on the 48 h retested trial, improving memory consolidation. On the other hand, verapamil in a dose of 5 mg/kg, that per se does not affect memory consolidation, significantly reversed the memory consolidation improvement induced by scopolamine (1 mg/kg, i.p., administered immediately after verapamil treatment) but did not change the passive avoidance response in rats treated by an ineffective dose of scopolamine (30 mg/kg). In conclusion, the present data suggest that (1) the post-training administration of verapamil, dose-dependently, improves the passive avoidance response; (2) verapamil, in ineffective dose, abolished the improvement of memory consolidation effect of scopolamine; and (3) exists interaction between cholinergic muscarinic receptors and calcium homeostasis-related mechanisms in the consolidation of emotional memory. PMID:28878678
Development of an in vitro bioassay for measuring susceptibility to macrocyclic lactone anthelmintics in Dirofilaria immitis.

PubMed

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

2013-12-01

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

PubMed

Bartell, S M; Ponce, R A; Sanga, R N; Faustman, E M

2000-10-01

Regulatory guidelines regarding methylmercury exposure depend on dose-response models relating observed mercury concentrations in maternal blood, cord blood, and maternal hair to developmental neurobehavioral endpoints. Generalized estimates of the maternal blood-to-hair, blood-to-intake, or hair-to-intake ratios are necessary for linking exposure to biomarker-based dose-response models. Most assessments have used point estimates for these ratios; however, significant interindividual and interstudy variability has been reported. For example, a maternal ratio of 250 ppm in hair per mg/L in blood is commonly used in models, but a 1990 WHO review reports mean ratios ranging from 140 to 370 ppm per mg/L. To account for interindividual and interstudy variation in applying these ratios to risk and safety assessment, some researchers have proposed representing the ratios with probability distributions and conducting probabilistic assessments. Such assessments would allow regulators to consider the range and like-lihood of mercury exposures in a population, rather than limiting the evaluation to an estimate of the average exposure or a single conservative exposure estimate. However, no consensus exists on the most appropriate distributions for representing these parameters. We discuss published reviews of blood-to-hair and blood-to-intake steady state ratios for mercury and suggest statistical approaches for combining existing datasets to form generalized probability distributions for mercury distribution ratios. Although generalized distributions may not be applicable to all populations, they allow a more informative assessment than point estimates where individual biokinetic information is unavailable. Whereas development and use of these distributions will improve existing exposure and risk models, additional efforts in data generation and model development are required.
Population variability in animal health: Influence on dose-exposure-response relationships: Part II: Modelling and simulation.

PubMed

Martinez, Marilyn N; Gehring, Ronette; Mochel, Jonathan P; Pade, Devendra; Pelligand, Ludovic

2018-05-28

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session on the influence of population variability on dose-exposure-response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals. © 2018 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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

PubMed

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

2016-02-10

Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure. Copyright © 2015 John Wiley & Sons, Ltd.
Factors modifying the response of large animals to low-intensity radiation exposure

NASA Technical Reports Server (NTRS)

Page, N. P.; Still, E. T.

1972-01-01

In assessing the biological response to space radiation, two of the most important modifying factors are dose protraction and dose distribution to the body. Studies are reported in which sheep and swine were used to compare the hematology and lethality response resulting from radiation exposure encountered in a variety of forms, including acute (high dose-rate), chronic (low dose-rate), combinations of acute and chronic, and whether received as a continuous or as fractionated exposure. While sheep and swine are basically similar in response to acute radiation, their sensitivity to chronic irradiation is markedly different. Sheep remain relatively sensitive as the radiation exposure is protracted while swine are more resistant and capable of surviving extremely large doses of chronic irradiation. This response to chronic irradiation correlated well with changes in radiosensitivity and recovery following an acute, sublethal exposure.
Cumulative childhood maltreatment and its dose-response relation with adult symptomatology: Findings in a sample of adult survivors of sexual abuse.

PubMed

Steine, Iris M; Winje, Dagfinn; Krystal, John H; Bjorvatn, Bjørn; Milde, Anne Marita; Grønli, Janne; Nordhus, Inger Hilde; Pallesen, Ståle

2017-03-01

In the present study, we examined the role of cumulative childhood maltreatment experiences for several health related outcomes in adulthood, including symptoms of psychological distress as well as perceived social support and hardiness. The sample comprised adult survivors of sexual abuse (N=278, 95.3% women, mean age at first abusive incident=6.4 years). One-way ANOVAs revealed a statistically significant dose-response relation between cumulative childhood maltreatment scores and self-reported symptoms of posttraumatic stress (PTSS), anxiety, depression, eating disorders, dissociation, insomnia, nightmare related distress, physical pain, emotional pain, relational problems, self-harm behaviors as well as on a measure of symptom complexity. Cumulative childhood maltreatment was also associated with lower levels of work functioning. An inverse dose-response relation was found for perceived social support and hardiness. Using a Bonferroni corrected alpha level, cumulative childhood maltreatment remained significantly associated with all outcome measures with the exception of eating disorder symptoms after controlling for abuse-related independent variables in hierarchical regression analyses. Results add to previous literature by showing that dose-response relation between cumulative childhood adversities and adult symptom outcomes could also be identified in a sample characterized by high exposure to adversities, and lends support to the notion put forth by previous authors that cumulative childhood adversities seem to be related to the severity of adult health outcomes in a rule-governed way. Copyright © 2017 Elsevier Ltd. All rights reserved.
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.
Vesicular Stomatitis Virus-Vectored Multi-Antigen Tuberculosis Vaccine Limits Bacterial Proliferation in Mice following a Single Intranasal Dose

PubMed Central

Zhang, Ming; Dong, Chunsheng; Xiong, Sidong

2017-01-01

Tuberculosis (TB) remains a serious health problem worldwide, and an urgent need exists to improve or replace the available vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG). Most vaccination protocols adapt two or three doses to induce long-term lasting immunity. Our previous study showed that the naked DNA encoding the triple-antigen fusion TFP846 (Rv3615c-Mtb10.4-Rv2660c) induced robust T cellular immune responses accompanying four inoculations against mycobacteria infection. However, a number of compliance issues exist in some areas lacking the appropriate medical infrastructure with multiple administrations. In this study, a novel vesicular stomatitis virus expressing TFP846 (VSV-846) was developed and the immune responses elicited by VSV-846 were evaluated. We observed that intranasal delivery of VSV-846 induced a potent antigen-specific T cell response following a single dose and VSV-846 efficiently controlled bacterial growth to levels ~10-fold lower than that observed in the mock group 6 weeks post-infection in BCG-infected mice. Importantly, mice immunized with VSV-846 provided long-term protection against mycobacteria infection compared with those receiving p846 or BCG immunization. Increased memory T cells were also observed in the spleens of VSV-846-vaccinated mice, which could be a potential mechanism associated with long-term protective immune response. These findings supported the use of VSV as an antigen delivery vector with the potential for TB vaccine development. PMID:28224119
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.
A comparison of two doses of omeprazole in the treatment of equine gastric ulcer syndrome: a blinded, randomised, clinical trial.

PubMed

Sykes, B W; Sykes, K M; Hallowell, G D

2014-07-01

Studies on omeprazole have reported that doses as low as 0.7 mg/kg bwt per os are potent suppressors of acid production. Yet, to date, no studies have compared treatment efficacy of different doses in clinical cases of equine gastric ulceration. Furthermore, no studies have been performed to compare the healing response of the squamous and glandular mucosa to acid suppression therapy. To compare: 1) the efficacy of 2 doses of omeprazole in the treatment of primary squamous and glandular gastric ulceration; and 2) the healing response of primary squamous and glandular gastric ulceration to acid suppression therapy. A blinded, randomised, dose-response clinical trial. Twenty Thoroughbred racehorses with grade ≥2/4 glandular ulceration were identified on gastroscopy. Seventeen horses also had grade ≥2/4 squamous ulceration. Horses were randomly assigned to one of 2 groups. Horses received either 2.0 g (high dose: 4.0 mg/kg bwt) or 0.8 g (low dose: 1.6 mg/kg bwt) of oral omeprazole per os once daily. Gastroscopy was repeated at 28-35 days. Time and dose significantly affected grades of squamous (P<0.0001, P = 0.02) and glandular (P = 0.006 and 0.005) ulceration. Data analysis did not support our hypothesis that the lower dose would have similar effects (i.e. be noninferior) to the higher dose when considering ulcer healing and ulcer improvement. Improvement was more likely with the high dose for the squamous (P = 0.05) but not glandular (P = 0.4) mucosa. The percentage of glandular ulcers that improved was less than squamous ulcers (P = 0.02). The results suggest that a dose-response exists for the treatment of both squamous and glandular ulcers. Improvement of glandular ulcers was not as complete as observed with squamous ulcers and current equine gastric ulcer syndrome treatment recommendations may not be appropriate for glandular disease. © 2013 EVJ Ltd.
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 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response. PMID:25574587
Determination of absorbed dose to water around a clinical HDR {sup 192}Ir source using LiF:Mg,Ti TLDs demonstrates an LET dependence of detector response

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

Carlsson Tedgren, Aasa; Elia, Rouba; Hedtjaern, Haakan

2012-02-15

Purpose: Experimental radiation dosimetry with thermoluminescent dosimeters (TLDs), calibrated in a {sup 60}Co or megavoltage (MV) photon beam, is recommended by AAPM TG-43U1for verification of Monte Carlo calculated absorbed doses around brachytherapy sources. However, it has been shown by Carlsson Tedgren et al.[Med. Phys. 38, 5539-5550 (2011)] that for TLDs of LiF:Mg,Ti, detector response was 4% higher in a {sup 137}Cs beam than in a {sup 60}Co one. The aim of this work was to investigate if similar over-response exists when measuring absorbed dose to water around {sup 192}Ir sources, using LiF:Mg,Ti dosimeters calibrated in a 6 MV photon beam.more » Methods: LiF dosimeters were calibrated to measure absorbed dose to water in a 6 MV photon beam and used to measure absorbed dose to water at distances of 3, 5, and 7 cm from a clinical high dose rate (HDR) {sup 192}Ir source in a polymethylmethacrylate (PMMA) phantom. Measured values were compared to values of absorbed dose to water calculated using a treatment planning system (TPS) including corrections for the difference in energy absorption properties between calibration quality and the quality in the users'{sup 192}Ir beam and for the use of a PMMA phantom instead of the water phantom underlying dose calculations in the TPS. Results: Measured absorbed doses to water around the {sup 192}Ir source were overestimated by 5% compared to those calculated by the TPS. Corresponding absorbed doses to water measured in a previous work with lithium formate electron paramagnetic resonance (EPR) dosimeters by Antonovic et al. [Med. Phys. 36, 2236-2247 (2009)], using the same irradiation setup and calibration procedure as in this work, were 2% lower than those calculated by the TPS. The results obtained in the measurements in this work and those obtained using the EPR lithium formate dosimeters were, within the expanded (k = 2) uncertainty, in agreement with the values derived by the TPS. The discrepancy between the results using LiF:Mg,Ti TLDs and the EPR lithium formate dosimeters was, however, statistically significant and in agreement with the difference in relative detector responses found for the two detector systems by Carlsson Tedgren et al. [Med. Phys. 38, 5539-5550 (2011)] and by Adolfsson et al.[Med. Phys. 37, 4946-4959 (2010)]. Conclusions: When calibrated in {sup 60}Co or MV photon beams, correction for the linear energy transfer (LET) dependence of LiF:Mg,Ti detector response will be needed as to measure absorbed doses to water in a {sup 192}Ir beam with highest accuracy. Such corrections will depend on the manufacturing process (MTS-N Poland or Harshaw TLD-100) and details of the annealing and read-out schemes used.« less
Determination of absorbed dose to water around a clinical HDR (192)Ir source using LiF:Mg,Ti TLDs demonstrates an LET dependence of detector response.

PubMed

Carlsson Tedgren, Asa; Elia, Rouba; Hedtjarn, Hakan; Olsson, Sara; Alm Carlsson, Gudrun

2012-02-01

Experimental radiation dosimetry with thermoluminescent dosimeters (TLDs), calibrated in a (60)Co or megavoltage (MV) photon beam, is recommended by AAPM TG-43U1for verification of Monte Carlo calculated absorbed doses around brachytherapy sources. However, it has been shown by Carlsson Tedgren et al. [Med. Phys. 38, 5539-5550 (2011)] that for TLDs of LiF:Mg,Ti, detector response was 4% higher in a (137)Cs beam than in a (60)Co one. The aim of this work was to investigate if similar over-response exists when measuring absorbed dose to water around (192)Ir sources, using LiF:Mg,Ti dosimeters calibrated in a 6 MV photon beam. LiF dosimeters were calibrated to measure absorbed dose to water in a 6 MV photon beam and used to measure absorbed dose to water at distances of 3, 5, and 7 cm from a clinical high dose rate (HDR) (192)Ir source in a polymethylmethacrylate (PMMA) phantom. Measured values were compared to values of absorbed dose to water calculated using a treatment planning system (TPS) including corrections for the difference in energy absorption properties between calibration quality and the quality in the users' (192)Ir beam and for the use of a PMMA phantom instead of the water phantom underlying dose calculations in the TPS. Measured absorbed doses to water around the (192)Ir source were overestimated by 5% compared to those calculated by the TPS. Corresponding absorbed doses to water measured in a previous work with lithium formate electron paramagnetic resonance (EPR) dosimeters by Antonovic et al. [Med. Phys. 36, 2236-2247 (2009)], using the same irradiation setup and calibration procedure as in this work, were 2% lower than those calculated by the TPS. The results obtained in the measurements in this work and those obtained using the EPR lithium formate dosimeters were, within the expanded (k = 2) uncertainty, in agreement with the values derived by the TPS. The discrepancy between the results using LiF:Mg,Ti TLDs and the EPR lithium formate dosimeters was, however, statistically significant and in agreement with the difference in relative detector responses found for the two detector systems by Carlsson Tedgren et al. [Med. Phys. 38, 5539-5550 (2011)] and by Adolfsson et al. [Med. Phys. 37, 4946-4959 (2010)]. When calibrated in (60)Co or MV photon beams, correction for the linear energy transfer (LET) dependence of LiF:Mg,Ti detector response will be needed as to measure absorbed doses to water in a (192)Ir beam with highest accuracy. Such corrections will depend on the manufacturing process (MTS-N Poland or Harshaw TLD-100) and details of the annealing and read-out schemes used.
Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003.

PubMed

Shimizu, Yukiko; Kodama, Kazunori; Nishi, Nobuo; Kasagi, Fumiyoshi; Suyama, Akihiko; Soda, Midori; Grant, Eric J; Sugiyama, Hiromi; Sakata, Ritsu; Moriwaki, Hiroko; Hayashi, Mikiko; Konda, Manami; Shore, Roy E

2010-01-14

To investigate the degree to which ionising radiation confers risk of mortality from heart disease and stroke. Prospective cohort study with more than 50 years of follow-up. Atomic bomb survivors in Hiroshima and Nagasaki, Japan. 86 611 Life Span Study cohort members with individually estimated radiation doses from 0 to >3 Gy (86% received <0.2 Gy). Mortality from stroke or heart disease as the underlying cause of death and dose-response relations with atomic bomb radiation. About 9600 participants died of stroke and 8400 died of heart disease between 1950 and 2003. For stroke, the estimated excess relative risk per gray was 9% (95% confidence interval 1% to 17%, P=0.02) on the basis of a linear dose-response model, but an indication of possible upward curvature suggested relatively little risk at low doses. For heart disease, the estimated excess relative risk per gray was 14% (6% to 23%, P<0.001); a linear model provided the best fit, suggesting excess risk even at lower doses. However, the dose-response effect over the restricted dose range of 0 to 0.5 Gy was not significant. Prospective data on smoking, alcohol intake, education, occupation, obesity, and diabetes had almost no impact on the radiation risk estimates for either stroke or heart disease, and misdiagnosis of cancers as circulatory diseases could not account for the associations seen. Doses above 0.5 Gy are associated with an elevated risk of both stroke and heart disease, but the degree of risk at lower doses is unclear. Stroke and heart disease together account for about one third as many radiation associated excess deaths as do cancers among atomic bomb survivors.
Dosing antiretroviral medication when crossing time zones: a review

PubMed Central

Lewis, Joseph M.; Volny-Anne, Alain; Waitt, Catriona; Boffito, Marta; Khoo, Saye

2016-01-01

International tourism continues to increase worldwide, and people living with HIV and their clinicians are increasingly confronted with the problem of how to dose antiretroviral therapy during transmeridian air travel across time zones. No guidance on this topic currently exists. This review is a response to requests from patient groups for clear, practical and evidence-based guidance for travelling on antiretroviral therapy; we present currently available data on the pharmacokinetic forgiveness and toxicity of various antiretroviral regimens, and synthesize this data to provide guidelines on how to safely dose antiretrovirals when travelling across time zones. PMID:26684823
Incidence of adrenal insufficiency and impact of corticosteroid supplementation in critically ill children with systemic inflammatory syndrome and vasopressor-dependent shock.

PubMed

Hebbar, Kiran B; Stockwell, Jana A; Leong, Traci; Fortenberry, James D

2011-05-01

Adrenal insufficiency may be common in adults and children with vasopressor-resistant shock. We developed a protocolized approach to low-dose adrenocorticotropin testing and empirical low-dose glucocorticoid/mineralocorticoid supplementation in children with systemic inflammatory response syndrome and persistent hypotension following fluid resuscitation and vasopressor infusion. We hypothesized that absolute and relative adrenal insufficiency was common in children with systemic inflammatory response syndrome requiring vasopressor support and that steroid administration would be associated with decreased vasopressor need. Retrospective review of pediatric patients with systemic inflammatory response syndrome and vasopressor-dependent shock receiving protocol-based adrenocorticotropin testing and low-dose steroid supplementation. The incidence of absolute and relative adrenal insufficiency was determined using several definitions. Vasopressor dose requirements were evaluated before, and following, initiation of corticosteroids. Seventy-eight patients met inclusion criteria for systemic inflammatory response syndrome and shock; 40 had septic shock. Median age was 84 months (range, 0.5-295). By adrenocorticotropin testing, 44 (56%) had absolute adrenal insufficiency, 39 (50%) had relative adrenal insufficiency, and 69 (88%) had either form of adrenal insufficiency. Adrenal insufficiency incidence was significantly higher in children >2 yrs (p = .0209). Therapeutic interventions included median 80-mL/kg fluid resuscitation; 65% of patients required dopamine, 58% norepinephrine, and 49% dopamine plus norepinephrine. With steroid supplementation, median dopamine dose decreased from 10 to 4 μg/kg/min at 4 hrs (p = .0001), and median dose of norepinephrine decreased from 0.175 μg/kg/min to 0.05 μg/kg/min at 4 hrs (p = .039). Absolute and relative adrenal insufficiency was prevalent in this cohort of children with systemic inflammatory response syndrome and vasopressor-dependent shock and increased with age. Introduction of steroids produced a significant reduction in vasopressor duration and dosage. Use of low-dose adrenocorticotropin testing may help further delineate populations who require steroid supplementation.
High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

PubMed Central

Jena, Rabindra Kumar; Swain, Kali Prasanna

2016-01-01

Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873
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
Chemotherapy dosing in achondroplastic dwarfism: a case report and review of literature.

PubMed

Elsoueidi, R; Gresham, C; Michael, L; Chaney, D; Mourad, H

2016-12-01

CASE DESCRIPTION: A 74-year-old female with achondroplastic dwarfism was diagnosed with ER-, BR- and HER2- breast cancer. No guideline currently exists to direct chemotherapy dosing in this population. She received neoadjuvant chemotherapy based on body surface area utilizing actual height and weight with dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with the use of granulocyte colony-stimulating factor. Satisfactory clinical response and remission were achieved, and treatment proceeded without any significant toxicity or delays. In the absence of guideline recommendations, dosing chemotherapy based on actual height and weight in patients with achondroplastic dwarfism may be safe and appropriate. © 2016 John Wiley & Sons Ltd.
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
Effect of toll-like receptor 3 agonists on the functionality and metastatic properties of breast cancer cell model.

PubMed

Alizadeh, Nastaran; Amiri, Mohammad Mehdi; Salek Moghadam, Alireza; Zarnani, Amir Hassan; Saadat, Farshid; Safavifar, Farnaz; Berahmeh, Azar; Khorramizadeh, Mohammad Reza

2013-05-15

There exists compelling evidence that Toll-like receptor 3 (TLR3) agonists can directly affect human cancer cells. The aim of this study was to investigate anti-cancer effects of TLR3 agonist in human breast cell line. We assessed potential effects of poly (A:U) on human breast cell line (MDA-MB-231) on a dose-response and time-course basis. Human breast cell line MDA-MB-231 was treated with different concentrations of poly (A:U) and lipopolysaccharide (LPS). Then, the following assays were performed on the treated cells: dose-response and time-course cytotoxicity using colorimetric method; matrix metalloproteinase-2 (MMP-2) activity using gelatin zymography method; apoptosis using annexin-v flowcytometry method; and relative expression of TLR3 and MMP-2 mRNA using reverse transcriptase polymerase chain reaction (RT-PCR) method. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, (MMP-2) activity (using gelatin zymography), apoptosis (using annexin-v flowcytometry method) assays and expression of TLR3 and MMP-2 genes (using PCR method) were performed. Cytotoxicity and flowcytometry analysis of poly (A:U) showed that poly (A:U) do not have any cytotoxic and apoptotic effects in different concentrations used. MMP-2 activity analysis showed significant decrease in higher concentrations (50 and 100 μg/ ml) between treated and untreated cells. Moreover, poly A:U treated cells demonstrated decreased expression of MMP-2 gene in higher concentrations. Collectively, our data indicated that human breast cancer cell line (MDA-MB-231) was highly responsive to poly (A:U). The antimetastatic effect of direct poly (A:U) and TLR3 interactions in MDA-MB-231 cells could provide new approaches in malignant tumor therapeutic strategy.
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...

Single administration of intra-articular bupivacaine in arthroscopic knee surgery: a systematic review and meta-analysis.

PubMed

Sun, Qi-Bin; Liu, Shi-Dong; Meng, Qin-Jun; Qu, Hua-Zheng; Zhang, Zheng

2015-02-10

Single administration of intra-articular (IA) bupivacaine for pain relief after arthroscopic knee surgery is effective, but its active duration and dose-response relationship is unclear. We conducted this meta-analysis to summarize all published randomized controlled trials (RCTs), thus providing the most recent information on the safety and efficacy of single-administration IA bupivacaine for pain relief after arthroscopic knee surgery, and to determine whether a dose-response relationship exists. A systematic electronic literature search (through April 2014) was conducted to identify those RCTs that addressed the safety and efficacy of a single administration of IA bupivacaine for pain management after arthroscopic knee surgery. Subgroup analysis was conducted to determine changes in visual analog scale (VAS) scores at seven postoperative time points. Meta-regression and subgroup analyses were carried out to assess the effects of various treatment factors on efficacy and to evaluate the dose-response relationship of bupivacaine. Weighted mean differences or relative risks were calculated and pooled using a random-effects model. Twenty-eight trials involving 1,560 patients who underwent arthroscopic knee surgery met the inclusion criteria. The trials were subject to medium risk of bias. VAS scores at 2, 4, 6, 12, and 24 h postoperatively were significantly lower, the number of patients requiring supplementary analgesia was smaller, and the time to first request for analgesia was longer in the IA bupivacaine group than in the placebo group. The analgesic effect of single-administration IA bupivacaine may be associated with the effect of concomitant administration of epinephrine and concentration of bupivacaine, and no dose-response relationship was identified. No significant difference in side effects was detected between groups. Current evidence shows that the use of single-administration IA bupivacaine is effective for postoperative pain management in patients undergoing arthroscopic knee surgery, with satisfactory short-term safety. Low-dose administration of IA bupivacaine 0.5% combined with epinephrine adjuvant in clinical practice should be performed. Additional high-quality RCTs with longer follow-up periods are required to examine the safety of single-administration IA bupivacaine.
Cancer mortality among coke oven workers.

PubMed Central

Redmond, C K

1983-01-01

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

PubMed

Sugiyama, Daisuke; Hattori, Takatoshi

2013-01-01

In environmental remediation after nuclear accidents, radioactive wastes have to be appropriately managed in existing exposure situations with contamination resulting from the emission of radionuclides by such accidents. In this paper, a framework of radiation protection from radioactive waste management in existing exposure situations for application to the practical and reasonable waste management in contaminated areas, referring to related ICRP recommendations was proposed. In the proposed concept, intermediate reference levels for waste management are adopted gradually according to the progress of the reduction in the existing ambient dose in the environment on the basis of the principles of justification and optimisation by taking into account the practicability of the management of radioactive waste and environmental remediation. It is essential to include the participation of relevant stakeholders living in existing exposure situations in the selection of reference levels for the existing ambient dose and waste management.
Radiological protection from radioactive waste management in existing exposure situations resulting from a nuclear accident

PubMed Central

Sugiyama, Daisuke; Hattori, Takatoshi

2013-01-01

In environmental remediation after nuclear accidents, radioactive wastes have to be appropriately managed in existing exposure situations with contamination resulting from the emission of radionuclides by such accidents. In this paper, a framework of radiation protection from radioactive waste management in existing exposure situations for application to the practical and reasonable waste management in contaminated areas, referring to related ICRP recommendations was proposed. In the proposed concept, intermediate reference levels for waste management are adopted gradually according to the progress of the reduction in the existing ambient dose in the environment on the basis of the principles of justification and optimisation by taking into account the practicability of the management of radioactive waste and environmental remediation. It is essential to include the participation of relevant stakeholders living in existing exposure situations in the selection of reference levels for the existing ambient dose and waste management. PMID:22719047
Direct-detection EPID dosimetry: investigation of a potential clinical configuration for IMRT verification.

PubMed

Vial, Philip; Gustafsson, Helen; Oliver, Lyn; Baldock, Clive; Greer, Peter B

2009-12-07

The routine use of electronic portal imaging devices (EPIDs) as dosimeters for radiotherapy quality assurance is complicated by the non-water equivalence of the EPID's dose response. A commercial EPID modified to a direct-detection configuration was previously demonstrated to provide water-equivalent dose response with d(max) solid water build-up and 10 cm solid water backscatter. Clinical implementation of the direct EPID (dEPID) requires a design that maintains the water-equivalent dose response, can be incorporated onto existing EPID support arms and maintains sufficient image quality for clinical imaging. This study investigated the dEPID dose response with different configurations of build-up and backscatter using varying thickness of solid water and copper. Field size output factors and beam profiles measured with the dEPID were compared with ionization chamber measurements of dose in water for both 6 MV and 18 MV. The dEPID configured with d(max) solid water build-up and no backscatter (except for the support arm) was within 1.5% of dose in water data for both energies. The dEPID was maintained in this configuration for clinical dosimetry and image quality studies. Close agreement between the dEPID and treatment planning system was obtained for an IMRT field with 98.4% of pixels within the field meeting a gamma criterion of 3% and 3 mm. The reduced sensitivity of the dEPID resulted in a poorer image quality based on quantitative (contrast-to-noise ratio) and qualitative (anthropomorphic phantom) studies. However, clinically useful images were obtained with the dEPID using typical treatment field doses. The dEPID is a water-equivalent dosimeter that can be implemented with minimal modifications to the standard commercial EPID design. The proposed dEPID design greatly simplifies the verification of IMRT dose delivery.
Evaluation of putative allelochemicals in rice root exudates for their role in the suppression of arrowhead root growth.

PubMed

Seal, Alexa N; Haig, Terry; Pratley, James E

2004-08-01

In previous studies, 15 putative allelopathic compounds detected in rice root exudates were quantified by GC/MS/MS. In this study, multiple regression analysis on these compounds determined that five selected phenolics, namely caffeic, p-hydroxybenzoic, vanillic, syringic, and p-coumaric acids, from rice exudates were best correlated with the observed allelopathic effect on arrowhead (Sagittaria montevidensis) root growth. Despite this positive association, determination of the phenolic acid dose-response curve established that the amount quantified in the exudates was much lower than the required threshold concentration for arrowhead inhibition. A similar dose-response curve resulted from a combination of all 15 quantified compounds. Significant differences between the amounts of trans-ferulic acid, abietic acid, and an indole also existed between allelopathic and non-allelopathic rice cultivars. The potential roles of these three compounds in rice allelopathy were examined by chemoassay. Overall, neither the addition of trans-ferulic acid nor 5-hydroxyindole-3-acetic acid to the phenolic mix significantly contributed to phytotoxicity, although at higher concentrations, trans-ferulic acid appeared to act antagonistically to the phytotoxic effects of the phenolic mix. The addition of abietic acid also decreased the inhibitory effect of the phenolic mix. These studies indicate that the compounds quantified are not directly responsible for the observed allelopathic response. It is possible that the amount of phenolic acids may be indirectly related to the chemicals finally responsible for the observed allelopathic effect.
Sublethal dose of phoxim and Bombyx mori nucleopolyhedrovirus interact to elevate silkworm mortality.

PubMed

Gu, ZhiYa; Li, FanChi; Hu, JingSheng; Ding, Chao; Wang, Chaoqian; Tian, JiangHai; Xue, Bin; Xu, KaiZun; Shen, WeiDe; Li, Bing

2017-03-01

Silkworm (Bombyx mori) is an economically important insect. It is relatively less resistant to certain chemicals and environment exposures such as pesticides and pathogens. After pesticide exposures, the silkworms are more susceptible to microbial infections. The mechanism underlying the susceptibility might be related to immune response and oxidative stress. A sublethal dose of phoxim combined with Bombyx mori nucleopolyhedrovirus (BmNPV) elevated the silkworm mortality at 96 h. We found a higher content of H 2 O 2 and increased levels of genes related to oxidative stress and immune response after treatment with a sublethal dose of phoxim for 24 h or 48 h. However, such response decreased with longer pesticide treatment. Mortality increased by 44% when B. mori was exposed to combined treatment with BmNPV and phoxim rather than BmNPV alone. The level of examined immune-related and oxidative-stress-related genes significantly decreased in the combined treatment group compared with the BmNPV group. Our results indicated that, with long-term exposure to pesticides such as OPs, even at sublethal dose, the oxidative stress response and immune responses in silkworm were inhibited, which may lead to further immune impairment and accumulation of oxidative stress, resulting in susceptibility to the virus and harm to the silkworm. Our study provided insights for understanding the susceptibility to pathogen after pesticide exposures, which may promote the development of better pesticide controls to avoid significant economic losses. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.
Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.

PubMed

Kamstrup, Maria R; Gniadecki, Robert; Iversen, Lars; Skov, Lone; Petersen, Peter Meidahl; Loft, Annika; Specht, Lena

2015-05-01

Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gy in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT. Copyright © 2015 Elsevier Inc. All rights reserved.
Low-Dose (10-Gy) Total Skin Electron Beam Therapy for Cutaneous T-Cell Lymphoma: An Open Clinical Study and Pooled Data Analysis

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

Kamstrup, Maria R., E-mail: mkam0004@bbh.regionh.dk; Gniadecki, Robert; Iversen, Lars

2015-05-01

Purpose: Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. Methods and Materials: In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gymore » in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. Results: The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. Conclusions: Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT.« less
Assessing the response to opioids in cancer patients: a methodological proposal and the results.

PubMed

Corli, O; Roberto, A; Greco, M T; Montanari, M

2015-07-01

The efficacy of treatment with opioids in cancer pain is variable. To evaluate this variability, we (1) applied two parameters, changes in pain intensity (PI) and opioid daily doses (DDs), to distinguish different responses to opioids. The need to switch to another opioid was recorded. We then (2) evaluated the distribution of the responses depending on these parameters, alone and taken together, in cancer patients with pain. The cutoffs between positive and negative responses related to PI and DD were defined on the basis of the literature. For PI, responders were patients who obtained simultaneously a decrease of 30% or more and a final score ≤4 points (numerical rating scale 0 to 10). For DD changes, we applied the opioid escalation index percentage, a positive response corresponding to a dose increase ≤5%. These criteria were applied to 201 cancer patients treated with WHO step III "strong" opioids for 21 days. The results were mainly analyzed case by case. Of the patients, 63.7% obtained a positive analgesic response and 80.1% a dose-related positive response. Combining the parameters, the response was double positive in 55.2% of cases, double negative in 11.4%, a good analgesic response with a large dose escalation in 8.5%, and no pain relief with a stable dose in 24.9%. Switches were made 21 times, 15 because of the lack of analgesia. Different degrees of response to opioids were observed, PI and DD changes both contributing. Only over half the patients had a full positive response.
Effects of pre-existing anti-carrier immunity and antigenic element multiplicity on efficacy of a modular virus-like particle vaccine.

PubMed

Chuan, Yap P; Rivera-Hernandez, Tania; Wibowo, Nani; Connors, Natalie K; Wu, Yang; Hughes, Fiona K; Lua, Linda H L; Middelberg, Anton P J

2013-09-01

Modularization of a peptide antigen for presentation on a microbially synthesized murine polyomavirus (MuPyV) virus-like particle (VLP) offers a new alternative for rapid and low-cost vaccine delivery at a global scale. In this approach, heterologous modules containing peptide antigenic elements are fused to and displayed on the VLP carrier, allowing enhancement of peptide immunogenicity via ordered and densely repeated presentation of the modules. This study addresses two key engineering questions pertaining to this platform, exploring the effects of (i) pre-existing carrier-specific immunity on modular VLP vaccine effectiveness and (ii) increase in the antigenic element number per VLP on peptide-specific immune response. These effects were studied in a mouse model and with modular MuPyV VLPs presenting a group A streptococcus (GAS) peptide antigen, J8i. The data presented here demonstrate that immunization with a modular VLP could induce high levels of J8i-specific antibodies despite a strong pre-existing anti-carrier immune response. Doubling of the J8i antigenic element number per VLP did not enhance J8i immunogenicity at a constant peptide dose. However, the strategy, when used in conjunction with increased VLP dose, could effectively increase the peptide dose up to 10-fold, leading to a significantly higher J8i-specific antibody titer. This study further supports feasibility of the MuPyV modular VLP vaccine platform by showing that, in the absence of adjuvant, modularized GAS antigenic peptide at a dose as low as 150 ng was sufficient to raise a high level of peptide-specific IgGs indicative of bactericidal activity. Copyright © 2013 Wiley Periodicals, Inc.
Evaluation of military field-water quality: Volume 6, Infectious organisms of military concern associated with nonconsumptive exposure: Assessment of health risks and recommendations for establishing related standards

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

Cooper, R.C.; Olivieri, A.W.; Danielson, R.E.

1986-02-01

This study is an assessment of the risk of illness due to exposure to water-related (i.e., water-based, water-washed) infectious organisms. The organisms under consideration are Aeromonas spp., Leptospira spp., Pseudomonas spp., Staphylococcus spp., non-cholerae Vibrio spp., Acanthamoeba spp., Balantidium coli, Naegleria spp., Ascaris lumbricoides, Dracunculus medinesis, Schistosoma spp., and the agents responsible for cercarial dermatitis (i.e., Trichobilharzia, Gigantobilharzia, and Austrobilharzia). Evaluation of the risk to disease associated with the above pathogens requires information in specific areas such as dose response, concentration of agents in the environment, and environmental persistence. The existing body of knowledge concerning these agents ranges from speculationmore » to established fact. Unfortunately, areas of information critical to risk assessment are frequently unavailable. Because of this lack of data, the risk assessment presented is semiquantitative and limited to the presentation of an environmental classification scheme. 14 refs., 2 figs., 57 tabs.« less
SU-E-T-264: Preliminary Results On New Optically Stimulated Luminescent Materials for Proton Therapy Dosimetry

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

Doull, B; Zheng, Y; Procure Proton Therapy Center, Oklahoma City, OK

2014-06-01

Purpose: The objective of this work is to test the premise that luminescence materials with less under-response to proton beams can be identified by testing their dose response to low-LET radiation. The goal is to develop new Optically Stimulated Luminescence (OSL) materials with improved response for proton therapy dosimetry. Methods: We first measured the dose response of new OSL materials, synthesized in our laboratory, to low-LET radiation (beta rays from a {sup 90}Sr/{sup 90}Y source) and selected two materials having different OSL saturation characteristics and good dosimetric properties, namely MgB4O7:Ce,Li and MgO:Li. Commercial Al2O3:C was also used for comparison. Thesemore » materials were then irradiated at several depths along a pristine proton beam. The luminescence responses of the materials, relative to the entrance response, were compared with the depth dose profile measured by a multiple-layer ion chamber. Results: The OSL signals of MgB4O7:Ce,Li and MgO:Li were characterized for signal stability, dose response, and response to a clinical proton beam. The materials were also compared with the commercial Al2O3:C. The signals from both MgB4O7:Ce,Li and MgO:Li were relatively stable after a one day delay following irradiation. The low-LET dose response of the materials showed that, over the dose range investigated (up to ∼800 Gy), MgB4O7:Ce,Li did not saturate, whereas MgO:Li and Al2O3:C saturated at doses of ∼100 Gy. MgB4O7:Ce,Li showed less underresponse to proton beams than MgO:Li and Al2O3:C. Conclusion: In general the material with the highest saturation doses for low-LET radiation (MgB4O7:Ce,Li) showed the least under-response to proton beams, which suggests that it may be possible to develop better OSL materials for proton dosimetry if the dose response can be controlled during synthesis. Nevertheless, the degree in which the response to proton beams can be controlled remains to be determined. The research is funded by the Oklahoma Center for the Advancement of Science and Technology (OCAST), project number HR12-055.« less
Mental and cognitive performance in the cold.

PubMed

Palinkas, L A

2001-08-01

Vigilance, attention, memory, and motivation are essential to adapting to the physiological changes that occur with prolonged exposure to the cold and to avoiding both the environmental hazards associated with cold and the health-related consequences of these hazards. This paper summarizes the effects of cold temperatures on cognitive performance and mood. Although the effects of hypothermic-induced cold temperatures on cognitive performance and mood have been well documented, evidence of nonhypothermic effects has been inconsistent. There is evidence of a dose-response relation involving decrements in cognitive performance with respect to decline in core body temperature and complexity of tasks performed. However, it is unclear whether these effects are due to distraction or increased arousal. Likewise, further research is required to test the efficacy of existing and proposed pharmacologic and nutritional countermeasures.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Kajimoto, Masaki; O'Kelly-Priddy, Colleen M.; Ledee, Dolena R.

Extracorporeal membrane oxygenation (ECMO) supports infants and children with severe cardiopulmonary compromise. Nutritional support for these children includes provision of medium- and long-chain fatty acids (FAs). However, ECMO induces a stress response, which could limit the capacity for FA oxidation. Metabolic impairment could induce new or exacerbate existing myocardial dysfunction. Using a clinically relevant piglet model, we tested the hypothesis that ECMO maintains the myocardial capacity for FA oxidation and preserves myocardial energy state. Provision of 13-Carbon labeled medium-chain FA (octanoate), longchain free FAs (LCFAs), and lactate into systemic circulation showed that ECMO promoted relative increases in myocardial LCFA oxidationmore » while inhibiting lactate oxidation. Loading of these labeled substrates at high dose into the left coronary artery demonstrated metabolic flexibility as the heart preferentially oxidized octanoate. ECMO preserved this octanoate metabolic response, but also promoted LCFA oxidation and inhibited lactate utilization. Rapid upregulation of pyruvate dehydrogenase kinase-4 (PDK4) protein appeared to participate in this metabolic shift during ECMO. ECMO also increased relative flux from lactate to alanine further supporting the role for pyruvate dehydrogenase inhibition by PDK4. High dose substrate loading during ECMO also elevated the myocardial energy state indexed by phosphocreatine to ATP ratio. ECMO promotes LCFA oxidation in immature hearts, while maintaining myocardial energy state. These data support the appropriateness of FA provision during ECMO support for the immature heart.« less
Do changes in biomarkers from space radiation reflect dose or risk?

NASA Astrophysics Data System (ADS)

Brooks, A.

The space environment is made up of many different kinds of radiation so that the proper use of biomarkers is essential to estimate radiation risk. This presentation will evaluate differences between biomarkers of dose and risk and demonstrate why they should not be confused following radiation exposures in deep space. Dose is a physical quantity, while risk is a biological quantity. Many examples exist w ereh dose or changes in biomarkers of dose are inappropriately used as predictors of risk. Without information on the biology of the system, the biomarkers of dose provide little help in predicting risk in tissues or radiation exposure types where no excess risk can be demonstrated. Many of these biomarkers of dose only reflect changes in radiation dose or exposure. However, these markers are often incorrectly used to predict risk. For example, exposure of the trachea or of the deep lung to high-LET alpha particles results in similar changes in the biomarker chromosome damage in these two tissues. Such an observation would predict that the risk for cancer induction would be similar in these two tissues. It has been noted , however, that there has never been a tracheal tumor observed in rats that inhaled radon, but with the same exposure, large numbers of tumors were produced in the deep lung. The biology of the different tissues is the major determinant of the risk rather than the radiation dose. Recognition of this fact has resulted in the generation of tissue weighting factors for use in radiation protection. When tissue weighting factors are used the values derived are still called "dose". It is important to recognize that tissue specific observations have been corrected to reflect risk, and therefore should no longer be viewed as dose. The relative biological effectiveness (RBE) is also used to estimate radiation risk. The use of biomarkers to derive RBE is a difficult since it involves the use of a biological response to a standard low-LET reference radiation. Following low-LET radiation exposure, the biological response often does not increase as a linear function of dose. Thus, the RBE and the subsequent risk predicted is dependent on the dose where the two radiation types are compared. To avoid this problem the standard procedure is to use the dose and dose-rate response and compare the linear components of the two r diation exposures. Important riska comparisons are often done at very low doses, where the reference radiation may either increase or decrease as a function of dose. Since the low-LET exposure often does not produce a significant change above the background level of damage, the derived RBE factors can become very large.Studies using micronuclei as biomarkers following exposure to mono-energetic neutrons, x-rays and gamma rays delivered at very low doses (up to 0.10 Gy) demonstrated the differences in the shape of each dose-response relationship and the problems associated with the RBE. These studies show that RBE may not accurately reflect the hazards or risk associated with space radiation exposure. As additional measures of biological change are developed, it may become possible to base risk on biological change and not on changes in radiation doses. Research funded through grants # DE-FG03-99ER62787 from DOE Office of Biological and Environmental Research and RO1 CA74053-01 from NIH/NASA to Washington State University Tri-Cities.
Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: a one-week clinical confinement study.

PubMed

Theophilus, Eugenia H; Coggins, Christopher R E; Chen, Peter; Schmidt, Eckhardt; Borgerding, Michael F

2015-03-01

Tobacco toxicant-related exposure reduction is an important tool in harm reduction. Cigarette per day reduction (CPDR) occurs as smokers migrate from smoking cigarettes to using alternative tobacco/nicotine products, or quit smoking. Few reports characterize the dose-response relationships between CPDR and effects on exposure biomarkers, especially at the low end of CPD exposure (e.g., 5 CPD). We present data on CPDR by characterizing magnitudes of biomarker reductions. We present data from a well-controlled, one-week clinical confinement study in healthy smokers who were switched from smoking 19-25 CPD to smoking 20, 10, 5 or 0 CPD. Biomarkers were measured in blood, plasma, urine, and breath, and included smoke-related toxicants, urine mutagenicity, smoked cigarette filter analyses (mouth level exposure), and vital signs. Many of the biomarkers (e.g., plasma nicotine) showed strong CPDR dose-response reductions, while others (e.g., plasma thiocyanate) showed weaker dose-response reductions. Factors that lead to lower biomarker reductions include non-CPD related contributors to the measured response (e.g., other exposure sources from environment, life style, occupation; inter-individual variability). This study confirms CPDR dose-responsive biomarkers and suggests that a one-week design is appropriate for characterizing exposure reductions when smokers switch from cigarettes to new tobacco products. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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
The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

PubMed

Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

2017-09-01

We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Microchips and controlled-release drug reservoirs.

PubMed

Staples, Mark

2010-01-01

This review summarizes and updates the development of implantable microchip-containing devices that control dosing from drug reservoirs integrated with the devices. As the expense and risk of new drug development continues to increase, technologies that make the best use of existing therapeutics may add significant value. Trends of future medical care that may require advanced drug delivery systems include individualized therapy and the capability to automate drug delivery. Implantable drug delivery devices that promise to address these anticipated needs have been constructed in a variety of ways using micro- and nanoelectromechanical systems (MEMS or NEMS)-based technology. These devices expand treatment options for addressing unmet medical needs related to dosing. Within the last few years, advances in several technologies (MEMS or NEMS fabrication, materials science, polymer chemistry, and data management) have converged to enable the construction of miniaturized implantable devices for controlled delivery of therapeutic agents from one or more reservoirs. Suboptimal performance of conventional dosing methods in terms of safety, efficacy, pain, or convenience can be improved with advanced delivery devices. Microchip-based implantable drug delivery devices allow localized delivery by direct placement of the device at the treatment site, delivery on demand (emergency administration, pulsatile, or adjustable continuous dosing), programmable dosing cycles, automated delivery of multiple drugs, and dosing in response to physiological and diagnostic feedback. In addition, innovative drug-medical device combinations may protect labile active ingredients within hermetically sealed reservoirs. Copyright (c) 2010 John Wiley & Sons, Inc.

WE-FG-202-09: Voxel-Level Analysis of Adverse Treatment Response in Pediatric Patients Treated for Ependymoma with Passive Scattering Proton Therapy

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

Peeler, C; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX; Mirkovic, D

2016-06-15

Purpose: We identified patients treated for ependymoma with passive scattering proton therapy who subsequently developed treatment-related imaging changes on MRI. We sought to determine if there is any spatial correlation between imaged response, dose, and LET. Methods: A group of 14 patients treated for ependymoma were identified as having post-treatment MR imaging changes observable as T2-FLAIR hyperintensity with or without enhancement on T1 post-contrast sequences. MR images were registered with treatment planning CT images and regions of treatment-related change contoured by a practicing radiation oncologist. The contoured regions were identified as response with voxels represented as 1 while voxels withinmore » the brain outside of the response region were represented as 0. An in-house Monte Carlo system was used to recalculate treatment plans to obtain dose and LET information. Voxels were binned according to LET values in 0.3 keV µm{sup −1} bins. Dose and corresponding response value (0 or 1) for each voxel for a given LET bin were then plotted and fit with the Lyman-Kutcher-Burman dose response model to determine TD{sub 50} and m parameters for each LET value. Response parameters from all patients were then collated, and linear fits of the data were performed. Results: The response parameters TD50 and m both show trends with LET. Outliers were observed due to low numbers of response voxels in some cases. TD{sub 50} values decreased with LET while m increased with LET. The former result would indicate that for higher LET values, the dose is more effective, which is consistent with relative biological effectiveness (RBE) models for proton therapy. Conclusion: A novel method of voxel-level analysis of image biomarker-based adverse patient treatment response in proton therapy according to dose and LET has been presented. Fitted TD{sub 50} values show a decreasing trend with LET supporting the typical models of proton RBE. Funding provided by NIH Program Project Grant 2U19CA021239-35.« less
Non-Monotonic Dose Responses in Studies of Endocrine Disrupting Chemicals: Bisphenol A as a Case Study

PubMed Central

Vandenberg, Laura N.

2014-01-01

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not ‘common enough’ to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where ‘safe’ low doses are predicted from high dose exposures. PMID:24910584
Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study.

PubMed

Vandenberg, Laura N

2014-05-01

Non-monotonic dose response curves (NMDRCs) have been demonstrated for natural hormones and endocrine disrupting chemicals (EDCs) in a variety of biological systems including cultured cells, whole organ cultures, laboratory animals and human populations. The mechanisms responsible for these NMDRCs are well known, typically related to the interactions between the ligand (hormone or EDC) and a hormone receptor. Although there are hundreds of examples of NMDRCs in the EDC literature, there are claims that they are not 'common enough' to influence the use of high-to-low dose extrapolations in risk assessments. Here, we chose bisphenol A (BPA), a well-studied EDC, to assess the frequency of non-monotonic responses. Our results indicate that NMDRCs are common in the BPA literature, occurring in greater than 20% of all experiments and in at least one endpoint in more than 30% of all studies we examined. We also analyzed the types of endpoints that produce NMDRCs in vitro and factors related to study design that influence the ability to detect these kinds of responses. Taken together, these results provide strong evidence for NMDRCs in the EDC literature, specifically for BPA, and question the current risk assessment practice where 'safe' low doses are predicted from high dose exposures.
Dose—response relationships for agents inhibiting the immune response

PubMed Central

Berenbaum, M. C.; Brown, I. N.

1964-01-01

Mice were injected with T.A.B. vaccine and, 2 days later, with various doses of different compounds. The relation between dose of compound, mortality and antibody production was studied, and therapeutic indices were calculated for a number of compounds. The most effective agent in suppressing antibody production at relatively non-toxic doses was cyclophosphamide, with next amethopterin (the effect of which was, however, inexplicably erratic), 6-thioguanine and 6-mercaptopurine, in that order. Vincaleukoblastine, triethylene melamine, triethylenethiophosphoramide, mannomustine and 5-fluorouracil were less effective. Compounds of a miscellaneous group (boric acid, caffeine, sodium nitrite, bacitracin, neomycin and polymyxin `B') were studied in the same way: they had no effect on antibody production, even in lethal doses. PMID:14113077
Blood phenylalanine concentrations in patients with PAH-deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: assessing responsiveness in a model of statistical process control.

PubMed

Lindner, M; Gramer, G; Garbade, S F; Burgard, P

2009-08-01

Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.
EXPERIMENTAL DESIGN STRATEGY FOR THE WEIBULL DOSE RESPONSE MODEL (JOURNAL VERSION)

EPA Science Inventory

The objective of the research was to determine optimum design point allocation for estimation of relative yield losses from ozone pollution when the true and fitted yield-ozone dose response relationship follows the Weibull. The optimum design is dependent on the values of the We...
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.
The impact of the oxygen scavenger on the dose-rate dependence and dose sensitivity of MAGIC type polymer gels

NASA Astrophysics Data System (ADS)

Khan, Muzafar; Heilemann, Gerd; Kuess, Peter; Georg, Dietmar; Berg, Andreas

2018-03-01

Recent developments in radiation therapy aimed at more precise dose delivery along with higher dose gradients (dose painting) and more efficient dose delivery with higher dose rates e.g. flattening filter free (FFF) irradiation. Magnetic-resonance-imaging based polymer gel dosimetry offers 3D information for precise dose delivery techniques. Many of the proposed polymer gels have been reported to exhibit a dose response, measured as relaxation rate ΔR2(D), which is dose rate dependent. A lack of or a reduced dose-rate sensitivity is very important for dosimetric accuracy, especially with regard to the increasing clinical use of FFF irradiation protocols with LINACs at high dose rates. Some commonly used polymer gels are based on Methacrylic-Acid-Gel-Initiated-by-Copper (MAGIC). Here, we report on the dose sensitivity (ΔR2/ΔD) of MAGIC-type gels with different oxygen scavenger concentration for their specific dependence on the applied dose rate in order to improve the dosimetric performance, especially for high dose rates. A preclinical x-ray machine (‘Yxlon’, E = 200 kV) was used for irradiation to cover a range of dose rates from low \\dot{D} min = 0.6 Gy min-1 to high \\dot{D} max = 18 Gy min-1. The dose response was evaluated using R2-imaging of the gel on a human high-field (7T) MR-scanner. The results indicate that all of the investigated dose rates had an impact on the dose response in polymer gel dosimeters, being strongest in the high dose region and less effective for low dose levels. The absolute dose rate dependence \\frac{(Δ R2/Δ D)}{Δ \\dot{D}} of the dose response in MAGIC-type gel is significantly reduced using higher concentrations of oxygen scavenger at the expense of reduced dose sensitivity. For quantitative dose evaluations the relative dose rate dependence of a polymer gel, normalized to its sensitivity is important. Based on this normalized sensitivity the dose rate sensitivity was reduced distinctly using an increased oxygen scavenger concentration with reference to standard MAGIC-type gel formulation at high dose rate levels. The proposed gel composition with high oxygen scavenger concentration exhibits a larger linear active dose response and might be used especially in FFF-radiation applications and preclinical dosimetry at high dose rates. We propose in general to use high dose rates for calibration and evaluation as the change in relative dose sensitivity is reduced at higher dose rates in all of the investigated gel types.
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
Caffeine Increases the Linearity of the Visual BOLD Response

PubMed Central

Liu, Thomas T.; Liau, Joy

2009-01-01

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

Devic, Slobodan; Tomic, Nada; Aldelaijan, Saad

Purpose: Despite numerous advantages of radiochromic film dosimeter (high spatial resolution, near tissue equivalence, low energy dependence) to measure a relative dose distribution with film, one needs to first measure an absolute dose (following previously established reference dosimetry protocol) and then convert measured absolute dose values into relative doses. In this work, we present result of our efforts to obtain a functional form that would linearize the inherently nonlinear dose-response curve of the radiochromic film dosimetry system. Methods: Functional form [{zeta}= (-1){center_dot}netOD{sup (2/3)}/ln(netOD)] was derived from calibration curves of various previously established radiochromic film dosimetry systems. In order to testmore » the invariance of the proposed functional form with respect to the film model used we tested it with three different GAFCHROMIC Trade-Mark-Sign film models (EBT, EBT2, and EBT3) irradiated to various doses and scanned on a same scanner. For one of the film models (EBT2), we tested the invariance of the functional form to the scanner model used by scanning irradiated film pieces with three different flatbed scanner models (Epson V700, 1680, and 10000XL). To test our hypothesis that the proposed functional argument linearizes the response of the radiochromic film dosimetry system, verification tests have been performed in clinical applications: percent depth dose measurements, IMRT quality assurance (QA), and brachytherapy QA. Results: Obtained R{sup 2} values indicate that the choice of the functional form of the new argument appropriately linearizes the dose response of the radiochromic film dosimetry system we used. The linear behavior was insensitive to both film model and flatbed scanner model used. Measured PDD values using the green channel response of the GAFCHROMIC Trade-Mark-Sign EBT3 film model are well within {+-}2% window of the local relative dose value when compared to the tabulated Cobalt-60 data. It was also found that criteria of 3%/3 mm for an IMRT QA plan and 3%/2 mm for a brachytherapy QA plan are passing 95% gamma function points. Conclusions: In this paper, we demonstrate the use of functional argument to linearize the inherently nonlinear response of a radiochromic film based reference dosimetry system. In this way, relative dosimetry can be conveniently performed using radiochromic film dosimetry system without the need of establishing calibration curve.« less
Deliverability and efficacy of R-CHOP chemotherapy in very elderly patients with diffuse large B-cell lymphoma: an Australian retrospective analysis.

PubMed

Millar, A; Ellis, M; Mollee, P; Cochrane, T; Fletcher, J; Caudron, A; Webster, B; Trotman, J

2015-11-01

Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis, due in part to advanced age and pre-existing comorbidities, with reduced tolerability and deliverability of standard R-CHOP chemotherapy. To examine the deliverability, toxicity and efficacy of R-CHOP and the prevalence of the germinal and non-germinal phenotype DLBCL in an elderly Australian cohort. This retrospective analysis included patients ≥75 years diagnosed with DLBCL. Comprehensive chemotherapy and toxicity data were collected for patients treated with R-CHOP. Baseline demographics and chemotherapy characteristics were compared with progression-free (PFS) and overall survival (OS). Immunohistochemical staining identified the prevalence of the non-germinal centre (non-GCB) phenotype. Of the 111 patients, 92 (83%) commenced R-CHOP with 26/92 (28%) receiving ≤4 cycles. Median average relative dose (ARD) was 0.80 (0.07-1.17). Median average relative dose intensity (ARDI) was 0.89 (0.33-1.18). Serious adverse events occurred in 77% of patients with ≥Gd3 adverse events in 74%. Overall response rate was 85%. Two-year PFS was 63% and OS 74%. ARD and performance status ≥2 were significant prognostic factors for PFS and OS but not ARDI. Non-GCB-phenotype was identified in 44/72 (61%) of patients with immunohistochemical data. Despite high response rates and respectable survival estimates, the absence of standard therapy in 17% of patients, and dose reductions and serious toxicity of R-CHOP in this Australian cohort highlights the need for the development of less toxic yet efficacious treatments for very elderly patients with DLBCL. The high prevalence of the non-GCB phenotype highlights the potential value of targeted biological therapy for this demographic. © 2015 Royal Australasian College of Physicians.
Mumijo attenuates chemically induced inflammatory pain in mice.

PubMed

Malekzadeh, Golnaz; Dashti-Rahmatabadi, Mohammad Hossein; Zanbagh, Samira; Akhavi Mirab-bashii, Atefehsadat

2015-01-01

Mumijo (shilajit) has been well known in traditional medicine as a remedy for a number of diseases, such as bone fractures, wounds, inflammation, and headache. It is also widely used as an analgesic agent in folk medicine, but no scientific documentation exists concerning that effect. The current study was conducted to evaluate the ability of mumijo to reduce sensitivity to painful stimuli when compared with morphine sulfate and sodium diclofenac. A total of 176 animals were randomly and equally divided into 2 groups with 88 mice each-one for formalin test and the other for writhing test. For each test, the animals were allocated into 10 equal groups, based on the dosage of the analgesic, plus a negative control group, with 8 mice in each group. The analgesic effect of mumijo extract in doses of 0.75, 7.5, 75, and 750 mg/kg was assessed and compared witha group receiving distilled water-the negative control group, and that for groups receiving 1, 2, or 4 mg/kg of morphine sulfate or 10, 20, or 30 mg/kg of sodium diclofenac-the positive control groups. The results showed a significant decrease in pain intensity for all mice receiving doses of mumijo extract during a 1-h formalin test when compared with the distilled water group. For all the mumijo groups except the one receiving 750 mg/kg, the analgesic effect was significantly lower than that for the morphine sulfate group receiving 4 mg/kg. No significant differences existed between all mumijo and all diclofenac groups. In a writhing test, a significant inhibition of the pain response induced by acetic acid also occurred in all 4 mumijo-administered groups as opposed to the group receiving distilled water. No significant differences existed between the writhing response in groups receiving 75 and 750 mg/kg of mumijo and any doses of diclofenac or morphine. The comparison among the different doses of mumijo in the formalin test did not show any significant differences, but in the writhing test, the maximum dose showed a more effective analgesic action. The findings indicated a significant analgesic effect for mumijo extract on chronic pain in mice, occurring in a dose-independent manner.
Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura.

PubMed

Emilia, Giovanni; Morselli, Monica; Luppi, Mario; Longo, Giuseppe; Marasca, Roberto; Gandini, Giovanna; Ferrara, Leonardo; D'Apollo, Nicola; Potenza, Leonardo; Bertesi, Marcello; Torelli, Giuseppe

2002-02-15

Treatment of severe, chronic idiopathic thrombocytopenic purpura (ITP) refractory to most usual therapies is a difficult challenge. Little information exists on the clinical use of cyclosporin A (CyA) in the treatment of ITP. This report describes long-term treatment with CyA (median, 40 months) and follow-up (median, 36.8 months) in 12 adult patients with resistant ITP. CyA used in relatively low doses (2.5-3 mg/kg of body weight per day) led to a clinical improvement in 10 patients (83.3%). Five had a complete response (41.1%), 4 a complete response to maintenance therapy (33.3%), and one a partial response (8.3%). Two patients had no response. Most patients with a response (60%) had a long-term remission (mean, 28.6 months) after discontinuation of CyA. One patient had a relapse of ITP 4 years after CyA therapy was stopped. Side effects were moderate and transient, even in patients dependent on continued CyA treatment. CyA seems to represent reasonable salvage treatment in severe, potentially life-threatening, refractory ITP.
OPTIMIZING THE PRECISION OF TOXICITY THRESHOLD ESTIMATION USING A TWO-STAGE EXPERIMENTAL DESIGN

EPA Science Inventory

An important consideration for risk assessment is the existence of a threshold, i.e., the highest toxicant dose where the response is not distinguishable from background. We have developed methodology for finding an experimental design that optimizes the precision of threshold mo...
MO-D-BRF-01: Pediatric Treatment Planning II: The PENTEC Report On Normal Tissue Complications

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

Constine, L; Hodgson, D; Bentzen, S

With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy may cause debilitating or even fatal ‘late effects’ that are critical to understand, mitigate, or prevent. QUANTEC identified the uncertainties relating to side-effects of adult treatments, but this is more complicated for children in whom a mosaic of tissues develops at different rates and temporal sequences. Childhood cancer survivors have long life expectancy and may develop treatmentinduced secondary cancers and severe organ/tissue injury decades after treatment. Collaborative long-term observational studies and clinical research programs for survivors of pediatric and adolescent cancer provide some dose-responsemore » data for follow-up periods exceeding 40 years. Data analysis is challenging due to the influence of both therapeutic and developmental variables. PENTEC is a group of radiation oncologists, pediatric oncologists, subsepcialty physicians, medical physicists, biomathematic modelers/statisticians, and epidemiologists charged with conducting a critical synthesis of existing literature aiming to: critically analyze radiation dose-volume effects on normal tissue tolerances as a function of age/development in pediatric cancer patients in order to inform treatment planning and improve outcomes for survivors; describe relevant physics issues specific to pediatric radiotherapy; propose dose-volumeoutcome reporting standards to improve the knowledge base to inform future treatment guidelines. PENTEC has developed guidelines for systematic literature reviews, data extraction tolls and data analysis. This education session will discuss:1. Special considerations for normal tissue radiation response of children/adolescents, e.g. the interplay between development and radiotherapy effects.2. Epidemiology of organ/tissue injuries and secondary cancers.3. Exploration of dose-response differences between children and adults4. Methodology for literature review, data mining of outcomes databases, and NTCP or longitudinal modeling of doseresponse. 5. PENTEC goals and timetable. Learning Objectives: Understand important differences between normal tissue effects of radiation therapy in pediatric and adult patients. Be able to identify situations where there is ‘interplay’ between organ development and radiation-induced complications. Identify methods to systematically extract quantitative dose-volumeresponse relationships from existing outcomes databases. Provide guidance for the medical physicist to properly understand, implement, guide and control contemporary technology and applications in pediatric radiation oncology.« less
Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide

PubMed Central

Clearie, Karine L; Williamson, Peter A; Meldrum, Karen; Gillen, Michael; Carlsson, Lars-Goran; Carlholm, Marie; Ekelund, Jan; Lipworth, Brian J

2011-01-01

AIMS A hydrofluoroalkane formulation of budesonide pressurized metered-dose inhaler has been developed to replace the existing chlorofluorocarbon one. The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic characteristics of both formulations. METHODS Systemic bioavailability and bioactivity of both hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler formulations at 800 µg twice daily was determined during a randomized crossover systemic pharmacokinetic/pharmacodynamic study at steady state in healthy volunteers. Measurements included the following: plasma cortisol AUC24h[area under the concentration-time curve (0–24 h)], budesonide AUC0–12h and Cmax. Clinical efficacy was determined during a randomized crossover pharmacodynamic study in asthmatic patients receiving 200 µg followed by 800 µg budesonide via chlorofluorocarbon or hydrofluoroalkane pressurized metered-dose inhaler each for 4 weeks. Methacholine PC20 (primary outcome), exhaled nitric oxide, spirometry, peak expiratory flow and symptoms were evaluated. RESULTS In the pharmacokinetic study, there were no differences in cortisol, AUC0–12h[area under the concentration-time curve (0–12 h)], Tmax (time to maximum concentration) or Cmax (peak serum concentration) between the hydrofluoroalkane and chlorofluorocarbon pressurized metered-dose inhaler. The ratio of budesonide hydrofluoroalkane vs. chlorofluorocarbon pressurized metered-dose inhaler for cortisol AUC24h was 1.02 (95% confidence interval 0.93–1.11) and budesonide AUC0–12h was 1.03 (90% confidence interval 0.9–1.18). In the asthma pharmacodynamic study, there was a significant dose response (P < 0.0001) for methacholine PC20 (provocative concentration of methacholine needed to produce a 20% fall in FEV1) with a relative potency ratio of 1.10 (95% confidence interval 0.49–2.66), and no difference at either dose. No significant differences between formulations were seen with the secondary outcome variables. CONCLUSIONS Hydrofluoroalkane and chlorofluorocarbon formulations of budesonide were therapeutically equivalent in terms of relative lung bioavailability, airway efficacy and systemic effects. PMID:21395643
Selective effect of irradiation on responses to thymus-independent antigen.

PubMed

Lee, S K; Woodland, R T

1985-02-01

Low doses of ionizing radiation have a selective immunosuppressive effect on in vivo B cell responses to thymus-independent (TI) antigens. The B cell response, assayed as direct anti-trinitrophenyl (TNP)-specific plaque-forming cells (PFC), induced by type 2, TI antigens (TNP-Ficoll or TNP-Dextran), was reduced, on the average, by 10-fold in animals exposed to 200 rad of ionizing radiation 24 hr before antigen challenge. In contrast, PFC responses to type 1, TI antigens (TNP-lipopolysaccharide or TNP-Brucella abortus) are unaffected in mice exposed to the same dose of radiation. Adoptive transfers showed that this selective immunosuppression is a result of the specific inactivation of the B cell subpopulation responding to type 2, TI antigens. These experiments suggest that physiologic differences exist in the B cell subpopulations of normal mice which respond to type 1, or type 2, TI antigens.
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
42 CFR 83.14 - How will NIOSH evaluate a petition by a claimant whose dose reconstruction NIOSH could not...

Code of Federal Regulations, 2011 CFR

2011-10-01

... RESEARCH AND RELATED ACTIVITIES PROCEDURES FOR DESIGNATING CLASSES OF EMPLOYEES AS MEMBERS OF THE SPECIAL... classes for evaluation, to permit the timely adjudication of the existing cancer claim: (1) A class of employees defined using the research and analyses already completed in attempting the dose reconstruction...

42 CFR 83.14 - How will NIOSH evaluate a petition by a claimant whose dose reconstruction NIOSH could not...

Code of Federal Regulations, 2012 CFR

2012-10-01

... RESEARCH AND RELATED ACTIVITIES PROCEDURES FOR DESIGNATING CLASSES OF EMPLOYEES AS MEMBERS OF THE SPECIAL... classes for evaluation, to permit the timely adjudication of the existing cancer claim: (1) A class of employees defined using the research and analyses already completed in attempting the dose reconstruction...
42 CFR 83.14 - How will NIOSH evaluate a petition by a claimant whose dose reconstruction NIOSH could not...

Code of Federal Regulations, 2014 CFR

2014-10-01

... RESEARCH AND RELATED ACTIVITIES PROCEDURES FOR DESIGNATING CLASSES OF EMPLOYEES AS MEMBERS OF THE SPECIAL... classes for evaluation, to permit the timely adjudication of the existing cancer claim: (1) A class of employees defined using the research and analyses already completed in attempting the dose reconstruction...
42 CFR 83.14 - How will NIOSH evaluate a petition by a claimant whose dose reconstruction NIOSH could not...

Code of Federal Regulations, 2010 CFR

2010-10-01

... RESEARCH AND RELATED ACTIVITIES PROCEDURES FOR DESIGNATING CLASSES OF EMPLOYEES AS MEMBERS OF THE SPECIAL... classes for evaluation, to permit the timely adjudication of the existing cancer claim: (1) A class of employees defined using the research and analyses already completed in attempting the dose reconstruction...
42 CFR 83.14 - How will NIOSH evaluate a petition by a claimant whose dose reconstruction NIOSH could not...

Code of Federal Regulations, 2013 CFR

2013-10-01

... RESEARCH AND RELATED ACTIVITIES PROCEDURES FOR DESIGNATING CLASSES OF EMPLOYEES AS MEMBERS OF THE SPECIAL... classes for evaluation, to permit the timely adjudication of the existing cancer claim: (1) A class of employees defined using the research and analyses already completed in attempting the dose reconstruction...
Effects of Increased Loading on In Vivo Tendon Properties: A Systematic Review

PubMed Central

WIESINGER, HANS-PETER; KÖSTERS, ALEXANDER; MÜLLER, ERICH; SEYNNES, OLIVIER R.

2015-01-01

ABSTRACT Introduction In vivo measurements have been used in the past two decades to investigate the effects of increased loading on tendon properties, yet the current understanding of tendon macroscopic changes to training is rather fragmented, limited to reports of tendon stiffening, supported by changes in material properties and/or tendon hypertrophy. The main aim of this review was to analyze the existing literature to gain further insights into tendon adaptations by extracting patterns of dose-response and time-course. Methods PubMed/Medline, SPORTDiscus, and Google Scholar databases were searched for studies examining the effect of training on material, mechanical, and morphological properties via longitudinal or cross-sectional designs. Results Thirty-five of 6440 peer-reviewed articles met the inclusion criteria. The key findings were i) the confirmation of a nearly systematic adaptation of tendon tissue to training, ii) the important variability in the observed changes in tendon properties between and within studies, and iii) the absence of a consistent incremental pattern regarding the dose-response or the time-course relation of tendon adaptation within the first months of training. However, long-term (years) training was associated with a larger tendon cross-sectional area, without any evidence of differences in material properties. Our analysis also highlighted several gaps in the existing literature, which may be addressed in future research. Conclusions In line with some cross-species observations about tendon design, tendon cross-sectional area allegedly constitutes the ultimate adjusting parameter to increased loading. We propose here a theoretical model placing tendon hypertrophy and adjustments in material properties as parts of the same adaptive continuum. PMID:25563908
Energy deposition evaluation for ultra-low energy electron beam irradiation systems using calibrated thin radiochromic film and Monte Carlo simulations

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

Matsui, S., E-mail: smatsui@gpi.ac.jp; Mori, Y.; Nonaka, T.

2016-05-15

For evaluation of on-site dosimetry and process design in industrial use of ultra-low energy electron beam (ULEB) processes, we evaluate the energy deposition using a thin radiochromic film and a Monte Carlo simulation. The response of film dosimeter was calibrated using a high energy electron beam with an acceleration voltage of 2 MV and alanine dosimeters with uncertainty of 11% at coverage factor 2. Using this response function, the results of absorbed dose measurements for ULEB were evaluated from 10 kGy to 100 kGy as a relative dose. The deviation between the responses of deposit energy on the films andmore » Monte Carlo simulations was within 15%. As far as this limitation, relative dose estimation using thin film dosimeters with response function obtained by high energy electron irradiation and simulation results is effective for ULEB irradiation processes management.« less
Energy deposition evaluation for ultra-low energy electron beam irradiation systems using calibrated thin radiochromic film and Monte Carlo simulations.

PubMed

Matsui, S; Mori, Y; Nonaka, T; Hattori, T; Kasamatsu, Y; Haraguchi, D; Watanabe, Y; Uchiyama, K; Ishikawa, M

2016-05-01

For evaluation of on-site dosimetry and process design in industrial use of ultra-low energy electron beam (ULEB) processes, we evaluate the energy deposition using a thin radiochromic film and a Monte Carlo simulation. The response of film dosimeter was calibrated using a high energy electron beam with an acceleration voltage of 2 MV and alanine dosimeters with uncertainty of 11% at coverage factor 2. Using this response function, the results of absorbed dose measurements for ULEB were evaluated from 10 kGy to 100 kGy as a relative dose. The deviation between the responses of deposit energy on the films and Monte Carlo simulations was within 15%. As far as this limitation, relative dose estimation using thin film dosimeters with response function obtained by high energy electron irradiation and simulation results is effective for ULEB irradiation processes management.
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
Profile, mean residence time of ACTH and cortisol responses after low and standard ACTH tests in healthy volunteers.

PubMed

Alía, P; Villabona, C; Giménez, O; Sospedra, E; Soler, J; Navarro, M A

2006-09-01

No consensus exists until now about the suitable dose of tetracosactin in the ACTH stimulation test for detecting adrenal insufficiency. Our aim was to characterize both the ACTH(1-24) and the cortisol profiles after standard high-dose test (250 microg) (HDT) and low-dose test (1 microg) (LDT) in healthy subjects in order to provide a deeper knowledge about the relationship between stimulus and response. ACTH tests were performed in 10 healthy volunteers (five men, five women) with at least 1 week of difference. Plasma ACTH(1-24) and ACTH(1-39) and serum cortisol were measured before tetracosactin i.v. injection and at 5, 15, 30, 45, 60, 75 and 90 min after stimulus. Area under the curve (AUC) of ACTH(1-24) and cortisol, as well as mean residence time (MRT) for ACTH(1-24) were calculated in both tests. Elimination of ACTH(1-24) was faster in HDT than in LDT (MRTs of 0.14 vs 0.37, respectively, P = 0.008), but plasma concentrations were higher up to 60 min cortisol production in HDT reaching a higher maximum concentration (Cmax: 1144 vs 960 nmol/l) but delayed in time (75 vs 52.5 min). No significant relationship was observed between AUC or Cmax of ACTH(1-24) and AUC, Cmax and increment of cortisol in any of the tests. However, a negative correlation of basal cortisol values was observed with relative cortisol increment (HDT: r = 0.77 P = 0.009; LDT: r = 0.94 P < 0.0001), but not so with Cmax (HDT: r = 0.22 P = 0.55; LDT: r = 0.57 P = 0.09). The elimination rate of ACTH in healthy volunteers was significantly lower in LDT than in HDT, but cortisol production rate appears to be identical in both tests, so that a maximum adrenal stimulation seems to exist. The use of LDT may be more adequate, although data from patients need studying.
IRIS Toxicological Review of Tetrachloroethylene ...

EPA Pesticide Factsheets

EPA conducted a peer review of the scientific basis supporting the human health hazard and dose-response assessment of tetrachloroethylene that will appear on the Integrated Risk Information System (IRIS) database. Peer review is meant to ensure that science is used credibly and appropriately in derivation of the toxicological characterization and dose-response assessments. This draft health assessment addresses both non-cancer and cancer human health effects that may result from chronic exposure to tetrachloroethylene (also called Perchloroethylene or Perc) . This is an update of an existing assessment posted on IRIS in 1988. This draft Toxicological Review includes a chronic Reference Concentration (RfC) and carcinogenicity assessment, which are not currently available on IRIS, as well as an update of the 1988 IRIS Reference Dose (RfD). Tetrachloroethylene is a chemical solvent that is widely used for dry cleaning of fabrics, metal degreasing, and in making some consumer products and other chemicals.
Statistical methods for clinical verification of dose response parameters related to esophageal stricture and AVM obliteration from radiotherapy

NASA Astrophysics Data System (ADS)

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

2004-08-01

The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and khgr2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.
Evaluation of Al2O3:C optically stimulated luminescence (OSL) dosimeters for passive dosimetry of high-energy photon and electron beams in radiotherapy.

PubMed

Yukihara, E G; Mardirossian, G; Mirzasadeghi, M; Guduru, S; Ahmad, S

2008-01-01

This article investigates the performance of Al2O3: C optically stimulated luminescence dosimeters (OSLDs) for application in radiotherapy. Central-axis depth dose curves and optically stimulated luminescence (OSL) responses were obtained in a water phantom for 6 and 18 MV photons, and for 6, 9, 12, 16, and 20 MeV electron beams from a Varian 21EX linear accelerator. Single OSL measurements could be repeated with a precision of 0.7% (one standard deviation) and the differences between absorbed doses measured with OSLDs and an ionization chamber were within +/- 1% for photon beams. Similar results were obtained for electron beams in the low-gradient region after correction for a 1.9% photon-to-electron bias. The distance-to-agreement values were of the order of 0.5-1.0 mm for electrons in high dose gradient regions. Additional investigations also demonstrated that the OSL response dependence on dose rate, field size, and irradiation temperature is less than 1% in the conditions of the present study. Regarding the beam energy/quality dependence, the relative response of the OSLD for 18 MV was (0.51 +/- 0.48)% of the response for the 6 MV photon beam. The OSLD response for the electron beams relative to the 6 MV photon beam. The OSLD response for the electron beams relative to the 6 MV photon beam was in average 1.9% higher, but this result requires further confirmation. The relative response did not seem to vary with electron energy at dmax within the experimental uncertainties (0.5% in average) and, therefore, a fixed correction factor of 1.9% eliminated the energy dependence in our experimental conditions.
Evaluation of Al{sub 2}O{sub 3}:C optically stimulated luminescence (OSL) dosimeters for passive dosimetry of high-energy photon and electron beams in radiotherapy

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

Yukihara, E. G.; Mardirossian, G.; Mirzasadeghi, M.

This article investigates the performance of Al{sub 2}O{sub 3}:C optically stimulated luminescence dosimeters (OSLDs) for application in radiotherapy. Central-axis depth dose curves and optically stimulated luminescence (OSL) responses were obtained in a water phantom for 6 and 18 MV photons, and for 6, 9, 12, 16, and 20 MeV electron beams from a Varian 21EX linear accelerator. Single OSL measurements could be repeated with a precision of 0.7% (one standard deviation) and the differences between absorbed doses measured with OSLDs and an ionization chamber were within {+-}1% for photon beams. Similar results were obtained for electron beams in the low-gradientmore » region after correction for a 1.9% photon-to-electron bias. The distance-to-agreement values were of the order of 0.5-1.0 mm for electrons in high dose gradient regions. Additional investigations also demonstrated that the OSL response dependence on dose rate, field size, and irradiation temperature is less than 1% in the conditions of the present study. Regarding the beam energy/quality dependence, the relative response of the OSLD for 18 MV was (0.51{+-}0.48)% of the response for the 6 MV photon beam. The OSLD response for the electron beams relative to the 6 MV photon beam. The OSLD response for the electron beams relative to the 6 MV photon beam was in average 1.9% higher, but this result requires further confirmation. The relative response did not seem to vary with electron energy at d{sub max} within the experimental uncertainties (0.5% in average) and, therefore, a fixed correction factor of 1.9% eliminated the energy dependence in our experimental conditions.« less
A tiered approach for integrating exposure and dosimetry with in vitro dose-response data in the modern risk assessment paradigm

EPA Science Inventory

High-throughput (HT) risk screening approaches apply in vitro dose-response data to estimate potential health risks that arise from exposure to chemicals. However, much uncertainty is inherent in relating bioactivities observed in an in vitro system to the perturbations of biolog...
Experimental design and statistical analysis for three-drug combination studies.

PubMed

Fang, Hong-Bin; Chen, Xuerong; Pei, Xin-Yan; Grant, Steven; Tan, Ming

2017-06-01

Drug combination is a critically important therapeutic approach for complex diseases such as cancer and HIV due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. One of the key issues is to identify which combinations are additive, synergistic, or antagonistic. While the value of multidrug combinations has been well recognized in the cancer research community, to our best knowledge, all existing experimental studies rely on fixing the dose of one drug to reduce the dimensionality, e.g. looking at pairwise two-drug combinations, a suboptimal design. Hence, there is an urgent need to develop experimental design and analysis methods for studying multidrug combinations directly. Because the complexity of the problem increases exponentially with the number of constituent drugs, there has been little progress in the development of methods for the design and analysis of high-dimensional drug combinations. In fact, contrary to common mathematical reasoning, the case of three-drug combinations is fundamentally more difficult than two-drug combinations. Apparently, finding doses of the combination, number of combinations, and replicates needed to detect departures from additivity depends on dose-response shapes of individual constituent drugs. Thus, different classes of drugs of different dose-response shapes need to be treated as a separate case. Our application and case studies develop dose finding and sample size method for detecting departures from additivity with several common (linear and log-linear) classes of single dose-response curves. Furthermore, utilizing the geometric features of the interaction index, we propose a nonparametric model to estimate the interaction index surface by B-spine approximation and derive its asymptotic properties. Utilizing the method, we designed and analyzed a combination study of three anticancer drugs, PD184, HA14-1, and CEP3891 inhibiting myeloma H929 cell line. To our best knowledge, this is the first ever three drug combinations study performed based on the original 4D dose-response surface formed by dose ranges of three drugs.
Differences in Normal Tissue Response in the Esophagus Between Proton and Photon Radiation Therapy for Non-Small Cell Lung Cancer Using In Vivo Imaging Biomarkers.

PubMed

Niedzielski, Joshua S; Yang, Jinzhong; Mohan, Radhe; Titt, Uwe; Mirkovic, Dragan; Stingo, Francesco; Liao, Zhongxing; Gomez, Daniel R; Martel, Mary K; Briere, Tina M; Court, Laurence E

2017-11-15

To determine whether there exists any significant difference in normal tissue toxicity between intensity modulated radiation therapy (IMRT) or proton therapy for the treatment of non-small cell lung cancer. A total of 134 study patients (n=49 treated with proton therapy, n=85 with IMRT) treated in a randomized trial had a previously validated esophageal toxicity imaging biomarker, esophageal expansion, quantified during radiation therapy, as well as esophagitis grade (Common Terminology Criteria for Adverse Events version 3.0), on a weekly basis during treatment. Differences between the 2 modalities were statically analyzed using the imaging biomarker metric value (Kruskal-Wallis analysis of variance), as well as the incidence and severity of esophagitis grade (χ 2 and Fisher exact tests, respectively). The dose-response of the imaging biomarker was also compared between modalities using esophageal equivalent uniform dose, as well as delivered dose to an isotropic esophageal subvolume. No statistically significant difference in the distribution of esophagitis grade, the incidence of grade ≥3 esophagitis (15 and 11 patients treated with IMRT and proton therapy, respectively), or the esophageal expansion imaging biomarker between cohorts (P>.05) was found. The distribution of imaging biomarker metric values had similar distributions between treatment arms, despite a slightly higher dose volume in the proton arm (P>.05). Imaging biomarker dose-response was similar between modalities for dose quantified as esophageal equivalent uniform dose and delivered esophageal subvolume dose. Regardless of treatment modality, there was high variability in imaging biomarker response, as well as esophagitis grade, for similar esophageal doses between patients. There was no significant difference in esophageal toxicity from either proton- or photon-based radiation therapy as quantified by esophagitis grade or the esophageal expansion imaging biomarker. Copyright © 2017 Elsevier Inc. All rights reserved.
Positive Emotion Correlates of Meditation Practice: A Comparison of Mindfulness Meditation and Loving-kindness Meditation.

PubMed

Fredrickson, Barbara L; Boulton, Aaron J; Firestine, Ann M; Van Cappellen, Patty; Algoe, Sara B; Brantley, Mary M; Kim, Sumi Loundon; Brantley, Jeffrey; Salzberg, Sharon

2017-12-01

The purpose of this study was to uncover the day-to-day emotional profiles and dose-response relations, both within-persons and between-persons, associated with initiating one of two meditation practices, either mindfulness meditation or loving-kindness meditation. Data were pooled across two studies of midlife adults ( N = 339) who were randomized to learn either mindfulness meditation or loving-kindness meditation in a six-week workshop. The duration and frequency of meditation practice was measured daily for nine weeks, commencing with the first workshop session. Likewise, positive and negative emotions were also measured daily, using the modified Differential Emotions Scale (Fredrickson, 2013). Analysis of daily emotion reports over the targeted nine-week period showed significant gains in positive emotions and no change in negative emotions, regardless of meditation type. Multilevel models also revealed significant dose-response relations between duration of meditation practice and positive emotions, both within-persons and between-persons. Moreover, the within-person dose-response relation was stronger for loving-kindness meditation than for mindfulness meditation. Similar dose-response relations were observed for the frequency of meditation practice. In the context of prior research on the mental and physical health benefits produced by subtle increases in day-to-day experiences of positive emotions, the present research points to evidence-based practices - both mindfulness meditation and loving-kindness meditation - that can improve emotional wellbeing.
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 within the context of limited resources. While the design is general enough to apply to many situations, future work is needed to address interim analyses and the incorporation of models for dose response.
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.
The Dose Response Relationship for Radiation Carcinogenesis

NASA Astrophysics Data System (ADS)

Hall, Eric

2008-03-01

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

Genetic Polymorphisms Associated with Rubella Virus-Specific Cellular Immunity Following MMR Vaccination

PubMed Central

Kennedy, Richard B.; Ovsyannikova, Inna G.; Haralambieva, Iana H.; Lambert, Nathaniel D.; Pankratz, V. Shane; Poland, Gregory A.

2014-01-01

Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single dose seroconversion rates ~95%. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects ages 11–22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (ages 18–40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination. PMID:25098560
Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination.

PubMed

Kennedy, Richard B; Ovsyannikova, Inna G; Haralambieva, Iana H; Lambert, Nathaniel D; Pankratz, V Shane; Poland, Gregory A

2014-11-01

Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single-dose seroconversion rates ~95 %. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects aged 11-22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (age 18-40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination.
Effects of Family History of Alcohol Dependence on the Subjective Response to Alcohol using the Intravenous Alcohol Clamp

PubMed Central

Kerfoot, Karin; Pittman, Brian; Ralevski, Elizabeth; Limoncelli, Diana; Koretski, Julia; Newcomb, Jenelle; Arias, Albert J.; Petrakis, Ismene L

2013-01-01

Background Alcohol use disorders are well recognized to be common, debilitating, and the risk of developing them is influenced by family history. The subjective response to alcohol may be determined familialy and related to the risk of developing alcoholism. The aim of this study was to evaluate differences between family history positive (FHP) and family history negative (FHN) individuals in their response to alcohol within the domains of subjective, coordination, and cognitive effects using an IV clamping method of alcohol administration. Methods Two groups of healthy subjects, those with a FHP (n=65) vs. those who were FHN (n=115), between the ages of 21-30, participated in three test days. Subjects were scheduled to receive placebo, low dose ethanol (target BrAC=40mg%), and high dose ethanol (target BrAC=100mg%) on three separate test days at least three days apart in a randomized order under double-blind conditions. Outcome measures included subjective effects, measures of coordination and cognitive function. Results Both low and high dose alcohol led to dose-related stimulant and sedative subjective effects as measured the Biphasic Alcohol Effects Scale (BAES) and subjective measures of “high” and “drowsy” measured on a visual analog scale (VAS) However, there were no effects of family history. Similar dose-related effects were observed on cognitive and coordination related outcomes, but were not moderated family history. Conclusions Results from this study showed that healthy individuals responded to an IV alcohol challenge in a dose-related manner; however, there were no significant differences on subjective response, or on ethanol-induced impairment of coordination or cognition, between individuals with a positive family history for alcoholism and those with a negative family history. Results suggest that FH may not be a specific enough marker of risk, particularly in individuals who are beyond the age where alcohol use disorders often develop. PMID:23895557
Pro-oxidant Induced DNA Damage in Human Lymphoblastoid Cells: Homeostatic Mechanisms of Genotoxic Tolerance

PubMed Central

Seager, Anna L.

2012-01-01

Oxidative stress contributes to many disease etiologies including ageing, neurodegeneration, and cancer, partly through DNA damage induction (genotoxicity). Understanding the i nteractions of free radicals with DNA is fundamental to discern mutation risks. In genetic toxicology, regulatory authorities consider that most genotoxins exhibit a linear relationship between dose and mutagenic response. Yet, homeostatic mechanisms, including DNA repair, that allow cells to tolerate low levels of genotoxic exposure exist. Acceptance of thresholds for genotoxicity has widespread consequences in terms of understanding cancer risk and regulating human exposure to chemicals/drugs. Three pro-oxidant chemicals, hydrogen peroxide (H2O2), potassium bromate (KBrO3), and menadione, were examined for low dose-response curves in human lymphoblastoid cells. DNA repair and antioxidant capacity were assessed as possible threshold mechanisms. H2O2 and KBrO3, but not menadione, exhibited thresholded responses, containing a range of nongenotoxic low doses. Levels of the DNA glycosylase 8-oxoguanine glycosylase were unchanged in response to pro- oxidant stress. DNA repair–focused gene expression arrays reported changes in ATM and BRCA1, involved in double-strand break repair, in response to low-dose pro-oxidant exposure; however, these alterations were not substantiated at the protein level. Determination of oxidatively induced DNA damage in H2O2-treated AHH-1 cells reported accumulation of thymine glycol above the genotoxic threshold. Further, the H2O2 dose-response curve was shifted by modulating the antioxidant glutathione. Hence, observed pro- oxidant thresholds were due to protective capacities of base excision repair enzymes and antioxidants against DNA damage, highlighting the importance of homeostatic mechanisms in “genotoxic tolerance.” PMID:22539617
Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.

PubMed

Bar-Or, Amit; Grove, Richard A; Austin, Daren J; Tolson, Jerry M; VanMeter, Susan A; Lewis, Eric W; Derosier, Frederick J; Lopez, Monica C; Kavanagh, Sarah T; Miller, Aaron E; Sorensen, Per S

2018-05-15

To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo ( p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing. Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells. This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation. © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis

PubMed Central

Grove, Richard A.; Austin, Daren J.; Tolson, Jerry M.; VanMeter, Susan A.; Lewis, Eric W.; Derosier, Frederick J.; Lopez, Monica C.; Kavanagh, Sarah T.; Miller, Aaron E.; Sorensen, Per S.

2018-01-01

Objective To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). Methods Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. Results The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1–4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing. Conclusion Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells. Classification of evidence This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation. PMID:29695594
Piracetam in the treatment of cortical myoclonus.

PubMed

Genton, P; Guerrini, R; Remy, C

1999-03-01

This paper reviews existing publications on the use of piracetam for the treatment of cortical myoclonus of various etiologies and includes the personal experience of the authors in progressive myoclonus epilepsy. Two double-blind comparisons with placebo provided results which allow recommendations for the dosage and usage of piracetam in cortical myoclonus. Wide individual variation (7-24g daily) exists in dosage requirements but responses are dose-related so that dosage should be increased until an optimum effect is obtained. Tolerability after long-term use of piracetam in high dosage has been very good and without toxicity or serious adverse effects. Side effects have been occasional, mild and transient. The authors present their experience of 12 patients with progressive myoclonus epilepsy in whom the administration of up to 45 g piracetam daily, when added to existing anti-epileptic treatment, caused marked and sometimes spectacular improvement and was without significant adverse effects. Improvement was maintained for up to 7 years. The use of piracetam for disabling cortical myoclonus of any etiology, either as an addition to existing antimyoclonic drugs or as monotherapy, may bring about profound improvement in disability and quality of life. Piracetam should be considered a first-line drug for the treatment of cortical myoclonus.
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 also aim to uncover protein mediators of the bystander responses using advanced proteomic screening of factors released from irradiated, bystander and unstable cells. Integral to these studies will be an assessment of the role of genetic susceptibility in these responses, using CBA/H and C57BL/6J mice. The relevance of in vivo interactions between stem cells and the stem cell niche will be explored in the future by re-implantation techniques of previously irradiated cells. The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program.« less
The plasma free amino acid dose-response technique: A proposed methodology for determining lysine relative bioavailability of rumen-protected lysine supplements.

PubMed

Whitehouse, N L; Schwab, C G; Brito, A F

2017-12-01

Estimates of Lys bioavailability of rumen-protected Lys (RP-Lys) supplements are often obtained using in vitro or 2-step in situ techniques, with little to no data determining efficacy and bioavailability in vivo. The objective of this study was to further evaluate and refine the use of the plasma free AA dose-response technique as a method for determining Lys relative bioavailability of RP-Lys supplements. Thirteen dose-response Latin square studies using 87 lactating, ruminally cannulated multiparous Holstein cows (days in milk from 55 to 315 and milk yield from 12 to 62 kg/d at the start of the studies) were conducted to measure the relative bioavailability of RP-Lys supplements. Intestinal (1 study) and abomasal (12 studies) infusions of Lys ranged from 0 to 84 g/d, and experimental periods ranged from 4 to 21 d. Basal diets were formulated to be adequate in metabolizable Met, but varied in predicted metabolizable Lys (5.04 to 6.81% of metabolizable protein). One to 4 daily blood samples were taken from the coccygeal vessels for 1 to 3 consecutive days in each period. Plasma Lys concentration in cows assigned to the control treatment (0 g/d Lys) ranged from 1.83 to 5.21% of total plasma AA, whereas that from cows duodenally or abomasally infused with Lys ranged from 2.53 to 7.51% of total plasma AA. Results from studies involving more than 2 amounts of infused Lys confirmed linearity of response. The following variables were regressed against the plasma Lys dose-response slopes generated from the Lys infusion treatments to examine their effects on the magnitude of the slopes: plasma Lys concentration of the control diet, plasma Lys concentration at the greatest amount of infused Lys, net energy of lactation and metabolizable protein balances, metabolizable protein supply, days in milk, milk yield, milk concentrations of fat, true protein, and lactose, milk true protein yield, and dry matter intake. The variable having the greatest effect on the magnitude of the dose-response slope was the plasma Lys concentration at the greatest amount infused. The relative bioavailability of evaluated RP-Lys supplements using the plasma free AA dose-response technique ranged from 5 to 87%. It was concluded that plasma free Lys increases in a linear fashion to increasing amounts of absorbed Lys and that the dose-response technique is an appropriate technique for evaluating RP-Lys supplements. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.
A mechanistic investigation of the oxygen fixation hypothesis and oxygen enhancement ratio.

PubMed

Grimes, David Robert; Partridge, Mike

2015-12-04

The presence of oxygen in tumours has substantial impact on treatment outcome; relative to anoxic regions, well-oxygenated cells respond better to radiotherapy by a factor 2.5-3. This increased radio-response is known as the oxygen enhancement ratio. The oxygen effect is most commonly explained by the oxygen fixation hypothesis, which postulates that radical-induced DNA damage can be permanently 'fixed' by molecular oxygen, rendering DNA damage irreparable. While this oxygen effect is important in both existing therapy and for future modalities such a radiation dose-painting, the majority of existing mathematical models for oxygen enhancement are empirical rather than based on the underlying physics and radiochemistry. Here we propose a model of oxygen-enhanced damage from physical first principles, investigating factors that might influence the cell kill. This is fitted to a range of experimental oxygen curves from literature and shown to describe them well, yielding a single robust term for oxygen interaction obtained. The model also reveals a small thermal dependency exists but that this is unlikely to be exploitable.
Cross-contamination of foods and implications for food allergic patients.

PubMed

Taylor, Steve L; Baumert, Joseph L

2010-07-01

Cross-contamination presents a risk of unknown magnitude for food allergic consumers. Published cases likely represent the tip of a rather large iceberg. Cross-contamination can occur in homes, restaurants, food manufacturing plants, and on farms. The frequency of cross-contamination as the cause of accidental exposures to allergenic foods is unknown. Food allergic individuals can react to ingestion of trace levels of the offending food, although a highly variable range of threshold doses exist among populations of food allergic individuals. The magnitude of the risk posed to food allergic consumers by cross-contamination is characterized by the frequency of exposure to cross-contaminated foods, the dose of exposure, and the individual's threshold dose. The food and food service industry (and food preparers in homes as well) have the responsibility to provide and prepare foods that are safe for food allergic consumers, but quality of life may be improved with the recognition that safe (though very low) thresholds do exist.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles

Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Bloodmore » flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.« less
Cannabis, 1977.

PubMed

1978-10-01

Recent advances in development of immunoassay methods for marijuana constituents in body fluids provide a rapid means of detection for forensic purposes and a useful research tool for accurate quantitation of dose-response relation. Therapeutic possibilities of cannabis, such as reduction in intraocular pressure and bronchodilatation, may stimulate development of synthetic cannabinoid derivatives that meet acceptable standards of safety and effiicacy for treatment of glaucoma and asthma. Cannabis use may have harmful short- and long-term impacts on health. Potentially serious short-term effects include predisposition to angina during exercise in patients with coronary artery disease. Even in healthy subjects, marijuana smoking decreases peak exercise performance, possibly because of its chronotropic effect with achievement of maximum heart rate at reduced work loads. Although no conclusive evidence exists for long-term biologic consequences of chronic cannabis use, preliminary evidence, suggesting impairment in pulmonary function and immune responses, requires further investigation with large-scale epidemiologic studies.
Dose response and structural injury in the disability of spinal injury.

PubMed

Patel, Mohammed Shakil; Sell, Philip

2013-03-01

In traumatic injury there is a clear relationship between the dose of energy involved, structural tissue damage and resultant disability after recovery. This relationship is often absent in cases of non-specific chronic low back pain that is perceived by patients as attributed to a workplace injury. There are many studies assessing risk factors for non-specific low back pain. However, studies addressing causality of back pain are deficient. To establish whether there exists a causal relationship between structural injury, low back pain and spinal disability. Retrospective analysis of prospectively gathered validated spinal outcome measures [Oswestry disability index (ODI), low back outcome score (LBO), modified somatic perception (MSP), modified Zung depression index (MZD)] between patients with healed high energy thoracolumbar spinal fractures and patients with self-perceived work-related low back pain. Causality was established according to two of Bradford Hill's criteria of medical causality, temporal and dose-response relationships. Twenty-three patients with spinal fractures (group 1) of average age 44 years were compared to 19 patients with self-reported back pain in the workplace pursuing claims for compensation (group 2) of average age 48 years. Both groups were comparable in terms of age and sex. The average ODI in group 1 was 28 % (SD 19) compared to 42 % (SD 19) in group 2 (P < 0.05). Similarly, LBOS was 39.7 versus 24.3 (P < 0.05), MSP 4.3 versus 9.3 (P < 0.05) and MZD 20.2 versus 34.8 (P < 0.05) in groups 1 and 2, respectively. Despite high-energy trauma and significant structural damage to the spine, patients with the high energy injuries had better spinal outcome scores in all measures. There is no 'dose-response' relationship between structural injury, low back pain and spinal disability. This is the reverse of what would be anticipated if structural injury was the cause of disability in workplace reported onset of low back pain.
SU-G-201-08: Energy Response of Thermoluminescent Microcube Dosimeters in Water for Kilovoltage X-Ray Beams

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

Di Maso, L; Lawless, M; Culberson, W

Purpose: To characterize the energy dependence for TLD-100 microcubes in water at kilovoltage energies. Methods: TLD-100 microcubes with dimensions of (1 × 1 × 1) mm{sup 3} were irradiated with kilovoltage x-rays in a custom-built thin-window liquid water phantom. The TLD-100 microcubes were held in Virtual Water™ probes and aligned at a 2 cm depth in water. Irradiations were performed using the M-series x-ray beams of energies ranging from 50-250 kVp and normalized to a {sup 60}Co beam located at the UWADCL. Simulations using the EGSnrc Monte Carlo Code System were performed to model the x-ray beams, the {sup 60}Comore » beam, the water phantom and the dosimeters in the phantom. The egs-chamber user code was used to tally the dose to the TLDs and the dose to water. The measurements and calculations were used to determine the intrinsic energy dependence, absorbed-dose energy dependence, and absorbed-dose sensitivity. These values were compared to TLD-100 chips with dimensions of (3.2 × 0.9 × 0.9) mm{sup 3}. Results: The measured TLD-100 microcube response per dose to water among all investigated x-ray energies had a maximum percent difference of 61% relative to {sup 60}Co. The simulated ratio of dose to water to the dose to TLD had a maximum percent difference of 29% relative to {sup 60}Co. The ratio of dose to TLD to the TLD output had a maximum percent difference of 13% relative to {sup 60}Co. The maximum percent difference for the absorbed-dose sensitivity was 15% more than the used value of 1.41. Conclusion: These results confirm that differences in beam quality have a significant effect on TLD response when irradiated in water. These results also indicated a difference in TLD-100 response between microcube and chip geometries. The intrinsic energy dependence and the absorbed-dose energy dependence deviated up to 10% between TLD-100 microcubes and chips.« less
Acute Toxicity of Permethrin, Deltamethrin, and Etofenprox to the Alfalfa Leafcutting Bee.

PubMed

Piccolomini, Alyssa M; Whiten, Shavonn R; Flenniken, Michelle L; O'Neill, Kevin M; Peterson, Robert K D

2018-05-28

Current regulatory requirements for insecticide toxicity to nontarget insects focus on the honey bee, Apis mellifera (L.; Hymenoptera: Apidae), but this species cannot represent all insect pollinator species in terms of response to insecticides. Therefore, we characterized the toxicity of pyrethroid insecticides used for adult mosquito management (permethrin, deltamethrin, and etofenprox) on a nontarget insect, the adult alfalfa leafcutting bee, Megachile rotundata (F.; Hymenoptera: Megachilidae) in two separate studies. In the first study, the doses causing 50 and 90% mortality (LD50 and LD90, respectively) were used as endpoints and 2-d-old adult females were exposed to eight concentrations ranging from 0.0075 to 0.076 μg/bee for permethrin and etofenprox, and 0.0013-0.0075 μg/bee for deltamethrin. For the second study, respiration rates of female M. rotundata were also recorded for 2 h after bees were dosed at the LD50 values to give an indication of stress response. Results indicated a relatively similar LD50 for permethrin and etofenprox, 0.057 and 0.051 μg/bee, respectively, and a more toxic response, 0.0016 μg/bee for deltamethrin. Comparatively, female A. mellifera workers have a LD50 value of 0.024 μg/bee for permethrin and 0.015 μg/bee for etofenprox indicating that female M. rotundata are less susceptible to topical doses of these insecticides, except for deltamethrin, where both A. mellifera and M. rotundata have an identical LD50 of 0.0016 μg/bee. Respiration rates comparing each active ingredient to control groups, as well as rates between each active ingredient, were statistically different (P < 0.0001). The addition of these results to existing information on A. mellifera may provide more insights on how other economically beneficial and nontarget bees respond to pyrethroids.
Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study.

PubMed

Berkowitz, Elchonon M; Moyle, Graeme; Stellbrink, Hans-Jürgen; Schürmann, Dirk; Kegg, Stephen; Stoll, Matthias; El Idrissi, Mohamed; Oostvogels, Lidia; Heineman, Thomas C

2015-04-15

Human immunodeficiency virus (HIV)-infected individuals are at increased risk of herpes zoster (HZ), even in the antiretroviral therapy (ART) era. Because concerns exist about the use of live-attenuated vaccines in immunocompromised individuals, a subunit vaccine may be an appropriate alternative. This phase 1/2, randomized, placebo-controlled study evaluated the immunogenicity and safety of an investigational HZ subunit vaccine (HZ/su). Three cohorts of HIV-infected adults aged ≥18 years were enrolled: 94 ART recipients with a CD4(+) T-cell count of ≥200 cells/mm(3), 14 ART recipients with a CD4(+) T-cell count of 50-199 cells/mm(3), and 15 ART-naive adults with a CD4(+) T-cell count of ≥500 cells/mm(3). Subjects received 3 doses of HZ/su (50 µg varicella-zoster virus glycoprotein E [gE] combined with AS01B adjuvant) or 3 doses of saline at months 0, 2, and 6. One month after dose 3, serum anti-gE antibody concentrations and frequencies of gE-specific CD4(+) T cells were higher following HZ/su vaccination than after receipt of saline (P < .0001). Median cell-mediated immune responses peaked after dose 2. Humoral and cell-mediated immune responses persisted until the end of the study (month 18). No vaccination-related serious adverse events were reported. No sustained impact on HIV load or CD4(+) T-cell count was noted following vaccinations. HZ/su was immunogenic and had a clinically acceptable safety profile in HIV-infected adults. NCT01165203. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
Incidence of salivary gland tumors among atomic bomb survivors, 1950-1987. Evaluation of radiation-related risk

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

Land, C.E.; Saku, Takashi; Tokuoka, Shoji

1996-07-01

A wide-ranging seach for benign and malignant tumors of the major and minor salivary glands among members of the Life Span Study sample of the Radiation Effects Research Foundation identified 41 malignant and 94 benign incident tumors, including 14 malignant and 12 benign tumors of the minor salivary gland, plus 10 major gland tumors of unknown behavior. Dose-response analyses found statistically significant increases in risk with increasing A-bomb dose for both cancer and benign tumors. Estimated relative risks at 1 Sv weighted tissue kerma (RR{sub 1}Sv, with 90% confidence interval in parentheses) were 4.5 (2.5-8.5) for cancer and 1.7 (1.1-2.7)more » for benign tumors. When analyzed by histological subtype within these two broad groups, it appeared that most of the dose response for malignant tumors was provided by an exceptionally strong dose response for mucoepidermoid carcinoma [11 exposed cases with dose estimates, RR{sub 1Sv} - 9.3 (3.5-30.6)], and most or all of that for benign tumors corresponded to Warthin`s tumor [12 cases, RR{sub 1Sv} = 4.1 (1.6-11.3)]. There was a marginal dose response for malignant tumors other than mucoepidermoid carcinoma [RR{sub 1Sv} = 2.4 (0.99-5.7)] but no significant trend for benign tumors other than Warthin`s tumor [RR{sub 1Sv} = 1.3 (0.9-2.2)]. Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study. 33 refs., 3 figs., 7 tabs.« less
Disposition of smoked cannabis with high {Delta}{sup 9}-tetrahydrocannabinol content: A kinetic model

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

Hunault, Claudine C., E-mail: claudine.hunault@rivm.n; Eijkeren, Jan C.H. van; Mensinga, Tjeert T.

Introduction: No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69 mg THC). Methods: Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3 mg, 49.1 mg, and 69.4 mg THC. Blood samples were collected over a period of 0-8 h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Results: Large inter-individual variability was observed in the pharmacokinetic parameters.more » The median pharmacokinetic parameters generated by the model were C{sub max} = 175 ng/mL, T{sub max} = 14 min, and AUC{sub 0-8h} = 8150 ng x min/mL for the 69.4 mg THC dose. Median model results show an almost linear dose response relation for C{sub max}/Dose = 2.8 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 136 x 10{sup -6} min/mL. However, for increasing dose level, there was a clear decreasing trend: C{sub max}/Dose = 3.4, 2.6 and 2.5 x 10{sup -6}/mL and AUC{sub 0-8h}/Dose = 157, 133 and 117 x 10{sup -6} min/mL for the 29.3, 49.1 and 69.4 mg dose, respectively. Within the restriction of 8 h of observation, the apparent terminal half life of THC was 150 min. Conclusion: The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8 h after smoking cannabis with a high THC content (up to 23%).« less
Disposition of smoked cannabis with high Δ(9)-tetrahydrocannabinol content: a kinetic model.

PubMed

Hunault, Claudine C; van Eijkeren, Jan C H; Mensinga, Tjeert T; de Vries, Irma; Leenders, Marianne E C; Meulenbelt, Jan

2010-08-01

No model exists to describe the disposition and kinetics of inhaled cannabis containing a high THC dose. We aimed to develop a kinetic model providing estimates of the THC serum concentrations after smoking cannabis cigarettes containing high THC doses (up to 69mg THC). Twenty-four male non-daily cannabis users smoked cannabis cigarettes containing 29.3mg, 49.1mg, and 69.4mg THC. Blood samples were collected over a period of 0-8h and serum THC concentrations were measured. A two-compartment open model was fitted on the individual observed data. Large inter-individual variability was observed in the pharmacokinetic parameters. The median pharmacokinetic parameters generated by the model were Cmax=175ng/mL, Tmax=14min, and AUC0-8h=8150ng×min/mL for the 69.4mg THC dose. Median model results show an almost linear dose response relation for Cmax/Dose=2.8×10(-6)/mL and AUC0-8h/Dose=136×10(-6)min/mL. However, for increasing dose level, there was a clear decreasing trend: Cmax/Dose=3.4, 2.6 and 2.5×10(-6)/mL and AUC0-8h/Dose=157, 133 and 117×10(-6)min/mL for the 29.3, 49.1 and 69.4mg dose, respectively. Within the restriction of 8h of observation, the apparent terminal half life of THC was 150min. The model offers insight into the pharmacokinetics of THC in recreational cannabis users smoking cannabis containing high doses of THC mixed with tobacco. The model is an objective method for providing serum THC concentrations up to 8h after smoking cannabis with a high THC content (up to 23%). Copyright © 2010 Elsevier Inc. All rights reserved.

Radiological characteristics of MRI-based VIP polymer gel under carbon beam irradiation

NASA Astrophysics Data System (ADS)

Maeyama, T.; Fukunishi, N.; Ishikawa, K. L.; Furuta, T.; Fukasaku, K.; Takagi, S.; Noda, S.; Himeno, R.; Fukuda, S.

2015-02-01

We study the radiological characteristics of VIP polymer gel dosimeters under carbon beam irradiation with energy of 135 and 290 AMeV. To evaluate dose response of VIP polymer gels, the transverse (or spin-spin) relaxation rate R2 of the dosimeters measured by magnetic resonance imaging (MRI) as a function of linear energy transfer (LET), rather than penetration depth, as is usually done in previous reports. LET is evaluated by use of the particle transport simulation code PHITS. Our results reveal that the dose response decreases with increasing dose-averaged LET and that the dose response-LET relation also varies with incident carbon beam energy. The latter can be explained by taking into account the contribution from fragmentation products.
Bayesian multimodel inference for dose-response studies

USGS Publications Warehouse

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

2007-01-01

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

PubMed Central

Wang, Bing; Tanaka, Kaoru; Ninomiya, Yasuharu; Maruyama, Kouichi; VarèS, Guillaume; Eguchi-Kasai, Kiyomi; Nenoi, Mitsuru

2013-01-01

Existence of adaptive response (AR) was previously demonstrated in C57BL/6J mice. Irradiations were performed by delivering a priming low dose of X-rays (0.50 Gy) in combination with a challenge high dose of accelerated carbon or neon ion particles. AR was characterized by significantly decreased mortality in the 30-day survival test. This mouse AR model (‘Yonezawa Effect’) was originally established by using X-rays as both the priming and challenge irradiations. The underlying mechanism was due to radio-resistance occurring in blood-forming tissues. In this study, we verified the existence of AR and further investigated residual damage in the hematopoietic system in surviving animals. Results showed that the priming low dose of X-rays could relieve the detrimental effects on the hematopoietic system. We observed both an improvement in the blood platelet count and the ratio of polychromatic erythrocytes (PCEs) to the sum of PCEs and normochromatic erythrocytes (NCEs) and a marked reduction of the incidences of micronucleated PCEs and micronucleated NCEs. These findings suggest that the priming low dose of low linear energy transfer (LET) X-rays induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (residual anhematopoiesis and delayed genotoxic effects) caused by exposure to a high challenge dose from low-LET (X-ray) or high-LET (carbon and neon ion) irradiations. These findings provide new knowledge of the characterization of the Yonezawa Effect by providing new insight into the mechanistic study of AR in vivo. PMID:22923746
Dose-response characteristics of an amorphous silicon EPID.

PubMed

Winkler, Peter; Hefner, Alfred; Georg, Dietmar

2005-10-01

Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output characteristics of the accelerator. If ghosting is prevented from affecting the results and all dose-response effects are properly corrected for, the EPID signal becomes independent of dose rate, dose, and exposure time.
Single dosing comparison of the relative cardiac beta 1/beta 2 activity of inhaled fenoterol and salbutamol in normal subjects.

PubMed Central

Newnham, D M; Wheeldon, N M; Lipworth, B J; McDevitt, D G

1993-01-01

BACKGROUND--The aim of the present study was to compare the dose related effects of fenoterol and salbutamol on cardiac beta 1 and beta 2 receptors using the beta 1 selective antagonist atenolol, in order to dissect out relative beta 1/beta 2 mediated responses. METHODS--Fourteen normal volunteers were randomised to receive pretreatment with either atenolol 25 mg or placebo, followed by inhaled fenoterol or salbutamol in equal doses by weight (cumulative doses of 1 mg and 4 mg). Measurements were made 30 minutes after inhaling each dose of beta 2 agonist. Values (mean and 95% CI) were expressed as a change from baseline. RESULTS--At 4 mg fenoterol produced equivalent falls in serum potassium and increases in tremor to salbutamol. The mean (95% CI) increase in heart rate (beats/min) with fenoterol at 4 mg after placebo was 47 (41-53) and after atenolol was 34 (28-40), with values for salbutamol being 46 (40-52) after placebo and 30 (24-36) after atenolol. The inotropic response (stroke distance) after atenolol at the 4 mg dose was 5.0 (3.9-6.1) cm for fenoterol and 4.7 (3.5-5.9) cm for salbutamol. There were no significant differences in heart rate or stroke distance response between the two drugs after either placebo or atenolol. Furthermore, ECG effects (Q-Tc and T wave) of fenoterol and salbutamol were comparable at both doses. CONCLUSIONS--These results show that there is no difference in the respective chronotropic or inotropic activities of fenoterol and salbutamol on cardiac beta 1 or beta 2 receptors when given at higher than conventional doses. PMID:8102213
Impact of chemical proportions on the acute neurotoxicity of a mixture of seven carbamates in preweanling and adult rats.

PubMed

Moser, Virginia C; Padilla, Stephanie; Simmons, Jane Ellen; Haber, Lynne T; Hertzberg, Richard C

2012-09-01

Statistical design and environmental relevance are important aspects of studies of chemical mixtures, such as pesticides. We used a dose-additivity model to test experimentally the default assumptions of dose additivity for two mixtures of seven N-methylcarbamates (carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, and propoxur). The best-fitting models were selected for the single-chemical dose-response data and used to develop a combined prediction model, which was then compared with the experimental mixture data. We evaluated behavioral (motor activity) and cholinesterase (ChE)-inhibitory (brain, red blood cells) outcomes at the time of peak acute effects following oral gavage in adult and preweanling (17 days old) Long-Evans male rats. The mixtures varied only in their mixing ratios. In the relative potency mixture, proportions of each carbamate were set at equitoxic component doses. A California environmental mixture was based on the 2005 sales of each carbamate in California. In adult rats, the relative potency mixture showed dose additivity for red blood cell ChE and motor activity, and brain ChE inhibition showed a modest greater-than additive (synergistic) response, but only at a middle dose. In rat pups, the relative potency mixture was either dose-additive (brain ChE inhibition, motor activity) or slightly less-than additive (red blood cell ChE inhibition). On the other hand, at both ages, the environmental mixture showed greater-than additive responses on all three endpoints, with significant deviations from predicted at most to all doses tested. Thus, we observed different interactive properties for different mixing ratios of these chemicals. These approaches for studying pesticide mixtures can improve evaluations of potential toxicity under varying experimental conditions that may mimic human exposures.
Altered locomotor and stereotyped responses to acute methamphetamine in adolescent, maternally separated rats

PubMed Central

Pritchard, Laurel M.; Hensleigh, Emily; Lynch, Sarah

2012-01-01

Rationale Neonatal maternal separation (MS) has been used to model the effects of early life stress in rodents. MS alters behavioral responses to a variety of abused drugs, but few studies have examined its effects on methamphetamine sensitivity. Objectives We sought to determine the effects of MS on locomotor and stereotyped responses to low-to-moderate doses of methamphetamine in male and female adolescent rats. Methods Male and female rat pups were subjected to three hours per day of MS on postnatal days (PN) 2–14, or a brief handling control procedure during the same period. During adolescence (approximately PN 40), all rats were tested for locomotor activity and stereotyped behavior in response to acute methamphetamine administration (0, 1.0 or 3.0 mg/kg, s.c.). Results MS rats of both sexes exhibited increased locomotor activity in a novel environment, relative to handled controls. MS increased the locomotor response to METH, and this effect occurred at different doses for male (3.0 mg/kg) and female (1.0 mg/kg) rats. MS also increased stereotyped behavior in response to METH (1.0 mg/kg) in both sexes. Conclusions MS enhances the locomotor response to METH in a dose- and sex-dependent manner. These results suggest that individuals with a history of early life stress may be particularly vulnerable to the psychostimulant effects of METH, even at relatively low doses. PMID:22414962
Radioimmunoassays and 2-site immunoradiometric "sandwich" assays: basic principles.

PubMed

Rodbard, D

1988-10-01

The "sandwich" or noncompetitive reagent-excess, 2-site immunoradiometric assay (2-site IRMA), ELISA, USERIA, and related techniques, have several advantages compared with the traditional or competitive radioimmunoassays. IRMAs can provide improved sensitivity and specificity. However, IRMAs present some practical problems with nonspecific binding, increased consumption of antibody, biphasic dose response curve, (high dose hook effect), and may require special techniques for dose response curve analysis. We anticipate considerable growth in the popularity and importance of 2-site IRMA.
Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

NASA Technical Reports Server (NTRS)

Williams, J. R.; Zhang, Y.; Zhou, H.; Osman, M.; Cha, D.; Kavet, R.; Cuccinotta, F.; Dicello, J. F.; Dillehay, L. E.

1999-01-01

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.
A randomized dose-response trial of aerobic exercise and health-related quality of life in colon cancer survivors.

PubMed

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

2018-04-01

To examine the dose-response effects of aerobic exercise on health-related quality of life (HRQoL) among colon cancer survivors. Thirty-nine stage I to III colon cancer survivors were randomized to 1 of 3 groups: usual-care control, 150 min·wk -1 of aerobic exercise (low-dose) and 300 min·wk -1 of aerobic exercise (high-dose) for 6 months. HRQoL outcomes included the Short Form (SF)-36 physical and mental component summary, Functional Assessment of Cancer Therapy-Colorectal, Pittsburgh Sleep Quality Index, Fear of Cancer Recurrence Inventory, Fatigue Symptom Inventory, and North Central Cancer Treatment Group bowel function questionnaire, assessed at baseline and post intervention. The primary hypothesis was that exercise would improve HRQoL outcomes in a dose-response fashion, such that high-dose aerobic exercise would yield the largest improvements in HRQoL outcomes. Over 6 months, the low-dose group completed 141 ± 10 min·wk -1 of aerobic exercise, and the high-dose group completed 247 ± 11 min·wk -1 of aerobic exercise. Over 6 months, exercise improved the physical component summary score of the SF-36 (P trend = 0.002), the Functional Assessment of Cancer Therapy-Colorectal (P trend = 0.025), the Pittsburgh Sleep Quality Index (P trend = 0.049), and the Fatigue Symptom Inventory (P trend = 0.045) in a dose-response fashion. Between-group standardized mean difference effects sizes for the above-described findings were small to moderate in magnitude (0.35-0.75). No dose-response effects were observed for the mental component summary score of the SF-36, the Fear of Cancer Recurrence Inventory, or bowel function. Higher doses of aerobic exercise, up to 300 min·wk -1 , improve multiple HRQoL outcomes among stage I to III colon cancer survivors. These findings provide evidence that aerobic exercise may provide multiple health benefits for colon cancer survivors. Copyright © 2018 John Wiley & Sons, Ltd.
In Vitro-In Vivo Dose Response of Ursolic Acid, Sulforaphane, PEITC, and Curcumin in Cancer Prevention.

PubMed

Ramirez, Christina N; Li, Wenji; Zhang, Chengyue; Wu, Renyi; Su, Shan; Wang, Chao; Gao, Linbo; Yin, Ran; Kong, Ah-Ng

2017-12-20

According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.
A Model for Precise and Uniform Pelvic- and Limb-Sparing Abdominal Irradiation to Study the Radiation-Induced Gastrointestinal Syndrome in Mice Using Small Animal Irradiation Systems.

PubMed

Brodin, N Patrik; Velcich, Anna; Guha, Chandan; Tomé, Wolfgang A

2017-01-01

Currently, no readily available mitigators exist for acute abdominal radiation injury. Here, we present an animal model for precise and homogenous limb-sparing abdominal irradiation (LSAIR) to study the radiation-induced gastrointestinal syndrome (RIGS). The LSAIR technique was developed using the small animal radiation research platform (SARRP) with image guidance capabilities. We delivered LSAIR at doses between 14 and 18 Gy on 8- to 10-week-old male C57BL/6 mice. Histological analysis was performed to confirm that the observed mortality was due to acute abdominal radiation injury. A steep dose-response relationship was found for survival, with no deaths seen at doses below 16 Gy and 100% mortality at above 17 Gy. All deaths occurred between 6 and 10 days after irradiation, consistent with the onset of RIGS. This was further confirmed by histological analysis showing clear differences in the number of regenerative intestinal crypts between animals receiving sublethal (14 Gy) and 100% lethal (18 Gy) radiation. The developed LSAIR technique provides uniform dose delivery with a clear dose response, consistent with acute abdominal radiation injury on histological examination. This model can provide a useful tool for researchers investigating the development of mitigators for accidental or clinical high-dose abdominal irradiation.
The response of Kodak EDR2 film in high-energy electron beams.

PubMed

Gerbi, Bruce J; Dimitroyannis, Dimitri A

2003-10-01

Kodak XV2 film has been a key dosimeter in radiation therapy for many years. The advantages of the recently introduced Kodak EDR2 film for photon beam dosimetry have been the focus of several IMRT verification dosimetry publications. However, no description of this film's response to electron beams exists in the literature. We initiated a study to characterize the response and utility of this film for electron beam dosimetry. We exposed a series of EDR2 films to 6, 9, 12, 16, and 20 MeV electrons in addition to 6 and 18 MV x rays to develop standard characteristic curves. The linac was first calibrated to ensure that the delivered dose was known accurately. All irradiations were done at dmax in polystyrene for both photons and electrons, all films were from the same batch, and were developed at the same time. We also exposed the EDR2 films in a solid water phantom to produce central axis depth dose curves. These data were compared against percent depth dose curves measured in a water phantom using an IC-10 ion chamber, Kodak XV2 film, and a PTW electron diode. The response of this film was the same for both 6 and 18 MV x rays, but showed an apparent energy-dependent enhancement for electron beams. The response of the film also increased with increasing electron energy. This caused the percent depth dose curves using film to be shifted toward the surface compared to the ion chamber data.
S220. BLONANSERIN AUGMENTATION IN PATIENTS WITH SCHIZOPHRENIA – WHO IS BENEFITED FROM BLONANSERIN AUGMENTATION? AN OPEN-LABEL, PROSPECTIVE, MULTI-CENTER STUDY

PubMed Central

Bahk, Won-Myong; Kwon, Young Joon; Yoon, Bo-Hyun; Lee, Sang-Yeol; Lee, Kwanghun; Jon, Duk-In; Kim, Moon Doo; Lim, Eunsung

2018-01-01

Abstract Background Evidences for antipsychotic augmentation for schizophrenic patients with sub-optimal efficacy have been lacking although it has been widespread therapeutic strategy in clinical practice. The purpose of this study was to investigate the efficacy and tolerability of blonanserin augmentation with an atypical antipsychotics (AAPs) in schizophrenic patients. Methods A total of 100 patients with schizophrenia partially or completely unresponsive to treatment with an AAP recruited in this 12-week, open-label, non-comparative, multicenter study. Blonanserin was added to existing AAPs which were maintained during the study period. Efficacy was primarily evaluated using Positive and Negative Syndrome Scale (PANSS) at baseline, week 2, 4, 8, and 12. Predictors for PANSS response (≥20% reduction) was investigated. Results The PANSS total score was significantly decreased at 12 weeks after blonanserin augmentation (-21.0 ± 18.1, F=105.849, p<0.001). Response rate on PANSS at week 12 was 51.0%. Premature discontinuation was occurred in 17 patients (17.0%) and 4 patients among them discontinued the study due to adverse events. Nine patients experienced significant weight gain during the study. Response to blonanserin augmentation was associated with severe (PANSS>85) baseline symptom (OR=10.298, p=0.007) and higher dose (>600mg/day of chlorpromazine equivalent dose) of existing AAPs (OR=4.594, p=0.014). Discussion Blonanserin augmentation improved psychiatric symptoms of schizophrenic patients in cases of partial or non-responsive to an AAP treatment with favorable tolerability. Patients with severe symptom despite treatment with higher dose of AAP were benefited from this augmentation. These results suggested that blonanserin augmentation could be an effective strategy for specific patients with schizophrenia.
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
Polymorphisms in the Vitamin A Receptor and Innate Immunity Genes Influence the Antibody Response to Rubella Vaccination

PubMed Central

Ovsyannikova, Inna G.; Haralambieva, Iana H.; Dhiman, Neelam; O’Byrne, Megan M.; Pankratz, V. Shane; Jacobson, Robert M.; Poland, Gregory A.

2009-01-01

Background Genetic polymorphisms play an important role in rubella vaccine-induced immunity. Methods We genotyped 714 healthy children after two age-appropriate doses of rubella-containing vaccine for 142 potential SNPs. Results Specific polymorphisms in the vitamin A receptor, RIG-I, TRIM5 and TRIM22 genes were significantly associated with rubella vaccine humoral immunity. The minor allele of the rs4416353 in the vitamin A receptor gene was associated with an allele dose-related decrease (P=.019) in rubella antibody response. The minor allele of rs6793694, in the vitamin A receptor gene, was associated with an allele dose-related antibody decrease (P=.039). The minor variant of nonsynonymous SNP rs10813831 (Arg7Cys) in the RIG-I gene was associated with an allele dose-related decrease in rubella antibody level from 37.4 IU/mL to 28.0 IU/mL (P=.035), while increased representation of the minor allele of the 5’UTR SNP (rs3824949, P=.015), in the antiretroviral TRIM5 gene, was associated with an allele dose-related increase in rubella antibody. It is of particular interest that the nonsynonymous SNP rs3740996 (His43Tyr) in the TRIM5 gene was associated with variations in rubella antibody response (P=.016) after having been previously found to have a significant functional role. Conclusions These findings further expand our immunogenetic understanding of mechanisms of rubella vaccine-induced immunity. PMID:20001730
Is ICRP guidance on the use of reference levels consistent?

PubMed

Hedemann-Jensen, Per; McEwan, Andrew C

2011-12-01

In ICRP 103, which has replaced ICRP 60, it is stated that no fundamental changes have been introduced compared with ICRP 60. This is true except that the application of reference levels in emergency and existing exposure situations seems to be applied inconsistently, and also in the related publications ICRP 109 and ICRP 111. ICRP 103 emphasises that focus should be on the residual doses after the implementation of protection strategies in emergency and existing exposure situations. If possible, the result of an optimised protection strategy should bring the residual dose below the reference level. Thus the reference level represents the maximum acceptable residual dose after an optimised protection strategy has been implemented. It is not an 'off-the-shelf item' that can be set free of the prevailing situation. It should be determined as part of the process of optimising the protection strategy. If not, protection would be sub-optimised. However, in ICRP 103 some inconsistent concepts have been introduced, e.g. in paragraph 279 which states: 'All exposures above or below the reference level should be subject to optimisation of protection, and particular attention should be given to exposures above the reference level'. If, in fact, all exposures above and below reference levels are subject to the process of optimisation, reference levels appear superfluous. It could be considered that if optimisation of protection below a fixed reference level is necessary, then the reference level has been set too high at the outset. Up until the last phase of the preparation of ICRP 103 the concept of a dose constraint was recommended to constrain the optimisation of protection in all types of exposure situations. In the final phase, the term 'dose constraint' was changed to 'reference level' for emergency and existing exposure situations. However, it seems as if in ICRP 103 it was not fully recognised that dose constraints and reference levels are conceptually different. The use of reference levels in radiological protection is reviewed. It is concluded that the recommendations in ICRP 103 and related ICRP publications seem to be inconsistent regarding the use of reference levels in existing and emergency exposure situations.
Association between dietary fiber intake and risk of coronary heart disease: A meta-analysis.

PubMed

Wu, Yihua; Qian, Yufeng; Pan, Yiwen; Li, Peiwei; Yang, Jun; Ye, Xianhua; Xu, Geng

2015-08-01

The association between coronary heart disease (CHD) and dietary fiber intake is not consistent, especially for the subtypes of dietary fiber. The aim of our study was to conduct a meta-analysis of existing cohort published studies assessing the association between dietary fiber intake and risk of CHD, and quantitatively estimating their dose-response relationships. We searched PubMed and EMBASE before May 2013. Random-effect model was used to calculate the pool relative risk (RRs) for the incidence and mortality of CHD. Dose-response, subgroup analyses based on fiber subtypes, heterogeneity and publication bias were also carried out. Eighteen studies involving 672,408 individuals were finally included in the present study. The pooled-adjusted RRs of coronary heart disease for the highest versus lowest category of fiber intake were 0.93 (95% confidence interval (CI), 0.91-0.96, P < 0.001) for incidence of all coronary events and 0.83 (95% CI, 0.76-0.91, P < 0.001) for mortality. Further subgroup analyses based on fiber subtypes (cereal, fruit, and vegetable fiber), indicated that RRs were 0.92 (95% CI, 0.85-0.99, P = 0.032), 0.92 (95% CI, 0.86-0.98, P = 0.01), 0.95 (95% CI, 0.89-1.01, P = 0.098) respectively for all coronary event and 0.81 (95% CI, 0.72-0.92, P = 0.001), 0.68 (95% CI, 0.43-1.07, P = 0.094), 0.91 (95% CI, 0.74-1.12, P = 0.383) for mortality. In addition, a significant dose-response relationship was observed between fiber intake and the incidence and mortality of CHD (P < 0.001). Our results indicate that consumption of dietary fiber is inversely associated with risk of coronary heart disease, especially for fiber from cereals and fruits. Besides, soluble and insoluble fibers have the similar effect. A significant dose-response relationship is also observed between fiber intake and CHD risk. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

PubMed

Goodson, William H; Lowe, Leroy; Carpenter, David O; Gilbertson, Michael; Manaf Ali, Abdul; Lopez de Cerain Salsamendi, Adela; Lasfar, Ahmed; Carnero, Amancio; Azqueta, Amaya; Amedei, Amedeo; Charles, Amelia K; Collins, Andrew R; Ward, Andrew; Salzberg, Anna C; Colacci, Annamaria; Olsen, Ann-Karin; Berg, Arthur; Barclay, Barry J; Zhou, Binhua P; Blanco-Aparicio, Carmen; Baglole, Carolyn J; Dong, Chenfang; Mondello, Chiara; Hsu, Chia-Wen; Naus, Christian C; Yedjou, Clement; Curran, Colleen S; Laird, Dale W; Koch, Daniel C; Carlin, Danielle J; Felsher, Dean W; Roy, Debasish; Brown, Dustin G; Ratovitski, Edward; Ryan, Elizabeth P; Corsini, Emanuela; Rojas, Emilio; Moon, Eun-Yi; Laconi, Ezio; Marongiu, Fabio; Al-Mulla, Fahd; Chiaradonna, Ferdinando; Darroudi, Firouz; Martin, Francis L; Van Schooten, Frederik J; Goldberg, Gary S; Wagemaker, Gerard; Nangami, Gladys N; Calaf, Gloria M; Williams, Graeme; Wolf, Gregory T; Koppen, Gudrun; Brunborg, Gunnar; Lyerly, H Kim; Krishnan, Harini; Ab Hamid, Hasiah; Yasaei, Hemad; Sone, Hideko; Kondoh, Hiroshi; Salem, Hosni K; Hsu, Hsue-Yin; Park, Hyun Ho; Koturbash, Igor; Miousse, Isabelle R; Scovassi, A Ivana; Klaunig, James E; Vondráček, Jan; Raju, Jayadev; Roman, Jesse; Wise, John Pierce; Whitfield, Jonathan R; Woodrick, Jordan; Christopher, Joseph A; Ochieng, Josiah; Martinez-Leal, Juan Fernando; Weisz, Judith; Kravchenko, Julia; Sun, Jun; Prudhomme, Kalan R; Narayanan, Kannan Badri; Cohen-Solal, Karine A; Moorwood, Kim; Gonzalez, Laetitia; Soucek, Laura; Jian, Le; D'Abronzo, Leandro S; Lin, Liang-Tzung; Li, Lin; Gulliver, Linda; McCawley, Lisa J; Memeo, Lorenzo; Vermeulen, Louis; Leyns, Luc; Zhang, Luoping; Valverde, Mahara; Khatami, Mahin; Romano, Maria Fiammetta; Chapellier, Marion; Williams, Marc A; Wade, Mark; Manjili, Masoud H; Lleonart, Matilde E; Xia, Menghang; Gonzalez, Michael J; Karamouzis, Michalis V; Kirsch-Volders, Micheline; Vaccari, Monica; Kuemmerle, Nancy B; Singh, Neetu; Cruickshanks, Nichola; Kleinstreuer, Nicole; van Larebeke, Nik; Ahmed, Nuzhat; Ogunkua, Olugbemiga; Krishnakumar, P K; Vadgama, Pankaj; Marignani, Paola A; Ghosh, Paramita M; Ostrosky-Wegman, Patricia; Thompson, Patricia A; Dent, Paul; Heneberg, Petr; Darbre, Philippa; Sing Leung, Po; Nangia-Makker, Pratima; Cheng, Qiang Shawn; Robey, R Brooks; Al-Temaimi, Rabeah; Roy, Rabindra; Andrade-Vieira, Rafaela; Sinha, Ranjeet K; Mehta, Rekha; Vento, Renza; Di Fiore, Riccardo; Ponce-Cusi, Richard; Dornetshuber-Fleiss, Rita; Nahta, Rita; Castellino, Robert C; Palorini, Roberta; Abd Hamid, Roslida; Langie, Sabine A S; Eltom, Sakina E; Brooks, Samira A; Ryeom, Sandra; Wise, Sandra S; Bay, Sarah N; Harris, Shelley A; Papagerakis, Silvana; Romano, Simona; Pavanello, Sofia; Eriksson, Staffan; Forte, Stefano; Casey, Stephanie C; Luanpitpong, Sudjit; Lee, Tae-Jin; Otsuki, Takemi; Chen, Tao; Massfelder, Thierry; Sanderson, Thomas; Guarnieri, Tiziana; Hultman, Tove; Dormoy, Valérian; Odero-Marah, Valerie; Sabbisetti, Venkata; Maguer-Satta, Veronique; Rathmell, W Kimryn; Engström, Wilhelm; Decker, William K; Bisson, William H; Rojanasakul, Yon; Luqmani, Yunus; Chen, Zhenbang; Hu, Zhiwei

2015-06-01

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015. Published by Oxford University Press.
Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

PubMed Central

Goodson, William H.; Lowe, Leroy; Carpenter, David O.; Gilbertson, Michael; Manaf Ali, Abdul; Lopez de Cerain Salsamendi, Adela; Lasfar, Ahmed; Carnero, Amancio; Azqueta, Amaya; Amedei, Amedeo; Charles, Amelia K.; Collins, Andrew R.; Ward, Andrew; Salzberg, Anna C.; Colacci, Anna Maria; Olsen, Ann-Karin; Berg, Arthur; Barclay, Barry J.; Zhou, Binhua P.; Blanco-Aparicio, Carmen; Baglole, Carolyn J.; Dong, Chenfang; Mondello, Chiara; Hsu, Chia-Wen; Naus, Christian C.; Yedjou, Clement; Curran, Colleen S.; Laird, Dale W.; Koch, Daniel C.; Carlin, Danielle J.; Felsher, Dean W.; Roy, Debasish; Brown, Dustin G.; Ratovitski, Edward; Ryan, Elizabeth P.; Corsini, Emanuela; Rojas, Emilio; Moon, Eun-Yi; Laconi, Ezio; Marongiu, Fabio; Al-Mulla, Fahd; Chiaradonna, Ferdinando; Darroudi, Firouz; Martin, Francis L.; Van Schooten, Frederik J.; Goldberg, Gary S.; Wagemaker, Gerard; Nangami, Gladys N.; Calaf, Gloria M.; Williams, Graeme P.; Wolf, Gregory T.; Koppen, Gudrun; Brunborg, Gunnar; Lyerly, H. Kim; Krishnan, Harini; Ab Hamid, Hasiah; Yasaei, Hemad; Sone, Hideko; Kondoh, Hiroshi; Salem, Hosni K.; Hsu, Hsue-Yin; Park, Hyun Ho; Koturbash, Igor; Miousse, Isabelle R.; Scovassi, A.Ivana; Klaunig, James E.; Vondráček, Jan; Raju, Jayadev; Roman, Jesse; Wise, John Pierce; Whitfield, Jonathan R.; Woodrick, Jordan; Christopher, Joseph A.; Ochieng, Josiah; Martinez-Leal, Juan Fernando; Weisz, Judith; Kravchenko, Julia; Sun, Jun; Prudhomme, Kalan R.; Narayanan, Kannan Badri; Cohen-Solal, Karine A.; Moorwood, Kim; Gonzalez, Laetitia; Soucek, Laura; Jian, Le; D’Abronzo, Leandro S.; Lin, Liang-Tzung; Li, Lin; Gulliver, Linda; McCawley, Lisa J.; Memeo, Lorenzo; Vermeulen, Louis; Leyns, Luc; Zhang, Luoping; Valverde, Mahara; Khatami, Mahin; Romano, Maria Fiammetta; Chapellier, Marion; Williams, Marc A.; Wade, Mark; Manjili, Masoud H.; Lleonart, Matilde E.; Xia, Menghang; Gonzalez Guzman, Michael J.; Karamouzis, Michalis V.; Kirsch-Volders, Micheline; Vaccari, Monica; Kuemmerle, Nancy B.; Singh, Neetu; Cruickshanks, Nichola; Kleinstreuer, Nicole; van Larebeke, Nik; Ahmed, Nuzhat; Ogunkua, Olugbemiga; Krishnakumar, P.K.; Vadgama, Pankaj; Marignani, Paola A.; Ghosh, Paramita M.; Ostrosky-Wegman, Patricia; Thompson, Patricia A.; Dent, Paul; Heneberg, Petr; Darbre, Philippa; Leung, Po Sing; Nangia-Makker, Pratima; Cheng, Qiang (Shawn); Robey, R.Brooks; Al-Temaimi, Rabeah; Roy, Rabindra; Andrade-Vieira, Rafaela; Sinha, Ranjeet K.; Mehta, Rekha; Vento, Renza; Di Fiore, Riccardo; Ponce-Cusi, Richard; Dornetshuber-Fleiss, Rita; Nahta, Rita; Castellino, Robert C.; Palorini, Roberta; Hamid, Roslida A.; Langie, Sabine A.S.; Eltom, Sakina E.; Brooks, Samira A.; Ryeom, Sandra; Wise, Sandra S.; Bay, Sarah N.; Harris, Shelley A.; Papagerakis, Silvana; Romano, Simona; Pavanello, Sofia; Eriksson, Staffan; Forte, Stefano; Casey, Stephanie C.; Luanpitpong, Sudjit; Lee, Tae-Jin; Otsuki, Takemi; Chen, Tao; Massfelder, Thierry; Sanderson, Thomas; Guarnieri, Tiziana; Hultman, Tove; Dormoy, Valérian; Odero-Marah, Valerie; Sabbisetti, Venkata; Maguer-Satta, Veronique; Rathmell, W.Kimryn; Engström, Wilhelm; Decker, William K.; Bisson, William H.; Rojanasakul, Yon; Luqmani, Yunus; Chen, Zhenbang; Hu, Zhiwei

2015-01-01

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. PMID:26106142

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 ascorbate, as high doses of this vitamin may impair protective mechanisms associated with nitrite or nitrate from dietary sources. Copyright © 2018 Elsevier Inc. All rights reserved.
Reducing the Risk of Posttraumatic Stress Disorder in Children Following Natural Disasters

ERIC Educational Resources Information Center

Mohay, Heather; Forbes, Nicole

2009-01-01

A significant number of children suffer long-term psychological disturbance following exposure to a natural disaster. Evidence suggests that a dose-response relationship exists, so that children and adolescents who experience the most intense or extensive exposure to the risk factors for posttraumatic stress disorder (PTSD) are likely to develop…
Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy.

PubMed

Gorski, Armin; Hamouda, Khaled; Özkur, Mehmet; Leistner, Markus; Sommer, Sebastian-Patrick; Leyh, Rainer; Schimmer, Christoph

2015-03-01

Ongoing debate exists concerning the optimal choice and duration of antibiotic prophylaxis as well as the reasonable calculated empiric antibiotic therapy for hospital-acquired infections in critically ill cardiac surgery patients. A nationwide questionnaire was distributed to all German heart surgery centers concerning antibiotic prophylaxis and the calculated empiric antibiotic therapy. The response to the questionnaire was 87.3%. All clinics that responded use antibiotic prophylaxis, 79% perform it not longer than 24 h (single-shot: 23%; 2 doses: 29%; 3 doses: 27%; 4 doses: 13%; and >5 doses: 8%). Cephalosporin was used in 89% of clinics (46% second-generation, 43% first-generation cephalosporin). If sepsis is suspected, the following diagnostics are performed routinely: wound inspection 100%; white blood cell count 100%; radiography 99%; C-reactive protein 97%; microbiological testing of urine 91%, blood 81%, and bronchial secretion 81%; procalcitonin 74%; and echocardiography 75%. The calculated empiric antibiotic therapy (depending on the suspected focus) consists of a multidrug combination with broad-spectrum agents. This survey shows that existing national guidelines and recommendations concerning perioperative antibiotic prophylaxis and calculated empiric antibiotic therapy are well applied in almost all German heart centers. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
Implementing the birth dose of hepatitis B vaccine in rural Indonesia.

PubMed

Creati, Mick; Saleh, Asmaniar; Ruff, Tilman A; Stewart, Tony; Otto, Bradley; Sutanto, Agustinus; Clements, C John

2007-08-10

Reaching mothers and their newborn infants around the time of birth with adequate health services has long been a difficult problem in developing countries. In parallel, similar problems have arisen in attempting to deliver hepatitis B (HepB) vaccine to infants born at home in many countries where mother-to-infant transmission is common. It is logical, and supported by experience in Indonesia, to find a combined solution for both problems. The World Health Organization (WHO) recommends that a timely birth dose of HepB vaccine be given, particularly in areas of high vertical transmission of hepatitis B virus (HBV). This can be achieved relatively easily in situations where almost all births occur in health facilities. But where a significant proportion of births occur at home and without birth attendants able to give injections, this is much more difficult. Barriers to the timely administration of the birth dose of HepB vaccine include weakness in policy development and implementation, difficulties in reliably supplying potent vaccine to community level, limited transport, poor communication, limited cold chain capacity, lack of effective training, and lack of a clear delineation of responsibility between health care professionals. Demonstration projects, such as those in Indonesia, suggest that there are significant opportunities to improve the timely delivery of HepB vaccine birth dose in existing maternal and child health programmes where health workers are trained to provide home delivery care.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Moura, Eduardo S., E-mail: emoura@wisc.edu; Micka, John A.; Hammer, Cliff G.

Purpose: This work presents the development of a phantom to verify the treatment planning system (TPS) algorithms used for high-dose-rate (HDR) brachytherapy. It is designed to measure the relative dose in a heterogeneous media. The experimental details used, simulation methods, and comparisons with a commercial TPS are also provided. Methods: To simulate heterogeneous conditions, four materials were used: Virtual Water™ (VM), BR50/50™, cork, and aluminum. The materials were arranged in 11 heterogeneity configurations. Three dosimeters were used to measure the relative response from a HDR {sup 192}Ir source: TLD-100™, Gafchromic{sup ®} EBT3 film, and an Exradin™ A1SL ionization chamber. Tomore » compare the results from the experimental measurements, the various configurations were modeled in the PENELOPE/penEasy Monte Carlo code. Images of each setup geometry were acquired from a CT scanner and imported into BrachyVision™ TPS software, which includes a grid-based Boltzmann solver Acuros™. The results of the measurements performed in the heterogeneous setups were normalized to the dose values measured in the homogeneous Virtual Water™ setup and the respective differences due to the heterogeneities were considered. Additionally, dose values calculated based on the American Association of Physicists in Medicine-Task Group 43 formalism were compared to dose values calculated with the Acuros™ algorithm in the phantom. Calculated doses were compared at the same points, where measurements have been performed. Results: Differences in the relative response as high as 11.5% were found from the homogeneous setup when the heterogeneous materials were inserted into the experimental phantom. The aluminum and cork materials produced larger differences than the plastic materials, with the BR50/50™ material producing results similar to the Virtual Water™ results. Our experimental methods agree with the PENELOPE/penEasy simulations for most setups and dosimeters. The TPS relative differences with the Acuros™ algorithm were similar in both experimental and simulated setups. The discrepancy between the BrachyVision™, Acuros™, and TG-43 dose responses in the phantom described by this work exceeded 12% for certain setups. Conclusions: The results derived from the phantom measurements show good agreement with the simulations and TPS calculations, using Acuros™ algorithm. Differences in the dose responses were evident in the experimental results when heterogeneous materials were introduced. These measurements prove the usefulness of the heterogeneous phantom for verification of HDR treatment planning systems based on model-based dose calculation algorithms.« less
Health Effects Related to Wind Turbine Noise Exposure: A Systematic Review

PubMed Central

Schmidt, Jesper Hvass; Klokker, Mads

2014-01-01

Background Wind turbine noise exposure and suspected health-related effects thereof have attracted substantial attention. Various symptoms such as sleep-related problems, headache, tinnitus and vertigo have been described by subjects suspected of having been exposed to wind turbine noise. Objective This review was conducted systematically with the purpose of identifying any reported associations between wind turbine noise exposure and suspected health-related effects. Data Sources A search of the scientific literature concerning the health-related effects of wind turbine noise was conducted on PubMed, Web of Science, Google Scholar and various other Internet sources. Study Eligibility Criteria All studies investigating suspected health-related outcomes associated with wind turbine noise exposure were included. Results Wind turbines emit noise, including low-frequency noise, which decreases incrementally with increases in distance from the wind turbines. Likewise, evidence of a dose-response relationship between wind turbine noise linked to noise annoyance, sleep disturbance and possibly even psychological distress was present in the literature. Currently, there is no further existing statistically-significant evidence indicating any association between wind turbine noise exposure and tinnitus, hearing loss, vertigo or headache. Limitations Selection bias and information bias of differing magnitudes were found to be present in all current studies investigating wind turbine noise exposure and adverse health effects. Only articles published in English, German or Scandinavian languages were reviewed. Conclusions Exposure to wind turbines does seem to increase the risk of annoyance and self-reported sleep disturbance in a dose-response relationship. There appears, though, to be a tolerable level of around LAeq of 35 dB. Of the many other claimed health effects of wind turbine noise exposure reported in the literature, however, no conclusive evidence could be found. Future studies should focus on investigations aimed at objectively demonstrating whether or not measureable health-related outcomes can be proven to fluctuate depending on exposure to wind turbines. PMID:25474326
Health effects related to wind turbine noise exposure: a systematic review.

PubMed

Schmidt, Jesper Hvass; Klokker, Mads

2014-01-01

Wind turbine noise exposure and suspected health-related effects thereof have attracted substantial attention. Various symptoms such as sleep-related problems, headache, tinnitus and vertigo have been described by subjects suspected of having been exposed to wind turbine noise. This review was conducted systematically with the purpose of identifying any reported associations between wind turbine noise exposure and suspected health-related effects. A search of the scientific literature concerning the health-related effects of wind turbine noise was conducted on PubMed, Web of Science, Google Scholar and various other Internet sources. All studies investigating suspected health-related outcomes associated with wind turbine noise exposure were included. Wind turbines emit noise, including low-frequency noise, which decreases incrementally with increases in distance from the wind turbines. Likewise, evidence of a dose-response relationship between wind turbine noise linked to noise annoyance, sleep disturbance and possibly even psychological distress was present in the literature. Currently, there is no further existing statistically-significant evidence indicating any association between wind turbine noise exposure and tinnitus, hearing loss, vertigo or headache. Selection bias and information bias of differing magnitudes were found to be present in all current studies investigating wind turbine noise exposure and adverse health effects. Only articles published in English, German or Scandinavian languages were reviewed. Exposure to wind turbines does seem to increase the risk of annoyance and self-reported sleep disturbance in a dose-response relationship. There appears, though, to be a tolerable level of around LAeq of 35 dB. Of the many other claimed health effects of wind turbine noise exposure reported in the literature, however, no conclusive evidence could be found. Future studies should focus on investigations aimed at objectively demonstrating whether or not measureable health-related outcomes can be proven to fluctuate depending on exposure to wind turbines.
Lemna minor plants chronically exposed to ionising radiation: RNA-seq analysis indicates a dose rate dependent shift from acclimation to survival strategies.

PubMed

Van Hoeck, Arne; Horemans, Nele; Nauts, Robin; Van Hees, May; Vandenhove, Hildegarde; Blust, Ronny

2017-04-01

Ecotoxicological research provides knowledge on ionising radiation-induced responses in different plant species. However, the sparse data currently available are mainly extracted from acute exposure treatments. To provide a better understanding of environmental exposure scenarios, the response to stress in plants must be followed in more natural relevant chronic conditions. We previously showed morphological and biochemical responses in Lemna minor plants continuously exposed for 7days in a dose-rate dependent manner. In this study responses on molecular (gene expression) and physiological (photosynthetic) level are evaluated in L. minor plants exposed to ionising radiation. To enable this, we examined the gene expression profiles of irradiated L. minor plants by using an RNA-seq approach. The gene expression data reveal indications that L. minor plants exposed at lower dose rates, can tolerate the exposure by triggering acclimation responses. In contrast, at the highest dose rate tested, a high number of genes related to antioxidative defense systems, DNA repair and cell cycle were differentially expressed suggesting that only high dose rates of ionising radiation drive L. minor plants into survival strategies. Notably, the photosynthetic process seems to be unaffected in L. minor plants among the tested dose rates. This study, supported by our earlier work, clearly indicates that plants shift from acclimation responses towards survival responses at increasing dose rates of ionising radiation. Copyright © 2017 Elsevier B.V. All rights reserved.
Statistical analysis of radioimmunoassay. In comparison with bioassay (in Japanese)

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

Nakano, R.

1973-01-01

Using the data of RIA (radioimmunoassay), statistical procedures for dealing with two problems of the linearization of dose response curve and calculation of relative potency were described. There were three methods for linearization of dose response curve of RIA. In each method, the following parameters were shown on the horizontal and vertical axis: dose x, (B/T)/sup -1/; c/x + c, B/T (C: dose which makes B/T 50%); log x, logit B/T. Among them, the last method seems to be most practical. The statistical procedures for bioassay were employed for calculating the relative potency of unknown samples compared to the standardmore » samples from dose response curves of standand and unknown samples using regression coefficient. It is desirable that relative potency is calculated by plotting more than 5 points in the standard curve and plotting more than 2 points in unknow samples. For examining the statistical limit of precision of measuremert, LH activity of gonadotropin in urine was measured and relative potency, precision coefficient and the upper and lower limits of relative potency at 95% confidence limit were calculated. On the other hand, bioassay (by the ovarian ascorbic acid reduction method and anteriol lobe of prostate weighing method) was done in the same samples, and the precision was compared with that of RIA. In these examinations, the upper and lower limits of the relative potency at 95% confidence limit were near each other, while in bioassay, a considerable difference was observed between the upper and lower limits. The necessity of standardization and systematization of the statistical procedures for increasing the precision of RIA was pointed out. (JA)« less
Effects of histamine and some related compounds on conditioned avoidance response in rats

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

Tasaka, K.; Kamei, C.; Akahori, H.

1985-11-25

When histamine (Hi) and other agonists were applied intraventricularly, Hi caused a dose-dependent inhibition of the avoidance response in rats; its ED50 was 3.60 ..mu..g. l-methylHi, l-methylimidazole acetic acid and imidazole acetic acid which are major metabolites of Hi produced no inhibitory effect even at 50 ..mu..g. H/sub 1/-agonists (2-methylHi and 2-thiazolylethylamine) also depressed the avoidance response; their dose-response lines run parallel to that of Hi. The depressant effects of H/sub 2/-agonists (4-methylHi and dimaprit) were relatively weak; their dose-response lines were not parallel to that of Hi. When antagonists were pretreated intravenously, Hi action was clearly antagonized by diphehydraminemore » and pyrilamine, but not by cimetidine or ranitidine. Intraventricular injection of Hi mixed with cimetidine or ranitidine did not change the effect induced by Hi alone. The avoidance response was not affected by noradrenaline, dopamine or 5-hydroxytryptamine. Although acetylcholine (ACh) suppressed the avoidance response dose-dependently, its effect was much weaker than that of Hi. Pretreatment with cholinergic blocking drugs (atropine and scopolamine) antagonized ACh action but not Hi action. From these results, it is assumed that the inhibitory effect of Hi on the avoidance response is preferentially linked to the H/sub 1/-receptor. After intraventricular application of /sup 3/H-Hi, the highest radioactivity was determined in the hypothalamus. 21 references, 4 figures, 4 tables.« less
Osmolarity: a decisive parameter of bowel agents in intestinal magnetic resonance imaging.

PubMed

Borthne, Arne S; Abdelnoor, Michael; Storaas, Trygve; Pierre-Jerome, Claude; Kløw, Nils-E

2006-06-01

The aim was to evaluate the importance of the osmolarity of different oral agents for bowel distension and the level of related adverse events. The longitudinal design included the exposition of different oral MR agents on two separate occasions. Four groups of volunteers were randomly given 350 ml gastrografin of three different concentrations and water. On the second occasion they received mannitol, iohexol or iodixanol with equivalent osmolarities, but the control group (water) received mannitol. We recorded the outcomes as the degree of bowel distension determined as the mean bowel section area and the total level of discomfort recorded from a visual analogue scale (VAS). The statistical analysis included scatter plots with the best-fitted line with linear regression to study the association between osmolarity and section area and the association between osmolarity and adverse events. A dose-response association was found between increasing osmolarity levels and bowel area in square centimeters (P = 0.00001). A similar dose-response association existed between increasing levels of osmolarity and adverse events (P = 0.001). Osmolarity appears to be more important for bowel distension than the physico-chemical characteristics of the nonabsorbable oral agents. The optimum osmolarity level is determined by the patient's tolerance of the adverse events.
Molecular, cellular, and genetic basis of radiosensitivity at low doses: a case of inducible repair?

PubMed

Skov, K A

1994-04-01

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

PubMed Central

Stoops, William W.; Lile, Joshua A.; Glaser, Paul E.A.; Hays, Lon R.; Rush, Craig R.

2011-01-01

Cocaine use disorders are an unrelenting public health concern. Behavioral treatments reduce cocaine use by providing non-drug alternative reinforcers. The purpose of this human laboratory experiment was to determine how response cost for non-drug alternative reinforcers influenced cocaine choice. Seven cocaine-using, non-treatment-seeking subjects completed a crossover, double-blind protocol in which they first sampled doses of intranasal cocaine (5, 10, 20 or 30 mg) and completed a battery of subject-rated and physiological measures. Subjects then made eight discrete choices between the sampled dose and an alternative reinforce (US$0.25). The response cost to earn a cocaine dose was always a fixed ratio (FR) of 100 responses. The response cost for the alternative reinforcer varied across sessions (FR1, FR10, FR100, FR1000). Dose-related increases were observed for cocaine choice. Subjects made fewer drug choices when the FR requirements for the alternative reinforcers were lower than that for drug relative to when the FR requirements were equal to or higher than that for drug. Intranasal cocaine also produced prototypical stimulant-like subject-rated and physiological effects (e.g., increased ratings of Like Drug; elevated blood pressure). These data demonstrate that making alternative reinforcers easier to earn reduces cocaine self-administration, which has implications for treatment efforts. PMID:22015480
A standard dose of radiation for microscopic disease is not appropriate

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

Marks, L.B.

1990-12-15

Elective irradiation of sites of potential occult tumor spread is often part of a patient's radiation therapy program. The required radiation dose (D) depends on the probability that occult disease exists (P(occ)), the number of sites at risk (A), the number of tumor clonogens present (Ni), their radiation sensitivity, and the desired control rate. An exponential model of cell survival is used to quantify the importance of these factors. Control Probability = (1 - Pocc x (1 - e-Ni x (SF2)D/2))A; SF2 = surviving fraction after 2 Gy. Implications for clinical radiation therapy include: 1. Since the number of clonogensmore » in an occult site may vary from 10 degrees to 10(8), Ni is the major determinant of the required dose. The intrinsic radiation sensitivity of the clonogens (SF2) is also extremely important in determining the dose. Other factors are less influential since they vary less. 2. The variability of Ni (8 logs) is larger than the variation in cell number seen with gross disease (1 cm3 versus 1000 cm3, 3 logs). When Ni approximately 10(8), the required dose approaches that needed for small volume gross disease (10(9) cells, 1 cm3). 3. The dose prescribed to elective sites should reflect the risk of occult disease based on the primary tumor site, stage, and grade. 4. Regions where clinicoradiologic evaluation is difficult (e.g., pelvis and obese neck) require higher doses because macroscopic tumor deposits may exist. 5. Relatively low doses (10 to 30 Gy) are often thought to be inadequate for microscopic tumor. However, similar doses have been reported to sterilize microscopic tumor in ovarian, rectal, bladder, breast, and head and neck carcinomas. Relatively low doses should not be discounted since they may be useful in select cases when normal tissue tolerances and/or previous irradiation treatment limit the radiation dose.« less
Modelling the effect of autotoxicity on density-dependent phytotoxicity.

PubMed

Sinkkonen, A

2007-01-21

An established method to separate resource competition from chemical interference is cultivation of monospecific, even-aged stands. The stands grow at several densities and they are exposed to homogenously spread toxins. Hence, the dose received by individual plants is inversely related to stand density. This results in distinguishable alterations in dose-response slopes. The method is often recommended in ecological studies of allelopathy. However, many plant species are known to release autotoxic compounds. Often, the probability of autotoxicity increases as sowing density increases. Despite this, the possibility of autotoxicity is ignored when experiments including monospecific stands are designed and when their results are evaluated. In this paper, I model mathematically how autotoxicity changes the outcome of dose-response slopes as different densities of monospecific stands are grown on homogenously phytotoxic substrata. Several ecologically reasonable relations between plant density and autotoxin exposure are considered over a range of parameter values, and similarities between different relations are searched for. The models indicate that autotoxicity affects the outcome of density-dependent dose-response experiments. Autotoxicity seems to abolish the effects of other phytochemicals in certain cases, while it may augment them in other cases. Autotoxicity may alter the outcome of tests using the method of monospecific stands even if the dose of autotoxic compounds per plant is a fraction of the dose of non-autotoxic phytochemicals with similar allelopathic potential. Data from the literature support these conclusions. A faulty null hypothesis may be accepted if the autotoxic potential of a test species is overlooked in density-response experiments. On the contrary, if test species are known to be non-autotoxic, the method of monospecific stands does not need fine-tuning. The results also suggest that the possibility of autotoxicity should be investigated in many density-response bioassays that are made with even-aged plants, and that measure plant growth or germination.
Molecular markers of trichloroethylene-induced toxicity in human kidney cells

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

Lash, Lawrence H.; Putt, David A.; Hueni, Sarah E.

Difficulties in evaluation of trichloroethylene (TRI)-induced toxicity in humans and extrapolation of data from laboratory animals to humans are due to the existence of multiple target organs, multiple metabolic pathways, sex-, species-, and strain-dependent differences in both metabolism and susceptibility to toxicity, and the lack or minimal amount of human data for many target organs. The use of human tissue for mechanistic studies is thus distinctly advantageous. The kidneys are one target organ for TRI and metabolism by the glutathione (GSH) conjugation pathway is responsible for nephrotoxicity. The GSH conjugate is processed further to produce the cysteine conjugate, S-(1,2-dichlorovinyl)-L-cysteine (DCVC),more » which is the penultimate nephrotoxic species. Confluent, primary cultures of human proximal tubular (hPT) cells were used as the model system. Although cells in log-phase growth, which are undergoing more rapid DNA synthesis, would give lower LD{sub 50} values, confluent cells more closely mimic the in vivo proximal tubule. DCVC caused cellular necrosis only at relatively high doses (>100 {mu}M) and long incubation times (>24 h). In contrast, both apoptosis and enhanced cellular proliferation occurred at relatively low doses (10-100 {mu}M) and early incubation times (2-8 h). These responses were associated with prominent changes in expression of several proteins that regulate apoptosis (Bcl-2, Bax, Apaf-1, Caspase-9 cleavage, PARP cleavage) and cellular growth, differentiation and stress response (p53, Hsp27, NF-{kappa}B). Effects on p53 and Hsp27 implicate function of protein kinase C, the mitogen activated protein kinase pathway, and the cytoskeleton. The precise pattern of expression of these and other proteins can thus serve as molecular markers for TRI exposure and effect in human kidney.« less
Developing chemical criteria for wildlife: The benchmark dose versus NOAEL approach

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

Linder, G.

1995-12-31

Wildlife may be exposed to a wide variety of chemicals in their environment, and various strategies for evaluating wildlife risk for these chemicals have been developed. One, a ``no-observable-adverse-effects-level`` or NOAEL-approach has increasingly been applied to develop chemical criteria for wildlife. In this approach, the NOAEL represents the highest experimental concentration at which there is no statistically significant change in some toxicity endpoint relative to a control. Another, the ``benchmark dose`` or BMD-approach relies on the lower confidence limit for a concentration that corresponds to a small, but statistically significant, change in effect over some reference condition. Rather than correspondingmore » to a single experimental concentration as does the NOAEL, the BMD-approach considers the full concentration response curve for derivation of the BMD. Here, using a variety of vertebrates and an assortment of chemicals (including carbofuran, paraquat, methylmercury, cadmium, zinc, and copper), the NOAEL-approach will be critically evaluated relative to the BMD approach. Statistical models used in the BMD approach suggest these methods are potentially available for eliminating safety factors in risk calculations. A reluctance to recommend this, however, stems from the uncertainty associated with the shape of concentration-response curves at low concentrations. Also, with existing data the derivation of BMDs has shortcomings when sample size is small (10 or fewer animals per treatment). The success of BMD models clearly depends upon the continued collection of wildlife data in the field and laboratory, the design of toxicity studies sufficient for BMD calculations, and complete reporting of these results in the literature. Overall, the BMD approach for developing chemical criteria for wildlife should be given further consideration, since it more fully evaluates concentration-response data.« less
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.
Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention.

PubMed

Battes, Linda C; Pedersen, Susanne S; Oemrawsingh, Rohit M; van Geuns, Robert J; Al Amri, Ibtihal; Regar, Evelyn; de Jaegere, Peter P T; Serruys, Patrick; van Domburg, Ron T

2012-02-01

Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between beta blocker dose and depressive symptoms. Patients treated with PCI (N=685) completed the depression scale of the Hospital Anxiety and Depression Scale 1 and 12 months post PCI. Information about type and dose of beta blocker use was extracted from medical records. Of all patients, 68% (466/685) were on beta blocker therapy at baseline. In adjusted analysis, beta blocker use at 1 month post PCI (OR: 0.82; 95% CI: 0.53-1.26) was not significantly associated with depressive symptoms. At 12 months post PCI, there was a significant relationship between beta blocker use and depressive symptoms (OR: 0.51; 95% CI: 0.31-0.84), with beta blocker therapy associated with a 49% risk reduction in depressive symptoms. There was a dose-response relationship between beta blocker dose and depressive symptoms 12 months post PCI, with the risk reduction in depressive symptoms in relation to a low dose being 36% (OR: 0.64; 95% CI: 0.37-1.10) and 58% (OR: 0.42; 95% CI: 0.24-0.76) in relation to a high dose. Patients treated with beta blocker therapy were less likely to experience depressive symptoms 12 months post PCI, with there being a dose-response relationship with a higher dose providing a more pronounced protective effect. Copyright © 2011 Elsevier B.V. All rights reserved.
Reply to: Mounting evidence indicates that escalating doses of allopurinol are unnecessary for cardiovascular protection.

PubMed

Coburn, Brian W; Michaud, Kaleb; Bergman, Debra A; Mikuls, Ted R

2018-05-08

We thank Dr. Bredemeier for his comments regarding our manuscript on allopurinol dose escalation and mortality. He raises important evidence to consider in support of an interesting hypothesis that dose escalation may be unnecessary for allopurinol's cardiovascular (CV) protection and may actually be related to adverse CV outcomes. While we agree that evidence exists suggesting that low doses of allopurinol may be sufficient for CV protection, we believe that the studies cited highlight a number of areas where knowledge gaps remain which preclude any definitive conclusions about the effect of dose escalation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Comparative Iron Oxide Nanoparticle Cellular Dosimetry and Response in Mice by the Inhalation and Liquid Cell Culture Exposure Routes

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

Teeguarden, Justin G.; Mikheev, Vladimir B.; Minard, Kevin R.

testing the rapidly growing number of nanomaterials requires large scale use of in vitro systems under the presumption that these systems are sufficiently predictive or descriptive of responses in in vivo systems for effective use in hazard ranking. We hypothesized that improved relationships between in vitro and in vivo models of experimental toxicology for nanomaterials would result from placing response data in vitro and in vivo on the same dose scale, the amount of material associated with cells (target cell dose). Methods: Balb/c mice were exposed nose-only to an aerosol of 12.8 nm (68.6 nm CMD, 19.9 mg/m3, 4 hours)more » super paramagnetic iron oxide particles, target cell doses were calculated and biomarkers of response anchored with histological evidence were identified by global transcriptomics. Representative murine epithelial and macrophage cell types were exposed in vitro to the same material in liquid suspension for four hours and levels nanoparticle regulated cytokine transcripts identified in vivo were quantified as a function of measured nanoparticle cellular dose. Results. Target tissue doses of 0.009-0.4 μg SPIO/cm2 lung led to an inflammatory response in the alveolar region characterized by interstitial inflammation and macrophage infiltration. In vitro, higher target tissue doses of ~1.2-4 μg SPIO/ cm2 of cells were required to induce transcriptional regulation of markers of inflammation, CXCL2 CCL3, in C10 lung epithelial cells. Estimated in vivo macrophage SPIO nanoparticle doses ranged from 1-100 pg/cell, and induction of inflammatory markers was observed in vitro in macrophages at doses of 8-35 pg/cell. Conclusions: Application of target tissue dosimetry revealed good correspondence between target cell doses triggering inflammatory processes in vitro and in vivo in the alveolar macrophage population, but not in the epithelial cells of the alveolar region. These findings demonstrate the potential for target tissue dosimetry to enable the more quantitative comparison of in vitro and in vivo systems advance their use for hazard assessment and extrapolation to humans. The mildly inflammogentic cellular doses experienced by mice were similar those calculated for humans exposed to the same at the existing permissible exposure limit of 10 mg/m3 iron oxide (as Fe).« less
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
From AAA to Acuros XB-clinical implications of selecting either Acuros XB dose-to-water or dose-to-medium.

PubMed

Zifodya, Jackson M; Challens, Cameron H C; Hsieh, Wen-Long

2016-06-01

When implementing Acuros XB (AXB) as a substitute for anisotropic analytic algorithm (AAA) in the Eclipse Treatment Planning System, one is faced with a dilemma of reporting either dose to medium, AXB-Dm or dose to water, AXB-Dw. To assist with decision making on selecting either AXB-Dm or AXB-Dw for dose reporting, a retrospective study of treated patients for head & neck (H&N), prostate, breast and lung is presented. Ten patients, previously treated using AAA plans, were selected for each site and re-planned with AXB-Dm and AXB-Dw. Re-planning was done with fixed monitor units (MU) as well as non-fixed MUs. Dose volume histograms (DVH) of targets and organs at risk (OAR), were analyzed in conjunction with ICRU-83 recommended dose reporting metrics. Additionally, comparisons of plan homogeneity indices (HI) and MUs were done to further highlight the differences between the algorithms. Results showed that, on average AAA overestimated dose to the target volume and OARs by less than 2.0 %. Comparisons between AXB-Dw and AXB-Dm, for all sites, also showed overall dose differences to be small (<1.5 %). However, in non-water biological media, dose differences between AXB-Dw and AXB-Dm, as large as 4.6 % were observed. AXB-Dw also tended to have unexpectedly high 3D maximum dose values (>135 % of prescription dose) for target volumes with high density materials. Homogeneity indices showed that AAA planning and optimization templates would need to be adjusted only for the H&N and Lung sites. MU comparison showed insignificant differences between AXB-Dw relative to AAA and between AXB-Dw relative to AXB-Dm. However AXB-Dm MUs relative to AAA, showed an average difference of about 1.3 % signifying an underdosage by AAA. In conclusion, when dose is reported as AXB-Dw, the effect that high density structures in the PTV has on the dose distribution should be carefully considered. As the results show overall small dose differences between the algorithms, when transitioning from AAA to AXB, no significant change to existing prescription protocols is expected. As most of the clinical experience is dose-to-water based and calibration protocols and clinical trials are also dose-to-water based and there still exists uncertainties in converting CT number to medium, selecting AXB-Dw is strongly recommended.
Physics must join with biology in better assessing risk from low-dose irradiation.

PubMed

Feinendegen, L E; Neumann, R D

2005-01-01

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

PubMed Central

Slob, Wout

2015-01-01

Background 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. Objectives We developed a unified framework for probabilistic dose–response assessment. Methods 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. Results 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. Conclusions 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. Citation Chiu WA, Slob W. 2015. A unified probabilistic framework for dose–response assessment of human health effects. Environ Health Perspect 123:1241–1254; http://dx.doi.org/10.1289/ehp.1409385 PMID:26006063
Development and characterization of a three-dimensional radiochromic film stack dosimeter for megavoltage photon beam dosimetry.

PubMed

McCaw, Travis J; Micka, John A; DeWerd, Larry A

2014-05-01

Three-dimensional (3D) dosimeters are particularly useful for verifying the commissioning of treatment planning and delivery systems, especially with the ever-increasing implementation of complex and conformal radiotherapy techniques such as volumetric modulated arc therapy. However, currently available 3D dosimeters require extensive experience to prepare and analyze, and are subject to large measurement uncertainties. This work aims to provide a more readily implementable 3D dosimeter with the development and characterization of a radiochromic film stack dosimeter for megavoltage photon beam dosimetry. A film stack dosimeter was developed using Gafchromic(®) EBT2 films. The dosimeter consists of 22 films separated by 1 mm-thick spacers. A Virtual Water™ phantom was created that maintains the radial film alignment within a maximum uncertainty of 0.3 mm. The film stack dosimeter was characterized using simulations and measurements of 6 MV fields. The absorbed-dose energy dependence and orientation dependence of the film stack dosimeter were investigated using Monte Carlo simulations. The water equivalence of the dosimeter was determined by comparing percentage-depth-dose (PDD) profiles measured with the film stack dosimeter and simulated using Monte Carlo methods. Film stack dosimeter measurements were verified with thermoluminescent dosimeter (TLD) microcube measurements. The film stack dosimeter was also used to verify the delivery of an intensity-modulated radiation therapy (IMRT) procedure. The absorbed-dose energy response of EBT2 film differs less than 1.5% between the calibration and film stack dosimeter geometries for a 6 MV spectrum. Over a series of beam angles ranging from normal incidence to parallel incidence, the overall variation in the response of the film stack dosimeter is within a range of 2.5%. Relative to the response to a normally incident beam, the film stack dosimeter exhibits a 1% under-response when the beam axis is parallel to the film planes. Measured and simulated PDD profiles agree within a root-mean-square difference of 1.3%. In-field film stack dosimeter and TLD measurements agree within 5%, and measurements in the field penumbra agree within 0.5 mm. Film stack dosimeter and TLD measurements have expanded (k = 2) overall measurement uncertainties of 6.2% and 5.8%, respectively. Film stack dosimeter measurements of an IMRT dose distribution have 98% agreement with the treatment planning system dose calculation, using gamma criteria of 3% and 2 mm. The film stack dosimeter is capable of high-resolution, low-uncertainty 3D dose measurements, and can be readily incorporated into an existing film dosimetry program.
Focal exposure of limited lung volumes to high-dose irradiation down-regulated organ development-related functions and up-regulated the immune response in mouse pulmonary tissues.

PubMed

Kim, Bu-Yeo; Jin, Hee; Lee, Yoon-Jin; Kang, Ga-Young; Cho, Jaeho; Lee, Yun-Sil

2016-01-27

Despite the emergence of stereotactic body radiotherapy (SBRT) for treatment of medically inoperable early-stage non-small-cell lung cancer patients, the molecular effects of focal exposure of limited lung volumes to high-dose radiation have not been fully characterized. This study was designed to identify molecular changes induced by focal high-dose irradiation using a mouse model of SBRT. Central areas of the mouse left lung were focally-irradiated (3 mm in diameter) with a single high-dose of radiation (90 Gy). Temporal changes in gene expression in the irradiated and non-irradiated neighboring lung regions were analyzed by microarray. For comparison, the long-term effect (12 months) of 20 Gy radiation on a diffuse region of lung was also measured. The majority of genes were down-regulated in the focally-irradiated lung areas at 2 to 3 weeks after irradiation. This pattern of gene expression was clearly different than gene expression in the diffuse region of lungs exposed to low-dose radiation. Ontological and pathway analyses indicated these down-regulated genes were mainly associated with organ development. Although the number was small, genes that were up-regulated after focal irradiation were associated with immune-related functions. The temporal patterns of gene expression and the associated biological functions were also similar in non-irradiated neighboring lung regions, although statistical significance was greatly reduced when compared with those from focally-irradiated areas of the lung. From network analysis of temporally regulated genes, we identified inter-related modules associated with diverse functions, including organ development and the immune response, in both the focally-irradiated regions and non-irradiated neighboring lung regions. Focal exposure of lung tissue to high-dose radiation induced expression of genes associated with organ development and the immune response. This pattern of gene expression was also observed in non-irradiated neighboring areas of lung tissue, indicating a global lung response to focal high-dose irradiation.
Statistical methods for biodosimetry in the presence of both Berkson and classical measurement error

NASA Astrophysics Data System (ADS)

Miller, Austin

In radiation epidemiology, the true dose received by those exposed cannot be assessed directly. Physical dosimetry uses a deterministic function of the source term, distance and shielding to estimate dose. For the atomic bomb survivors, the physical dosimetry system is well established. The classical measurement errors plaguing the location and shielding inputs to the physical dosimetry system are well known. Adjusting for the associated biases requires an estimate for the classical measurement error variance, for which no data-driven estimate exists. In this case, an instrumental variable solution is the most viable option to overcome the classical measurement error indeterminacy. Biological indicators of dose may serve as instrumental variables. Specification of the biodosimeter dose-response model requires identification of the radiosensitivity variables, for which we develop statistical definitions and variables. More recently, researchers have recognized Berkson error in the dose estimates, introduced by averaging assumptions for many components in the physical dosimetry system. We show that Berkson error induces a bias in the instrumental variable estimate of the dose-response coefficient, and then address the estimation problem. This model is specified by developing an instrumental variable mixed measurement error likelihood function, which is then maximized using a Monte Carlo EM Algorithm. These methods produce dose estimates that incorporate information from both physical and biological indicators of dose, as well as the first instrumental variable based data-driven estimate for the classical measurement error variance.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Otake, M.; Schull, W.J.

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

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

Papiez, Lech; Abolfath, Ramin M.

2008-11-15

Derivation of formulas relating leaf speeds and beam dose rates for delivering planned intensity profiles to static and moving targets in dynamic multileaf collimator (DMLC) intensity modulated radiation therapy (IMRT) is presented. The analysis of equations determining algorithms for DMLC IMRT delivery under a variable beam dose rate reveals a multitude of possible delivery strategies for a given intensity map and for any given target motion patterns. From among all equivalent delivery strategies for DMLC IMRT treatments specific subclasses of strategies can be selected to provide deliveries that are particularly suitable for clinical applications providing existing delivery devices are used.more » Special attention is devoted to the subclass of beam dose rate variable DMLC delivery strategies to moving body anatomy that generalize existing techniques of such deliveries in Varian DMLC irradiation methodology to static body anatomy. Few examples of deliveries from this subclass of DMLC IMRT irradiations are investigated to illustrate the principle and show practical benefits of proposed techniques.« less
Study of antirabies immunization of man; observations with HEP Flury and other vaccines, with and without hyperimmune serum, in primary and recall immunizations.

PubMed

FOX, J P; KOPROWSKI, H; CONWELL, D P; BLACK, J; GELFAND, H M

1957-01-01

Detailed results are presented of primary immunizations of 387 persons with various courses of HEP Flury vaccine and of 54 persons with Harris- or Semple-type vaccines. Antibody response to HEP Flury vaccine was at least as rapid as that to the conventional type, but fell short in uniformity and level of response. The most promising course involved a 4-dose schedule, intradermal alone or combined with intramuscular, at 5-day intervals. A similar subcutaneous course of Semple vaccine yielded results completely equivalent to those of a 14-dose course of Harris vaccine. It is concluded that, although living, the HEP Flury virus does not multiply in man and that its lesser antigenic potency, as compared with Semple or Harris vaccines, is due to its relatively small content of viral antigen.Further evidence has been obtained that hyperimmune serum may exert a slight suppressive effect on active response, but the opinion is expressed that, with vaccines of full potency, this will not be of practical significance.Restimulation of immunity by a booster dose of HEP Flury vaccine was studied in 64 experimentally immunized persons and in 136 persons with history of previous Pasteur treatment. In both instances small intradermal inocula were as effective as larger intramuscular inocula in recalling pre-existing immunity.Study of recipients of Pasteur treatment indicated that antibody commonly persists for at least 5 years after a single course and for 15 or more years after re-treatment. It was also observed that the ability to respond to a booster of HEP Flury vaccine persists for at least 25 years. The response elicited by the booster is prompt and is usually at least equal to that resulting from a full primary course. The suggested conclusion is that previously treated persons need not receive more than a single booster on re-exposure, and that Pasteur treatment provides a solid basis for long-sustained immunity.
A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients.

PubMed

Maier, Andrew; Vincent, Melissa J; Parker, Ann; Gadagbui, Bernard K; Jayjock, Michael

2015-12-01

Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses. We have developed a safety assessment approach tailored to the screening of asthma risks from residential consumer product ingredients as a proactive risk management tool. Several key features of the proposed approach advance the assessment resources often used for asthma issues. First, a quantitative health benchmark for asthma or related endpoints (irritation and sensitization) is provided that extends qualitative hazard classification methods. Second, a parallel structure is employed to include dose-response methods for asthma endpoints and methods for scenario specific exposure estimation. The two parallel tracks are integrated in a risk characterization step. Third, a tiered assessment structure is provided to accommodate different amounts of data for both the dose-response assessment (i.e., use of existing benchmarks, hazard banding, or the threshold of toxicological concern) and exposure estimation (i.e., use of empirical data, model estimates, or exposure categories). Tools building from traditional methods and resources have been adapted to address specific issues pertinent to asthma toxicology (e.g., mode-of-action and dose-response features) and the nature of residential consumer product use scenarios (e.g., product use patterns and exposure durations). A case study for acetic acid as used in various sentinel products and residential cleaning scenarios was developed to test the safety assessment methodology. In particular, the results were used to refine and verify relationships among tiered approaches such that each lower data tier in the approach provides a similar or greater margin of safety for a given scenario. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Cell-type specificity of lung cancer associated with low-dose soil heavy metal contamination in Taiwan: An ecological study

PubMed Central

2013-01-01

Background Numerous studies have examined the association between heavy metal contamination (including arsenic [As], cadmium [Cd], chromium [Cr], copper [Cu], mercury [Hg], nickel [Ni], lead [Pb], and zinc [Zn]) and lung cancer. However, data from previous studies on pathological cell types are limited, particularly regarding exposure to low-dose soil heavy metal contamination. The purpose of this study was to explore the association between soil heavy metal contamination and lung cancer incidence by specific cell type in Taiwan. Methods We conducted an ecological study and calculated the annual averages of eight soil heavy metals (i.e., As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) by using data from the Taiwan Environmental Protection Administration from1982 to 1986. The age-standardized incidence rates of lung cancer according to two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]) were obtained from the National Cancer Registry Program conducted in Taiwan from 2001 to 2005. A geographical information system was used to plot the maps of soil heavy metal concentration and lung cancer incidence rates. Poisson regression models were used to obtain the adjusted relative ratios (RR) and 95% confidence intervals (CI) for the lung cancer incidence associated with soil heavy metals. Results For males, the trend test for lung SCC incidence caused by exposure to Cr, Cu, Hg, Ni, and Zn showed a statistically significant dose–response relationship. However, for lung AC, only Cu and Ni had a significant dose–response relationship. As for females, those achieving a statistically significant dose–response relationship for the trend test were Cr (P = 0.02), Ni (P = 0.02), and Zn (P= 0.02) for lung SCC, and Cu (P < 0.01) and Zn (P = 0.02) for lung AC. Conclusion The current study suggests that a dose–response relationship exists between low-dose soil heavy metal concentration and lung cancer occurrence by specific cell-type; however, the relevant mechanism should be explored further. PMID:23575356
The development of fetal dosimetry and its application to A-bomb survivors exposed in utero.

PubMed

Chen, Jing

2012-03-01

The cohort of the atomic bomb survivors of Hiroshima and Nagasaki comprises the major basis for investigations of health effects induced by ionising radiation in humans. To study the health effects associated with radiation exposure before birth, fetal dosimetry is needed if significant differences exist between the fetal absorbed dose and the mother's uterine dose. Combining total neutron and gamma ray free-in-air fluences at 1 m above ground with fluence-to-absorbed dose conversion coefficients, fetal doses were calculated for various exposure orientations at the ground distance of 1500 m from the hypocentres in Hiroshima and Nagasaki. The results showed that the mother's uterine dose can serve as a good surrogate for the dose of the embryo and fetus in the first trimester. However, significant differences exist between doses of the fetus of different ages. If the mother's uterine dose were used as a surrogate, doses to the fetus in the last two trimesters could be overestimated by more than 20 % for exposure orientations facing towards and away from the hypocentre while significantly underestimated for lateral positions relative to the hypocentre. In newer fetal models, the brain is modelled for all fetal ages. Brain doses to the 3-month fetus are generally higher than those to an embryo and fetus of other ages. In most cases, brain absorbed doses differ significantly from the doses to the entire fetal body. In order to accurately assess radiation effects to the fetal brain, it is necessary to determine brain doses separately.
Radiobiological effectiveness of laser accelerated electrons in comparison to electron beams from a conventional linear accelerator.

PubMed

Laschinsky, Lydia; Baumann, Michael; Beyreuther, Elke; Enghardt, Wolfgang; Kaluza, Malte; Karsch, Leonhard; Lessmann, Elisabeth; Naumburger, Doreen; Nicolai, Maria; Richter, Christian; Sauerbrey, Roland; Schlenvoigt, Hans-Peter; Pawelke, Jörg

2012-01-01

The notable progress in laser particle acceleration technology promises potential medical application in cancer therapy through compact and cost effective laser devices that are suitable for already existing clinics. Previously, consequences on the radiobiological response by laser driven particle beams characterised by an ultra high peak dose rate have to be investigated. Therefore, tumour and non-malignant cells were irradiated with pulsed laser accelerated electrons at the JETI facility for the comparison with continuous electrons of a conventional therapy LINAC. Dose response curves were measured for the biological endpoints clonogenic survival and residual DNA double strand breaks. The overall results show no significant differences in radiobiological response for in vitro cell experiments between laser accelerated pulsed and clinical used electron beams. These first systematic in vitro cell response studies with precise dosimetry to laser driven electron beams represent a first step toward the long term aim of the application of laser accelerated particles in radiotherapy.
Effects of γ ray irradiation on Vibrio Qinghaiensis sp. Q67

NASA Astrophysics Data System (ADS)

Wei, Yan; Linping, Kuai

2017-12-01

In order to investigate the luminous responses of γ ray irradiation on Vibrio Qinghaiensis sp. Q67, two γ ray sources, 60Co and 137Cs, were used. Following the dose rates between 0.05Gy/min and 0.2Gy/min of 60Co, the relative luminous value (RLV ) of Q67 was less than 1 after 5 minutes irradiation and inversely related to dose rate. Irradiated 1 hour at dose rates range from 100nGy/h to 10mGy/h of 137Cs, two successive stages in the luminous response were found: hormesis and inhibition. It was found that RLV was interleaved and could not be distinguished until inhibition stage appearance. The time when RLV drops to less than 1 (T0 ) was linear with the logarithm of dose rate. Experimental result indicates that Q67 is sensitive to acute γray radiation, which could be used to monitor γray radiation.
Pilocarpine disposition and salivary flow responses following intravenous administration to dogs.

PubMed

Weaver, M L; Tanzer, J M; Kramer, P A

1992-08-01

Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225-600 micrograms/kg; plasma concentrations were 10-120 micrograms/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 +/- 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 +/- 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.
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.
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.

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
Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature.

PubMed

Hughes, Ian P; Harris, Mark; Choong, Catherine S; Ambler, Geoff; Cutfield, Wayne; Hofman, Paul; Cowell, Chris T; Werther, George; Cotterill, Andrew; Davies, Peter S W

2012-07-01

To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious. © 2012 Blackwell Publishing Ltd.
Subclinical hyperthyroidism: possible danger of overzealous thyroxine replacement therapy.

PubMed

Ross, D S

1988-12-01

Many patients taking customary doses of levothyroxine have slightly elevated serum thyroxine (T4), apparently normal serum triiodothyronine, suppressed serum thyrotropin (thyroid-stimulating hormone; TSH) concentrations, and no clinical symptoms of hyperthyroidism. Recent reports suggest that these patients may have adverse effects from subclinical hyperthyroidism, including abnormally short systolic time intervals, elevations in liver enzymes, and reductions in bone density. Controversy exists about which thyroid function tests should be used to monitor patients taking levothyroxine. A review of currently available data suggests that replacement doses of levothyroxine given to hypothyroid patients should be adjusted so that serum TSH measured by the new sensitive assays is within the normal range. Patients requiring suppressive doses of levothyroxine to shrink goitrous thyroid tissue or to prevent growth of abnormal tissue should be given the minimal dose needed to accomplish the desired clinical or biochemical response.
Long-term Pulmonary Responses to Quadweekly Intermittent Intratracheal Spray Instillations of Magnetite (Fe3O4) Nanoparticles for 52 Weeks in Fischer 344 Rats.

PubMed

Tada, Yukie; Yano, Norio; Takahashi, Hiroshi; Yuzawa, Katsuhiro; Ando, Hiroshi; Kubo, Yoshikazu; Nagasawa, Akemichi; Inomata, Akiko; Ogata, Akio; Nakae, Dai

2013-12-01

Information about potential risks of iron nanomaterials is still limited, while a wide variety of applications are expected. We recently reported acute phase responses of male and female Fischer 344 rats after a single intratracheal spray instillation of Fe3O4 nanoparticles (magnetite), clearly showing dose-dependent pulmonary inflammatory changes (Tada et al., J Toxicol Pathol 25, 233-239, 2012). The present study assessed long-term responses of male and female Fischer 344 rats to multiple administrations of magnetite. Ten-week-old male and female Fischer 344 rats (n=20/group) were exposed to a total of 13 quadweekly intermittent intratracheal spray instillations of magnetite during the experimental period of 52 weeks, at doses of 0, 0.2 (low), 1.0 (medium) and 5.0 (high-dose) mg/kg body weight per administration. Absolute and relative lung weights of the high-dose group were significantly higher than those of the control group. Macroscopically, slight enlargement and scattered black patches were recognized in the lungs and the lung-associated lymph nodes of the high-dose group. Histopathologically, infiltration of macrophages phagocytosing magnetite (all dose groups) and of chronic inflammatory cells (medium- and high-dose males and high-dose females), alveolar bronchiolization and granuloma (high-dose group) were observed. In addition, alveolar hyperplasias were observed in some rats of the high-dose group, and cytoplasmic overexpression of β-catenin protein was immunohistochemically found in such lesions. The present results clearly show that instilled magnetite causes chronic inflammatory responses in the lung. These responses occur in a dose-dependent manner without apparent differences among sexes.
Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

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

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

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

PubMed

Rhomberg, Lorenz R; Mayfield, David B; Goodman, Julie E; Butler, Eric L; Nascarella, Marc A; Williams, Daniel R

2015-01-01

The International Agency for Research on Cancer qualitatively characterized occupational exposure to oxidized bitumen emissions during roofing as probably carcinogenic to humans (Group 2A). We examine chemistry, exposure, epidemiology and animal toxicity data to explore quantitative risks for roofing workers applying built-up roofing asphalt (BURA). Epidemiology studies do not consistently report elevated risks, and generally do not have sufficient exposure information or adequately control for confounders, precluding their use for dose-response analysis. Dermal carcinogenicity bioassays using mice report increased tumor incidence with single high doses. In order to quantify potential cancer risks, we develop time-to-tumor model methods [consistent with U.S. Environmental Protection Agency (EPA) dose-response analysis and mixtures guidelines] using the dose-time-response shape of concurrent exposures to benzo[a]pyrene (B[a]P) as concurrent controls (which had several exposure levels) to infer presumed parallel dose-time-response curves for BURA-fume condensate. We compare EPA relative potency factor approaches, based on observed relative potency of BURA to B[a]P in similar experiments, and direct observation of the inferred BURA dose-time-response (scaled to humans) as means for characterizing a dermal unit risk factor. We apply similar approaches to limited data on asphalt-fume inhalation and respiratory cancers in rats. We also develop a method for adjusting potency estimates for asphalts that vary in composition using measured fluorescence. Overall, the various methods indicate that cancer risks to roofers from both dermal and inhalation exposure to BURA are within a range typically deemed acceptable within regulatory frameworks. The approaches developed may be useful in assessing carcinogenic potency of other complex mixtures of polycyclic aromatic compounds.
Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients.

PubMed

Ellebaek, Eva; Iversen, Trine Zeeberg; Junker, Niels; Donia, Marco; Engell-Noerregaard, Lotte; Met, Özcan; Hölmich, Lisbet Rosenkrantz; Andersen, Rikke Sick; Hadrup, Sine Reker; Andersen, Mads Hald; thor Straten, Per; Svane, Inge Marie

2012-08-21

Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day. Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.
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.
The specifics of dosimetry for food irradiation applications

NASA Astrophysics Data System (ADS)

Kuntz, Florent; Strasser, Alain

2016-12-01

Dose measurement applied to food irradiation is obviously a very important and critical aspect of this process. It is described in many standards and guides. The application of appropriate dosimetry tools is explained. This helps to ensure traceability of this measurement and number of dosimeters available on the market are well studied even though theirs response should be characterized while used in routine processing conditions. When employed in low energy radiation fields, these dosimeters may exhibit specific response compared to the usual Cobalt 60 source irradiation. Traceable calibration or correction factor assessment of this energy dependency is mandatory. It is to mention that the absorbed dose is measured in the dosimeter itself and unfortunately not in/on the food product. However, existing dosimetry systems fulfill all relevant requirements.
Modification of an Existing In vitro Method to Predict Relative Bioavailable Arsenic in Soils

EPA Science Inventory

The soil matrix can sequester arsenic (As) and reduces its exposure by soil ingestion. In vivo dosing studies and in vitro gastrointestinal (IVG) methods have been used to predict relative bioavailable (RBA) As. Originally, the Ohio State University (OSU-IVG) method predicted R...
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.
Safety and Immunogenicity of a rAd35-EnvA Prototype HIV-1 Vaccine in Combination with rAd5-EnvA in Healthy Adults (VRC 012).

PubMed

Crank, Michelle C; Wilson, Eleanor M P; Novik, Laura; Enama, Mary E; Hendel, Cynthia S; Gu, Wenjuan; Nason, Martha C; Bailer, Robert T; Nabel, Gary J; McDermott, Adrian B; Mascola, John R; Koup, Richard A; Ledgerwood, Julie E; Graham, Barney S

2016-01-01

VRC 012 was a Phase I study of a prototype recombinant adenoviral-vector serotype-35 (rAd35) HIV vaccine, the precursor to two recently published clinical trials, HVTN 077 and 083. On the basis of prior evaluation of multiclade rAd5 HIV vaccines, Envelope A (EnvA) was selected as the standard antigen for a series of prototype HIV vaccines to compare various vaccine platforms. In addition, prior studies of rAd5-vectored vaccines suggested pre-existing human immunity may be a confounding factor in vaccine efficacy. rAd35 is less seroprevalent across human populations and was chosen for testing alone and in combination with a rAd5-EnvA vaccine in the present two-part phase I study. First, five subjects each received a single injection of 109, 1010, or 1011 particle units (PU) of rAd35-EnvA in an open-label, dose-escalation study. Next, 20 Ad5/Ad35-seronegative subjects were randomized to blinded, heterologous prime-boost schedules combining rAd5-EnvA and rAd35-EnvA with a three month interval. rAd35-EnvA was given at 1010 or 1011 PU to ten subjects each; all rAd5-EnvA injections were 1010 PU. EnvA-specific immunogenicity was assessed four weeks post-injection. Solicited reactogenicity and clinical safety were followed after each injection. Vaccinations were well tolerated at all dosages. Antibody responses measured by ELISA were detected at 4 weeks in 30% and 50% of subjects after single doses of 1010 or 1011 PU rAd35, respectively, and in 89% after a single rAd5-EnvA 1010 PU injection. EnvA-specific IFN-γ ELISpot responses were detected at four weeks in 0%, 70%, and 50% of subjects after the respective rAd35-EnvA dosages compared to 89% of subjects after rAd5. T cell responses were higher after a single rAd5-EnvA 1010 PU injection than after a single rAd35-EnvA 1010 PU injection, and humoral responses were low after a single dose of either vector. Of those completing the vaccine schedule, 100% of rAd5-EnvA recipients and 90% of rAd35-EnvA recipients had both T cell and humoral responses after boosting with the heterologous vector. ELISpot response magnitude was similar in both regimens and comparable to a single dose of rAd5. A trend toward more robust CD8 T cell responses using rAd5-EnvA prime and rAd35-EnvA boost was observed. Humoral response magnitude was also similar after either heterologous regimen, but was several fold higher than after a single dose of rAd5. Adverse events (AEs) related to study vaccines were in general mild and limited to one episode of hematuria, Grade two. Activated partial thromboplastin time (aPTT) AEs were consistent with an in vitro effect on the laboratory assay for aPTT due to a transient induction of anti-phospholipid antibody, a phenomenon that has been reported in other adenoviral vector vaccine trials. Limitations of the rAd vaccine vectors, including the complex interactions among pre-existing adenoviral immunity and vaccine-induced immune responses, have prompted investigators to include less seroprevalent vectors such as rAd35-EnvA in prime-boost regimens. The rAd35-EnvA vaccine described here was well tolerated and immunogenic. While it effectively primed and boosted antibody responses when given in a reciprocal prime-boost regimen with rAd5-EnvA using a three-month interval, it did not significantly improve the frequency or magnitude of T cell responses above a single dose of rAd5. The humoral and cellular immunogenicity data reported here may inform future vaccine and study design. ClinicalTrials.gov NCT00479999.
Effects of Computer-Based Early-Reading Academic Learning Time on Early-Reading Achievement: A Dose-Response Approach

ERIC Educational Resources Information Center

Heuston, Edward Benjamin Hull

2010-01-01

Academic learning time (ALT) has long had the theoretical underpinnings sufficient to claim a causal relationship with academic achievement, but to this point empirical evidence has been lacking. This dearth of evidence has existed primarily due to difficulties associated with operationalizing ALT in traditional educational settings. Recent…
Irradiation with low-dose gamma ray enhances tolerance to heat stress in Arabidopsis seedlings.

PubMed

Zhang, Liang; Zheng, Fengxia; Qi, Wencai; Wang, Tianqi; Ma, Lingyu; Qiu, Zongbo; Li, Jingyuan

2016-06-01

Gamma irradiation at low doses can stimulate the tolerance to environmental stress in plants. However, the knowledge regarding the mechanisms underlying the enhanced tolerance induced by low-dose gamma irradiation is far from fully understood. In this study, to investigate the physiological and molecular mechanisms of heat stress alleviated by low-dose gamma irradiation, the Arabidopsis seeds were exposed to a range of doses before subjected to heat treatment. Our results showed that 50-Gy gamma irradiation maximally promoted seedling growth in response to heat stress. The production rate of superoxide radical and contents of hydrogen peroxide and malondialdehyde in the seedlings irradiated with 50-Gy dose under heat stress were significantly lower than those of controls. The activities of antioxidant enzymes, glutathione (GSH) content and proline level in the gamma-irradiated seedlings were significantly increased compared with the controls. Furthermore, transcriptional expression analysis of selected genes revealed that some components related to heat tolerance were stimulated by low-dose gamma irradiation under heat shock. Our results suggest that low-dose gamma irradiation can modulate the physiological responses as well as gene expression related to heat tolerance, thus alleviating the stress damage in Arabidopsis seedlings. Copyright © 2016 Elsevier Inc. All rights reserved.
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.
Intraluminal radiation for esophageal cancer: a Howard University technique.

PubMed

Moorthy, C R; Nibhanupudy, J R; Ashayeri, E; Goldson, A L; Espinoza, M C; Nidiry, J J; Warner, O G; Roux, V J

1982-03-01

The objective of radiotherapeutic management in esophageal cancer is to accomplish maximum tumor sterilization with minimal normal tissue damage. This sincere effort is most often countered by the differential in tumor dose response vs normal tissue tolerance. Intraluminal isotope radiation, with its inherent advantage of rapid dose falloff, spares the lungs, the spinal cord, and other vital structures, yet yields adequately high doses to esophageal tumor. Though in existence since the turn of the century, the method of intracavitary radium bougie application dropped out of favor due to technical difficulties imposed by the size of the radium source and radiation exposure to the personnel involved. The authors describe a simple "iridium 192 afterloading intraluminal technique" that eliminates technical problems and reduces radiation exposure considerably.
Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response.

PubMed

Tavira, Beatriz; Cheramy, Mikael; Axelsson, Stina; Åkerman, Linda; Ludvigsson, Johnny; Casas, Rosaura

2017-07-01

A European Phase III trial of GAD formulated with aluminium hydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response. In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD 65 -induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum. GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was ≥210 days (p < 0.05). In the group that received two doses of GAD-alum, levels of several GAD 65 -induced cytokines were higher in participants who received the H1N1 vaccination and the first GAD-alum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum. In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. <150 days, seemed to affect both GAD 65 -induced immune response and C-peptide preservation. ClinicalTrials.gov NCT00723411.
Hand-arm vibration syndrome and dose-response relation for vibration induced white finger among quarry drillers and stonecarvers. Italian Study Group on Physical Hazards in the Stone Industry.

PubMed Central

Bovenzi, M

1994-01-01

OBJECTIVES--To investigate the occurrence of disorders associated with the hand arm vibration syndrome in a large population of stone workers in Italy. The dose-response relation for vibration induced white finger (VWF) was also studied. METHODS--The study population consisted of 570 quarry drillers and stonecarvers exposed to vibration and 258 control stone workers who performed only manual activity. Each subject was interviewed with health and workplace assessment questionnaires. Sensorineural and VWF disorders were staged according to the Stockholm workshop scales. Vibration was measured on a representative sample of percussive and rotary tools. The 8 h energy equivalent frequency weighted acceleration (A (8)) and lifetime vibration doses were calculated for each of the exposed stone workers. RESULTS--Sensorineural and musculoskeletal symptoms occurred more frequently in the workers exposed to vibration than in the controls, but trend statistics did not show a linear exposure-response relation for these disorders. The prevalence of VWF was found to be 30.2% in the entire group exposed to vibration. Raynaud's phenomenon was discovered in 4.3% of the controls. VWF was strongly associated with exposure to vibration and a monotonic dose-response relation was found. According to the exposure data of this study, the expected percentage of stone workers affected with VWF tends to increase roughly in proportion to the square root of A(8) (for a particular exposure period) or in proportion to the square root of the duration of exposure (for a constant magnitude of vibration). CONCLUSION--Even although limited to a specific work situation, the dose-response relation for VWF estimated in this study suggests a time dependency such that halving the years of exposure allows a doubling of the energy equivalent vibration. According to these findings, the vibration exposure levels currently under discussion within the European Community seem to represent reasonable exposure limits for the protection of workers against the harmful effects of hand transmitted vibration. PMID:7951792
High dose-per-pulse electron beam dosimetry - A model to correct for the ion recombination in the Advanced Markus ionization chamber.

PubMed

Petersson, Kristoffer; Jaccard, Maud; Germond, Jean-François; Buchillier, Thierry; Bochud, François; Bourhis, Jean; Vozenin, Marie-Catherine; Bailat, Claude

2017-03-01

The purpose of this work was to establish an empirical model of the ion recombination in the Advanced Markus ionization chamber for measurements in high dose rate/dose-per-pulse electron beams. In addition, we compared the observed ion recombination to calculations using the standard Boag two-voltage-analysis method, the more general theoretical Boag models, and the semiempirical general equation presented by Burns and McEwen. Two independent methods were used to investigate the ion recombination: (a) Varying the grid tension of the linear accelerator (linac) gun (controls the linac output) and measuring the relative effect the grid tension has on the chamber response at different source-to-surface distances (SSD). (b) Performing simultaneous dose measurements and comparing the dose-response, in beams with varying dose rate/dose-per-pulse, with the chamber together with dose rate/dose-per-pulse independent Gafchromic™ EBT3 film. Three individual Advanced Markus chambers were used for the measurements with both methods. All measurements were performed in electron beams with varying mean dose rate, dose rate within pulse, and dose-per-pulse (10 -2 ≤ mean dose rate ≤ 10 3 Gy/s, 10 2 ≤ mean dose rate within pulse ≤ 10 7 Gy/s, 10 -4 ≤ dose-per-pulse ≤ 10 1 Gy), which was achieved by independently varying the linac gun grid tension, and the SSD. The results demonstrate how the ion collection efficiency of the chamber decreased as the dose-per-pulse increased, and that the ion recombination was dependent on the dose-per-pulse rather than the dose rate, a behavior predicted by Boag theory. The general theoretical Boag models agreed well with the data over the entire investigated dose-per-pulse range, but only for a low polarizing chamber voltage (50 V). However, the two-voltage-analysis method and the Burns & McEwen equation only agreed with the data at low dose-per-pulse values (≤ 10 -2 and ≤ 10 -1 Gy, respectively). An empirical model of the ion recombination in the chamber was found by fitting a logistic function to the data. The ion collection efficiency of the Advanced Markus ionization chamber decreases for measurements in electron beams with increasingly higher dose-per-pulse. However, this chamber is still functional for dose measurements in beams with dose-per-pulse values up toward and above 10 Gy, if the ion recombination is taken into account. Our results show that existing models give a less-than-accurate description of the observed ion recombination. This motivates the use of the presented empirical model for measurements with the Advanced Markus chamber in high dose-per-pulse electron beams, as it enables accurate absorbed dose measurements (uncertainty estimation: 2.8-4.0%, k = 1). The model depends on the dose-per-pulse in the beam, and it is also influenced by the polarizing chamber voltage, with increasing ion recombination with a lowering of the voltage. © 2017 American Association of Physicists in Medicine.
Lateral response heterogeneity of Bragg peak ionization chambers for narrow-beam photon and proton dosimetry

NASA Astrophysics Data System (ADS)

Kuess, Peter; Böhlen, Till T.; Lechner, Wolfgang; Elia, Alessio; Georg, Dietmar; Palmans, Hugo

2017-12-01

Large area ionization chambers (LAICs) can be used to measure output factors of narrow beams. Dose area product measurements are proposed as an alternative to central-axis point dose measurements. Using such detectors requires detailed information on the uniformity of the response along the sensitive area. Eight LAICs were investigated in this study: four of type PTW-34070 (LAICThick) and four of type PTW-34080 (LAICThin). Measurements were performed in an x-ray unit using peak voltages of 100-200 kVp and a collimated beam of 3.1 mm (FWHM). The LAICs were moved with a step size of 5 mm to measure the chamber response at lateral positions. To account for beam positions where only a fraction of the beam impinged within the sensitive area of the LAICs, a corrected response was calculated which was the basis to calculate the relative response. The impact of a heterogeneous LAIC response, based on the obtained response maps was henceforth investigated for proton pencil beams and small field photon beams. A pronounced heterogeneity of the responses was observed in the investigated LAICs. The response of LAICThick generally decreased with increasing radius, resulting in a response correction of up to 5%. This correction was more pronounced and more diverse (up to 10%) for LAICThin. Considering a proton pencil beam the systematic offset for reference dosimetry was 2.4-4.1% for LAICThick and -9.5 to 9.4% for LAICThin. For relative dosimetry (e.g. integral depth-dose curves) systematic response variation by 0.8-1.9% were found. For a decreasing photon field size the systematic offset for absolute dose measurements showed a 2.5-4.5% overestimation of the response for 6 × 6 mm2 field sizes for LAICThick. For LAICThin the response varied even over a range of 20%. This study highlights the need for chamber-dependent response maps when using LAICs for absolute and relative dosimetry with proton pencil beams or small photon beams.

The Management of Patients with Chronic Subdural Hematoma Treated with Low-Dose Acetylsalicylic Acid: An International Survey of Practice.

PubMed

Soleman, Jehuda; Kamenova, Maria; Guzman, Raphael; Mariani, Luigi

2017-11-01

The aim of this international survey was to investigate the current management of patients undergoing surgery for chronic subdural hematoma (cSDH) treated with low-dose acetylsalicylic acid (ASA). We administered a survey via e-mail to neurosurgeons with questions relating to the surgical treatment of cSDH, emphasizing their practices with patients treated with low-dose ASA. We received 157 responses, with a response rate of 22.4%. Almost 80% of the responders discontinue ASA treatment at least 5 days before surgery and 80.7% resume treatment after 5 days or more, and 27.6% discontinue treatment for at least 30 days. The main factor influencing ASA resumption time is the indication for ASA (54.5%), and postoperative imaging is concluded in 71.7%, Postoperative thrombosis prophylaxis is administered by 60% of the responders, and 50% apply it 24 hours after surgery. Almost 95% of the responders believe that better evidence is needed for the management of patients with cSDH treated with ASA. Guidelines for these patients exist in only 24.3% of the institutes. Most neurosurgeons discontinue ASA treatment for at least 7 days in the perioperative period of surgical evacuation of cSDH, even though recent studies show that early ASA resumption might be safe. Thrombosis prophylaxis is administered by only 60%, even though patients with cSDH are at high risk of developing thromboembolic complications. Better evidence and guidelines are warranted because the incidence of patients with cSDH under the treatment of ASA is increasing. Copyright © 2017 Elsevier Inc. All rights reserved.
A Review of Current and Emerging Approaches to Pain Management in the Emergency Department.

PubMed

Todd, Knox H

2017-12-01

Pain is the most common symptom prompting an emergency department visit and emergency physicians are responsible for managing both acute pain and acute exacerbations of chronic pain resulting from a broad range of illnesses and injuries. The responsibility to treat must be balanced by the duty to limit harm resulting from analgesics. In recent years, opioid-related adverse effects, including overdose and deaths, have increased dramatically in the USA. In response to the US opioid crisis, emergency physicians have broadened their analgesic armamentarium to include a variety of non-opioid approaches. For some of these therapies, sparse evidence exists to support their efficacy for emergency department use. The purpose of this paper is to review historical trends and emerging approaches to emergency department analgesia, with a particular focus on the USA and Canada. We conducted a qualitative review of past and current descriptive studies of emergency department pain practice, as well as clinical trials of emerging pain treatment modalities. The review considers the increasing use of non-opioid and multimodal analgesic therapies, including migraine therapies, regional anesthesia, subdissociative-dose ketamine, nitrous oxide, intravenous lidocaine and gabapentinoids, as well as broad programmatic initiatives promoting the use of non-opioid analgesics and nonpharmacologic interventions. While migraine therapies, regional anesthesia, nitrous oxide and subdissociative-dose ketamine are supported by a relatively robust evidence base, data supporting the emergency department use of intravenous lidocaine, gabapentinoids and various non-pharmacologic analgesic interventions remain sparse. Additional research on the relative safety and efficacy of non-opioid approaches to emergency department analgesia is needed. Despite a limited research base, it is likely that non-opioid analgesic modalities will be employed with increasing frequency. A new generation of emergency physicians is seeking additional training in pain medicine and increasing dialogue between emergency medicine and pain medicine researchers, educators and clinicians could contribute to better management of emergency department pain.
Common mental disorder and obesity: insight from four repeat measures over 19 years: prospective Whitehall II cohort study.

PubMed

Kivimäki, Mika; Lawlor, Debbie A; Singh-Manoux, Archana; Batty, G David; Ferrie, Jane E; Shipley, Martin J; Nabi, Hermann; Sabia, Séverine; Marmot, Michael G; Jokela, Markus

2009-10-06

To examine potential reciprocal associations between common mental disorders and obesity, and to assess whether dose-response relations exist. Prospective cohort study with four measures of common mental disorders and obesity over 19 years (Whitehall II study). Civil service departments in London. 4363 adults (28% female, mean age 44 years at baseline). Common mental disorder defined as general health questionnaire "caseness;" overweight and obesity based on Word Health Organization definitions. In models adjusted for age, sex, and body mass index at baseline, odds ratios for obesity at the fourth screening were 1.33 (95% confidence interval 1.00 to 1.77), 1.64 (1.13 to 2.36), and 2.01 (1.21 to 3.34) for participants with common mental disorder at one, two, or three preceding screenings compared with people free from common mental disorder (P for trend<0.001). The corresponding mean differences in body mass index at the most recent screening were 0.20, 0.31, and 0.50 (P for trend<0.001). These associations remained after adjustment for baseline characteristics related to mental health and exclusion of participants who were obese at baseline. In addition, obesity predicted future risk of common mental disorder, again with evidence of a dose-response relation (P for trend=0.02, multivariable model). However, this association was lost when people with common mental disorder at baseline were excluded (P for trend=0.33). These findings suggest that in British adults the direction of association between common mental disorders and obesity is from common mental disorder to increased future risk of obesity. This association is cumulative such that people with chronic or repeat episodes of common mental disorder are particularly at risk of weight gain.
Individual differences in the reinforcing and punishing effects of nicotine in rhesus monkeys.

PubMed

Koffarnus, Mikhail N; Winger, Gail

2015-07-01

The relatively weak reinforcing effects of nicotine in experimental studies have been attributed to possible aversive effects or the need to space nicotine administrations over time to expose reinforcing effects. This study was designed to determine if the response-maintaining effects of nicotine are increased when availability is spaced through time, and whether nicotine is an effective punisher of remifentanil-maintained responding. Compared to a cocaine reference dose, nicotine dose and timeout (TO) value were varied in eight rhesus monkeys responding for intravenous (i.v.) nicotine on varying fixed-ratio (FR) schedules of reinforcement.The aversive effects of nicotine were evaluated in four animals choosing between a standard dose of remifentanil alone or in combination with one of several doses of nicotine. In three of eight self-administration monkeys, 0.01 mg/kg/inj nicotine did not maintain responding at any FR value. In the other five animals, nicotine-maintained response rates increased with either FR or TO values to a certain point, and then slowed. Maximum nicotine-maintained response rates were much slower than those maintained by cocaine, and demand for nicotine was less than demand for cocaine. Nicotine was an effective punisher of remifentanil-maintained responding at doses ranging from 0.01 to 0.3 mg/kg/inj. Lower punishing dose seemed to be related to the absence of reinforcing effects within subject. There are an order of magnitude individual differences in sensitivity to both the reinforcing and punishing effects of nicotine, and this drug may be unique in being a weak positive reinforcer in small doses and aversive in large doses.
Approaches for characterizing threshold dose-response relationships for DNA-damage pathways involved in carcinogenicity in vivo and micronuclei formation in vitro.

PubMed

Clewell, Rebecca A; Andersen, Melvin E

2016-05-01

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

PubMed

Warnaby, Catherine E; Sleigh, Jamie W; Hight, Darren; Jbabdi, Saad; Tracey, Irene

2017-10-01

Previously, we showed experimentally that saturation of slow-wave activity provides a potentially individualized neurophysiologic endpoint for perception loss during anesthesia. Furthermore, it is clear that induction and emergence from anesthesia are not symmetrically reversible processes. The observed hysteresis is potentially underpinned by a neural inertia mechanism as proposed in animal studies. In an advanced secondary analysis of 393 individual electroencephalographic data sets, we used slow-wave activity dose-response relationships to parameterize slow-wave activity saturation during induction and emergence from surgical anesthesia. We determined whether neural inertia exists in humans by comparing slow-wave activity dose responses on induction and emergence. Slow-wave activity saturation occurs for different anesthetics and when opioids and muscle relaxants are used during surgery. There was wide interpatient variability in the hypnotic concentrations required to achieve slow-wave activity saturation. Age negatively correlated with power at slow-wave activity saturation. On emergence, we observed abrupt decreases in slow-wave activity dose responses coincident with recovery of behavioral responsiveness in ~33% individuals. These patients are more likely to have lower power at slow-wave activity saturation, be older, and suffer from short-term confusion on emergence. Slow-wave activity saturation during surgical anesthesia implies that large variability in dosing is required to achieve a targeted potential loss of perception in individual patients. A signature for neural inertia in humans is the maintenance of slow-wave activity even in the presence of very-low hypnotic concentrations during emergence from anesthesia.
Improving power and robustness for detecting genetic association with extreme-value sampling design.

PubMed

Chen, Hua Yun; Li, Mingyao

2011-12-01

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

PubMed

Hogstrom, K R; Irifune, T

1980-07-01

The thermoluminescent (TL) response of LiF (TLD-100, TLD-600, TLD-700) and Li2B4O7 (TLD-800) has been measured as a function of depth and off-axis position in a therapeutic negative-pion beam in order to evaluate their usefulness in pion radiotherapy. TLD-100, TLD-600, and TLD-800 have been shown to be of little use as in vivo dosemeters because the neutron kerma relative to that in tissue changes grossly with depth. The neutron source comes primarily from pion absorption in the lead-alloy collimator. The 200 degrees C TLD-700 response agrees well with the depth dose spectra, except for small changes due to the varying linear energy transfer (LET) distributions. This variation can be partially accounted for by incorporating the known LET response of LiF. The 260 degrees C peak of TLD-700 has been found to be approximately four times more sensitive than the 200 degrees C peak to high LET dose. Using a simple model of the LET responses, the measured 200 degrees C and 260 degrees C peaks predict total dose within +/- 4% and high LET dose within +/- 50%, therefore indicating TLD-700 to be a good in vivo dosemeter for total dose but only an indicator of high LET dose.
Measurement of relative depth-dose distribution in radiochromic film dosimeters irradiated with 43-70 keV electron beam for industrial application

NASA Astrophysics Data System (ADS)

Matsui, Shinjiro; Hattori, Takeaki; Nonaka, Takashi; Watanabe, Yuki; Morita, Ippei; Kondo, Junichi; Ishikawa, Masayoshi; Mori, Yoshitaka

2018-05-01

The relative dose in a layer, which is thinner than the thickness of the dosimeter is evaluated using simulated depth-dose distributions, and the measured responses of dosimeters with acceleration voltages from 43 to 70 kV, via ultra-low-energy electron beam (ULEB) irradiation. By stacking thin film dosimeters, we confirmed that the simulated depth-dose distributions coincided with the measured depth-dose curve within the measurement uncertainty (k = 2). Using the measurement dose of the 47 μm dosimeter and the simulated depth-dose distribution, the dose of 11 μm dosimeters in the surface was evaluated within the measurement uncertainty (k = 2). We also verified the effectiveness of this method for a thinner layer by changing the acceleration voltage of the irradiation source. We evaluated the relative dose for an adjusted depth of energy deposition from 4.4 μm to 22.8 μm. As a result, this method was found to be effective for a thickness, which is less than the thickness of the dosimeter. When irradiation conditions are well known with accuracy, using the confirmed relative depth-dose distributions across any dosimeter thickness range, a dose evaluation, in several μm steps will possibly improve the design of industrial ULEB processes.
Issues related to sex differences in antipsychotic treatment.

PubMed

Crawford, Mitchell B; DeLisi, Lynn E

2016-05-01

The effectiveness, side-effect profiles, and numerous other characteristics of antipsychotic medications have been extensively studied. However, the majority of publications do not address the many potential sex differences in efficacy and doses of medications, as well as other sex-specific considerations. Of studies that exist, some suggest that female patients respond to lower doses of antipsychotic medications than males and that side-effect profiles vary between the sexes. However, the majority of preclinical trials use only male laboratory animals, and human clinical trials consist of too few women to analyze their response as a separate group. Although changes in hormone production occurring at multiple stages throughout a women's life (such as during pregnancy, breast feeding, menopause, and postmenopausal) are presented as too complex to deal with in clinical trials, they could instead be embraced as clinical dilemmas that require additional study and consideration. We suggest that a focus should be made to reanalyze data from existing major treatment trials of antipsychotics to determine what medications specifically provide the most efficacy for female patients and at what dose range. In addition, new prospective studies are needed to specifically address appropriate adjustments in psychopharmacologic treatment for female patients during pregnancy, and when postmenopausal. More studies of the effects of antipsychotics on male and female fetuses in utero and during breast feeding are also needed to better manage women with schizophrenia and their offspring on a long-term basis in the community. There is currently too little known about sex differences in neuropharmacology. With the new USA National Institutes of Health policy to include sex in all new proposals, the time has come to close this gap in knowledge.
Effects of sub-chronic oral cyanide on endothelial function in rabbit aortic rings.

PubMed

Ozolu, R I; Okolie, N P; Ebeigbe, A B; Karikari, N

2007-02-01

We have investigated how the endothelium affects vascular responses following sub-chronic low dose cyanide administration. Cyanide exists in low levels in cassava foods, which are widely consumed in tropical Africa. Adult rabbits were administered 0.38 mg/kg per day KCN po for 25 days, and responses of the isolated aortic rings to noradrenaline (NA), calcium chloride (Ca2+) and acetylcholine (ACh) were measured in vitro in the presence and absence of the endothelium. In order to establish that the dose was not toxic, animal weight, some haematological indices, plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. Results show that endothelium denudation significantly (P <0.05) attenuates NA-induced contraction in rings from cyanide-treated rabbits. There was a similar reduction in response in Ca2+-depleted NA-precontracted endothelium-denuded aortic rings from cyanide-treated rabbits. Endothelium-denuded rings from cyanide-treated rabbits showed significantly (P <0.05) enhanced relaxation to ACh. In rings from control animals, the responses to NA and Ca2+ were not significantly altered, whether in the presence or absence of the endothelium. There were no significant changes in the studied toxicological indices. We conclude that endothelial compromise is necessary for low-dose sub-chronic cyanide-induced to alter vascular reactivity to NA and ACh.
Aminosalicylates for induction of remission or response in Crohn's disease.

PubMed

Lim, Wee-Chian; Hanauer, Stephen

2010-12-08

Controlled clinical trials investigating the efficacy of aminosalicylates for the treatment of mildly to moderately active Crohn's disease have yielded conflicting results. A systematic review was conducted to critically examine current available data on the efficacy of sulfasalazine and mesalamine for inducing remission or clinical response in patients with mildly to moderately active Crohn's disease. To evaluate the efficacy of aminosalicylates compared to placebo, corticosteroids, and other aminosalicylates (alone or in combination with corticosteroids) for the treatment of mildly to moderately active Crohn's disease. Separate MEDLINE (1966-July 2010), Cochrane Central Register of Controlled Trials (CENTRAL; Issue 3, 2010) and EMBASE database searches (1985-July 2010) of all relevant English and non-English language articles were performed, followed by manual searches of the reference list from potentially relevant papers and review articles, as well as proceedings from annual meetings (1991-2010) of the American Gastroenterological Association (AGA) and American College of Gastroenterology (ACG). Randomized controlled trials that evaluated the efficacy of sulfasalazine or mesalamine in the treatment of mildly to moderately active Crohn's disease compared to placebo, corticosteroids, and other aminosalicylates (alone or in combination with corticosteroids) were included. Data extraction and assessment of methodological quality of each selected study was independently performed by the investigators and any disagreement was resolved by discussion and consensus. The primary outcome measure was a well defined clinical endpoint of induction of remission or response to treatment. Nineteen studies met the inclusion criteria and were analyzed. Pooled relative risks (RR) for inducing remission or clinical response and their 95% confidence intervals were calculated (random effects model) where appropriate. Sulfasalazine was more likely to induce remission (RR 1.38; 95% CI 1.02 to 1.87; n = 263) compared to placebo with benefit confined mainly to patients with colitis. Sulfasalazine was less effective than corticosteroids (RR 0.66; 95% CI 0.53 to 0.81; n = 260). Olsalazine was less effective than placebo in a single trial. Low dose mesalamine (1 to 2 g/day) was not superior to placebo (RR = 1.46, 95% CI 0.89-2.40; n = 302) and was less effective than corticosteroids. High dose mesalamine (3 to 4.5 g/day) was not superior to placebo for induction of remission (RR 2.02; 95% CI 0.75 to 5.45) or response (Weighted Mean Difference -19.8 points; 95% CI -46.2 to 6.7; n = 615). In a single randomized controlled trial, 5-ASA was inferior to budesonide (RR 0.56; 95% CI 0.40 to 0.78). No statistically significant difference was found between high dose mesalamine and conventional corticosteroids (RR 1.04; 95% CI 0.79 to 1.36; n = 178). However, relatively few patients were available for analysis. There was a lack of good quality clinical trials comparing sulfasalazine with other mesalamine formulations. Sulfasalazine has modest efficacy compared to placebo and is inferior to corticosteroids for the treatment of mild to moderately active Crohn's disease. Olsalazine and low dose mesalamine (1 to 2 g/day) are not superior to placebo. High dose mesalamine (3 to 4.5 g/day) is not more effective than placebo for inducing response or remission. High dose mesalamine was inferior to budesonide for inducing remission in a single trial. In conclusion, sulfasalazine shows modest efficacy for the treatment of active Crohn's disease. However, the existing data show little benefit for 5-aminosalicylates.
Nonclinical Safety Assessment of Anti-Factor D: Key Strategies and Challenges for the Nonclinical Development of Intravitreal Biologics.

PubMed

Bantseev, Vladimir; Erickson, Rebecca; Leipold, Douglas; Amaya, Caroline; Miller, Paul E; Booler, Helen; Thackaberry, Evan A

The nonclinical toxicology program described here was designed to characterize the safety profile of anti-factor D (AFD; FCFD4514S, lampalizumab) to support intravitreal (ITV) administration in patients with geographic atrophy (GA). The toxicity of AFD was assessed in a single-dose and 6-month repeat-dose study in monkeys at doses up to 10 mg/eye. Toxicity was assessed by clinical ophthalmic examinations, intraocular pressure measurements, ocular photography, electroretinography, fluorescein angiography, optical coherence tomography, and anatomic pathology. Systemic exposure to AFD generally increased with the increase in dose level. The increases in mean maximal concentration and area under the curve values were roughly dose proportional. No accumulation of AFD was observed following 10 doses, and drug exposures were not affected by anti-drug antibodies. AFD was locally and systemically well tolerated in monkeys following ITV doses of up to 10 mg/eye. Ocular effects associated with AFD were limited to transient, reversible, dose-related, aqueous cell responses and injection-related, mild, vitreal cell responses. In the 6-month repeat-dose study, 2 monkeys had a nonspecific immune response to AFD that resulted in severe ocular inflammation, attributed to administration of a heterologous (humanized) protein. The comprehensive toxicology program in monkeys described here was designed to evaluate the safety profile of AFD and to support multiple ITV injections in the clinic. Administration of a heterologous (humanized) protein presents a challenge, and immunogenicity in nonclinical species is not predictive of immunogenicity in humans. Taken together, the results of the nonclinical program described here support the use of AFD in patients with GA.
Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats.

PubMed

Hulin, Mary W; Lawrence, Michelle N; Amato, Russell J; Weed, Peter F; Winsauer, Peter J

2015-03-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under a FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the interval of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the interval for food reinforcement was low and maintained under a variable-interval schedule. Copyright © 2015 Elsevier Inc. All rights reserved.
Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

PubMed Central

Hulin, Mary W.; Lawrence, Michelle N.; Amato, Russell J.; Weed, Peter F.; Winsauer, Peter J.

2015-01-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under an FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the density of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the density for food reinforcement was low and maintained under a variable-interval schedule. PMID:25620274
Induction of adaptive response in human blood lymphocytes exposed to radiofrequency radiation.

PubMed

Sannino, Anna; Sarti, Maurizio; Reddy, Siddharth B; Prihoda, Thomas J; Vijayalaxmi; Scarfì, Maria Rosaria

2009-06-01

The incidence of micronuclei was evaluated to assess the induction of an adaptive response to non-ionizing radiofrequency (RF) radiation in peripheral blood lymphocytes collected from five different human volunteers. After stimulation with phytohemagglutinin for 24 h, the cells were exposed to an adaptive dose of 900 MHz RF radiation used for mobile communications (at a peak specific absorption rate of 10 W/kg) for 20 h and then challenged with a single genotoxic dose of mitomycin C (100 ng/ml) at 48 h. Lymphocytes were collected at 72 h to examine the frequency of micronuclei in cytokinesis-blocked binucleated cells. Cells collected from four donors exhibited the induction of adaptive response (i.e., responders). Lymphocytes that were pre-exposed to 900 MHz RF radiation had a significantly decreased incidence of micronuclei induced by the challenge dose of mitomycin C compared to those that were not pre-exposed to 900 MHz RF radiation. These preliminary results suggested that the adaptive response can be induced in cells exposed to non-ionizing radiation. A similar phenomenon has been reported in cells as well as in animals exposed to ionizing radiation in several earlier studies. However, induction of adaptive response was not observed in the remaining donor (i.e., non-responder). The incidence of micronuclei induced by the challenge dose of mitomycin C was not significantly different between the cells that were pre-exposed and unexposed to 900 MHz RF radiation. Thus the overall data indicated the existence of heterogeneity in the induction of an adaptive response between individuals exposed to RF radiation and showed that the less time-consuming micronucleus assay can be used to determine whether an individual is a responder or non-responder.
Low-dose Photofrin-induced PDT offers excellent clinical response with minimal morbidity in chest wall recurrence of breast cancer

NASA Astrophysics Data System (ADS)

Allison, Ron; Mang, Thomas S.

2000-03-01

Limited therapeutic options exist when chest wall recurrence form breast cancer progresses despite standard salvage treatment. As photodynamic therapy offers excellent response for cutaneous lesions this may be a possible indication for PDT. A total of 102 treatment fields were illuminated on 9 women with biopsy proven chest wall recurrence of breast cancer which was progressing despite salvage surgery, radiation, and chemi-hormonal therapy. PDT consisted of outpatient IV infusion of Photofrin at 0.8 mg/kg followed 48 hours laser by illumination at 140-170 J/cm2 via a KTP Yag laser coupled to a dye unit. No patient was lost to follow up. At 6 months post PDT; complete response, defined as total lesion elimination was 89 percent, partial response 8 percent, and no response 3 percent. No photosensitivity was seen and no patient developed scarring, fibrosis, or healing difficulties. Low dose Photofrin induced PDT is very active against chest wall lesions. Despite fragile and heavily pre-treated tissues, excellent clinical and cosmetic outcome was obtained. PDT is an underutilized modality for this indication.
A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

PubMed

Hall, David B; Meier, Ulrich; Diener, Hans-Cristoph

2005-06-01

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.
The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2-adrenoceptor blockade.

PubMed

Wheeldon, N M; McDevitt, D G; Lipworth, B J

1994-08-01

1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

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
Human MAIT-cell responses to Escherichia coli: activation, cytokine production, proliferation, and cytotoxicity.

PubMed

Dias, Joana; Sobkowiak, Michał J; Sandberg, Johan K; Leeansyah, Edwin

2016-07-01

Mucosa-associated invariant T cells are a large and relatively recently described innate-like antimicrobial T-cell subset in humans. These cells recognize riboflavin metabolites from a range of microbes presented by evolutionarily conserved major histocompatibility complex, class I-related molecules. Given the innate-like characteristics of mucosa-associated invariant T cells and the novel type of antigens they recognize, new methodology must be developed and existing methods refined to allow comprehensive studies of their role in human immune defense against microbial infection. In this study, we established protocols to examine a range of mucosa-associated invariant T-cell functions as they respond to antigen produced by Escherichia coli These improved and dose- and time-optimized experimental protocols allow detailed studies of MR1-dependent mucosa-associated invariant T-cell responses to Escherichia coli pulsed antigen-presenting cells, as assessed by expression of activation markers and cytokines, by proliferation, and by induction of apoptosis and death in major histocompatibility complex, class I-related-expressing target cells. The novel and optimized protocols establish a framework of methods and open new possibilities to study mucosa-associated invariant T-cell immunobiology, using Escherichia coli as a model antigen. Furthermore, we propose that these robust experimental systems can also be adapted to study mucosa-associated invariant T-cell responses to other microbes and types of antigen-presenting cells. © The Author(s).
Systematic review of the effect of radiation dose on tumor control and morbidity in the treatment of prostate cancer by 3D-CRT

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

Tol-Geerdink, Julia J. van; Stalmeier, Peep F.M.; Department of Medical Technology Assessment, Radboud University Nijmegen Medical Center, Nijmegen

Purpose: A higher radiation dose is believed to result in a larger probability of tumor control and a higher risk of side effects. To make an evidence-based choice of dose, the relation between dose and outcome needs to be known. This study focuses on the dose-response relation for prostate cancer. Methods and Materials: A systematic review was carried out on the literature from 1990 to 2003. From the selected studies, the radiation dose, the associated 5-year survival, 5-year bNED (biochemical no evidence of disease), acute and late gastrointestinal (GI) and genitourinary (GU) morbidity Grade 2 or more, and sexual dysfunctionmore » were extracted. With logistic regression models, the relation between dose and outcome was described. Results: Thirty-eight studies met our criteria, describing 87 subgroups and involving up to 3000 patients per outcome measure. Between the (equivalent) dose of 70 and 80 Gy, various models estimated an increase in 5-year survival (ranging from 10% to 11%), 5-year bNED for low-risk patients (5-7%), late GI complications (12-16%), late GU complications (8-10%), and erectile dysfunction (19-24%). Only for the overall 5-year bNED, results were inconclusive (range, 0-18%). Conclusions: The data suggest a relationship between dose and outcome measures, including survival. However, the strength of these conclusions is limited by the sometimes small number of studies, the incompleteness of the data, and above all, the correlational nature of the data. Unambiguous proof for the dose-response relationships can, therefore, only be obtained by conducting randomized trials.« less
Differential patterns of lifetime multiple anxiety disorder comorbidity between Latino adults with bipolar I and major depressive disorders.

PubMed

Dilsaver, Steven C; Benazzi, Franco; Akiskal, Kareen K; Akiskal, Hagop S

2008-01-01

To determine the lifetime rates of panic disorder, obsessive-compulsive disorder (OCD), social phobia, and posttraumatic stress disorder (PTSD) among adult Latino patients with major depressive disorder (MDD) and bipolar disorder (BPD), and whether there are dose-response relationships between loading for comorbid anxiety disorders, the probability of having BPD, and attributes of severity of illness. In a public sector clinic for the indigent located in a semiclosed rural community, 187 consecutively presenting affectively ill Latino patients were evaluated by use of the Structured Clinical Interview for DSM-IV. Polarity and the lifetime prevalence of panic disorder, OCD, social phobia, and PTSD were determined. Logistic regression was used to test associations. Trends in positive predictive values (PPVs) and likelihood ratios were assessed to determine whether dose-response relationships existed between loading for comorbid anxiety disorders and the likelihood of having BPD as opposed to MDD, psychosis, suicidal ideation, and suicide attempts. Of 187 subjects, 118 (63.1%) had MDD and 69 (36.9%) had BPD. The odds ratio of a patient with BPD, relative to MDD, of having panic disorder was 4.6 (p< .0001), OCD 7.6 (p< .0001), social phobia 6.0 (p< .0001) and PTSD 5.3 (p< .0001). The PPV of having BPD was 91.3% and of having psychotic features 83.0% if one had all four anxiety disorders. There was a dose-response relationship between loading for comorbid anxiety disorders and the likelihood of having had a suicide attempt (but not suicidal ideation). As previously reported by us for juvenile patients, Latino adults with BPD had a remarkably high risk of having each anxiety disorder relative to patients with MDD. The results indicate that the risk of having BPD, having a psychosis, and making a suicide attempt becomes increasingly great as the number of comorbid anxiety disorders increases. These data, which are consistent with the notion of anxious bipolarity, provide further support for a possible anxious diathesis in bipolar disorder.
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
Sphere of equivalence--a novel target volume concept for intraoperative radiotherapy using low-energy X rays.

PubMed

Herskind, Carsten; Griebel, Jürgen; Kraus-Tiefenbacher, Uta; Wenz, Frederik

2008-12-01

Accelerated partial breast radiotherapy with low-energy photons from a miniature X-ray machine is undergoing a randomized clinical trial (Targeted Intra-operative Radiation Therapy [TARGIT]) in a selected subgroup of patients treated with breast-conserving surgery. The steep radial dose gradient implies reduced tumor cell control with increasing depth in the tumor bed. The purpose was to compare the expected risk of local recurrence in this nonuniform radiation field with that after conventional external beam radiotherapy. The relative biologic effectiveness of low-energy photons was modeled using the linear-quadratic formalism including repair of sublethal lesions during protracted irradiation. Doses of 50-kV X-rays (Intrabeam) were converted to equivalent fractionated doses, EQD2, as function of depth in the tumor bed. The probability of local control was estimated using a logistic dose-response relationship fitted to clinical data from fractionated radiotherapy. The model calculations show that, for a cohort of patients, the increase in local control in the high-dose region near the applicator partly compensates the reduction of local control at greater distances. Thus a "sphere of equivalence" exists within which the risk of recurrence is equal to that after external fractionated radiotherapy. The spatial distribution of recurrences inside this sphere will be different from that after conventional radiotherapy. A novel target volume concept is presented here. The incidence of recurrences arising in the tumor bed around the excised tumor will test the validity of this concept and the efficacy of the treatment. Recurrences elsewhere will have implications for the rationale of TARGIT.
ESTIMATING A DOSE-RESPONSE RELATIONSHIP BETWEEN LENGTH OF STAY AND FUTURE RECIDIVISM IN SERIOUS JUVENILE OFFENDERS*

PubMed Central

Loughran, Thomas A.; Mulvey, Edward P.; Schubert, Carol A.; Fagan, Jeffrey; Piquero, Alex R.; Losoya, Sandra H.

2009-01-01

The effect of sanctions on subsequent criminal activity is of central theoretical importance in criminology. A key question for juvenile justice policy is the degree to which serious juvenile offenders respond to sanctions and/or treatment administered by the juvenile court. The policy question germane to this debate is finding the level of confinement within the juvenile justice system that maximizes the public safety and therapeutic benefits of institutional confinement. Unfortunately, research on this issue has been limited with regard to serious juvenile offenders. We use longitudinal data from a large sample of serious juvenile offenders from two large cities to 1) estimate a causal treatment effect of institutional placement, as opposed to probation, on future rate of rearrest and 2) investigate the existence of a marginal effect (i.e., benefit) for longer length of stay once the institutional placement decision had been made. We accomplish the latter by determining a dose-response relationship between the length of stay and future rates of rearrest and self-reported offending. The results suggest that an overall null effect of placement exists on future rates of rearrest or self-reported offending for serious juvenile offenders. We also find that, for the group placed out of the community, it is apparent that little or no marginal benefit exists for longer lengths of stay. Theoretical, empirical, and policy issues are outlined. PMID:20052309
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.
Assessing the health effects associated with occupational radiation exposure in Korean radiation workers: protocol for a prospective cohort study.

PubMed

Seo, Songwon; Lim, Wan Young; Lee, Dal Nim; Kim, Jung Un; Cha, Eun Shil; Bang, Ye Jin; Lee, Won Jin; Park, Sunhoo; Jin, Young Woo

2018-03-30

The cancer risk of radiation exposure in the moderate-to-high dose range has been well established. However, the risk remains unclear at low-dose ranges with protracted low-dose rate exposure, which is typical of occupational exposure. Several epidemiological studies of Korean radiation workers have been conducted, but the data were analysed retrospectively in most cases. Moreover, groups with relatively high exposure, such as industrial radiographers, have been neglected. Therefore, we have launched a prospective cohort study of all Korean radiation workers to assess the health effects associated with occupational radiation exposure. Approximately 42 000 Korean radiation workers registered with the Nuclear Safety and Security Commission from 2016 to 2017 are the initial target population of this study. Cohort participants are to be enrolled through a nationwide self-administered questionnaire survey between 24 May 2016 and 30 June 2017. As of 31 March 2017, 22 982 workers are enrolled in the study corresponding to a response rate of 75%. This enrolment will be continued at 5-year intervals to update information on existing study participants and recruit newly hired workers. Survey data will be linked with the national dose registry, the national cancer registry, the national vital statistics registry and national health insurance data via personal identification numbers. Age-specific and sex-specific standardised incidence and mortality ratios will be calculated for overall comparisons of cancer risk. For dose-response assessment, excess relative risk (per Gy) and excess absolute risk (per Gy) will be estimated with adjustments for birth year and potential confounders, such as lifestyle factors and socioeconomic status. This study has received ethical approval from the institutional review board of the Korea Institute of Radiological and Medical Sciences (IRB No. K-1603-002-034). All participants provided written informed consent prior to enrolment. The findings of the study will be disseminated through scientific peer-reviewed journals and be provided to the public, including radiation workers, via the study website (http://www.rhs.kr/) and onsite radiation safety education. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Dose algorithm for EXTRAD 4100S extremity dosimeter for use at Sandia National Laboratories.

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

Potter, Charles Augustus

An updated algorithm for the EXTRAD 4100S extremity dosimeter has been derived. This algorithm optimizes the binning of dosimeter element ratios and uses a quadratic function to determine the response factors for low response ratios. This results in lower systematic bias across all test categories and eliminates the need for the 'red strap' algorithm that was used for high energy beta/gamma emitting radionuclides. The Radiation Protection Dosimetry Program (RPDP) at Sandia National Laboratories uses the Thermo Fisher EXTRAD 4100S extremity dosimeter, shown in Fig 1.1 to determine shallow dose to the extremities of potentially exposed individuals. This dosimeter consists ofmore » two LiF TLD elements or 'chipstrates', one of TLD-700 ({sup 7}Li) and one of TLD-100 (natural Li) separated by a tin filter. Following readout and background subtraction, the ratio of the responses of the two elements is determined defining the penetrability of the incident radiation. While this penetrability approximates the incident energy of the radiation, X-rays and beta particles exist in energy distributions that make determination of dose conversion factors less straightforward in their determination.« less
Development and Testing of a Laboratory Spray Table Methodology to Bioassay Simulated Levels of Aerial Spray Drift

DTIC Science & Technology

2009-05-01

was measured on Mylar cards through fluorometric analysis. Plant health measures height and normalized difference vegetation index NDVI were...plant health data were used to generate dose-response relationships. Dose-response curves relating change in plant height and change in measured NDVI ...Held Sensor Model 505, NTech Industries, Inc., Ukiah, California to measure the normalized difference vegetation index NDVI which is directly
TH-A-BRD-01: Radiation Biology for Radiation Therapy Physicists

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

Orton, C; Borras, C; Carlson, D

Mechanisms by which radiation kills cells and ways cell damage can be repaired will be reviewed. The radiobiological parameters of dose, fractionation, delivery time, dose rate, and LET will be discussed. The linear-quadratic model for cell survival for high and low dose rate treatments and the effect of repopulation will be presented and discussed. The rationale for various radiotherapy techniques such as conventional fractionation, hyperfractionation, hypofractionation, and low and high dose rate brachytherapy, including permanent implants, will be presented. The radiobiological principles underlying radiation protection guidelines and the different radiation dosimetry terms used in radiation biology and in radiation protectionmore » will be reviewed. Human data on radiation induced cancer, including increases in the risk of second cancers following radiation therapy, as well as data on radiation induced tissue reactions, such as cardiovascular effects, for follow up times up to 20–40 years, published by ICRP, NCRP and BEIR Committees, will be examined. The latest risk estimates per unit dose will be presented. Their adoption in recent radiation protection standards and guidelines and their impact on patient and workers safety in radiotherapy will be discussed. Biologically-guided radiotherapy (BGRT) provides a systematic method to derive prescription doses that integrate patient-specific information about tumor and normal tissue biology. Treatment individualization based on patient-specific biology requires the identification of biological objective functions to facilitate the design and comparison of competing treatment modalities. Biological objectives provide a more direct approach to plan optimization instead of relying solely on dose-based surrogates and can incorporate factors that alter radiation response, such as DNA repair, tumor hypoxia, and relative biological effectiveness. We review concepts motivating biological objectives and provide examples of how they might be used to address clinically relevant problems. Underlying assumptions and limitations of existing models and their proper application will be discussed. This multidisciplinary educational session combines the fundamentals of radiobiology for radiation therapy and radiation protection with the practical application of biophysical models for treatment planning and evaluation. Learning Objectives: To understand fractionation in teletherapy and dose rate techniques in brachytherapy. To understand how the linear-quadratic models the effect of radiobiological parameters for radiotherapy. To understand the radiobiological basis of radiation protection standards applied to radiotherapy. To distinguish between stochastic effects and tissue reactions. To learn how to apply concepts of biological effective dose and RBE-weighted dose and to incorporate biological factors that alter radiation response. To discuss clinical strategies to increase therapeutic ratio, i.e., maximize local control while minimizing the risk of acute and late normal tissue effects.« less
The current state of knowledge on the use of the benchmark dose concept in risk assessment.

PubMed

Sand, Salomon; Victorin, Katarina; Filipsson, Agneta Falk

2008-05-01

This review deals with the current state of knowledge on the use of the benchmark dose (BMD) concept in health risk assessment of chemicals. The BMD method is an alternative to the traditional no-observed-adverse-effect level (NOAEL) and has been presented as a methodological improvement in the field of risk assessment. The BMD method has mostly been employed in the USA but is presently given higher attention also in Europe. The review presents a number of arguments in favor of the BMD, relative to the NOAEL. In addition, it gives a detailed overview of the several procedures that have been suggested and applied for BMD analysis, for quantal as well as continuous data. For quantal data the BMD is generally defined as corresponding to an additional or extra risk of 5% or 10%. For continuous endpoints it is suggested that the BMD is defined as corresponding to a percentage change in response relative to background or relative to the dynamic range of response. Under such definitions, a 5% or 10% change can be considered as default. Besides how to define the BMD and its lower bound, the BMDL, the question of how to select the dose-response model to be used in the BMD and BMDL determination is highlighted. Issues of study design and comparison of dose-response curves and BMDs are also covered. Copyright (c) 2007 John Wiley & Sons, Ltd.
Management of Myositis-Related Interstitial Lung Disease.

PubMed

Morisset, Julie; Johnson, Cheilonda; Rich, Eric; Collard, Harold R; Lee, Joyce S

2016-11-01

Interstitial lung disease (ILD) is a frequent pulmonary manifestation and an important cause of morbidity and mortality in patients with idiopathic inflammatory myopathy. Myositis-related ILD presents a therapeutic challenge for clinicians, as there are no available guidelines to help with management decisions. This review covers the existing evidence on the pharmacologic and nonpharmacologic management of myositis-related ILD, highlighting the lack of randomized controlled data to guide treatment. Given the absence of existing guidelines to inform treatment decisions, we provide a comprehensive summary, including dosing, side effects, and suggested monitoring of the commonly used immunosuppressive agents and a proposed treatment algorithm based on the existing literature. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
Organ Doses Associated with Partial-Body Irradiation with 2.5% Bone Marrow Sparing of the Non-Human Primate: A Retrospective Study.

PubMed

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

2017-12-01

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

PubMed

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

1987-12-01

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

PubMed Central

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

1987-01-01

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

PubMed

Mandapaka, A K; Ghebremedhin, A; Patyal, B; Marinelli, Marco; Prestopino, G; Verona, C; Verona-Rinati, G

2013-12-01

To investigate the dosimetric properties of a synthetic single crystal diamond Schottky diode for accurate relative dose measurements in large and small field high-energy clinical proton beams. The dosimetric properties of a synthetic single crystal diamond detector were assessed by comparison with a reference Markus parallel plate ionization chamber, an Exradin A16 microionization chamber, and Exradin T1a ion chamber. The diamond detector was operated at zero bias voltage at all times. Comparative dose distribution measurements were performed by means of Fractional depth dose curves and lateral beam profiles in clinical proton beams of energies 155 and 250 MeV for a 14 cm square cerrobend aperture and 126 MeV for 3, 2, and 1 cm diameter circular brass collimators. ICRU Report No. 78 recommended beam parameters were used to compare fractional depth dose curves and beam profiles obtained using the diamond detector and the reference ionization chamber. Warm-up∕stability of the detector response and linearity with dose were evaluated in a 250 MeV proton beam and dose rate dependence was evaluated in a 126 MeV proton beam. Stem effect and the azimuthal angle dependence of the diode response were also evaluated. A maximum deviation in diamond detector signal from the average reading of less than 0.5% was found during the warm-up irradiation procedure. The detector response showed a good linear behavior as a function of dose with observed deviations below 0.5% over a dose range from 50 to 500 cGy. The detector response was dose rate independent, with deviations below 0.5% in the investigated dose rates ranging from 85 to 300 cGy∕min. Stem effect and azimuthal angle dependence of the diode signal were within 0.5%. Fractional depth dose curves and lateral beam profiles obtained with the diamond detector were in good agreement with those measured using reference dosimeters. The observed dosimetric properties of the synthetic single crystal diamond detector indicate that its behavior is proton energy independent and dose rate independent in the investigated energy and dose rate range and it is suitable for accurate relative dosimetric measurements in large as well as in small field high energy clinical proton beams.
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.
Applying a Hypoxia-Incorporating TCP Model to Experimental Data on Rat Sarcoma

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

Ruggieri, Ruggero, E-mail: ruggieri.ruggero@gmail.com; Stavreva, Nadejda; Naccarato, Stefania

2012-08-01

Purpose: To verify whether a tumor control probability (TCP) model which mechanistically incorporates acute and chronic hypoxia is able to describe animal in vivo dose-response data, exhibiting tumor reoxygenation. Methods and Materials: The investigated TCP model accounts for tumor repopulation, reoxygenation of chronic hypoxia, and fluctuating oxygenation of acute hypoxia. Using the maximum likelihood method, the model is fitted to Fischer-Moulder data on Wag/Rij rats, inoculated with rat rhabdomyosarcoma BA1112, and irradiated in vivo using different fractionation schemes. This data set is chosen because two of the experimental dose-response curves exhibit an inverse dose behavior, which is interpreted as duemore » to reoxygenation. The tested TCP model is complex, and therefore, in vivo cell survival data on the same BA1112 cell line from Reinhold were added to Fischer-Moulder data and fitted simultaneously with a corresponding cell survival function. Results: The obtained fit to the combined Fischer-Moulder-Reinhold data was statistically acceptable. The best-fit values of the model parameters for which information exists were in the range of published values. The cell survival curves of well-oxygenated and hypoxic cells, computed using the best-fit values of the radiosensitivities and the initial number of clonogens, were in good agreement with the corresponding in vitro and in situ experiments of Reinhold. The best-fit values of most of the hypoxia-related parameters were used to recompute the TCP for non-small cell lung cancer patients as a function of the number of fractions, TCP(n). Conclusions: The investigated TCP model adequately describes animal in vivo data exhibiting tumor reoxygenation. The TCP(n) curve computed for non-small cell lung cancer patients with the best-fit values of most of the hypoxia-related parameters confirms previously obtained abrupt reduction in TCP for n < 10, thus warning against the adoption of severely hypofractionated schedules.« less

Personalized medicine: is it a pharmacogenetic mirage?

PubMed Central

Shah, Rashmi R; Shah, Devron R

2012-01-01

The notion of personalized medicine has developed from the application of the discipline of pharmacogenetics to clinical medicine. Although the clinical relevance of genetically-determined inter-individual differences in pharmacokinetics is poorly understood, and the genotype-phenotype association data on clinical outcomes often inconsistent, officially approved drug labels frequently include pharmacogenetic information concerning the safety and/or efficacy of a number of drugs and refer to the availability of the pharmacogenetic test concerned. Regulatory authorities differ in their approach to these issues. Evidence emerging subsequently has generally revealed the pharmacogenetic information included in the label to be premature. Revised drugs labels, together with a flurry of other collateral activities, have raised public expectations of personalized medicine, promoted as ‘the right drug at the right dose the first time.’ These expectations place the prescribing physician in a dilemma and at risk of litigation, especially when evidence-based information on genotype-related dosing schedules is to all intent and purposes non-existent and guidelines, intended to improve the clinical utility of available pharmacogenetic information or tests, distance themselves from any responsibility. Lack of efficacy or an adverse drug reaction is frequently related to non-genetic factors. Phenoconversion, arising from drug interactions, poses another often neglected challenge to any potential success of personalized medicine by mimicking genetically-determined enzyme deficiency. A more realistic promotion of personalized medicine should acknowledge current limitations and emphasize that pharmacogenetic testing can only improve the likelihood of diminishing a specific toxic effect or increasing the likelihood of a beneficial effect and that application of pharmacogenetics to clinical medicine cannot adequately predict drug response in individual patients. PMID:22591598
Low doses of arsenic, via perturbing p53, promotes tumorigenesis

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

Ganapathy, Suthakar, E-mail: s.ganapathy@neu.edu

In drinking water and in workplace or living environments, low doses of arsenic can exist and operate as a potent carcinogen. Due to insufficient understanding and information on the pervasiveness of environmental exposures to arsenic, there is an urgent need to elucidate the underlying molecular mechanisms of arsenic regarding its carcinogenic effect on human health. In this study, we demonstrate that low doses of arsenic exposure mitigate or mask p53 function and further perturb intracellular redox state, which triggers persistent endoplasmic reticulum (ER) stress and activates UPR (unfolded protein response), leading to transformation or tumorigenesis. Thus, the results suggest thatmore » low doses of arsenic exposure, through attenuating p53-regulated tumor suppressive function, change the state of intracellular redox and create a microenvironment for tumorigenesis. Our study also provides the information for designing more effective strategies to prevent or treat human cancers initiated by arsenic exposure.« less
Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature.

PubMed

Kriström, Berit; Aronson, A Stefan; Dahlgren, Jovanna; Gustafsson, Jan; Halldin, Maria; Ivarsson, Sten A; Nilsson, Nils-Osten; Svensson, Johan; Tuvemo, Torsten; Albertsson-Wikland, Kerstin

2009-02-01

Weight-based GH dosing results in a wide variation in growth response in children with GH deficiency (GHD) or idiopathic short stature (ISS). The hypothesis tested was whether individualized GH doses, based on variation in GH responsiveness estimated by a prediction model, reduced variability in growth response around a set height target compared with a standardized weight-based dose. A total of 153 short prepubertal children diagnosed with isolated GHD or ISS (n = 43) and at least 1 SD score (SDS) below midparental height SDS (MPH(SDS)) were included in this 2-yr multicenter study. The children were randomized to either a standard (43 microg/kg.d) or individualized (17-100 microg/kg.d) GH dose. We measured the deviation of height(SDS) from individual MPH(SDS) (diffMPH(SDS)). The primary endpoint was the difference in the range of diffMPH(SDS) between the two groups. The diffMPH(SDS) range was reduced by 32% in the individualized-dose group relative to the standard-dose group (P < 0.003), whereas the mean diffMPH(SDS) was equal: -0.42 +/- 0.46 and -0.48 +/- 0.67, respectively. Gain in height(SDS) 0-2 yr was equal for the GH-deficient and ISS groups: 1.31 +/- 0.47 and 1.36 +/- 0.47, respectively, when ISS was classified on the basis of maximum GH peak on the arginine-insulin tolerance test or 24-h profile. Individualized GH doses during catch-up growth significantly reduce the proportion of unexpectedly good and poor responders around a predefined individual growth target and result in equal growth responses in children with GHD and ISS.
African Americans with LVH demonstrate depressed sensitivity of the coronary microcirculation to stimulated relaxation.

PubMed

Houghton, Jan Laws; Strogatz, David S; Torosoff, Mikhail T; Smith, Vivienne E; Fein, Steven A; Kuhner, Patricia A; Philbin, Edward F; Carr, Albert A

2003-09-01

Excess coronary heart disease morbidity and mortality among African Americans remains an important yet unexplained public health problem. We hypothesized that adverse outcome is in part due to intrinsic or acquired abnormalities in coronary endothelial function and vasoreactivity. We compared dose-response curves relating changes in coronary blood flow and epicardial diameter to graded infusions of acetylcholine in 50 African American and 65 white subjects with hypertensive left ventricular hypertrophy (LVH) and normal coronary arteries. These groups were similar for age, body mass index, mean arterial pressure, and indexed left ventricular mass. The same protocol was conducted in 24 normotensive African American and 56 similar white subjects. We found significant depression in the coronary blood flow dose-response curve relation among African Americans when compared with white subjects with similar LVH (P<0.03). Racial differences were observed at all doses of acetylcholine but were less precisely estimated at the highest dose. The same testing among normotensive subjects revealed similar dose-response curves with no significant effect of race. Qualitatively similar results were found with respect to coronary diameter. Adenosine responses, a measure of endothelium-independent function, were similar after partitioning by LVH. Our study demonstrates that there are racial differences in sensitivity of coronary arteries to acetylcholine-stimulated relaxation among those with LVH. These results provide a mechanism whereby racial differences in coronary vasoreactivity might contribute to adverse coronary heart disease outcome among African Americans, a group in whom LVH is prevalent.
Application of a computational decision model to examine acute drug effects on human risk taking.

PubMed

Lane, Scott D; Yechiam, Eldad; Busemeyer, Jerome R

2006-05-01

In 3 previous experiments, high doses of alcohol, marijuana, and alprazolam acutely increased risky decision making by adult humans in a 2-choice (risky vs. nonrisky) laboratory task. In this study, a computational modeling analysis known as the expectancy valence model (J. R. Busemeyer & J. C. Stout, 2002) was applied to individual-participant data from these studies, for the highest administered dose of all 3 drugs and corresponding placebo doses, to determine changes in decision-making processes that may be uniquely engendered by each drug. The model includes 3 parameters: responsiveness to rewards and losses (valence or motivation); the rate of updating expectancies about the value of risky alternatives (learning/memory); and the consistency with which trial-by-trial choices match expected outcomes (sensitivity). Parameter estimates revealed 3 key outcomes: Alcohol increased responsiveness to risky rewards and decreased responsiveness to risky losses (motivation) but did not alter expectancy updating (learning/memory); both marijuana and alprazolam produced increases in risk taking that were related to learning/memory but not motivation; and alcohol and marijuana (but not alprazolam) produced more random response patterns that were less consistently related to expected outcomes on the 2 choices. No significant main effects of gender or dose by gender interactions were obtained, but 2 dose by gender interactions approached significance. These outcomes underscore the utility of using a computational modeling approach to deconstruct decision-making processes and thus better understand drug effects on risky decision making in humans.
Actions of the crude venom of the Sydney funnel-web spider, Atrax robustus on autonomic neuromuscular transmission

PubMed Central

Harris, J.B.; Sutherland, S.; Zar, M.A.

1981-01-01

1 The effects on mammalian autonomic neuromuscular transmission of the crude venom of the female Sydney funnel-web spider Atrax robustus, have been investigated. 2 At doses of 10 μg/ml or lower the indirectly elicited twitch-like responses of the rat anococcygeus preparation were inhibited. At doses greater than 10 μg/ml there was an initial reduction in the twitch-like response followed by a sustained contracture of the tissue. 3 The long-lasting contracture caused by the venom was abolished by the application of phentolamine. It was virtually non-existent in muscle preparations isolated from reserpine-treated rats. 4 In the presence of tetrodotoxin the contracture was smaller and less well maintained than in its absence. 5 The venom caused a small reduction in the amplitude of the indirectly elicited twitch-like response of the longitudinal muscle of the guinea-pig ileum, followed by an increase in the tone of the preparation. The increase in tone was maintained for several minutes and was rapidly abolished by the application of atropine. The presence of venom did not affect control responses to either histamine or acetylcholine. 6 Inhibitory transmission in the rat anococcygeus preparation was unaffected by the venom. 7 The neurally-mediated twitch-like responses of both guinea-pig and rat vas deferens were inhibited by the venom at doses below 10 μg/ml. At higher doses the inhibition was accompanied by spontaneous contractions, and at doses in excess of 100 μg/ml the inhibition of twitch-like responses was transient and was followed by a potentiation of the motor response and extensive spontaneous activity. The preparation became quiescent 20 min after the application of venom and the evoked response was abolished after 60 min. 8 The venom had qualitatively similar effects on motor transmission in the human vas deferens as on the rat and guinea-pig preparations. However, the human preparations were 50 to 100 times more sensitive to the effects of the venom. PMID:6260279
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.
BMDExpress Data Viewer: A Visualization Tool to Analyze BMDExpress Datasets(SoTC)

EPA Science Inventory

Background: Benchmark Dose (BMD) modelling is a mathematical approach used to determine where a dose-response change begins to take place relative to controls following chemical exposure. BMDs are being increasingly applied in regulatory toxicology to estimate acceptable exposure...
BMDExpress Data Viewer: A Visualization Tool to Analyze BMDExpress Datasets (STC symposium)

EPA Science Inventory

Background: Benchmark Dose (BMD) modelling is a mathematical approach used to determine where a dose-response change begins to take place relative to controls following chemical exposure. BMDs are being increasingly applied in regulatory toxicology to estimate acceptable exposure...
Testing equality and interval estimation in binary responses when high dose cannot be used first under a three-period crossover design.

PubMed

Lui, Kung-Jong; Chang, Kuang-Chao

2015-01-01

When comparing two doses of a new drug with a placebo, we may consider using a crossover design subject to the condition that the high dose cannot be administered before the low dose. Under a random-effects logistic regression model, we focus our attention on dichotomous responses when the high dose cannot be used first under a three-period crossover trial. We derive asymptotic test procedures for testing equality between treatments. We further derive interval estimators to assess the magnitude of the relative treatment effects. We employ Monte Carlo simulation to evaluate the performance of these test procedures and interval estimators in a variety of situations. We use the data taken as a part of trial comparing two different doses of an analgesic with a placebo for the relief of primary dysmenorrhea to illustrate the use of the proposed test procedures and estimators.
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.
Characterization of the Exradin W1 scintillator for use in radiotherapy.

PubMed

Carrasco, P; Jornet, N; Jordi, O; Lizondo, M; Latorre-Musoll, A; Eudaldo, T; Ruiz, A; Ribas, M

2015-01-01

To evaluate the main characteristics of the Exradin W1 scintillator as a dosimeter and to estimate measurement uncertainties when used in radiotherapy. We studied the calibration procedure, energy and modality dependence, short-term repeatability, dose-response linearity, angular dependence, temperature dependence, time to reach thermal equilibrium, dose-rate dependence, water-equivalent depth of the effective measurement point, and long-term stability. An uncertainty budget was derived for relative and absolute dose measurements in photon and electron beams. Exradin W1 showed a temperature dependence of -0.225% °C(-1). The loss of sensitivity with accumulated dose decreased with use. The sensitivity of Exradin W1 was energy independent for high-energy photon and electron beams. All remaining dependencies of Exradin W1 were around or below 0.5%, leading to an uncertainty budget of about 1%. When a dual channel electrometer with automatic trigger was not used, timing effects became significant, increasing uncertainties by one order of magnitude. The Exradin W1 response is energy independent for high energy x-rays and electron beams, and only one calibration coefficient is needed. A temperature correction factor should be applied to keep uncertainties around 2% for absolute dose measurements and around 1% for relative measurements in high-energy photon and electron beams. The Exradin W1 scintillator is an excellent alternative to detectors such as diodes for relative dose measurements.
Regulation of the Low Dose Radiation Paracrine-Specific Anchorage-Independent Growth Response by Annexin A2

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

Weber, Thomas J.; Opresko, Lee K.; Waisman, David M.

2009-07-13

ABSTRACT-Here we identify release of annexin A2 into the culture medium in response to low dose X-ray radiation exposure and establish functional linkages to an established paracrine factor-mediated anchorage-independent growth response. Using a standard bicameral coculture model, we observe that annexin A2 levels associated with non-irradiated neighboring cells seeded in the lower chamber (annexin A2 silenced [shRNA] JB6 cells) are increased upon coculture with irradiated (10-50 cGy) JB6 cells seeded in the upper chamber, relative to coculture with sham exposed JB6 cells seeded in the upper chamber, suggesting that annexin A2 released into the medium is capable of communicating inmore » a paracrine fashion. Using a previously established coculture model, we observed that the paracrine factor-mediated anchorage-independent growth response to low dose X-ray radiation is markedly reduced when irradiated annexin A2 silenced (shRNA) JB6 cells are used, relative to coculture with irradiated annexin A2 competent vector control counterparts. These observations suggest that annexin A2 is functionally linked to the radiation paracrine factor-specific anchorage-independent growth response in JB6 cells.« less
Electron paramagnetic resonance (EPR) dosimetry using lithium formate in radiotherapy: comparison with thermoluminescence (TL) dosimetry using lithium fluoride rods.

PubMed

Vestad, Tor Arne; Malinen, Eirik; Olsen, Dag Rune; Hole, Eli Olaug; Sagstuen, Einar

2004-10-21

Solid-state radiation dosimetry by electron paramagnetic resonance (EPR) spectroscopy and thermoluminescence (TL) was utilized for the determination of absorbed doses in the range of 0.5-2.5 Gy. The dosimeter materials used were lithium formate and lithium fluoride (TLD-100 rods) for EPR dosimetry and TL dosimetry, respectively. 60Co gamma-rays and 4, 6, 10 and 15 MV x-rays were employed. The main objectives were to compare the variation in dosimeter reading of the respective dosimetry systems and to determine the photon energy dependence of the two dosimeter materials. The EPR dosimeter sensitivity was constant over the dose range in question, while the TL sensitivity increased by more than 5% from 0.5 to 2.5 Gy, thus displaying a supralinear dose response. The average relative standard deviation in the dosimeter reading per dose was 3.0% and 1.2% for the EPR and TL procedures, respectively. For EPR dosimeters, the relative standard deviation declined significantly from 4.3% to 1.1% over the dose range in question. The dose-to-water energy response for the megavoltage x-ray beams relative to 60Co gamma-rays was in the range of 0.990-0.979 and 0.984-0.962 for lithium formate and lithium fluoride, respectively. The results show that EPR dosimetry with lithium formate provides dose estimates with a precision comparable to that of TL dosimetry (using lithium fluoride) for doses above 2 Gy, and that lithium formate is slightly less dependent on megavoltage photon beam energy than lithium fluoride.
Electron paramagnetic resonance (EPR) dosimetry using lithium formate in radiotherapy: comparison with thermoluminescence (TL) dosimetry using lithium fluoride rods

NASA Astrophysics Data System (ADS)

Vestad, Tor Arne; Malinen, Eirik; Rune Olsen, Dag; Olaug Hole, Eli; Sagstuen, Einar

2004-10-01

Solid-state radiation dosimetry by electron paramagnetic resonance (EPR) spectroscopy and thermoluminescence (TL) was utilized for the determination of absorbed doses in the range of 0.5-2.5 Gy. The dosimeter materials used were lithium formate and lithium fluoride (TLD-100 rods) for EPR dosimetry and TL dosimetry, respectively. 60Co ggr-rays and 4, 6, 10 and 15 MV x-rays were employed. The main objectives were to compare the variation in dosimeter reading of the respective dosimetry systems and to determine the photon energy dependence of the two dosimeter materials. The EPR dosimeter sensitivity was constant over the dose range in question, while the TL sensitivity increased by more than 5% from 0.5 to 2.5 Gy, thus displaying a supralinear dose response. The average relative standard deviation in the dosimeter reading per dose was 3.0% and 1.2% for the EPR and TL procedures, respectively. For EPR dosimeters, the relative standard deviation declined significantly from 4.3% to 1.1% over the dose range in question. The dose-to-water energy response for the megavoltage x-ray beams relative to 60Co ggr-rays was in the range of 0.990-0.979 and 0.984-0.962 for lithium formate and lithium fluoride, respectively. The results show that EPR dosimetry with lithium formate provides dose estimates with a precision comparable to that of TL dosimetry (using lithium fluoride) for doses above 2 Gy, and that lithium formate is slightly less dependent on megavoltage photon beam energy than lithium fluoride.
Pond-raised hybrid catfish, male Ictalurus punctatus X female Ictalurus furcatus, do not respond to microbial phytase “super-dosing”

USDA-ARS?s Scientific Manuscript database

Two experiments were conducted in consecutive years to evaluate responses of hybrid catfish, male Ictalurus punctatus X female Ictalurus furcatus, to “super-dosing” of 6-phytase added to existing commercial catfish feeds. In each experiment, two diets with or without a phytase super-dose (2,500 and ...
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.
Gestational exposure to perfluorooctanoic acid (PFOA): alterations in motor related behaviors

PubMed Central

Goulding, David R.; White, Sally S.; McBride, Sandra J.; Fenton, Suzanne E.; Harry, G. Jean

2016-01-01

Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0 mg/kg/day) via oral gavage from gestational day 1–17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0 mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80 µg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18 days of 400µg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0 mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose level under 1.0 mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted. PMID:27888120
2D dosimetry in a proton beam with a scintillating GEM detector

NASA Astrophysics Data System (ADS)

Seravalli, E.; de Boer, M. R.; Geurink, F.; Huizenga, J.; Kreuger, R.; Schippers, J. M.; van Eijk, C. W. E.

2009-06-01

A two-dimensional position-sensitive dosimetry system based on a scintillating gas detector is being developed for pre-treatment verification of dose distributions in particle therapy. The dosimetry system consists of a chamber filled with an Ar/CF4 scintillating gas mixture, inside which two gas electron multiplier (GEM) structures are mounted (Seravalli et al 2008b Med. Phys. Biol. 53 4651-65). Photons emitted by the excited Ar/CF4 gas molecules during the gas multiplication in the GEM holes are detected by a mirror-lens-CCD camera system. The intensity distribution of the measured light spot is proportional to the 2D dose distribution. In this work, we report on the characterization of the scintillating GEM detector in terms of those properties that are of particular importance in relative dose measurements, e.g. response reproducibility, dose dependence, dose rate dependence, spatial and time response, field size dependence, response uniformity. The experiments were performed in a 150 MeV proton beam. We found that the detector response is very stable for measurements performed in succession (σ = 0.6%) and its response reproducibility over 2 days is about 5%. The detector response was found to be linear with the dose in the range 0.05-19 Gy. No dose rate effects were observed between 1 and 16 Gy min-1 at the shallow depth of a water phantom and 2 and 38 Gy min-1 at the Bragg peak depth. No field size effects were observed in the range 120-3850 mm2. A signal rise and fall time of 2 µs was recorded and a spatial response of <=1 mm was measured.
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

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.
Low dose evaluation of the antiandrogen flutamide following a Mode of Action approach.

PubMed

Sarrabay, A; Hilmi, C; Tinwell, H; Schorsch, F; Pallardy, M; Bars, R; Rouquié, D

2015-12-15

The dose-response characterization of endocrine mediated toxicity is an on-going debate which is controversial when exploring the nature of the dose-response curve and the effect at the low-end of the curve. To contribute to this debate we have assessed the effects of a wide range of dose levels of the antiandrogen flutamide (FLU) on 7-week male Wistar rats. FLU was administered by oral gavage at doses of 0, 0.001, 0.01, 0.1, 1 and 10mg/kg/day for 28 days. To evaluate the reproducibility, the study was performed 3 times. The molecular initiating event (MIE; AR antagonism), the key events (LH increase, Leydig cell proliferation and hyperplasia increases) and associated events involved in the mode of action (MOA) of FLU induced testicular toxicity were characterized to address the dose response concordance. Results showed no effects at low doses (<0.1mg/kg/day) for the different key events studied. The histopathological changes (Leydig cell hyperplasia) observed at 1 and 10mg/kg/day were associated with an increase in steroidogenesis gene expression in the testis from 1mg/kg/day, as well as an increase in testosterone blood level at 10mg/kg/day. Each key event dose-response was in good concordance with the MOA of FLU on the testis. From the available results, only monotonic dose-response curves were observed for the MIE, the key events, associated events and in effects observed in other sex related tissues. All the results, so far, show that the reference endocrine disruptor FLU induces threshold effects in a standard 28-day toxicity study on adult male rats. Copyright © 2015 Elsevier Inc. All rights reserved.
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.

PubMed

El-Khoueiry, Anthony B; Sangro, Bruno; Yau, Thomas; Crocenzi, Todd S; Kudo, Masatoshi; Hsu, Chiun; Kim, Tae-You; Choo, Su-Pin; Trojan, Jörg; Welling, Theodore H; Meyer, Tim; Kang, Yoon-Koo; Yeo, Winnie; Chopra, Akhil; Anderson, Jeffrey; Dela Cruz, Christine; Lang, Lixin; Neely, Jaclyn; Tang, Hao; Dastani, Homa B; Melero, Ignacio

2017-06-24

For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (≥18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0·1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. Bristol-Myers Squibb. Copyright © 2017 Elsevier Ltd. All rights reserved.
Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure–response relations from two phase II clinical trials

PubMed Central

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

2017-01-01

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

PubMed Central

Kimmel, Stephen E

2010-01-01

Background Warfarin therapy has been used clinically for over 60 years, yet continues to be problematic because of its narrow therapeutic index and large inter-individual variability in patient response. As a result, warfarin is a leading cause of serious medication-related adverse events, and its efficacy is also suboptimal. Objective To review factors that are responsible for variable response to warfarin, including clinical, environmental, and genetic factors, and to explore some possible approaches to improving warfarin therapy. Results Recent efforts have focused on developing dosing algorithms that included genetic information to try to improve warfarin dosing. These dosing algorithms hold promise, but have not been fully validated or tested in rigorous clinical trials. Perhaps equally importantly, adherence to warfarin is a major problem that should be addressed with innovative and cost-effective interventions. Conclusion Additional research is needed to further test whether interventions can be used to improve warfarin dosing and outcomes. PMID:18345947
Tremelimumab combined with durvalumab in patients with mesothelioma (NIBIT-MESO-1): an open-label, non-randomised, phase 2 study.

PubMed

Calabrò, Luana; Morra, Aldo; Giannarelli, Diana; Amato, Giovanni; D'Incecco, Armida; Covre, Alessia; Lewis, Arthur; Rebelatto, Marlon C; Danielli, Riccardo; Altomonte, Maresa; Di Giacomo, Anna Maria; Maio, Michele

2018-05-14

Tremelimumab, an anti-CTLA4 monoclonal antibody, initially showed good activity when used alone in patients with mesothelioma, but did not improve the overall survival of patients who failed on first-line or second-line chemotherapy compared with placebo in the DETERMINE study. We aimed to investigate the efficacy and safety of first-line or second-line tremelimumab combined with durvalumab, an anti-PD-L1 monoclonal antibody, in patients with malignant mesothelioma. In this open-label, non-randomised, phase 2 trial, patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. The primary endpoint was the proportion of patients with an immune-related objective response according to the immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST; for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma). The primary analysis was done by intention to treat, whereas the safety analysis included patients who received at least one dose of study drug. This trial is registered with the European Clinical Trials Database, number 2015-001995-23, and ClinicalTrials.gov, number NCT02588131, and is ongoing but no longer recruiting patients. From Oct 30, 2015, to Oct 12, 2016, 40 patients with mesothelioma were enrolled and received at least one dose each of tremelimumab and durvalumab. Patients were followed-up for a median of 19·2 months (IQR 13·8-20·5). 11 (28%) of 40 patients had an immune-related objective response (all partial responses; confirmed in ten patients), with a median response duration of 16·1 months (IQR 11·5-20·5). 26 (65%) patients had immune-related disease control and 25 (63%) had disease control. Median immune-related progression-free survival was 8·0 months (95% CI 6·7-9·3), median progression-free survival was 5·7 months (1·7-9·7), and median overall survival was 16·6 months (13·1-20·1). Baseline tumour PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related progression-free survival, or with overall survival. 30 (75%) patients experienced treatment-related adverse events of any grade, of whom seven (18%) had grade 3-4 treatment-related adverse events. Treatment-related toxicity was generally manageable and reversible with protocol guidelines. The combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration. Network Italiano per la Bioterapia dei Tumori Foundation, Associazione Italiana per la Ricerca sul Cancro, AstraZeneca, and Istituto Toscano Tumori. Copyright © 2018 Elsevier Ltd. All rights reserved.
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.
Dose-response study of spinal hyperbaric ropivacaine for cesarean section

PubMed Central

Chen, Xin-zhong; Chen, Hong; Lou, Ai-fei; Lü, Chang-cheng

2006-01-01

Background: Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind, randomized, dose-response study determined the ED50 (50% effective dose) and ED95 (95% effective dose) of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods: Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1~L2 vertebral interspace, then lumbar puncture was performed at the L3~L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels (pinprick) were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective if an upper sensory level to pin prick of T7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results: ED50 (95% confidence interval) of spinal hyperbaric ropivacaine was determined to be 10.37 (5.23~11.59) mg and ED95 (95% confidence interval) to be 15.39 (13.81~23.59) mg. The maximum sensory block levels and the duration of motor block and the rate of hypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion: The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery. PMID:17111469
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
Relative Biological Effectiveness of HZE Particles for Chromosomal Exchanges and Other Surrogate Cancer Risk Endpoints.

PubMed

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

2016-01-01

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

DOE PAGES

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

2016-04-25

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

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

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

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

EPA Science Inventory

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 w...
TH-E-BRF-04: Characterizing the Response of Texture-Based CT Image Features for Quantification of Radiation-Induced Normal Lung Damage

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

Krafft, S; Court, L; Briere, T

2014-06-15

Purpose: Radiation induced lung damage (RILD) is an important dose-limiting toxicity for patients treated with radiation therapy. Scoring systems for RILD are subjective and limit our ability to find robust predictors of toxicity. We investigate the dose and time-related response for texture-based lung CT image features that serve as potential quantitative measures of RILD. Methods: Pre- and post-RT diagnostic imaging studies were collected for retrospective analysis of 21 patients treated with photon or proton radiotherapy for NSCLC. Total lung and selected isodose contours (0–5, 5–15, 15–25Gy, etc.) were deformably registered from the treatment planning scan to the pre-RT and availablemore » follow-up CT studies for each patient. A CT image analysis framework was utilized to extract 3698 unique texture-based features (including co-occurrence and run length matrices) for each region of interest defined by the isodose contours and the total lung volume. Linear mixed models were fit to determine the relationship between feature change (relative to pre-RT), planned dose and time post-RT. Results: Seventy-three follow-up CT scans from 21 patients (median: 3 scans/patient) were analyzed to describe CT image feature change. At the p=0.05 level, dose affected feature change in 2706 (73.1%) of the available features. Similarly, time affected feature change in 408 (11.0%) of the available features. Both dose and time were significant predictors of feature change in a total of 231 (6.2%) of the extracted image features. Conclusion: Characterizing the dose and time-related response of a large number of texture-based CT image features is the first step toward identifying objective measures of lung toxicity necessary for assessment and prediction of RILD. There is evidence that numerous features are sensitive to both the radiation dose and time after RT. Beyond characterizing feature response, further investigation is warranted to determine the utility of these features as surrogates of clinically significant lung injury.« less
Effects of levodopa-carbidopa-entacapone and smoked cocaine on facial affect recognition in cocaine smokers.

PubMed

Bedi, Gillinder; Shiffrin, Laura; Vadhan, Nehal P; Nunes, Edward V; Foltin, Richard W; Bisaga, Adam

2016-04-01

In addition to difficulties in daily social functioning, regular cocaine users have decrements in social processing (the cognitive and affective processes underlying social behavior) relative to non-users. Little is known, however, about the effects of clinically-relevant pharmacological agents, such as cocaine and potential treatment medications, on social processing in cocaine users. Such drug effects could potentially alleviate or compound baseline social processing decrements in cocaine abusers. Here, we assessed the individual and combined effects of smoked cocaine and a potential treatment medication, levodopa-carbidopa-entacapone (LCE), on facial emotion recognition in cocaine smokers. Healthy non-treatment-seeking cocaine smokers (N = 14; two female) completed this 11-day inpatient within-subjects study. Participants received LCE (titrated to 400mg/100mg/200mg b.i.d.) for five days with the remaining time on placebo. The order of medication administration was counterbalanced. Facial emotion recognition was measured twice during target LCE dosing and twice on placebo: once without cocaine and once after repeated cocaine doses. LCE increased the response threshold for identification of facial fear, biasing responses away from fear identification. Cocaine had no effect on facial emotion recognition. Results highlight the possibility for candidate pharmacotherapies to have unintended impacts on social processing in cocaine users, potentially exacerbating already existing difficulties in this population. © The Author(s) 2016.
Development of an enzyme-linked immunosorbent assay for the serological detection of exposure of poultry in New Zealand to Erysipelothrix rhusiopathiae and their serological response to vaccination.

PubMed

Kurian, A; Neumann, E J; Hall, W F; Christensen, N

2012-03-01

To modify and validate an existing swine erysipelas ELISA for use with poultry serum and to assess the safety of a swine erysipelas vaccine for use in New Zealand layer birds. An existing swine erysipelas ELISA was modified for use in domestic poultry and was validated using sera from birds injected with either 2 mL of a commercially available killed swine erysipelas vaccine (low-dose; n=12 birds), 4 mL of vaccine (high-dose; n=11 birds), or 2 mL saline (control; n=11 birds) on Day 0 and again on Day 21. Blood samples were collected on Days 0, 21, 42, and 63, and safety of the vaccine for use in layer birds was determined by assessing cloacal temperature and injection site reactions in birds at 0, 4, 24, 48, 72 and 96 h post-vaccination. The ELISA that was developed had a diagnostic sensitivity and specificity of 93% and 98%, respectively, after being optimised for a positive cut-off at an optical density (OD) ≥ 1.50 read at 450-nm wavelength. OD readings were higher on Days 21, 42, and 63 than Day 0 in both the low-dose and high-dose groups (p<0.05), and differed amongst the three groups on Days 21, 42, and 63 (p<0.05), suggesting that vaccination using either dose induced detectable levels of antibody, even after a single dose. In addition, the high-dose protocol induced higher levels of antibody production than the low-dose protocol. No local or systemic reactions to the vaccine were observed and cloacal temperatures remained in the normal biological range after vaccination. The ELISA that was developed had satisfactory diagnostic performance characteristics and the vaccine appeared to be safe for use in layer birds. However, the study design did not permit an assessment of the vaccine's efficacy to protect birds from clinical erysipelas. A diagnostic ELISA has been developed for determining the exposure of layer birds to E. rhusiopathiae. The test will be useful for monitoring flock-level erysipelas, response to vaccination, and in epidemiological studies designed to identify risk factors for exposure to the disease.
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.
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.
Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro.

PubMed

Nicholson, S A; Adrian, T E; Gillham, B; Jones, M T; Bloom, S R

1984-02-01

The effect of six hypothalamic peptides on the basal release of ACTH and that induced by arginine vasopressin (AVP) or by ovine corticotrophin releasing factor (oCRF) from fragments of the rat anterior pituitary gland incubated in vitro was investigated. Dose-response curves to AVP and to oCRF were obtained, and the response to a low dose of oCRF was potentiated by a low dose of AVP. Basal release of ACTH was not affected by any of the peptides in concentrations in the range 10(-12) to 10(-6) mol/l, and only substance P (SP) and somatostatin (SRIF) inhibited significantly the response to oCRF in a dose-related manner. The responses to a range of doses of oCRF or AVP were reduced by 10(-8) and 10(-6) mol SP or SRIF/l, and to a greater extent by the higher dose. Except in the case of 10(-6) mol SRIF/l on the response to AVP, the response was not further diminished by preincubation of the tissue with the peptide before the stimulating agent was added. The inhibition of the responses to AVP or oCRF by 10(-9) mol SP/l was not potentiated by its combination with either 5 X 10(-10) or 10(-8) mol SRIF/l; the inhibitory effects were merely additive. The results suggest that although SRIF and SP are able to modulate the release of ACTH from the anterior pituitary gland, they do so only at a high concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related dose response of selected reproductive parameters to acute cadmium chloride exposure in the male Long-Evans rat

EPA Science Inventory

Groups of Long Evans rats 30, 50, or 70 days old were injected subcutaneously (s.c.) with a single dose of between 0 and 52 micromoles Cd/Kg as cadmium (CD) chloride. Sixty days post dosing and two hours prior to sacrifice the rats were injected s.c. with 100 IU of hCG to stimula...
Dose-Response Relationship between Cumulative Occupational Lead Exposure and the Associated Health Damages: A 20-Year Cohort Study of a Smelter in China

PubMed Central

Wu, Yue; Gu, Jun-Ming; Huang, Yun; Duan, Yan-Ying; Huang, Rui-Xue; Hu, Jian-An

2016-01-01

Long-term airborne lead exposure, even below official occupational limits, has been found to cause lead poisoning at higher frequencies than expected, which suggests that China’s existing occupational exposure limits should be reexamined. A retrospective cohort study was conducted on 1832 smelting workers from 1988 to 2008 in China. These were individuals who entered the plant and came into continuous contact with lead at work for longer than 3 months. The dose-response relationship between occupational cumulative lead exposure and lead poisoning, abnormal blood lead, urinary lead and erythrocyte zinc protoporphyrin (ZPP) were analyzed and the benchmark dose lower bound confidence limits (BMDLs) were calculated. Statistically significant positive correlations were found between cumulative lead dust and lead fumes exposures and workplace seniority, blood lead, urinary lead and ZPP values. A dose-response relationship was observed between cumulative lead dust or lead fumes exposure and lead poisoning (p < 0.01). The BMDLs of the cumulative occupational lead dust and fumes doses were 0.68 mg-year/m3 and 0.30 mg-year/m3 for lead poisoning, respectively. The BMDLs of workplace airborne lead concentrations associated with lead poisoning were 0.02 mg/m3 and 0.01 mg/m3 for occupational exposure lead dust and lead fume, respectively. In conclusion, BMDLs for airborne lead were lower than occupational exposure limits, suggesting that the occupational lead exposure limits need re-examination and adjustment. Occupational cumulative exposure limits (OCELs) should be established to better prevent occupational lead poisoning. PMID:26999177
Dose-response relations between second-hand smoke exposure and depressive symptoms among middle-aged women.

PubMed

Ye, Xiaohua; Li, LiXia; Gao, Yanhui; Zhou, Shudong; Yang, Yi; Chen, Sidong

2015-09-30

A growing body of evidence indicates a strong association between smoking and depression. However, little is known about the possible effects of second-hand smoke (SHS) exposure on depression. This study aimed to examine the potential dose-response relation between SHS exposure and depressive symptoms among non-smoking middle-aged women. A cross-sectional survey was conducted using a stratified three-stage sampling method. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale with a cut-off point of 16. Self-reported SHS exposure was defined as non-smokers׳ inhalation of the smoke exhaled from smokers on at least one day a week. The multivariable logistic regression analysis was completed with adjustment for potential confounders. Among 1280 middle-aged women, 19.4% were classified as having depressive symptoms. There was a 104% increased odds of depressive symptoms corresponding to SHS exposure in general (OR=2.04, 95% CI 1.48-2.79) using no exposure as reference. There were significant positive relations between SHS exposure in general and depressive symptoms in a dose-response manner. These significant trends were observed consistently whether SHS exposure occurred in homes or workplaces. Our findings suggest that long-term and regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Trigeminal Neuralgia Treated With Stereotactic Radiosurgery: The Effect of Dose Escalation on Pain Control and Treatment Outcomes

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

Kotecha, Rupesh; Kotecha, Ritesh; Modugula, Sujith

Purpose: To analyze the effect of dose escalation on treatment outcome in patients undergoing stereotactic radiosurgery (SRS) for trigeminal neuralgia (TN). Methods and Materials: A retrospective review was performed of 870 patients who underwent SRS for a diagnosis of TN from 2 institutions. Patients were typically treated using a single 4-mm isocenter placed at the trigeminal nerve dorsal root entry zone. Patients were divided into groups based on treatment doses: ≤82 Gy (352 patients), 83 to 86 Gy (85 patients), and ≥90 Gy (433 patients). Pain response was classified using a categorical scoring system, with fair or poor pain control representing treatment failure.more » Treatment-related facial numbness was classified using the Barrow Neurological Institute scale. Log-rank tests were performed to test differences in time to pain failure or development of facial numbness for patients treated with different doses. Results: Median age at first pain onset was 63 years, median age at time of SRS was 71 years, and median follow-up was 36.5 months from the time of SRS. A majority of patients (827, 95%) were clinically diagnosed with typical TN. The 4-year rate of excellent to good pain relief was 87% (95% confidence interval 84%-90%). The 4-year rate of pain response was 79%, 82%, and 92% in patients treated to ≤82 Gy, 83 to 86 Gy, and ≥90 Gy, respectively. Patients treated to doses ≤82 Gy had an increased risk of pain failure after SRS, compared with patients treated to ≥90 Gy (hazard ratio 2.0, P=.0007). Rates of treatment-related facial numbness were similar among patients treated to doses ≥83 Gy. Nine patients (1%) were diagnosed with anesthesia dolorosa. Conclusions: Dose escalation for TN to doses >82 Gy is associated with an improvement in response to treatment and duration of pain relief. Patients treated at these doses, however, should be counseled about the increased risk of treatment-related facial numbness.« less
Low doses of fludrocortisone and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers

PubMed Central

Laviolle, Bruno; Donal, Erwan; Le Maguet, Pascale; Lainé, Fabrice; Bellissant, Eric

2013-01-01

Aims A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for fludrocortisone. Since there continues to be disagreement about the utility of fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and fludrocortisone (50 μg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose–response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. Methods This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 × 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then fludrocortisone 50 μg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 μg kg−1 min−1), each dose being infused during 5 min. Results Both fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (fludrocortisone × hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. Conclusions Single administrations of fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo-aldosteronism. These similar effects of hydrocortisone and fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading. PMID:22703532
A new way of thinking: hydrocortisone in traumatic brain-injured patients.

PubMed

Roquilly, Antoine; Vourc'h, Mickael; Cinotti, Raphael; Asehnoune, Karim

2013-12-04

Data suggest that treatment of critical illness-related corticosteroid insufficiency after traumatic brain injury (TBI) with a stress dose of hydrocortisone may improve the neurological outcome and the mortality rate. The mineralocorticoid properties of hydrocortisone may reduce the rate of hyponatremia and of brain swelling. The exaggerated inflammatory response may cause critical illness-related corticosteroid insufficiency by altering the function of the hypothalamic-pituitary-adrenal axis, and hydrocortisone is able to restore a balanced inflammatory response rather than inducing immunosuppression. Hydrocortisone could also prevent neuronal apoptosis. Considering side effects, corticosteroids are not equal; when a high dose of synthetic corticosteroids seems detrimental, a strategy using a stress dose of hydrocortisone seems attractive. Finally, results from a large multicenter study are needed to close the debate regarding the use of hydrocortisone in TBI patients.
Fulminant 2-chlorodeoxyadenosine-related peripheral neuropathy in a patient with paraneoplastic neurological syndrome associated with lymphoma.

PubMed

Warzocha, K; Krykowksi, E; Góra-Tybor, J; Fronczak, A; Robak, T

1996-04-01

2-chlorodeoxyadenosine (2-CdA) has been demonstrated to be a neurotoxic agent when used at significantly greater doses than currently recommended for clinical use. In this report we describe a case of a 37-years-old man lymphoplasmacytoid malignant lymphoma and pre-existing paraneoplastic neurological syndrome who died of an apparent rapidly progressive sensorimotor peripheral neuropathy after completing treatment with two courses of low-doses of 2-CdA.
SU-C-16A-02: A Beryllium Oxide (BeO) Fibre-Coupled Luminescence Dosimeter for High Dose Rate Brachytherapy

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

Santos, A; Institute for Photonics and Advanced Sensing and School of Chem and Phys, Adelaide, South Australia; Mohammadi, M

Purpose: Beryllium oxide (BeO) ceramics have an effective atomic number, zeff ∼7.1, closely matched to water, zeff ∼7.4. The purpose of this study was to evaluate the use of a beryllium oxide (BeO) ceramic fibrecoupled luminescence dosimeter, named RL/OSL BeO FOD, for high dose rate (HDR) brachytherapy dosimetry. In our dosimetry system the radioluminescence (RL) of BeO ceramics is utilized for dose-rate measurements, and the optically stimulated luminescence (OSL) can be read post exposure for accumulated dose measurements. Methods: The RL/OSL BeO FOD consists of a 1 mm diameter × 1 mm long cylinder of BeO ceramic coupled to amore » 15 m long silica-silica optical fibre. The optical fibre is connected to a custom developed portable RL and OSL reader, located outside of the treatment suite. The x-ray energy response was evaluated using superficial x-rays, an Ir-192 source and high energy linear accelerators. The RL/OSL BeO FOD was then characterised for an Ir-192 source, investigating the dose response and angular dependency. A depth dose curve for the Ir-192 source was also measured. Results: The RL/OSL BeO FOD shows an under-response at low energy x-rays as expected. Though at higher x-ray energies, the OSL response continued to increase, while the RL response remained relatively constant. The dose response for the RL is found to be linear up to doses of 15 Gy, while the OSL response becomes more supralinear to doses above 15 Gy. Little angular dependency is observed and the depth dose curve measured agreed within 4% of that calculated based on TG-43. Conclusion: This works shows that the RL/OSL BeO FOD can be useful in HDR dosimetry. With the RL/OSL BeO FODs current size, it is capable of being inserted into intraluminal catheters and interstitial needles to verify HDR treatments.« less
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.
Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo

PubMed Central

Koskiniemi, M.; Van Vleymen, B.; Hakamies, L.; Lamusuo, S.; Taalas, J.

1998-01-01

OBJECTIVE—To compare the efficacy, tolerability, and safety of three daily dosage regimens of oral piracetam in patients with progressive myoclonus epilepsy. METHODS—Twenty patients (12 men, eight women), aged 17-43 years, with classical Unverricht-Lundborg disease were enrolled in a multicentre, randomised, double blind trial of crossover design in which the effects of daily doses of 9.6 g, 16.8 g, and 24 g piracetam, given in two divided doses, were compared with placebo. The crossover design was such that patients received placebo and two of the three dosage regimens of piracetam, each for two weeks, for a total treatment period of six weeks and thus without wash out between each treatment phase. The primary outcome measure was a sum score representing the adjusted total of the ratings of six components of a myoclonus rating scale in which stimulus sensitivity, motor impairment, functional disability, handwriting, and global assessments by investigators and patients were scored. Sequential clinical assessments were made by the same neurologist in the same environment at the same time of day. RESULTS—Treatment with 24 g/day piracetam produced significant and clinically relevant improvement in the primary outcome measure of mean sum score (p=0.005) and in the means of its subtests of motor impairment (p=0.02), functional disability (p=0.003), and in global assessments by both investigator (p=0.002) and patient (p=0.01). Significant improvement in functional disability was also found with daily doses of 9.6 g and 16.8 g. The dose-effect relation was linear and significant. More patients showed clinically relevant improvement with the highest dosage and, in individual patients, increasing the dose improved response. Piracetam was well tolerated and adverse effects were few, mild, and transient. CONCLUSIONS—This study provides further evidence that piracetam is an effective and safe medication in patients with Unverricht-Lundborg disease. In addition, it shows that a dose of 24 g is highly beneficial, more effective than lower doses and that a dose-effect relation exists. There is considerable variation in optimal individual dosage.   PMID:9527146
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.
Dose-response curve of EBT, EBT2, and EBT3 radiochromic films to synchrotron-produced monochromatic x-ray beams

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

Brown, Thomas A. D.; Hogstrom, Kenneth R.; Alvarez, Diane

Purpose: This work investigates the dose-response curves of GAFCHROMIC{sup Registered-Sign} EBT, EBT2, and EBT3 radiochromic films using synchrotron-produced monochromatic x-ray beams. EBT2 film is being utilized for dose verification in photoactivated Auger electron therapy at the Louisiana State University Center for Advanced Microstructures and Devices (CAMD) synchrotron facility. Methods: Monochromatic beams of 25, 30, and 35 keV were generated on the tomography beamline at CAMD. Ion chamber depth-dose measurements were used to determine the dose delivered to films irradiated at depths from 0.7 to 8.5 cm in a 10 Multiplication-Sign 10 Multiplication-Sign 10-cm{sup 3} polymethylmethacrylate phantom. AAPM TG-61 protocol wasmore » applied to convert measured ionization into dose. Films were digitized using an Epson 1680 Professional flatbed scanner and analyzed using the net optical density (NOD) derived from the red channel. A dose-response curve was obtained at 35 keV for EBT film, and at 25, 30, and 35 keV for EBT2 and EBT3 films. Calibrations of films for 4 MV x-rays were obtained for comparison using a radiotherapy accelerator at Mary Bird Perkins Cancer Center. Results: The sensitivity (NOD per unit dose) of EBT film at 35 keV relative to that for 4-MV x-rays was 0.73 and 0.76 for doses 50 and 100 cGy, respectively. The sensitivity of EBT2 film at 25, 30, and 35 keV relative to that for 4-MV x-rays varied from 1.09-1.07, 1.23-1.17, and 1.27-1.19 for doses 50-200 cGy, respectively. For EBT3 film the relative sensitivity was within 3% of unity for all three monochromatic x-ray beams. Conclusions: EBT and EBT2 film sensitivity showed strong energy dependence over an energy range of 25 keV-4 MV, although this dependence becomes weaker for larger doses. EBT3 film shows weak energy dependence, indicating that it would be a better dosimeter for kV x-ray beams where beam hardening effects can result in large changes in the effective energy.« less
Psychopharmacology of theobromine in healthy volunteers.

PubMed

Baggott, Matthew J; Childs, Emma; Hart, Amy B; de Bruin, Eveline; Palmer, Abraham A; Wilkinson, Joy E; de Wit, Harriet

2013-07-01

Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, current evidence for this is limited. We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1,000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Caffeine had the expected effects on mood including feelings of alertness and cardiovascular parameters. Theobromine responses differed according to dose; it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses, we also examined individual differences in the drug's effects in relation to genes related to their target receptors, but few associations were detected. This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes, effects become negative.
Psychopharmacology of theobromine in healthy volunteers

PubMed Central

Baggott, Matthew J.; Childs, Emma; Hart, Amy B.; de Bruin, Eveline; Palmer, Abraham A.; Wilkinson, Joy E.; de Wit, Harriet

2013-01-01

Background Theobromine, a methylxanthine related to caffeine and present in high levels in cocoa, may contribute to the appeal of chocolate. However, currently evidence for this is limited. Objectives We conducted a within-subjects placebo-controlled study of a wide range of oral theobromine doses (250, 500, and 1000 mg) using an active control dose of caffeine (200 mg) in 80 healthy participants. Results Caffeine had the expected effects on mood including feelings of alertness, and cardiovascular parameters. Theobromine responses differed according to dose: it showed limited subjective effects at 250 mg and negative mood effects at higher doses. It also dose-dependently increased heart rate. In secondary analyses we also examined individual differences in the drugs' effects in relation to genes related to their target receptors, but few associations were detected. Conclusions This study represents the highest dose of theobromine studied in humans. We conclude that theobromine at normal intake ranges may contribute to the positive effects of chocolate, but at higher intakes effects become negative. PMID:23420115
BMDExpress Data Viewer - A visualization Tool to Analyze BMDExpress Datasets (Health Canada Science Forum)

EPA Science Inventory

Benchmark Dose (BMD) modelling is a mathematical approach used to determine where a dose-response change begins to take place relative to controls following chemical exposure. BMDs are being increasingly applied in regulatory toxicology to determine points of departure. BMDExpres...
Development and characterization of a three-dimensional radiochromic film stack dosimeter for megavoltage photon beam dosimetry

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

McCaw, Travis J., E-mail: mccaw@wisc.edu; Micka, John A.; DeWerd, Larry A.

Purpose: Three-dimensional (3D) dosimeters are particularly useful for verifying the commissioning of treatment planning and delivery systems, especially with the ever-increasing implementation of complex and conformal radiotherapy techniques such as volumetric modulated arc therapy. However, currently available 3D dosimeters require extensive experience to prepare and analyze, and are subject to large measurement uncertainties. This work aims to provide a more readily implementable 3D dosimeter with the development and characterization of a radiochromic film stack dosimeter for megavoltage photon beam dosimetry. Methods: A film stack dosimeter was developed using Gafchromic{sup ®} EBT2 films. The dosimeter consists of 22 films separated bymore » 1 mm-thick spacers. A Virtual Water™ phantom was created that maintains the radial film alignment within a maximum uncertainty of 0.3 mm. The film stack dosimeter was characterized using simulations and measurements of 6 MV fields. The absorbed-dose energy dependence and orientation dependence of the film stack dosimeter were investigated using Monte Carlo simulations. The water equivalence of the dosimeter was determined by comparing percentage-depth-dose (PDD) profiles measured with the film stack dosimeter and simulated using Monte Carlo methods. Film stack dosimeter measurements were verified with thermoluminescent dosimeter (TLD) microcube measurements. The film stack dosimeter was also used to verify the delivery of an intensity-modulated radiation therapy (IMRT) procedure. Results: The absorbed-dose energy response of EBT2 film differs less than 1.5% between the calibration and film stack dosimeter geometries for a 6 MV spectrum. Over a series of beam angles ranging from normal incidence to parallel incidence, the overall variation in the response of the film stack dosimeter is within a range of 2.5%. Relative to the response to a normally incident beam, the film stack dosimeter exhibits a 1% under-response when the beam axis is parallel to the film planes. Measured and simulated PDD profiles agree within a root-mean-square difference of 1.3%. In-field film stack dosimeter and TLD measurements agree within 5%, and measurements in the field penumbra agree within 0.5 mm. Film stack dosimeter and TLD measurements have expanded (k = 2) overall measurement uncertainties of 6.2% and 5.8%, respectively. Film stack dosimeter measurements of an IMRT dose distribution have 98% agreement with the treatment planning system dose calculation, using gamma criteria of 3% and 2 mm. Conclusions: The film stack dosimeter is capable of high-resolution, low-uncertainty 3D dose measurements, and can be readily incorporated into an existing film dosimetry program.« less
An algorithm for intelligent sorting of CT-related dose parameters.

PubMed

Cook, Tessa S; Zimmerman, Stefan L; Steingall, Scott R; Boonn, William W; Kim, Woojin

2012-02-01

Imaging centers nationwide are seeking innovative means to record and monitor computed tomography (CT)-related radiation dose in light of multiple instances of patient overexposure to medical radiation. As a solution, we have developed RADIANCE, an automated pipeline for extraction, archival, and reporting of CT-related dose parameters. Estimation of whole-body effective dose from CT dose length product (DLP)--an indirect estimate of radiation dose--requires anatomy-specific conversion factors that cannot be applied to total DLP, but instead necessitate individual anatomy-based DLPs. A challenge exists because the total DLP reported on a dose sheet often includes multiple separate examinations (e.g., chest CT followed by abdominopelvic CT). Furthermore, the individual reported series DLPs may not be clearly or consistently labeled. For example, "arterial" could refer to the arterial phase of the triple liver CT or the arterial phase of a CT angiogram. To address this problem, we have designed an intelligent algorithm to parse dose sheets for multi-series CT examinations and correctly separate the total DLP into its anatomic components. The algorithm uses information from the departmental PACS to determine how many distinct CT examinations were concurrently performed. Then, it matches the number of distinct accession numbers to the series that were acquired and anatomically matches individual series DLPs to their appropriate CT examinations. This algorithm allows for more accurate dose analytics, but there remain instances where automatic sorting is not feasible. To ultimately improve radiology patient care, we must standardize series names and exam names to unequivocally sort exams by anatomy and correctly estimate whole-body effective dose.
An algorithm for intelligent sorting of CT-related dose parameters

NASA Astrophysics Data System (ADS)

Cook, Tessa S.; Zimmerman, Stefan L.; Steingal, Scott; Boonn, William W.; Kim, Woojin

2011-03-01

Imaging centers nationwide are seeking innovative means to record and monitor CT-related radiation dose in light of multiple instances of patient over-exposure to medical radiation. As a solution, we have developed RADIANCE, an automated pipeline for extraction, archival and reporting of CT-related dose parameters. Estimation of whole-body effective dose from CT dose-length product (DLP)-an indirect estimate of radiation dose-requires anatomy-specific conversion factors that cannot be applied to total DLP, but instead necessitate individual anatomy-based DLPs. A challenge exists because the total DLP reported on a dose sheet often includes multiple separate examinations (e.g., chest CT followed by abdominopelvic CT). Furthermore, the individual reported series DLPs may not be clearly or consistently labeled. For example, Arterial could refer to the arterial phase of the triple liver CT or the arterial phase of a CT angiogram. To address this problem, we have designed an intelligent algorithm to parse dose sheets for multi-series CT examinations and correctly separate the total DLP into its anatomic components. The algorithm uses information from the departmental PACS to determine how many distinct CT examinations were concurrently performed. Then, it matches the number of distinct accession numbers to the series that were acquired, and anatomically matches individual series DLPs to their appropriate CT examinations. This algorithm allows for more accurate dose analytics, but there remain instances where automatic sorting is not feasible. To ultimately improve radiology patient care, we must standardize series names and exam names to unequivocally sort exams by anatomy and correctly estimate whole-body effective dose.
Low- and high-dose laser irradiation effects on cell migration and destruction

NASA Astrophysics Data System (ADS)

Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

2018-02-01

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.
Radiation exposure from work-related medical X-rays at the Portsmouth Naval Shipyard.

PubMed

Daniels, Robert D; Kubale, Travis L; Spitz, Henry B

2005-03-01

Previous analyses suggest that worker radiation dose may be significantly increased by routine occupational X-ray examinations. Medical exposures are investigated for 570 civilian workers employed at the Portsmouth Naval Shipyard (PNS) at Kittery, Maine. The research objective was to determine the radiation exposure contribution of work-related chest X-rays (WRX) relative to conventional workplace radiation sources. Methods were developed to estimate absorbed doses to the active (hematopoietic) bone marrow from X-ray examinations and workplace exposures using data extracted from worker dosimetry records (8,468) and health records (2,453). Dose distributions were examined for radiation and non-radiation workers. Photofluorographic chest examinations resulted in 82% of the dose from medical sources. Radiation workers received 26% of their collective dose from WRX and received 66% more WRX exposure than non-radiation workers. WRX can result in a significant fraction of the total dose, especially for radiation workers who were more likely to be subjected to routine medical monitoring. Omission of WRX from the total dose is a likely source of bias that can lead to dose category misclassification and may skew the epidemiologic dose-response assessment for cancers induced by the workplace.

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

PubMed

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

2016-12-01

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

NASA Astrophysics Data System (ADS)

Van Uffelen, Marco; Berghmans, Francis; Brichard, Benoit; Borgermans, Paul; Decréton, Marc C.

2002-09-01

Optical fibers stimulate much interest since many years for their potential use in various nuclear environments, both for radiation tolerant and EMI-free data communication as well as for distributed sensing. Besides monitoring temperature and stress, measuring ionizing doses with optical fibers is particularly essential in applications such as long-term nuclear waste disposal monitoring, and for real-time aging monitoring of power and signal cables installed inside a reactor containment building. Two distinct options exist to perform optical fiber dosimetry. First, find an accurate model for a restricted application field that accounts for all the parameters that influence the radiation response of a standard fiber, or second, develop a dedicated fiber with a response that will solely depend on the deposited energy. Using various models presented in literature, we evaluate both standard commercially available and custom-made optical fibers under gamma radiation, particularly for distributed dosimetry applications with an optical time domain reflectometer (OTDR). We therefore present the radiation induced attenuation at near-infrared telecom wavelengths up to MGy total dose levels, with dose rates ranging from about 1 Gy/h up to 1 kGy/h, whereas temperature was raised step-wise from 25 °C to 85 °C. Our results allow to determine and compare the practical limitations of distributed dose measurements with both fiber types in terms of temperature sensitivity, dose estimation accuracy and spatial resolution.
A phase I human trial of mitoguazone and gemcitabine sequential bi-weekly treatment of cancer patients.

PubMed

Ishmael, D Richard; Chen, Wei R; Hamilton, Steven A; Liu, Hong; Nordquist, Robert E

2003-01-01

Our previous studies have demonstrated the existence of synergism in a combination therapy using mitoguazone and gemcitabine when the mitoguazone is administered 24 hours before gemcitabine. Based on the cell culture and animal experimental results, a phase I clinical trial was performed in order to determine the toxicity of the combined treatment. Mitoguazone and gemcitabine were administered sequentially: mitoguazone on day 1 and gemcitabine on day 2. This cycle was repeated every 2 weeks. The dosages of these two drugs were varied between patients. Ten patients were enrolled in the study. Six patients began treatment at dose level 1 (mitoguazone 500 mg/m2, gemcitabine 1500 mg/m2), three at dose level 2 (mitoguazone 500 mg/m2, gemcitabine 2000 mg/m2), and one at dose level 3 (mitoguazone 600 mg/m2, gemcitabine 2000 mg/m2). Dose-limiting toxicity (DLT) was only observed in two patients treated at dose level 1 and one patient treated at dose level 3, while all the other patients only experienced nonhematologic toxicity, such as asthenia and mucositis. Two melanoma patients showed responses (one partial and one minor) to the treatment. One lymphoma patient also showed a brief partial response. This phase I trial indicated that the combination of mitoguazone and gemcitabine had limited but noticeable activity for treatment of cancer patients. Further study on the toxicity and on the effect of the scheduled mitoguazone-gemcitabine combination is needed.
Advanced Computational Approaches for Characterizing Stochastic Cellular Responses to Low Dose, Low Dose Rate Exposures

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

Scott, Bobby, R., Ph.D.

2003-06-27

OAK - B135 This project final report summarizes modeling research conducted in the U.S. Department of Energy (DOE), Low Dose Radiation Research Program at the Lovelace Respiratory Research Institute from October 1998 through June 2003. The modeling research described involves critically evaluating the validity of the linear nonthreshold (LNT) risk model as it relates to stochastic effects induced in cells by low doses of ionizing radiation and genotoxic chemicals. The LNT model plays a central role in low-dose risk assessment for humans. With the LNT model, any radiation (or genotoxic chemical) exposure is assumed to increase one¡¯s risk of cancer.more » Based on the LNT model, others have predicted tens of thousands of cancer deaths related to environmental exposure to radioactive material from nuclear accidents (e.g., Chernobyl) and fallout from nuclear weapons testing. Our research has focused on developing biologically based models that explain the shape of dose-response curves for low-dose radiation and genotoxic chemical-induced stochastic effects in cells. Understanding the shape of the dose-response curve for radiation and genotoxic chemical-induced stochastic effects in cells helps to better understand the shape of the dose-response curve for cancer induction in humans. We have used a modeling approach that facilitated model revisions over time, allowing for timely incorporation of new knowledge gained related to the biological basis for low-dose-induced stochastic effects in cells. Both deleterious (e.g., genomic instability, mutations, and neoplastic transformation) and protective (e.g., DNA repair and apoptosis) effects have been included in our modeling. Our most advanced model, NEOTRANS2, involves differing levels of genomic instability. Persistent genomic instability is presumed to be associated with nonspecific, nonlethal mutations and to increase both the risk for neoplastic transformation and for cancer occurrence. Our research results, based on applications of NEOTRANS2, indicate that nonlinear threshold-type, dose-response relationships for excess stochastic effects (problematic nonlethal mutations, neoplastic transformation) should be expected after exposure to low linear energy transfer (LET) gamma rays or gamma rays in combination with high-LET alpha radiation. Similar thresholds are expected for low-dose-rate low-LET beta irradiation. We attribute the thresholds to low-dose, low-LET radiation induced protection against spontaneous mutations and neoplastic transformations. The protection is presumed mainly to involve selective elimination of problematic cells via apoptosis. Low-dose, low-LET radiation is presumed to trigger wide-area cell signaling, which in turn leads to problematic bystander cells (e.g., mutants, neoplastically transformed cells) selectively undergoing apoptosis. Thus, this protective bystander effect leads to selective elimination of problematic cells (a tissue cleansing process in vivo). However, this protective bystander effects is a different process from low-dose stimulation of the immune system. Low-dose, low-LET radiation stimulation of the immune system may explain why thresholds for inducing excess cancer appear much larger (possibly more than 100-fold larger) than thresholds for inducing excess mutations and neoplastic transformations, when the dose rate is low. For ionizing radiation, the current risk assessment paradigm is such that the relative risk (RR) is always ¡Ý 1, no matter how small the dose. Our research results indicate that for low-dose or low-dose-rate, low-LET irradiation, RR < 1 may be more the rule than the exception. Directly tied to the current RR paradigm are the billion-dollar cleanup costs for radionuclide-contaminated DOE sites. Our research results suggest that continued use of the current RR paradigm for which RR ¡Ý 1 could cause more harm than benefit to society (e.g., by spreading unwarranted fear about phantom excess risks associated with low-dose low-LET radiation). Such phantom risks also may arise from risk assessments conducted for combined exposure to low- and high-LET radiations when based on the LNT or other models that exclude RR < 1. Our results for high-LET radiation are consistent with the LNT hypothesis but only where there is no additional low-LET contribution (e.g., gamma rays) to the total dose. For high-LET neutron sources, gamma rays arise (especially in vivo) for large mammals such as humans from neutron interactions with tissue. The gamma rays might provide some protection from low-dose-related stochastic effects via inducing the protective bystander apoptosis effect that is considered to contribute to tissue cleansing via removal of problematic cells.« less
Intravenous gammaglobulin treatment for immune thrombocytopenia associated with infectious mononucleosis.

PubMed

Cyran, E M; Rowe, J M; Bloom, R E

1991-10-01

Severe thrombocytopenia is an uncommon (incidence less than 1%) but serious complication of infectious mononucleosis. Corticosteroids have been used for therapy with variable responses reported. Five consecutive patients with infectious mononucleosis-related severe thrombocytopenia were treated with intravenous gammaglobulin (IVIG) at a dose of 400 mg/kg/day for 2-5 days. All patients appear to have had an immunologic or consumptive etiology for their thrombocytopenia as determined by increased marrow megakaryocytes. All patients were initially treated with oral prednisone 1 mg/kg/day. Due to the relatively slow response to prednisone (platelet count less than 20,000/microliters on the 8th to 13th hospital day) or increased bleeding symptoms, IVIG was initiated. Four of the five patients rapidly developed significant increases in their platelet counts (range 44,000/microliters to 97,000/microliters). Two of these responses were sustained and two relapses occurred (while on continued steroid therapy) which again responded to booster doses of IVIG at similar doses. IVIG has been previously shown to be effective in treating patients with idiopathic thrombocytopenia purpura. Historically, patients with infectious mononucleosis-related severe thrombocytopenia often are refractory to corticosteroid therapy and our limited experience suggests that IVIG may also be effective in infectious mononucleosis-related severe thrombocytopenia.
Case-control study of urinary bladder cancer in metropolitan Nagoya.

PubMed

Ohno, Y; Aoki, K; Obata, K; Morrison, A S

1985-12-01

We conducted a population-based case-control study of patients with bladder cancer and of controls drawn randomly from the general population of Metropolitan Nagoya and interviewed both groups. The incidence rates of bladder cancer were 2.42 and 7.05/100,000 for females and males, respectively. The analysis, based on 293 patients and 589 controls who were frequency matched for age, sex, and residence, provided the following major findings. Age-adjusted relative risks of 1.89 (1.15-3.10) and 3.53 (1.71-7.27) were found in male and female cigarette smokers, respectively. Significant relative risk was also found in males who drank cocoa. Elevated risk with a dose-response relationship was observed among women who used hair dye and who smoke, but this risk was insignificant, with the disappearance of a dose-response relationship, when it was adjusted for smoking. Age- and smoking-adjusted relative risk of coffee drinking was insignificant with no dose-response relationship. Relative risk of artificial sweetener use was below 1 with adjustment for age and smoking. Intake of alcoholic beverages and cola was insignificantly associated. Reduced risk of significance was suggested for the intake of black tea and matcha (powdered green tea) in females and of fruit juice in males.
Microstructural characterization and density change of 304 stainless steel reflector blocks after long-term irradiation in EBR-II

NASA Astrophysics Data System (ADS)

Huang, Y.; Wiezorek, J. M. K.; Garner, F. A.; Freyer, P. D.; Okita, T.; Sagisaka, M.; Isobe, Y.; Allen, T. R.

2015-10-01

While thin reactor structural components such as cladding and ducts do not experience significant gradients in dpa rate, gamma heating rate, temperature or stress, thick components can develop strong local variations in void swelling and irradiation creep in response to gradients in these variables. In this study we conducted microstructural investigations by transmission electron microscopy of two 52 mm thick 304-type stainless steel hex-blocks irradiated for 12 years in the EBR-II reactor with accumulated doses ranging from ∼0.4 to 33 dpa. Spatial variations in the populations of voids, precipitates, Frank loops and dislocation lines have been determined for 304 stainless steel sections exposed to different temperatures, different dpa levels and at different dpa rates, demonstrating the existence of spatial gradients in the resulting void swelling. The microstructural measurements compare very well with complementary density change measurements regarding void swelling gradients in the 304 stainless steel hex-block components. The TEM studies revealed that the original cold-worked-state microstructure of the unirradiated blocks was completely erased by irradiation, replaced by high densities of interstitial Frank loops, voids and carbide precipitates at both the lowest and highest doses. At large dose levels the amount of volumetric void swelling correlated directly with the gamma heating gradient-related temperature increase (e.g. for 28 dpa, ∼2% swelling at 418 °C and ∼2.9% swelling at 448 °C). Under approximately iso-thermal local conditions, volumetric void swelling was found to increase with dose level (e.g. ∼0.2% swelling at 0.4 dpa, ∼0.5% swelling at 4 dpa and ∼2% swelling at 28 dpa). Carbide precipitate formation levels were found to be relatively independent of both dpa level and temperature and induced a measurable densification. Void swelling was dominant at the higher dose levels and caused measurable decreases in density. Void swelling at the lowest doses was larger than might be expected based on the dpa level, an observation in agreement with earlier studies showing that the onset of void swelling is accelerated by decreasing dpa rates.
Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis.

PubMed

Xu, Ying; Hackett, Maree; Carter, Gregory; Loo, Colleen; Gálvez, Verònica; Glozier, Nick; Glue, Paul; Lapidus, Kyle; McGirr, Alexander; Somogyi, Andrew A; Mitchell, Philip B; Rodgers, Anthony

2016-04-01

Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5 mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50 mg intra-nasal spray, another assessed 0.1-0.4 mg/kg i.v., and another assessed 0.1-0.5 mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6-7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2-5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety. © The Author 2015. Published by Oxford University Press on behalf of CINP.
Effects of Low-Dose and Very Low-Dose Ketamine among Patients with Major Depression: a Systematic Review and Meta-Analysis

PubMed Central

Xu, Ying; Hackett, Maree; Carter, Gregory; Gálvez, Verònica; Glozier, Nick; Glue, Paul; Lapidus, Kyle; McGirr, Alexander; Somogyi, Andrew A.; Mitchell, Philip B.; Rodgers, Anthony

2016-01-01

Background: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. Methods: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. Results: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50mg intra-nasal spray, another assessed 0.1–0.4mg/kg i.v., and another assessed 0.1–0.5mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2–5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. Conclusion: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety. PMID:26578082
Experimental investigation of the 100 keV X-ray dose response of the high-temperature thermoluminescence in LiF:Mg,Ti (TLD-100): theoretical interpretation using the unified interaction model.

PubMed

Livingstone, J; Horowitz, Y S; Oster, L; Datz, H; Lerch, M; Rosenfeld, A; Horowitz, A

2010-03-01

The dose response of LiF:Mg,Ti (TLD-100) chips was measured from 1 to 50,000 Gy using 100 keV X rays at the European Synchroton Radiation Facility. Glow curves were deconvoluted into component glow peaks using a computerised glow curve deconvolution (CGCD) code based on first-order kinetics. The normalised dose response, f(D), of glow peaks 4 and 5 and 5b (the major components of composite peak 5), as well as peaks 7 and 8 (two of the major components of the high-temperature thermoluminescence (HTTL) at high levels of dose) was separately determined and theoretically interpreted using the unified interaction model (UNIM). The UNIM is a nine-parameter model encompassing both the irradiation/absorption stage and the thermally induced relaxation/recombination stage with an admixture of both localised and delocalised recombination mechanisms. The effects of radiation damage are included in the present modelling via the exponential removal of luminescent centres (LCs) at high dose levels. The main features of the experimentally measured dose response are: (i) increase in f(D)(max) with glow peak temperature, (ii) increase in D(max) (the dose level at which f(D)(max) occurs) with increasing glow peak temperature, and (iii) decreased effects of radiation damage with increasing glow peak temperature. The UNIM interpretation of this behaviour requires both strongly decreasing values of ks (the relative contribution of localised recombination) as a function of glow peak temperature and, as well, significantly different values of the dose-filling constants of the trapping centre (TC) and LC for peaks 7 and 8 than those used for peaks 4 and 5. This suggests that different TC/LC configurations are responsible for HTTL. The relative intensity of peak 5a (a low-temperature satellite of peak 5 arising from localised recombination) was found to significantly increase at higher dose levels due to preferential electron and hole population of the trapping/recombination complex giving rise to composite glow peak 5. It is also demonstrated that possible changes in the trapping cross section of the LC and the competitive centres due to increasing sample/glow peak temperature do not significantly influence these observations/conclusions.
TH-C-18A-09: Exam and Patient Parameters Affecting the DNA Damage Response Following CT Studies

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

Elgart, S; Adibi, A; Bostani, M

Purpose: To identify exam and patient parameters affecting the biological response to CT studies using in vivo and ex vivo blood samples. Methods: Blood samples were collected under IRB approval from 16 patients undergoing clinically-indicated CT exams. Blood was procured prior to, immediately after and 30minutes following irradiation. A sample of preexam blood was placed on the patient within the exam region for ex vivo analysis. Whole blood samples were fixed immediately following collection and stained for γH2AX to assess DNA damage response (DDR). Median fluorescence of treated samples was compared to non-irradiated control samples for each patient. Patients weremore » characterized by observed biological kinetic response: (a) fast — phosphorylation increased by 2minutes and fell by 30minutes, (b) slow — phosphorylation continued to increase to 30minutes and (c) none — little change was observed or irradiated samples fell below controls. Total dose values were normalized to exam time for an averaged dose-rate in dose/sec for each exam. Relationships between patient biological responses and patient and exam parameters were investigated. Results: A clearer dose response at 30minutes is observed for young patients (<61yoa; R2>0.5) compared to old patients (>61yoa; R{sup 2}<0.11). Fast responding patients were significantly younger than slow responding patients (p<0.05). Unlike in vivo samples, age did not significantly affect the patient response ex vivo. Additionally, fast responding patients received exams with significantly smaller dose-rate than slow responding patients (p<0.05). Conclusion: Age is a significant factor in the biological response suggesting that DDR may be more rapid in a younger population and slower as the population ages. Lack of an agerelated response ex vivo suggests a systemic response to radiation not present when irradiated outside the body. Dose-rate affects the biological response suggesting that patient response may be related to scan timing and dose delivery within an exam protocol. All authors receive(d) funding from a Master Research Agreement from Siemens Healthcare with UCLA Radiological Sciences.« less
Polyunsaturated fatty acid intake and risk of lung cancer: a meta-analysis of prospective studies.

PubMed

Zhang, Yu-Fei; Lu, Jian; Yu, Fei-Fei; Gao, Hong-Fang; Zhou, Yu-Hao

2014-01-01

Studies have reported inconsistent results for the existence of an association between polyunsaturated fatty acid (PUFA) intake and risk of lung cancer. The purpose of this study is to summarize the evidence regarding this relationship using a dose response meta-analytic approach. We searched the PubMed, EmBase, and Cochrane Library electronic databases for related articles published through July 2013. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of lung cancer incidence for greater than 2 categories of PUFA intake were included. We did random-effects meta-analyses of study-specific incremental estimates to determine the risk of lung cancer associated with a 5 g per day increase in PUFA intake. Overall, we included 8 prospective cohort studies reporting data on 1,268,442 individuals. High PUFA intake had little or no effect on lung cancer risk (risk ratio [RR], 0.91; 95% CI, 0.78-1.06; P = 0.230). Furthermore, the dose-response meta-analysis also suggested that a 5 g per day increase in PUFA has no significant effect on the risk of lung cancer (RR, 0.98; 95%CI: 0.96-1.01; P = 0.142). Finally, the findings of dose response curve suggested that PUFA intake of up to 15 g/d seemed to increase the risk of lung cancer. Furthermore, PUFA intake greater than 15 g/d was associated with a small beneficial effect and borderline statistical significance. Subgroup analyses for 5 g per day increment in PUFA indicated that the protective effect of PUFA was more evident in women (RR, 0.94; 95% CI, 0.87-1.01; P = 0.095) than in men (RR, 1.00; 95% CI, 0.98-1.02; P = 0.784). Our study indicated that PUFA intake had little or no effect on lung cancer risk. PUFA intake might play an important role in lung cancer prevention in women.
The Effects of Lidocaine on Central Respiratory Neuron Activity and Nociceptive-Related Responses in the Brainstem-Spinal Cord Preparation of the Newborn Rat.

PubMed

Shakuo, Tomoharu; Lin, Shih-Tien; Onimaru, Hiroshi

2016-05-01

Lidocaine is widely used in the clinical setting as a local anesthetic and antiarrhythmic drug. Although it has been suggested that lidocaine exerts inhibitory effects on the central and peripheral neurons, there are no reports on its effects on central respiratory activity in vertebrates. In this study, we examined the effects of lidocaine on respiratory rhythm generation and nociceptive response in brainstem-spinal cord preparations from the newborn rats. Preparations were isolated from Wistar rats (postnatal day 0-3) and superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25°C to 26°C. We examined the effects of lidocaine on the fourth cervical ventral root (C4)-inspiratory activity and on the preinspiratory and inspiratory neurons in the rostral medulla. We also examined the effects on the C4/C5 reflex responses induced by ipsilateral C7/C8 dorsal root stimulation, which are thought to be related to the nociceptive response. The application of low doses of lidocaine (10-20 μM) resulted in a slight increase of the C4 burst rate, whereas high doses of lidocaine (100-400 μM) decreased the burst rate in a dose-dependent manner, eventually resulting in the complete cessation of respiratory rhythm. High doses of lidocaine decreased the burst duration and negative slope conductance of preinspiratory neurons, suggesting that lidocaine blocked persistent Na+ current. After the burst generation of the respiratory neurons ceased, depolarizing current stimulation continued to induce action potentials; however, the induction of the spike train was depressed because of strong adaptation. A low dose of lidocaine (20 μM) depressed C4/C5 spinal reflex responses. Our findings indicate that lidocaine depressed nociception-related responses at lower concentrations than those that induced respiratory depression. Our report provides the basic neuronal mechanisms to support the clinical use of lidocaine, which shows antinociceptive effects with minimal side effects on breathing.
Use of aspartame-based sweetener tablets in emergency dosimetry using EPR.

PubMed

Maghraby, A; Salama, E

2010-06-01

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

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

Chetty, K.G.; Moran, E.M.; Sassoon, C.S.

1989-03-01

We evaluated the effect of radiation therapy in 57 patients with obstruction of a large bronchus with NSCC. Response with aeration of the atelectatic lung was seen in 12 patients (21 percent). Three patients (5 percent) showed partial response with persistent partial atelectasis, and nine patients (16 percent) showed good response with complete aeration of the atelectatic lung. In these patients the response appeared to be related to the dose of radiation. All of the patients who responded received more than 50 Gy. The difference in the response rate related to the dose of radiation was statistically significant (p lessmore » than 0.05). The rates were similar with all histologic types of NSCC. Regardless of the clinical response observed, bronchoscopy performed two to four months after completion of radiation therapy in 14 patients revealed persistent endobronchial tumor. There was no significant relationship between the persistence of endobronchial tumor, the dose of radiation therapy, and the tumor's histologic type. Of the 12 patients with radiographic improvement in atelectasis, fibrotic changes developed in four (33 percent) patients and pneumonitis in two (17 percent). Progression of disease with distant metastases occurred in 58 percent (seven) of the 12 patients who showed a clinical response of their bronchial obstruction. The median time to survival was nearly identical in responders and nonresponders.« less
Dose-response of women's health-related quality of life (HRQoL) and life satisfaction to physical activity.

PubMed

Eime, Rochelle; Harvey, Jack; Payne, Warren

2014-02-01

To examine the dose-response relationship between health related quality of life (HRQoL) and life satisfaction (outcomes) and duration of recreational physical activity (exposure). Further, to explore whether these relationships depend on type of physical activity (PA). 793 Australian rural-living women self-reported on duration of recreational PA; HRQoL via SF-36 Mental Component Summary (MCS) and Physical Component Summary (PCS); and a life satisfaction scale. ANOVAs and ANCOVAs investigated differences in outcomes (MCS, PCS, and life satisfaction) between tertiles of exposure to recreational PA, and types of PA (club sport, gymnasium, walking), with adjustment for potential confounders. A significant positive dose-response relationship was found between PCS and level of PA. Furthermore, this relationship depended on type of PA, with club-sport participants recording higher PCS than non-club-sport participants in all but the highest tertile of exposure. Life satisfaction and MCS were not significantly related to level of PA. Physical health was positively associated with level of recreational PA, with club sport participation contributing greater benefits at low to moderate exposures than participation in gymnasium or walking activities.
Cellular stress responses, mitostress and carnitine insufficiencies as critical determinants in aging and neurodegenerative disorders: role of hormesis and vitagenes.

PubMed

Calabrese, Vittorio; Cornelius, Carolin; Stella, Anna Maria Giuffrida; Calabrese, Edward J

2010-12-01

The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.
Thermally-assisted optically stimulated luminescence from deep electron traps in α-Al2O3:C,Mg

NASA Astrophysics Data System (ADS)

Kalita, J. M.; Chithambo, M. L.; Polymeris, G. S.

2017-07-01

We report thermally-assisted optically stimulated luminescence (TA-OSL) in α-Al2O3:C,Mg. The OSL was measured at elevated temperatures between 50 and 240 °C from a sample preheated to 500 °C after irradiation to 100 Gy. That OSL could be measured even after the preheating is direct evidence of the existence of deep electron traps in α-Al2O3:C,Mg. The TA-OSL intensity goes through a peak with measurement temperature. The initial increase is ascribed to thermal assistance to optical stimulation whereas the subsequent decrease in intensity is deduced to reflect increasing incidences of non-radiative recombination, that is, thermal quenching. The activation energy for thermal assistance corresponding to a deep electron trap was estimated as 0.667 ± 0.006 eV whereas the activation energy for thermal quenching was calculated as 0.90 ± 0.04 eV. The intensity of the TA-OSL was also found to increase with irradiation dose. The dose response is sublinear from 25 to 150 Gy but saturates with further increase of dose. The TA-OSL dose response has been discussed by considering the competition for charges at the deep traps. This study incidentally shows that TA-OSL can be effectively used in dosimetry involving large doses.
Effects of Intranasal Oxytocin on Aggressive Responding in Antisocial Personality Disorder.

PubMed

Alcorn, Joseph L; Rathnayaka, Nuvan; Swann, Alan C; Moeller, F Gerard; Lane, Scott D

2015-12-01

The oxytocin receptor is important in several domains of social behavior, and administration of oxytocin modulates social responding in several mammalian species, including humans. Oxytocin has both therapeutic and scientific potential for elucidating the neural and behavioral mechanisms governing social behavior. In the present study, operationally-defined aggressive behavior of six males with Antisocial Personality Disorder (ASPD) was measured following acute intranasal oxytocin dosing (12, 24, and 48 international units) and placebo, using a well-validated laboratory task of human aggression (Point-Subtraction Aggression Paradigm, or PSAP). The PSAP provides participants with concurrently available monetary-earning and operationally-defined aggressive response options, maintained by fixed ratio schedules of consequences. Shifts in response rates and inter-response time (IRT) distributions were observed on the aggressive response option following oxytocin doses, relative to placebo. Few changes were observed in monetary-reinforced responding. However, across participants the direction and magnitude of changes in aggressive responding were not systematically related to dose. No trends were observed between psychometric or physiological data and oxytocin dosing or aggressive behavior. While this report is to our knowledge the first to examine the acute effects of oxytocin in this population at high risk for violence and other forms of antisocial behavior, several limitations in the experimental design and the results cast the study as a preliminary report. Strategies for more extensive future projects are discussed.

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.
Mobile-Dose: A Dose-Meter Designed for Use in Automatic Machineries for Dose Manipulation in Nuclear Medicine

NASA Astrophysics Data System (ADS)

de Asmundis, Riccardo; Boiano, Alfonso; Ramaglia, Antonio

2008-06-01

Mobile-Dose has been designed for a very innovative use: the integration in a robotic machinery for automatic preparation of radioactive doses, to be injected to patients in Nuclear Medicine Departments, with real time measurement of the activity under preparation. Mobile-Dose gives a constant measurement of the dose during the filling of vials or syringes, triggering the end of the filling process based on a predefined dose limit. Several applications of Mobile-Dose have been delivered worldwide, from Italian hospitals and clinics to European and Japanese ones. The design of such an instrument and its integration in robotic machineries, was required by an Italian company specialised in radiation protection tools for nuclear applications, in the period 2001-2003. At the time of its design, apparently no commercial instruments with a suitable interfacing capability to the external world existed: we designed it in order to satisfy all the strict requirements coming from the medical aspects (precision within 10%, repeatability, stability, time response) and from the industrial conceiving principles that are mandatory to ensure a good reliability in such a complicated environment. The instrument is suitable to be used in standalone mode too, thanks to its portability and compactness and to the intelligent operator panel programmed for this purpose.
Infrastructure to Support Ultra High Throughput Biodosimetry Screening after a Radiological Event

PubMed Central

Garty, G.; Karam, P.A.; Brenner, D. J.

2011-01-01

Purpose After a large-scale radiological event, there will be a pressing need to assess, within a few days, the radiation doses received by tens or hundreds of thousands of individuals. This is for triage, to prevent treatment locations from being overwhelmed, in what is sure to be a resource limited scenario, as well as to facilitate dose-dependent treatment decisions. In addition there are psychosocial considerations, in that active reassurance of minimal exposure is a potentially effective antidote to mass panic, as well as long-term considerations, to facilitate later studies of cancer and other long-term disease risks. Materials and Methods As described elsewhere in this issue, we are developing a Rapid Automated Biodosimetry Tool (RABiT). The RABiT allows high throughput analysis of thousands of blood samples per day, providing a dose estimate that can be used to support clinical triage and treatment decisions. Results Development of the RABiT has motivated us to consider the logistics of incorporating such a system into the existing emergency response scenarios of a large metropolitan area. We present here a view of how one or more centralized biodosimetry readout devices might be incorporated into an infrastructure in which fingerstick blood samples are taken at many distributed locations within an affected city or region and transported to centralized locations. Conclusions High throughput biodosimetry systems offer the opportunity to perform biodosimetric assessments on a large number of persons. As such systems reach a high level of maturity, emergency response scenarios will need to be tweaked to make use of these powerful tools. This can be done relatively easily within the framework of current scenarios. PMID:21675819
Dose- and time-dependent increase of lysosomal enzymes in embryonic cartilage in vitro after ionizing radiation

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

Cornelissen, M.; de Ridder, L.

Radiation doses of 20, 50 or 100 Gy caused the same time related decrease for RNA and proteoglycan (PG) synthesis in embryonic cartilage in vitro (4 days culture). In this paper, participation of lysosomes in this radiation response is investigated. Therefore, we employ a cytochemical method using beta-glycerophosphate as substrate for acid phosphatase (AP) detection. Increase of AP was found 2 days after irradiation and increased during the whole culture period. The increase was more pronounced with a higher radiation dose. Stimulation of AP activity explains the observed radiation response of RNA and PG synthesis.
Kinetic microplate bioassays for relative potency of antibiotics improved by partial Least Square (PLS) regression.

PubMed

Francisco, Fabiane Lacerda; Saviano, Alessandro Morais; Almeida, Túlia de Souza Botelho; Lourenço, Felipe Rebello

2016-05-01

Microbiological assays are widely used to estimate the relative potencies of antibiotics in order to guarantee the efficacy, safety, and quality of drug products. Despite of the advantages of turbidimetric bioassays when compared to other methods, it has limitations concerning the linearity and range of the dose-response curve determination. Here, we proposed to use partial least squares (PLS) regression to solve these limitations and to improve the prediction of relative potencies of antibiotics. Kinetic-reading microplate turbidimetric bioassays for apramacyin and vancomycin were performed using Escherichia coli (ATCC 8739) and Bacillus subtilis (ATCC 6633), respectively. Microbial growths were measured as absorbance up to 180 and 300min for apramycin and vancomycin turbidimetric bioassays, respectively. Conventional dose-response curves (absorbances or area under the microbial growth curve vs. log of antibiotic concentration) showed significant regression, however there were significant deviation of linearity. Thus, they could not be used for relative potency estimations. PLS regression allowed us to construct a predictive model for estimating the relative potencies of apramycin and vancomycin without over-fitting and it improved the linear range of turbidimetric bioassay. In addition, PLS regression provided predictions of relative potencies equivalent to those obtained from agar diffusion official methods. Therefore, we conclude that PLS regression may be used to estimate the relative potencies of antibiotics with significant advantages when compared to conventional dose-response curve determination. Copyright © 2016 Elsevier B.V. All rights reserved.
Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer.

PubMed

Gettinger, Scott N; Horn, Leora; Gandhi, Leena; Spigel, David R; Antonia, Scott J; Rizvi, Naiyer A; Powderly, John D; Heist, Rebecca S; Carvajal, Richard D; Jackman, David M; Sequist, Lecia V; Smith, David C; Leming, Philip; Carbone, David P; Pinder-Schenck, Mary C; Topalian, Suzanne L; Hodi, F Stephen; Sosman, Jeffrey A; Sznol, Mario; McDermott, David F; Pardoll, Drew M; Sankar, Vindira; Ahlers, Christoph M; Salvati, Mark; Wigginton, Jon M; Hellmann, Matthew D; Kollia, Georgia D; Gupta, Ashok K; Brahmer, Julie R

2015-06-20

Programmed death 1 is an immune checkpoint that suppresses antitumor immunity. Nivolumab, a fully human immunoglobulin G4 programmed death 1 immune checkpoint inhibitor antibody, was active and generally well tolerated in patients with advanced solid tumors treated in a phase I trial with expansion cohorts. We report overall survival (OS), response durability, and long-term safety in patients with non-small-cell lung cancer (NSCLC) receiving nivolumab in this trial. Patients (N = 129) with heavily pretreated advanced NSCLC received nivolumab 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. Tumor burden was assessed by RECIST (version 1.0) after each cycle. Median OS across doses was 9.9 months; 1-, 2-, and 3-year OS rates were 42%, 24%, and 18%, respectively, across doses and 56%, 42%, and 27%, respectively, at the 3-mg/kg dose (n = 37) chosen for further clinical development. Among 22 patients (17%) with objective responses, estimated median response duration was 17.0 months. An additional six patients (5%) had unconventional immune-pattern responses. Response rates were similar in squamous and nonsquamous NSCLC. Eighteen responding patients discontinued nivolumab for reasons other than progressive disease; nine (50%) of those had responses lasting > 9 months after their last dose. Grade 3 to 4 treatment-related adverse events occurred in 14% of patients. Three treatment-related deaths (2% of patients) occurred, each associated with pneumonitis. Nivolumab monotherapy produced durable responses and encouraging survival rates in patients with heavily pretreated NSCLC. Randomized clinical trials with nivolumab in advanced NSCLC are ongoing. © 2015 by American Society of Clinical Oncology.
Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

PubMed Central

Norris, Stephen; Ramael, Steven; Ikushima, Ippei; Haazen, Wouter; Harada, Akiko; Moschetti, Viktoria; Imazu, Susumu; Reilly, Paul A.; Lang, Benjamin; Stangier, Joachim

2017-01-01

Aims Idarucizumab, a humanized monoclonal anti‐dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre‐existing and treatment‐emergent anti‐idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre‐existing and treatment‐emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab. Methods Data were pooled from three Phase I, randomized, double‐blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre‐existing ADA. Results Pre‐existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre‐existing and treatment‐emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre‐existing ADA had no impact on dose‐normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran‐induced anticoagulation by idarucizumab. Treatment‐emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C‐terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions. Conclusion Pre‐existing and treatment‐emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre‐existing ADA. PMID:28230262
Symptoms, airway responsiveness, and exposure to dust in beech and oak wood workers

PubMed Central

Bohadana, A.; Massin, N.; Wild, P.; Toamain, J.; Engel, S.; Goutet, P.

2000-01-01

OBJECTIVES—To investigate the relation between levels of cumulative exposure to wood dust and respiratory symptoms and the occurrence of bronchial hyperresponsiveness among beech and oak workers. METHODS—114 Male woodworkers from five furniture factories and 13 male unexposed controls were examined. The unexposed control group was supplemented by 200 male historical controls. Statistical analyses were performed excluding and including the historical controls. Dust concentration was measured by personal sampling methods. Cumulative exposure to dust was calculated for each woodworker by multiplying the duration of the work by the intensity of exposure (years.mg/m3). Bronchial hyperresponsiveness was assessed by the methacholine bronchial challenge test. Subjects were labelled methacholine bronchial challenge positive if forced expiratory volume in 1 second (FEV1) fell by ⩾20%. The linear dose-response slope was calculated as the last dose divided by the total dose given. RESULTS—443 Dust samples were collected. The median cumulative exposure to dust was 110 years.mg/m3 with lower and upper quartiles at 70 and 160 years.mg/m3 Overall, no declines in FEV1 and forced vital capacity (FVC) were found with increasing exposures. A dose-response relation was found between intensity of exposure on the one hand, and sore throat, increased prevalence of positive methacholine bronchial challenge tests, and steeper dose-response slope, on the other. CONCLUSION—Exposure to oak and beech dust may lead to the development of sore throat and bronchial hyperresponsiveness.   Keywords: bronchial hyperresponsiveness; wood dust; beech; oak PMID:10810114
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
The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats.

PubMed

Aarde, S M; Huang, P K; Creehan, K M; Dickerson, T J; Taffe, M A

2013-08-01

Recreational use of the cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") has increased worldwide in past years, accompanied by accounts of health and legal problems in the popular media and efforts to criminalize possession in numerous jurisdictions. Minimal information exists on the effects of MDPV in laboratory models. This study determined the effects of MDPV, alongside those of the better studied stimulant d-methamphetamine (METH), using rodent models of intravenous self-administration (IVSA), thermoregulation and locomotor activity. Male Wistar rats were trained to self-administer MDPV or METH (0.05 mg/kg/infusion, i.v.) or were prepared with radiotelemetry implants for the assessment of body temperature and activity responses to MDPV or METH (0-5.6 mg/kg s.c.). METH and MDPV were consistently self-administered within 10 training sessions (mg/kg/h; METH Mean = 0.4 and Max = 1.15; MDPV Mean = 0.9 and Max = 5.8). Dose-substitution studies demonstrated that behavior was sensitive to dose for both drugs, but MDPV (0.01-0.50 mg/kg/inf) showed greater potency and efficacy than METH (0.1-0.25 mg/kg/inf). In addition, both MDPV and METH increased locomotor activity at lower doses (0.5-1.0 mg/kg, s.c.) and transiently decreased activity at the highest dose (5.6 mg/kg, s.c.). Body temperature increased monotonically with increasing doses of METH but MDPV had a negligible effect on temperature. Stereotypy was associated with relatively high self-administered cumulative doses of MDPV (∼1.5 mg/kg/h) as well as with non-contingent MDPV administration wherein the intensity and duration of stereotypy increased as MDPV dose increased. Thus, MDPV poses a substantial threat for compulsive use that is potentially greater than that for METH. Copyright © 2013 Elsevier Ltd. All rights reserved.
A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.

PubMed

Bedard, Philippe L; Tabernero, Josep; Janku, Filip; Wainberg, Zev A; Paz-Ares, Luis; Vansteenkiste, Johan; Van Cutsem, Eric; Pérez-García, José; Stathis, Anastasios; Britten, Carolyn D; Le, Ngocdiep; Carter, Kirsten; Demanse, David; Csonka, Denes; Peters, Malte; Zubel, Angela; Nauwelaerts, Heidi; Sessa, Cristiana

2015-02-15

MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer. Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. ©2014 American Association for Cancer Research.
Dose and risk in diagnostic radiology: How big How little Lecture Number 16

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

Webster, E.W.

1992-01-01

This lecture is divided into two parts: dose and risk. The dose segment is technical and noncontroversial since it deals with straightforward measurements or calculations which do not depend on unproven hypotheses. Some conflicting contributions of low dose epidemiological studies to the appraisal of risk are briefly presented. Attention is focused on the following: dose reduction in radiography; dose reduction in fluoroscopy; limitations of dose reduction; estimated radiation risks for diagnostic radiology examinations; excess breast cancer following X-ray examinations for scoliosis; dose-response relation for human mammary cancer; lung cancer from protracted X-irradiation; leukemia and diagnostic X-ray exposure; and thyroid cancermore » after diagnostic dose of I-131.« less
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.
The biological impacts of ingested radioactive materials on the pale grass blue butterfly

NASA Astrophysics Data System (ADS)

Nohara, Chiyo; Hiyama, Atsuki; Taira, Wataru; Tanahara, Akira; Otaki, Joji M.

2014-05-01

A massive amount of radioactive materials has been released into the environment by the Fukushima Dai-ichi Nuclear Power Plant accident, but its biological impacts have rarely been examined. Here, we have quantitatively evaluated the relationship between the dose of ingested radioactive cesium and mortality and abnormality rates using the pale grass blue butterfly, Zizeeria maha. When larvae from Okinawa, which is likely the least polluted locality in Japan, were fed leaves collected from polluted localities, mortality and abnormality rates increased sharply at low doses in response to the ingested cesium dose. This dose-response relationship was best fitted by power function models, which indicated that the half lethal and abnormal doses were 1.9 and 0.76 Bq per larva, corresponding to 54,000 and 22,000 Bq per kilogram body weight, respectively. Both the retention of radioactive cesium in a pupa relative to the ingested dose throughout the larval stage and the accumulation of radioactive cesium in a pupa relative to the activity concentration in a diet were highest at the lowest level of cesium ingested. We conclude that the risk of ingesting a polluted diet is realistic, at least for this butterfly, and likely for certain other organisms living in the polluted area.
The biological impacts of ingested radioactive materials on the pale grass blue butterfly.

PubMed

Nohara, Chiyo; Hiyama, Atsuki; Taira, Wataru; Tanahara, Akira; Otaki, Joji M

2014-05-15

A massive amount of radioactive materials has been released into the environment by the Fukushima Dai-ichi Nuclear Power Plant accident, but its biological impacts have rarely been examined. Here, we have quantitatively evaluated the relationship between the dose of ingested radioactive cesium and mortality and abnormality rates using the pale grass blue butterfly, Zizeeria maha. When larvae from Okinawa, which is likely the least polluted locality in Japan, were fed leaves collected from polluted localities, mortality and abnormality rates increased sharply at low doses in response to the ingested cesium dose. This dose-response relationship was best fitted by power function models, which indicated that the half lethal and abnormal doses were 1.9 and 0.76 Bq per larva, corresponding to 54,000 and 22,000 Bq per kilogram body weight, respectively. Both the retention of radioactive cesium in a pupa relative to the ingested dose throughout the larval stage and the accumulation of radioactive cesium in a pupa relative to the activity concentration in a diet were highest at the lowest level of cesium ingested. We conclude that the risk of ingesting a polluted diet is realistic, at least for this butterfly, and likely for certain other organisms living in the polluted area.
Detailed qualitative dynamic knowledge representation using a BioNetGen model of TLR-4 signaling and preconditioning.

PubMed

An, Gary C; Faeder, James R

2009-01-01

Intracellular signaling/synthetic pathways are being increasingly extensively characterized. However, while these pathways can be displayed in static diagrams, in reality they exist with a degree of dynamic complexity that is responsible for heterogeneous cellular behavior. Multiple parallel pathways exist and interact concurrently, limiting the ability to integrate the various identified mechanisms into a cohesive whole. Computational methods have been suggested as a means of concatenating this knowledge to aid in the understanding of overall system dynamics. Since the eventual goal of biomedical research is the identification and development of therapeutic modalities, computational representation must have sufficient detail to facilitate this 'engineering' process. Adding to the challenge, this type of representation must occur in a perpetual state of incomplete knowledge. We present a modeling approach to address this challenge that is both detailed and qualitative. This approach is termed 'dynamic knowledge representation,' and is intended to be an integrated component of the iterative cycle of scientific discovery. BioNetGen (BNG), a software platform for modeling intracellular signaling pathways, was used to model the toll-like receptor 4 (TLR-4) signal transduction cascade. The informational basis of the model was a series of reference papers on modulation of (TLR-4) signaling, and some specific primary research papers to aid in the characterization of specific mechanistic steps in the pathway. This model was detailed with respect to the components of the pathway represented, but qualitative with respect to the specific reaction coefficients utilized to execute the reactions. Responsiveness to simulated lipopolysaccharide (LPS) administration was measured by tumor necrosis factor (TNF) production. Simulation runs included evaluation of initial dose-dependent response to LPS administration at 10, 100, 1000 and 10,000, and a subsequent examination of preconditioning behavior with increasing LPS at 10, 100, 1000 and 10,000 and a secondary dose of LPS at 10,000 administered at approximately 27h of simulated time. Simulations of 'knockout' versions of the model allowed further examination of the interactions within the signaling cascade. The model demonstrated a dose-dependent TNF response curve to increasing stimulus by LPS. Preconditioning simulations demonstrated a similar dose-dependency of preconditioning doses leading to attenuation of response to subsequent LPS challenge - a 'tolerance' dynamic. These responses match dynamics reported in the literature. Furthermore, the simulated 'knockout' results suggested the existence and need for dual negative feedback control mechanisms, represented by the zinc ring-finger protein A20 and inhibitor kappa B proteins (IkappaB), in order for both effective attenuation of the initial stimulus signal and subsequent preconditioned 'tolerant' behavior. We present an example of detailed, qualitative dynamic knowledge representation using the TLR-4 signaling pathway, its control mechanisms and overall behavior with respect to preconditioning. The intent of this approach is to demonstrate a method of translating the extensive mechanistic knowledge being generated at the basic science level into an executable framework that can provide a means of 'conceptual model verification.' This allows for both the 'checking' of the dynamic consequences of a mechanistic hypothesis and the creation of a modular component of an overall model directed at the engineering goal of biomedical research. It is hoped that this paper will increase the use of knowledge representation and communication in this fashion, and facilitate the concatenation and integration of community-wide knowledge.
Radiation-induced cataracts: the Health Protection Agency's response to the ICRP statement on tissue reactions and recommendation on the dose limit for the eye lens.

PubMed

Bouffler, Simon; Ainsbury, Elizabeth; Gilvin, Phil; Harrison, John

2012-12-01

This paper presents the response of the Health Protection Agency (HPA) to the 2011 statement from the International Commission on Radiological Protection (ICRP) on tissue reactions and recommendation of a reduced dose limit for the lens of the eye. The response takes the form of a brief review of the most recent epidemiological and mechanistic evidence. This is presented together with a discussion of dose limits in the context of the related risk and the current status of eye dosimetry, which is relevant for implementation of the limits. It is concluded that although further work is desirable to quantify better the risk at low doses and following protracted exposures, along with research into the mechanistic basis for radiation cataractogenesis to inform selection of risk projection models, the HPA endorses the conclusion reached by the ICRP in their 2011 statement that the equivalent dose limit for the lens of the eye should be reduced from 150 to 20 mSv per year, averaged over a five year period, with no year's dose exceeding 50 mSv.
Genetic effects on heavy ions in drosophila

NASA Technical Reports Server (NTRS)

Kale, P. G.

1986-01-01

Drosophila sex-linked recessive lethal mutation test was used to study the dose response relation and relative biological effectiveness of heavy ions. The experiments were performed using the heavy ion beams at BEVALAC of Lawrence Berkeley Laboratory. These experiments were undertaken according to the proposed milestones and included Ne-20, A-40 and Fe-65 ions with respective energies of 600 MeV, 840 MeV and 850 MeV. At these energies several doses of these radiations ranging from 20 to 1280 R were used. Space radiation exposure to astronauts is supposed to be quite low and therefore very low dose experiments i.e., 20 R, were also performed for the three ions. The mutation response was measured in all germ cell types i.e., spermatozoa, spermatids, spermatocytes and spermatogonia of treated Drosophila males. A linear dose frequency relation was observed for most of the range except at high doses where the saturation effect was observed. Also, a very significant difference was observed among the sensitivity of the four germ cell stages where spermatozoa and spermatids were more sensitive. At the higher doses of this range, most of the spermatogonia and spermatocytes were killed. Although comparative and identical experiments with X-rays or neutrons have not been performed, the compassion of our data with the ones available in literature suggest that the heavy ions have a high rbe and that they are several times more effective than low LET X-rays. The rbe compared to neutrons however appears to be only slightly higher.
Hydrocortisone infusion exerts dose- and sex-dependent effects on attention to emotional stimuli.

PubMed

Breitberg, Alaina; Drevets, Wayne C; Wood, Suzanne E; Mah, Linda; Schulkin, Jay; Sahakian, Barbara J; Erickson, Kristine

2013-03-01

Glucocorticoid administration has been shown to exert complex effects on cognitive and emotional processing. In the current study we investigated the effects of glucocorticoid administration on attention towards emotional words, using an Affective Go/No-go task on which healthy humans have shown an attentional bias towards positive as compared to negative words. Healthy volunteers received placebo and either low-dose (0.15mg/kg) or high-dose (0.45mg/kg) hydrocortisone intravenously during two separate visits in a double-blind, randomized design. Seventy-five minutes post-infusion, the subjects performed tests of attention (Rapid Visual Information Processing [RVIP]), spatial working memory (Spatial Span) and emotional processing (Affective Go/No-go task [AGNG]). On the attention task, performance was impaired under both hydrocortisone doses relative to placebo, though the effect on error rate was not significant after controlling for age; Spatial Span performance was unaffected by hydrocortisone administration. On the AGNG task, relative to the placebo condition the low-dose hydrocortisone infusion decreased response time to emotional words while high-dose hydrocortisone increased response time. In the females specifically, both high and low dose hydrocortisone administration attenuated the normal attentional bias toward positively valenced words. These data suggest that, in healthy women, the modulation of attention by the emotional salience of stimuli is influenced by glucocorticoid hormone concentrations. Copyright © 2012 Elsevier Inc. All rights reserved.
Evaluation of zinc oxide nanoparticle toxicity in sludge products applied to agricultural soil using multispecies soil systems.

PubMed

Fernández, María Dolores; Alonso-Blázquez, María Nieves; García-Gómez, Concepción; Babin, Mar

2014-11-01

To study the environmental impact of nanoparticles, the sludges of wastewater (WWTS) and water treatment (WTS) plants enriched with ZnO nanoparticles were added to agricultural soil, and the toxic effects of the nanoparticles were studied using a microcosm system based on the soil. The WWTS treated soils were characterised by statistically significant decreases (p<0.05) in Vicia sativa germination at the lowest (76.2%) and medium (95.2%) application rates, decreases in the fresh biomass for Triticum aestivum (19.5%), Raphanus sativus (64.1%), V. sativa (37.4%) and Eisenia fetida (33.6%) at the highest application rate and a dose-related significant increase (p<0.05) in earthworm mortality. In WTS amended soils, significant reductions (p<0.05) of the fresh biomass (17.2%) and the chlorophyll index (24.4%) for T. aestivum and the fresh biomass for R. sativus (31.4%) were only recorded at the highest application doses. In addition, the soil phosphatase enzymatic activity decreased significantly (p<0.05) in both WWTS (dose related) and WTS treatments. For water organisms, a slight inhibition of the growth of Chlorella vulgaris was observed (WWTS treated soils), along with statistically significant dose-related inhibition responses on total glutathione cell content, and statistically significant dose-related induction responses on the glutathione S-transferase enzyme activity and the reactive oxygen species generation on the RTG-2 fish cell line. Copyright © 2014 Elsevier B.V. All rights reserved.

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.
Effects of ethanol on Pavlovian autoshaping in rats.

PubMed

Tomie, A; Cunha, C; Mosakowski, E M; Quartarolo, N M; Pohorecky, L A; Benjamin, D

1998-09-01

Approach responses, consummatory behaviors, and directed motor responses maintained by food reward resemble autoshaping CRs and are increased by lower doses of ethanol. This study evaluated the effects of presession i.p. injections of ethanol doses (0.00, 0.25, 0.50, 0.70. or 1.00 g/kg) on the acquisition of lever-press autoshaping CR performance in groups of male Long-Evans hooded rats. Paired groups received 15 daily sessions of Pavlovian autoshaping procedures, wherein the insertion of a retractable lever for 5 s (CS) was followed by the response-independent presentation of food (US). Ethanol facilitated lever-press autoshaping CR acquisition, as revealed by dose-related increases in the number of trials on which CRs were performed. The form of the dose-effect curve was inverted U-shaped with maximal responding induced during sessions 1-5 by the 0.70 g/kg ethanol dose. A similar dose-effect curve was observed during sessions 11-15, revealing that the effects of ethanol on autoshaping CR performance were relatively stable. A pseudoconditioning control group injected presession with 0.50 g/kg ethanol received training wherein the food US was presented randomly with respect to the lever CS. Few lever-presses were performed by the Random 0.50 group, indicating that ethanol's effects on autoshaping CR acquisition and maintenance observed in the Paired 0.50 group were not due to its psychomotor activating effects. A non-injection control group performed more autoshaping CRs than did the control group injected presession with saline, indicating that daily presession i.p. injections per se suppress autoshaping CR performance. Results reveal that low doses of ethanol enhance Pavlovian conditioning of directed motor and consummatory-like responding maintained by food reward. Implications for autoshaping accounts of impulsivity and drug abuse are considered.
Adapting Dry Cask Storage for Aging at a Geologic Repository

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

C. Sanders; D. Kimball

2005-08-02

A Spent Nuclear Fuel (SNF) Aging System is a crucial part of operations at the proposed Yucca Mountain repository in the United States. Incoming commercial SNF that does not meet thermal limits for emplacement will be aged on outdoor pads. U.S. Department of Energy SNF will also be managed using the Aging System. Proposed site-specific designs for the Aging System are closely based upon designs for existing dry cask storage (DCS) systems. This paper evaluates the applicability of existing DCS systems for use in the SNF Aging System at Yucca Mountain. The most important difference between existing DCS facilities andmore » the Yucca Mountain facility is the required capacity. Existing DCS facilities typically have less than 50 casks. The current design for the aging pad at Yucca Mountain calls for a capacity of over 2,000 casks (20,000 MTHM) [1]. This unprecedented number of casks poses some unique problems. The response of DCS systems to off-normal and accident conditions needs to be re-evaluated for multiple storage casks. Dose calculations become more complicated, since doses from multiple or very long arrays of casks can dramatically increase the total boundary dose. For occupational doses, the geometry of the cask arrays and the order of loading casks must be carefully considered in order to meet ALARA goals during cask retrieval. Due to the large area of the aging pad, skyshine must also be included when calculating public and worker doses. The expected length of aging will also necessitate some design adjustments. Under 10 CFR 72.236, DCS systems are initially certified for a period of 20 years [2]. Although the Yucca Mountain facility is not intended to be a storage facility under 10 CFR 72, the operational life of the SNF Aging System is 50 years [1]. Any cask system selected for use in aging will have to be qualified to this design lifetime. These considerations are examined, and a summary is provided of the adaptations that must be made in order to use DCS technologies successfully at a geologic repository.« less
UV Disinfection System for Cabin Air

NASA Astrophysics Data System (ADS)

Lim, Soojung

Ultraviolet (UV) radiation is commonly used for disinfection of water. As a result of advancements made in the last 10-15 years, the analysis and design of UV disinfection systems for water is well developed. UV disinfection is also used for disinfection of air; however, despite the fact the UV-air systems have a longer record of application than UV-water systems, the methods used to analyze and design UV-air disinfection systems remain quite empirical. It is well-established that the effectiveness of UV-air systems is strongly affected by the type of microorganisms, the irradiation level/type (lamp power and wavelength), duration of irradiation (exposure time), air movement pattern (mixing degree), and relative humidity. This paper will describe ongoing efforts to evaluate, design and test a UV-air system based on first principles. Specific issues to be addressed in this work will include laboratory measurements of relevant kinetics (i.e., UV dose-response behavior) and numerical simulations designed to represent fluid mechanics and the radiation intensity field. UV dose-response behavior of test microorganism was measured using a laboratory (bench-scale) system. Target microorganisms (e.g., bacterial spores) were first applied to membrane filters at sub-monolayer coverage. The filters were then transferred to an environmental chamber at fixed relative humidity (RH) and allowed to equilibrate with their surroundings. Microorganisms were then subjected to UV exposure under a collimated beam. The experiment was repeated at RH values ranging from 20% to 100%. UV dose-response behavior was observed to vary with RH. For example, at 100% RH, a UV dose of 20 mJ/cm2 accomplished 90% (1 log10 units) of the B. subtilis spore inactivation, whereas 99 % (2 log10 units) inactivation was accomplished at this same UV dose under 20% RH conditions. However, at higher doses, the result was opposite of that in low dose. Reactor behavior is simulated using an integrated application of computational fluid dynamics (CFD) and radiation intensity field models. These simulations followed a Lagrangian approach, wherein the UV radiation intensity field was mapped onto simulated particle trajectories for prediction of the UV dose delivered to each particle. By repeating these calculations for a large number of simulated particle trajectories, an estimate of the UV dose distribution delivered by the reactor can be made. In turn, these dose distribution estimates are integrated with the UV dose-response behavior described above to yield an estimate of microbial inactivation accomplished by the reactor. This modeling approach has the advantage of allowing simulation of many reactor configurations in a relatively short period of time. Moreover, by following this approach of "numerical prototyping," it is possible to "build" and analyze several virtual reactors before the construction of a physical prototype. As such, this procedure allows effective development of efficient reactors.
Synergistic interaction between fentanyl and the histamine H3 receptor agonist R-(alpha)-methylhistamine, on the inhibition of nociception and plasma extravasation in mice.

PubMed

Poveda, Raquel; Fernández-Dueñas, Víctor; Fernández, Alejandro; Sánchez, Sílvia; Puig, Margarita M; Planas, Eulàlia

2006-07-10

Here we report a synergistic interaction between fentanyl and the histamine H(3) receptor agonist R-(alpha)-methylhistamine on the inhibition of nociception and plasma extravasation in mice. Chronic inflammation was induced by subplantar injection of Complete Freund's Adjuvant into the right hind paw, and the effect of the drugs was evaluated 7 days later. Nociception and plasma extravasation were assessed by hot-plate and Evans blue tests respectively. Subcutaneous administration of fentanyl (0.01-0.1 mg/kg) induced dose-related anti-nociceptive and anti-extravasation effects (E(max)=100% and 62%, respectively). R-(alpha)-methylhistamine administration (0.3-3 mg/kg) showed a dose-related inhibitory effect on extravasation (E(max)=65%) but not on nociception. To analyze possible interaction between these two drugs, a dose-response curve to fentanyl plus a fixed dose of R-(alpha)-methylhistamine (0.5 mg/kg) was obtained. The dose-response curve for the combined treatment showed a shift to the left compared with that for fentanyl alone. Our results confirm that fentanyl and R-(alpha)-methylhistamine interact in a synergic way, inhibiting nociception and plasma extravasation.
Antiinflammatory activity of lymphomyosot during chronic deseases.

PubMed

Ratiani, L; Terunashvili, G; Sanikidze, T

2012-04-01

Every pathology generally refers to an inadequate response to the influence brought by endo- and exotoxins, which is carried out via natural compensative and protective pathways of the body. Scientific conception of bioregulative therapy and homotoxicology implies treatment by modulation of own protective mechanisms and neutralization of already existing toxins. This endo- and exogenic homotoxins influence on the development of various immune responses of immunocompetent cells. Lymphomyosot, a complex nutural detoxifier drug, providing the effective detoxication of extracellular matrix via lymphatic system. As a huge amount of immunocompetent cells are located in the lymphatic system are, regulation of their immune responses by Lymphomyosot is very the essence of the treatment applicable to different chronic pathologies. determining of dose-dependent immunomodulating activity of Lymphomyosot on T lymphocytes modelled system of Jurkat cells. The modelled systems of Jurkat cells, incubated under moderate oxidative stress conditions inherent chronic inflammatory processes, and stimulated with mytogene Phytohemaglutinine (PHA) was used. Effectiveness of Lypmhomyosot was studied by regulatory capacity of the cells bioviability (MTT test) immunological activity (cytokine expression, respiratory burst) and of mytogene-induced apoptosis intensity of Jurkat cells. Lymphomyosot shows antioxidant effect and dose-dependent immunomodulatory activity. Lymphomyosot, as anti-inflammatory, recovering agent is effective for profilactic aims. Low (therapeutic) doses of lymphomyosot are effective for the treatment of.
Oral iodine supplementation does not reduce neutralizing antibody responses to oral poliovirus vaccine.

PubMed Central

Taffs, R. E.; Enterline, J. C.; Rusmil, K.; Muhilal; Suwardi, S. S.; Rustama, D.; Djatnika; Cobra, C.; Semba, R. D.; Cohen, N.; Asher, D. M.

1999-01-01

Iodine deficiency is a major cause of impaired mental development, goitre, and cretinism in many parts of the world. Because existing immunization programmes can be used to deliver oral iodized oil (OIO) to infants at risk, it was important to know whether OIO could adversely affect the antibody response to vaccines, such as trivalent oral poliovirus vaccine (OPV). A randomized, double-blind, placebo-controlled clinical trial was conducted in Subang, West Java, Indonesia, in which 617 eight-week-old infants received either OIO or a placebo (poppy-seed oil) during a routine visit for their first dose of OPV as part of the Expanded Programme on Immunization (EPI). The infants received two boosters of OPV at 4-week intervals after the first dose, and were followed up when 6 months old. Neutralizing antibody titres to poliovirus serotypes 1, 2, and 3 were compared in serum samples that were taken from 478 of these infants just before the first dose of OPV and at 6 months. It was found that oral iodized oil did not reduce the antibody responses to any of the three serotypes of OPV. These results indicate that oral iodine may safely be delivered to infants at the same time as oral poliovirus vaccine according to current EPI immunization schedules. PMID:10427933
Irradiation biology of male brown marmorated stink bugs: is there scope for the sterile insect technique?

PubMed

Welsh, T J; Stringer, L D; Caldwell, R; Carpenter, J E; Suckling, D M

2017-12-01

Brown marmorated stink bugs, Halyomorpha halys Stål (Hemiptera: Pentatomidae), are regularly intercepted, but there are few eradication tools. Currently, no sterile insect technique program exists for Hemiptera. Adult males were irradiated at 4-60 Gy, mated and their progeny reared for two generations, with mortality assessed at F 1 egg, F 1 adult and F 2 egg stages. The F 1 eggs showed a dose response to irradiation between 4 and 36 Gy, with 97% sterility at 16 Gy, and higher doses producing complete egg mortality. Only rare F 1 survivors had progeny, but the F 2 generation showed identical responses between maternal and paternal lines; most egg batches showed either very low or very high mortality. Irradiation with 16 Gy resulted in 98.5% sterility, cumulative over F 1 and F 2 . Lack of a dose response at the F 2 generation precludes the use of irradiation-induced inherited sterility. The conventional sterile insect technique appears possible by irradiation of males from ∼12 to 16 Gy. The effect of radiation dose on females is not known, thus we cannot conclude whether bi-sex release is feasible so for now the release of males only is recommended. More work is needed on the competitive fitness of irradiated males, and logistics such as mass rearing or field collection, in order to determine the feasibility of the approach.
I-131 Dose Response for Incident Thyroid Cancers in Ukraine Related to the Chornobyl Accident

PubMed Central

Tronko, Mykola D.; Hatch, Maureen; Bogdanova, Tetyana I.; Oliynik, Valery A.; Lubin, Jay H.; Zablotska, Lydia B.; Tereschenko, Valery P.; McConnell, Robert J.; Zamotaeva, Galina A.; O’Kane, Patrick; Bouville, Andre C.; Chaykovskaya, Ludmila V.; Greenebaum, Ellen; Paster, Ihor P.; Shpak, Victor M.; Ron, Elaine

2011-01-01

Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case–control studies, and studies of prevalent cancers. Objective: To address this limitation, we evaluated the dose–response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study. Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of I-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models. Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose–response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43–6.34], and the EAR per 104 PY/Gy was 2.21 (95% CI, 0.04–5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size. Conclusions: I-131–related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies. PMID:21406336
Individualized versus standard FSH dosing in women starting IVF/ICSI: an RCT. Part 1: The predicted poor responder.

PubMed

van Tilborg, Theodora C; Torrance, Helen L; Oudshoorn, Simone C; Eijkemans, Marinus J C; Koks, Carolien A M; Verhoeve, Harold R; Nap, Annemiek W; Scheffer, Gabrielle J; Manger, A Petra; Schoot, Benedictus C; Sluijmer, Alexander V; Verhoeff, Arie; Groen, Henk; Laven, Joop S E; Mol, Ben Willem J; Broekmans, Frank J M

2017-12-01

Does an increased FSH dose result in higher cumulative live birth rates in women with a predicted poor ovarian response, apparent from a low antral follicle count (AFC), scheduled for IVF or ICSI? In women with a predicted poor ovarian response (AFC < 11) undergoing IVF/ICSI, an increased FSH dose (225/450 IU/day) does not improve cumulative live birth rates as compared to a standard dose (150 IU/day). In women scheduled for IVF/ICSI, an ovarian reserve test (ORT) can predict ovarian response to stimulation. The FSH starting dose is often adjusted based on the ORT from the belief that it will improve live birth rates. However, the existing RCTs on this topic, most of which show no benefit, are underpowered. Between May 2011 and May 2014, we performed an open-label multicentre RCT in women with an AFC < 11 (Dutch Trial Register NTR2657). The primary outcome was ongoing pregnancy achieved within 18 months after randomization and resulting in a live birth. We needed 300 women to assess whether an increased dose strategy would increase the cumulative live birth rate from 25 to 40% (two-sided alpha-error 0.05, power 80%). Women with an AFC ≤ 7 were randomized to an FSH dose of 450 IU/day or 150 IU/day, and women with an AFC 8-10 were randomized to 225 IU or 150 IU/day. In the standard group, dose adjustment was allowed in subsequent cycles based on pre-specified criteria. Both effectiveness and cost-effectiveness of the strategies were evaluated from an intention-to-treat perspective. In total, 511 women were randomized, 234 with an AFC ≤ 7 and 277 with an AFC 8-10. The cumulative live birth rate for increased versus standard dosing was 42.4% (106/250) versus 44.8% (117/261), respectively [relative risk (RR): 0.95 (95%CI, 0.78-1.15), P = 0.58]. As an increased dose strategy was more expensive [delta costs/woman: €1099 (95%CI, 562-1591)], standard FSH dosing was the dominant strategy in our economic analysis. Despite our training programme, the AFC might have suffered from inter-observer variation. As this open study permitted small dose adjustments between cycles, potential selective cancelling of cycles in women treated with 150 IU could have influenced the cumulative results. However, since first cycle live birth rates point in the same direction we consider it unlikely that the open design masked a potential benefit for the individualized strategy. Since an increased dose in women scheduled for IVF/ICSI with a predicted poor response (AFC < 11) does not improve live birth rates and is more expensive, we recommend using a standard dose of 150 IU/day in these women. This study was funded by The Netherlands Organisation for Health Research and Development (ZonMW number 171102020). T.C.T., H.L.T. and S.C.O. received an unrestricted personal grant from Merck BV. H.R.V. receives monetary compensation as a member on an external advisory board for Ferring pharmaceutical BV. B.W.J.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for OvsEva, Merck and Guerbet. F.J.M.B. receives monetary compensation as a member of the external advisory board for Ferring pharmaceutics BV (the Netherlands) and Merck Serono (the Netherlands) for consultancy work for Gedeon Richter (Belgium) and Roche Diagnostics on automated AMH assay development (Switzerland) and for a research cooperation with Ansh Labs (USA). All other authors have nothing to declare. Registered at the ICMJE-recognized Dutch Trial Registry (www.trialregister.nl). Registration number NTR2657. 20 December 2010. 12 May 2011. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
Non-Malignant Thyroid Diseases Following a Wide Range of Radiation Exposures

PubMed Central

Ron, Elaine; Brenner, Alina

2013-01-01

Background The thyroid gland is one of the most radiosensitive human organs. While it is well known that radiation exposure increases the risk of thyroid cancer, less is known about its effects in relation to non-malignant thyroid diseases. Objectives The aim of this review is to evaluate the effects of high and low dose radiation on benign structural and functional diseases of the thyroid. Methods We examined the results of major studies from cancer patients treated with high-dose radiotherapy or thyrotoxicosis patients treated with high doses of iodine-131, patients treated with moderate to high dose radiotherapy for benign diseases, persons exposed to low doses from environmental radiation and survivors of the atomic bombings who were exposed to a range of doses. We evaluated radiation effects on structural (tumors, nodules), functional (hyper- and hypothyroidism), and autoimmune thyroid diseases. Results Following a wide range of doses of ionizing radiation, an increased risk of thyroid adenomas and nodules was observed in a variety of populations and settings. The dose response appeared to be linear at low to moderate doses, but in one study there was some suggestion of a reduction in risk above 5 Gy. The elevated risk for benign tumors continues for decades following exposure. Considerably less consistent findings are available regarding functional thyroid diseases including autoimmune diseases. In general, associations for these outcomes were fairly weak and significant radiation effects were most often observed following high doses, particularly for hypothyroidism. Conclusions A significant radiation dose-response relation was demonstrated for benign nodules and follicular adenomas. The effects of radiation on functional thyroid diseases are less clear, partly due to the greater difficulties studying these diseases. PMID:21128812
PEG spacer gel and adaptive planning vs single plan in external prostate radiotherapy—clinical dosimetry evaluation

PubMed Central

2015-01-01

Objective: Spacer gel is used to reduce the rectal dose in prostate radiotherapy. It is injected to increase the distance between the prostate and rectum. During the course of external radiotherapy treatment, physiological changes in rectal volume exist. When using polyethylene glycol material, such as DuraSeal® (Covidien, Mansfield, MA), gel resorption also occurs. Together, these factors alter the original dose plan distribution. Methods: External dose planning and calculations were simulated using images acquired from 10 patients who were treated with brachytherapy and gel. The CT series was taken relative to gel injection: pre 1 day, post 1 day, post 1 month and post 2 months. Adaptive planning was compared with a single plan. Results: Adaptive planning shows better results compared with the single plan used in the total treatment course; however, the effect is minor. Conclusion: Gel usage is clearly favourable to rectal DVH. Using adaptive planning with gel improves rectal DVH but is not necessary according to this study. Advances in knowledge: Spacer gel is used in prostate radiotherapy to increase distance between the prostate and the rectum, thus reducing the rectal doses. During the treatment course, gel resorption exists which affects the rectal doses. The usefulness of adaptive planning to compensate this resorption effect has not been studied before. PMID:26370300
A Bivariate Generalized Linear Item Response Theory Modeling Framework to the Analysis of Responses and Response Times.

PubMed

Molenaar, Dylan; Tuerlinckx, Francis; van der Maas, Han L J

2015-01-01

A generalized linear modeling framework to the analysis of responses and response times is outlined. In this framework, referred to as bivariate generalized linear item response theory (B-GLIRT), separate generalized linear measurement models are specified for the responses and the response times that are subsequently linked by cross-relations. The cross-relations can take various forms. Here, we focus on cross-relations with a linear or interaction term for ability tests, and cross-relations with a curvilinear term for personality tests. In addition, we discuss how popular existing models from the psychometric literature are special cases in the B-GLIRT framework depending on restrictions in the cross-relation. This allows us to compare existing models conceptually and empirically. We discuss various extensions of the traditional models motivated by practical problems. We also illustrate the applicability of our approach using various real data examples, including data on personality and cognitive ability.
Uncertainty analysis of absorbed dose calculations from thermoluminescence dosimeters.

PubMed

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

1992-01-01

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

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

Schaue, Doerthe, E-mail: dschaue@mednet.ucla.edu; Ratikan, Josephine A.; Iwamoto, Keisuke S.

Purpose: Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. Methods and Materials: Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-{gamma}more » enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4{sup +}CD25{sup hi}Foxp3{sup +} T cells. Results: After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. Conclusions: Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy.« less
Long-Term Safety and Immunogenicity of a Tetravalent Live-Attenuated Dengue Vaccine and Evaluation of a Booster Dose Administered to Healthy Thai Children

PubMed Central

Watanaveeradej, Veerachai; Simasathien, Sriluck; Mammen, Mammen P.; Nisalak, Ananda; Tournay, Elodie; Kerdpanich, Phirangkul; Samakoses, Rudiwilai; Putnak, Robert J.; Gibbons, Robert V.; Yoon, In-Kyu; Jarman, Richard G.; De La Barrera, Rafael; Moris, Philippe; Eckels, Kenneth H.; Thomas, Stephen J.; Innis, Bruce L.

2016-01-01

We evaluated the safety and immunogenicity of two doses of a live-attenuated, tetravalent dengue virus vaccine (F17/Pre formulation) and a booster dose in a dengue endemic setting in two studies. Seven children (7- to 8-year-olds) were followed for 1 year after dose 2 and then given a booster dose (F17/Pre formulation), and followed for four more years (Child study). In the Infant study, 49 2-year-olds, vaccinated as infants, were followed for approximately 3.5 years after dose 2 and then given a booster dose (F17) and followed for one additional year. Two clinically notable events were observed, both in dengue vaccine recipients in the Infant study: 1 case of dengue approximately 2.7 years after dose 2 and 1 case of suspected dengue after booster vaccinations. The booster vaccinations had a favorable safety profile in terms of reactogenicity and adverse events reported during the 1-month follow-up periods. No vaccine-related serious adverse events were reported during the studies. Neutralizing antibodies against dengue viruses 1–4 waned during the 1–3 years before boosting, which elicited a short-lived booster response but did not provide a long-lived, multivalent antibody response in most subjects. Overall, this candidate vaccine did not elicit a durable humoral immune response. PMID:27022153
Polybutadiene and Styrene-Butadiene rubbers for high-dose dosimetry

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

Oliveira, Lucas N.; Instituto de Pesquisas Energeticas e Nucleares -IPEN, Sao Paulo-SP; Vieira, Silvio L.

2015-07-01

Polybutadiene and Styrene-Butadiene are synthetical rubbers used widely for pneumatic tires manufacturing. In this research, the dosimeter characteristics of those rubbers were studied for application in high-dose dosimetry. The rubber samples were irradiated with doses of 10 Gy up to 10 kGy, using a {sup 60}Co Gamma Cell-220 system (dose rate of 1.089 kGy/h) and their readings were taken on a Fourier Transform Infrared Spectroscopy-FTIR system (model Frontier/Perkin Elmer). The ratios of two absorbance peaks were taken for each kind of rubber spectrum, Polybutadiene (1306/1130 cm{sup -1}) and Styrene-Butadiene (1449/1306 cm{sup -1}). The ratio calculated was used as the responsemore » to the irradiation, and is not uniform across the sample. From the results, it can be concluded for both rubbers: a) the dose-response curves may be useful for high-dose dosimetry (greater than 250 Gy); b) their response for reproducibility presented standard deviations lower than 2.5%; c) the relative sensitivity was higher for Styrene-Butadiene (1.86 kGy{sup -1}) than for Polybutadiene (1.81 kGy{sup -1}), d) for doses of 10 kGy to 200 kGy, there was no variation in the dosimetric response. Both types of rubber samples showed usefulness as high-dose dosimeters. (authors)« less
Effect of noopept and afobazole on the development of neurosis of learned helplessness in rats.

PubMed

Uyanaev, A A; Fisenko, V P; Khitrov, N K

2003-08-01

We studied the effects of new psychotropic preparations noopept and afobazole on acquisition of the conditioned active avoidance response and development of neurosis of learned helplessness in rats. Noopept in doses of 0.05-0.10 mg/kg accelerated acquisition of conditioned active avoidance response and reduced the incidence of learned helplessness in rats. Afobazole in a dose of 5 mg/kg produced an opposite effect, which is probably related to high selective anxiolytic activity of this preparation.
Investigation of EBT2 and EBT3 films for proton dosimetry in the 4-20 MeV energy range.

PubMed

Reinhardt, S; Würl, M; Greubel, C; Humble, N; Wilkens, J J; Hillbrand, M; Mairani, A; Assmann, W; Parodi, K

2015-03-01

Radiochromic films such as Gafchromic EBT2 or EBT3 films are widely used for dose determination in radiation therapy because they offer a superior spatial resolution compared to any other digital dosimetric 2D detector array. The possibility to detect steep dose gradients is not only attractive for intensity-modulated radiation therapy with photons but also for intensity-modulated proton therapy. Their characteristic dose rate-independent response makes radiochromic films also attractive for dose determination in cell irradiation experiments using laser-driven ion accelerators, which are currently being investigated as future medical ion accelerators. However, when using these films in ion beams, the energy-dependent dose response in the vicinity of the Bragg peak has to be considered. In this work, the response of these films for low-energy protons is investigated. To allow for reproducible and background-free irradiation conditions, the films were exposed to mono-energetic protons from an electrostatic accelerator, in the 4-20 MeV energy range. For comparison, irradiation with clinical photons was also performed. It turned out that in general, EBT2 and EBT3 films show a comparable performance. For example, dose-response curves for photons and protons with energies as low as 11 MeV show almost no differences. However, corrections are required for proton energies below 11 MeV. Care has to be taken when correction factors are related to an average LET from depth-dose measurements, because only the dose-averaged LET yields similar results as obtained in mono-energetic measurements.
Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.

Monte Carlo simulation of the dose response of a novel 2D silicon diode array for use in hybrid MRI-LINAC systems.

PubMed

Gargett, Maegan; Oborn, Brad; Metcalfe, Peter; Rosenfeld, Anatoly

2015-02-01

MRI-guided radiation therapy systems (MRIgRT) are being developed to improve online imaging during treatment delivery. At present, the operation of single point dosimeters and an ionization chamber array have been characterized in such systems. This work investigates a novel 2D diode array, named "magic plate," for both single point calibration and 2D positional performance, the latter being a key element of modern radiotherapy techniques that will be delivered by these systems. geant4 Monte Carlo methods have been employed to study the dose response of a silicon diode array to 6 MV photon beams, in the presence of in-line and perpendicularly aligned uniform magnetic fields. The array consists of 121 silicon diodes (dimensions 1.5 × 1.5 × 0.38 mm(3)) embedded in kapton substrate with 1 cm pitch, spanning a 10 × 10 cm(2) area in total. A geometrically identical, water equivalent volume was simulated concurrently for comparison. The dose response of the silicon diode array was assessed for various photon beam field shapes and sizes, including an IMRT field, at 1 T. The dose response was further investigated at larger magnetic field strengths (1.5 and 3 T) for a 4 × 4 cm(2) photon field size. The magic plate diode array shows excellent correspondence (< ± 1%) to water dose in the in-line orientation, for all beam arrangements and magnetic field strengths investigated. The perpendicular orientation, however, exhibits a dose shift with respect to water at the high-dose-gradient beam edge of jaw-defined fields [maximum (4.3 ± 0.8)% over-response, maximum (1.8 ± 0.8)% under-response on opposing side for 1 T, uncertainty 1σ]. The trend is not evident in areas with in-field dose gradients typical of IMRT dose maps. A novel 121 pixel silicon diode array detector has been characterized by Monte Carlo simulation for its performance inside magnetic fields representative of current prototype and proposed MRI-linear accelerator systems. In the in-line orientation, the silicon dose is directly proportional to the water dose. In the perpendicular orientation, there is a shift in dose response relative to water in the highest dose gradient regions, at the edge of jaw-defined and single-segment MLC fields. The trend was not observed in-field for an IMRT beam. The array is expected to be a valuable tool in MRIgRT dosimetry.
Monte Carlo simulation of the dose response of a novel 2D silicon diode array for use in hybrid MRI–LINAC systems

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

Gargett, Maegan, E-mail: mg406@uowmail.edu.au; Rosenfeld, Anatoly; Oborn, Brad

2015-02-15

Purpose: MRI-guided radiation therapy systems (MRIgRT) are being developed to improve online imaging during treatment delivery. At present, the operation of single point dosimeters and an ionization chamber array have been characterized in such systems. This work investigates a novel 2D diode array, named “magic plate,” for both single point calibration and 2D positional performance, the latter being a key element of modern radiotherapy techniques that will be delivered by these systems. Methods: GEANT4 Monte Carlo methods have been employed to study the dose response of a silicon diode array to 6 MV photon beams, in the presence of in-linemore » and perpendicularly aligned uniform magnetic fields. The array consists of 121 silicon diodes (dimensions 1.5 × 1.5 × 0.38 mm{sup 3}) embedded in kapton substrate with 1 cm pitch, spanning a 10 × 10 cm{sup 2} area in total. A geometrically identical, water equivalent volume was simulated concurrently for comparison. The dose response of the silicon diode array was assessed for various photon beam field shapes and sizes, including an IMRT field, at 1 T. The dose response was further investigated at larger magnetic field strengths (1.5 and 3 T) for a 4 × 4 cm{sup 2} photon field size. Results: The magic plate diode array shows excellent correspondence (< ± 1%) to water dose in the in-line orientation, for all beam arrangements and magnetic field strengths investigated. The perpendicular orientation, however, exhibits a dose shift with respect to water at the high-dose-gradient beam edge of jaw-defined fields [maximum (4.3 ± 0.8)% over-response, maximum (1.8 ± 0.8)% under-response on opposing side for 1 T, uncertainty 1σ]. The trend is not evident in areas with in-field dose gradients typical of IMRT dose maps. Conclusions: A novel 121 pixel silicon diode array detector has been characterized by Monte Carlo simulation for its performance inside magnetic fields representative of current prototype and proposed MRI–linear accelerator systems. In the in-line orientation, the silicon dose is directly proportional to the water dose. In the perpendicular orientation, there is a shift in dose response relative to water in the highest dose gradient regions, at the edge of jaw-defined and single-segment MLC fields. The trend was not observed in-field for an IMRT beam. The array is expected to be a valuable tool in MRIgRT dosimetry.« less
Identification of Differential Gene Expression Patterns after Acute Exposure to High and Low Doses of Low-LET Ionizing Radiation in a Reconstituted Human Skin Tissue

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

Tilton, Susan C.; Markillie, Lye Meng; Hays, Spencer

Our goal here was to identify dose and temporal dependent radiation responses in a complex tissue, reconstituted human skin. Direct sequencing of RNA (RNA-seq) was used to quantify altered transcripts following exposure to 0.1, 2 and 10 Gy of ionizing radiation at 3 and 8 hours. These doses include a low dose in the range of some medical diagnostic procedures (0.1 Gy), a dose typically received during radiotherapy (2.0 Gy) and a lethal dose (10 Gy). These doses could be received after an intentional or accidental radiation exposure and biomarkers are needed to rapidly and accurately triage exposed individuals. Amore » total of 1701 genes were deemed to be significantly affected by high dose radiation exposure with the majority of genes affected at 10 Gy. A group of 29 genes including GDF15, BBC3, PPM1D, FDXR, GADD45A, MDM2, CDKN1A, TP53INP1, CYCSP27, SESN1, SESN2, PCNA, and AEN were similarly altered at both 2 and 10 Gy, but not 0.1 Gy, at multiple time points. A much larger group of up regulated genes, including those involved in inflammatory responses, was significantly altered only after a 10 Gy exposure. At high doses, down regulated genes were associated with cell cycle regulation and exhibited an apparent linear response between 2 and 10 Gy. While only a handful of genes were significantly affected by 0.1 Gy exposure using stringent statistical filters, groups of related genes regulating cell cycle progression and inflammatory responses consistently exhibited opposite trends in their regulation compared to the high dose exposures. Differential regulation of PLK1 signaling at low and high doses was confirmed using qRT-PCR. These results indicate that some alterations in gene expression are qualitatively different at low and high doses of radiation in this model system.« less
Proton dose distribution measurements using a MOSFET detector with a simple dose-weighted correction method for LET effects.

PubMed

Kohno, Ryosuke; Hotta, Kenji; Matsuura, Taeko; Matsubara, Kana; Nishioka, Shie; Nishio, Teiji; Kawashima, Mitsuhiko; Ogino, Takashi

2011-04-04

We experimentally evaluated the proton beam dose reproducibility, sensitivity, angular dependence and depth-dose relationships for a new Metal Oxide Semiconductor Field Effect Transistor (MOSFET) detector. The detector was fabricated with a thinner oxide layer and was operated at high-bias voltages. In order to accurately measure dose distributions, we developed a practical method for correcting the MOSFET response to proton beams. The detector was tested by examining lateral dose profiles formed by protons passing through an L-shaped bolus. The dose reproducibility, angular dependence and depth-dose response were evaluated using a 190 MeV proton beam. Depth-output curves produced using the MOSFET detectors were compared with results obtained using an ionization chamber (IC). Since accurate measurements of proton dose distribution require correction for LET effects, we developed a simple dose-weighted correction method. The correction factors were determined as a function of proton penetration depth, or residual range. The residual proton range at each measurement point was calculated using the pencil beam algorithm. Lateral measurements in a phantom were obtained for pristine and SOBP beams. The reproducibility of the MOSFET detector was within 2%, and the angular dependence was less than 9%. The detector exhibited a good response at the Bragg peak (0.74 relative to the IC detector). For dose distributions resulting from protons passing through an L-shaped bolus, the corrected MOSFET dose agreed well with the IC results. Absolute proton dosimetry can be performed using MOSFET detectors to a precision of about 3% (1 sigma). A thinner oxide layer thickness improved the LET in proton dosimetry. By employing correction methods for LET dependence, it is possible to measure absolute proton dose using MOSFET detectors.
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. Using this approach, we have identified novel biological responses and potential absorbed dose-related biomarkers to (131)I exposure. Our research shows the importance of embracing technological advances and multi-disciplinary collaboration in order to apply them in radiation therapy, nuclear medicine, and radiation biology. This work may contribute with new knowledge of potential normal tissue effects or complications that may occur after exposure to ionizing radiation in diagnostic and therapeutic nuclear medicine, and due to radioactive fallout or accident with radionuclide spread. Copyright © 2014 Elsevier Inc. All rights reserved.
Chromosomal Aberrations in DNA Repair Defective Cell Lines: Comparisons of Dose Rate and Radiation Quality

NASA Technical Reports Server (NTRS)

George, K. A.; Hada, M.; Patel, Z.; Huff, J.; Pluth, J. M.; Cucinotta, F. A.

2009-01-01

Chromosome aberration yields were assessed in DNA double-strand break repair (DSB) deficient cells after acute doses of gamma-rays or high-LET iron nuclei, or low dose-rate (0.018 Gy/hr) gamma-rays. We studied several cell lines including fibroblasts deficient in ATM (product of the gene that is mutated in ataxia telangiectasia patients) or NBS (product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase, DNA-PK activity. Chromosomes were analyzed using the fluorescence in-situ hybridization (FISH) chromosome painting method in cells at the first division post-irradiation and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). Gamma radiation induced higher yields of both simple and complex exchanges in the DSB repair defective cells than in the normal cells. The quadratic dose-response terms for both chromosome exchange types were significantly higher for the ATM and NBS defective lines than for normal fibroblasts. However, the linear dose-response term was significantly higher only for simple exchanges in the NBS cells. Large increases in the quadratic dose response terms indicate the important roles of ATM and NBS in chromatin modifications that facilitate correct DSB repair and minimize aberration formation. Differences in the response of AT and NBS deficient cells at lower doses suggests important questions about the applicability of observations of radiation sensitivity at high dose to low dose exposures. For all iron nuclei irradiated cells, regression models preferred purely linear and quadratic dose responses for simple and complex exchanges, respectively. All the DNA repair defective cell lines had lower Relative biological effectiveness (RBE) values than normal cells, the lowest being for the DNA-PK-deficient cells, which was near unity. To further investigate the sensitivity differences for low and low high doses, we performed chronic low dose-rate irradiation, and have begun studies with ATM and Nibrin inhibitors and siRNA knockout of these proteins. Results support the conclusion that for the endpoint of simple chromosomal aberrations (translocation or dicentrics), the increased radiation sensitivity of AT cells found at high doses (>1 Gy) does not carry over to low doses or doserates, while NBS cells show increased sensitivity for both high and low dose exposures.
Hormesis as a biological hypothesis.

PubMed Central

Calabrese, E J; Baldwin, L A

1998-01-01

A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer database searches by using various key word descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biological end points were assessed; growth responses were the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude. The average low-dose maximum stimulation was approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude, with the upper end of the hormetic curve approaching the estimated no observable effect level for the particular end point. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of > 6 doses; with > 3 doses in the hormetic zone. The present analysis suggests that chemical hormesis is a reproducible and relatively common biological phenomenon. A quantitative scheme is presented for future application to the database. PMID:9539030
Reducing radiation dose to the female breast during conventional and dedicated breast computed tomography

NASA Astrophysics Data System (ADS)

Rupcich, Franco John

The purpose of this study was to quantify the effectiveness of techniques intended to reduce dose to the breast during CT coronary angiography (CTCA) scans with respect to task-based image quality, and to evaluate the effectiveness of optimal energy weighting in improving contrast-to-noise ratio (CNR), and thus the potential for reducing breast dose, during energy-resolved dedicated breast CT. A database quantifying organ dose for several radiosensitive organs irradiated during CTCA, including the breast, was generated using Monte Carlo simulations. This database facilitates estimation of organ-specific dose deposited during CTCA protocols using arbitrary x-ray spectra or tube-current modulation schemes without the need to run Monte Carlo simulations. The database was used to estimate breast dose for simulated CT images acquired for a reference protocol and five protocols intended to reduce breast dose. For each protocol, the performance of two tasks (detection of signals with unknown locations) was compared over a range of breast dose levels using a task-based, signal-detectability metric: the estimator of the area under the exponential free-response relative operating characteristic curve, AFE. For large-diameter/medium-contrast signals, when maintaining equivalent AFE, the 80 kV partial, 80 kV, 120 kV partial, and 120 kV tube-current modulated protocols reduced breast dose by 85%, 81%, 18%, and 6%, respectively, while the shielded protocol increased breast dose by 68%. Results for the small-diameter/high-contrast signal followed similar trends, but with smaller magnitude of the percent changes in dose. The 80 kV protocols demonstrated the greatest reduction to breast dose, however, the subsequent increase in noise may be clinically unacceptable. Tube output for these protocols can be adjusted to achieve more desirable noise levels with lesser dose reduction. The improvement in CNR of optimally projection-based and image-based weighted images relative to photon-counting was investigated for six different energy bin combinations using a bench-top energy-resolving CT system with a cadmium zinc telluride (CZT) detector. The non-ideal spectral response reduced the CNR for the projection-based weighted images, while image-based weighting improved CNR for five out of the six investigated bin combinations, despite this non-ideal response, indicating potential for image-based weighting to reduce breast dose during dedicated breast CT.
A living cell quartz crystal microbalance biosensor for continuous monitoring of cytotoxic responses of macrophages to single-walled carbon nanotubes

PubMed Central

2011-01-01

Background Numerous engineered nanomaterials (ENMs) exist and new ENMs are being developed. A challenge to nanotoxicology and environmental health and safety is evaluating toxicity of ENMs before they become widely utilized. Cellular assays remain the predominant test platform yet these methods are limited by using discrete time endpoints and reliance on organic dyes, vulnerable to interference from ENMs. Label-free, continuous, rapid response systems with biologically meaningful endpoints are needed. We have developed a device to detect and monitor in real time responses of living cells to ENMs. The device, a living cell quartz crystal microbalance biosensor (QCMB), uses macrophages adherent to a quartz crystal. The communal response of macrophages to treatments is monitored continuously as changes in crystal oscillation frequency (Δf). We report the ability of this QCMB to distinguish benign from toxic exposures and reveal unique kinetic information about cellular responses to varying doses of single-walled carbon nanotubes (SWCNTs). Results We analyzed macrophage responses to additions of Zymosan A, polystyrene beads (PBs) (benign substances) or SWCNT (3-150 μg/ml) in the QCMB over 18 hrs. In parallel, toxicity was monitored over 24/48 hrs using conventional viability assays and histological stains to detect apoptosis. In the QCMB, a stable unchanging oscillation frequency occurred when cells alone, Zymosan A alone, PBs alone or SWCNTs without cells at the highest dose alone were used. With living cells in the QCMB, when Zymosan A, PBs or SWCNTs were added, a significant decrease in frequency occurred from 1-6 hrs. For SWCNTs, this Δf was dose-dependent. From 6-18 hrs, benign substances or low dose SWCNT (3-30 μg/ml) treatments showed a reversal of the decrease of oscillation frequency, returning to or exceeding pre-treatment levels. Cell recovery was confirmed in conventional assays. The lag time to see the Δf reversal in QCMB plots was linearly SWCNT-dose dependent. Lastly, the frequency never reversed at high dose SWCNT (100-150 μg/ml), and apoptosis/necrosis was documented in conventional 24 and 48 hr-assays. Conclusion These data suggest that the new QCMB detects and provides unique information about peak, sub-lethal and toxic exposures of living cells to ENMs before they are detected using conventional cell assays. PMID:21266033
Characteristics and Predictors of Early and Delayed Responders to Ranibizumab Treatment in Neovascular Age-Related Macular Degeneration: A Retrospective Analysis from the ANCHOR, MARINA, HARBOR, and CATT Trials.

PubMed

Gale, Richard; Korobelnik, Jean-Francois; Yang, Yit; Wong, Tien Y

2016-01-01

This retrospective review examined visual acuity (VA) in subjects with neovascular age-related macular degeneration and identified early and delayed response to ranibizumab. MARINA, ANCHOR, HARBOR, and CATT published data were examined for response with monthly versus individualized dosing and predictors of early versus delayed response. Data were available for 1,631 subjects; 18-29% were early gainers and 15-16% were delayed gainers. Of the early gainers, 72-83% maintained their best-corrected VA gain at month 12 with monthly or individualized dosing. Delayed gainers in HARBOR almost reached the same level of response as early gainers by 12 months who were able to maintain their response. The main predictor of response was baseline VA. There are two distinct types of ranibizumab response; some responded by month 3, while others took up to 12 months. In delayed responders, this may have implications for switching or not switching therapies. © 2016 The Author(s) Published by S. Karger AG, Basel.
Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation.

PubMed

Loveman, E; Cooper, K; Bryant, J; Colquitt, J L; Frampton, G K; Clegg, A

2012-01-01

The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib. This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib. Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references. This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted. Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are summarised in this report, but caution in interpretation is required. One economic evaluation was identified that compared dasatinib with high-dose imatinib in patients with chronic-phase CML who were CML resistant to standard-dose imatinib. Two industry submissions and the PenTAG economic evaluation were critiqued and differences in the assumptions and results were identified. The PenTAG economic model was adapted and new analyses conducted for the interventions dasatinib, nilotinib and high-dose imatinib and the comparators interferon alfa, standard-dose imatinib, stem cell transplantation and hydroxycarbamide. The results suggest that the three interventions, dasatinib, nilotinib and high-dose imatinib, have similar costs and cost-effectiveness compared with hydroxycarbamide, with a cost-effectiveness of around £30,000 per quality-adjusted life-year gained. However, it is not possible to derive firm conclusions about the relative cost-effectiveness of the three interventions owing to great uncertainty around data inputs. Uncertainty was explored using deterministic sensitivity analyses, threshold analyses and probabilistic sensitivity analyses. The paucity of good-quality evidence should be considered when interpreting this report. This review has identified very limited new information on clinical effectiveness of the interventions over that already shown in the PenTAG report. Limitations in the data exist; however, the results of single-arm studies suggest that the interventions can lead to improvements in haematological and cytogenetic responses in people with imatinib-resistant CML. The economic analyses do not highlight any one of the interventions as being the most cost-effective; however, the analysis results are highly uncertain owing to lack of agreement on appropriate assumptions. Recommendations for future research made by PenTAG, for a good-quality RCT comparing the three treatments remain.
Dosimetric considerations and early clinical experience of accelerated partial breast irradiation using multi-lumen applicators in the setting of breast augmentation.

PubMed

Akhtari, Mani; Pino, Ramiro; Scarboro, Sarah B; Bass, Barbara L; Miltenburg, Darlene M; Butler, E Brian; Teh, Bin S

2015-12-01

Accelerated partial breast irradiation (APBI) is an accepted treatment option in breast-conserving therapy for early stage breast cancer. However, data regarding outcomes of patients treated with multi-lumen catheter systems who have existing breast implants is limited. The purpose of this study was to report treatment parameters, outcomes, and possible dosimetric correlation with cosmetic outcome for this population of patients at our institution. We report the treatment and outcome of seven consecutive patients with existing breast implants and early stage breast cancer who were treated between 2009 and 2013 using APBI following lumpectomy. All patients were treated twice per day for five days to a total dose of 34 Gy using a high-dose-rate (192)Ir source. Cosmetic outcomes were evaluated using the Harvard breast cosmesis scale, and late toxicities were reported using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity schema. After a mean follow-up of 32 months, all patients have remained cancer free. Six out of seven patients had an excellent or good cosmetic outcome. There were no grade 3 or 4 late toxicities. The average total breast implant volume was 279.3 cc, received an average mean dose of 12.1 Gy, and a maximum dose of 234.1 Gy. The average percentage of breast implant volume receiving 50%, 75%, 100%, 150%, and 200% of the prescribed dose was 15.6%, 7.03%, 4.6%, 1.58%, and 0.46%, respectively. Absolute volume of breast implants receiving more than 50% of prescribed dose correlated with worse cosmetic outcomes. Accelerated partial breast irradiation using a multi-lumen applicator in patients with existing breast implants can safely be performed with promising early clinical results. The presence of the implant did not compromise the ability to achieve dosimetric criteria; however, dose to the implant and the irradiated implant volume may be related with worse cosmetic outcomes.
Dosimetric considerations and early clinical experience of accelerated partial breast irradiation using multi-lumen applicators in the setting of breast augmentation

PubMed Central

Akhtari, Mani; Pino, Ramiro; Scarboro, Sarah B.; Bass, Barbara L.; Miltenburg, Darlene M.; Butler, E. Brian

2015-01-01

Purpose Accelerated partial breast irradiation (APBI) is an accepted treatment option in breast-conserving therapy for early stage breast cancer. However, data regarding outcomes of patients treated with multi-lumen catheter systems who have existing breast implants is limited. The purpose of this study was to report treatment parameters, outcomes, and possible dosimetric correlation with cosmetic outcome for this population of patients at our institution. Material and methods We report the treatment and outcome of seven consecutive patients with existing breast implants and early stage breast cancer who were treated between 2009 and 2013 using APBI following lumpectomy. All patients were treated twice per day for five days to a total dose of 34 Gy using a high-dose-rate 192Ir source. Cosmetic outcomes were evaluated using the Harvard breast cosmesis scale, and late toxicities were reported using the Radiation Therapy Oncology Group (RTOG) late radiation morbidity schema. Results After a mean follow-up of 32 months, all patients have remained cancer free. Six out of seven patients had an excellent or good cosmetic outcome. There were no grade 3 or 4 late toxicities. The average total breast implant volume was 279.3 cc, received an average mean dose of 12.1 Gy, and a maximum dose of 234.1 Gy. The average percentage of breast implant volume receiving 50%, 75%, 100%, 150%, and 200% of the prescribed dose was 15.6%, 7.03%, 4.6%, 1.58%, and 0.46%, respectively. Absolute volume of breast implants receiving more than 50% of prescribed dose correlated with worse cosmetic outcomes. Conclusions Accelerated partial breast irradiation using a multi-lumen applicator in patients with existing breast implants can safely be performed with promising early clinical results. The presence of the implant did not compromise the ability to achieve dosimetric criteria; however, dose to the implant and the irradiated implant volume may be related with worse cosmetic outcomes. PMID:26816499
Alternative chitosan-based EPR dosimeter applicable for a relatively wide range of gamma radiation doses

NASA Astrophysics Data System (ADS)

Piroonpan, Thananchai; Katemake, Pichayada; Panritdam, Eagkapong; Pasanphan, Wanvimol

2017-12-01

Chitosan biopolymer is proposed as an alternative EPR dosimeter. Its ability to be EPR dosimeter was studied in comparison with the conventional alanine, sugars (i.e., glucose and sucrose), formate derivatives (i.e., lithium (Li), magnesium (Mg), and calcium (Ca) formate). Ethylene vinyl acetate (EVA) and paraffin were used as binder for the preparation of composite EPR dosimeter. Dose responses of all materials were investigated in a wide dose range of radiation doses, i.e., low-level (0-1 kGy), medium-level (1-10 kGy) and high-level (10-100 kGy). The EPR dosimeter properties were studied under different parameters, i.e., microwave power, materials contents, absorbed doses, storage conditions and post-irradiation effects. Li-formate showed a simple EPR spectrum and exhibited superior radiation response for low-dose range; whereas chitosan and sucrose exhibited linear dose response in all studied dose ranges. The EPR signals of chitosan exhibited similar stability as glucose, Li-formate and alanine at ambient temperature after irradiation as long as a year. All EPR signals of the studied materials were affected post-irradiation temperature and humidity after gamma irradiation. The EPR signal of chitosan exhibited long-term stability and it was not sensitive to high storage temperatures and humidity values after irradiation. Chitosan has a good merit as the alternative bio-based material for a stable EPR dosimeter in a wide range of radiation-absorbed doses.
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.
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.
An approach to assessing stochastic radiogenic risk in medical imaging

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

Wolbarst, Anthony B.; Hendee, William R.; Department of Radiology, Mayo Clinic, Rochester, Minnesota 55901

2011-12-15

Purpose: This letter suggests a formalism, the medical effective dose (MED), that is suitable for assessing stochastic radiogenic risks in diagnostic medical procedures. Methods: The MED is derived from radiobiological and probabilistic first principals, including: (1) The independence of radiation-induced biological effects in neighboring voxels at low doses; (2) the linear no-threshold assumption for stochastic radiation injury (although other dose-response relationships could be incorporated, instead); (3) the best human radiation dose-response data currently available; and (4) the built-in possibility that the carcinogenic risk to an irradiated organ may depend on its volume. The MED involves a dose-risk summation over irradiatedmore » voxels at high spatial resolution; it reduces to the traditional effective dose when every organ is irradiated uniformly and when the dependence of risk on organ volumes is ignored. Standard relative-risk tissue weighting factors can be used with the MED approach until more refined data become available. Results: The MED is intended for clinical and phantom dosimetry, and it provides an estimate of overall relative radiogenic stochastic risk for any given dose distribution. A result of the MED derivation is that the stochastic risk may increase with the volume of tissue (i.e., the number of cells) irradiated, a feature that can be activated when forthcoming radiobiological research warrants it. In this regard, the MED resembles neither the standard effective dose (E) nor the CT dose index (CTDI), but it is somewhat like the CT dose-length product (DLP). Conclusions: The MED is a novel, probabilistically and biologically based means of estimating stochastic-risk-weighted doses associated with medical imaging. Built in, ab initio, is the ability to link radiogenic risk to organ volume and other clinical factors. It is straightforward to implement when medical dose distributions are available, provided that one is content, for the time being, to accept the relative tissue weighting factors published by the International Commission of Radiological Protection (ICRP). It requires no new radiobiological data and avoids major problems encountered by the E, CTDI, and CT-E formalisms. It makes possible relative inter-patient dosimetry, and also realistic intercomparisons of stochastic risks from different protocols that yield images of comparable quality.« less
TH-CD-201-08: Flexible Dosimeter Bands for Whole-Body Dosimetry

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

Kim, T; Fahimian, B; Pratx, G

Purpose: The two commonly used radiotherapy techniques are total body irradiation (TBI) and the total skin irradiation (TSI). In order to ensure the accuracy of the prescription beams, the dose received throughout the entire body must be checked using dosimetry. However, the available number of data points is limited as the dosimeters are manually placed on the patient. We developed a flexible and wearable dosimeter that can collect 1D continuous dose information around the peripheral of the patients’ body, including areas obscured from the beam path. Methods: The flexible dosimeter bands are fabricated by embedding storage phosphor powders in amore » thin layer of non-toxic silicone based elastomer (PDMS). An additional elastomer layer is formed on top of the phosphor layer to provide additional mechanical support for the dosimeter. Once the curing process is complete, the dosimeter is cut into multiple bands and rolled into spools prior to use. Results: The dose responses are tested using a preclinical cabinet X-ray system, where the readout is performed with a storage phosphor reader. Results show that the dose calibration factor is ∼1400 (A.U./Gy) from the beam center. Also, 1-D dose distribution experiment was performed in water phantoms, where preliminary results demonstrate that the dose in water is indeed attenuated compared to in air. Conclusion: Dose response and high-resolution 1-D dosimetry is demonstrated using the flexible dosimeters. By providing a detailed spatial description of the beam dose profile, we expect that the dosimeter bands may aid in enhancing the current existing modality in dosimetry. Since the dosimeter is flexible (can retract back to its original length), they can be comfortably worn around the patient. Potentially, multiple 1-D dose information can be stitched together and extrapolated to provide a coarse 3-D image of the dose distribution. This work was supported by funding from the Cutaneous Lymphoma Foundation under the CLARIONS grant.« less
Induction of potent local cellular immunity with low dose X4 SHIV{sub SF33A} vaginal exposure

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

Tasca, Silvana; Tsai, Lily; Trunova, Nataliya

2007-10-10

Intravaginal inoculation of rhesus macaques with varying doses of the CXCR4 (X4)-tropic SHIV{sub SF33A} isolate revealed a threshold inoculum for establishment of systemic virus infection and a dose dependency in overall viral burden and CD4+ T cell depletion. While exposure to inoculum size of 1000 or greater 50% tissue infectious dose (TCID{sub 50}) resulted in high viremia and precipitous CD4+ T cell loss, occult infection was observed in seven of eight macaques exposed to 500 TCID{sub 50} of the same virus. The latter was characterized by intermittent detection of low level virus with no evidence of seroconversion or CD4+ Tmore » cell decline, but with signs of an ongoing antiviral T cell immune response. Upon vaginal re-challenge with the same limiting dose 11-12 weeks after the first, classic pathogenic X4 SHIV{sub SF33A} infection was established in four of the seven previously exposed seronegative macaques, implying enhanced susceptibility to systemic infection with prior exposure. Pre-existing peripheral SIV gag-specific CD4+ T cells were more readily demonstrable in macaques that became systemically infected following re-exposure than those that were not. In contrast, early presence of circulating polyfunctional cytokine secreting CD8+ T cells or strong virus-specific proliferative responses in draining lymph nodes and in the gut associated lymphoid tissue (GALT) following the first exposure was associated with protection from systemic re-infection. These studies identify the gut and lymphoid tissues proximal to the genital tract as sites of robust CD8 T lymphocyte responses that contribute to containment of virus spread following vaginal transmission.« less
The 10th anniversary of the publication of genes and environment: memoir of establishing the Japanese environmental mutagen society and a proposal for a new collaborative study on mutagenic hormesis.

PubMed

Sutou, Shizuyo

2017-01-01

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

Discriminative stimulus effects of cocaine and amphetamine in rats following developmental exposure to polychlorinated biphenyls (PCBs)

PubMed Central

Sable, Helen J. K.; Monaikul, Supida; Poon, Emily; Eubig, Paul A.; Schantz, Susan L.

2010-01-01

Polychlorinated biphenyls (PCBs) are environmental neurotoxicants known to affect the brain dopaminergic (DA) system. This project investigated whether developmental exposure to PCBs would alter the discriminative stimulus effects of psychostimulant drugs known to act on the DA system. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day of an environmentally relevant PCB mixture from four weeks prior to breeding through weaning of their litters on PND 21. When they reached adulthood one male and female/litter were trained to discriminate cocaine (10.0 mg/kg, IP) from saline by repeatedly pairing cocaine injections with reinforcement on one operant response lever, and saline injections with reinforcement on the other lever. After response training, generalization tests to four lower doses of cocaine (7.5, 5.0, 2.5, and 1.25 mg/kg, IP) and to amphetamine (1.0, 0.5, 0.25, and 0.125 mg/kg, IP) were given two days/week, with additional training dose days in-between. Percent responding of the PCB-exposed rats on the cocaine-paired lever was significantly higher than that of controls for the highest generalization dose of cocaine, and lower than that of controls for the highest dose of amphetamine. Response rate and percent responding on the cocaine lever did not differ among the exposure groups on the days when the training dose of cocaine was given, suggesting the generalization test results were not due to pre-existing differences in discrimination ability or rate of responding. These findings suggest developmental PCB exposure can alter the interoceptive cues of psychostimulants. PMID:20933596
Dose-response relationships in gene expression profiles in rainbow trout, Oncorhyncus mykiss, exposed to ethynylestradiol.

PubMed

Hook, Sharon E; Skillman, Ann D; Small, Jack A; Schultz, Irvin R

2006-07-01

Determining how gene expression profiles change with toxicant dose will improve the utility of arrays in identifying biomarkers and modes of toxic action. Isogenic rainbow trout, Oncorhyncus mykiss,were exposed to 10, 50 or 100 ng/L ethynylestradiol (a xeno-estrogen) for 7 days. Following exposure hepatic RNA was extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNAs. Transcript expression in treated vs control fish was analyzed via Genespring (Silicon Genetics) to identify genes with altered expression, as well as to determine gene clustering patterns that can be used as "expression signatures". Array results were confirmed via qRT PCR. Our analysis indicates that gene expression profiles varied somewhat with dose. Established biomarkers of exposure to estrogenic chemicals, such as vitellogenin, vitelline envelope proteins, and the estrogen receptor alpha, were induced at every dose. Other genes were dose specific, suggesting that different doses induce distinct physiological responses. These findings demonstrate that cDNA microarrays could be used to identify both toxicant class and relative dose.
Linking fluorescence induction curve and biomass in herbicide screening.

PubMed

Christensen, Martin G; Teicher, Harald B; Streibig, Jens C

2003-12-01

A suite of dose-response bioassays with white mustard (Sinapis alba L) and sugar beet (Beta vulgaris L) in the greenhouse and with three herbicides was used to analyse how the fluorescence induction curves (Kautsky curves) were affected by the herbicides. Bentazone, a photosystem II (PSII) inhibitor, completely blocked the normal fluorescence decay after the P-step. In contrast, fluorescence decay was still obvious for flurochloridone, a PDS inhibitor, and glyphosate, an EPSP inhibitor, which indicated that PSII inhibition was incomplete. From the numerous parameters that can be derived from OJIP-steps of the Kautsky curve the relative changes at the J-step [Fvj = (Fm - Fj)/Fm] was selected to be a common response parameter for the herbicides and yielded consistent dose-response relationships. Four hours after treatment, the response Fvj on the doses of bentazone and flurochloridone could be measured. For glyphosate, the changes of the Kautsky curve could similarly be detected 4 h after treatment in sugar beet, but only after 24 hs in S alba. The best prediction of biomass in relation to Fvj was found for bentazone. The experiments were conducted between May and August 2002 and showed that the ambient temperature and solar radiation in the greenhouse could affect dose-response relationships. If the Kautsky curve parameters should be used to predict the outcome of herbicide screening experiments in the greenhouse, where ambient radiation and temperature can only partly be controlled, it is imperative that the chosen fluorescence parameters can be used to predict accurately the resulting biomass used in classical bioassays.
Mortality among mound workers exposed to polonium-210 and other sources of radiation, 1944-1979.

PubMed

Boice, John D; Cohen, Sarah S; Mumma, Michael T; Ellis, Elizabeth Dupree; Cragle, Donna L; Eckerman, Keith F; Wallace, Phillip W; Chadda, Bandana; Sonderman, Jennifer S; Wiggs, Laurie D; Richter, Bonnie S; Leggett, Richard W

2014-02-01

Polonium-210 is a naturally occurring radioactive element that decays by emitting an alpha particle. It is in the air we breathe and also a component of tobacco smoke. Polonium-210 is used as an anti-static device in printing presses and gained widespread notoriety in 2006 after the poisoning and subsequent death of a Russian citizen in London. More is known about the lethal effects of polonium-210 at high doses than about late effects from low doses. Cancer mortality was examined among 7,270 workers at the Mound nuclear facility near Dayton, OH where polonium-210 was used (1944-1972) in combination with beryllium as a source of neutrons for triggering nuclear weapons. Other exposures included external gamma radiation and to a lesser extent plutonium-238, tritium and neutrons. Vital status and cause of death was determined through 2009. Standardized mortality ratios (SMRs) were computed for comparisons with the general population. Lifetime occupational doses from all places of employment were sought and incorporated into the analysis. Over 200,000 urine samples were analyzed to estimate radiation doses to body organs from polonium and other internally deposited radionuclides. Cox proportional hazards models were used to evaluate dose-response relationships for specific organs and tissues. Vital status was determined for 98.7% of the workers of which 3,681 had died compared with 4,073.9 expected (SMR 0.90; 95% CI 0.88-0.93). The mean dose from external radiation was 26.1 mSv (maximum 939.1 mSv) and the mean lung dose from external and internal radiation combined was 100.1 mSv (maximum 17.5 Sv). Among the 4,977 radiation workers, all cancers taken together (SMR 0.86; 95% CI 0.79-0.93), lung cancer (SMR 0.85; 95% CI 0.74-0.98), and other types of cancer were not significantly elevated. Cox regression analysis revealed a significant positive dose-response trend for esophageal cancer [relative risk (RR) and 95% confidence interval at 100 mSv of 1.54 (1.15-2.07)] and a negative dose-response trend for liver cancer [RR (95% CI) at 100 mSv of 0.55 (0.23-1.32)]. For lung cancer the RR at 100 mSv was 1.00 (95% CI 0.97-1.04) and for all leukemias other than chronic lymphocytic leukemia (CLL) it was 1.04 (95% CI 0.63-1.71). There was no evidence that heart disease was associated with exposures [RR at 100 mSv of 1.06 (0.95-1.18)]. Assuming a relative biological effectiveness factor of either 10 or 20 for polonium and plutonium alpha particle emissions had little effect on the dose-response analyses. Polonium was the largest contributor to lung dose, and a relative risk of 1.04 for lung cancer at 100 mSv could be excluded with 95% confidence. A dose related increase in cancer of the esophagus was consistent with a radiation etiology but based on small numbers. A dose-related decrease in liver cancer suggests the presence of other modifying factors of risk and adds caution to interpretations. The absence of a detectable increase in total cancer deaths and lung cancer in particular associated with occupational exposures to polonium (mean lung dose 159.8 mSv), and to plutonium to a lesser extent (mean lung dose 13.7 mSv), is noteworthy but based on small numbers. Larger combined studies of U.S. workers are needed to clarify radiation risks following prolonged exposures and radionuclide intakes.
Mortality Among Mound Workers Exposed to Polonium-210 and Other Sources of Radiation, 1944–1979

DOE PAGES

Boice, John D.; Cohen, Sarah S.; Mumma, Michael T.; ...

2014-02-14

Polonium-210 is a naturally occurring radioactive element that decays by emitting an alpha particle. It is in the air we breathe and also a component of tobacco smoke. Polonium-210 is used as an anti-static device in printing presses and gained widespread notoriety in 2006 after the poisoning and subsequent death of a Russian citizen in London. More is known about the lethal effects of polonium-210 at high doses than about late effects from low doses. In this paper, cancer mortality was examined among 7,270 workers at the Mound nuclear facility near Dayton, OH where polonium-210 was used (1944–1972) in combinationmore » with beryllium as a source of neutrons for triggering nuclear weapons. Other exposures included external gamma radiation and to a lesser extent plutonium-238, tritium and neutrons. Vital status and cause of death was determined through 2009. Standardized mortality ratios (SMRs) were computed for comparisons with the general population. Lifetime occupational doses from all places of employment were sought and incorporated into the analysis. Over 200,000 urine samples were analyzed to estimate radiation doses to body organs from polonium and other internally deposited radionuclides. Cox proportional hazards models were used to evaluate dose-response relationships for specific organs and tissues. Vital status was determined for 98.7% of the workers of which 3,681 had died compared with 4,073.9 expected (SMR 0.90; 95% CI 0.88–0.93). The mean dose from external radiation was 26.1 mSv (maximum 939.1 mSv) and the mean lung dose from external and internal radiation combined was 100.1 mSv (maximum 17.5 Sv). Among the 4,977 radiation workers, all cancers taken together (SMR 0.86; 95% CI 0.79–0.93), lung cancer (SMR 0.85; 95% CI 0.74–0.98), and other types of cancer were not significantly elevated. Cox regression analysis revealed a significant positive dose-response trend for esophageal cancer [relative risk (RR) and 95% confidence interval at 100 mSv of 1.54 (1.15–2.07)] and a negative dose-response trend for liver cancer [RR (95% CI) at 100 mSv of 0.55 (0.23–1.32)]. For lung cancer the RR at 100 mSv was 1.00 (95% CI 0.97–1.04) and for all leukemias other than chronic lymphocytic leukemia (CLL) it was 1.04 (95% CI 0.63–1.71). There was no evidence that heart disease was associated with exposures [RR at 100 mSv of 1.06 (0.95–1.18)]. Assuming a relative biological effectiveness factor of either 10 or 20 for polonium and plutonium alpha particle emissions had little effect on the dose-response analyses. Polonium was the largest contributor to lung dose, and a relative risk of 1.04 for lung cancer at 100 mSv could be excluded with 95% confidence. A dose related increase in cancer of the esophagus was consistent with a radiation etiology but based on small numbers. A dose-related decrease in liver cancer suggests the presence of other modifying factors of risk and adds caution to interpretations. The absence of a detectable increase in total cancer deaths and lung cancer in particular associated with occupational exposures to polonium (mean lung dose 159.8 mSv), and to plutonium to a lesser extent (mean lung dose 13.7 mSv), is noteworthy but based on small numbers. Finally, larger combined studies of U.S. workers are needed to clarify radiation risks following prolonged exposures and radionuclide intakes.« less
Mortality Among Mound Workers Exposed to Polonium-210 and Other Sources of Radiation, 1944–1979

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

Boice, John D.; Cohen, Sarah S.; Mumma, Michael T.

Polonium-210 is a naturally occurring radioactive element that decays by emitting an alpha particle. It is in the air we breathe and also a component of tobacco smoke. Polonium-210 is used as an anti-static device in printing presses and gained widespread notoriety in 2006 after the poisoning and subsequent death of a Russian citizen in London. More is known about the lethal effects of polonium-210 at high doses than about late effects from low doses. In this paper, cancer mortality was examined among 7,270 workers at the Mound nuclear facility near Dayton, OH where polonium-210 was used (1944–1972) in combinationmore » with beryllium as a source of neutrons for triggering nuclear weapons. Other exposures included external gamma radiation and to a lesser extent plutonium-238, tritium and neutrons. Vital status and cause of death was determined through 2009. Standardized mortality ratios (SMRs) were computed for comparisons with the general population. Lifetime occupational doses from all places of employment were sought and incorporated into the analysis. Over 200,000 urine samples were analyzed to estimate radiation doses to body organs from polonium and other internally deposited radionuclides. Cox proportional hazards models were used to evaluate dose-response relationships for specific organs and tissues. Vital status was determined for 98.7% of the workers of which 3,681 had died compared with 4,073.9 expected (SMR 0.90; 95% CI 0.88–0.93). The mean dose from external radiation was 26.1 mSv (maximum 939.1 mSv) and the mean lung dose from external and internal radiation combined was 100.1 mSv (maximum 17.5 Sv). Among the 4,977 radiation workers, all cancers taken together (SMR 0.86; 95% CI 0.79–0.93), lung cancer (SMR 0.85; 95% CI 0.74–0.98), and other types of cancer were not significantly elevated. Cox regression analysis revealed a significant positive dose-response trend for esophageal cancer [relative risk (RR) and 95% confidence interval at 100 mSv of 1.54 (1.15–2.07)] and a negative dose-response trend for liver cancer [RR (95% CI) at 100 mSv of 0.55 (0.23–1.32)]. For lung cancer the RR at 100 mSv was 1.00 (95% CI 0.97–1.04) and for all leukemias other than chronic lymphocytic leukemia (CLL) it was 1.04 (95% CI 0.63–1.71). There was no evidence that heart disease was associated with exposures [RR at 100 mSv of 1.06 (0.95–1.18)]. Assuming a relative biological effectiveness factor of either 10 or 20 for polonium and plutonium alpha particle emissions had little effect on the dose-response analyses. Polonium was the largest contributor to lung dose, and a relative risk of 1.04 for lung cancer at 100 mSv could be excluded with 95% confidence. A dose related increase in cancer of the esophagus was consistent with a radiation etiology but based on small numbers. A dose-related decrease in liver cancer suggests the presence of other modifying factors of risk and adds caution to interpretations. The absence of a detectable increase in total cancer deaths and lung cancer in particular associated with occupational exposures to polonium (mean lung dose 159.8 mSv), and to plutonium to a lesser extent (mean lung dose 13.7 mSv), is noteworthy but based on small numbers. Finally, larger combined studies of U.S. workers are needed to clarify radiation risks following prolonged exposures and radionuclide intakes.« less
Low-dose carcinogenicity of 2-amino-3-methylimidazo[4,5-f ]quinoline in rats: Evidence for the existence of no-effect levels and a mechanism involving p21(Cip / WAF1).

PubMed

Wei, Min; Wanibuchi, Hideki; Nakae, Dai; Tsuda, Hiroyuki; Takahashi, Satoru; Hirose, Masao; Totsuka, Yukari; Tatematsu, Masae; Fukushima, Shoji

2011-01-01

The carcinogenicity of the low amounts of genotoxic carcinogens present in food is of pressing concern. The purpose of the present study was to determine the carcinogenicity of low doses of the dietary genotoxic carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and to investigate mechanisms by which IQ exerts its carcinogenic effects. A total of 1595 male F344 rats were divided into seven groups and administered with IQ at doses of 0, 0.001, 0.01, 0.1, 1, 10 and 100 p.p.m. in the diet for 16 weeks. We found that IQ doses of 1 p.p.m. and below did not induce preneoplastic lesions in either the liver or the colon, while IQ doses of 10 and 100 p.p.m. induced preneoplastic lesions in both of these organs. These results demonstrate the presence of no-effect levels of IQ for both liver and colon carcinogenicity in rats. The finding that p21(Cip/WAF1) was significantly induced in the liver at doses well below those required for IQ mediated carcinogenic effects suggests that induction of p21(Cip/WAF1) is one of the mechanisms responsible for the observed no-effect of low doses of IQ. Furthermore, IQ administration caused significant induction of CYP1A2 at doses of 0.01-10 p.p.m., but administration of 100 p.p.m. IQ induced CYP1A1 rather than CYP1A2. This result indicates the importance of dosage when interpreting data on the carcinogenicity and metabolic activation of IQ. Overall, our results suggest the existence of no-effect levels for the carcinogenicity of this genotoxic compound. © 2010 Japanese Cancer Association.
Contraction of guinea-pig lung parenchymal strips by substance P and related peptides.

PubMed

Foreman, J C; Shelly, R; Webber, S E

1985-12-01

A dose-response relationship for substance P and contraction of the lung parenchyma strip of the guinea-pig could only be obtained in the presence of a mixture of bacitracin, 1,4 dithio-L-threitol and ethylenediamine tetracetic acid, all at 100 microM, or in the presence of captopril, 1.8 mM. Substance P (50 nM) caused no contraction by itself but produced a shift to the left of the dose-response curve for histamine with a mean dose-ratio of 1.4 +/- 0.2 (S.E. of mean). The peptides physalaemin, eledoisin and kassinin were all approximately equipotent with substance P on the lung strip, in the presence of peptides inhibitors. [D-Pro4, D-Trp7,9,10]-SP4-11, produced dose-related inhibition of the contraction induced by substance P. Substance P activity in guinea-pig lung declined exponentially with a half-time of 2.3 min: bacitracin, dithiothreitol and EDTA (all 100 microM) increased this to 7.2 min and captopril (1.8 mM) to 5.1 min.
Body condition and response to pesticides in woodcocks

USGS Publications Warehouse

Stickel, William H.; Dodge, Wendell E.; Sheldon, William G.; DeWitt, James B.; Stickel, Lucille F.

1965-01-01

Response of woodcocks (Philohela minor) to heptachlor dosage was closely related to the physical condition of the birds, as reflected by body weight and by body weight in relation to capture weight: in a series of tests with underweight birds, nearly all woodcocks died at dosage levels well below those at which nearly all the birds in a normal-weight series lived. Heptachlor residues in tissues were determined and their loss with time was estimated. Dieldrin proved more toxic than heptachlor to birds of similar weight. Birds in good weight survived massive doses of DDT; some succumbed to smaller spaced serial doses, but only when these were accompanied by starvation rations. When birds were placed in foil-lined boxes after doses of heptachlor added to butter oil or corn oil, it became evident that they passed quantities of oil in about 3 hours, thus very likely ridding themselves of a large part of the heptachlor dose. It was concluded that other methods than dosage with encapsulated chemicals would be needed for appraisal of field effects of toxicants on woodcocks.
The influence of TRP53 in the dose response of radiation-induced apoptosis, DNA repair and genomic stability in murine haematopoietic cells

DOE PAGES

Lemon, Jennifer A.; Taylor, Kristina; Verdecchia, Kyle; ...

2014-01-01

Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type ( Trp53+/+) and heterozygous ( Trp53+/-) mice. The dose response for Trp53+/+ mice showed highermore » initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.« less
Premilitary Tobacco Use by Male Marine Corps Recruits

DTIC Science & Technology

2007-10-01

numerous dele- terious effects on dental health, including gingival recession, tooth loss , periodontal soft and hard tissue destruction, and cancers of the...decreased readiness. A pronounced, negative dose-response relationship exists between smoking and physical performance,5 and to- bacco use is one of the...Colby SM, Tiffany ST, Shiffman S, Niaura RS: Are adolescent smokers dependent on nicotine: a review of the evidence. Drug Alcohol Depend 2000; 59(Suppl 1
Investigating Genomic Mechanisms of Treatment Resistance in Castration ResistantProstate Cancer

DTIC Science & Technology

2017-07-01

be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. San Francisco, CA...hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and...dose of abiraterone at the time of clinical resistance does not result in second PSA declines. • A clinical research paper summarizing these findings as
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
tcpl: the ToxCast pipeline for high-throughput screening data.

PubMed

Filer, Dayne L; Kothiya, Parth; Setzer, R Woodrow; Judson, Richard S; Martin, Matthew T

2017-02-15

Large high-throughput screening (HTS) efforts are widely used in drug development and chemical toxicity screening. Wide use and integration of these data can benefit from an efficient, transparent and reproducible data pipeline. Summary: The tcpl R package and its associated MySQL database provide a generalized platform for efficiently storing, normalizing and dose-response modeling of large high-throughput and high-content chemical screening data. The novel dose-response modeling algorithm has been tested against millions of diverse dose-response series, and robustly fits data with outliers and cytotoxicity-related signal loss. tcpl is freely available on the Comprehensive R Archive Network under the GPL-2 license. martin.matt@epa.gov. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.
DOE Office of Scientific and Technical Information (OSTI.GOV)

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

Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studiesmore » of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of ≥60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques.« less
Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial.

PubMed

van Lunzen, Jan; Maggiolo, Franco; Arribas, José R; Rakhmanova, Aza; Yeni, Patrick; Young, Benjamin; Rockstroh, Jürgen K; Almond, Steve; Song, Ivy; Brothers, Cindy; Min, Sherene

2012-02-01

Dolutegravir (S/GSK1349572) is a new HIV-1 integrase inhibitor that has antiviral activity with once daily, unboosted dosing. SPRING-1 is an ongoing study designed to select a dose for phase 3 assessment. We present data from preplanned primary and interim analyses. In a phase 2b, multicentre, dose-ranging study, treatment-naive adults were randomly assigned (1:1:1:1) to receive 10 mg, 25 mg, or 50 mg dolutegravir or 600 mg efavirenz. Dose but not drug allocation was masked. Randomisation was by a central integrated voice-response system according to a computer-generated code. Study drugs were given with either tenofovir plus emtricitabine or abacavir plus lamivudine. Our study was done at 34 sites in France, Germany, Italy, Russia, Spain, and the USA beginning on July 9, 2009. Eligible participants were seropositive for HIV-1, aged 18 years or older, and had plasma HIV RNA viral loads of at least 1000 copies per mL and CD4 counts of at least 200 cells per μL. Our primary endpoint was the proportion of participants with viral load of less than 50 copies per mL at week 16 and we present data to week 48. Analyses were done on the basis of allocation group and included all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00951015. 205 patients were randomly allocated and received at least one dose of study drug: 53, 51, and 51 to receive 10 mg, 25 mg, and 50 mg dolutegravir, respectively, and 50 to receive efavirenz. Week 16 response rates to viral loads of at most 50 copies per mL were 93% (144 of 155 participants) for all doses of dolutegravir (with little difference between dose groups) and 60% (30 of 50) for efavirenz; week 48 response rates were 87% (139 of 155) for all doses of dolutegravir and 82% (41 of 50) for efavirenz. Response rates between nucleoside reverse transcriptase inhibitor subgroups were similar. We identified three virological failures in the dolutegravir groups and one in the efavirenz group-we did not identify any integrase inhibitor mutations. We did not identify any dose-related clinical or laboratory toxic effects, with more drug-related adverse events of moderate-or-higher intensity in the efavirenz group (20%) than the dolutegravir group (8%). We did not judge that any serious adverse events were related to dolutegravir. Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials. Copyright © 2012 Elsevier Ltd. All rights reserved.
Leisure-time physical activity dose-response effects on obesity among US adults: results from the 1999-2006 National Health and Nutrition Examination Survey.

PubMed

Seo, Dong-Chul; Li, Kaigang

2010-05-01

It is not well established whether total volume of leisure-time physical activity (LTPA) has dose-response effects on obesity. The dose-response relationship was examined using 12 227 non-institutionalised individuals, aged 20-64 years, drawn from the 8 years (1999-2006) of the continuous National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. The age-adjusted prevalence of women's obesity was 41.4% for those with no LTPA in the past month; 39.1% for those who engaged in LTPA but fell short of the recommended minimum amount of LTPA (ie, <450 metabolic equivalent minutes per week (MET min/week)); 31.0% for those who met the recommended minimum guideline (ie, 450 to < 750); 28.0% for those whose LTPA exceeded the minimum guideline but less than the first quartile among the overachievers (ie, 750 to <1260); 23.4% for the overachievers between the first and third quartile (ie, 1260 to <3556); and 19.5% for the overachievers at or above the third quartile (ie, 3556 MET min/week or above). This association was maintained even after occupational physical activity (OPA) was controlled. However, this pattern was not observed for Mexican and black adults and showed a floor effect as LTPA increased. There is a crude graded inverse dose-response relationship between total volume of LTPA and obesity in US adult women, but not in men. Gender and racial/ethnic differences exist in the relationship of accumulated LTPA with obesity due, in part, to differential ratios of LTPA to OPA.
Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies.

PubMed

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

2011-11-01

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

PubMed

Gutzmer, R; Rivoltini, L; Levchenko, E; Testori, A; Utikal, J; Ascierto, P A; Demidov, L; Grob, J J; Ridolfi, R; Schadendorf, D; Queirolo, P; Santoro, A; Loquai, C; Dreno, B; Hauschild, A; Schultz, E; Lesimple, T P; Vanhoutte, N; Salaun, B; Gillet, M; Jarnjak, S; De Sousa Alves, P M; Louahed, J; Brichard, V G; Lehmann, F F

2016-01-01

The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. NCT01149343, Results.
DOE Office of Scientific and Technical Information (OSTI.GOV)

Richter, Christian; Pawelke, Joerg; Karsch, Leonhard

Purpose: The aim of this article is to investigate the energy dependence of the radiochromic film type, Gafchromic EBT-1, when scanned with a flatbed scanner for film readout. Methods: Dose response curves were determined for 12 different beam qualities ranging from a 10 kVp x-ray beam to a 15 MVp x-ray beam and include also two high energy electron beam qualities (6 and 18 MeV). The dose responses measured as net optical density (netOD) for the different beam qualities were normalized to the response of a reference beam quality (6 MVp). Results: A strong systematic energy dependence of the filmmore » response was found. The lower the effective beam energy, the less sensitive the EBT-1 films get. The maximum decrease in dose for the same film response between the 25 kVp and 6 MVp beam qualities was 44%. Additionally, a difference in energy dependence for different doses was discovered, meaning that higher doses show a smaller dependency on energy than lower doses. The maximum decrease in the normalized netOD was found to be 25% for a dose of 0.5 Gy relative to the normalized netOD for 10 Gy. Moreover, a scaling procedure is introduced, allowing the correction of the energy dependence for the investigated beam qualities and also for comparable x-ray beam qualities within the energy range studied. Conclusions: A strong energy dependence for EBT-1 radiochromic films was found. The films were readout with a flatbed scanner. If the effective beam energy is known, the energy dependence can be corrected with the introduced scaling procedure. Further investigation of the influence of the spectral band of the readout device on energy dependence is needed to understand the reason for the different energy dependences found in this and previous works.« less

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