Opposing roles for GABAA and GABAC receptors in short-term memory formation in young chicks.

PubMed

Gibbs, M E; Johnston, G A R

2005-01-01

The inhibitory neurotransmitter GABA has both inhibitory and enhancing effects on short-term memory for a bead discrimination task in the young chick. Low doses of GABA (1-3 pmol/hemisphere) injected into the multimodal association area of the chick forebrain, inhibit strongly reinforced memory, whereas higher doses (30-100 pmol/hemisphere) enhance weakly reinforced memory. The effect of both high and low doses of GABA is clearly on short-term memory in terms of both the time of injection and in the time that the memory loss occurs. We argue on the basis of relative sensitivities to GABA and to selective GABA receptor antagonists that low doses of GABA act at GABAC receptors (EC50 approximately 1 microM) and the higher doses of GABA act via GABAA receptors (EC50 approximately 10 microM). The selective GABAA receptor antagonist bicuculline inhibited strongly reinforced memory in a dose and time dependent manner, whereas the selective GABAC receptor antagonists TPMPA and P4MPA enhanced weakly reinforced in a dose and time dependent manner. Confirmation that different levels of GABA affect different receptor subtypes was demonstrated by the shift in the GABA dose-response curves to the selective antagonists. It is clear that GABA is involved in the control of short-term memory formation and its action, enhancing or inhibiting, depends on the level of GABA released at the time of learning.

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

Mysteries of LiF TLD response following high ionisation density irradiation: nanodosimetry and track structure theory, dose response and glow curve shapes.

PubMed

Horowitz, Y; Fuks, E; Datz, H; Oster, L; Livingstone, J; Rosenfeld, A

2011-06-01

Three outstanding effects of ionisation density on the thermoluminescence (TL) mechanisms giving rise to the glow peaks of LiF:Mg,Ti (TLD-100) are currently under investigation: (1) the dependence of the heavy charged particle (HCP) relative efficiency with increasing ionisation density and the effectiveness of its modelling by track structure theory (TST), (2) the behaviour of the TL efficiency, f(D), as a function of photon energy and dose. These studies are intended to promote the development of a firm theoretical basis for the evaluation of relative TL efficiencies to assist in their application in mixed radiation fields. And (3) the shape of composite peak 5 in the glow curve for various HCP types and energies and following high-dose electron irradiation, i.e. the ratio of the intensity of peak 5a to peak 5. Peak 5a is a low-temperature satellite of peak 5 arising from electron-hole capture in a spatially correlated trapping centre/luminescent centre (TC/LC) complex that has been suggested to possess a potential as a solid-state nanodosemeter due to the preferential electron/hole population of the TC/LC at high ionisation density. It is concluded that (1) the predictions of TST are very strongly dependent on the choice of photon energy used in the determination of f(D); (2) modified TST employing calculated values of f(D) at 2 keV is in agreement with 5-MeV alpha particle experimental results for composite peak 5 but underestimates the 1.5-MeV proton relative efficiencies. Both the proton and alpha particle relative TL efficiencies of the high-temperature TL (HTTL) peaks 7 and 8 are underestimated by an order of magnitude suggesting that the HTTL efficiencies are affected by other factors in addition to radial electron dose; (3) the dose-response supralinearity of peaks 7 and 8 change rapidly with photon energy: this behaviour is explained in the framework of the unified interaction model as due to a very strong dependence on photon energy of the relative intensity of localised recombination and (4) the increased width and decrease in T(max) of composite peak 5 as a function of ionisation density is due to the greater relative intensity of peak 5a (a low-temperature component of peak 5 arising from two-energy transfer events, which leads to localised recombination).

Paradox effects of binge drinking on response inhibition processes depending on mental workload.

PubMed

Stock, Ann-Kathrin; Riegler, Lea; Chmielewski, Witold X; Beste, Christian

2016-06-01

Binge drinking is an increasing problem in Western societies, but we are still only beginning to unravel the effects of binge drinking on a cognitive level. While common sense suggests that all cognitive functions are compromised during high-dose ethanol intoxication, several studies suggest that the effects might instead be rather specific. Moreover, some results suggest that the degrees of automaticity and complexity of cognitive operations during response control modulate effects of binge drinking. However, this has not been tested in detail. In the current study, we therefore parametrically modulate cognitive/"mental" workload during response inhibition and examine the effects of high-dose ethanol intoxication (~1.1 ‰) in n = 18 male participants. The results suggest that detrimental effects of high-dose ethanol intoxication strongly depend on the complexity of processes involved in response inhibition. The results revealed strong effects (η (2) = .495) and are in line with findings showing that even high doses of ethanol have very specific effects on a cognitive level. Opposed to common sense, more complex cognitive operations seem to be less affected by a high-dose ethanol intoxication. Complementing this, high-dose ethanol intoxication is increasingly detrimental for action control, as stronger automated response tendencies are in charge and need to be controlled. Binge-like ethanol intoxication may take a heavier toll on cognitive control processes than on automated responses/response tendencies. Therefore, ethanol effects are more pronounced in supposedly "easier" control conditions because those facilitate the formation of automated response tendencies.

Measuring the incentive value of escalating doses of heroin in heroin-dependent Fischer rats during acute spontaneous withdrawal

PubMed Central

Reed, Brian; Ho, Ann; Kreek, Mary Jeanne

2011-01-01

Rationale/objectives Although continued heroin use and relapse are thought to be motivated, in part, by the positive incentive-motivational value attributed to heroin, little is understood about heroin’s incentive value during the relapse-prone state of withdrawal. This study uses place preference to measure the incentive value attributed to escalating-dose heroin in the context of heroin dependence. Methods Male Fischer rats were exposed chronically to escalating doses of heroin in the homecage and during place preference conditioning sessions. Conditioned preference for the context paired with escalating-dose heroin was tested after homecage exposure was discontinued and rats entered acute spontaneous withdrawal. Individuals’ behavioral and locomotor responses to heroin and somatic withdrawal signs were recorded. Results Conditioned preference for the heroin-paired context was strong in rats that received chronic homecage exposure to escalating-dose heroin and were tested in acute withdrawal. Behavioral responses to heroin (e.g., stereotypy) varied widely across individuals, with rats that expressed stronger heroin preference also expressing stronger behavioral activation in response to heroin. Individual differences in preference were also related to locomotor responses to heroin but not to overt somatic withdrawal signs. Conclusions Escalating doses of heroin evoked place preference in rats, suggesting that positive incentive-motivational value is attributed to this clinically relevant pattern of drug exposure. This study offers an improved preclinical model for studying dependence and withdrawal and provides insight into individual vulnerabilities to addiction-like behavior. PMID:21748254

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

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

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

NASA Technical Reports Server (NTRS)

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

1999-01-01

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

Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion.

PubMed

Pilkinton, Mark A; Nicholas, Katherine J; Warren, Christian M; Smith, Rita M; Yoder, Sandra M; Talbot, H Keipp; Kalams, Spyros A

2017-01-05

Influenza related morbidity and mortality disproportionately impacts older adults. The serologic response to vaccine is diminished in older adults; however, high dose inactivated influenza vaccine (HD IIV) has shown improved rates of seroconversion compared to standard dose (SD IIV). We hypothesize this may be due to the superior ability of high dose vaccine to activate T follicular helper (Tfh) cells and provide B cell dependent T cell help. We measured peripheral Tfh (pTfh) activation in 50 community dwelling adults 65years or older who were randomly assigned to receive either the HD IIV or SD IIV. The HD vaccination elicited significantly higher levels of ICOS expression on pTfh cells, at day 7 compared to SD vaccination (p=0.02). The magnitude of the increase in ICOS+ pTfh cells from baseline to day 7 was predictive of seroconversion for both influenza A and B vaccination. Strong Tfh activation in response to influenza vaccination forecasts successful seroconversion in older adults, and HD IIV elicits greater Tfh activation than SD IIV. Future vaccine studies should focus on ways to further optimize the Tfh response. Copyright © 2016 Elsevier Ltd. All rights reserved.

Safe uses of Hill's model: an exact comparison with the Adair-Klotz model

PubMed Central

2011-01-01

Background The Hill function and the related Hill model are used frequently to study processes in the living cell. There are very few studies investigating the situations in which the model can be safely used. For example, it has been shown, at the mean field level, that the dose response curve obtained from a Hill model agrees well with the dose response curves obtained from a more complicated Adair-Klotz model, provided that the parameters of the Adair-Klotz model describe strongly cooperative binding. However, it has not been established whether such findings can be extended to other properties and non-mean field (stochastic) versions of the same, or other, models. Results In this work a rather generic quantitative framework for approaching such a problem is suggested. The main idea is to focus on comparing the particle number distribution functions for Hill's and Adair-Klotz's models instead of investigating a particular property (e.g. the dose response curve). The approach is valid for any model that can be mathematically related to the Hill model. The Adair-Klotz model is used to illustrate the technique. One main and two auxiliary similarity measures were introduced to compare the distributions in a quantitative way. Both time dependent and the equilibrium properties of the similarity measures were studied. Conclusions A strongly cooperative Adair-Klotz model can be replaced by a suitable Hill model in such a way that any property computed from the two models, even the one describing stochastic features, is approximately the same. The quantitative analysis showed that boundaries of the regions in the parameter space where the models behave in the same way exhibit a rather rich structure. PMID:21521501

Comparison of two indices of exposure to polycyclic aromatic hydrocarbons in a retrospective aluminium smelter cohort.

PubMed

Friesen, Melissa C; Demers, Paul A; Spinelli, John J; Lorenzi, Maria F; Le, Nhu D

2007-04-01

The association between coal tar-derived substances, a complex mixture of polycyclic aromatic hydrocarbons, and cancer is well established. However, the specific aetiological agents are unknown. To compare the dose-response relationships for two common measures of coal tar-derived substances, benzene-soluble material (BSM) and benzo(a)pyrene (BaP), and to evaluate which among these is more strongly related to the health outcomes. The study population consisted of 6423 men with > or =3 years of work experience at an aluminium smelter (1954-97). Three health outcomes identified from national mortality and cancer databases were evaluated: incidence of bladder cancer (n = 90), incidence of lung cancer (n = 147) and mortality due to acute myocardial infarction (AMI, n = 184). The shape, magnitude and precision of the dose-response relationships and cumulative exposure levels for BSM and BaP were evaluated. Two model structures were assessed, where 1n(relative risk) increased with cumulative exposure (log-linear model) or with log-transformed cumulative exposure (log-log model). The BaP and BSM cumulative exposure metrics were highly correlated (r = 0.94). The increase in model precision using BaP over BSM was 14% for bladder cancer and 5% for lung cancer; no difference was observed for AMI. The log-linear BaP model provided the best fit for bladder cancer. The log-log dose-response models, where risk of disease plateaus at high exposure levels, were the best-fitting models for lung cancer and AMI. BaP and BSM were both strongly associated with bladder and lung cancer and modestly associated with AMI. Similar conclusions regarding the associations could be made regardless of the exposure metric.

Therapeutic Response to Twice-daily Rabeprazole on Health-related Quality of Life and Symptoms in Patients with Refractory Reflux Esophagitis: A Multicenter Observational Study

PubMed Central

Kinoshita, Yoshikazu; Hongo, Michio; Kusano, Motoyasu; Furuhata, Yoshinori; Miyagishi, Hideaki; Ikeuchi, Satoshi

2017-01-01

Objective To investigate the effect of twice-daily rabeprazole doses on health-related quality of life in refractory patients. Methods and Patients Reflux esophagitis patients with an insufficient response to once-daily proton pump inhibitor therapy (Los Angeles Classification grade A-D) received rabeprazole 10 mg or 20 mg twice daily for 8 weeks. The health-related quality of life (SF-8™) and symptoms, using the Frequency Scale for the Symptoms of Gastroesophageal reflux disease, were evaluated before treatment and at weeks 4 and 8. Endoscopy was performed at baseline and at weeks 8 and 32 where possible. The rabeprazole dose was determined by the attending physician. Results There were 1,796 patients analyzed for the efficacy of the twice-daily treatment. Of these cases, 1,462 were treated with rabeprazole 10 mg twice daily, and 334 were treated with rabeprazole 20 mg twice daily. The factors that affected the selection of the twice-daily rabeprazole dose by physicians were evaluated, and as expected, “endoscopic findings when treatment was started” had a strong effect on the selection of the rabeprazole dose. With both regimens, health-related quality of life and subjective symptoms were significantly improved at weeks 4 and 8 compared to baseline (p<0.001). The recurrence rate of erosive esophagitis at week 32 was 9.7% in rabeprazole twice daily-treated patients and 28.4% in proton pump inhibitor (PPI) once daily-treated patients. Both regimens were well tolerated. Conclusion Twice-daily treatment with rabeprazole improved the subjective symptoms and health-related quality of life in patients with refractory reflux esophagitis more effectively than the standard once-daily dose. PMID:28502925

WE-D-210-04: Radiation-Induced Polymerization of Ultrasound Contrast Agents in View of Non-Invasive Dosimetry in External Beam Radiation Therapy

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

Callens, M; Verboven, E; Van Den Abeele, K

2015-06-15

Purpose: Ultrasound contrast agents (UCA’s) based on gas-filled microbubbles encapsulated by an amphiphilic shell are well established as safe and effective echo-enhancers in diagnostic imaging. In view of an alternative application of UCA’s, we investigated the use of targeted microbubbles as radiation sensors for external beam radiation therapy. As radiation induces permanent changes in the microbubble’s physico-chemical properties, a robust measure of these changes can provide a direct or indirect estimate of the applied radiation dose. For instance, by analyzing the ultrasonic dispersion characteristics of microbubble distributions before and after radiation treatment, an estimate of the radiation dose at themore » location of the irradiated volume can be made. To increase the radiation sensitivity of microbubbles, polymerizable diacetylene molecules can be incorporated into the shell. This study focuses on characterizing the acoustic response and quantifying the chemical modifications as a function of radiation dose. Methods: Lipid/diacetylene microbubbles were irradiated with a 6 MV photon beam using dose levels in the range of 0–150 Gy. The acoustic response of the microbubbles was monitored by ultrasonic through-transmission measurements in the range of 500 kHz to 20 MHz, thereby providing the dispersion relations of the phase velocity, attenuation and nonlinear coefficient. In addition, the radiation-induced chemical modifications were quantified using UV-VIS spectroscopy. Results: UV-VIS spectroscopy measurements indicate that ionizing radiation induces the polymerization of diacetylenes incorporated in the microbubble shell. The polymer yield strongly depends on the shell composition and the radiation-dose. The acoustic response is inherently related to the visco-elastic properties of the shell and is strongly influenced by the shell composition and the physico-chemical changes in the environment. Conclusion: Diacetylene-containing microbubbles are polymerizable under influence of ionizing radiation and are a promising design concept within the development of a novel non-invasive in-vivo radiation dosimeter for external beam radiation therapy. This work was funded by the Research Foundation - Flanders (FWO)« less

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.

Monte Carlo calculation of the sensitivity of a commercial dose calibrator to gamma and beta radiation.

PubMed

Laedermann, Jean-Pascal; Valley, Jean-François; Bulling, Shelley; Bochud, François O

2004-06-01

The detection process used in a commercial dose calibrator was modeled using the GEANT 3 Monte Carlo code. Dose calibrator efficiency for gamma and beta emitters, and the response to monoenergetic photons and electrons was calculated. The model shows that beta emitters below 2.5 MeV deposit energy indirectly in the detector through bremsstrahlung produced in the chamber wall or in the source itself. Higher energy beta emitters (E > 2.5 MeV) deposit energy directly in the chamber sensitive volume, and dose calibrator sensitivity increases abruptly for these radionuclides. The Monte Carlo calculations were compared with gamma and beta emitter measurements. The calculations show that the variation in dose calibrator efficiency with measuring conditions (source volume, container diameter, container wall thickness and material, position of the source within the calibrator) is relatively small and can be considered insignificant for routine measurement applications. However, dose calibrator efficiency depends strongly on the inner-wall thickness of the detector.

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

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

PubMed

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

1999-07-15

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

The dose-response ratio in electroconvulsive therapy a preliminary study.

PubMed

Price, T R; Mackenzie, T B; Tucker, G J; Culver, C

1978-09-01

To investigate pretreatment patient variables that might correlate with dose-response characteristics of electroconvulsive therapy (ECT) and treatment outcomes, 14 patients were assessed on a daily basis, before and during treatment, using self-report affective scales, three simple paper-and-pencil tests of cognitive function,and finger-tapping speed. From these data, dose-response ratios and treatment outcome measures were derived. The dose-response ratio of ECT was found to correlate with age--the younger the patient, the more favorable the ratio. This finding is discussed in terms of the known relationships between brain monoamine oxidase levels and age, and the established relationship between seizure duration and treatment efficacy. The dose-response ratio over the first two electroconvulsive treatments as well as lesser degrees of initial congnitive and greater degrees of initial affective impairment correlated strongly with greater overall affective improvement. Some clinical and research implications of these findings are discussed.

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

Testosterone influences spatial strategy preferences among adult male rats

PubMed Central

Spritzer, Mark D.; Fox, Elliott C.; Larsen, Gregory D.; Batson, Christopher G.; Wagner, Benjamin A.; Maher, Jack

2013-01-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats’ strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. PMID:23597827

Testosterone influences spatial strategy preferences among adult male rats.

PubMed

Spritzer, Mark D; Fox, Elliott C; Larsen, Gregory D; Batson, Christopher G; Wagner, Benjamin A; Maher, Jack

2013-05-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats' strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

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.

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...

Mysteries of LiF TLD response following high ionisation density irradiation: nanodosimetry and track structure theory, dose response and glow curve shapes

PubMed Central

Horowitz, Y.; Fuks, E.; Datz, H.; Oster, L.; Livingstone, J.; Rosenfeld, A.

2011-01-01

Three outstanding effects of ionisation density on the thermoluminescence (TL) mechanisms giving rise to the glow peaks of LiF:Mg,Ti (TLD-100) are currently under investigation: (1) the dependence of the heavy charged particle (HCP) relative efficiency with increasing ionisation density and the effectiveness of its modelling by track structure theory (TST), (2) the behaviour of the TL efficiency, f(D), as a function of photon energy and dose. These studies are intended to promote the development of a firm theoretical basis for the evaluation of relative TL efficiencies to assist in their application in mixed radiation fields. And (3) the shape of composite peak 5 in the glow curve for various HCP types and energies and following high-dose electron irradiation, i.e. the ratio of the intensity of peak 5a to peak 5. Peak 5a is a low-temperature satellite of peak 5 arising from electron-hole capture in a spatially correlated trapping centre/luminescent centre (TC/LC) complex that has been suggested to possess a potential as a solid-state nanodosemeter due to the preferential electron/hole population of the TC/LC at high ionisation density. It is concluded that (1) the predictions of TST are very strongly dependent on the choice of photon energy used in the determination of f(D); (2) modified TST employing calculated values of f(D) at 2 keV is in agreement with 5-MeV alpha particle experimental results for composite peak 5 but underestimates the 1.5-MeV proton relative efficiencies. Both the proton and alpha particle relative TL efficiencies of the high-temperature TL (HTTL) peaks 7 and 8 are underestimated by an order of magnitude suggesting that the HTTL efficiencies are affected by other factors in addition to radial electron dose; (3) the dose–response supralinearity of peaks 7 and 8 change rapidly with photon energy: this behaviour is explained in the framework of the unified interaction model as due to a very strong dependence on photon energy of the relative intensity of localised recombination and (4) the increased width and decrease in Tmax of composite peak 5 as a function of ionisation density is due to the greater relative intensity of peak 5a (a low-temperature component of peak 5 arising from two-energy transfer events, which leads to localised recombination). PMID:21106636

Limitations of body surface area-based activity calculation for radioembolization of hepatic metastases in colorectal cancer.

PubMed

Lam, Marnix G E H; Louie, John D; Abdelmaksoud, Mohamed H K; Fisher, George A; Cho-Phan, Cheryl D; Sze, Daniel Y

2014-07-01

To calculate absorbed radiation doses in patients treated with resin microspheres prescribed by the body surface area (BSA) method and to analyze dose-response and toxicity relationships. A retrospective review was performed of 45 patients with colorectal carcinoma metastases who received single-session whole-liver resin microsphere radioembolization. Prescribed treatment activity was calculated using the BSA method. Liver volumes and whole-liver absorbed doses (D(WL)) were calculated. D(WL) was correlated with toxicity and radiographic and biochemical response. The standard BSA-based administered activity (range, 0.85-2.58 GBq) did not correlate with D(WL) (mean, 50.4 Gy; range, 29.8-74.7 Gy; r = -0.037; P = .809) because liver weight was highly variable (mean, 1.89 kg; range, 0.94-3.42 kg) and strongly correlated with D(WL) (r = -0.724; P < .001) but was not accounted for in the BSA method. Patients with larger livers were relatively underdosed, and patients with smaller livers were relatively overdosed. Patients who received D(WL) > 50 Gy experienced more toxicity and adverse events (> grade 2 liver toxicity, 46% vs 17%; P < .05) but also responded better to the treatment than patients who received D(WL)< 50 Gy (disease control, 88% vs 24%; P < .01). Using the standard BSA formula, the administered activity did not correlate with D(WL). Based on this short-term follow-up after salvage therapy in patients with late stage metastatic colorectal carcinoma, dose-response and dose-toxicity relationships support using a protocol based on liver volume rather than BSA to prescribe the administered activity. Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.

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.

The frequency of U-shaped dose responses in the toxicological literature.

PubMed

Calabrese, E J; Baldwin, L A

2001-08-01

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.

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.

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.

Reference dosimetry using radiochromic film

PubMed Central

Girard, Frédéric; Bouchard, Hugo

2012-01-01

The objectives of this study are to identify and quantify factors that influence radiochromic film dose response and to determine whether such films are suitable for reference dosimetry. The influence of several parameters that may introduce systematic dose errors when performing reference dose measurements were investigated. The effect of the film storage temperature was determined by comparing the performance of three lots of GAFCHROMIC EBT2 films stored at either 4°C or room temperature. The effect of high (>80%) or low (<20%) relative humidity was also determined. Doses measured in optimal conditions with EBT and EBT2 films were then compared with an A12 ionization chamber measurement. Intensity‐modulated radiation therapy quality controls using EBT2 films were also performed in reference dose. The results obtained using reference dose measurements were compared with those obtained using relative dose measurements. Storing the film at 4°C improves the stability of the film over time, but does not eliminate the noncatalytic film development, seen as a rise in optical density over time in the absence of radiation. Relative humidity variations ranging from 80% to 20% have a strong impact on the optical density and could introduce dose errors of up to 15% if the humidity were not controlled during the film storage period. During the scanning procedure, the film temperature influences the optical density that is measured. When controlling for these three parameters, the dose differences between EBT or EBT2 and the A12 chamber are found to be within ±4% (2σ level) over a dose range of 20–350 cGy. Our results also demonstrate the limitation of the Anisotropic Analytical Algorithm for dose calculation of highly modulated treatment plans. PACS numbers: 87.55.Qr; 87.56.Fc PMID:23149793

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

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.

Probabilistic hazard assessment for skin sensitization potency by dose-response modeling using feature elimination instead of quantitative structure-activity relationships.

PubMed

Luechtefeld, Thomas; Maertens, Alexandra; McKim, James M; Hartung, Thomas; Kleensang, Andre; Sá-Rocha, Vanessa

2015-11-01

Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose-response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimensionality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high-quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals' potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter-relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose-informed random forest/hidden Markov model was superior to the dose-naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose-informed hidden Markov model strongly reduced " false-negatives" (i.e. extreme sensitizers as non-sensitizer) on all data sets. Copyright © 2015 John Wiley & Sons, Ltd.

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.

Radiation and breast cancer: a review of current evidence

PubMed Central

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

2005-01-01

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

Search for ionisation density effects in the radiation absorption stage in LiF:Mg,Ti.

PubMed

Nail, I; Horowitz, Y S; Oster, L; Brandan, M E; Rodríguez-Villafuerte, M; Buenfil, A E; Ruiz-Trejo, C; Gamboa-Debuen, I; Avila, O; Tovar, V M; Olko, P; Ipe, N

2006-01-01

Optical absorption (OA) dose-response of LiF:Mg,Ti (TLD-100) is studied as a function of electron energy (ionisation density) and irradiation dose. Contrary to the situation in thermoluminescence dose-response where the supralinearity is strongly energy-dependent, no dependence of the OA dose filling constants on energy is observed. This result is interpreted as indicating a lack of competitive process in the radiation absorption stage. The lack of an energy dependence of the dose filling constant also suggests that the charge carrier migration distances are sufficiently large to smear out the differences in the non-uniform distribution of ionisation events created by the impinging gamma/electron radiation of various energies.

Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression12

PubMed Central

Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J

2014-01-01

Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an ∼20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses. PMID:24563621

Increasing Stem Cell Dose Promotes Posttransplant Immune Reconstitution.

PubMed

Xu, Ning; Shen, Sylvie; Dolnikov, Alla

2017-04-01

Umbilical cord blood (UCB) transplantation can provide a successful therapeutic option for patients that have no suitable related donor. UCB transplantation is often limited by the relatively small hematopoietic stem cell (HSC) numbers in UCB especially for adult recipients. Early neutrophil and platelet engraftment correlates with the stem cell numbers in UCB transplant. Compared to other HSC sources, immune reconstitution following UCB transplant is slower and complicated by increased frequency of opportunistic infections. The effect of HSC numbers in UCB transplant on immune reconstitution was not thoroughly examined. Using immunocompromised mice transplanted with purified UCB CD34+ stem cells, we have demonstrated that increasing the numbers of CD34+ cells in the transplant promotes hematopoietic and immune reconstitution. At early stages posttransplant, high stem cell dose generated relatively more B cells, while lower dose generated more myeloid and T cells. Thus, the size of the stem cell graft appears to modulate the differentiation potential of infused stem cells. In addition, increasing stem cell dose in the transplant improved CD8+ T cell development and delayed late memory T cell skewing in expense of naive T cells highlighting the importance of HSC dose to maintain the pool of naive T cells able to develop strong immune responses. Transplantation of ex vivo expanded CD34+ cells did not promote, but rather delayed immune reconstitution suggesting the loss of primitive lymphoid precursor cells during ex vivo expansion.

Scopolamine effects on visual discrimination: modifications related to stimulus control

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

Evans, H.L.

1975-01-01

Stumptail monkeys (Macaca arctoides) performed a discrete trial, three-choice visual discrimination. The discrimination behavior was controlled by the shape of the visual stimuli. Strength of the stimuli in controlling behavior was systematically related to a physical property of the stimuli, luminance. Low luminance provided weak control, resulting in a low accuracy of discrimination, a low response probability and maximal sensitivity to scopolamine (7.5-60 ..mu..g/kg). In contrast, high luminance provided strong control of behavior and attenuated the effects of scopolamine. Methylscopolamine had no effect in doses of 30 to 90 ..mu..g/kg. Scopolamine effects resembled the effects of reducing stimulus control inmore » undrugged monkeys. Since behavior under weak control seems to be especially sensitive to drugs, manipulations of stimulus control may be particularly useful whenever determination of the minimally-effective dose is important, as in behavioral toxicology. Present results are interpreted as specific visual effects of the drug, since nonsensory factors such as base-line response rate, reinforcement schedule, training history, motor performance and motivation were controlled. Implications for state-dependent effects of drugs are discussed.« less

Frequency-risk and duration-risk relations between occupational livestock contact and methicillin-resistant Staphylococcus aureus carriage among workers in Guangdong, China.

PubMed

Ye, Xiaohua; Liu, Weidong; Fan, Yanping; Wang, Xiaolin; Zhou, Junli; Yao, Zhenjiang; Chen, Sidong

2015-07-01

Increasing evidence indicates a strong association between occupational livestock contact and methicillin-resistant Staphylococcus aureus (MRSA) carriage. However, it remains unclear whether there are frequency-risk and duration-risk relations between occupational livestock contact and human MRSA carriage. A cross-sectional survey was conducted in Guangdong, China, using a multistage sampling method. Participants were interviewed and provided a nasal swab for S aureus analysis. All MRSA isolates were genotyped by multilocus sequence typing. The dose-response relation was examined using logistic regression models. Among the 1,860 participants, 1.4% of controls tested positive for MRSA (characterized as sequence type [ST] 59 and ST7), and 7% of workers with livestock contact tested positive for MRSA (characterized as ST9, ST59, and ST7). There was a 5.31 times increased risk of MRSA carriage corresponding to occupational livestock contact (odds ratio = 6.31; 95% confidence interval, 3.44-11.57) using no contact as reference. We found frequency and short-term duration of occupational livestock contact were associated with increased risk of MRSA carriage in a dose-response manner. These significant trends were observed consistently among workers with occupational pig contact. However, no long-term duration-risk increasing trend was observed for occupational livestock or pig contact. Our findings suggest that there may be dose-response relations between occupational livestock contact and human MRSA carriage. Nasal MRSA clonal complex 9 is not found in controls, but it is found in workers with livestock contact. Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

Risk of second bone sarcoma following childhood cancer: role of radiation therapy treatment.

PubMed

Schwartz, Boris; Benadjaoud, Mohamed Amine; Cléro, Enora; Haddy, Nadia; El-Fayech, Chiraz; Guibout, Catherine; Teinturier, Cécile; Oberlin, Odile; Veres, Cristina; Pacquement, Hélène; Munzer, Martine; N'guyen, Tan Dat; Bondiau, Pierre-Yves; Berchery, Delphine; Laprie, Anne; Hawkins, Mike; Winter, David; Lefkopoulos, Dimitri; Chavaudra, Jean; Rubino, Carole; Diallo, Ibrahima; Bénichou, Jacques; de Vathaire, Florent

2014-05-01

Bone sarcoma as a second malignancy is rare but highly fatal. The present knowledge about radiation-absorbed organ dose-response is insufficient to predict the risks induced by radiation therapy techniques. The objective of the present study was to assess the treatment-induced risk for bone sarcoma following a childhood cancer and particularly the related risk of radiotherapy. Therefore, a retrospective cohort of 4,171 survivors of a solid childhood cancer treated between 1942 and 1986 in France and Britain has been followed prospectively. We collected detailed information on treatments received during childhood cancer. Additionally, an innovative methodology has been developed to evaluate the dose-response relationship between bone sarcoma and radiation dose throughout this cohort. The median follow-up was 26 years, and 39 patients had developed bone sarcoma. It was found that the overall incidence was 45-fold higher [standardized incidence ratio 44.8, 95 % confidence interval (CI) 31.0-59.8] than expected from the general population, and the absolute excess risk was 35.1 per 100,000 person-years (95 % CI 24.0-47.1). The risk of bone sarcoma increased slowly up to a cumulative radiation organ absorbed dose of 15 Gy [hazard ratio (HR) = 8.2, 95 % CI 1.6-42.9] and then strongly increased for higher radiation doses (HR for 30 Gy or more 117.9, 95 % CI 36.5-380.6), compared with patients not treated with radiotherapy. A linear model with an excess relative risk per Gy of 1.77 (95 % CI 0.6213-5.935) provided a close fit to the data. These findings have important therapeutic implications: Lowering the radiation dose to the bones should reduce the incidence of secondary bone sarcomas. Other therapeutic solutions should be preferred to radiotherapy in bone sarcoma-sensitive areas.

Wood Ash Induced pH Changes Strongly Affect Soil Bacterial Numbers and Community Composition

PubMed Central

Bang-Andreasen, Toke; Nielsen, Jeppe T.; Voriskova, Jana; Heise, Janine; Rønn, Regin; Kjøller, Rasmus; Hansen, Hans C. B.; Jacobsen, Carsten S.

2017-01-01

Recirculation of wood ash from energy production to forest soil improves the sustainability of this energy production form as recycled wood ash contains nutrients that otherwise would be lost at harvest. In addition, wood-ash is beneficial to many soils due to its inherent acid-neutralizing capabilities. However, wood ash has several ecosystem-perturbing effects like increased soil pH and pore water electrical conductivity both known to strongly impact soil bacterial numbers and community composition. Studies investigating soil bacterial community responses to wood ash application remain sparse and the available results are ambiguous and remain at a general taxonomic level. Here we investigate the response of bacterial communities in a spruce forest soil to wood ash addition corresponding to 0, 5, 22, and 167 t wood ash ha-1. We used culture-based enumerations of general bacteria, Pseudomonas and sporeforming bacteria combined with 16S rRNA gene amplicon sequencing to valuate soil bacterial responses to wood ash application. Results showed that wood ash addition strongly increased soil pH and electrical conductivity. Soil pH increased from acidic through neutral at 22 t ha-1 to alkaline at 167 t ha-1. Bacterial numbers significantly increased up to a wood ash dose of 22 t ha-1 followed by significant decrease at 167 t ha-1 wood ash. The soil bacterial community composition changed after wood ash application with copiotrophic bacteria responding positively up to a wood ash dose of 22 t ha-1 while the adverse effect was seen for oligotrophic bacteria. Marked changes in bacterial community composition occurred at a wood ash dose of 167 t ha-1 with a single alkaliphilic genus dominating. Additionally, spore-formers became abundant at an ash dose of 167 t ha-1 whereas this was not the case at lower ash doses. Lastly, bacterial richness and diversity strongly decreased with increasing amount of wood ash applied. All of the observed bacterial responses can be directly explained by the wood ash induced changes in pH, electrical conductivity and the addition of wood ash inherent nutrients. PMID:28804476

Wood Ash Induced pH Changes Strongly Affect Soil Bacterial Numbers and Community Composition.

PubMed

Bang-Andreasen, Toke; Nielsen, Jeppe T; Voriskova, Jana; Heise, Janine; Rønn, Regin; Kjøller, Rasmus; Hansen, Hans C B; Jacobsen, Carsten S

2017-01-01

Recirculation of wood ash from energy production to forest soil improves the sustainability of this energy production form as recycled wood ash contains nutrients that otherwise would be lost at harvest. In addition, wood-ash is beneficial to many soils due to its inherent acid-neutralizing capabilities. However, wood ash has several ecosystem-perturbing effects like increased soil pH and pore water electrical conductivity both known to strongly impact soil bacterial numbers and community composition. Studies investigating soil bacterial community responses to wood ash application remain sparse and the available results are ambiguous and remain at a general taxonomic level. Here we investigate the response of bacterial communities in a spruce forest soil to wood ash addition corresponding to 0, 5, 22, and 167 t wood ash ha -1 . We used culture-based enumerations of general bacteria, Pseudomonas and sporeforming bacteria combined with 16S rRNA gene amplicon sequencing to valuate soil bacterial responses to wood ash application. Results showed that wood ash addition strongly increased soil pH and electrical conductivity. Soil pH increased from acidic through neutral at 22 t ha -1 to alkaline at 167 t ha -1 . Bacterial numbers significantly increased up to a wood ash dose of 22 t ha -1 followed by significant decrease at 167 t ha -1 wood ash. The soil bacterial community composition changed after wood ash application with copiotrophic bacteria responding positively up to a wood ash dose of 22 t ha -1 while the adverse effect was seen for oligotrophic bacteria. Marked changes in bacterial community composition occurred at a wood ash dose of 167 t ha -1 with a single alkaliphilic genus dominating. Additionally, spore-formers became abundant at an ash dose of 167 t ha -1 whereas this was not the case at lower ash doses. Lastly, bacterial richness and diversity strongly decreased with increasing amount of wood ash applied. All of the observed bacterial responses can be directly explained by the wood ash induced changes in pH, electrical conductivity and the addition of wood ash inherent nutrients.

Characterization of nanoDot optically stimulated luminescence detectors and high-sensitivity MCP-N thermoluminescent detectors in the 40-300 kVp energy range.

PubMed

Poirier, Yannick; Kuznetsova, Svetlana; Villarreal-Barajas, Jose Eduardo

2018-01-01

To investigate empirically the energy dependence of the detector response of two in vivo luminescence detectors, LiF:Mg,Cu,P (MCP-N) high-sensitivity TLDs and Al 2 O 3 :C OSLDs, in the 40-300-kVp energy range in the context of in vivo surface dose measurement. As these detectors become more prevalent in clinical and preclinical in vivo measurements, knowledge of the variation in the empirical dependence of the measured response of these detectors across a wide spectrum of beam qualities is important. We characterized a large range of beam qualities of three different kilovoltage x-ray units: an Xstrahl 300 Orthovoltage unit, a Precision x-Ray X-RAD 320ix biological irradiator, and a Varian On-Board Imaging x-ray unit. The dose to water was measured in air according to the AAPM's Task Group 61 protocol. The OSLDs and TLDs were irradiated under reference conditions on the surface of a water phantom to provide full backscatter conditions. To assess the change in sensitivity in the long term, we separated the in vivo dosimeters of each type into an experimental and a reference group. The experimental dosimeters were irradiated using the kilovoltage x-ray units at each beam quality used in this investigation, while the reference group received a constant 10 cGy irradiation at 6 MV from a Varian clinical linear accelerator. The individual calibration of each detector was verified in cycles where both groups received a 10 cGy irradiation at 6 MV. The nanoDot OSLDs were highly reproducible, with ±1.5% variation in response following >40 measurement cycles. The TLDs lost ~20% of their signal sensitivity over the course of the study. The relative light output per unit dose to water of the MCP-N TLDs did not vary with beam quality for beam qualities with effective energies <50 keV (~150 kVp/6 mm Al). At higher energies, they showed a reduced (~75-85%) light output per unit dose relative to 6 MV x rays. The nanoDot OSLDs exhibited a very strong (120-408%) dependency of the light output relative to 6 MV x rays. Variations up to 15% between different x-ray units with equivalent effective energies were also observed. While convenient for clinical use, nanoDot OSLDs exhibit a strong variation in their measured light output per unit dose relative to 6 MV in the 40-300 kV x-ray range. This variability differs unit-to-unit, limiting their effective use for in vivo dosimetry applications in the kilovoltage x-ray energy range. MCP-N TLDs offer a much more stable response, but suffer from variations in sensitivity over time dependent on radiation history, which requires careful experimental handling. © 2017 American Association of Physicists in Medicine.

Autonomic control of adrenal function.

PubMed Central

Edwards, A V; Jones, C T

1993-01-01

Recent studies of adrenal function in conscious calves are reviewed. These have involved collecting the whole of the adrenal effluent blood from the right adrenal gland at intervals and, where necessary, prior functional hypophysectomy by destruction of the pituitary stalk under general halothane anaesthesia 3 d previously. The adrenal medulla was found to release numerous neuropeptides, in addition to catecholamines, in response to stimulation of the peripheral end of the right splanchnic nerve, which was carried out below behavioural threshold. Many of these responses were enhanced by stimulating intermittently at a relatively high frequency. Intra-aortic infusions of a relatively low dose of acetylcholine (4.5 nmol min-1 kg-1) elicited similar responses. In the adrenal cortex, agonists which either potentiated the steroidogenic response to ACTH or exerted a direct steroidogenic action included VIP, CGRP, CRF and ACh acting via muscarinic receptors. Stimulation of the peripheral end of the right splanchnic nerve strongly potentiated the steroidogenic response to ACTH and there is compelling evidence that the innervation normally plays an important part in cortisol secretion. PMID:8300417

Antibody persistence of two pentavalent DTwP-HB-Hib vaccines to the age of 15-18 months, and response to the booster dose of quadrivalent DTwP-Hib vaccine.

PubMed

Sharma, Hitt; Yadav, Sangeeta; Lalwani, Sanjay; Kapre, Subhash; Jadhav, Suresh; Parekh, Sameer; Palkar, Sonali; Ravetkar, Satish; Bahl, Sunil; Kumar, Rakesh; Shewale, Sunil

2013-01-07

Antibody persistence in children following three doses of primary vaccination with diphtheria, tetanus, whole-cell-pertussis (DTwP), hepatitis B, and Haemophilus influenzae type b (Hib) vaccines (SIIL Pentavac vaccine vs. Easyfive(®) of Panacea Biotec), and response to the booster dose of DTwP-Hib (Quadrovax(®)) vaccine. Children who completed their primary immunization were assessed for antibodies at 15-18 months of age, and then given a booster dose of DTwP-Hib vaccine. Reactogenicity and safety of the booster dose was evaluated. Both pentavalent vaccines demonstrated a good immune response at 15-18 months. Following the booster dose, all vaccinated subjects achieved protective titers against diphtheria, tetanus and Hib, whereas the response to pertussis antigen was ~78%. Fever and irritability was noted in 24%, local pain in 51%, and swelling in 36% of the children following booster dose. Primary immunization with either pentavalent vaccine induced an excellent immunity lasting till the second year of life. A booster dose with DTwP-Hib (Quadrovax(®)) vaccine effectuated a good anamnestic response to all vaccine components, being specially strong for Hib in children previously vaccinated with SIIL liquid pentavalent vaccine (Pentavac(®)). Also, the safety profile of SIIL quadrivalent vaccine (Quadrovax(®)) administered as booster dose was acceptable. Copyright © 2012 Elsevier Ltd. All rights reserved.

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...

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.

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

PubMed Central

Bel, E. H.; Zwinderman, A. H.; Timmers, M. C.; Dijkman, J. H.; Sterk, P. J.

1991-01-01

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease. PMID:1871705

Age-specific changes in the regulation of LH-dependent testosterone secretion: assessing responsiveness to varying endogenous gonadotropin output in normal men.

PubMed

Liu, Peter Y; Takahashi, Paul Y; Roebuck, Pamela D; Iranmanesh, Ali; Veldhuis, Johannes D

2005-09-01

Pulsatile and thus total testosterone (Te) secretion declines in older men, albeit for unknown reasons. Analytical models forecast that aging may reduce the capability of endogenous luteinizing hormone (LH) pulses to stimulate Leydig cell steroidogenesis. This notion has been difficult to test experimentally. The present study used graded doses of a selective gonadotropin releasing hormone (GnRH)-receptor antagonist to yield four distinct strata of pulsatile LH release in each of 18 healthy men ages 23-72 yr. Deconvolution analysis was applied to frequently sampled LH and Te concentration time series to quantitate pulsatile Te secretion over a 16-h interval. Log-linear regression was used to relate pulsatile LH secretion to attendant pulsatile Te secretion (LH-Te drive) across the four stepwise interventions in each subject. Linear regression of the 18 individual estimates of LH-Te feedforward dose-response slopes on age disclosed a strongly negative relationship (r = -0.721, P < 0.001). Accordingly, the present data support the thesis that aging in healthy men attenuates amplitude-dependent LH drive of burst-like Te secretion. The experimental strategy of graded suppression of neuroglandular outflow may have utility in estimating dose-response adaptations in other endocrine 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...

A reusable OSL-film for 2D radiotherapy dosimetry

NASA Astrophysics Data System (ADS)

Wouter, Crijns; Dirk, Vandenbroucke; Paul, Leblans; Tom, Depuydt

2017-11-01

Optical stimulated luminescence (OSL) combines reusability, sub-mm resolution, and a linear dose response in a single radiation detection technology. Such a combination is currently lacking in radiotherapy dosimetry. But OSL-films have a strong energy dependent response to keV photons due to a relative high effective atomic number (Z eff). The current work studied the applicability of a 2D OSL-film with a reduced Z eff as (IMRT/VMAT) dosimeter. Based on their commercial OSL-film experience, Agfa Healthcare N.V. produced a new experimental OSL-film for RT dosimetry. This film had a lower effective atomic number compared to the films used in radiology. Typical 2D dosimeter requirements such as uniformity, dose response, signal stability with time, and angular dependence were evaluated. Additionally, the impact of a possible residual energy dependence was assessed for the infield as well as the out-of-field region of both static beams and standard intensity modulated patterns (chair and pyramid). The OSL-film’s reusable nature allowed for a film specific absolute and linear calibration including a flood-field uniformity correction. The OSL-film was scanned with a CR-15X engine based reader using a strict timing (i.e. 4 min after ‘beam on’ or as soon as possible) to account for spontaneous recombination. The OSL-film had good basic response properties: non-uniformities  ⩽2.6%, a linear dose response (0-32 Gy), a linear signal decay (0.5% min-1) over the 20 min measured, and limited angular dependence  ⩽2.6%. Due to variations of the energy spectrum, larger dose differences were noted outside the central region of the homogenous phantom and outside both static and IMRT fields. However, the OSL-film’s measured dose differences of the IMRT patterns were lower than those of Gafchromic EBT measurements ([-1.6%, 2.1%] versus [-2.9%, 3.6%]). The current OSL-film could be used as a reusable high resolution dosimeter with read-out immediately after irradiation. Inside the (IMRT) treatment fields residual energy dependent effects were not observed. Novelty and significance: Implementing a reusable optical stimulated luminescence (OSL) film for radiotherapy dosimetry would enable user-friendly, sub(mm) resolution 2D dosimetry with instantaneous read-out. Radiology OSL-films have a strong energy dependent response which hampers accurate dosimetry. The current work reports measurements with a first 2D OSL-film tailored to the radiotherapy needs: including an improved water equivalent composition. The dosimeter adds the ability for sub-mm resolution repeated measurements to the portfolio of radiotherapy dosimetry.

A reusable OSL-film for 2D radiotherapy dosimetry.

PubMed

Wouter, Crijns; Dirk, Vandenbroucke; Paul, Leblans; Tom, Depuydt

2017-10-19

Optical stimulated luminescence (OSL) combines reusability, sub-mm resolution, and a linear dose response in a single radiation detection technology. Such a combination is currently lacking in radiotherapy dosimetry. But OSL-films have a strong energy dependent response to keV photons due to a relative high effective atomic number (Z eff ). The current work studied the applicability of a 2D OSL-film with a reduced Z eff as (IMRT/VMAT) dosimeter. Based on their commercial OSL-film experience, Agfa Healthcare N.V. produced a new experimental OSL-film for RT dosimetry. This film had a lower effective atomic number compared to the films used in radiology. Typical 2D dosimeter requirements such as uniformity, dose response, signal stability with time, and angular dependence were evaluated. Additionally, the impact of a possible residual energy dependence was assessed for the infield as well as the out-of-field region of both static beams and standard intensity modulated patterns (chair and pyramid). The OSL-film's reusable nature allowed for a film specific absolute and linear calibration including a flood-field uniformity correction. The OSL-film was scanned with a CR-15X engine based reader using a strict timing (i.e. 4 min after 'beam on' or as soon as possible) to account for spontaneous recombination. The OSL-film had good basic response properties: non-uniformities  ⩽2.6%, a linear dose response (0-32 Gy), a linear signal decay (0.5% min -1 ) over the 20 min measured, and limited angular dependence  ⩽2.6%. Due to variations of the energy spectrum, larger dose differences were noted outside the central region of the homogenous phantom and outside both static and IMRT fields. However, the OSL-film's measured dose differences of the IMRT patterns were lower than those of Gafchromic EBT measurements ([-1.6%, 2.1%] versus [-2.9%, 3.6%]). The current OSL-film could be used as a reusable high resolution dosimeter with read-out immediately after irradiation. Inside the (IMRT) treatment fields residual energy dependent effects were not observed. Novelty and significance: Implementing a reusable optical stimulated luminescence (OSL) film for radiotherapy dosimetry would enable user-friendly, sub(mm) resolution 2D dosimetry with instantaneous read-out. Radiology OSL-films have a strong energy dependent response which hampers accurate dosimetry. The current work reports measurements with a first 2D OSL-film tailored to the radiotherapy needs: including an improved water equivalent composition. The dosimeter adds the ability for sub-mm resolution repeated measurements to the portfolio of radiotherapy dosimetry.

Immune responses in Eimeria acervulina infected one-day-old broilers compared to amount of Eimeria in the duodenum, measured by real-time PCR.

PubMed

Swinkels, W J C; Post, J; Cornelissen, J B; Engel, B; Boersma, W J A; Rebel, J M J

2006-06-15

T-cell responses are supposed to be the major immune reactions in broilers infected with Eimeria. The nature of such T-cell responses is influenced by the species of Eimeria involved, age of the host, amount of parasites and the preceding infection history. In young chicks the intestine is still developing in length while the lymphocyte populations in the gut develop and differentiate. In chicks infected at young age the immune response may be different in quality as compared to responses in adults. We investigated the (T-cell) immune responses of young broilers to a primary Eimeria acervulina infection in relation to the number of parasites used for infection. In our experiment we infected one-day-old broilers with a low (5 x 10(2) oocysts) and a high (5 x 10(4) oocysts) dose of E. acervulina. We used a newly developed species specific real-time PCR to quantify total amount of parasites in the duodenum as the number of oocysts in faeces may not be representative for the exposure of the gut immune system. We characterized T-cell subsets in the duodenum by means of FACS-analyses, lymphocyte proliferation assays with spleen lymphocytes and the mRNA profiles of different cytokines (TGF-beta2, -4, IFN-gamma, IL-2, -6, -8 and -18) in the duodenum by means of real-time PCR. From day 5 p.i. broilers with a high dose of E. acervulina had a significantly lower body weight than the control group. No increase in CD4(+) cells, but a strong increase in CD8(+) cells was observed at days 7 and 9 p.i. in the duodenum of broilers infected with a high dose E. acervulina. IL-8 mRNA responses were observed after infection with low and with high infection doses, but no IFN-gamma and TGF-beta mRNA responses were found in the duodenum. The specific proliferative T-cell responses to a low infectious dose were not significantly different as compared to the control group. In conclusion, based on the kinetics of observed responses a primary infection with a high dose of E. acervulina in one-day-old broilers seems to generate an immune response that shows a peak at the time of oocyst excretion, whereas the immune response to a low dose is less explicit.

Tumors of the brain and nervous system after radiotherapy in childhood

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

Ron, E.; Modan, B.; Boice, J.D. Jr.

1988-10-20

We investigated the relation between radiotherapy in childhood for tinea capitis and the later development of tumors of the brain and nervous system among 10,834 patients treated between 1948 and 1960 in Israel. Benign and malignant tumors were identified from the pathology records of all Israeli hospitals and from Israeli national cancer and death registries. Doses of radiation to the neural tissue were retrospectively estimated for each patient (mean, 1.5 Gy). Sixty neural tumors developed in the patients exposed as children, and the 30-year cumulative risk (+/- SE) was 0.8 +/- 0.2 percent. The incidence of tumors was 1.8 permore » 10,000 persons per year. The estimated relative risk as compared with that for 10,834 matched general-population controls and 5392 siblings who had not been irradiated was 6.9 (95 percent confidence interval, 4.1 to 11.6) for all tumors and 8.4 (confidence interval, 4.8 to 14.8) when the analysis was restricted to neural tumors of the head and neck. Increased risks were apparent for meningiomas (relative risk, 9.5; n = 19), gliomas (relative risk, 2.6; n = 7), nerve-sheath tumors (relative risk, 18.8; n = 25), and other neural tumors (relative risk, 3.4; n = 9). A strong dose--response relation was found, with the relative risk approaching 20 after estimated doses of approximately 2.5 Gy. Our study confirms that radiation doses on the order of 1 to 2 Gy can significantly increase the risk of neural tumors.« less

MAGIC with formaldehyde applied to dosimetry of HDR brachytherapy source

NASA Astrophysics Data System (ADS)

Marques; T; Fernandes; J; Barbi; G; Nicolucci; P; Baffa; O

2009-05-01

The use of polymer gel dosimeters in brachytherapy can allow the determination of three-dimensional dose distributions in large volumes and with high spatial resolution if an adequate calibration process is performed. One of the major issues in these experiments is the polymer gel response dependence on dose rate when high dose rate sources are used and the doses in the vicinity of the sources are to be determinated. In this study, the response of a modified MAGIC polymer gel with formaldehyde around an Iridium-192 HDR brachytherapy source is presented. Experimental results obtained with this polymer gel were compared with ionization chamber measurements and with Monte Carlo simulation with PENELOPE. A maximum difference of 3.10% was found between gel dose measurements and Monte Carlo simulation at a radial distance of 18 mm from the source. The results obtained show that the gel's response is strongly influenced by dose rate and that a different calibration should be used for the vicinity of the source and for regions of lower dose rates. The results obtained in this study show that, provided the proper calibration is performed, MAGIC with formaldehyde can be successfully used to accurate determinate dose distributions form high dose rate brachytherapy sources.

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

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

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

Phase II, randomized, open, controlled study of AS03-adjuvanted H5N1 pre-pandemic influenza vaccine in children aged 3 to 9 years: follow-up of safety and immunogenicity persistence at 24 months post-vaccination.

PubMed

Díez-Domingo, Javier; Baldó, José-María; Planelles-Catarino, Maria Victoria; Garcés-Sánchez, María; Ubeda, Isabel; Jubert-Rosich, Angels; Marès, Josep; Garcia-Corbeira, Pilar; Moris, Philippe; Teko, Maurice; Vanden Abeele, Carline; Gillard, Paul

2015-03-01

An AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3-9 years. In this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3-9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. (NCT00502593). The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4(+) T cells with a TH 1 profile were observed. Two doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination. © 2014 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

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

PubMed

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

2018-06-01

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

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

Errors introduced by dose scaling for relative dosimetry

PubMed Central

Watanabe, Yoichi; Hayashi, Naoki

2012-01-01

Some dosimeters require a relationship between detector signal and delivered dose. The relationship (characteristic curve or calibration equation) usually depends on the environment under which the dosimeters are manufactured or stored. To compensate for the difference in radiation response among different batches of dosimeters, the measured dose can be scaled by normalizing the measured dose to a specific dose. Such a procedure, often called “relative dosimetry”, allows us to skip the time‐consuming production of a calibration curve for each irradiation. In this study, the magnitudes of errors due to the dose scaling procedure were evaluated by using the characteristic curves of BANG3 polymer gel dosimeter, radiographic EDR2 films, and GAFCHROMIC EBT2 films. Several sets of calibration data were obtained for each type of dosimeters, and a calibration equation of one set of data was used to estimate doses of the other dosimeters from different batches. The scaled doses were then compared with expected doses, which were obtained by using the true calibration equation specific to each batch. In general, the magnitude of errors increased with increasing deviation of the dose scaling factor from unity. Also, the errors strongly depended on the difference in the shape of the true and reference calibration curves. For example, for the BANG3 polymer gel, of which the characteristic curve can be approximated with a linear equation, the error for a batch requiring a dose scaling factor of 0.87 was larger than the errors for other batches requiring smaller magnitudes of dose scaling, or scaling factors of 0.93 or 1.02. The characteristic curves of EDR2 and EBT2 films required nonlinear equations. With those dosimeters, errors larger than 5% were commonly observed in the dose ranges of below 50% and above 150% of the normalization dose. In conclusion, the dose scaling for relative dosimetry introduces large errors in the measured doses when a large dose scaling is applied, and this procedure should be applied with special care. PACS numbers: 87.56.Da, 06.20.Dk, 06.20.fb PMID:22955658

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

EPA Science Inventory

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

Long-chain omega 3 fatty acids: molecular bases of potential antioxidant actions.

PubMed

Giordano, Elena; Visioli, Francesco

2014-01-01

Several lines of investigation are being developed to assess the impact of polyunsaturated fatty acids, namely those of the omega 3 series, intake on oxidative stress. Keeping in mind that there might be a dose-response relation, in vivo and in vitro data strongly suggest that omega 3 fatty acids might act as anti- rather than pro-oxidant in several cells such as vascular cells, hence diminishing inflammation, oxidative stress, and, in turn, the risk of atherosclerosis and degenerative disorders such as cardiovascular disease. © 2013 Published by Elsevier Ltd.

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.

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

PubMed

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

2011-09-01

In the present study we report dosimetric properties of iodized salt aiming at using it as an accidental luminescent dosimeter. It was found that the very good sensitivity of its main dosimetric peak is strongly affected by thermal treatments. This is also the case for OSL emission. The sensitivity loss due to heating implies that caution should be exercised while applying single aliquot protocols for dose evaluation. The sequence of dissolution and subsequent re-crystallization was established to be an extremely effective zeroing mechanism for the TL signal. The linearity in the dose response was also monitored in the case of dissolved and subsequently re-crystallized salt. In the case of naturally occurring salt, zeroing of the TL signal due to dissolution as well as the linearity of dose response up to doses as large as 100 Gy were found to be very promising features for dating applications. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

Second Malignant Neoplasms in Digestive Organs After Childhood Cancer: A Cohort-Nested Case-Control Study

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

Tukenova, Markhaba; Diallo, Ibrahima; University Paris Sud 11, UMRS, Villejuif

Purpose: Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer. Methods and Materials: Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58more » case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated. Results: The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose-response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7-16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6-35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO. Conclusions: This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.« less

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.

Prediction of Psilocybin Response in Healthy Volunteers

PubMed Central

Studerus, Erich; Gamma, Alex; Kometer, Michael; Vollenweider, Franz X.

2012-01-01

Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin. PMID:22363492

Prediction of psilocybin response in healthy volunteers.

PubMed

Studerus, Erich; Gamma, Alex; Kometer, Michael; Vollenweider, Franz X

2012-01-01

Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin.

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...

Experimental evaluation of a MOSFET dosimeter for proton dose measurements.

PubMed

Kohno, Ryosuke; Nishio, Teiji; Miyagishi, Tomoko; Hirano, Eriko; Hotta, Kenji; Kawashima, Mitsuhiko; Ogino, Takashi

2006-12-07

The metal oxide semiconductor field-effect transistor (MOSFET) dosimeter has been widely studied for use as a dosimeter for patient dose verification. The major advantage of this detector is its size, which acts as a point dosimeter, and also its ease of use. The commercially available TN502RD MOSFET dosimeter manufactured by Thomson and Nielsen has never been used for proton dosimetry. Therefore we used the MOSFET dosimeter for the first time in proton dose measurements. In this study, the MOSFET dosimeter was irradiated with 190 MeV therapeutic proton beams. We experimentally evaluated dose reproducibility, linearity, fading effect, beam intensity dependence and angular dependence for the proton beam. Furthermore, the Bragg curve and spread-out Bragg peak were also measured and the linear-energy transfer (LET) dependence of the MOSFET response was investigated. Many characteristics of the MOSFET response for proton beams were the same as those for photon beams reported in previous papers. However, the angular MOSFET responses at 45, 90, 135, 225, 270 and 315 degrees for proton beams were over-responses of about 15%, and moreover the MOSFET response depended strongly on the LET of the proton beam. This study showed that the angular dependence and LET dependence of the MOSFET response must be considered very carefully for quantitative proton dose evaluations.

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

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

PubMed

Guckenberger, Matthias; Klement, Rainer J; Allgäuer, Michael; Andratschke, Nicolaus; Blanck, Oliver; Boda-Heggemann, Judit; Dieckmann, Karin; Duma, Marciana; Ernst, Iris; Ganswindt, Ute; Hass, Peter; Henkenberens, Christoph; Holy, Richard; Imhoff, Detlef; Kahl, Henning K; Krempien, Robert; Lohaus, Fabian; Nestle, Ursula; Nevinny-Stickel, Meinhard; Petersen, Cordula; Semrau, Sabine; Streblow, Jan; Wendt, Thomas G; Wittig, Andrea; Flentje, Michael; Sterzing, Florian

2016-03-01

To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.

PubMed

Beraha, Esther M; Salemink, Elske; Goudriaan, Anna E; Bakker, Abraham; de Jong, David; Smits, Natasha; Zwart, Jan Willem; Geest, Dick van; Bodewits, Pieter; Schiphof, Tom; Defourny, Harma; van Tricht, Mirjam; van den Brink, Wim; Wiers, Reinout W

2016-12-01

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30-60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ 2 =0.41; p=0.813) or the 16-weeks complete medication period (χ 2 =0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Probabilistic hazard assessment for skin sensitization potency by dose–response modeling using feature elimination instead of quantitative structure–activity relationships

PubMed Central

McKim, James M.; Hartung, Thomas; Kleensang, Andre; Sá-Rocha, Vanessa

2016-01-01

Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose–response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimension-ality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high-quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals’ potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter-relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose-informed random forest/hidden Markov model was superior to the dose-naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose-informed hidden Markov model strongly reduced "false-negatives" (i.e. extreme sensitizers as non-sensitizer) on all data sets. PMID:26046447

Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

PubMed

Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

2016-05-01

The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

Optimisation of the imaging and dosimetric characteristics of an electronic portal imaging device employing plastic scintillating fibres using Monte Carlo simulations.

PubMed

Blake, S J; McNamara, A L; Vial, P; Holloway, L; Kuncic, Z

2014-11-21

A Monte Carlo model of a novel electronic portal imaging device (EPID) has been developed using Geant4 and its performance for imaging and dosimetry applications in radiotherapy has been characterised. The EPID geometry is based on a physical prototype under ongoing investigation and comprises an array of plastic scintillating fibres in place of the metal plate/phosphor screen in standard EPIDs. Geometrical and optical transport parameters were varied to investigate their impact on imaging and dosimetry performance. Detection efficiency was most sensitive to variations in fibre length, achieving a peak value of 36% at 50 mm using 400 keV x-rays for the lengths considered. Increases in efficiency for longer fibres were partially offset by reductions in sensitivity. Removing the extra-mural absorber surrounding individual fibres severely decreased the modulation transfer function (MTF), highlighting its importance in maximising spatial resolution. Field size response and relative dose profile simulations demonstrated a water-equivalent dose response and thus the prototype's suitability for dosimetry applications. Element-to-element mismatch between scintillating fibres and underlying photodiode pixels resulted in a reduced MTF for high spatial frequencies and quasi-periodic variations in dose profile response. This effect is eliminated when fibres are precisely matched to underlying pixels. Simulations strongly suggest that with further optimisation, this prototype EPID may be capable of simultaneous imaging and dosimetry in radiotherapy.

Urethane anesthesia blocks the development and expression of kindled seizures

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

Cain, D.P.; Raithby, A.; Corcoran, M.E.

1989-01-01

The effect of anesthetic and subanesthetic doses of urethane on the development of amygdala kindled seizures and on the expression of previously kindled seizures was studied in hooded rats. An anesthetic dose of urethane almost completely eliminated evoked after discharge and completely eliminated convulsive behavior in both groups. It also eliminated the seizure response to pentylenetetrazol. Subanesthetic doses of urethane strongly attenuated the expression of previously kindled seizures. These results suggest that urethane may not be an appropriate anesthetic for the study of epileptiform phenomena.

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

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.

Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data.

PubMed

Fassoni, Artur C; Baldow, Christoph; Roeder, Ingo; Glauche, Ingmar

2018-06-28

Continuing tyrosine kinase inhibitor mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of the optimally responding patients, a systematic assessment of long-term tyrosine kinase inhibitor dose de-escalation is missing. We use a mathematical model to analyze and consistently describe biphasic treatment responses from tyrosine kinase inhibitor treated patients from two independent clinical phase-3 trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence suggesting that tyrosine kinase inhibitor dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, which have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose not decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose halving should be considered as a long-term treatment option for well-responding chronic myeloid leukemia patients under continuing maintenance therapy with tyrosine kinase inhibitors. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and therapy costs. Copyright © 2018, Ferrata Storti Foundation.

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

A Critique of Recent Epidemiologic Studies of Cancer Mortality Among Nuclear Workers.

PubMed

Scott, Bobby R

2018-01-01

Current justification by linear no-threshold (LNT) cancer risk model advocates for its use in low-dose radiation risk assessment is now mainly based on results from flawed and unreliable epidemiologic studies that manufacture small risk increases (ie, phantom risks). Four such studies of nuclear workers, essentially carried out by the same group of epidemiologists, are critiqued in this article. Three of the studies that forcibly applied the LNT model (inappropriate null hypothesis) to cancer mortality data and implicated increased mortality risk from any radiation exposure, no matter how small the dose, are demonstrated to manufacture risk increases for doses up to 100 mSv (or 100 mGy). In a study where risk reduction (hormetic effect/adaptive response) was implicated for nuclear workers, it was assumed by the researchers to relate to a "strong healthy worker effect" with no consideration of the possibility that low radiation doses may help prevent cancer mortality (which is consistent with findings from basic radiobiological research). It was found with basic research that while large radiation doses suppress our multiple natural defenses (barriers) against cancer, these barriers are enhanced by low radiation doses, thereby decreasing cancer risk, essentially rendering the LNT model to be inconsistent with the data.

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.

Variations in energy spectra and water-to-material stopping-power ratios in three-dimensional conformal and intensity-modulated photon fields

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

Jang, Si Young; Liu, H. Helen; Mohan, Radhe

Because of complex dose distributions and dose gradients that are created in three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiation therapy (IMRT), photon- and electron-energy spectra might change significantly with spatial locations and doses. This study examined variations in photon- and electron-energy spectra in 3D-CRT and IMRT photon fields. The effects of spectral variations on water-to-material stopping-power ratios used in Monte Carlo treatment planning systems and the responses of energy-dependent dosimeters, such as thermoluminescent dosimeters (TLDs) and radiographic films were further studied. The EGSnrc Monte Carlo code was used to simulate megavoltage 3D-CRT and IMRT photon fields. The photon- and electron-energymore » spectra were calculated in 3D water phantoms and anthropomorphic phantoms based on the fluence scored in voxel grids. We then obtained the water-to-material stopping-power ratios in the local voxels using the Spencer-Attix cavity theory. Changes in the responses of films and TLDs were estimated based on the calculated local energy spectra and published data on the dosimeter energy dependency. Results showed that the photon-energy spectra strongly depended on spatial positions and doses in both the 3D-CRT and IMRT fields. The relative fraction of low-energy photons (<100 keV) increased inversely with the photon dose in low-dose regions of the fields. A similar but smaller effect was observed for electrons in the phantoms. The maximum variation of the water-to-material stopping-power ratio over the range of calculated dose for both 3D-CRT and IMRT was negligible (<1.0%) for ICRU tissue, cortical bone, and soft bone and less than 3.6% for dry air and lung. Because of spectral softening at low doses, radiographic films in the phantoms could over-respond to dose by more than 30%, whereas the over-response of TLDs was less than 10%. Thus, spatial variations of the photon- and electron-energy spectra should be considered as important factors in 3D-CRT and IMRT dosimetry.« less

CRH-stimulated cortisol release and food intake in healthy, non-obese adults.

PubMed

George, Sophie A; Khan, Samir; Briggs, Hedieh; Abelson, James L

2010-05-01

There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamic-pituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans. We infused healthy adults with corticotropin-releasing hormone (CRH) at a dose that is subjectively undetectable but elicits a robust endogenous cortisol response, and measured subsequent intake of snack foods, allowing analysis of HPA reactivity effects on food intake without the complex psychological effects of a stress paradigm. CRH elevated cortisol levels relative to placebo but did not impact subjective anxious distress. Subjects ate more following CRH than following placebo and peak cortisol response to CRH was strongly related to both caloric intake and total consumption. These data show that HPA axis reactivity to pharmacological stimulation predicts subsequent food intake and suggest that cortisol itself may directly stimulate food consumption in humans. Understanding the physiological mechanisms that underlie stress-related eating may prove useful in efforts to attack the public health crises created by obesity. Copyright 2009 Elsevier Ltd. All rights reserved.

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

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

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

2012-03-15

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

Characterization and long-term persistence of immune response following two doses of an AS03A-adjuvanted H1N1 influenza vaccine in healthy Japanese adults.

PubMed

Ikematsu, Hideyuki; Nagai, Hideaki; Kawashima, Masahiro; Kawakami, Yasunobu; Tenjinbaru, Kazuyoshi; Li, Ping; Walravens, Karl; Gillard, Paul; Roman, François

2012-02-01

Background Long-term persistence of immune response and safety of two doses of an A/California/07/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based Adjuvant System) administered 21 d apart was evaluated in Japanese adults [NCT00989612]. Methods One-hundred healthy subjects aged 20-64 y (stratified [1:1] into two age strata 20-40 y and 41-64 y) received 21 d apart, two doses of AS03-adjuvanted 3.75µg haemagglutinin (HA) H1N1 2009 vaccine. Immunogenicity data by haemagglutination inhibition (HI) assay six months after the first vaccine dose (Day 182) and microneutralization assay following each of the two vaccine doses (Days 21 and 42) and at Day 182 are reported here. Results Persistence of strong HI immune response was observed at Day 182 that met the US and European regulatory thresholds for pandemic influenza vaccines (seroprotection rate: 95%; seroconversion rate: 93%; geometric mean fold-rise: 20). The neutralizing antibody response against the A/Netherlands/602/2009 strain (antigenically similar to vaccine-strain) persisted for at least up to Day 182 (vaccine response rate: 76%; geometric mean titer: 114.4) and paralleled the HI immune response at all time points. No marked difference was observed in HI antibody persistence and neutralising antibody response between the two age strata. The vaccine had a clinically-acceptable safety profile. Conclusion Two priming doses of H1N1 2009 pandemic influenza vaccine induced an immune response persisting for at least six months after the first vaccine dose. This could be beneficial in evaluating the importance and effect of vaccination with this AS03-adjuvanted pandemic influenza vaccine.

Towards improved quantification of post-fire conifer mortality and recovery: Impacts of fire radiative flux on seedling and mature tree mortality, physiology, and growth

NASA Astrophysics Data System (ADS)

Sparks, A. M.; Kolden, C.; Smith, A. M.

2016-12-01

Fire activity, in terms of intensity, frequency, and total area burned, is expected to increase with changing climate. A challenge for landscape level assessment of fire effects, termed burn severity, is that current assessments provide very little information regarding vegetation physiological performance and recovery, limiting our understanding of fire effects on ecosystem services such as carbon storage/cycling. To address these limitations, we evaluated an alternative dose-response methodology for quantifying fire effects that attempts to bridge fire combustion dynamics and ecophysiology. Specifically, we conducted a highly controlled, laboratory assessment of seedling response to increasing doses of fire radiative energy applied through surface fires, for two western U.S. conifer species. Seedling physiology and spectral reflectance were acquired pre- and up to 1 year post-fire. Post-fire mortality, physiological performance, and spectral reflectance were strongly related with fire radiative energy density (FRED: J m-2) dose. To examine how these relationships change with tree size and age, we conducted small prescribed fires at the tree scale (35 m2) in a mature conifer stand. Radial growth and resin duct defenses were assessed on the mature conifer trees following the prescribed fires. Differences in dose-response relationships between seedlings and mature trees indicate the importance of fire behavior (e.g., flaming-dominated versus smoldering-dominated combustion) in characterizing these relationships. Ultimately, these results suggest that post-fire impacts on growth of surviving seedlings and mature trees require modes of heat transfer to impact tree canopies.

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

PubMed

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

2011-08-01

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

Dose response of bone-targeted enzyme replacement for murine hypophosphatasia

PubMed Central

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

2011-01-01

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

Dose-dependent intracellular reactive oxygen and nitrogen species (ROS/RNS) production from particulate matter exposure: comparison to oxidative potential and chemical composition

NASA Astrophysics Data System (ADS)

Tuet, Wing Y.; Fok, Shierly; Verma, Vishal; Tagle Rodriguez, Marlen S.; Grosberg, Anna; Champion, Julie A.; Ng, Nga L.

2016-11-01

Elevated particulate matter (PM) concentrations have been associated with cardiopulmonary risks. In this study, alveolar macrophages and ventricular myocytes were exposed to PM extracts from 104 ambient filters collected in multiple rural and urban sites in the greater Atlanta area. PM-induced reactive oxygen/nitrogen species (ROS/RNS) were measured to investigate the effect of chemical composition and determine whether chemical assays are representative of cellular responses. For summer samples, the area under the ROS/RNS dose-response curve per volume of air (AUCvolume) was significantly correlated with dithiothreitol (DTT) activity, water-soluble organic carbon (WSOC), brown carbon, titanium, and iron, while a relatively flat response was observed for winter samples. EC50 was also correlated with max response for all filters investigated, which suggests that certain PM constituents may be involved in cellular protective pathways. Although few metal correlations were observed, exposure to laboratory-prepared metal solutions induced ROS/RNS production, indicating that a lack of correlation does not necessarily translate to a lack of response. Collectively, these results suggest that complex interactions may occur between PM species. Furthermore, the strong correlation between organic species and ROS/RNS response highlights a need to understand the contribution of organic aerosols, especially photochemically driven secondary organic aerosols (SOA), to PM-induced health effects.

Multiple Low-Dose Challenges in a Rhesus Macaque AIDS Vaccine Trial Result in an Evolving Host Response That Affects Protective Outcome

PubMed Central

Selinger, Christian; Strbo, Natasa; Gonzalez, Louis; Aicher, Lauri; Weiss, Jeffrey M.; Law, G. Lynn; Palermo, Robert E.; Vaccari, Monica; Franchini, Genoveffa; Podack, Eckhard R.

2014-01-01

Using whole-blood transcriptional profiling, we investigated differences in the host response to vaccination and challenge in a rhesus macaque AIDS vaccine trial. Samples were collected from animals prior to and after vaccination with live, irradiated vaccine cells secreting the modified endoplasmic reticulum chaperone gp96-Ig loaded with simian immunodeficiency virus (SIV) peptides, either alone or in combination with a SIV-gp120 protein boost. Additional samples were collected following multiple low-dose rectal challenges with SIVmac251. Animals in the boosted group had a 73% reduced risk of infection. Surprisingly, few changes in gene expression were observed during the vaccination phase. Focusing on postchallenge comparisons, in particular for protected animals, we identified a host response signature of protection comprised of strong interferon signaling after the first challenge, which then largely abated after further challenges. We also identified a host response signature, comprised of early macrophage-mediated inflammatory responses, in animals with undetectable viral loads 5 days after the first challenge but with unusually high viral titers after subsequent challenges. Statistical analysis showed that prime-boost vaccination significantly lowered the probability of infection in a time-consistent manner throughout several challenges. Given that humoral responses in the prime-boost group were highly significant prechallenge correlates of protection, the strong innate signaling after the first challenge suggests that interferon signaling may enhance vaccine-induced antibody responses and is an important contributor to protection from infection during repeated low-dose exposure to SIV. PMID:25274805

The relation between modeled odor exposure from livestock farming and odor annoyance among neighboring residents.

PubMed

Boers, D; Geelen, L; Erbrink, H; Smit, L A M; Heederik, D; Hooiveld, M; Yzermans, C J; Huijbregts, M; Wouters, I M

2016-04-01

Odor annoyance is an important environmental stressor for neighboring residents of livestock farms and may affect their quality of life and health. However, little is known about the relation between odor exposure due to livestock farming and odor annoyance. Even more, the relation between odor exposure and odor annoyance is rather complicated due to variable responses among individuals to comparable exposure levels and a large number of factors (such as age, gender, education) that may affect the relation. In this study, we (1) investigated the relation between modeled odor exposure and odor annoyance; (2) investigated whether other factors can affect this relation; and (3) compared our dose-response relation to a dose-response relation established in a previous study carried out in the Netherlands, more than 10 years ago, in order to investigate changes in odor perception and appreciation over time. We used data from 582 respondents who participated in a questionnaire survey among neighboring residents of livestock farms in the south of the Netherlands. Odor annoyance was established by two close-ended questions in a questionnaire; odor exposure was estimated using the Stacks dispersion model. The results of our study indicate a statistically significant and positive relation between modeled odor exposure and reported odor annoyance from livestock farming (OR 1.92; 95 % CI 1.53-2.41). Furthermore, age, asthma, education and perceived air pollution in the environment are all related to odor annoyance, although they hardly affect the relation between estimated livestock odor exposure and reported odor annoyance. We also found relatively more odor annoyance reported among neighboring residents than in a previous study conducted in the Netherlands. We found a strong relation between modeled odor exposure and odor annoyance. However, due to some uncertainties and small number of studies on this topic, further research and replication of results is recommended.

[Association between the methylenetetrahydrofolate reductase gene polymorphisms and haplotype with toxicity response of high dose methotrexate chemotherapy].

PubMed

Liao, Qing-Chuan; Li, Xiao-Lei; Liu, Si-Ting; Zhang, Yong; Li, Tian-Yuan; Qiu, Jin-Chun

2012-07-01

To investigate the association between single nucleotide polymorphisms (SNP) and its haplotypes of methylenetetrahydrofolate reductase (MTHFR) gene with high dose methotrexate (HDMTX)-induced toxicity in children with acute lymphoblastic leukemia (ALL). HDMTX-treated children with ALL (1.2 to 14-years old) were selected from inpatient and followed for a retrospective study. The toxicity response of HDMTX chemotherapy was evaluated using WHO common toxicity criteria. Sixty-one patients with therapy-related toxicity and 36 patients without therapy-related toxicity were genotyped for 2 SNP (677C > T and 1298A > C) of the MTHFR gene by polymerase chain reaction-restriction fragment length polymorphism. Frequency of haplotypes and linkage disequilibrium of MTHFR gene were analyzed by SHEsis program. The distribution of MTHFR gene 677C > T polymorphism did not appeare different between groups with or without toxicity response (χ(2) = 4.609, P = 0.100), but the 1298A > C polymorphism was significantly different (χ(2) = 10.192, P = 0.006). Individuals who carried C allele (AC + CC genotype) had a decreased risk of toxicity response compared to AA genotype (OR = 0.245, 95%CI: 0.099 - 0.607, P = 0.002). 677C > T and 1298A > C polymorphisms showed strong linkage disequilibrium (D' = 0.895). The CC haplotype was significantly associated with decreased risk of toxicity response (OR = 0.338, 95%CI: 0.155 - 0.738, P = 0.005), while the TA haplotype was significantly associated with the increased risk of toxicity response (OR = 1.907, 95%CI: 1.045 - 3.482, P = 0.035). MTHFR gene 1298C allele and CC haplotype might serve as protective factors while TA haplotype as a risk factor for the susceptibility to toxicity response of HDMTX chemotherapy in children with ALL.

Smoking and Risk of Ischemic Stroke in Young Men.

PubMed

Markidan, Janina; Cole, John W; Cronin, Carolyn A; Merino, Jose G; Phipps, Michael S; Wozniak, Marcella A; Kittner, Steven J

2018-05-01

There is a strong dose-response relationship between smoking and risk of ischemic stroke in young women, but there are few data examining this association in young men. We examined the dose-response relationship between the quantity of cigarettes smoked and the odds of developing an ischemic stroke in men under age 50 years. The Stroke Prevention in Young Men Study is a population-based case-control study of risk factors for ischemic stroke in men ages 15 to 49 years. The χ 2 test was used to test categorical comparisons. Logistic regression models were used to calculate the odds ratio for ischemic stroke occurrence comparing current and former smokers to never smokers. In the first model, we adjusted solely for age. In the second model, we adjusted for potential confounding factors, including age, race, education, hypertension, myocardial infarction, angina, diabetes mellitus, and body mass index. The study population consisted of 615 cases and 530 controls. The odds ratio for the current smoking group compared with never smokers was 1.88. Furthermore, when the current smoking group was stratified by number of cigarettes smoked, there was a dose-response relationship for the odds ratio, ranging from 1.46 for those smoking <11 cigarettes per day to 5.66 for those smoking 40+ cigarettes per day. We found a strong dose-response relationship between the number of cigarettes smoked daily and ischemic stroke among young men. Although complete smoking cessation is the goal, even smoking fewer cigarettes may reduce the risk of ischemic stroke in young men. © 2018 American Heart Association, Inc.

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen.

PubMed

Andersen, Rikke; Donia, Marco; Ellebaek, Eva; Borch, Troels Holz; Kongsted, Per; Iversen, Trine Zeeberg; Hölmich, Lisbet Rosenkrantz; Hendel, Helle Westergren; Met, Özcan; Andersen, Mads Hald; Thor Straten, Per; Svane, Inge Marie

2016-08-01

Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen. Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625). Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment. TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 22(15); 3734-45. ©2016 AACR. ©2016 American Association for Cancer Research.

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.

Response to noise from modern wind farms in The Netherlands.

PubMed

Pedersen, Eja; van den Berg, Frits; Bakker, Roel; Bouma, Jelte

2009-08-01

The increasing number and size of wind farms call for more data on human response to wind turbine noise, so that a generalized dose-response relationship can be modeled and possible adverse health effects avoided. This paper reports the results of a 2007 field study in The Netherlands with 725 respondents. A dose-response relationship between calculated A-weighted sound pressure levels and reported perception and annoyance was found. Wind turbine noise was more annoying than transportation noise or industrial noise at comparable levels, possibly due to specific sound properties such as a "swishing" quality, temporal variability, and lack of nighttime abatement. High turbine visibility enhances negative response, and having wind turbines visible from the dwelling significantly increased the risk of annoyance. Annoyance was strongly correlated with a negative attitude toward the visual impact of wind turbines on the landscape. The study further demonstrates that people who benefit economically from wind turbines have a significantly decreased risk of annoyance, despite exposure to similar sound levels. Response to wind turbine noise was similar to that found in Sweden so the dose-response relationship should be generalizable.

Strong inflammatory cytokine response in male and strong anti-inflammatory response in female kidney transplant recipients with urinary tract infection.

PubMed

Sadeghi, Mahmoud; Daniel, Volker; Naujokat, Cord; Wiesel, Manfred; Hergesell, Olaf; Opelz, Gerhard

2005-02-01

Urinary tract infection (UTI) is the most common post-transplant infection in renal transplant recipients. The relationship of plasma and urine cytokines with UTI after kidney transplantation has not yet been delineated and literature reports on cytokine and UTI are rare. In a retrospective study, we compared post-transplant plasma and urine cytokine levels of 132 outpatient renal transplant recipients with or without UTI. Soluble interleukin-1 receptor antagonist (sIL-1RA), IL-2, sIL-2R, IL-3, IL-4, IL-6, sIL-6R, IL-8, IL-10, transforming growth factor-beta2 (TGF-beta2), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) levels were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits. We found gender-related urine cytokine patterns. Anti-inflammatory sIL-1RA was significantly higher in females than in males and this gender-related difference was more pronounced in bacteriuric (P < 0.0001) than in nonbacteriuric (P = 0.001) patients. Urine proinflammatory cytokines IL-6 (P = 0.001) and IL-8 (P = 0.007) were significantly higher in male patients with bacteriuria than in males without bacteriuria and sIL-2R (P = 0.001) and sIL-6R (P = 0.03) were significantly higher in males with leukocyturia than in males without leukocyturia. Bacteriuria in males was associated with higher doses of immunosuppressive drugs (P = 0.02). Male renal transplant recipients with UTI have a strong inflammatory cytokine response with activation of IL-6, IL-8, sIL-2R and sIL-6R producing cells, whereas female patients with UTI block the inflammatory response to UTI by production of sIL-1RA.

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.

Evaluation of a poliomyelitis immunization campaign in Madras city.

PubMed

Balraj, V; John, T J

1986-01-01

An annual pulse immunization campaign with oral polio vaccine (OPV) was evaluated to determine vaccine coverage, relative success of publicity methods and reasons for lack of response. The campaign was directed at 3-36 month olds in Madras city, India, in January-March 1985. The evaluation method was the "30-cluster" sample survey technique, designed by WHO, where surveys were done in 30 districts of the city on 10 children in each age group. The survey was conducted in April 1985 by 5 trained and supervised interviewers. This campaign increased the vaccine coverage to 94%, 88% and 72% for first, second and third doses of OPV. Coverage was higher in older children. Percent coverage decreased slightly over 1-3 doses, and from there rapidly up to 6-7 doses. The campaign accounted for 27% of all the OPV the study children had received. 47% of parents heard about the vaccination through word of mouth, either from health workers, volunteers or "balwadi ayahs," women day-care workers. 17% learned through television or radio. 3% cited mobile loudspeakers, handbills, posters or slides in cinemas. Many parents did not avail themselves of the vaccine because they believed that 3 doses are sufficient. Actually the WHO recommends 4 doses; the Indian Academy of Pediatrics recommends 5 doses; while criteria from research on Indian children would suggest that 5-7 doses are required to raise strong immunity.

Association of plasma IL-6 and Hsp70 with HRV at different levels of PAHs metabolites.

PubMed

Ye, Jian; Zhu, Rui; He, Xiaosheng; Feng, Yingying; Yang, Liangle; Zhu, Xiaoyan; Deng, Qifei; Wu, Tangchun; Zhang, Xiaomin

2014-01-01

Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all Ptrend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (Ptrend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all Ptrend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all Ptrend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups.

Association of Plasma IL-6 and Hsp70 with HRV at Different Levels of PAHs Metabolites

PubMed Central

He, Xiaosheng; Feng, Yingying; Yang, Liangle; Zhu, Xiaoyan; Deng, Qifei; Wu, Tangchun; Zhang, Xiaomin

2014-01-01

Background Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with reduced heart rate variability (HRV), a strong predictor of cardiovascular diseases, but the mechanism is not well understood. Objectives We hypothesized that PAHs might induce systemic inflammation and stress response, contributing to altered cardiac autonomic function. Methods HRV indices were measured using a 3-channel digital Holter monitor in 800 coke oven workers. Plasma levels of interleukin-6 (IL-6) and heat shock protein 70 (Hsp70) were determined using ELISA. Twelve urinary PAHs metabolites (OH-PAHs) were measured by gas chromatography-mass spectrometry. Results We found that significant dose-dependent relationships between four urinary OH-PAHs and IL-6 (all P trend<0.05); and an increase in quartiles of IL-6 was significantly associated with a decrease in total power (TP) and low frequency (LF) (P trend = 0.014 and 0.006, respectively). In particular, elevated IL-6 was associated in a dose-dependent manner with decreased TP and LF in the high-PAHs metabolites groups (all P trend<0.05), but not in the low-PAHs metabolites groups. No significant association between Hsp70 and HRV in total population was found after multivariate adjustment. However, increased Hsp70 was significantly associated with elevated standard deviation of NN intervals (SDNN), TP and LF in the low-PAHs metabolites groups (all P trend<0.05). We also observed that both IL-6 and Hsp70 significantly interacted with multiple PAHs metabolites in relation to HRV. Conclusions In coke oven workers, increased IL-6 was associated with a dose-response decreased HRV in the high-PAHs metabolites groups, whereas increase of Hsp70 can result in significant dose-related increase in HRV in the low-PAHs metabolites groups. PMID:24722336

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

ATM and KAT5 safeguard replicating chromatin against formaldehyde damage

PubMed Central

Ortega-Atienza, Sara; Wong, Victor C.; DeLoughery, Zachary; Luczak, Michal W.; Zhitkovich, Anatoly

2016-01-01

Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA. PMID:26420831

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.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) balance in developmental outcomes.

PubMed

Colombo, John; Jill Shaddy, D; Kerling, Elizabeth H; Gustafson, Kathleen M; Carlson, Susan E

2017-06-01

The DHA Intake and Measurement of Neural Development (DIAMOND) trial represents one of only a few studies of the long-term dose-response effects of LCPUFA-supplemented formula feeding during infancy. The trial contrasted the effects of four formulations: 0.00% docosahexaenoic acid (DHA)/0.00% arachidonic acid (ARA), 0.32% DHA/0.64% ARA, 0.64% DHA/0.64% ARA, and 0.96% DHA/0.64% ARA against a control condition (0.00% DHA/0.00% ARA). The results of this trial have been published elsewhere, and show improved cognitive outcomes for infants fed supplemented formulas, but a common finding among many of the outcomes show a reduction of benefit for the highest DHA dose (i.e., 0.96%DHA/0.64% ARA, that is, a DHA: ARA ratio 1.5:1.0). The current paper gathers and summarizes the evidence for the reduction of benefit at this dose, and in an attempt to account for this reduced benefit, presents for the first time data from infants' red blood cell (RBC) assays taken at 4 and 12 months of age. Those assays indicate that blood DHA levels generally rose with increased DHA supplementation, although those levels tended to plateau as the DHA-supplemented level exceeded 0.64%. Perhaps more importantly, ARA levels showed a strong inverted-U function in response to increased DHA supplementation; indeed, infants assigned to the formula with the highest dose of DHA (and highest DHA/ARA ratio) showed a reduction in blood ARA relative to more intermediate DHA doses. This finding raises the possibility that reduced ARA may be responsible for the reduction in benefit on cognitive outcomes seen at this dose. The findings implicate the DHA/ARA balance as an important variable in the contribution of LCPUFAs to cognitive and behavioral development in infancy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Caffeine Induces the Stress Response and Up-Regulates Heat Shock Proteins in Caenorhabditis elegans.

PubMed

Al-Amin, Mohammad; Kawasaki, Ichiro; Gong, Joomi; Shim, Yhong-Hee

2016-02-01

Caffeine has both positive and negative effects on physiological functions in a dose-dependent manner. C. elegans has been used as an animal model to investigate the effects of caffeine on development. Caffeine treatment at a high dose (30 mM) showed detrimental effects and caused early larval arrest. We performed a comparative proteomic analysis to investigate the mode of action of high-dose caffeine treatment in C. elegans and found that the stress response proteins, heat shock protein (HSP)-4 (endoplasmic reticulum [ER] chaperone), HSP-6 (mitochondrial chaperone), and HSP-16 (cytosolic chaperone), were induced and their expression was regulated at the transcriptional level. These findings suggest that high-dose caffeine intake causes a strong stress response and activates all three stress-response pathways in the worms, including the ER-, mitochondrial-, and cytosolic pathways. RNA interference of each hsp gene or in triple combination retarded growth. In addition, caffeine treatment stimulated a food-avoidance behavior (aversion phenotype), which was enhanced by RNAi depletion of the hsp-4 gene. Therefore, up-regulation of hsp genes after caffeine treatment appeared to be the major responses to alleviate stress and protect against developmental arrest.

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit.

PubMed

Stamenić, Tamara Timić; Poe, Michael M; Rehman, Sabah; Santrač, Anja; Divović, Branka; Scholze, Petra; Ernst, Margot; Cook, James M; Savić, Miroslav M

2016-11-15

We have synthesized and characterized MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABA A receptors containing the α5 subunit (α5GABA A Rs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1-10mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABA A receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2'F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200mg/kg), but at the price of activating non-α5 GABA A Rs as well as the desired α5GABA A Rs at the highest dose. At the dose of 10mg/kg, which elicits a strong positive modulation of α5GABA A Rs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of α5GABA A Rs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism. Copyright © 2016 Elsevier B.V. All rights reserved.

Ester to amide substitution improves selectivity, efficacy and kinetic behavior of a benzodiazepine positive modulator of GABAA receptors containing the α5 subunit

PubMed Central

Stamenić, Tamara Timić; Poe, Michael M.; Rehman, Sabah; Santrač, Anja; Divović, Branka; Scholze, Petra; Ernst, Margot; Cook, James M.; Savić, Miroslav M.

2016-01-01

We have synthesized and characterized MP-III-022 ((R)-8-ethynyl-6-(2-fluorophenyl)-N,4-dimethyl-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxamide) in vitro and in vivo as a binding- and efficacy-selective positive allosteric modulator of GABAA receptors containing the α5 subunit (α5GABAARs). By approximation of the electrophysiological responses which the estimated free rat brain concentrations can induce, we demonstrated that convenient systemic administration of MP-III-022 in the dose range 1-10 mg/kg may result in a selective potentiation, over a wide range from mild to moderate to strong, of α5βγ2 GABAA receptors. For eliciting a comparable range of potentiation, the widely studied parent ligand SH-053-2′F-R-CH3 containing an ester moiety needs to be administered over a much wider dose range (10-200 mg/kg), but at the price of activating non-α5 GABAARs as well as the desired α5GABAARs at the highest dose. At the dose of 10 mg/kg, which elicits a strong positive modulation of α5GABAARs, MP-III-022 caused mild, but significant muscle relaxation, while at doses 1-10 mg/kg was devoid of ataxia, sedation or an influence on the anxiety level, characteristic for non-selective benzodiazepines. As an amide compound with improved stability and kinetic properties, MP-III-022 may represent an optimized tool to study the influence of α5GABAARs on the neuronal pathways related to CNS disorders such as schizophrenia, Alzheimer's disease, Down syndrome or autism. PMID:27639297

Precision-Cut Liver Slices of Salmo salar as a tool to investigate the oxidative impact of CYP1A-mediated PCB 126 and 3-methylcholanthrene metabolism.

PubMed

Lemaire, Benjamin; Beck, Michaël; Jaspart, Mélanie; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean-Pierre; Rees, Jean-François

2011-02-01

Fish isolated cell systems have long been used to predict in vivo toxicity of man-made chemicals. In present study, we tested the suitability of Precision-Cut Liver Slices (PCLS) as an alternative to these models that allows the evaluation of a global tissue response to toxicants, to investigate oxidative stress response to cytochrome P450 1A (CYP1A) induction in fish liver. PCLS of Salmo salar were exposed for 21 h to increasing doses of 3-methylcholanthrene (3-MC) and Polychlorobiphenyl 126 (PCB 126). 3-MC (25 μM) strongly induced CYP1A transcription. In dose-response analysis (25-100 μM), EROD activity was strongly increased at intermediate 3-MC concentrations. We found the counter-intuitive decline of EROD at the highest 3-MC doses to result from reversible competition with ethoxyresorufin. No increases of H(2)O(2) production, antioxidant enzymes activities or oxidative damage to lipids were found with 3-MC treatments. PCLS subjected to PCB 126 (2-200 nM) showed increased contamination levels and a parallel increased CYP1A mRNA synthesis and EROD activity. H(2)O(2) production tended to increase but no oxidative damage to lipids was found. As antioxidant enzymes activities declined at the highest PCB 126 dose, it is suggested that longer incubation periods could be required to generate oxidative stress in PCLS. Copyright © 2010 Elsevier Ltd. All rights reserved.

Mechanism of the cardiovascular activity of dibenzoxazepine in cats.

PubMed

Lundy, P M

1978-04-01

Small i.v. doses of dibenzoxazepine (DBO) (50--400 microgram/kg) given to anesthetized cats resulted in dose related increases in heart rate (up to 70 beats/min) and blood pressure (up to 80 mm Hg). The pressor response was blocked by pretreatment of the animals with phentolamine; pretreatment for 3 days with 6-hydroxdopamine; with mecamylamine and spinal transection between C1 and C2 but not by propranolol or adrenalectomy. The increase in heart rate was blocked by pretreatment with propranolol, 6-hydroxydopamine, mecamylamine and spinal transection whereas adrenalectomy only affected the response slightly. DBO produced only negative effects on the isolated rabbit heart. Bioassay of arterial blood showed an increased level of circulating catecholamines corresponding to the cardiovascular stimulation. DBO had no tyramine-like activity on the isolated rabbit aortic strip but slightly potentiated the contraction induced by noradrenaline. These findings strongly suggest that the cardiovascular effects resulted from central stimulation of the sympathetic nervous system. A minor part of the observed sympathomimetic effects may also be the result of the ability of DBO to potentiate the effects of noradrenaline perhaps by blocking catecholamine uptake.

Space-type radiation induces multimodal responses in the mouse gut microbiome and metabolome.

PubMed

Casero, David; Gill, Kirandeep; Sridharan, Vijayalakshmi; Koturbash, Igor; Nelson, Gregory; Hauer-Jensen, Martin; Boerma, Marjan; Braun, Jonathan; Cheema, Amrita K

2017-08-18

Space travel is associated with continuous low dose rate exposure to high linear energy transfer (LET) radiation. Pathophysiological manifestations after low dose radiation exposure are strongly influenced by non-cytocidal radiation effects, including changes in the microbiome and host gene expression. Although the importance of the gut microbiome in the maintenance of human health is well established, little is known about the role of radiation in altering the microbiome during deep-space travel. Using a mouse model for exposure to high LET radiation, we observed substantial changes in the composition and functional potential of the gut microbiome. These were accompanied by changes in the abundance of multiple metabolites, which were related to the enzymatic activity of the predicted metagenome by means of metabolic network modeling. There was a complex dynamic in microbial and metabolic composition at different radiation doses, suggestive of transient, dose-dependent interactions between microbial ecology and signals from the host's cellular damage repair processes. The observed radiation-induced changes in microbiota diversity and composition were analyzed at the functional level. A constitutive change in activity was found for several pathways dominated by microbiome-specific enzymatic reactions like carbohydrate digestion and absorption and lipopolysaccharide biosynthesis, while the activity in other radiation-responsive pathways like phosphatidylinositol signaling could be linked to dose-dependent changes in the abundance of specific taxa. The implication of microbiome-mediated pathophysiology after low dose ionizing radiation may be an unappreciated biologic hazard of space travel and deserves experimental validation. This study provides a conceptual and analytical basis of further investigations to increase our understanding of the chronic effects of space radiation on human health, and points to potential new targets for intervention in adverse radiation effects.

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.

Cyclophosphamide dose intensification may circumvent anthracycline resistance of p53 mutant breast cancers.

PubMed

Lehmann-Che, Jacqueline; André, Fabrice; Desmedt, Christine; Mazouni, Chafika; Giacchetti, Sylvie; Turpin, Elisabeth; Espié, Marc; Plassa, Louis-François; Marty, Michel; Bertheau, Philippe; Sotiriou, Christos; Piccart, Martine; Symmans, W Fraser; Pusztai, Lajos; de Thé, Hugues

2010-01-01

The predictive value of p53 for the efficacy of front-line anthracycline-based chemotherapy regimens has been a matter of significant controversy. Anthracyclines are usually combined with widely different doses of alkylating agents, which may significantly modulate tumor response to these combinations. We analyzed three series of de novo stage II-III breast cancer patients treated front line with anthracycline-based regimens of various cyclophosphamide dose intensities: 65 patients with estrogen receptor (ER)(-) tumors treated with anthracyclines alone (Institut Jules Bordet, Brussels), 51 unselected breast cancer patients treated with intermediate doses of cyclophosphamide (MD Anderson Cancer Center, Houston, TX), and 128 others treated with a dose-dense anthracycline-cyclophosphamide combination (St. Louis, Paris). After chemotherapy and surgery, pathologic complete response (pCR) was evaluated. p53 status was determined by a yeast functional assay on the pretreatment tumor sample. In a multivariate analysis of the pooled results, a lack of ER expression and high-dose cyclophosphamide administration were associated with a higher likelihood of pCR. A sharp statistical interaction was detected between p53 status and cyclophosphamide dose intensity. Indeed, when restricting our analysis to patients with ER(-) tumors, we confirmed that a mutant p53 status was associated with anthracycline resistance, but found that p53 inactivation was required for response to the dose-intense alkylating regimen. The latter allowed very high levels of pCR in triple-negative tumors. Thus, our data strongly suggest that cyclophosphamide dose intensification in ER(-) p53-mutated breast cancer patients could significantly improve their response.

Quantifying Cancer Risk from Radiation.

PubMed

Keil, Alexander P; Richardson, David B

2017-12-06

Complex statistical models fitted to data from studies of atomic bomb survivors are used to estimate the human health effects of ionizing radiation exposures. We describe and illustrate an approach to estimate population risks from ionizing radiation exposure that relaxes many assumptions about radiation-related mortality. The approach draws on developments in methods for causal inference. The results offer a different way to quantify radiation's effects and show that conventional estimates of the population burden of excess cancer at high radiation doses are driven strongly by projecting outside the range of current data. Summary results obtained using the proposed approach are similar in magnitude to those obtained using conventional methods, although estimates of radiation-related excess cancers differ for many age, sex, and dose groups. At low doses relevant to typical exposures, the strength of evidence in data is surprisingly weak. Statements regarding human health effects at low doses rely strongly on the use of modeling assumptions. © 2017 Society for Risk Analysis.

Heterogeneity in the pharmacodynamics of two long-acting methylphenidate formulations for children with attention deficit/hyperactivity disorder. A growth mixture modelling analysis.

PubMed

Sonuga-Barke, Edmund J S; Van Lier, Pol; Swanson, James M; Coghill, David; Wigal, Sharon; Vandenberghe, Mieke; Hatch, Simon

2008-06-01

To use growth mixture modelling (GMM) to identify subgroups of children with attention deficit hyperactive disorder (ADHD) who have different pharmacodynamic profiles in response to extended release methylphenidate as assessed in a laboratory classroom setting. GMM analysis was performed on data from the COMACS study (Comparison of Methylphenidates in the Analog Classroom Setting): a large (n = 184) placebo-controlled cross-over study comparing three treatment conditions in the Laboratory School Protocol (with a 1.5-h cycle of attention and deportment assessments). Two orally administered, once-daily methylphenidate (MPH) bioequivalent formulations [Metadate CD/Equasym XL (MCD-EQXL) and Concerta XL (CON)] were compared with placebo (PLA). Three classes of children with distinct severity profiles in the PLA condition were identified. For both MCD-EQXL and CON, the more severe their PLA symptoms the better, the children's response. However, the formulations produced different growth curves by class, with CON having essentially a flat profile for all three classes (i.e. no effect of PLA severity) and MCD-EQXL showing a marked decline in symptoms immediately post-dosing in the two most severe classes compared with the least severe. Comparison of daily doses matched for immediate-release (IR) components accounted for this difference. The results suggest considerable heterogeneity in the pharmacodynamics of MPH response by children with ADHD. When treatment response for near-equal, bioequivalent daily doses the two formulations was compared, marked differences were seen for children in the most severe classes with a strong curvilinear trajectory for MCD-EQXL related to the greater IR component.

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

Experimental evolution of insect immune memory versus pathogen resistance.

PubMed

Khan, Imroze; Prakash, Arun; Agashe, Deepa

2017-12-20

Under strong pathogen pressure, insects often evolve resistance to infection. Many insects are also protected via immune memory (immune priming), whereby sublethal exposure to a pathogen enhances survival after secondary infection. Theory predicts that immune memory should evolve when the pathogen is highly virulent, or when pathogen exposure is relatively rare. However, there are no empirical tests of these hypotheses, and the adaptive benefits of immune memory relative to direct resistance against a pathogen are poorly understood. To determine the selective pressures and ecological conditions that shape immune evolution, we imposed strong pathogen selection on flour beetle ( Tribolium castaneum ) populations, infecting them with Bacillus thuringiensis (Bt) for 11 generations. Populations injected first with heat-killed and then live Bt evolved high basal resistance against multiple Bt strains. By contrast, populations injected only with a high dose of live Bt evolved a less effective but strain-specific priming response. Control populations injected with heat-killed Bt did not evolve priming; and in the ancestor, priming was effective only against a low Bt dose. Intriguingly, one replicate population first evolved priming and subsequently evolved basal resistance, suggesting the potential for dynamic evolution of different immune strategies. Our work is the first report showing that pathogens can select for rapid modulation of insect priming ability, allowing hosts to evolve divergent immune strategies (generalized resistance versus specific immune memory) with potentially distinct mechanisms. © 2017 The Author(s).

[High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].

PubMed

Selle, Frédéric; Gligorov, Joseph; Soares, Daniele G; Lotz, Jean-Pierre

2016-10-01

The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

The effects of chronic oral methyl mercury exposure on the lysosome system of rat kidney. Morphometric and biochemical studies.

PubMed

Fowler, B A; Brown, H W; Lucier, G W; Krigman, M R

1975-03-01

This report describes morphometric and biochemical changes in the renal lysosome system of rats exposed to 3, 5, or 10 p.p.m. concentrations of methyl mercury hydroxide in their drinking water for 4 weeks. Increased numbers of dense, granular lysosomes, previously found to contain mercury, were observed in tubule cells of rats receiving the 3 and 5 p.p.m. dose levels but not those of the 10 p.p.m. group. Tubule cells from animals given the 10 p.p;m. dose level displayed proteinaceous vacuoles with dense crystalloid structures, apical cytoplasmic extrusion, and cellular degeneration; Mitochondrial swelling within tubule cells of treated animals showed a marked dose-response relationship. Renal microsomal activity levels of ss-glucuronidase were strongly inhibited by methyl mercury hydroxide exposure at all dose levels, whereas the activity levels of acid phosphatase were unchanged. Lysosomal beta-glucuronidase was also inhibited by methyl mercury hydroxide exposure, whereas lysosomal acid phosphatase showed approximately a 2-fold increase in activity. The results are discussed in relation to the role of lysosomes in mediating the nephrotoxic effects of methyl mercury and other toxic trace metals.

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.

Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia

PubMed Central

Dolzhikova, I. V.; Zubkova, O. V.; Tukhvatulin, A. I.; Dzharullaeva, A. S.; Tukhvatulina, N. M.; Shcheblyakov, D. V.; Shmarov, M. M.; Tokarskaya, E. A.; Simakova, Y. V.; Egorova, D. A.; Scherbinin, D. N.; Tutykhina, I. L.; Lysenko, A. A.; Kostarnoy, A. V.; Gancheva, P. G.; Ozharovskaya, T. A.; Belugin, B. V.; Kolobukhina, L. V.; Pantyukhov, V. B.; Syromyatnikova, S. I.; Shatokhina, I. V.; Sizikova, T. V.; Rumyantseva, I. G.; Andrus, A. F.; Boyarskaya, N. V.; Voytyuk, A. N.; Babira, V. F.; Volchikhina, S. V.; Kutaev, D. A.; Bel'skih, A. N.; Zhdanov, K. V.; Zakharenko, S. M.; Borisevich, S. V.; Logunov, D. Y.; Naroditsky, B. S.; Gintsburg, A. L.

2017-01-01

ABSTRACT Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401–4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055). PMID:28152326

Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia.

PubMed

Dolzhikova, I V; Zubkova, O V; Tukhvatulin, A I; Dzharullaeva, A S; Tukhvatulina, N M; Shcheblyakov, D V; Shmarov, M M; Tokarskaya, E A; Simakova, Y V; Egorova, D A; Scherbinin, D N; Tutykhina, I L; Lysenko, A A; Kostarnoy, A V; Gancheva, P G; Ozharovskaya, T A; Belugin, B V; Kolobukhina, L V; Pantyukhov, V B; Syromyatnikova, S I; Shatokhina, I V; Sizikova, T V; Rumyantseva, I G; Andrus, A F; Boyarskaya, N V; Voytyuk, A N; Babira, V F; Volchikhina, S V; Kutaev, D A; Bel'skih, A N; Zhdanov, K V; Zakharenko, S M; Borisevich, S V; Logunov, D Y; Naroditsky, B S; Gintsburg, A L

2017-03-04

Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).

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

PubMed

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

2014-10-15

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

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.

Accurate condensed history Monte Carlo simulation of electron transport. II. Application to ion chamber response simulations.

PubMed

Kawrakow, I

2000-03-01

In this report the condensed history Monte Carlo simulation of electron transport and its application to the calculation of ion chamber response is discussed. It is shown that the strong step-size dependencies and lack of convergence to the correct answer previously observed are the combined effect of the following artifacts caused by the EGS4/PRESTA implementation of the condensed history technique: dose underprediction due to PRESTA'S pathlength correction and lateral correlation algorithm; dose overprediction due to the boundary crossing algorithm; dose overprediction due to the breakdown of the fictitious cross section method for sampling distances between discrete interaction and the inaccurate evaluation of energy-dependent quantities. These artifacts are now understood quantitatively and analytical expressions for their effect are given.

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.

In vivo proton dosimetry using a MOSFET detector in an anthropomorphic phantom with tissue inhomogeneity.

PubMed

Kohno, Ryosuke; Hotta, Kenji; Matsubara, Kana; Nishioka, Shie; Matsuura, Taeko; Kawashima, Mitsuhiko

2012-03-08

When in vivo proton dosimetry is performed with a metal-oxide semiconductor field-effect transistor (MOSFET) detector, the response of the detector depends strongly on the linear energy transfer. The present study reports a practical method to correct the MOSFET response for linear energy transfer dependence by using a simplified Monte Carlo dose calculation method (SMC). A depth-output curve for a mono-energetic proton beam in polyethylene was measured with the MOSFET detector. This curve was used to calculate MOSFET output distributions with the SMC (SMC(MOSFET)). The SMC(MOSFET) output value at an arbitrary point was compared with the value obtained by the conventional SMC(PPIC), which calculates proton dose distributions by using the depth-dose curve determined by a parallel-plate ionization chamber (PPIC). The ratio of the two values was used to calculate the correction factor of the MOSFET response at an arbitrary point. The dose obtained by the MOSFET detector was determined from the product of the correction factor and the MOSFET raw dose. When in vivo proton dosimetry was performed with the MOSFET detector in an anthropomorphic phantom, the corrected MOSFET doses agreed with the SMC(PPIC) results within the measurement error. To our knowledge, this is the first report of successful in vivo proton dosimetry with a MOSFET detector.

Differential gene expression responses distinguish contact and respiratory sensitizers and nonsensitizing irritants in the local lymph node assay.

PubMed

Adenuga, David; Woolhiser, Michael R; Gollapudi, B Bhaskar; Boverhof, Darrell R

2012-04-01

Genomic approaches have the potential to enhance the specificity and predictive accuracy of existing toxicology endpoints, including those for chemical sensitization. The present study was conducted to determine whether gene expression responses can distinguish contact sensitizers (1-chloro-2,4-dinitrobenzene [DNCB] and hexyl cinnamic aldehyde [HCA]), respiratory sensitizers (ortho-phthalaldehyde and trimellitic anhydride [TMA]), and nonsensitizing irritants (methyl salicylate [MS] and nonanoic acid [NA]) in the local lymph node assay (LLNA). Female Balb/c mice received doses of each chemical as per the standard LLNA dosing regimen on days 1, 2, and 3. Auricular lymph nodes were analyzed for tritiated thymidine ((3)HTdR) incorporation on day 6 and for gene expression responses on days 6 and 10. All chemicals induced dose-dependent increases in stimulation index, which correlated strongly with the number of differentially expressed genes. A majority of genes modulated by the irritants were similarly altered by the sensitizers, consistent with the irritating effects of the sensitizers. However, a select number of responses involved with immune-specific functions, such as dendritic cell activation, were unique to the sensitizers and may offer the ability to distinguish sensitizers from irritants. Genes for the mast cell proteases 1 and 8, Lgals7, Tim2, Aicda, Il4, and Akr1c18 were more strongly regulated by respiratory sensitizers compared with contact sensitizers and may represent potential biomarkers for discriminating between contact and respiratory sensitizers. Collectively, these data suggest that gene expression responses may serve as useful biomarkers to distinguish between respiratory and contact sensitizers and nonsensitizing irritants in the LLNA.

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:…

Chromium uptake and consequences for metabolism and oxidative stress in chamomile plants.

PubMed

Kováčik, Jozef; Babula, Petr; Klejdus, Bořivoj; Hedbavny, Josef

2013-08-21

Chromium Cr(III) toxicity toward chamomile metabolism and oxidative stress-related parameters after 7 days of exposure was studied. Cr preferentially accumulated in the roots and evoked extensive both dose-dependent and dose-independent increase in fluorescence signals of ROS, NO and thiols. Superoxide increased mainly at the highest Cr dose, whereas H2O2 accumulation revealed a discontinuous trend in relation to external Cr supply, and this could be owing to variation in activities of peroxidases. Glutathione and ascorbate quantification, using LC-MS/MS equipment, revealed strong stimulation despite low shoot Cr amounts. Phenolic enzyme activities, except for PAL, were depressed by Cr presence, whereas phenolic metabolites were stimulated, indicating various time dynamics. Among free amino acids, their sum and even proline decreased in the roots, whereas soluble proteins increased. Mineral nutrients showed negligible responses with only Zn and Cu being depleted in both shoots and roots. Cr staining using Cr(III)-specific (naphthalimide-rhodamine) and metal nonspecific (Phen Green) dyes indicated that the former correlated well with AAS quantification of Cr amount. Use of Phen Green is also discussed. These data indicate that Cr-induced oxidative stress is not simply a function of exposure time and applied concentration. Microscopic observations in terms of oxidative stress and chromium uptake are presented here for the first time.

Feasibility of a semiconductor dosimeter to monitor skin dose in interventional radiology.

PubMed

Meyer, P; Regal, R; Jung, M; Siffert, P; Mertz, L; Constantinesco, A

2001-10-01

The design and preliminary test results of a semiconductor silicon dosimeter are presented in this article. Use of this dosimeter is foreseen for real-time skin dose control in interventional radiology. The strong energy dependence of this kind of radiation detector is well overcome by filtering the silicon diode. Here, the optimal filter features have been calculated by numerical Monte Carlo simulations. A prototype has been built and tested in a radiological facility. The first experimental results show a good match between the filtered semiconductor diode response and an ionization chamber response, within 2% fluctuation in a 2.2 to 4.1 mm Al half-value layer (HVL) energy range. Moreover, the semiconductor sensor response is linear from 0.02 Gy/min to at least 6.5 Gy/min, covering the whole dose rate range found in interventional radiology. The results show that a semiconductor dosimeter could be used to monitor skin dose during the majority of procedures using x-rays below 150 keV. The use of this device may assist in avoiding radiation-induced skin injuries and lower radiation levels during interventional procedures.

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

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.

Transcriptomics of the Vaccine Immune Response: Priming With Adjuvant Modulates Recall Innate Responses After Boosting.

PubMed

Santoro, Francesco; Pettini, Elena; Kazmin, Dmitri; Ciabattini, Annalisa; Fiorino, Fabio; Gilfillan, Gregor D; Evenroed, Ida M; Andersen, Peter; Pozzi, Gianni; Medaglini, Donata

2018-01-01

Transcriptomic profiling of the immune response induced by vaccine adjuvants is of critical importance for the rational design of vaccination strategies. In this study, transcriptomics was employed to profile the effect of the vaccine adjuvant used for priming on the immune response following re-exposure to the vaccine antigen alone. Mice were primed with the chimeric vaccine antigen H56 of Mycobacterium tuberculosis administered alone or with the CAF01 adjuvant and boosted with the antigen alone. mRNA sequencing was performed on blood samples collected 1, 2, and 7 days after priming and after boosting. Gene expression analysis at day 2 after priming showed that the CAF01 adjuvanted vaccine induced a stronger upregulation of the innate immunity modules compared with the unadjuvanted formulation. The immunostimulant effect of the CAF01 adjuvant, used in the primary immunization, was clearly seen after a booster immunization with a low dose of antigen alone. One day after boost, we observed a strong upregulation of multiple genes in blood of mice primed with H56 + CAF01 compared with mice primed with the H56 alone. In particular, blood transcription modules related to innate immune response, such as monocyte and neutrophil recruitment, activation of antigen-presenting cells, and interferon response were activated. Seven days after boost, differential expression of innate response genes faded while a moderate differential expression of T cell activation modules was appreciable. Indeed, immunological analysis showed a higher frequency of H56-specific CD4+ T cells and germinal center B cells in draining lymph nodes, a strong H56-specific humoral response and a higher frequency of antibody-secreting cells in spleen of mice primed with H56 + CAF01. Taken together, these data indicate that the adjuvant used for priming strongly reprograms the immune response that, upon boosting, results in a stronger recall innate response essential for shaping the downstream adaptive response.

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

NASA Astrophysics Data System (ADS)

Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

2017-03-01

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

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…

Reducing risk of Anthracycline-related heart failure after childhood cancer | Division of Cancer Prevention

Cancer.gov

Childhood cancer survivors are at a 15-fold risk of developing heart failure (HF) compared to age-matched controls. There is a strong dose-dependent association between anthracyclines and risk of HF; the incidence approaches 20% at cumulative doses between 300-600 mg/m2, and exceeds 30% for doses >600 mg/m2. Outcome following HF is poor; 5-year survival rate is |

Chronic toxic and carcinogenic effects of oral cadmium in the Noble (NBL/Cr) rat: induction of neoplastic and proliferative lesions of the adrenal, kidney, prostate, and testes.

PubMed

Waalkes, M P; Anver, M R; Diwan, B A

1999-10-29

Based on the occurrence of pulmonary cancers in exposed populations, cadmium is classified as a human carcinogen. More controversial target sites for cadmium in humans include the prostate and kidney, where some studies have shown a link between cadmium and cancer. In Wistar rats cadmium induces tumors in the ventral prostate. The relevance of such lesions to humans is debated since the rat ventral lobe, unlike the dorsolateral lobe, has no embryological homolog in the human prostate. Cadmium has not been linked with renal tumors in rodents but is a potent nephrotoxin. In this work we studied the effects of oral cadmium in the Noble (NBL/Cr) rat with particular attention to proliferative lesions of the prostate and kidneys. Cadmium (as CdCl2) was given ad libitum throughout the study in the drinking water at doses of 0, 25, 50, 100, and 200 ppm Cd to groups (initial n = 30) of male rats, which were observed for up to 102 wk. At the lower doses of cadmium (< or =50 ppm) a clear dose-related increase in total proliferative lesions of the prostate (ventral and dorsolateral lesions combined) occurred (0 ppm = 21% incidence, 25 ppm = 46%, 50 ppm = 50%; trend p < .03). These lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells without stromal invasion. The lesions occurred primarily in the dorsolateral prostate with cadmium exposure and most frequently showed three or more foci within each specimen. At higher doses, prostatic proliferative lesions declined to control levels. The loss of prostatic response at the higher doses was likely due to diminished testicular function secondary to cadmium treatment. This was reflected in lesions indicative of testicular hypofunction at the highest cadmium dose, namely, interstitial cell hyperplasia, and a strong correlation between cadmium dose and total proliferative lesions of the testes (hyperplasias and tumors combined). Renal tumors (mainly mesenchymal and pelvic transitional cell), although few in number, showed a positive correlation with cadmium dose, as did pelvic transitional epithelial hyperplasia. Renal lesions were not associated with any cadmium-induced changes in age-related chronic nephropathy. The incidence of pheochromocytomas of the adrenal was increased by cadmium but only at the 50 ppm dose. Inflammatory lesions of the liver and spleen were common at higher doses and showed strong trends based on dose. These results indicate that oral cadmium can induce proliferative lesions in the prostate and kidney of the Noble rat. The finding of proliferative lesions of dorsolateral prostate in rats has presumed relevance to human prostate cancers.

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.

Trichinella spiralis: strong antibody response to a 49 kDa newborn larva antigen in infected rats.

PubMed

Salinas-Tobon, Maria Del Rosario; Navarrete-Leon, Anaid; Mendez-Loredo, Blanca Esther; Esquivel-Aguirre, Dalia; Martínez-Abrajan, Dulce Maria; Hernandez-Sanchez, Javier

2007-02-01

In this work, we analyzed the kinetics of anti-Trichinella spiralis newborn larva (NBL) antibodies (Ab) and the antigenic recognition pattern of NBL proteins and its dose effects. Wistar rats were infected with 0, 700, 2000, 4000 and 8000 muscle larvae (ML) and bled at different time intervals up to day 31 post infection (p.i.). Ab production was higher with 2000 ML dose and decreased with 8000, 4000 and 700 ML. Abs were not detected until day 10, peaked on day 14 for the 2000 ML dose and on day 19 for the other doses and thereafter declined slowly from 19 to 31 days p.i. In contrast, Abs to ML increased from day 10, peaked on day 19 and remained high until the end of the study. Abs bound strongly at least to three NBL components of 188, 205 and 49 kDa. NBL antigen of 188 and 205 kDa were recognized 10-26 days p.i. and that of 49 kDa from day 10 to day 31 p.i. A weak recognition towards antigens of 52, 54, 62 and 83 kDa was also observed during the infection. An early recognition of 31, 43, 45, 55, 68 and 85 kDa ML antigens was observed whereas the response to those of 43, 45, 48, 60, 64 and 97 kDa (described previously as TSL-1 antigens) occurred late in the infection. A follow-up of antigen recognition up to day 61 with the optimal immunization dose (2000 ML) evidenced a decline of Ab production to the 49 kDa NBL antigen 42 days p.i., which suggested antigenic differences with the previously reported 43 kDa ML antigen strongly recognized late in the infection. To analyze the stage-specificity of the 49 kDa NBL antigen, polyclonal antibodies (PoAb) were obtained in rats immunized with 49 kDa NBL antigen. PoAb reacted strongly with the 49 kDa NBL component in NBL total soluble extract but no reactivity was observed with soluble antigen of the other T. spiralis stages. Albeit with less intensity, the 49 kDa component was also recognized by PoAb together with other antigens of 53, 97 and 107 kDa, in NBL excretory-secretory products (NBL-ESP). Thus, our results reveal differences in the kinetics of anti-NBL and ML Ab responses. While anti-NBL Abs declined slowly from day 19 until the end of the experiment, Abs to ML antigen remained high in the same period. It is remarkable the optimal Ab response to NBL antigens with 2000 ML infective dose and the reduced number of NBL antigens identified throughout the experimental T. spiralis infection, standing out the immunodominant 49 kDa antigen. Interestingly, this antigen, which was prominently expressed in NBL somatic proteins, was also detected in NBL-ESP.

A Phase I and pharmacodynamic study of AT9283, a small molecule inhibitor of aurora kinases in patients with relapsed/refractory leukemia or myelofibrosis

PubMed Central

Foran, James; Ravandi, Farhad; Wierda, William; Garcia-Manero, Guillermo; Verstovsek, Srdan; Kadia, Tapan; Burger, Jan; Yule, Murray; Langford, Gillian; Lyons, John; Ayrton, John; Lock, Victoria; Borthakur, Gautham; Cortes, Jorge; Kantarjian, Hagop

2014-01-01

Purpose To identify the MTD of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics and preliminary evidence of efficacy. Patients and Methods AT9283 was administered as a continuous 72h infusion every 21 days. Doses were escalated by a standard 3+3 design. After the MTD for the 72h infusion was identified, infusion duration was increased incrementally to 96h and 120h. In total, 48 patients received ≥1 cycle of AT9283. Median age was 61 years (range 22–86 years), with 56% men, 75% diagnosed with AML, and 89% having received ≥3 (up to 16) prior lines of therapy. Results 324 mg/m2/72h AT9283 was determined to be the MTD. DLTs were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leucopenia and mucositis. Bone marrow blasts decreased ≥38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of aurora kinase B inhibition. Two patients with accelerated phase CML showed evidence of benefit, manifest as a cytogenetic response in one case; one patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional. Conclusion AT9283 tolerability was strongly dose dependent with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations. PMID:24355079

GABAergic influences on ORX receptor-dependent abnormal motor behaviors and neurodegenerative events in fish

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

Facciolo, Rosa Maria, E-mail: rm.facciolo@unical.i; Crudo, Michele; Giusi, Giuseppina

2010-02-15

At date the major neuroreceptors i.e. gamma-aminobutyric acid{sub A} (GABA{sub A}R) and orexin (ORXR) systems are beginning to be linked to homeostasis, neuroendocrine and emotional states. In this study, intraperitoneal treatment of the marine teleost Thalassoma pavo with the highly selective GABA{sub A}R agonist (muscimol, MUS; 0,1 mug/g body weight) and/or its antagonist bicuculline (BIC; 1 mug/g body weight) have corroborated a GABA{sub A}ergic role on motor behaviors. In particular, MUS induced moderate (p < 0.05) and great (p < 0.01) increases of swimming towards food sources and resting states after 24 (1 dose) and 96 (4 doses) h treatmentmore » sessions, respectively, when compared to controls. Conversely, BIC caused a very strong (p < 0.001) reduction of the former behavior and in some cases convulsive swimming. From the correlation of BIC-dependent behavioral changes to neuronal morphological and ORXR transcriptional variations, it appeared that the disinhibitory action of GABA{sub A}R was very likely responsible for very strong and strong ORXR mRNA reductions in cerebellum valvula and torus longitudinalis, respectively. Moreover these effects were linked to evident ultra-structural changes such as shrunken cell membranes and loss of cytoplasmic architecture. In contrast, MUS supplied a very low, if any, argyrophilic reaction in hypothalamic and mesencephalic regions plus a scarce level of ultra-structural damages. Interestingly, combined administrations of MUS + BIC were not related to consistent damages, aside mild neuronal alterations in motor-related areas such as optic tectum. Overall it is tempting to suggest, for the first time, a neuroprotective role of GABA{sub A}R inhibitory actions against the overexcitatory ORXR-dependent neurodegeneration and consequently abnormal swimming events in fish.« less

Measuring methylphenidate response in attention-deficit/hyperactvity disorder: how are laboratory classroom-based measures related to parent ratings?

PubMed

Sonuga-Barke, Edmund J S; Coghill, David; DeBacker, Marc; Swanson, James

2009-12-01

Methylphenidate (MPH) is an efficacious and normally well-tolerated treatment for attention-deficit/hyperactivity disorder (ADHD). Although treatment effects are usually assessed using parent-rating scales, these can be supplemented by more objective methods. Here we examine the associations between ratings and one such method, assessments made across the day in the laboratory classroom. Comparison of Methylphenidates in the Analog Classroom Setting (COMACS) was made in a large (n = 184) placebo-controlled trial comparing Equasym XL/Metadate CD, Concerta, and placebo (PLA) using a Laboratory School protocol. Therapeutic effects were measured using direct observation, scores on a simple math productivity task and parent ratings. Treatment effects were observed on all measures. Laboratory measures were correlated with each other, most strongly between Swanson, Kotkin, Agler, M-Flynn and Pelham Scale (SKAMP) inattention and Permanent Product Measure of Performance (PERMP). Parental ratings were correlated with classroom measures during the main morning period (1.5-4.5 hours after dosing) and to a lesser extent in the afternoon (6.0-7.5 hours after dosing), but not, by and large, immediately after dosing or in the evening. The morning correlations seemed stronger for female than for male participants. The results suggest that parental ratings and direct observations tap different aspects of MPH response and that both may be required for comprehensive assessment.

Exercise, oxidants, and antioxidants change the shape of the bell-shaped hormesis curve.

PubMed

Radak, Zsolt; Ishihara, Kazunari; Tekus, Eva; Varga, Csaba; Posa, Aniko; Balogh, Laszlo; Boldogh, Istvan; Koltai, Erika

2017-08-01

It is debated whether exercise-induced ROS production is obligatory to cause adaptive response. It is also claimed that antioxidant treatment could eliminate the adaptive response, which appears to be systemic and reportedly reduces the incidence of a wide range of diseases. Here we suggest that if the antioxidant treatment occurs before the physiological function-ROS dose-response curve reaches peak level, the antioxidants can attenuate function. On the other hand, if the antioxidant treatment takes place after the summit of the bell-shaped dose response curve, antioxidant treatment would have beneficial effects on function. We suggest that the effects of antioxidant treatment are dependent on the intensity of exercise, since the adaptive response, which is multi pathway dependent, is strongly influenced by exercise intensity. It is further suggested that levels of ROS concentration are associated with peak physiological function and can be extended by physical fitness level and this could be the basis for exercise pre-conditioning. Physical inactivity, aging or pathological disorders increase the sensitivity to oxidative stress by altering the bell-shaped dose response curve. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation

PubMed Central

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F.; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

Objective CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). Methods and Results CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. Conclusions These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression. PMID:26335690

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

PubMed

Tardy, Claudine; Goffinet, Marine; Boubekeur, Nadia; Cholez, Guy; Ackermann, Rose; Sy, Gavin; Keyserling, Constance; Lalwani, Narendra; Paolini, John F; Dasseux, Jean-Louis; Barbaras, Ronald; Baron, Rudi

2015-01-01

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3). CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively. These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

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.

Review of human studies investigating the post-prandial blood-glucose lowering ability of oat and barley food products.

PubMed

Tosh, S M

2013-04-01

Oat and barley foods have been shown to reduce human glycaemic response, compared to similar wheat foods or a glucose control. The strength of the evidence supporting the hypothesis that the soluble fibre, mixed linkage β-glucan, reduces glycaemic response was evaluated. A search of the literature was conducted to find clinical trials with acute glycaemic response as an end point using oat or barley products. Of the 76 human studies identified, 34 met the inclusion and exclusion criteria. Dose response and ratio of β-glucan to available carbohydrate as predictors of glycaemic response were assessed. Meals provided 0.3-12.1 g oat or barley β-glucan, and reduced glycaemic response by an average of 48 ± 33 mmol · min/l compared to a suitable control. Regression analysis on 119 treatments indicated that change in glycaemic response (expressed as incremental area under the post-prandial blood-glucose curve) was greater for intact grains than for processed foods. For processed foods, glycaemic response was more strongly related to the β-glucan dose alone (r(2)=0.48, P<0.0001) than to the ratio of β-glucan to the available carbohydrate (r(2)=0.25, P<0.0001). For processed foods containing 4 g of β-glucan, the linear model predicted a decrease in glycaemic response of 27 ± 3 mmol · min/l, and 76% of treatments significantly reduced glycaemic response. Thus, intact grains as well as a variety of processed oat and barley foods containing at least 4 g of β-glucan and 30-80 g available carbohydrate can significantly reduce post-prandial blood glucose.

Knowledge of medical imaging radiation dose and risk among doctors.

PubMed

Brown, Nicholas; Jones, Lee

2013-02-01

The growth of computed tomography (CT) and nuclear medicine (NM) scans has revolutionised healthcare but also greatly increased population radiation doses. Overuse of diagnostic radiation is becoming a feature of medical practice, leading to possible unnecessary radiation exposures and lifetime-risks of developing cancer. Doctors across all medical specialties and experience levels were surveyed to determine their knowledge of radiation doses and potential risks associated with some diagnostic imaging. A survey relating to knowledge and understanding of medical imaging radiation was distributed to doctors at 14 major Queensland public hospitals, as well as fellows and trainees in radiology, emergency medicine and general practice. From 608 valid responses, only 17.3% correctly estimated the radiation dose from CT scans and almost 1 in 10 incorrectly believed that CT radiation is not associated with any increased lifetime risk of developing cancer. There is a strong inverse relationship between a clinician's experience and their knowledge of CT radiation dose and risks, even among radiologists. More than a third (35.7%) of doctors incorrectly believed that typical NM imaging either does not use ionising radiation or emits doses equal to or less than a standard chest radiograph. Knowledge of CT and NM radiation doses is poor across all specialties, and there is a significant inverse relationship between experience and awareness of CT dose and risk. Despite having a poor understanding of these concepts, most doctors claim to consider them prior to requesting scans and when discussing potential risks with patients. © 2012 The Authors. Journal of Medical Imaging and Radiation Oncology © 2012 The Royal Australian and New Zealand College of Radiologists.

Plant-derived H7 VLP vaccine elicits protective immune response against H7N9 influenza virus in mice and ferrets.

PubMed

Pillet, S; Racine, T; Nfon, C; Di Lenardo, T Z; Babiuk, S; Ward, B J; Kobinger, G P; Landry, N

2015-11-17

In March 2013, the Chinese Centre for Disease Control and Prevention confirmed the first reported case of human infection with an avian influenza A H7N9 virus. Infection with this virus often caused severe pneumonia and acute respiratory distress syndrome resulting in a case fatality rate >35%. The risk of pandemic highlighted, once again, the need for a more rapid and scalable vaccine response capability. Here, we describe the rapid (19 days) development of a plant-derived VLP vaccine based on the hemagglutinin sequence of influenza H7N9 A/Hangzhou/1/2013. The immunogenicity of the H7 VLP vaccine was assessed in mice and ferrets after one or two intramuscular dose(s) with and without adjuvant (alum or GLA-SE™). In ferrets, we also measured H7-specific cell-mediated immunity. The mice and ferrets were then challenged with H7N9 A/Anhui/1/2013 influenza virus. A single immunization with the adjuvanted vaccine elicited a strong humoral response and protected mice against an otherwise lethal challenge. Two doses of unadjuvanted vaccine significantly increased humoral response and resulted in 100% protection with significant reduction of clinical signs leading to nearly asymptomatic infections. In ferrets, a single immunization with the alum-adjuvanted H7 VLP vaccine induced strong humoral and CMI responses with antigen-specific activation of CD3(+) T cells. Compared to animals injected with placebo, ferrets vaccinated with alum-adjuvanted vaccine displayed no weight loss during the challenge. Moreover, the vaccination significantly reduced the viral load in lungs and nasal washes 3 days after the infection. This candidate plant-made H7 vaccine therefore induced protective responses after either one adjuvanted or two unadjuvanted doses. Studies are currently ongoing to better characterize the immune response elicited by the plant-derived VLP vaccines. Regardless, these data are very promising for the rapid production of an immunogenic and protective vaccine against this potentially pandemic virus. Copyright © 2015 Elsevier Ltd. All rights reserved.

Tobacco smoking and oral clefts: a meta-analysis.

PubMed Central

Little, Julian; Cardy, Amanda; Munger, Ronald G.

2004-01-01

OBJECTIVE: To examine the association between maternal smoking and non-syndromic orofacial clefts in infants. METHODS: A meta-analysis of the association between maternal smoking during pregnancy was carried out using data from 24 case-control and cohort studies. FINDINGS: Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35). There was evidence of a modest dose-response effect for cleft lip with or without cleft palate. CONCLUSION: The evidence of an association between maternal tobacco smoking and orofacial clefts is strong enough to justify its use in anti-smoking campaigns. PMID:15112010

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.

Thyroid Adenomas After Solid Cancer in Childhood

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

Haddy, Nadia; El-Fayech, Chiraz; Guibout, Catherine

Purpose: Very few childhood cancer survivor studies have been devoted to thyroid adenomas. We assessed the role of chemotherapy and the radiation dose to the thyroid in the risk of thyroid adenoma after childhood cancer. Methods and Materials: A cohort of 3254 2-year survivors of a solid childhood cancer treated in 5 French centers before 1986 was established. The dose received by the isthmus and the 2 lobes of the thyroid gland during each course of radiation therapy was estimated after reconstruction of the actual radiation therapy conditions in which each child was treated as well as the dose receivedmore » at other anatomical sites of interest. Results: After a median follow-up of 25 years, 71 patients had developed a thyroid adenoma. The risk strongly increased with the radiation dose to the thyroid up to a few Gray, plateaued, and declined for high doses. Chemotherapy slightly increased the risk when administered alone but also lowered the slope of the dose-response curve for the radiation dose to the thyroid. Overall, for doses up to a few Gray, the excess relative risk of thyroid adenoma per Gray was 2.8 (90% CI: 1.2-6.9), but it was 5.5 (90% CI: 1.9-25.9) in patients who had not received chemotherapy or who had received only 1 drug, and 1.1 (90% CI: 0.4-3.4) in the children who had received more than 1 drug (P=.06, for the difference). The excess relative risk per Gray was also higher for younger children at the time of radiation therapy than for their older counterparts and was higher before attaining 40 years of age than subsequently. Conclusions: The overall pattern of thyroid adenoma after radiation therapy for a childhood cancer appears to be similar to that observed for thyroid carcinoma.« less

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.

Hypothyroidism after Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

PubMed

Inskip, Peter D; Veiga, Lene H S; Brenner, Alina V; Sigurdson, Alice J; Ostroumova, Evgenia; Chow, Eric J; Stovall, Marilyn; Smith, Susan A; Weathers, Rita E; Leisenring, Wendy; Robison, Leslie L; Armstrong, Gregory T; Sklar, Charles A; Lubin, Jay H

2018-05-15

While thyroid cancer risks from exposure to ionizing radiation early in life are well characterized quantitatively, the association of radiation with nonmalignant, functional thyroid disorders has been less studied. Here, we report on a risk analysis study of hypothyroidism with radiation dose to the thyroid gland and the hypothalamic-pituitary axis among survivors of childhood cancer. Utilizing data from the Childhood Cancer Survivor Study, a cohort of 14,364 five-year survivors of childhood cancer diagnosed at 26 hospitals in the U.S. and Canada between 1970 and 1986 and followed through 2009, the occurrence of hypothyroidism was ascertained among 12,015 survivors through serial questionnaires. Radiation doses to the thyroid gland and pituitary gland were estimated from radiotherapy records. Binary outcome regression was used to estimate prevalence odds ratios for hypothyroidism at five years from diagnosis of childhood cancer and Poisson regression to model incidence rate ratios (RR) after the first five years. A total of 1,193 cases of hypothyroidism were observed, 777 (65%) of which occurred five or more years after cancer diagnosis. The cumulative proportion affected with hypothyroidism (prevalence at five years after cancer diagnosis plus incidence through 30 years after cancer diagnosis) was highest among five-year survivors of Hodgkin lymphoma (32.3%; 95% CI: 29.5-34.9) and cancers of the central nervous system (17.7%; 95% CI: 15.2-20.4). The incidence rate was significantly associated with radiation dose to the thyroid and pituitary. The joint association of hypothyroidism with thyroid and pituitary dose was sub-additive for pituitary doses greater than 16 Gy. In particular, a very strong thyroid radiation dose dependence at low-to-moderate pituitary/hypothalamic doses was diminished at high pituitary doses. Radiation-related risks were higher in males than females and inversely associated with age at exposure and time since exposure but remained elevated more than 25 years after exposure. Our findings indicated that hypothyroidism was significantly associated with treatment with bleomycin (RR = 3.4; 95% CI: 1.6-7.3) and the alkylating agents cyclohexyl-chloroethyl-nitrosourea (CCNU) (RR = 3.0; 95% CI: 1.5-5.3) and cyclophosphamide (RR = 1.3; 95% CI: 1.0-1.8), with a significant dose response for CCNU ( P < 0.01). The risk of hypothyroidism among childhood cancer survivors treated with radiation depends both on direct, dose-dependent radiation-induced damage to the thyroid gland and on dose-dependent indirect effects secondary to irradiation of the hypothalamic-pituitary axis. The dose-response relationship for each site depends on dose to the other. Radiation-related risk persists for more than 25 years after treatment. Treatment with certain chemotherapy agents may increase the risk of hypothyroidism.

Hypoalgesia in response to transcutaneous electrical nerve stimulation (TENS) depends on stimulation intensity.

PubMed

Moran, Fidelma; Leonard, Tracey; Hawthorne, Stephanie; Hughes, Ciara M; McCrum-Gardner, Evie; Johnson, Mark I; Rakel, Barbara A; Sluka, Kathleen A; Walsh, Deirdre M

2011-08-01

Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS naïve healthy individuals (18-64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P < .0001) at the forearm; Transient Placebo TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r(2) = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

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

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

Calabrese, Edward J.; Blain, Robyn

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

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

PubMed

Calabrese, Edward J; Blain, Robyn

2005-02-01

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

Space radiation effects on plant and mammalian cells

NASA Astrophysics Data System (ADS)

Arena, C.; De Micco, V.; Macaeva, E.; Quintens, R.

2014-11-01

The study of the effects of ionizing radiation on organisms is related to different research aims. The current review emphasizes the studies on the effects of different doses of sparsely and densely ionizing radiation on living organisms, with the final purpose of highlighting specific and common effects of space radiation in mammals and plants. This topic is extremely relevant in the context of radiation protection from space environment. The response of different organisms to ionizing radiation depends on the radiation quality/dose and/or the intrinsic characteristics of the living system. Macromolecules, in particular DNA, are the critical targets of radiation, even if there is a strong difference between damages encountered by plant and mammalian cells. The differences in structure and metabolism between the two cell types are responsible for the higher resistance of the plant cell compared with its animal counterpart. In this review, we report some recent findings from studies performed in Space or on Earth, simulating space-like levels of radiation with ground-based facilities, to understand the effect of ionizing radiation on mammalian and plant cells. In particular, our attention is focused on genetic alterations and repair mechanisms in mammalian cells and on structures and mechanisms conferring radioresistance to plant cells.

Use of anticonvulsants as prophylaxis for seizures in patients on clozapine.

PubMed

Caetano, Dorgival

2014-02-01

The aim of this study is to conduct a critical review of the literature regarding the use of anticonvulsants in the prophylaxis of clozapine-induced seizures, to examine the relationship of the latter with clozapine daily dose, serum concentration and other factors than dosage that effect clozapine blood concentration, and to make recommendations for the management of clozapine-induced seizures. A systematic review of English-language MEDLINE articles was undertaken. Clozapine-induced seizures may occur at any dose; the risk increases with dose and goes up to 4% at ≥ 600 mg/day. Some authors have advocated that patients on that dose regimen have anticonvulsant added as a primary prophylactic measure. The author discusses the pitfalls of this recommendation and highlights that seizures are better predicted from serum concentration (1300 ng/ml) rather than dose alone, and that serum concentration is strongly influenced by sex, age, smoking habit, drug-drug interactions and variations in the 1A2, 2D6 and 3A4 genotypes. Anticonvulsants are not recommended as a primary prophylaxis for clozapine-induced seizures. When deemed necessary as secondary prophylaxis, the clinician's choice should consider drug-drug interactions that may increase/decrease clozapine serum concentration and lead to more side effects, including neutropenia/agranulocytosis and seizures, or compromise therapeutic response. Recommendations for primary and secondary prophylaxis of clozapine related-seizures are provided.

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

Stress responses, vitagenes and hormesis as critical determinants in aging and longevity: Mitochondria as a "chi".

PubMed

Cornelius, Carolin; Perrotta, Rosario; Graziano, Antonio; Calabrese, Edward J; Calabrese, Vittorio

2013-04-25

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by coordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having 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. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against energy and stress resistance homeostasis dysiruption with consequent impact on longevity processes.

In vivo proton dosimetry using a MOSFET detector in an anthropomorphic phantom with tissue inhomogeneity

PubMed Central

Hotta, Kenji; Matsubara, Kana; Nishioka, Shie; Matsuura, Taeko; Kawashima, Mitsuhiko

2012-01-01

When in vivo proton dosimetry is performed with a metal‐oxide semiconductor field‐effect transistor (MOSFET) detector, the response of the detector depends strongly on the linear energy transfer. The present study reports a practical method to correct the MOSFET response for linear energy transfer dependence by using a simplified Monte Carlo dose calculation method (SMC). A depth‐output curve for a mono‐energetic proton beam in polyethylene was measured with the MOSFET detector. This curve was used to calculate MOSFET output distributions with the SMC (SMCMOSFET). The SMCMOSFET output value at an arbitrary point was compared with the value obtained by the conventional SMCPPIC, which calculates proton dose distributions by using the depth‐dose curve determined by a parallel‐plate ionization chamber (PPIC). The ratio of the two values was used to calculate the correction factor of the MOSFET response at an arbitrary point. The dose obtained by the MOSFET detector was determined from the product of the correction factor and the MOSFET raw dose. When in vivo proton dosimetry was performed with the MOSFET detector in an anthropomorphic phantom, the corrected MOSFET doses agreed with the SMCPPIC results within the measurement error. To our knowledge, this is the first report of successful in vivo proton dosimetry with a MOSFET detector. PACS number: 87.56.‐v PMID:22402385

Phase I trial of a yeast-based therapeutic cancer vaccine (GI-6301) targeting the transcription factor brachyury

PubMed Central

Heery, Christopher R.; Singh, B. Harpreet; Rauckhorst, Myrna; Marté, Jennifer L.; Donahue, Renee N.; Grenga, Italia; Rodell, Timothy C.; Dahut, William; Arlen, Philip M.; Madan, Ravi A.; Schlom, Jeffrey; Gulley, James L.

2015-01-01

The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling. PMID:26130065

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.

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

NASA Astrophysics Data System (ADS)

Mothersill, Carmel; Seymour, Colin

2012-07-01

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

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

PubMed

Daftarian, Pirouz M; Stone, Geoffrey W; Kovalski, Leticia; Kumar, Manoj; Vosoughi, Aram; Urbieta, Maitee; Blackwelder, Pat; Dikici, Emre; Serafini, Paolo; Duffort, Stephanie; Boodoo, Richard; Rodríguez-Cortés, Alhelí; Lemmon, Vance; Deo, Sapna; Alberola, Jordi; Perez, Victor L; Daunert, Sylvia; Ager, Arba L

2013-12-01

Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host. We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB. PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice. PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

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.

TH-C-19A-05: Evaluation of a New Reusable 3D Dosimeter

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

Juang, T; Adamovics, J; Oldham, M

Purpose: PRESAGE is a radiochromic plastic which has demonstrated strong potential for high resolution single-use 3D dosimetry. This study evaluates a new PRESAGE formulation (Presage-RU) in which the radiochromic response is reversible (the dosimeter optically clears after irradiation), enabling the potential for reusability. Methods: Presage-RU dose response and optical-clearing rates were evaluated in both small volume dosimeters (1×1×4.5cm) and a larger cylindrical dosimeter (8cm diameter, 4.5cm length). All dosimeters were allowed to fully optically clear in dark, room temperature conditions between irradiations. Dose response was determined by irradiating small volume samples from 0–8.0Gy and measuring change in optical density. Themore » cylindrical dosimeter was irradiated with a simple 4-field box plan (parallel opposed pairs of 4cm×4cm AP-PA beams and 2cm×4cm lateral beams) to 20Gy. High resolution 3D dosimetry was achieved utilizing optical-CT readout. Readings were tracked up to 14 days to characterize optical clearing. Results: Initial irradiation yielded a response of 0.0119△OD/(Gy*cm) while two subsequent reirradiations yielded a lower but consistent response of 0.0087△OD/(Gy*cm). Strong linearity of dose response was observed for all irradiations. In the large cylindrical dosimeter, the integral dose within the high dose region exhibited an exponential decay in signal over time (halflife= 23.9 hours), with the dosimeter effectively cleared (0.04% of the initial signal) after 10 days. Subsequent irradiation resulted in 19.5% lower initial signal but demonstrated that the exponential clearing rate remained consistent. Results of additional subsequent irradiations will also be presented. Conclusion: This work introduces a new re-usable radiochromic dosimeter (Presage-RU) compatible with high resolution (sub-millimeter) 3D dosimetry. Sensitivity of the initial radiation was observed to be slightly higher than subsequent irradiations, but the clearing time remained constant, indicating the dosimeter can be re-used after 10 days. Presage-RU has potential to dramatically improve cost-effectiveness and thereby lower the barrier for implementing comprehensive, high resolution 3D dosimetry. John Adamovics is the president of Heuris Inc., which commercializes PRESAGE.« less

Adolescents' leisure activities, parental monitoring and cigarette smoking - a cross-sectional study

PubMed Central

2011-01-01

Background Adolescent participation in leisure activities is developmentally beneficial, but certain activities may increase health compromising behaviours, such as tobacco smoking. A limited range of leisure activities has been studied, with little research on out-of-school settings where parental supervision is a potential protective factor. Tobacco smoking is an important, potentially modifiable health determinant, so understanding associations between adolescent leisure activities, parental monitoring, demographic factors and daily smoking may inform preventive strategies. These associations are reported for a New Zealand adolescent sample. Methods Randomly selected schools (n = 145) participated in the 2006 Youth In-depth Survey, a national, biennial study of Year 10 students (predominantly 14-15 years). School classes were randomly selected and students completed a self-report questionnaire in class time. Adjustment for clustering at the school level was included in all analyses. Since parental monitoring and demographic variables potentially confound relations between adolescent leisure activities and smoking, variables were screened before multivariable modelling. Given prior indications of demographic differences, gender and ethnic specific regression models were built. Results and Discussion Overall, 8.5% of the 3,161 students were daily smokers, including more females (10.5%) than males (6.5%). In gender and ethnic specific multivariate analysis of associations with daily smoking (adjusted for age, school socioeconomic decile rating, leisure activities and ethnicity or gender, respectively), parental monitoring exhibited a consistently protective, dose response effect, although less strongly among Māori. Attending a place of worship and going to the movies were protective for non-Māori, as was watching sports, whereas playing team sport was protective for all, except males. Attending a skate park was a risk factor for females and Māori which demonstrated a strong dose response effect. Conclusions There were significant differences in the risk of daily smoking across leisure activities by gender and ethnicity. This reinforces the need to be alert for, and respond to, gender and ethnic differences in the pattern of risk and protective factors. However, given the consistently protective, dose response effect of parental monitoring, our findings confirm that assisting oversight of adolescent leisure activities may be a key component in public health policy and prevention programmes. PMID:21645407

Adolescents' leisure activities, parental monitoring and cigarette smoking--a cross-sectional study.

PubMed

Guo, Hui; Reeder, Anthony I; McGee, Rob; Darling, Helen

2011-06-06

Adolescent participation in leisure activities is developmentally beneficial, but certain activities may increase health compromising behaviours, such as tobacco smoking. A limited range of leisure activities has been studied, with little research on out-of-school settings where parental supervision is a potential protective factor. Tobacco smoking is an important, potentially modifiable health determinant, so understanding associations between adolescent leisure activities, parental monitoring, demographic factors and daily smoking may inform preventive strategies. These associations are reported for a New Zealand adolescent sample. Randomly selected schools (n = 145) participated in the 2006 Youth In-depth Survey, a national, biennial study of Year 10 students (predominantly 14-15 years). School classes were randomly selected and students completed a self-report questionnaire in class time. Adjustment for clustering at the school level was included in all analyses. Since parental monitoring and demographic variables potentially confound relations between adolescent leisure activities and smoking, variables were screened before multivariable modelling. Given prior indications of demographic differences, gender and ethnic specific regression models were built. Overall, 8.5% of the 3,161 students were daily smokers, including more females (10.5%) than males (6.5%). In gender and ethnic specific multivariate analysis of associations with daily smoking (adjusted for age, school socioeconomic decile rating, leisure activities and ethnicity or gender, respectively), parental monitoring exhibited a consistently protective, dose response effect, although less strongly among Māori. Attending a place of worship and going to the movies were protective for non-Māori, as was watching sports, whereas playing team sport was protective for all, except males. Attending a skate park was a risk factor for females and Māori which demonstrated a strong dose response effect. There were significant differences in the risk of daily smoking across leisure activities by gender and ethnicity. This reinforces the need to be alert for, and respond to, gender and ethnic differences in the pattern of risk and protective factors. However, given the consistently protective, dose response effect of parental monitoring, our findings confirm that assisting oversight of adolescent leisure activities may be a key component in public health policy and prevention programmes.

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

Three hundred and eight nanometer excimer light therapy for alopecia universalis that is resistant to other treatments: A clinical study of 11 patients.

PubMed

Arakawa, Yukiyasu; Nomiyama, Tomoko; Katoh, Norito

2016-12-01

Three hundred and eight nanometer excimer light therapy has recently been reported to be effective against patchy alopecia areata (AA) in several clinical studies. However, these studies only included a few patients with severe forms of AA, and all of them exhibited poor outcomes. We further investigated the use of excimer light as a therapeutic option for cases of alopecia universalis (AU) that are resistant to other treatments. Eleven treatment-resistant AU patients were treated with a 308-nm excimer light at 2-week intervals for more than 16 sessions. Four patients achieved good responses and two patients exhibited poor responses. Three patients had Japanese skin type 1 and all of them achieved good responses. The radiation dose was increased until the patients exhibited marked erythema. The patients with Japanese skin type 3 who achieved good responses exhibited strong pigmentation at the irradiated sites. In conclusion, 308-nm excimer light therapy has significant effects on some AU patients who are resistant to other treatments and may be an alternative therapeutic option for AU. During the treatment of AU, high doses of radiation should be administrated until a strong inflammatory skin reaction is seen. © 2016 Japanese Dermatological Association.

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...

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

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

Recent trends in vaccine delivery systems: A review

PubMed Central

Saroja, CH; Lakshmi, PK; Bhaskaran, Shyamala

2011-01-01

Vaccines are the preparations given to patients to evoke immune responses leading to the production of antibodies (humoral) or cell-mediated responses that will combat infectious agents or noninfectious conditions such as malignancies. Alarming safety profile of live vaccines, weak immunogenicity of sub-unit vaccines and immunization, failure due to poor patient compliance to booster doses which should potentiate prime doses are few strong reasons, which necessitated the development of new generation of prophylactic and therapeutic vaccines to promote effective immunization. Attempts are being made to deliver vaccines through carriers as they control the spatial and temporal presentation of antigens to immune system thus leading to their sustained release and targeting. Hence, lower doses of weak immunogens can be effectively directed to stimulate immune responses and eliminate the need for the administration of prime and booster doses as a part of conventional vaccination regimen. This paper reviews carrier systems such as liposomes, microspheres, nanoparticles, dendrimers, micellar systems, ISCOMs, plant-derived viruses which are now being investigated and developed as vaccine delivery systems. This paper also describes various aspects of “needle-free technologies” used to administer the vaccine delivery systems through different routes into the human body. PMID:23071924

Integrated analysis of genetic variation and gene expression reveals novel variant for increased warfarin dose requirement in African Americans.

PubMed

Hernandez, W; Gamazon, E R; Aquino-Michaels, K; Smithberger, E; O'Brien, T J; Harralson, A F; Tuck, M; Barbour, A; Cavallari, L H; Perera, M A

2017-04-01

Essentials Genetic variants controlling gene regulation have not been explored in pharmacogenomics. We tested liver expression quantitative trait loci for association with warfarin dose response. A novel predictor for increased warfarin dose response in African Americans was identified. Precision medicine must take into account population-specific variation in gene regulation. Background Warfarin is commonly used to control and prevent thromboembolic disorders. However, because of warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). Objectives We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs. Patients/Methods We identified a total of 56 expression quantitative trait loci (eQTLs) for CYP2C9, VKORC1 and CALU derived from human livers and evaluated their association with warfarin dose response in two independent AA warfarin patient cohorts. Results We found that rs4889606, a strong cis-eQTL for VKORC1 (log 10 Bayes Factor = 12.02), is significantly associated with increased warfarin daily dose requirement (β = 1.1; 95% confidence interval [CI] 0.46 to 1.8) in the discovery cohort (n = 305) and in the replication cohort (β = 1.04; 95% CI 0.33 -1.7; n = 141) after conditioning on relevant covariates and the VKORC1 -1639G>A (rs9923231) variant. Inclusion of rs4889606 genotypes, along with CYP2C9 alleles, rs9923231 genotypes and clinical variables, explained 31% of the inter-patient variability in warfarin dose requirement. We demonstrate different linkage disequilibrium patterns in the region encompassing rs4889606 and rs9923231 between AAs and European Americans, which may explain the increased dose requirement found in AAs. Conclusion Our approach of interrogating eQTLs identified in liver has revealed a novel predictor of warfarin dose response in AAs. Our work highlights the utility of leveraging information from regulatory variants mapped in the liver to uncover novel variants associated with drug response and the importance of population-specific research. © 2017 International Society on Thrombosis and Haemostasis.

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

Determinants of cell-to-cell variability in protein kinase signaling.

PubMed

Jeschke, Matthias; Baumgärtner, Stephan; Legewie, Stefan

2013-01-01

Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability.

AF03-adjuvanted and non-adjuvanted pandemic influenza A (H1N1) 2009 vaccines induce strong antibody responses in seasonal influenza vaccine-primed and unprimed mice.

PubMed

Caillet, Catherine; Piras, Fabienne; Bernard, Marie-Clotilde; de Montfort, Aymeric; Boudet, Florence; Vogel, Frederick R; Hoffenbach, Agnès; Moste, Catherine; Kusters, Inca

2010-04-19

Pandemic influenza vaccines have been manufactured using the A/California/07/2009 (H1N1) strain as recommended by the World Health Organization. We evaluated in mice the immunogenicity of pandemic (H1N1) 2009 vaccine and the impact of prior vaccination against seasonal trivalent influenza vaccines (TIV) on antibody responses against pandemic (H1N1) 2009. In naïve mice, a single dose of unadjuvanted H1N1 vaccine (3 microg of HA) was shown to elicit hemagglutination inhibition (HI) antibody titers >40, a titer associated with protection in humans against seasonal influenza. A second vaccine dose of pandemic (H1N1) 2009 vaccine strongly increased these titers, which were consistently higher in mice previously primed with TIV than in naïve mice. At a low immunization dose (0.3 microg of HA), the AF03-adjuvanted vaccine elicited higher HI antibody titers than the corresponding unadjuvanted vaccines in both naïve and TIV-primed animals, suggesting a potential for antigen dose-sparing. These results are in accordance with the use in humans of a split-virion inactivated pandemic (H1N1) 2009 vaccine formulated with or without AF03 adjuvant to protect children and young adults against influenza A (H1N1) 2009 infection. Copyright 2010 Elsevier Ltd. All rights reserved.

Pathology, Organ Distribution, and Immune Response after Single and Repeated Intravenous Injection of Rats with Clinical-Grade Parvovirus H1

PubMed Central

Geletneky, Karsten; Leoni, Anne-Laure; Pohlmeyer-Esch, Gabriele; Loebhard, Stephanie; Baetz, Andrea; Leuchs, Barbara; Roscher, Mandy; Hoefer, Constance; Jochims, Karin; Dahm, Michael; Huber, Bernard; Rommelaere, Jean; Krebs, Ottheinz; Hajda, Jacek

2015-01-01

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID:25730754

Long Term Use of Aspirin and the Risk of Gastrointestinal Bleeding

PubMed Central

Huang, Edward S.; Strate, Lisa L.; Ho, Wendy W.; Lee, Salina S.; Chan, Andrew T.

2011-01-01

Background In short-term trials, aspirin is associated with gastrointestinal bleeding. However, the effect of dose and duration of aspirin use on risk remains unclear. Methods We conducted a prospective study of 87,680 women enrolled in the Nurses' Health Study in 1990 who provided biennial data on aspirin use. We examined the relative risk (RR) of major gastrointestinal bleeding requiring hospitalization or blood transfusion. Results Over a 24-year follow-up, 1537 women reported a major gastrointestinal bleeding. Among women who used aspirin regularly (≥2 standard [325-mg] tablets/week), the multivariate RR of gastrointestinal bleeding was 1.43 (95% confidence interval [CI], 1.29-1.59) compared with non-regular users. Compared with women who denied any aspirin use, the multivariate RRs of gastrointestinal bleeding were 1.03 (95% CI, 0.85-1.24) for women who used 0.5 to 1.5 standard aspirin tablets/week, 1.30 (95% CI, 1.07-1.58) for 2 to 5 tablets/week, 1.77 (95% CI, 1.44-2.18) for 6-14 tablets/week, and 2.24 (95% CI, 1.66-3.03) for >14 tablets/week (Ptrend<.001). Similar dose-response relationships were observed among short-terms users (≤ 5 years; Ptrend<.001) and long-term users (>5 years; Ptrend<.001). In contrast, after adjustments were made for dose, increasing duration of use did not confer greater risk of bleeding (Ptrend=0.28). Conclusions Regular aspirin use is associated with gastrointestinal bleeding. Risk appears more strongly related to dose than duration of aspirin use. Efforts to minimize adverse effects of aspirin therapy should emphasize using the lowest effective dose among both short-term and long-term users. PMID:21531232

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

Strong Antibody Responses Induced by Protein Antigens Conjugated onto the Surface of Lecithin-Based Nanoparticles

PubMed Central

Sloat, Brian R.; Sandoval, Michael A.; Hau, Andrew M.; He, Yongqun; Cui, Zhengrong

2009-01-01

An accumulation of research over the years has demonstrated the utility of nanoparticles as antigen carriers with adjuvant activity. Herein we defined the adjuvanticity of a novel lecithin-based nanoparticle engineered from emulsions. The nanoparticles were spheres of around 200 nm. Model protein antigens, bovine serum albumin (BSA) or Bacillus anthracis protective antigen (PA) protein, were covalently conjugated onto the nanoparticles. Mice immunized with the BSA-conjugated nanoparticles developed strong anti-BSA antibody responses comparable to that induced by BSA adjuvanted with incomplete Freund's adjuvant and 6.5-fold stronger than that induced by BSA adsorbed onto aluminum hydroxide. Immunization of mice with the PA-conjugated nanoparticles elicited a quick, strong, and durable anti-PA antibody response that afforded protection of the mice against a lethal dose of anthrax lethal toxin challenge. The potent adjuvanticity of the nanoparticles was likely due to their ability to move the antigens into local draining lymph nodes, to enhance the uptake of the antigens by antigen-presenting cells (APCs), and to activate APCs. This novel nanoparticle system has the potential to serve as a universal protein-based vaccine carrier capable of inducing strong immune responses. PMID:19729045

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.

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

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

Are the colors and shapes of current psychotropics designed to maximize the placebo response?

PubMed

Khan, Arif; Bomminayuni, Eswara Prasad; Bhat, Amritha; Faucett, James; Brown, Walter A

2010-07-01

Patient expectations are an important aspect of the placebo response. Color and shape of a medication lead to perceptions that an agent is stimulating or calming, strong or weak. We assessed the degree to which central nervous system medications match the perceived drug action and thereby harness the placebo response. We consulted the 2009 Physicians' Desk Reference and recorded the formulation and color of each referenced dose of central nervous system therapeutics approved for sale in the USA. On the basis of the expectations they engender, orange, yellow, and red pills were categorized stimulating; green, blue, and purple pills calming. White and gray pills were considered neutral. The majority of the 176 unique doses that were included in the study were in tablet (55%) and capsule (33%) form. Stimulants (75%) were the only drug category primarily formulated as capsules. Of the 176 unique doses included, 43% were stimulating, 23% calming, 23% neutral, and 12% were a formulation other than pill or capsule. There were no instances in which over 50% of the pills of an indication were stimulating or calming in color. Our study did not confirm the hypothesis that pharmaceutical companies color and formulate the shape of drugs to enhance the treatment response. In several instances, each approved dose of a given medication was a different color, and the majority of doses were in tablet form. Further research into the effect of different colors and formulations of medications on perceptions and efficacy evaluations should be considered.

Regional relation between skin blood flow and sweating to passive heating and local administration of acetylcholine in young, healthy humans.

PubMed

Smith, Caroline J; Kenney, W Larry; Alexander, Lacy M

2013-04-01

Regional variation in sweating over the human body is widely recognized yet variation in vasomotor responses and mechanisms causing this variation remain unclear. This study aimed to explore the relation between regional sweating rates (RSR) and skin blood flow (SkBF) responses to thermal and pharmacological stimuli in young, healthy subjects. In nine subjects (23 ± 3 yr), intradermal microdialysis (MD) probes were inserted into the ventral forearm, abdomen, thigh, and lower back and perfused with lactated Ringer solution. RSR over each MD membrane were measured using ventilated capsules with a laser Doppler probe housed in each capsule for measurement of red cell flux (laser Doppler flux, LDF) as an index of SkBF. Subjects completed a whole body heating protocol to 1°C rise in oral temperature and an acetylcholine dose response (ACh 1 × 10(-7)-0.1 M; mean skin temperature 34°C). Maximal LDF were obtained at the end of both protocols (50 mM sodium nitroprusside).During heating RSR varied among sites (P < 0.0001) and was greater on the back versus other sites (P < 0.05), but LDF was similar between sites (P = 0.343). RSR and SkBF showed a strong relation during initial (arm: r = 0.77 ± 0.09, thigh: r = 0.81 ± 0.08, abdomen: r = 0.89 ± 0.04, back: r = 0.86 ± 0.04) but not latter stages of heating. No differences in RSR (P = 0.160) or SkBF (LDF, P = 0.841) were observed between sites during ACh perfusion. Taken together, these data suggest that increases in SkBF are necessary to initiate and increase sweating, but further rises in RSR are not fully dependent on SkBF in a dose-response manner. Furthermore, RSR cannot be explained by cholinergic sensitivity or variation in SkBF.

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...

The climate benefits of high-sugar grassland may be compromised by ozone pollution.

PubMed

Hewitt, D K L; Mills, G; Hayes, F; Davies, W

2016-09-15

High sugar ryegrasses (HSG) have been developed to improve the uptake, digestion and nitrogen (N)-utilisation of grazing stock, with the potential to increase production yields and benefit climate by reducing methane (CH4) and nitrous oxide (N2O) emissions from livestock farming. In this study, the effects of tropospheric ozone pollution on the seasonal growth dynamics of HSG pasture mesocosms containing Lolium perenne cv. AberMagic and Trifolium repens cv. Crusader were investigated. Species-specific ozone (O3) dose-response relationships (seasonal means: 35, 41, 47, 51, 59 & 67ppb) based on the Phytotoxic Ozone Dose (PODy) were constructed for above and below ground biomass, injury, N-fixation and forage quality. The dynamics of effects of ozone exposure on HSG pasture changed over the course of a season, with the strongest responses occurring in the first 4-8weeks. Overall, strong negative responses to ozone flux were found for root biomass, root nodule mass and N-fixation rates, and ozone adversely impacted a range of forage quality parameters including total sugar content and relative and consumable food values. These results indicate that increasing ozone pollution could decrease the N-use efficiency and reduce the sugar content of managed pasture, and thereby partially detract from some of the suggested benefits of HSG. Copyright © 2016 Elsevier B.V. All rights reserved.

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

PubMed

Reichard, John F; Haber, Lynne T

2016-12-01

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

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

Respiratory dysfunction in swine production facility workers: dose-response relationships of environmental exposures and pulmonary function.

PubMed

Donham, K J; Reynolds, S J; Whitten, P; Merchant, J A; Burmeister, L; Popendorf, W J

1995-03-01

Human respiratory health hazards for people working in livestock confinement buildings have been recognized since 1974. However, before comprehensive control programs can be implemented, more knowledge is needed of specific hazardous substances present in the air of these buildings, and at what concentrations they are harmful. Therefore, a medical epidemiological and exposure-response study was conducted on 207 swine producers using intensive housing systems (108 farms). Dose-response relationships between pulmonary function and exposures are reported here. Positive correlations were seen between change in pulmonary function over a work period and exposure to total dust, respirable dust, ammonia, respirable endotoxin, and the interactions of age-of-producer and dust exposure and years-of-working-in-the-facility and dust exposure. Relationships between baseline pulmonary function and exposures were not strong and therefore, not pursued in this study. The correlations between exposure and response were stronger after 6 years of exposure. Multiple regression models were used to identify total dust and ammonia as the two primary environmental predictors of pulmonary function decrements over a work period. The regression models were then used to determine exposure concentrations related to pulmonary function decrements suggestive of a health hazard. Total dust concentrations > or = 2.8 mg/m3 were predictive of a work period decrement of > or = 10% in FEV1. Ammonia concentrations of > or = 7.5 ppm were predictive of a > or = 3% work period decrement in FEV1. These predictive concentrations were similar to a previous dose-response study, which suggested 2.5 mg/m3 of total dust and 7 ppm of NH3 were associated with significant work period decrements. Therefore, dust > or = 2.8 mg/m3 and ammonia > or = 7.5 ppm should be considered reasonable evidence for guidelines regarding hazardous exposure concentrations in this work environment.

Influenza vaccine-mediated protection in older adults: Impact of influenza infection, cytomegalovirus serostatus and vaccine dosage.

PubMed

Merani, Shahzma; Kuchel, George A; Kleppinger, Alison; McElhaney, Janet E

2018-07-01

Age-related changes in T-cell function are associated with a loss of influenza vaccine efficacy in older adults. Both antibody and cell-mediated immunity plays a prominent role in protecting older adults, particularly against the serious complications of influenza. High dose (HD) influenza vaccines induce higher antibody titers in older adults compared to standard dose (SD) vaccines, yet its impact on T-cell memory is not clear. The aim of this study was to compare the antibody and T-cell responses in older adults randomized to receive HD or SD influenza vaccine as well as determine whether cytomegalovirus (CMV) serostatus affects the response to vaccination, and identify differences in the response to vaccination in those older adults who subsequently have an influenza infection. Older adults (≥65years) were enrolled (n=106) and randomized to receive SD or HD influenza vaccine. Blood was collected pre-vaccination, followed by 4, 10 and 20weeks post-vaccination. Serum antibody titers, as well as levels of inducible granzyme B (iGrB) and cytokines were measured in PBMCs challenged ex vivo with live influenza virus. Surveillance conducted during the influenza season identified those with laboratory confirmed influenza illness or infection. HD influenza vaccination induced a high antibody titer and IL-10 response, and a short-lived increase in Th1 responses (IFN-γ and iGrB) compared to SD vaccination in PBMCs challenged ex vivo with live influenza virus. Of the older adults who became infected with influenza, a high IL-10 and iGrB response in virus-challenged cells was observed post-infection (week 10 to 20), as well as IFN-γ and TNF-α at week 20. Additionally, CMV seropositive older adults had an impaired iGrB response to influenza virus-challenge, regardless of vaccine dose. This study illustrates that HD influenza vaccines have little impact on the development of functional T-cell memory in older adults. Furthermore, poor outcomes of influenza infection in older adults may be due to a strong IL-10 response to influenza following vaccination, and persistent CMV infection. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Tuning of automatic exposure control strength in lumbar spine CT.

PubMed

D'Hondt, A; Cornil, A; Bohy, P; De Maertelaer, V; Gevenois, P A; Tack, D

2014-05-01

To investigate the impact of tuning the automatic exposure control (AEC) strength curve (specific to Care Dose 4D®; Siemens Healthcare, Forchheim, Germany) from "average" to "strong" on image quality, radiation dose and operator dependency during lumbar spine CT examinations. Two hospitals (H1, H2), both using the same scanners, were considered for two time periods (P1 and P2). During P1, the AEC curve was "average" and radiographers had to select one of two protocols according to the body mass index (BMI): "standard" if BMI <30.0 kg m(-2) (120 kV-330 mAs) or "large" if BMI >30.0 kg m(-2) (140 kV-280 mAs). During P2, the AEC curve was changed to "strong", and all acquisitions were obtained with one protocol (120 kV and 270 mAs). Image quality was scored and patients' diameters calculated for both periods. 497 examinations were analysed. There was no significant difference in mean diameters according to hospitals and periods (p > 0.801) and in quality scores between periods (p > 0.172). There was a significant difference between hospitals regarding how often the "large" protocol was assigned [13 (10%)/132 patients in H1 vs 37 (28%)/133 in H2] (p < 0.001). During P1, volume CT dose index (CTDIvol) was higher in H2 (+13%; p = 0.050). In both hospitals, CTDIvol was reduced between periods (-19.2% in H1 and -29.4% in H2; p < 0.001). An operator dependency in protocol selection, unexplained by patient diameters or highlighted by image quality scores, has been observed. Tuning the AEC curve from average to strong enables suppression of the operator dependency in protocol selection and related dose increase, while preserving image quality. CT acquisition protocols based on weight are responsible for biases in protocol selection. Using an appropriate AEC strength curve reduces the number of protocols to one. Operator dependency of protocol selection is thereby eliminated.

Landscape of dietary factors associated with risk of gastric cancer: A systematic review and dose-response meta-analysis of prospective cohort studies.

PubMed

Fang, Xuexian; Wei, Jiayu; He, Xuyan; An, Peng; Wang, Hao; Jiang, Li; Shao, Dandan; Liang, Han; Li, Yi; Wang, Fudi; Min, Junxia

2015-12-01

The associations between dietary factors and gastric cancer risk have been analysed by many studies, but with inconclusive results. We conducted a meta-analysis of prospective studies to systematically investigate the associations. Relevant studies were identified through searching Medline, Embase, and Web of Science up to June 30, 2015. We included prospective cohort studies of intake of dietary factors with risk estimates and 95% confidence intervals for gastric cancer. Seventy-six prospective cohort studies were eligible and included in the analysis. We ascertained 32,758 gastric cancer cases out of 6,316,385 participants in relations to intake of 67 dietary factors, covering a wide ranging of vegetables, fruit, meat, fish, salt, alcohol, tea, coffee, and nutrients, during 3.3 to 30 years of follow-up. Evidence from this study indicates that consumption of total fruit and white vegetables, but not total vegetables, was inversely associated with gastric cancer risk. Both fruit and white vegetables are rich sources of vitamin C, which showed significant protective effect against gastric cancer by our analysis too. Furthermore, we found concordant positive associations between high-salt foods and gastric cancer risk. In addition, a strong effect of alcohol consumption, particularly beer and liquor but not wine, on gastric cancer risk was observed compared with nondrinkers. Dose-response analysis indicated that risk of gastric cancer was increased by 12% per 5 g/day increment of dietary salt intake or 5% per 10 g/day increment of alcohol consumption, and that a 100 g/day increment of fruit consumption was inversely associated with 5% reduction of risk. This study provides comprehensive and strong evidence that there are a number of protective and risk factors for gastric cancer in diet. Our findings may have significant public health implications with regard to prevention of gastric cancer and provide insights into future cohort studies and the design of related clinical trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of an Adjuvanted HIV-1 Gag-Pol-Nef Fusion Protein and Adenovirus 35 Gag-RT-Int-Nef Vaccine in Healthy HIV-Uninfected African Adults

PubMed Central

Omosa-Manyonyi, Gloria; Mpendo, Juliet; Ruzagira, Eugene; Kilembe, William; Chomba, Elwyn; Roman, François; Bourguignon, Patricia; Koutsoukos, Marguerite; Collard, Alix; Voss, Gerald; Laufer, Dagna; Stevens, Gwynn; Hayes, Peter; Clark, Lorna; Cormier, Emmanuel; Dally, Len; Barin, Burc; Ackland, Jim; Syvertsen, Kristen; Zachariah, Devika; Anas, Kamaal; Sayeed, Eddy; Lombardo, Angela; Gilmour, Jill; Cox, Josephine; Fast, Patricia; Priddy, Frances

2015-01-01

Background Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses. Methods In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured. Results The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration. Conclusion Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses. Trial Registration ClinicalTrials.gov NCT01264445 PMID:25961283

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

A Systems Genetic Approach to Identify Low Dose Radiation-Induced Lymphoma Susceptibility/DOE2013FinalReport

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

Balmain, Allan; Song, Ihn Young

2013-05-15

The ultimate goal of this project is to identify the combinations of genetic variants that confer an individual's susceptibility to the effects of low dose (0.1 Gy) gamma-radiation, in particular with regard to tumor development. In contrast to the known effects of high dose radiation in cancer induction, the responses to low dose radiation (defined as 0.1 Gy or less) are much less well understood, and have been proposed to involve a protective anti-tumor effect in some in vivo scientific models. These conflicting results confound attempts to develop predictive models of the risk of exposure to low dose radiation, particularlymore » when combined with the strong effects of inherited genetic variants on both radiation effects and cancer susceptibility. We have used a Systems Genetics approach in mice that combines genetic background analysis with responses to low and high dose radiation, in order to develop insights that will allow us to reconcile these disparate observations. Using this comprehensive approach we have analyzed normal tissue gene expression (in this case the skin and thymus), together with the changes that take place in this gene expression architecture a) in response to low or high- dose radiation and b) during tumor development. Additionally, we have demonstrated that using our expression analysis approach in our genetically heterogeneous/defined radiation-induced tumor mouse models can uniquely identify genes and pathways relevant to human T-ALL, and uncover interactions between common genetic variants of genes which may lead to tumor susceptibility.« less

Pharmacogenomics and Patient Treatment Parameters to Opioid Treatment in Chronic Pain: A Focus on Morphine, Oxycodone, Tramadol, and Fentanyl.

PubMed

Lloyd, Renae A; Hotham, Elizabeth; Hall, Catherine; Williams, Marie; Suppiah, Vijayaprakash

2017-12-01

Opioids are one of the most commonly prescribed medicines for chronic pain. However, their use for chronic pain has been controversial. The objective of this literature review was to identify the role of genetic polymorphisms on patient treatment parameters (opioid dose requirements, response, and adverse effects) for opioids used in malignant and nonmalignant chronic pain. The opioids that this review focuses on are codeine, morphine, oxycodone, tramadol, and fentanyl. A literature search of databases Medline and Embase was carried out, and studies up to April 2016 were included in this review. Studies were included based on a combination of key words: chronic pain and related terms, pharmacogenetics and related terms, and opioids and related terms. Among the 1,408 individual papers retrieved from the search in Medline and Embase, 32 original articles were included in this review, with none related to codeine. The 32 papers reported various study designs, opioids, and polymorphisms being studied for associations with treatment outcomes. This literature review reveals that variants in ABCB1, OPRM1, and COMT have been replicated for opioid dosing and variants in ABCB1 have been replicated for both treatment response and adverse effects. Currently, there are few validated studies to form a strong evidence base to support pharmacogenomics testing when initiating opioid therapy. However, the field of pharmacogenomics in chronic pain is likely to expand over the coming years, with the increasing number of treatment options available and larger cohorts being assembled in order to identify true associations. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Indoor Tanning and Melanoma Risk: Long-Term Evidence From a Prospective Population-Based Cohort Study.

PubMed

Ghiasvand, Reza; Rueegg, Corina S; Weiderpass, Elisabete; Green, Adele C; Lund, Eiliv; Veierød, Marit B

2017-02-01

Indoor tanning is associated with increased risk of melanoma, but most evidence comes from case-control studies. Using data from the Norwegian Women and Cancer Study, a large prospective cohort study, we investigated the associations of age at initiation of indoor tanning, duration of tanning-device use, and dose response with melanoma risk and examined the role of indoor tanning in age at melanoma diagnosis. We used Poisson regression to estimate relative risks and 95% confidence intervals for the relationship of indoor tanning to melanoma risk and linear regression to examine age of indoor tanning initiation in relation to age at diagnosis. During follow-up of 141,045 women (1991-2012; mean duration follow-up = 13.7 years), 861 women were diagnosed with melanoma. Melanoma risk increased with increasing cumulative number of tanning sessions (for highest tertile of use vs. never use, adjusted relative risk = 1.32, 95% confidence interval (CI): 1.08, 1.63); P-trend = 0.006. Age at initiation <30 years was associated with a higher risk in comparison with never use (adjusted relative risk = 1.31, 95% CI: 1.07, 1.59). Moreover, women who started indoor tanning prior to 30 years of age were 2.2 years (95% CI: 0.9, 3.4) younger at diagnosis, on average, than never users. This cohort study provides strong evidence of a dose-response association between indoor tanning and risk of melanoma and supports the hypothesis that vulnerability to the harmful effects of indoor tanning is greater at a younger age. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Novel Approaches for Visualizing and Analyzing Dose-Timing Data from Electronic Drug Monitors, or "How the 'Broken Window' Theory Pertains to ART Adherence".

PubMed

Gill, Christopher J; DeSilva, Mary Bachman; Hamer, Davidson H; Keyi, Xu; Wilson, Ira B; Sabin, Lora

2015-11-01

Adherence to antiretroviral medications is usually expressed in terms of the proportion of doses taken. However, the timing of doses taken may also be an important dimension to overall adherence. Little is known about whether patients who mistime doses are also more likely to skip doses. Using data from the completed Adherence for Life randomized controlled trial, we created visual and statistical models to capture and analyze dose timing data collected longitudinally with electronic drug monitors (EDM). From scatter plots depicting dose time versus calendar date, we identified dominant patterns of dose taking and calculated key features [slope of line over calendar date; residual mean standard error (RMSE)]. Each was assessed for its ability to categorize subjects with 'sub-optimal' (<95 % of doses taken) using area under the receiver operating characteristic (AROC) curve analysis. Sixty eight subjects contributed EDM data, with ~300 to 400 observations/subject. While regression line slopes did not predict 'sub-optimal' adherence (AROC 0.51, 95 % CI 0.26-0.75), the variability in dose timing (RMSE) was strongly predictive (AROC 0.79, 95 % CI 0.62-0.97). Compared with the lowest quartile of RMSE (minimal dose time variability), each successive quartile roughly doubled the odds of 'sub-optimal' adherence (OR 2.1, 95 % CI 1.3-3.4). Patterns of dose timing and mistiming are strongly related to overall adherence behavior. Notably, individuals who skip doses are more likely to mistime doses, with the degree of risk positively correlated with the extent of dose timing variability.

A Novel Therapy for Melanoma Developed in Mice: Transformation of Melanoma into Dendritic Cells with Listeria monocytogenes

PubMed Central

Bronchalo-Vicente, Lucia; Rodriguez-Del Rio, Estela; Freire, Javier; Calderon-Gonzalez, Ricardo; Frande-Cabanes, Elisabet; Gomez-Roman, Jose Javier; Fernández-Llaca, Hector; Yañez-Diaz, Sonsoles; Alvarez-Dominguez, Carmen

2015-01-01

Listeria monocytogenes is a gram-positive bacteria and human pathogen widely used in cancer immunotherapy because of its capacity to induce a specific cytotoxic T cell response in tumours. This bacterial pathogen strongly induces innate and specific immunity with the potential to overcome tumour induced tolerance and weak immunogenicity. Here, we propose a Listeria based vaccination for melanoma based in its tropism for these tumour cells and its ability to transform in vitro and in vivo melanoma cells into matured and activated dendritic cells with competent microbicidal and antigen processing abilities. This Listeria based vaccination using low doses of the pathogen caused melanoma regression by apoptosis as well as bacterial clearance. Vaccination efficacy is LLO dependent and implies the reduction of LLO-specific CD4+ T cell responses, strong stimulation of innate pro-inflammatory immune cells and a prevalence of LLO-specific CD8+ T cells involved in tumour regression and Listeria elimination. These results support the use of low doses of pathogenic Listeria as safe melanoma therapeutic vaccines that do not require antibiotics for bacterial removal. PMID:25760947

Randomized, phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma.

PubMed

Baker, Laurence H; Rowinsky, Eric K; Mendelson, David; Humerickhouse, Rod A; Knight, Raymond A; Qian, Jiang; Carr, Robert A; Gordon, Gary B; Demetri, George D

2008-12-01

Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients. Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety. Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies. ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.

Echinacea purpurea (L.) Moench modulates human T-cell cytokine response☆

PubMed Central

Fonseca, Fabiana N.; Papanicolaou, Genovefa; Lin, Hong; Lau, Clara B.S.; Kennelly, Edward J.; Cassileth, Barrie R.; Cunningham-Rundles, Susanna

2014-01-01

The study objective was to evaluate the composition of a neutral and weakly acidic water-soluble extract from Echinacea purpurea (L.) Moench (EchNWA) previously shown to modify murine influenza infection, and to assess immunomodulatory effects on human T-cells. EchNWA extract from fresh aerial parts was extracted with water, ethanolic precipitation, and size-exclusion chromatography. The chemical profile of EchNWA was characterized by chromatography (size-exclusion, HPLC, GC–MS), and small molecule finger-print analysis performed by HPLC–PDA. Jurkat T-cells at high and low cell density were pretreated or not with doses of EchNWA, followed by activation with phorbol 12-myristate 13-acetate plus ionomycin (PMA+I). Interleukin-2 (IL-2) and interferon gamma (IFNg) cytokine secretions were measured by multi-cytokine luminex technology. Results showed that EchNWA contains 80% polysaccharides, predominantly a 10 kDa entity; phenolic compounds, cynarin, cichoric and caftaric acids, but no detectable alkylamides. Cytokine production required stimulation and was lower after PMA+I activation in high-density compared to low-density conditions. EchNWA mediated a strong dose-dependent enhancement of high-density T-cell production of IL-2 and IFNg response to PMA+I. EchNWA alone did not stimulate T-cells. EchNWA enhanced mean fluorescence intensity of IL-2 in Jurkat T-cells activated by PMA+1 or ionomycin alone. Conversely EchNWA mediated modest but significant suppression of IFNg response and reduced the percentage of CD25+ T-cells under low-density conditions. Conclusions are that EchNWA polysaccharides, but not phenolic compounds have dose-related adjuvant effects on human T-cell cytokine responses characterized by enhancing and suppressive effects that are regulated by T-cell density. PMID:24434371

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.

Real-time volumetric relative dosimetry for magnetic resonance—image-guided radiation therapy (MR-IGRT)

NASA Astrophysics Data System (ADS)

Lee, Hannah J.; Kadbi, Mo; Bosco, Gary; Ibbott, Geoffrey S.

2018-02-01

The integration of magnetic resonance imaging (MRI) with linear accelerators (linac) has enabled the use of 3D MR-visible gel dosimeters for real-time verification of volumetric dose distributions. Several iron-based radiochromic 3D gels were created in-house then imaged and irradiated in a pre-clinical 1.5 T-7 MV MR-Linac. MR images were acquired using a range of balanced-fast field echo (b-FFE) sequences during irradiation to assess the contrast and dose response in irradiated regions and to minimize the presence of MR artifacts. Out of four radiochromic 3D gel formulations, the FOX 3D gel was found to provide superior MR contrast in the irradiated regions. The FOX gels responded linearly with respect to real-time dose and the signal remained stable post-irradiation for at least 20 min. The response of the FOX gel also was found to be unaffected by the radiofrequency and gradient fields created by the b-FFE sequence during irradiation. A reusable version of the FOX gel was used for b-FFE sequence optimization to reduce artifacts by increasing the number of averages at the expense of temporal resolution. Regardless of the real-time MR sequence used, the FOX 3D gels responded linearly to dose with minimal magnetic field effects due to the strong 1.5 T field or gradient fields present during imaging. These gels can easily be made in-house using non-reusable and reusable formulations depending on the needs of the clinic, and the results of this study encourage further applications of 3D gels for MR-IGRT applications.

Poster — Thur Eve — 20: CTDI Measurements using a Radiochromic Film-based clinical protocol

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

Quintero, C.; Bekerat, H.; DeBlois, F.

2014-08-15

The purpose of the study was evaluating accuracy and reproducibility of a radiochromic film-based protocol to measure computer tomography dose index (CTDI) as a part of annual QA on CT scanners and kV-CBCT systems attached to linear accelerators. Energy dependence of Gafchromic XR-QA2 ® film model was tested over imaging beam qualities (50 – 140 kVp). Film pieces were irradiated in air to known values of air-kerma (up to 10 cGy). Calibration curves for each beam quality were created (Film reflectance change Vs. Air-kerma in air). Film responses for same air-kerma values were compared. Film strips were placed into holesmore » of a CTDI phantom and irradiated for several clinical scanning protocols. Film reflectance change was converted into dose to water and used to calculate CTDIvol values. Measured and tabulated CTDIvol values were compared. Average variations of ±5.2% in the mean film reflectance change were observed in the energy range of 80 to 140 keV, and 11.1% between 50 and 140 keV. Measured CTDI values were in average 10% lower than tabulated CTDI values for CT-simulators, and 44% higher for CBCT systems. Results presented a mean variation for the same machine and protocol of 2.6%. Variation of film response is within ±5% resulting in ±15% systematic error in dose estimation if a single calibration curve is used. Relatively large discrepancy between measured and tabulated CTDI values strongly support the trend towards replacing CTDI value with equilibrium dose measurement in the center of cylindrical phantom, as suggested by TG- 111.« less

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

Sci—Fri PM: Topics — 06: The influence of regional dose sensitivity on salivary loss and recovery in the parotid gland

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

Clark, H; BC Cancer Agency, Surrey, B.C.; BC Cancer Agency, Vancouver, B.C.

Purpose: The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC 2010) survey of radiation dose-volume effects on salivary gland function has called for improved understanding of intragland dose sensitivity and the effectiveness of partial sparing in salivary glands. Regional dose susceptibility of sagittally- and coronally-sub-segmented parotid gland has been studied. Specifically, we examine whether individual consideration of sub-segments leads to improved prediction of xerostomia compared with whole parotid mean dose. Methods: Data from 102 patients treated for head-and-neck cancers at the BC Cancer Agency were used in this study. Whole mouth stimulated saliva was collected before (baseline), threemore » months, and one year after cessation of radiotherapy. Organ volumes were contoured using treatment planning CT images and sub-segmented into regional portions. Both non-parametric (local regression) and parametric (mean dose exponential fitting) methods were employed. A bootstrap technique was used for reliability estimation and cross-comparison. Results: Salivary loss is described well using non-parametric and mean dose models. Parametric fits suggest a significant distinction in dose response between medial-lateral and anterior-posterior aspects of the parotid (p<0.01). Least-squares and least-median squares estimates differ significantly (p<0.00001), indicating fits may be skewed by noise or outliers. Salivary recovery exhibits a weakly arched dose response: the highest recovery is seen at intermediate doses. Conclusions: Salivary function loss is strongly dose dependent. In contrast no useful dose dependence was observed for function recovery. Regional dose dependence was observed, but may have resulted from a bias in dose distributions.« less

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...

Radiation Pneumopathy in the Rat After Intravenous Application of {sup 188}Re-Labeled Microspheres

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

Liepe, Knut; Faulhaber, Diana; Wunderlich, Gerd

2011-10-01

Purpose: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ({sup 188}Re)-labeled microspheres in a rat model. Methods and Materials: {sup 188}Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 {+-} 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks.more » An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses. Results: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 {+-} 0.6 Gy and 20.4 {+-} 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component. Conclusions: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar.« less

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.

Low-dose radiation: a cause of breast cancer

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

Land, C.E.

1980-08-15

It is likely that the breast is the organ most sensitive to radiation carcinogenesis in postpubertal women. Studies of different exposed populations have yielded remarkably consistent results, in spite of wide differences in underlying breast cancer rates and conditions of exposure. Excess risk is approximately proportional to dose, and is relatively independent of ionization density and fractionization of dose. This implies that the risk associated with low-dose exposures to ionizing radiation can be estimated with some confidence from higher-dose data. Excess risk is heavily dependent on age at exposure but relatively independent of population differences in normal risk. The temporalmore » patterns after exposure of both radiation-induced and naturally occurring breast cancer are similar, suggesting a strong influence of factors other than radiation on radiation-induced breast cancer. Uncertainties remain about risks from exposures before puberty and after menopause.« 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.

SU-G-IeP3-13: Real-Time Patient and Staff Dose Monitoring in Fluoroscopy Guided Interventions

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

Vergoossen, L; Sailer, A; Paulis, L

Purpose: Interventional radiology procedures involve the use of X-rays, which can pose a large radiation burden on both patients and staff. Although some reports on radiation dose are available, most studies focus on limited types of procedures and only report patient dose. In our cathlabs a dedicated real-time patient and staff monitoring system was installed in November 2015. The aim of this study was to investigate the patient and staff dose exposure for different types of interventions. Methods: Radiologists involved in fluoroscopy guided interventional radiology procedures wore personal dose meters (PDM, DoseAware, Philips) on their lead-apron that measured the personalmore » dose equivalent Hp(10), a measure for the effective dose (E). Furthermore, reference PDMs were installed in the C-arms of the fluoroscopy system (Allura XPer, Philips). Patient dose-area-product (DAP) and PDM doses were retrieved from the monitoring system (DoseWise, Philips) for each procedure. A total of 399 procedures performed between November 2015 and February 2016 were analyzed with respect to the type of intervention. Interventions were grouped by anatomy and radiologist position. Results: The mean DAP for the different types of interventions ranged from 2.86±2.96 Gycm{sup 2} (percutaneous gastrostomy) to 147±178 Gycm{sup 2} (aortic repair procedures). The radiologist dose (E) ranged from 5.39±7.38 µSv (cerebral interventions) to 84.7±106 µSv (abdominal interventions) and strongly correlated with DAP (R{sup 2}=0.83). The E normalized to DAP showed that the relative radiologist dose was higher for interventions in larger body parts (e.g. abdomen) compared to smaller body parts (e.g. head). Conclusion: Using a real-time dose monitoring system we were able to assess the staff and patient dose revealing that the relative staff dose strongly depended on the type of procedure and patient anatomy. This could be explained by the position of the radiologist with respect to the patient and X-ray tube. To facilitate this study L Vergoossen received a scholarship from Philips Medical Systems.« less

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

PubMed

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

2017-01-01

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

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

Dose-specific effects of transcutaneous electrical nerve stimulation (TENS) on experimental pain: a systematic review.

PubMed

Claydon, Leica S; Chesterton, Linda S; Barlas, Panos; Sim, Julius

2011-09-01

To determine the hypoalgesic effects of transcutaneous electrical nerve stimulation (TENS) parameter combinations on experimental models in healthy humans. Searches were performed using the electronic databases Ovid MEDLINE, CINAHL, AMED, and Web of Science (from inception to December 2009). Manual searches of journals and reference lists of retrieved trials were also performed. Randomized controlled trials (RCTs) were included in the review if they compared the hypoalgesic effect of TENS relative with placebo and control, using an experimental pain model in healthy human participants. Two reviewers independently selected the trials, assessed their methodologic quality and extracted data. Forty-three RCTs were eligible for inclusion. A best evidence synthesis revealed: Overall "conflicting" (inconsistent findings in multiple RCTs) evidence of TENS efficacy on experimental pain irrespective of TENS parameters used. Overall intense TENS has "moderate" evidence of efficacy (1 high-quality and 2 low-quality trials). Conventional TENS has overall conflicting evidence of efficacy, this is derived from "strong" evidence of efficacy (generally consistent findings in multiple high-quality RCTs) on pressure pain but strong evidence of inefficacy on other pain models. "Limited" evidence (positive findings from 1 RCT) of hypoalgesia exists for some novel parameters. Low-intensity, low-frequency, local TENS has strong evidence of inefficacy. Inappropriate TENS (using "barely perceptible" intensities) has moderate evidence of inefficacy. The level of hypoalgesic efficacy of TENS is clearly dependent on TENS parameter combination selection (defined in terms of intensity, frequency, and stimulation site) and experimental pain model. Future clinical RCTs may consider these TENS dose responses.

Evaluation of the safety and immunogenicity of two antigen concentrations of the Mtb72F/AS02(A) candidate tuberculosis vaccine in purified protein derivative-negative adults.

PubMed

Leroux-Roels, Isabel; Leroux-Roels, Geert; Ofori-Anyinam, Opokua; Moris, Philippe; De Kock, Els; Clement, Frédéric; Dubois, Marie-Claude; Koutsoukos, Marguerite; Demoitié, Marie-Ange; Cohen, Joe; Ballou, W Ripley

2010-11-01

Tuberculosis (TB) remains a major cause of illness and death worldwide, making a new TB vaccine an urgent public health priority. Purified protein derivative (PPD)-negative adults (n = 50) were equally randomized to receive 3 doses at 1-month intervals (at 0, 1, and 2 months) of one of the following vaccines: Mtb72F/AS02(A) (10 or 40 μg antigen), Mtb72F/saline (10 or 40 μg antigen), or AS02(A). Mtb72F/AS02(A) recipients received an additional dose 1 year after the first dose to evaluate if the elicited immune response could be boosted. Mtb72F/AS02(A) vaccines were locally reactogenic but clinically well tolerated, with transient adverse events (usually lasting between 1 and 4 days) that resolved without sequelae being observed. No vaccine-related serious adverse events were reported. Vaccination with Mtb72F/AS02(A) induced a strong Mtb72F-specific humoral response and a robust Mtb72F-specific CD4(+) T-cell response, both of which persisted at 9 months after primary immunization and for 1 year after the booster immunization. There was no significant difference between the magnitude of the CD4(+) T-cell response induced by the 10-μg and 40-μg Mtb72F/AS02(A) vaccines. The Mtb72F-specific CD4(+) T cells predominantly expressed CD40L; CD40L and interleukin-2 (IL-2); CD40L and tumor necrosis factor alpha (TNF-α); CD40L, IL-2, and TNF-α; and CD40L, IL-2, TNF-α, and gamma interferon (IFN-γ). Serum IFN-γ, but not TNF-α, was detected 1 day after doses 2 and 3 for the Mtb72F/AS02(A) vaccine but did not persist. Vaccine-induced CD8(+) T-cell responses were not detected, and no immune responses were elicited with AS02(A) alone. In conclusion, Mtb72F/AS02(A) is clinically well tolerated and is highly immunogenic in TB-naïve adults. The 10- and 40-μg Mtb72F/AS02(A) vaccines show comparable safety and immunogenicity profiles.

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.

Targeted delivery of TLR ligands to human and mouse dendritic cells strongly enhances adjuvanticity.

PubMed

Tacken, Paul J; Zeelenberg, Ingrid S; Cruz, Luis J; van Hout-Kuijer, Maaike A; van de Glind, Gerline; Fokkink, Remco G; Lambeck, Annechien J A; Figdor, Carl G

2011-12-22

Effective vaccines consist of 2 components: immunodominant antigens and effective adjuvants. Whereas it has been demonstrated that targeted delivery of antigens to dendritic cells (DCs) improves vaccine efficacy, we report here that co-targeting of TLR ligands (TLRLs) to DCs strongly enhances adjuvanticity and immunity. We encapsulated ligands for intracellular TLRs within biodegradable nanoparticles coated with Abs recognizing DC-specific receptors. Targeted delivery of TLRLs to human DCs enhanced the maturation and production of immune stimulatory cytokines and the Ag-specific activation of naive CD8(+) T cells. In vivo studies demonstrated that nanoparticles carrying Ag induced cytotoxic T-lymphocyte responses at 100-fold lower adjuvant dose when TLRLs were co-encapsulated instead of administered in soluble form. Moreover, the efficacy of these targeted TLRLs reduced the serum cytokine storm and related toxicity that is associated with administration of soluble TLRLs. We conclude that the targeted delivery of adjuvants may improve the efficacy and safety of DC-based vaccines.

A Reduced Antigen Load In Vivo, Rather Than Weak Inflammation, Causes a Substantial Delay in CD8+ T Cell Priming against Mycobacterium bovis (Bacillus Calmette-Guérin)1

PubMed Central

Russell, Marsha S.; Iskandar, Monica; Mykytczuk, Oksana L.; Nash, John H. E.; Krishnan, Lakshmi; Sad, Subash

2014-01-01

Regardless of the dose of Ag, Ag presentation occurs rapidly within the first few days which results in rapid expansion of the CD8+ T cell response that peaks at day 7. However, we have previously shown that this rapid priming of CD8+ T cells is absent during infection of mice with Mycobacterium bovis (bacillus Calmette-Guérin (BCG)). In this study, we have evaluated the mechanisms responsible for the delayed CD8+ T cell priming. Because BCG replicates poorly and survives within phagosomes we considered whether 1) generation of reduced amounts of Ag or 2) weaker activation by pathogen-associated molecular patterns (PAMPs) during BCG infection is responsible for the delay in CD8+ T cell priming. Using rOVA-expressing bacteria, our results indicate that infection of mice with BCG-OVA generates greatly reduced levels of OVA, which are 70-fold lower in comparison to the levels generated during infection of mice with Listeria monocytogenes-expressing OVA. Furthermore, increasing the dose of OVA, but not PAMP signaling during BCG-OVA infection resulted in rapid Ag presentation and consequent expansion of the CD8+ T cell response, indicating that the generation of reduced Ag levels, not lack of PAMP-associated inflammation, was responsible for delayed priming of CD8+ T cells. There was a strong correlation between the relative timing of Ag presentation and the increase in the level of OVA in vivo. Taken together, these results reveal that some slowly replicating pathogens, such as mycobacteria, may facilitate their chronicity by generating reduced Ag levels which causes a substantial delay in the development of acquired immune responses. PMID:17579040

Microneedle-based vaccines

PubMed Central

Prausnitz, Mark R.; Mikszta, John A.; Cormier, Michel; Andrianov, Alexander K.

2010-01-01

The threat of pandemic influenza and other public health needs motivates development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (i) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (ii) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin and (iii) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmid encoding the influenza hemagglutinin to rodents and found strong antibody responses. In addition, ChimeriVax™-JE against yellow fever was administered to non-human primates and generated protective levels of neutralizing antibodies more than seven times greater than subcutaneous delivery; DNA plasmid encoding hepatitis B surface antigen was administered to mice and generated antibody and T cell responses at least as strong as hypodermic injections; recombinant Protective Antigen of Baccilus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmid encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model vaccine ovalbumin. At low dose (1 µg), specific antibody titers from microneedles were one order of magnitude greater than subcutaneous injection and two orders of magnitude greater than intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20–80 µg), the route of administration had no significant effect on the immune response. Concerning safety, no infections or other serious adverse events have been observed in well over 1000 microneedle insertions in human and animal subjects. Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild and transient erythema is often observed. Microneedle pain has been reported as non-existent to mild, and always much less than a hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and effective method to deliver vaccines with possible added attributes of requiring lower vaccines doses, permitting low-cost manufacturing, and enabling simple distribution and administration. PMID:19768415

Cerebrovascular Diseases in Childhood Cancer Survivors: Role of the Radiation Dose to Willis Circle Arteries

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

El-Fayech, Chiraz; Haddy, Nadia; Allodji, Rodrigue Sètchéou

Background and Purpose: The aim of this study was to investigate the role of radiation dose received to the circle of Willis (WC) during radiation therapy (RT) and of potential dose-response modifiers on the risk of stroke after treatment of childhood cancer. Methods: We evaluated the risk factors for stroke in a cohort of 3172 5-year survivors of childhood cancer who were followed up for a median time of 26 years. Radiation doses to the WC and brain structures were estimated for each of the 2202 children who received RT. Results: Fifty-four patients experienced a confirmed stroke; 39 were ischemic. Patientsmore » not receiving RT had a stroke risk similar to that of the general population, whereas those who received RT had an 8.5-fold increased risk (95% confidence interval [CI]: 6.3-11.0). The excess of incidence of stroke increased yearly. The dose of radiation to the WC, rather than to other brain structures, was found to be the best predictor of stroke. The relative risk was 15.7 (95% CI: 4.9-50.2) for doses of 40 Gy or more. At 45 years of age, the cumulative stroke incidence was 11.3% (95% CI: 7.1%-17.7%) in patients who received 10 Gy or more to the WC, compared with 1% expected from general population data. Radiation doses received to the heart and neck also increased the risk. Surgery for childhood brain cancer was linked to hemorrhagic strokes in these patients. Conclusion: The WC should be considered as a major organ at risk during RT for childhood brain cancers. The incidence of radiation-induced ischemic stroke strongly increases with long-term follow-up.« less

Induction of defence gene expression by oligogalacturonic acid requires increases in both cytosolic calcium and hydrogen peroxide in Arabidopsis thaliana.

PubMed

Hu, Xiang Yang; Neill, Steven J; Cai, Wei Ming; Tang, Zhang Cheng

2004-06-01

Responses to oligogalacturonic acid (OGA) were determined in transgenic Arabidopsis thaliana seedlings expressing the calcium reporter protein aequorin. OGA stimulated a rapid, substantial and transient increase in the concentration of cytosolic calcium ([Ca2+]cyt) that peaked after ca. 15 s. This increase was dose-dependent, saturating at ca. 50 ug Gal equiv/ml of OGA. OGA also stimulated a rapid generation of H2O2. A small, rapid increase in H2O2 content was followed by a much larger oxidative burst, with H2O2 content peaking after ca. 60 min and declining thereafter. Induction of the oxidative burst by OGA was also dose-dependent, with a maximum response again being achieved at ca. 50 ug Gal equiv/mL. Inhibitors of calcium fluxes inhibited both increases in [Ca2+]cyt and [H2O2], whereas inhibitors of NADPH oxidase blocked only the oxidative burst. OGA increased strongly the expression of the defence-related genes CHS, GST, PAL and PR-1. This induction was suppressed by inhibitors of calcium flux or NADPH oxidase, indicating that increases in both cytosolic calcium and H2O2 are required for OGA-induced gene expression.

The targeted histone deacetylase inhibitor tefinostat (CHR-2845) shows selective in vitro efficacy in monocytoid-lineage leukaemias

PubMed Central

Zabkiewicz, Joanna; Gilmour, Marie; Hills, Robert; Vyas, Pares; Bone, Elizabeth; Davidson, Alan; Burnett, Alan; Knapper, Steven

2016-01-01

Tefinostat (CHR-2845) is a novel monocyte/macrophage-targeted histone deacetylase (HDAC) inhibitor which is cleaved into its active acid by the intracellular esterase human carboxylesterase-1 (hCE-1). The in vitro efficacy of tefinostat was characterised in cell lines and in a cohort of 73 primary AML and CMML samples. Dose-dependent induction of apoptosis and significant growth inhibitory effects were seen in myelomonocytic (M4), monocytic/monoblastic (M5) and CMML samples in comparison to non-monocytoid AML sub-types (p = 0.007). Importantly, no growth inhibitory effects were seen in normal bone marrow CD34+ cells exposed to AML-toxic doses of tefinostat in clonogenic assays. Expression of hCE-1 was measured by intracellular flow cytometry and immunoblotting across the cohort, with highest levels seen in M5 AML patients. hCE-1 levels correlated with significantly increased tefinostat sensitivity (low EC50) as measured by growth inhibition assays (p = 0.001) and concomitant elevation of the mature monocytoid marker CD14+. Strong induction of intracellular histone protein acetylation was observed in tefinostat-responsive samples, as were high levels of the DNA damage sensor γ-H2A.X, highlighting potential biomarkers of patient responsiveness. Synergistic interaction between tefinostat and the current standard treatment cytarabine was demonstrated in dose response and clonogenic assays using simultaneous drug addition in primary samples (median Combination Index value = 0.51). These data provide a strong rationale for the further clinical evaluation of tefinostat in monocytoid-lineage haematological neoplasms including CMML and monocyte-lineage AMLs. PMID:26934551

Comparison of the effects of the antiestrogens EM-800 and tamoxifen on the growth of human breast ZR-75-1 cancer xenografts in nude mice.

PubMed

Couillard, S; Gutman, M; Labrie, C; Bélanger, A; Candas, B; Labrie, F

1998-01-01

Although estrone supplementation in ovariectomized (OVX) nude mice bearing ZR-75-1 xenografts caused a 365% increase in average tumor size during the 4-month treatment period, administration of the antiestrogen EM-800 at the daily oral doses of 50, 150, or 400 microg completely prevented estrogen-stimulated tumor growth. At the same doses of tamoxifen, tumor size was inhibited to 189, 117, and 120% above pretreatment values. However, when EM-800 (150 microg/day) was added to the daily 150- and 400-microg doses of tamoxifen, final tumor size was decreased further to 12 and 38% above pretreatment values, respectively. EM-800 (400 microg daily) administered to estrone-supplemented OVX mice caused complete, partial, and stable responses in 11, 22, and 49% of estrone-stimulated tumors, respectively, whereas 19% (7 of 37) progressed. At the same dose of tamoxifen, the corresponding responses were 3% (complete response), 3% (partial response), and 25% (no change), whereas 69% (22 of 32) of tumors progressed. In the absence of estrone supplementation, tamoxifen (400 microg) alone administered to OVX mice stimulated tumor growth to 161% compared with initial size whereas the same dose of EM-800 reduced tumor size by 55%, a value superimposable to that observed in OVX control animals. The agonistic effect of tamoxifen is thus illustrated by the observation that 73% of tumors progressed when tamoxifen was administered alone to OVX animals whereas no tumor progressed with EM-800. The present data strongly suggest that at least part of the initial lack of response and resistance to tamoxifen during tamoxifen treatment in women is due to the estrogenic activity of this compound, whereas the new antiestrogen EM-800 exerts pure antagonistic action.

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

Effect of stimulus intensity and number of treatments on ECS-related seizure duration and retrograde amnesia in rats.

PubMed

Andrade, Chittaranjan; Thyagarajan, S; Vinod, P S; Srikanth, S N; Rao, N S K; Chandra, J Suresh

2002-12-01

Animal models are frequently used to generate and test hypotheses about amnesia resulting from electroconvulsive therapy (ECT). Although many predictors of ECT-induced amnesia are known, their relative effects have been inadequately researched in the context of the animal models. We sought to determine the relative retrograde amnestic effects of electroconvulsive shock (ECS) stimulus intensity (dose) and number on strong memories in rats. We also sought to identify dose-dependent ceiling amnestic effects, if any. Adult rats (n = 144) were overtrained in a passive avoidance task using a step down apparatus. The rats were then randomized in a factorial design to receive one, two, or three once-daily bilateral ECS at 0-mC (sham ECS), 30-mC, 60-mC, 120-mC, or 180-mC doses. Recall of the pre-ECS training was assessed 1 day after the last ECS. Retrograde amnesia was observed only in rats that received 3 ECS; dose-dependent amnestic effects did not emerge. Higher stimulus intensity was associated with a small (13%) but significant increase in motor seizure duration, but only at the first ECS; stimulus intensity did not influence the attenuation of seizure duration across repeated occasions of ECS. With bilateral ECS, the number of ECSs administered is a more important variable than the ECS dose in weakening a strong, recently acquired, noxious memory; this finding may have important clinical implications. Higher stimulus intensity marginally increases motor seizure duration at the first ECS but does not influence the decrease in seizure duration across repeated ECSs.

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

Proteome-wide muscle protein fractional synthesis rates predict muscle mass gain in response to a selective androgen receptor modulator in rats.

PubMed

Shankaran, Mahalakshmi; Shearer, Todd W; Stimpson, Stephen A; Turner, Scott M; King, Chelsea; Wong, Po-Yin Anne; Shen, Ying; Turnbull, Philip S; Kramer, Fritz; Clifton, Lisa; Russell, Alan; Hellerstein, Marc K; Evans, William J

2016-03-15

Biomarkers of muscle protein synthesis rate could provide early data demonstrating anabolic efficacy for treating muscle-wasting conditions. Androgenic therapies have been shown to increase muscle mass primarily by increasing the rate of muscle protein synthesis. We hypothesized that the synthesis rate of large numbers of individual muscle proteins could serve as early response biomarkers and potentially treatment-specific signaling for predicting the effect of anabolic treatments on muscle mass. Utilizing selective androgen receptor modulator (SARM) treatment in the ovariectomized (OVX) rat, we applied an unbiased, dynamic proteomics approach to measure the fractional synthesis rates (FSR) of 167-201 individual skeletal muscle proteins in triceps, EDL, and soleus. OVX rats treated with a SARM molecule (GSK212A at 0.1, 0.3, or 1 mg/kg) for 10 or 28 days showed significant, dose-related increases in body weight, lean body mass, and individual triceps but not EDL or soleus weights. Thirty-four out of the 94 proteins measured from the triceps of all rats exhibited a significant, dose-related increase in FSR after 10 days of SARM treatment. For several cytoplasmic proteins, including carbonic anhydrase 3, creatine kinase M-type (CK-M), pyruvate kinase, and aldolase-A, a change in 10-day FSR was strongly correlated (r(2) = 0.90-0.99) to the 28-day change in lean body mass and triceps weight gains, suggesting a noninvasive measurement of SARM effects. In summary, FSR of multiple muscle proteins measured by dynamics of moderate- to high-abundance proteins provides early biomarkers of the anabolic response of skeletal muscle to SARM. Copyright © 2016 the American Physiological Society.

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.

Specific memory B cell response and participation of CD4+ central and effector memory T cells in mice immunized with liposome encapsulated recombinant NE protein based Hepatitis E vaccine candidate.

PubMed

Kulkarni, Shruti P; Thanapati, Subrat; Arankalle, Vidya A; Tripathy, Anuradha S

2016-11-21

Liposome encapsulated neutralizing epitope protein of Hepatitis E virus (HEV), rNEp, our Hepatitis E vaccine candidate, was shown to be immunogenic and safe in pregnant and non-pregnant mice and yielded sterilizing immunity in rhesus monkeys. The current study in Balb/c mice assessed the levels and persistence of anti-HEV IgG antibodies by ELISA, frequencies of B, memory B, T and memory T cells by flow cytometry and HEV-specific IgG secreting memory B cells by ELISPOT till 420days post immunization (PI) with 5?g rNEp encapsulated in liposome based adjuvant (2 doses, 4weeks apart). Mice immunized with a lower dose (1?g) were assessed only for anamnestic response post booster dose. Vaccine candidate immunized mice (5?g dose) elicited strong anti-HEV IgG response that was estimated to persist for lifetime. At day 120 PI, frequency of memory B cells was higher in immunized mice than those receiving adjuvant alone. Anti-HEV IgG titers were lower in mice immunized with 1?g dose. A booster dose yielded a heightened antibody response in mice with both high (>800GMT, 5?g) and low (?100GMT, 1?g) anti-HEV IgG titers. At day 6th post booster dose, HEV-specific antibody secreting plasma cells (ASCs) were detected in 100% and 50% of mice with high and low anti-HEV IgG titers, respectively, whereas the frequencies of CD4 + central and effector memory T cells were high in mice with high anti-HEV IgG titers only. Taken together, the vaccine candidate effectively generates persistent and anamnestic antibody response, elicits participation of CD4 + memory T cells and triggers memory B cells to differentiate into ASCs upon boosting. This approach of assessing the immunogenicity of vaccine candidate could be useful to explore the longevity of HEV-specific memory response in future HEV vaccine trials in human. Copyright © 2016. Published by Elsevier Ltd.

Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis

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

Dimopoulou, Myrto, E-mail: myrto.dimopoulou@wur.nl

Differential gene expression analysis in the rat whole embryo culture (WEC) assay provides mechanistic insight into the embryotoxicity of test compounds. In our study, we hypothesized that comparative analysis of the transcriptomes of rat embryos exposed to six azoles (flusilazole, triadimefon, ketoconazole, miconazole, difenoconazole and prothioconazole) could lead to a better mechanism-based understanding of their embryotoxicity and pharmacological action. For evaluating embryotoxicity, we applied the total morphological scoring system (TMS) in embryos exposed for 48 h. The compounds tested showed embryotoxicity in a dose-response fashion. Functional analysis of differential gene expression after 4 h exposure at the ID{sub 10} (effectivemore » dose for 10% decreased TMS), revealed the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the retinoic acid (RA) pathway, albeit in a differential way. Flusilazole, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. Dose-dependent analysis of the effects of flusilazole revealed that the RA pathway related genes were already differentially expressed at low dose levels while the sterol pathway showed strong regulation at higher embryotoxic doses, suggesting that this pathway is less predictive for the observed embryotoxicity. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by flusilazole. In summary, the rat WEC assay in combination with transcriptomics could add a mechanistic insight into the embryotoxic potency ranking and pharmacological mode of action of the tested compounds. - Highlights: • Embryonic exposure to azoles revealed concentration-dependent malformations. • Transcriptomics could enhance the mechanistic knowledge of embryotoxicants. • Retinoic acid gene set identifies early embryotoxic responses to azoles. • Toxic versus pharmacologic potency determines functional efficacy.« less

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

PubMed

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

2013-10-01

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

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.

Ethanol- or acetone-pretreatment of mice strongly enhances the bacterial mutagenicity of dimethylnitrosamine in assays mediated by liver subcellular fraction, but not in host-mediated assays.

PubMed

Glatt, H; de Balle, L; Oesch, F

1981-01-01

The activation of dimethylnitrosamine (DMN) to a bacterial mutagen in liver subcellular fraction and in intrasanguinous host-mediated assays was studied, in particular the effect of pretreatment of the animals with ethanol or acetone. Salmonella typhimurium TA 92 was much more sensitive to DMN mutagenicity than TA 100 and TA 1535 or Escherichia coli WP2uvrA and was used for the main part of the study. Noteworthy, in part already known, features of the in vitro activation are the relatively low pH optimum (pH 6-6.4), the non-linear dose-mutagenic response-relationship and the relatively high doses of DMN required for activation with control preparations. Pretreatment of mice with ethanol or acetone greatly reduced the minimal mutagenically effective concentration of DMN in the in vitro assay. Pretreatment with Aroclor 1254, an inducer frequently used in mutagenicity research, showed little effect when used alone, but reduced the potentiation by acetone. The results of the host-mediated assays substantially differed from those of the in vitro activation assays (a) in the relatively low dose of DMN required for mutagenicity to occur and (b) in the lack of potentiation by acetone-or ethanol-pretreatment. Acetone even led to a marginal decrease in mutagenicity. As a possible explantation for this apparent discrepancy were assume that with the in vitro system the activity of the dilute metabolizing system is limiting for the activation of DMN and induction therefore will increase the mutagenicity, whereas in vivo DMN is quantitatively metabolized in both induced and non-induced animals. The results show that caution has to be taken in the interpretation from in vitro results to the in vivo situation. In particular our in vivo experiments do not support the hypothesis that the induction by ethanol of an activating system with a low Km (which would strongly activate traces of DMN ingested with many foods) is one of the reasons for the increased risk of liver tumors in alcoholics.

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.

Superior induction of T cell responses to conserved HIV-1 regions by electroporated alphavirus replicon DNA compared to that with conventional plasmid DNA vaccine.

PubMed

Knudsen, Maria L; Mbewe-Mvula, Alice; Rosario, Maximillian; Johansson, Daniel X; Kakoulidou, Maria; Bridgeman, Anne; Reyes-Sandoval, Arturo; Nicosia, Alfredo; Ljungberg, Karl; Hanke, Tomás; Liljeström, Peter

2012-04-01

Vaccination using "naked" DNA is a highly attractive strategy for induction of pathogen-specific immune responses; however, it has been only weakly immunogenic in humans. Previously, we constructed DNA-launched Semliki Forest virus replicons (DREP), which stimulate pattern recognition receptors and induce augmented immune responses. Also, in vivo electroporation was shown to enhance immune responses induced by conventional DNA vaccines. Here, we combine these two approaches and show that in vivo electroporation increases CD8(+) T cell responses induced by DREP and consequently decreases the DNA dose required to induce a response. The vaccines used in this study encode the multiclade HIV-1 T cell immunogen HIVconsv, which is currently being evaluated in clinical trials. Using intradermal delivery followed by electroporation, the DREP.HIVconsv DNA dose could be reduced to as low as 3.2 ng to elicit frequencies of HIV-1-specific CD8(+) T cells comparable to those induced by 1 μg of a conventional pTH.HIVconsv DNA vaccine, representing a 625-fold molar reduction in dose. Responses induced by both DREP.HIVconsv and pTH.HIVconsv were further increased by heterologous vaccine boosts employing modified vaccinia virus Ankara MVA.HIVconsv and attenuated chimpanzee adenovirus ChAdV63.HIVconsv. Using the same HIVconsv vaccines, the mouse observations were supported by an at least 20-fold-lower dose of DNA vaccine in rhesus macaques. These data point toward a strategy for overcoming the low immunogenicity of DNA vaccines in humans and strongly support further development of the DREP vaccine platform for clinical evaluation.

The nonuniformity of antibody distribution in the kidney and its influence on dosimetry.

PubMed

Flynn, Aiden A; Pedley, R Barbara; Green, Alan J; Dearling, Jason L; El-Emir, Ethaar; Boxer, Geoffrey M; Boden, Robert; Begent, Richard H J

2003-02-01

The therapeutic efficacy of radiolabeled antibody fragments can be limited by nephrotoxicity, particularly when the kidney is the major route of extraction from the circulation. Conventional dose estimates in kidney assume uniform dose deposition, but we have shown increased antibody localization in the cortex after glomerular filtration. The purpose of this study was to measure the radioactivity in cortex relative to medulla for a range of antibodies and to assess the validity of the assumption of uniformity of dose deposition in the whole kidney and in the cortex for these antibodies with a range of radionuclides. Storage phosphor plate technology (radioluminography) was used to acquire images of the distributions of a range of antibodies of various sizes, labeled with 125I, in kidney sections. This allowed the calculation of the antibody concentration in the cortex relative to the medulla. Beta-particle point dose kernels were then used to generate the dose-rate distributions from 14C, 131I, 186Re, 32P and 90Y. The correlation between the actual dose-rate distribution and the corresponding distribution calculated assuming uniform antibody distribution throughout the kidney was used to test the validity of estimating dose by assuming uniformity in the kidney and in the cortex. There was a strong inverse relationship between the ratio of the radioactivity in the cortex relative to that in the medulla and the antibody size. The nonuniformity of dose deposition was greatest with the smallest antibody fragments but became more uniform as the range of the emissions from the radionuclide increased. Furthermore, there was a strong correlation between the actual dose-rate distribution and the distribution when assuming a uniform source in the kidney for intact antibodies along with medium- to long-range radionuclides, but there was no correlation for small antibody fragments with any radioisotope or for short-range radionuclides with any antibody. However, when the cortex was separated from the whole kidney, the correlation between the actual dose-rate distribution and the assumed dose-rate distribution, if the source was uniform, increased significantly. During radioimmunotherapy, the extent of nonuniformity of dose deposition in the kidney depends on the properties of the antibody and radionuclide. For dosimetry estimates, the cortex should be taken as a separate source region when the radiopharmaceutical is small enough to be filtered by the glomerulus.

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

SU-E-T-486: In Vivo Skin Dosimetry Using the Exradin W1 Plastic Scintillation Detector for Passively Scattered Proton Beam Therapy

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

Alsanea, F; Kudchadker, R; Usama, M

Purpose: To evaluate the accuracy and usefulness of plastic scintillation detectors used for skin dosimetry of patients undergoing passive scatter proton therapy. Methods: Following an IRB approved protocol, six patients undergoing passively scattered proton beam therapy for prostate cancer were selected for in vivo skin dosimetry using the Exradin W1 plastic scintillator. The detector was calibrated on a Cobalt-60 unit, and phantom measurements in the proton beam with the W1 and a calibrated parallel plate ion chamber were used to account for the under-response due to high LET at energies used for treatment. Measurements made in a heated water tankmore » were used to account for temperature dependence. For in vivo measurements, the W1 is fixed to the patient’s skin with medical tape in the center of each of two laterally opposed treatment fields. Measurements will be performed once per week for each patient for the duration of treatment, for a total of thirty six measurements. The measured dose will be compared to the expected dose, extracted from the Eclipse treatment planning system. The average difference over all measurements and per-patient will be computed, as well as standard deviations. Results: The calibrated detector exhibited a 7% under-response in 225 and 250 MeV beams, and a 4% under-response when used at 37 °C (relative to the response at the calibration temperature of 20 °C). Patient measurements are ongoing. Conclusion: The Exradin W1 plastic scintillator detector is a strong candidate for in vivo skin dosimetry in passively scattered proton beams as PSDs are water equivalent and very small (2mm in diameter), permitting accurate measurements that do not perturb the delivered dose. This project was supported in part by award number CA182450 from the National Cancer Institute.« less

Hematopoietic tissue repair under chronic low daily dose irradiation

NASA Astrophysics Data System (ADS)

Seed, T. M.

The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). In our laboratory we have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d^-1). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific (three major responding subgroups identified) and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup 1), the failure to augment basic repair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments (particularly marked within erythroid compartments) that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccommodated and either prone- or not prone to ML, subgroup 2 & 3) appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high-tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity. The kinetics of these repair-mediated, regenerative hematopoietic responses within the major subgroups are under study and should provide useful insights into the nature of hematopoietic accommodation (or its failure) under greatly extended periods of chronic, low-daily-dose ionizing radiation exposure.

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

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

Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity.

PubMed

Calabrese, Vittorio; Cornelius, Carolin; Cuzzocrea, Salvatore; Iavicoli, Ivo; Rizzarelli, Enrico; Calabrese, Edward J

2011-08-01

Understanding mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing reactive oxygen species (ROS)-mediated oxidative damage. But ROS formation, which is positively implicated in cellular stress response mechanisms, is a highly regulated process controlled by a complex network of intracellular signaling pathways. By sensing the intracellular nutrient and energy status, the functional state of mitochondria, and the concentration of ROS produced in mitochondria, the longevity network regulates life span across species by co-ordinating information flow along its convergent, divergent and multiply branched signaling pathways, including vitagenes which are genes involved in preserving cellular homeostasis during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. Dietary antioxidants, such as carnosine, carnitines or polyphenols, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways, including vitagenes. The hormetic dose-response, challenges long-standing beliefs about the nature of the dose-response in a lowdose zone, having 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. In this review we discuss the most current and up to date understanding of the possible signaling mechanisms by which caloric restriction, as well hormetic caloric restriction-mimetics compounds by activating vitagenes can enhance defensive systems involved in bioenergetic and stress resistance homeostasis with consequent impact on longevity processes. Copyright © 2011 Elsevier Ltd. All rights reserved.

Dose-dependent difference of nuclear receptors involved in murine liver hypertrophy by piperonyl butoxide.

PubMed

Sakamoto, Yohei; Yoshida, Midori; Tamura, Kei; Takahashi, Miwa; Kodama, Yukio; Inoue, Kaoru

2015-12-01

Nuclear receptors play important roles in chemically induced liver hypertrophy in rodents. To clarify the involvement of constitutive androstane receptor (CAR) and other nuclear receptors in mouse liver hypertrophy induced by different doses of piperonyl butoxide (PBO), wild-type and CAR-knockout mice were administered PBO (200, 1,000, or 5,000 ppm) in the basal diet for 1 week. Increased liver weight and diffuse hepatocellular hypertrophy were observed at 5,000 ppm for both genotypes, accompanied by increased Cyp3a11 mRNA and CYP3A protein expression, suggesting that CAR-independent pathway, possibly pregnane X receptor (PXR), plays a major role in the induction of hypertrophy. Moreover, wild-type mice at 5,000 ppm showed enhanced hepatocellular hypertrophy and strong positive staining for CYP2B in the centrilobular area, suggesting the localized contribution of CAR. At 1,000 ppm, only wild-type mice showed liver weight increase and centrilobular hepatocellular hypertrophy concurrent with elevated Cyp2b10 mRNA expression and strong CYP2B staining, indicating that CAR was essential at 1,000 ppm. We concluded that high-dose PBO induced hypertrophy via CAR and another pathway, while lower dose of PBO induced a pathway mediated predominantly by CAR. The dose-responsiveness on liver hypertrophy is important for understanding the involvement of nuclear receptors.

Ovarian sensitivity index is strongly related to circulating AMH and may be used to predict ovarian response to exogenous gonadotropins in IVF

PubMed Central

2011-01-01

Background Serum anti-Mullerian hormone (AMH) is currently considered the best marker of ovarian reserve and of ovarian responsiveness to gonadotropins in in-vitro fertilization (IVF). AMH assay, however, is not available in all IVF Units and is quite expensive, a reason that limits its use in developing countries. The aim of this study is to assess whether the "ovarian sensitivity index" precisely reflects AMH so that this index may be used as a surrogate for AMH in prediction of ovarian response during an IVF cycle. Methods AMH serum levels were measured in 61 patients undergoing IVF with a "long" stimulation protocol including the GnRH agonist buserelin and recombinant follicle-stimulating hormone (rFSH). Patients were divided into four subgroups according to the percentile of serum AMH and their ovarian stimulation was prospectively followed. Ovarian sensitivity index (OSI) was calculated dividing the total administered FSH dose by the number of retrieved oocytes. Results AMH and OSI show a highly significant negative correlation (r = -0.67; p = 0.0001) that is stronger than the one between AMH and the total number of retrieved oocytes and than the one between AMH and the total FSH dose. Conclusions OSI reflects quite satisfactory the AMH level and may be proposed as a surrogate of AMH assay in predicting ovarian responsiveness to FSH in IVF. Being very easy to calculate and costless, its use could be proposed where AMH measurement is not available or in developing countries where limiting costs is of primary importance. PMID:21824441

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.

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

Self-Recognition Sensitizes Mouse and Human Regulatory T Cells to Low-Dose CD28 Superagonist Stimulation.

PubMed

Langenhorst, Daniela; Tabares, Paula; Gulde, Tobias; Becklund, Bryan R; Berr, Susanne; Surh, Charles D; Beyersdorf, Niklas; Hünig, Thomas

2017-01-01

In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4 + T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro , the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity.

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

Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

PubMed Central

Ayala, Victor I.; Trivett, Matthew T.; Barsov, Eugene V.; Jain, Sumiti; Piatak, Michael; Trubey, Charles M.; Alvord, W. Gregory; Chertova, Elena; Roser, James D.; Smedley, Jeremy; Komin, Alexander; Keele, Brandon F.; Ohlen, Claes

2016-01-01

ABSTRACT AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4+ T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively (P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus. IMPORTANCE The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower. PMID:27558423

Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques.

PubMed

Ayala, Victor I; Trivett, Matthew T; Barsov, Eugene V; Jain, Sumiti; Piatak, Michael; Trubey, Charles M; Alvord, W Gregory; Chertova, Elena; Roser, James D; Smedley, Jeremy; Komin, Alexander; Keele, Brandon F; Ohlen, Claes; Ott, David E

2016-11-01

AIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4 + T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measure in vivo antiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes; P = 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively (P = 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus. The establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma.

PubMed

Liu, Qi; Cai, Xu-Wei; Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-10-13

To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study.

Tolerance and dose-volume relationship of intrathoracic stomach irradiation after esophagectomy for patients with thoracic esophageal squamous cell carcinoma

PubMed Central

Fu, Xiao-Long; Chen, Jun-Chao; Xiang, Jia-Qing

2015-01-01

Purpose To identify the tolerance of radiation with a high prescribed dose and predictors for the development of intrathoracic stomach toxicity in patients with thoracic esophageal squamous cell carcinoma (SCC) after esophagectomy followed by gastric conduit reconstruction. Methods and Materials From 2011 to 2013, 105 patients after esophagectomy were treated with postoperative radiotherapy. The intrathoracic stomach was outlined with the calculation of a dose-volume histogram (DVH) for the initial intended treatment of 6020 cGy or 6300 cGy. The volume of the intrathoracic stomach receiving each dose was recorded at 10-Gy intervals between 10 and 40 Gy and at 5-Gy intervals between 40 and 60 Gy. The grade of toxicities was defined by the National Cancer Institute Common Toxicity Criteria version 4.0. Results The mean and maximum doses of the intrathoracic stomach were 2449 ± 986 cGy and 6519 ± 406 cGy, respectively. Sixteen (15.2%) and three (2.9%) experienced Common Toxicity Criteria Grade 2 and Grade 3 acute gastric toxicity. There were no Grade 4 toxicities. Fourteen patients (13.3%) exhibited late gastric complications possibly related to radiation. The volume percent of the intrathoracic stomach receiving at least 50 Gy (V50) was strongly associated with the degree of toxicity (p = 0.024, respectively). Multivariate analysis of patient and treatment-related factors revealed no other significant predictors of severe toxicities. Conclusions The intrathoracic stomach is well tolerated with a high-dose irradiation for patients with esophageal SCC receiving radiotherapy after esophagectomy. A strong dose-volume relationship exists for the development of Grade 2 acute intrathoracic stomach toxicity in our study. PMID:26314958

Recombinant influenza H7 hemagglutinins induce lower neutralizing antibody titers in mice than do seasonal hemagglutinins

PubMed Central

Blanchfield, Kristy; Kamal, Ram P; Tzeng, Wen-Pin; Music, Nedzad; Wilson, Jason R; Stevens, James; Lipatov, Aleksander S; Katz, Jacqueline M; York, Ian A

2014-01-01

Background Vaccines against avian influenza viruses often require high hemagglutinin (HA) doses or adjuvants to achieve serological titers associated with protection against disease. In particular, viruses of the H7 subtype frequently do not induce strong antibody responses following immunization. Objectives To evaluate whether poor immunogenicity of H7 viruses is an intrinsic property of the H7 hemagglutinin. Methods We compared the immunogenicity, in naïve mice, of purified recombinant HA from two H7 viruses [A/Netherlands/219/2003(H7N7) and A/New York/107/2003(H7N2)] to that of HA from human pandemic [A/California/07/2009(H1N1pdm09)] and seasonal [A/Perth16/2009(H3N2)] viruses. Results After two intramuscular injections with purified hemagglutinin, mice produced antibodies to all HAs, but the response to the human virus HAs was greater than to H7 HAs. The difference was relatively minor when measured by ELISA, greater when measured by hemagglutination inhibition assays, and more marked still by microneutralization assays. H7 HAs induced little or no neutralizing antibody response in mice at either dose tested. Antibodies induced by H7 were of significantly lower avidity than for H3 or H1N1pdm09. Conclusions We conclude that H7 HAs may be intrinsically less immunogenic than HA from seasonal human influenza viruses. PMID:25213778

Neurotoxicogenomic investigations to assess mechanisms of action of the munitions constituents RDX and 2,6-DNT in Northern bobwhite (Colinus virginianus).

PubMed

Gust, Kurt A; Pirooznia, Mehdi; Quinn, Michael J; Johnson, Mark S; Escalon, Lynn; Indest, Karl J; Guan, Xin; Clarke, Joan; Deng, Youping; Gong, Ping; Perkins, Edward J

2009-07-01

Munitions constituents (MCs) including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), 2,4,6-trinitrotoluene (TNT), and TNT derivatives are recognized to elicit aberrant neuromuscular responses in many species. The onset of seizures resulting in death was observed in the avian model Northern bobwhite after oral dosing with RDX beginning at 8 mg/kg/day in subacute (14 days) exposures, whereas affective doses of the TNT derivative, 2,6-dinitrotoluene (2,6-DNT), caused gastrointestinal impacts, lethargy, and emaciation in subacute and subchronic (60 days) exposures. To assess and contrast the potential neurotoxicogenomic effects of these MCs, a Northern bobwhite microarray was developed consisting of 4119 complementary DNA (cDNA) features enriched for differentially-expressed brain transcripts from exposures to RDX and 2,6-DNT. RDX affected hundreds of genes in brain tissue, whereas 2,6-DNT affected few (

A bench-top megavoltage fan-beam CT using CdWO4-photodiode detectors. I. System description and detector characterization.

PubMed

Rathee, S; Tu, D; Monajemi, T T; Rickey, D W; Fallone, B G

2006-04-01

We describe the components of a bench-top megavoltage computed tomography (MVCT) scanner that uses an 80-element detector array consisting of CdWO4 scintillators coupled to photodiodes. Each CdWO4 crystal is 2.75 x 8 x 10 mm3. The detailed design of the detector array, timing control, and multiplexer are presented. The detectors show a linear response to dose (dose rate was varied by changing the source to detector distance) with a correlation coefficient (R2) nearly unity with the standard deviation of signal at each dose being less than 0.25%. The attenuation of a 6 MV beam by solid water measured by this detector array indicates a small, yet significant spectral hardening that needs to be corrected before image reconstruction. The presampled modulation transfer function is strongly affected by the detector's large pitch and a large improvement can be obtained by reducing the detector pitch. The measured detective quantum efficiency at zero spatial frequency is 18.8% for 6 MV photons which will reduce the dose to the patient in MVCT applications. The detector shows a less than a 2% reduction in response for a dose of 24.5 Gy accumulated in 2 h; however, the lost response is recovered on the following day. A complete recovery can be assumed within the experimental uncertainty (standard deviation <0.5%); however, any smaller permanent damage could not be assessed.

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

Paclitaxel and carboplatin in early phase studies: Roswell Park Cancer Institute experience in the subset of patients with lung cancer.

PubMed

Creaven, P J; Raghavan, D; Pendyala, L; Loewen, G; Kindler, H L; Berghorn, E J

1997-08-01

The combination of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given by 3-hour infusion followed by carboplatin infused over 30 minutes has been evaluated in a series of phase I studies and is currently being explored in a phase II study in patients with limited- and extensive-stage small cell lung cancer. Pharmacokinetic measurements were performed at all dose levels in the phase I studies, in which the use of granulocyte colony-stimulating factor in previously treated patients enabled more than twice the dose of paclitaxel to be given with low to moderate doses of carboplatin (dosed to a target area under the concentration-time curve of 4.0 mg x min x mL[-1]). Treatment-naive patients tolerated high paclitaxel doses (270 mg/m2) with carboplatin (dosed to a target area under the curve of 4.5 mg x min x mL[-1]) without granulocyte colony-stimulating factor support. Twenty-three patients (including previously treated and untreated) with non-small cell lung cancer were entered at a variety of paclitaxel doses in the phase I studies. At 100 to 205 mg/m2 paclitaxel, none of nine treated patients responded; at 230 to 290 mg/m2, four (29%) of 14 responded. In the phase II study of paclitaxel 250 mg/m2 in previously untreated patients with small cell lung cancer, two of five evaluable patients with extensive-stage disease have shown a partial response. In a preliminary analysis of the pharmacodynamics of paclitaxel in relation to neurotoxicity (dose limiting in two of three phase I studies), neurotoxicity correlated with the total dose of paclitaxel, the area under the curve, and the peak paclitaxel concentration, but not with the length of time plasma paclitaxel levels remained above 0.05 micromol/L. These correlations were not strong, however, and analysis of these data is ongoing.

Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology.

PubMed

Robinson, Joshua F; Theunissen, Peter T; van Dartel, Dorien A M; Pennings, Jeroen L; Faustman, Elaine M; Piersma, Aldert H

2011-09-01

Toxicogenomic evaluations may improve toxicity prediction of in vitro-based developmental models, such as whole embryo culture (WEC) and embryonic stem cells (ESC), by providing a robust mechanistic marker which can be linked with responses associated with developmental toxicity in vivo. While promising in theory, toxicogenomic comparisons between in vivo and in vitro models are complex due to inherent differences in model characteristics and experimental design. Determining factors which influence these global comparisons are critical in the identification of reliable mechanistic-based markers of developmental toxicity. In this study, we compared available toxicogenomic data assessing the impact of the known teratogen, methylmercury (MeHg) across a diverse set of in vitro and in vivo models to investigate the impact of experimental variables (i.e. model, dose, time) on our comparative assessments. We evaluated common and unique aspects at both the functional (Gene Ontology) and gene level of MeHg-induced response. At the functional level, we observed stronger similarity in MeHg-response between mouse embryos exposed in utero (2 studies), ESC, and WEC as compared to liver, brain and mouse embryonic fibroblast MeHg studies. These findings were strongly correlated to the presence of a MeHg-induced developmentally related gene signature. In addition, we identified specific MeHg-induced gene expression alterations associated with developmental signaling and heart development across WEC, ESC and in vivo systems. However, the significance of overlap between studies was highly dependent on traditional experimental variables (i.e. dose, time). In summary, we identify promising examples of unique gene expression responses which show in vitro-in vivo similarities supporting the relevance of in vitro developmental models for predicting in vivo developmental toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

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

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

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

1990-02-01

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

Lot-to-lot consistency study of the fully liquid pentavalent DTwP-HepB-Hib vaccine Quinvaxem® demonstrating clinical equivalence, suitability of the vaccine as a booster and concomitant administration with measles vaccine

PubMed Central

Aspinall, Sanet; Traynor, Deirdre; Bedford, Philip; Hartmann, Katharina

2012-01-01

This double-blind, randomized study evaluated the immunogenicity and safety of three production lots of the fully liquid combination DTwP-Hep-Hib vaccine, Quinvaxem® (Crucell, The Netherlands) in 360 healthy infants aged 42–64 d old given at 6, 10 and 14 weeks of age (Core Study). The Core Study was followed by an open-label Booster Phase evaluating immunogenicity and safety of a booster dose of Quinvaxem® given with either concomitant or deferred measles vaccine in 227 infants who completed the Core Study. One month after the third dose of Quinvaxem® immune responses reflecting seroprotection or seroconversion were observed in more than 90% of infants for all three vaccine lots. Quinvaxem® elicited a strong booster response as demonstrated by a large increase in antibodies against all antigens, which appeared to be unaffected by concomitant administration of the measles vaccine. Safety results were in line with previous reports for Quinvaxem® with no unexpected adverse events (AEs) being reported. In the Core Study and Booster Phase, Quinvaxem® was well tolerated. No study vaccine-related serious AEs were reported. Thus, Quinvaxem® was immunogenic and well-tolerated when administered to infants according to a 6–10–14 week vaccination schedule. The three production lots had consistent reactogenicity and immunogenicity profiles. The booster dose of Quinvaxem® was also immunogenic and safe, regardless of whether a monovalent measles vaccine was administered concomitantly or one month later. PMID:22854660

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.

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.

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

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

PubMed Central

2011-01-01

Background Hydroxyurea (HU) is the first approved pharmacological treatment of sickle cell anemia (SCA). The objectives of this study were to develop population pharmacokinetic(PK)-pharmacodynamic(PD) models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF%) and mean corpuscular volume (MCV) were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV)) of clearance was 11.6 L/h (30%), the central volume was 45.3 L (35%). PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%); the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and to pharmacodynamics. The steady-state value of MCV at month 3 is not predictive of the HbF% value at month 26. Hence, HbF% level may be a better biomarker for monitoring HU treatment. Continuous dosing might be more advantageous in terms of HbF% for patients who have a strong response to HU. Trial Registration The clinical studies whose data are analysed and reported in this work were not required to be registered in France at their time. Both studies were approved by local ethics committees (of Mondor Hospital and of Kremlin-Bicetre Hospital) and written informed consent was obtained from each patient. PMID:21619673

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.

Androstenedione response to recombinant human FSH is the most valid predictor of the number of selected follicles in polycystic ovarian syndrome: (a case-control study).

PubMed

Ozyurek, Eser Sefik; Yoldemir, Tevfik; Artar, Gokhan

2017-05-12

We aimed to test the hypothesis that the correlation of the changes in the blood Androstenedione (A 4 ) levels to the number of selected follicles during ovulation induction with low-dose recombinant human follicle stimulating hormone (rhFSH) is as strong as the correlation to changes in the blood Estradiol (E 2 ) levels in polycystic ovary syndrome (PCOS). Prospective Case-control study conducted from October 2014 to January 2016. 61 non-PCOS control (Group I) and 46 PCOS (Group II) patients treated with the chronic low-dose step up protocosl with rhFSH. A 4 , E 2 , progesterone blood levels and follicular growth were monitored.. Univariate and hierarchical multivariable analysis were performed for age, BMI, HOMA-IR, A 4 and E 2 (with the number of selected follicles as the dependent variable in both groups). ROC analysis was performed to define threshold values for the significant determinants of the number of selected follicles to predict cyle cancellations due to excessive ovarian response. The control group (Group I) was comprised of 61 cycles from a group of primary infertile non-PCOS patients, and the study group (Group II) of 46 cycles of PCOS patients. The analysis revealed that the strongest independent predictor of the total number of selected follicles in Group I was the E 2 (AUC) (B = 0.0006[0.0003-0.001]; P < 0.001); whereas for Group II, it was the A 4 (AUC) (B = 0.114[0.04-0.25]; P = 0.01). Optimum thresholds for the A 4 related parameters were defined to predict excessive response within Group II were 88.7%, 3.1 ng/mL and 5.4 ng*days for the percentage increase in A 4 , the maximum A 4 value and area under the curve values for A 4 , respectively. A 4 response to low-dose rhFSH in PCOS has a stronger association with the number of follicles selected than the E 2 reponse. A 4 response preceding the E 2 response is essential for progressive follicle development. Monitoring A 4 rather than E 2 may be more preemptive to define the initial ovarian response and accurate titration of the rhFSH doses. The study was registered as a prospective case-control study in the ClinicalTrials.gov registry with the identifier NCT02329483 .

The 5-HT(2C) receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity.

PubMed

Harvey-Lewis, Colin; Li, Zhaoxia; Higgins, Guy A; Fletcher, Paul J

2016-02-01

Lorcaserin (Lorqess, Belviq(®)) is a selective 5-HT(2C) receptor agonist that has received FDA approval for the treatment of obesity. 5-HT(2C) receptor agonists are also efficacious in decreasing multiple aspects of cocaine motivation and reward in preclinical models. This would suggest that lorcaserin is a clinically available therapeutic with the potential to treat cocaine addiction. Here we report the effects of lorcaserin (0.1 mg/kg-1.0 mg/kg) on multiple aspects of cocaine-related behaviours in rats. We find that lorcaserin dose-dependently decreases cocaine self-administration on progressive and fixed ratio schedules of reinforcement. Lorcaserin also reduces reinstatement of cocaine-seeking behaviour in response to priming injections of cocaine and/or reintroduction of cocaine-associated cues. Finally, lorcaserin dose-dependently decreases cocaine-induced hyperlocomotion. Our results, when considered in concert with similar emergent findings in non-human primates, strongly support continued research into the potential of lorcaserin as a clinical treatment for cocaine addiction. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

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.

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.

TLR7 imidazoquinoline ligand 3M-019 is a potent adjuvant for pure protein prototype vaccines.

PubMed

Johnston, Dean; Zaidi, Bushra; Bystryn, Jean-Claude

2007-08-01

Cancer vaccines, while theoretically attractive, present difficult challenges that must be overcome to be effective. Cancer vaccines are often poorly immunogenic and may require augmentation of immunogenicity through the use of adjuvants and/or immune response modifiers. Toll-like receptor (TLR) ligands are a relatively new class of immune response modifiers that may have great potential in inducing and augmenting both cellular and humoral immunity to vaccines. TLR7 ligands produce strong cellular responses and specific IgG2a and IgG2b antibody responses to protein immunogens. This study shows that a new TLR7 ligand, 3M-019, in combination with liposomes produces very strong immune responses to a pure protein prototype vaccine in mice. Female C57BL/6 mice were immunized subcutaneously with ovalbumin (OVA, 0.1 mg/dose) weekly 4x. Some groups were immunized to OVA plus 3M-019 or to OVA plus 3M-019 encapsulated in liposomes. Both antibody and cellular immune responses against OVA were measured after either two or four immunizations. Anti-OVA IgG antibody responses were significantly increased after two immunizations and were substantially higher after four immunizations in mice immunized with OVA combined with 3M-019. Encapsulation in liposomes further augmented antibody responses. IgM responses, on the other hand, were lowered by 3M-019. OVA-specific IgG2a levels were increased 625-fold by 3M-019 in liposomes compared to OVA alone, while anti-OVA IgG2b levels were over 3,000 times higher. In both cases encapsulation of 3M-019 in liposomes was stronger than either liposomes alone or 3M-019 without liposomes. Cellular immune responses were likewise increased by 3M-019 but further enhanced when it was encapsulated in liposomes. The lack of toxicity also indicates that this combination may by safe, effective method to boost immune response to cancer vaccines.

MO-F-CAMPUS-J-05: Using 2D Relative Gamma Analysis From EPID Image as a Predictor of Plan Deterioration Due to Anatomical Changes

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

Piron, O; Varfalvy, N; Archambault, L

2015-06-15

Purpose: One of the side effects of radiotherapy for head and neck (H&N) cancer is the patient’s anatomical changes. The changes can strongly affect the planned dose distribution. In this work, our goal is to demonstrate that relative analysis of EPID images is a fast and simple method to detect anatomical changes that can have a strong dosimetric impact on the treatment plan for H&N patients. Methods: EPID images were recorded at every beam and all fractions for 50 H&N patients. Of these, five patients that showed important anatomical changes were selected to evaluate dosimetric impacts of these changes andmore » to correlate them with a 2D relative gamma analysis of EPID images. The planning CT and original contours were deformed onto CBCTs (one mid treatment and one at the end of treatment). By using deformable image registration, it was possible to map accurate CT numbers from the planning CT to the anatomy of the day obtained with CBCTs. Clinical treatment plan were then copied on the deformed dataset and dose was re-computed. In parallel, EPID images were analysed using the gamma index (3%3mm) relative to the first image. Results: It was possible to divide patients in two distinct, statistically different (p<0.001) categories using an average gamma index of 0.5 as a threshold. Below this threshold no significant dosimetric degradation of the plan are observed. Above this threshold two types of plan deterioration were seen: (1) target dose increases, but coverage remains adequate while dose to at least one OAR increases beyond tolerances; (2) the OAR doses remain low, but the target dose is reduced and coverage becomes inadequate. Conclusion: Relative analysis gamma of EPID images could indeed be a fast and simple method to detect anatomical changes that can potentially deteriorates treatment plan for H&N patients. This work was supported in part by Varian Medical System.« less

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.

Acid Hydrolysis of Wheat Gluten Induces Formation of New Epitopes but Does Not Enhance Sensitizing Capacity by the Oral Route: A Study in “Gluten Free” Brown Norway Rats

PubMed Central

Kroghsbo, Stine; Andersen, Nanna B.; Rasmussen, Tina F.; Madsen, Charlotte B.

2014-01-01

Background Acid hydrolyzed wheat proteins (HWPs) are used in the food and cosmetic industry as emulsifiers. Cases of severe food allergic reactions caused by HWPs have been reported. Recent data suggest that these reactions are caused by HWPs produced by acid hydrolysis. Objectives To examine the sensitizing capacity of gluten proteins per se when altered by acid or enzymatic hydrolysis relative to unmodified gluten in rats naïve to gluten. Methods High IgE-responder Brown Norway (BN) rats bred on a gluten-free diet were sensitized without the use of adjuvant to three different gluten products (unmodified, acid hydrolyzed and enzymatic hydrolyzed). Rats were sensitized by intraperitoneal (i.p.) immunization three times with 200 µg gluten protein/rat or by oral dosing for 35 days with 0.2, 2 or 20 mg gluten protein/rat/day. Sera were analyzed for specific IgG and IgE and IgG-binding capacity by ELISA. IgE functionality was measured by rat basophilic leukemia (RBL) assay. Results Regardless of the route of dosing, all products had sensitizing capacity. When sensitized i.p., all three gluten products induced a strong IgG1 response in all animals. Acid hydrolyzed gluten induced the highest level of specific IgE but with a low functionality. Orally all three gluten products induced specific IgG1 and IgE but with different dose-response relations. Sensitizing rats i.p. or orally with unmodified or enzymatic hydrolyzed gluten induced specific IgG1 responses with similar binding capacity which was different from that of acid hydrolyzed gluten indicating that acid hydrolysis of gluten proteins induces formation of ‘new’ epitopes. Conclusions In rats not tolerant to gluten acid hydrolysis of gluten enhances the sensitizing capacity by the i.p. but not by the oral route. In addition, acid hydrolysis induces formation of new epitopes. This is in contrast to the enzymatic hydrolyzed gluten having an epitope pattern similar to unmodified gluten. PMID:25207551

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

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

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

2016-06-15

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

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

Linear β-1,3 Glucans Are Elicitors of Defense Responses in Tobacco

PubMed Central

Klarzynski, Olivier; Plesse, Bertrand; Joubert, Jean-Marie; Yvin, Jean-Claude; Kopp, Marguerite; Kloareg, Bernard; Fritig, Bernard

2000-01-01

Laminarin, a linear β-1,3 glucan (mean degree of polymerization of 33) was extracted and purified from the brown alga Laminaria digitata. Its elicitor activity on tobacco (Nicotiana tabacum) was compared to that of oligogalacturonides with a mean degree of polymerization of 10. The two oligosaccharides were perceived by suspension-cultured cells as distinct chemical stimuli but triggered a similar and broad spectrum of defense responses. A dose of 200 μg mL−1 laminarin or oligogalacturonides induced within a few minutes a 1.9-pH-units alkalinization of the extracellular medium and a transient release of H2O2. After a few hours, a strong stimulation of Phe ammonia-lyase, caffeic acid O-methyltransferase, and lipoxygenase activities occurred, as well as accumulation of salicylic acid. Neither of the two oligosaccharides induced tissue damage or cell death nor did they induce accumulation of the typical tobacco phytoalexin capsidiol, in contrast with the effects of the proteinaceous elicitor β-megaspermin. Structure activity studies with laminarin, laminarin oligomers, high molecular weight β-1,3–1,6 glucans from fungal cell walls, and the β-1,6–1,3 heptaglucan showed that the elicitor effects observed in tobacco with β-glucans are specific to linear β-1,3 linkages, with laminaripentaose being the smallest elicitor-active structure. In accordance with its strong stimulating effect on defense responses in tobacco cells, infiltration of 200 μg mL−1 laminarin in tobacco leaves triggered accumulation within 48 h of the four families of antimicrobial pathogenesis-related proteins investigated. Challenge of the laminarin-infiltrated leaves 5 d after treatment with the soft rot pathogen Erwinia carotovora subsp. carotovora resulted in a strong reduction of the infection when compared with water-treated leaves. PMID:11080280

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.

Safety and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (IMOJEV®) in children.

PubMed

Chokephaibulkit, K; Houillon, G; Feroldi, E; Bouckenooghe, A

2016-01-01

JE-CV (IMOJEV®, Sanofi Pasteur, France) is a live attenuated virus vaccine constructed by inserting coding sequences of the prM and E structural proteins of the Japanese encephalitis SA14-14-2 virus into the genome of yellow fever 17D virus. Primary immunization with JE-CV requires a single dose of the vaccine. This article reviews clinical trials of JE-CV in children aged up to 6 years conducted in countries across South-East Asia. Strong and persistent antibody responses were observed after single primary and booster doses, with 97% of children seroprotected up to five years after booster vaccination. Models of long-term antibody persistence predict a median duration of protection of approximately 30 years after a booster dose. The safety and reactogenicity profiles of JE-CV primary and booster doses are comparable to other widely used childhood vaccines.

A glycoprotein subunit vaccine elicits a strong Rift Valley fever virus neutralizing antibody response in sheep.

PubMed

Faburay, Bonto; Lebedev, Maxim; McVey, D Scott; Wilson, William; Morozov, Igor; Young, Alan; Richt, Juergen A

2014-10-01

Rift Valley fever virus (RVFV), a member of the Bunyaviridae family, is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. The recent spread of the virus beyond its traditional endemic boundaries in Africa to the Arabian Peninsula coupled with the presence of susceptible vectors in nonendemic countries has created increased interest in RVF vaccines. Subunit vaccines composed of specific virus proteins expressed in eukaryotic or prokaryotic expression systems are shown to elicit neutralizing antibodies in susceptible hosts. RVFV structural proteins, amino-terminus glycoprotein (Gn), and carboxyl-terminus glycoprotein (Gc), were expressed using a recombinant baculovirus expression system. The recombinant proteins were reconstituted as a GnGc subunit vaccine formulation and evaluated for immunogenicity in a target species, sheep. Six sheep were each immunized with a primary dose of 50 μg of each vaccine immunogen with the adjuvant montanide ISA25; at day 21, postvaccination, each animal received a second dose of the same vaccine. The vaccine induced a strong antibody response in all animals as determined by indirect enzyme-linked immunosorbent assay (ELISA). A plaque reduction neutralization test (PRNT80) showed the primary dose of the vaccine was sufficient to elicit potentially protective virus neutralizing antibody titers ranging from 40 to 160, and the second vaccine dose boosted the titer to more than 1280. Furthermore, all animals tested positive for neutralizing antibodies at day 328 postvaccination. ELISA analysis using the recombinant nucleocapsid protein as a negative marker antigen indicated that the vaccine candidate is DIVA (differentiating infected from vaccinated animals) compatible and represents a promising vaccine platform for RVFV infection in susceptible species.

A Glycoprotein Subunit Vaccine Elicits a Strong Rift Valley Fever Virus Neutralizing Antibody Response in Sheep

PubMed Central

Lebedev, Maxim; McVey, D. Scott; Wilson, William; Morozov, Igor; Young, Alan

2014-01-01

Abstract Rift Valley fever virus (RVFV), a member of the Bunyaviridae family, is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. The recent spread of the virus beyond its traditional endemic boundaries in Africa to the Arabian Peninsula coupled with the presence of susceptible vectors in nonendemic countries has created increased interest in RVF vaccines. Subunit vaccines composed of specific virus proteins expressed in eukaryotic or prokaryotic expression systems are shown to elicit neutralizing antibodies in susceptible hosts. RVFV structural proteins, amino-terminus glycoprotein (Gn), and carboxyl-terminus glycoprotein (Gc), were expressed using a recombinant baculovirus expression system. The recombinant proteins were reconstituted as a GnGc subunit vaccine formulation and evaluated for immunogenicity in a target species, sheep. Six sheep were each immunized with a primary dose of 50 μg of each vaccine immunogen with the adjuvant montanide ISA25; at day 21, postvaccination, each animal received a second dose of the same vaccine. The vaccine induced a strong antibody response in all animals as determined by indirect enzyme-linked immunosorbent assay (ELISA). A plaque reduction neutralization test (PRNT80) showed the primary dose of the vaccine was sufficient to elicit potentially protective virus neutralizing antibody titers ranging from 40 to 160, and the second vaccine dose boosted the titer to more than 1280. Furthermore, all animals tested positive for neutralizing antibodies at day 328 postvaccination. ELISA analysis using the recombinant nucleocapsid protein as a negative marker antigen indicated that the vaccine candidate is DIVA (differentiating infected from vaccinated animals) compatible and represents a promising vaccine platform for RVFV infection in susceptible species. PMID:25325319

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 Risk of Cataract among Survivors of Childhood and Adolescent Cancer: A Report from the Childhood Cancer Survivor Study

PubMed Central

Chodick, Gabriel; Sigurdson, Alice J.; Kleinerman, Ruth A.; Sklar, Charles A.; Leisenring, Wendy; Mertens, Ann C.; Stovall, Marilyn; Smith, Susan A.; Weathers, Rita E.; Veiga, Lene H. S.; Robison, Leslie L.; Inskip, Peter D.

2016-01-01

With therapeutic successes and improved survival after a cancer diagnosis in childhood, increasing numbers of cancer survivors are at risk of subsequent treatment-related morbidities, including cataracts. While it is well known that the lens of the eye is one of the most radiosensitive tissues in the human body, the risks associated with radiation doses less than 2 Gy are less understood, as are the long- and short-term cataract risks from exposure to ionizing radiation at a young age. In this study, we followed 13,902 five-year survivors of childhood cancer in the Childhood Cancer Survivor Study cohort an average of 21.4 years from the date of first cancer diagnosis. For patients receiving radiotherapy, lens dose (mean: 2.2 Gy; range: 0–66 Gy) was estimated based on radiotherapy records. We used unconditional multivariable logistic regression models to evaluate prevalence of self-reported cataract in relationship to cumulative radiation dose both at five years after the initial cancer diagnosis and at the end of follow-up. We modeled the radiation effect in terms of the excess odds ratio (EOR) per Gy. We also analyzed cataract incidence starting from five years after initial cancer diagnosis to the end of follow-up using Cox regression. A total of 483 (3.5%) cataract cases were identified, including 200 (1.4%) diagnosed during the first five years of follow-up. In a multivariable logistic regression model, cataract prevalence at the end of follow-up was positively associated with lens dose in a manner consistent with a linear dose-response relationship (EOR per Gy = 0.92; 95% CI: 0.65–1.20). The odds ratio for doses between 0.5 and 1.5 Gy was elevated significantly relative to doses <0.5 Gy (OR = 2.2; 95% CI: 1.3–3.7). The results from this study indicate a strong association between ocular exposure to ionizing radiation and long-term risk of pre-senile cataract. The risk of cataract increased with increasing exposure, beginning at lens doses as low as 0.5 Gy. Our findings are in agreement with a growing body of evidence of an elevated risk for lens opacities in populations exposed to doses of ionizing radiation below the previously suggested threshold level of 2 Gy. PMID:27023263

Acute subjective response to alcohol as a function of reward and punishment sensitivity.

PubMed

Morris, David H; Treloar, Hayley; Tsai, Chia-Lin; McCarty, Kayleigh N; McCarthy, Denis M

2016-09-01

Individual differences in subjective response to alcohol play a crucial role in the development of heavy drinking and related problems. In light of this, a growing focus of research has been identifying factors that contribute to differences in response. The aim of the present study was to determine whether individual differences in the subjective experience of rewarding and aversive effects of alcohol are a specific manifestation of general differences in reward and punishment sensitivity. Eighty-nine participants (M age=22.4, SD=1.9; 47.2% women) consumed a moderate dose of alcohol, i.e., peak breath alcohol concentration (BrAC)≈0.080g%, and rated their level of stimulation and sedation at seven timepoints over the BrAC curve. Sensitivity to reward and punishment were assessed by a self-report questionnaire prior to consumption. Multilevel growth models showed that post-consumption changes in stimulation ratings varied as a function of participants' level of reward and punishment sensitivity. Drinkers more sensitive to reward reported feeling more stimulated shortly after drinking and exhibited an attenuated rate of decline in stimulation over the blood alcohol curve, relative to drinkers with less strong reward sensitivity. Reward sensitivity was not related to subjective ratings of sedation, and punishment sensitivity was not related to either stimulation or sedation ratings. Findings suggest that reward sensitivity may increase risk for alcohol misuse among young adult social drinkers by increasing their subjective feelings of stimulation while drinking. Copyright © 2016. Published by Elsevier Ltd.

Radiation effects in Caenorhabditis elegans - Mutagenesis by high and low LET ionizing radiation

NASA Technical Reports Server (NTRS)

Nelson, Gregory A.; Schubert, Wayne W.; Marshall, Tamara M.; Benton, Eric R.; Benton, Eugene V.

1989-01-01

The nematode C. elegans was used to measure the effectiveness of high-energy ionized particles in the induction of three types of genetic lesions. Recessive lethal mutations in a 40-map unit autosomal region, sterility, and X-chromosome nondisjunction or damage were investigated. Induction rates were measured as a function of linear energy transfer, LET(infinity), for nine ions of atomic nunmber 1-57 accelerated at the BEVALAC accelerator. Linear kinetics were observed for all three types of lesions within the dose/fluence ranges tested and were found to vary strongly as a function of particle LET(infinity). Relative biological effectiveness (RBE) values of up to 4.2 were measured, and action cross sections were calculated and compared to mutagenic responses in other systems.

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.

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.

Impacts of nitrogen addition on plant biodiversity in mountain grasslands depend on dose, application duration and climate: a systematic review.

PubMed

Humbert, Jean-Yves; Dwyer, John M; Andrey, Aline; Arlettaz, Raphaël

2016-01-01

Although the influence of nitrogen (N) addition on grassland plant communities has been widely studied, it is still unclear whether observed patterns and underlying mechanisms are constant across biomes. In this systematic review, we use meta-analysis and metaregression to investigate the influence of N addition (here referring mostly to fertilization) upon the biodiversity of temperate mountain grasslands (including montane, subalpine and alpine zones). Forty-two studies met our criteria of inclusion, resulting in 134 measures of effect size. The main general responses of mountain grasslands to N addition were increases in phytomass and reductions in plant species richness, as observed in lowland grasslands. More specifically, the analysis reveals that negative effects on species richness were exacerbated by dose (ha(-1) year(-1) ) and duration of N application (years) in an additive manner. Thus, sustained application of low to moderate levels of N over time had effects similar to short-term application of high N doses. The climatic context also played an important role: the overall effects of N addition on plant species richness and diversity (Shannon index) were less pronounced in mountain grasslands experiencing cool rather than warm summers. Furthermore, the relative negative effect of N addition on species richness was more pronounced in managed communities and was strongly negatively related to N-induced increases in phytomass, that is the greater the phytomass response to N addition, the greater the decline in richness. Altogether, this review not only establishes that plant biodiversity of mountain grasslands is negatively affected by N addition, but also demonstrates that several local management and abiotic factors interact with N addition to drive plant community changes. This synthesis yields essential information for a more sustainable management of mountain grasslands, emphasizing the importance of preserving and restoring grasslands with both low agricultural N application and limited exposure to N atmospheric deposition. © 2015 John Wiley & Sons Ltd.

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.

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.

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.

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.

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.

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.

An exploratory, open-label, randomized, multicenter study to investigate the pharmacodynamics of a glycoengineered antibody (imgatuzumab) and cetuximab in patients with operable head and neck squamous cell carcinoma.

PubMed

Temam, S; Spicer, J; Farzaneh, F; Soria, J C; Oppenheim, D; McGurk, M; Hollebecque, A; Sarini, J; Hussain, K; Soehrman Brossard, S; Manenti, L; Evers, S; Delmar, P; Di Scala, L; Mancao, C; Feuerhake, F; Andries, L; Ott, M G; Passioukov, A; Delord, J P

2017-11-01

In addition to inhibiting epidermal growth factor receptor (EGFR) signaling, anti-EGFR antibodies of the IgG1 'subtype' can induce a complementary therapeutic effect through the induction of antibody-dependent cell-mediated cytotoxicity (ADCC). Glycoengineering of therapeutic antibodies increases the affinity for the Fc-gamma receptor, thereby enhancing ADCC. We investigated the changes in immune effector cells and EGFR pathway biomarkers in 44 patients with operable, advanced stage head and neck squamous cell carcinoma treated with two preoperative doses of either glycoengineered imgatuzumab (GA201; 700 or 1400 mg) or cetuximab (standard dosing) in a neoadjuvant setting with paired pre- and post-treatment tumor biopsies. Significant antitumor activity was observed with both antibodies after just two infusions. Metabolic responses were seen in 23 (59.0%) patients overall. One imgatuzumab-treated patient (700 mg) achieved a 'pathological' complete response. An immediate and sustained decrease in peripheral natural killer cells was consistently observed with the first imgatuzumab infusion but not with cetuximab. The functionality of the remaining peripheral natural killer cells was maintained. Similarly, a pronounced increase in circulating cytokines was seen following the first infusion of imgatuzumab but not cetuximab. Overall, tumor-infiltrating CD3+ cell counts increased following treatment with both antibodies. A significant increase from baseline in CD3+/perforin+ cytotoxic T cells occurred only in the 700-mg imgatuzumab group (median 95% increase, P < 0.05). The most prominent decrease of EGFR-expressing cells was recorded after treatment with imgatuzumab (700 mg, -34.6%; 1400 mg, -41.8%). The post-treatment inflammatory tumor microenvironment was strongly related to baseline tumor-infiltrating immune cell density, and baseline levels of EGFR and pERK in tumor cells most strongly predicted therapeutic response. These pharmacodynamic observations and relationship with efficacy are consistent with the proposed mode of action of imgatuzumab combining efficient EGFR pathway inhibition with ADCC-related immune antitumor effects. NCT01046266 (ClinicalTrials.gov). © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Efficacy of radiation safety glasses in interventional radiology.

PubMed

van Rooijen, Bart D; de Haan, Michiel W; Das, Marco; Arnoldussen, Carsten W K P; de Graaf, R; van Zwam, Wim H; Backes, Walter H; Jeukens, Cécile R L P N

2014-10-01

This study was designed to evaluate the reduction of the eye lens dose when wearing protective eyewear in interventional radiology and to identify conditions that optimize the efficacy of radiation safety glasses. The dose reduction provided by different models of radiation safety glasses was measured on an anthropomorphic phantom head. The influence of the orientation of the phantom head on the dose reduction was studied in detail. The dose reduction in interventional radiological practice was assessed by dose measurements on radiologists wearing either leaded or no glasses or using a ceiling suspended screen. The different models of radiation safety glasses provided a dose reduction in the range of a factor of 7.9-10.0 for frontal exposure of the phantom. The dose reduction was strongly reduced when the head is turned to the side relative to the irradiated volume. The eye closest to the tube was better protected due to side shielding and eyewear curvature. In clinical practice, the mean dose reduction was a factor of 2.1. Using a ceiling suspended lead glass shield resulted in a mean dose reduction of a factor of 5.7. The efficacy of radiation protection glasses depends on the orientation of the operator's head relative to the irradiated volume. Glasses can offer good protection to the eye under clinically relevant conditions. However, the performance in clinical practice in our study was lower than expected. This is likely related to nonoptimized room geometry and training of the staff as well as measurement methodology.

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

Reanalysis of the start of the UK 1967 to 1968 foot-and-mouth disease epidemic to calculate airborne transmission probabilities.

PubMed

Sanson, R L; Gloster, J; Burgin, L

2011-09-24

The aims of this study were to statistically reassess the likelihood that windborne spread of foot-and-mouth disease (FMD) virus (FMDV) occurred at the start of the UK 1967 to 1968 FMD epidemic at Oswestry, Shropshire, and to derive dose-response probability of infection curves for farms exposed to airborne FMDV. To enable this, data on all farms present in 1967 in the parishes near Oswestry were assembled. Cases were infected premises whose date of appearance of first clinical signs was within 14 days of the depopulation of the index farm. Logistic regression was used to evaluate the association between infection status and distance and direction from the index farm. The UK Met Office's NAME atmospheric dispersion model (ADM) was used to generate plumes for each day that FMDV was excreted from the index farm based on actual historical weather records from October 1967. Daily airborne FMDV exposure rates for all farms in the study area were calculated using a geographical information system. Probit analyses were used to calculate dose-response probability of infection curves to FMDV, using relative exposure rates on case and control farms. Both the logistic regression and probit analyses gave strong statistical support to the hypothesis that airborne spread occurred. There was some evidence that incubation period was inversely proportional to the exposure rate.

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

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

5-HT receptor subtypes as key targets in mediating pigment dispersion within melanophores of teleost, Oreochromis mossambicus.

PubMed

Salim, Saima; Ali, Ayesha S; Ali, Sharique A

2013-02-01

The presence of distinct class of 5-HT receptors in the melanophores of tilapia (Oreochromis mossambicus) is reported. The cellular responses to 5-HT (5-hydroxytryptamine), 5-HT(1), and 5-HT(2), agonists on isolated scale melanophores were observed with regard to pigment translocation within the cells. It was found that 5-HT exerted rapid and strong concentration dependent pigment granule dispersion within the melanophores. The threshold pharmacological dose of 5-HT that could elicit a measurable response was as low as 4.7×10(-12) M/L. Selective 5-HT(1) and 5-HT(2) agonists, sumatriptan and myristicin were investigated and resulted in dose-dependent pigment dispersion. The dispersing effects were effectively antagonized by receptor specific antagonists. It is suggested that 5-HT-induced physiological effects are mediated via distinct classes of receptors that possibly participate in modulation of pigmentary responses of the fish. Copyright © 2012 Elsevier Inc. All rights reserved.

The validated sun exposure questionnaire: association of objective and subjective measures of sun exposure in a Danish population-based sample.

PubMed

Køster, B; Søndergaard, J; Nielsen, J B; Allen, M; Olsen, A; Bentzen, J

2017-02-01

Few questionnaires used in monitoring sun-related behaviour have been tested for validity. We established the criteria validity of a questionnaire developed for monitoring population sun-related behaviour. During May-August 2013, 664 Danes wore a personal electronic ultraviolet radiation (UVR) dosimeter for 1 week that measured their outdoor time and dose of erythemal UVR exposure. In the following week, they answered a questionnaire on their sun-related behaviour in the measurement week. Outdoor time measured by dosimetry correlated strongly with both outdoor time and the developed exposure scale measured in the questionnaire. Exposure measured in standard erythema dose (SED) by dosimetry correlated strongly with the exposure scale. In a linear regression model of UVR (SED) received, 41% of the variation was explained by skin type, age, week of participation and exposure scale, with exposure scale as the main contributor. The weekly sunburn fraction correlated strongly with the number of ambient sun hours (r = 0·73, P < 0·001). This criteria-validated questionnaire provides evidence of the exposure that the questionnaire aimed to measure. The evidence provided showed a strong link between the objectively measured behaviour and the behaviour measured by this survey construct. The questionnaire is the first validated tool to measure the UVR exposure in a national population-based sample. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Monte Carlo simulations and benchmark measurements on the response of TE(TE) and Mg(Ar) ionization chambers in photon, electron and neutron beams

NASA Astrophysics Data System (ADS)

Lin, Yi-Chun; Huang, Tseng-Te; Liu, Yuan-Hao; Chen, Wei-Lin; Chen, Yen-Fu; Wu, Shu-Wei; Nievaart, Sander; Jiang, Shiang-Huei

2015-06-01

The paired ionization chambers (ICs) technique is commonly employed to determine neutron and photon doses in radiology or radiotherapy neutron beams, where neutron dose shows very strong dependence on the accuracy of accompanying high energy photon dose. During the dose derivation, it is an important issue to evaluate the photon and electron response functions of two commercially available ionization chambers, denoted as TE(TE) and Mg(Ar), used in our reactor based epithermal neutron beam. Nowadays, most perturbation corrections for accurate dose determination and many treatment planning systems are based on the Monte Carlo technique. We used general purposed Monte Carlo codes, MCNP5, EGSnrc, FLUKA or GEANT4 for benchmark verifications among them and carefully measured values for a precise estimation of chamber current from absorbed dose rate of cavity gas. Also, energy dependent response functions of two chambers were calculated in a parallel beam with mono-energies from 20 keV to 20 MeV photons and electrons by using the optimal simple spherical and detailed IC models. The measurements were performed in the well-defined (a) four primary M-80, M-100, M120 and M150 X-ray calibration fields, (b) primary 60Co calibration beam, (c) 6 MV and 10 MV photon, (d) 6 MeV and 18 MeV electron LINACs in hospital and (e) BNCT clinical trials neutron beam. For the TE(TE) chamber, all codes were almost identical over the whole photon energy range. In the Mg(Ar) chamber, MCNP5 showed lower response than other codes for photon energy region below 0.1 MeV and presented similar response above 0.2 MeV (agreed within 5% in the simple spherical model). With the increase of electron energy, the response difference between MCNP5 and other codes became larger in both chambers. Compared with the measured currents, MCNP5 had the difference from the measurement data within 5% for the 60Co, 6 MV, 10 MV, 6 MeV and 18 MeV LINACs beams. But for the Mg(Ar) chamber, the derivations reached 7.8-16.5% below 120 kVp X-ray beams. In this study, we were especially interested in BNCT doses where low energy photon contribution is less to ignore, MCNP model is recognized as the most suitable to simulate wide photon-electron and neutron energy distributed responses of the paired ICs. Also, MCNP provides the best prediction of BNCT source adjustment by the detector's neutron and photon responses.

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.

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

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.

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.

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

PubMed Central

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID:25692350

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study.

PubMed

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

Herbicide-related signaling in plants reveals novel insights for herbicide use strategies, environmental risk assessment and global change assessment challenges.

PubMed

Alberto, Diana; Serra, Anne-Antonella; Sulmon, Cécile; Gouesbet, Gwenola; Couée, Ivan

2016-11-01

Herbicide impact is usually assessed as the result of a unilinear mode of action on a specific biochemical target with a typical dose-response dynamics. Recent developments in plant molecular signaling and crosstalk between nutritional, hormonal and environmental stress cues are however revealing a more complex picture of inclusive toxicity. Herbicides induce large-scale metabolic and gene-expression effects that go far beyond the expected consequences of unilinear herbicide-target-damage mechanisms. Moreover, groundbreaking studies have revealed that herbicide action and responses strongly interact with hormone signaling pathways, with numerous regulatory protein-kinases and -phosphatases, with metabolic and circadian clock regulators and with oxidative stress signaling pathways. These interactions are likely to result in mechanisms of adjustment that can determine the level of sensitivity or tolerance to a given herbicide or to a mixture of herbicides depending on the environmental and developmental status of the plant. Such regulations can be described as rheostatic and their importance is discussed in relation with herbicide use strategies, environmental risk assessment and global change assessment challenges. Copyright © 2016 Elsevier B.V. All rights reserved.

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

Interaction between Salmonella typhimurium and phagocytic cells in pigs. Phagocytosis, oxidative burst and killing in polymorphonuclear leukocytes and monocytes.

PubMed

Riber, U; Lind, P

1999-02-22

Interactions between Salmonella typhimurium and peripheral blood leucocytes from healthy, Salmonella-free pigs were investigated in vitro. Both granulocytes and monocytes phagocytized FITC-labelled heat-killed Salmonella bacteria as shown by flow cytometry. Phagocytosis in whole blood and isolated leucocytes was measured as acquired fluorescence in the leukocytes and was both time and dose related. Living, serum-opsonized Salmonella bacteria induced a dose-dependent oxidative burst in PMNs and monocytes as measured by luminol-enhanced chemiluminescence (LC). When opsonized in normal serum the Salmonella bacteria, in the range of 2-5 x 10(7) cfu, induced a LC response in monocytes comparable to the level of responses induced by phorbol myristate acetate (PMA) and opsonized zymosan, and the Salmonella-induced response was only marginally reduced by superoxide dismutase (SOD). Intracellular killing of Salmonella by monocytes was assessed from plate colony counts of lysed monocytes and showed that Salmonella typhimurium was able to survive and proliferate in adherent monocytes in vitro despite a reduction in intracellular cfu during the first hour's incubation in cells from some pigs. Experiments with the exhaustion of oxidative burst in non-adherent monocytes were performed by prestimulation with PMA, heat-killed Salmonella or buffer. Prestimulation with PMA led to a strong reduction in oxidative burst induced by living opsonized Salmonella bacteria, whereas prestimulation with heat-killed bacteria gave rise to an enhanced response. In these experiments intracellular killing of the added living Salmonella gave variable results, in that monocytes from two out of three pigs showed no essential change in intracellular bactericidal activity, but with cells from one pig a less pronounced bactericidal activity was found after prestimulation with PMA.

An evidence-based analysis of epidemiologic associations between lymphatic and hematopoietic cancers and occupational exposure to gasoline.

PubMed

Keenan, J J; Gaffney, S; Gross, S A; Ronk, C J; Paustenbach, D J; Galbraith, D; Kerger, B D

2013-10-01

The presence of benzene in motor gasoline has been a health concern for potential increased risk of acute myelogenous leukemia and perhaps other lymphatic/hematopoietic cancers for approximately 40 years. Because of the widespread and increasing use of gasoline by consumers and the high exposure potential of occupational cohorts, a thorough understanding of this issue is important. The current study utilizes an evidence-based approach to examine whether or not the available epidemiologic studies demonstrate a strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers. Among 67 epidemiologic studies initially identified, 54 were ranked according to specific criteria relating to the relevance and robustness of each study for answering the research question. The 30 highest-ranked studies were sorted into three tiers of evidence and were analyzed for strength, specificity, consistency, temporality, dose-response trends and coherence. Meta statistics were also calculated for each general and specific lymphatic/hematopoietic cancer category with adequate data. The evidence-based analysis did not confirm any strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers based on the epidemiologic studies available to date. These epidemiologic findings, combined with the evidence showing relatively low occupational benzene vapor exposures associated with gasoline formulations during the last three decades, suggest that current motor gasoline formulations are not associated with increased lymphatic/hematopoietic cancer risks related to benzene.

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.

Biological and behavioral factors modify urinary arsenic metabolic profiles in a U.S. population.

PubMed

Hudgens, Edward E; Drobna, Zuzana; He, Bin; Le, X C; Styblo, Miroslav; Rogers, John; Thomas, David J

2016-05-26

Because some adverse health effects associated with chronic arsenic exposure may be mediated by methylated arsenicals, interindividual variation in capacity to convert inorganic arsenic into mono- and di-methylated metabolites may be an important determinant of risk associated with exposure to this metalloid. Hence, identifying biological and behavioral factors that modify an individual's capacity to methylate inorganic arsenic could provide insights into critical dose-response relations underlying adverse health effects. A total of 904 older adults (≥45 years old) in Churchill County, Nevada, who chronically used home tap water supplies containing up to 1850 μg of arsenic per liter provided urine and toenail samples for determination of total and speciated arsenic levels. Effects of biological factors (gender, age, body mass index) and behavioral factors (smoking, recent fish or shellfish consumption) on patterns of arsenicals in urine were evaluated with bivariate analyses and multivariate regression models. Relative contributions of inorganic, mono-, and di-methylated arsenic to total speciated arsenic in urine were unchanged over the range of concentrations of arsenic in home tap water supplies used by study participants. Gender predicted both absolute and relative amounts of arsenicals in urine. Age predicted levels of inorganic arsenic in urine and body mass index predicted relative levels of mono- and di-methylated arsenic in urine. Smoking predicted both absolute and relative levels of arsenicals in urine. Multivariate regression models were developed for both absolute and relative levels of arsenicals in urine. Concentration of arsenic in home tap water and estimated water consumption were strongly predictive of levels of arsenicals in urine as were smoking, body mass index, and gender. Relative contributions of arsenicals to urinary arsenic were not consistently predicted by concentrations of arsenic in drinking water supplies but were more consistently predicted by gender, body mass index, age, and smoking. These findings suggest that analyses of dose-response relations in arsenic-exposed populations should account for biological and behavioral factors that modify levels of inorganic and methylated arsenicals in urine. Evidence of significant effects of these factors on arsenic metabolism may also support mode of action studies in appropriate experimental models.

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.

Defence strategies and antibiotic resistance gene abundance in enterococci under stress by exposure to low doses of peracetic acid.

PubMed

Turolla, Andrea; Sabatino, Raffaella; Fontaneto, Diego; Eckert, Ester M; Colinas, Noemi; Corno, Gianluca; Citterio, Barbara; Biavasco, Francesca; Antonelli, Manuela; Mauro, Alessandro; Mangiaterra, Gianmarco; Di Cesare, Andrea

2017-10-01

Peracetic acid (PAA) is an organic compound used efficiently as disinfectant in wastewater treatments. Yet, at low doses it may cause selection; thus, the effect of low doses of PAA on Enterococcus faecium as a proxy of human-related microbial waste was evaluated. Bacteria were treated with increasing doses of PAA (from 0 to 25 mg L -1 min) and incubated in regrowth experiments under non-growing, limiting conditions and under growing, favorable conditions. The changes in bacterial abundance, in bacterial phenotype (number and composition of small cell clusters), and in the abundance of an antibiotic resistance gene (ARG) was evaluated. The experiment demonstrated that the selected doses of PAA efficiently removed enterococci, and induced a long-lasting effect after PAA inactivation. The relative abundance of small clusters increased during the experiment when compared with that of the inoculum. Moreover, under growing favorable conditions the relative abundance of small clusters decreased and the number of cells per cluster increased with increasing PAA doses. A strong stability of the measured ARG was found, not showing any effect during the whole experiment. The results demonstrated the feasibility of low doses of PAA to inactivate bacteria. However, the stress induced by PAA disinfection promoted a bacterial adaptation, even if potentially without affecting the abundance of the ARG. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacogenomics-guided policy in opioid use disorder (OUD) management: An ethnically-diverse case-based approach.

PubMed

Ettienne, Earl B; Chapman, Edwin; Maneno, Mary; Ofoegbu, Adaku; Wilson, Bradford; Settles-Reaves, Beverlyn; Clarke, Melissa; Dunston, Georgia; Rosenblatt, Kevin

2017-12-01

Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse. Clinical pharmacogenomics studies the effect that inherited genetic variations have on drug response. Our objective is to demonstrate the impact of pharmacogenetic testing on OUD management outcomes. We analyzed a patient who reported discomfort at daily buprenorphine dose of 24 mg, which was a mandated daily maximum by the pharmacy benefits manager. Regular urine screenings were conducted to detect the presence of unauthorized substances, and pharmacogenetic testing was used to determine the appropriate dose of buprenorphine for OUD management. At the 24 mg buprenorphine daily dose, the patient had multiple relapses with unauthorized substances. Pharmacogenetic testing revealed that the patient exhibited a cytochrome P450 3A4 ultrarapid metabolizer phenotype, which necessitated a higher than recommended daily dose of buprenorphine (32 mg) for adequate OUD management. The patient exhibited a reduction in the number of relapses on the pharmacogenetic-based dose recommendation compared to standard dosing. Pharmacogenomic testing as clinical decision support helped to individualize OUD management. Collaboration by key stakeholders is essential to establishing pharmacogenetic testing as standard of care in OUD management.

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.

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.

Inter-patient image registration algorithms to disentangle regional dose bioeffects.

PubMed

Monti, Serena; Pacelli, Roberto; Cella, Laura; Palma, Giuseppe

2018-03-20

Radiation therapy (RT) technological advances call for a comprehensive reconsideration of the definition of dose features leading to radiation induced morbidity (RIM). In this context, the voxel-based approach (VBA) to dose distribution analysis in RT offers a radically new philosophy to evaluate local dose response patterns, as an alternative to dose-volume-histograms for identifying dose sensitive regions of normal tissue. The VBA relies on mapping patient dose distributions into a single reference case anatomy which serves as anchor for local dosimetric evaluations. The inter-patient elastic image registrations (EIRs) of the planning CTs provide the deformation fields necessary for the actual warp of dose distributions. In this study we assessed the impact of EIR on the VBA results in thoracic patients by identifying two state-of-the-art EIR algorithms (Demons and B-Spline). Our analysis demonstrated that both the EIR algorithms may be successfully used to highlight subregions with dose differences associated with RIM that substantially overlap. Furthermore, the inclusion for the first time of covariates within a dosimetric statistical model that faces the multiple comparison problem expands the potential of VBA, thus paving the way to a reliable voxel-based analysis of RIM in datasets with strong correlation of the outcome with non-dosimetric variables.

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.

A novel toxic alkaloid from poison hemlock (Conium maculatum L., Apiaceae): identification, synthesis and antinociceptive activity.

PubMed

Radulović, Niko; Dorđević, Nevenka; Denić, Marija; Pinheiro, Mariana Martins Gomes; Fernandes, Patricia Dias; Boylan, Fabio

2012-02-01

2-Pentylpiperidine, named conmaculatin, a novel volatile alkaloid related to coniine was identified from the renowned toxic weed Conium maculatum L. (Apiaceae). The structure of conmaculatin was corroborated by synthesis (8 steps starting from cyclohexanol, overall yield 12%). Conmaculatin's strong peripheral and central antinociceptive activity in mice was observed in a narrow dose range (10-20mg/kg). It was found to be lethal in doses higher than 20mg/kg. Copyright © 2011 Elsevier Ltd. All rights reserved.

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.

Updated mortality analysis of radiation workers at Rocketdyne (Atomics International), 1948-2008

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

Boice, John; Cohen, Sarah; Mumma, Michael

Updated analyses of mortality data are presented on 5,801 radiation workers, including 2,232 monitored for radionuclide intakes, and 41,169 non-radiation workers employed 1948-1999 at Rocketdyne (Atomics International). The worker population is unique in that lifetime occupational doses from all places of employment were sought and incorporated into the analyses. Further, radiation doses from intakes of 14 different radionuclides were calculated for 16 organs or tissues using biokinetic models of the International Commission on Radiation Protection (ICRP). The mean dose from external radiation was 13.5 mSv (maximum 1 Sv), and the mean lung dose from external and internal radiation combined wasmore » 19.0 mSv (maximum 3.6 Sv). An additional nine years of follow-up, from December 31,1999 through 2008, increased the person-years of observation by 21.7% to 196,674 (mean 33.9 years) and the number of cancer deaths by 50% to 684. Analyses included comparisons with the general population and the computation of standardized mortality ratios (SMRs), and internal comparisons using proportional hazards models. All cancers taken together (SMR 0.88; 95% CI 0.81-0.95), lung cancer (SMR 0.87; 95% CI 0.76-1.00) and leukemia other than chronic lymphocytic leukemia (CLL) (SMR 1.04; 95% 0.67-1.53) were not significantly elevated. Cox regression analyses revealed no significant dose-response trends for any cancer. For all cancers excluding leukemia, the relative risk (RR) at 100 mSv was estimated as 0.98 (95% CI 0.82-1.17) and for all leukemia other than CLL it was 1.06 (95% CI 0.50-2.23). Uranium was the primary radionuclide contributing to internal exposures, but significant increases in lung and kidney disease were not seen. The extended follow-up re-enforces the findings in the previous study in failing to observe a detectable increase in cancer deaths associated with radiation, but strong conclusions still cannot be drawn because of small numbers and relatively low career doses. Larger combined studies of early workers in the United States following similar methodologies are warranted to refine and clarify radiation risks following protracted exposures.« less

Shared Dosimetry Error in Epidemiological Dose-Response Analyses

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

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

2015-03-23

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

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.

Synergistic interaction between choline and aspirin against acute inflammation induced by carrageenan and lipopolysaccharide.

PubMed

Pan, Zhi-Yuan; Wang, Hai

2014-05-01

The simultaneous use of drugs with different mechanisms of anti-inflammatory action is a strategy for achieving effective control of inflammation while minimizing dose-related side effects. Choline was described to potentiate the antinociceptive action of aspirin at small doses in several inflammatory pain models. However, these findings are only limited to alleviating pain, more associated data are required to confirm the effectiveness of the combined choline and aspirin therapy against inflammatory disorders. Moreover, no report is available regarding the mechanism responsible for their synergism. Here, we first investigated the anti-inflammatory activity and pharmacological mechanisms of co-administration of choline and aspirin in 2 commonly studied inflammation models, carrageenan-induced paw edema and lipopolysaccharide (LPS)-induced sepsis in mice. Isobolographic analysis revealed that combined choline and aspirin administration exhibited a strong synergistic interaction in reducing carrageenan-mediated edema, and the estimated combination index values at 50%, 75%, and 90% effective dose (ED50, ED75, and ED90) were 0.25, 0.32, and 0.44. Drug co-administration also afforded synergistic protection against LPS-induced sepsis and mortality, since aspirin or choline alone was inadequate to improve survival. The effects of choline-aspirin co-administration were blocked by methyllycaconitine, suggesting that activation of alpha 7 nicotinic acetylcholine receptor participates in the interaction between choline and aspirin. Furthermore, co-administration of choline and aspirin was more likely to inhibit the production of pro-inflammatory mediators induced by LPS. Our results indicated that combined choline and aspirin therapy represented a significant synergistic interaction in attenuating acute inflammatory response. This preclinical relevant evidence provides a promising approach to treat inflammation-based diseases such as arthritis and sepsis. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Quantitative analysis of the role of fiber length on phagocytosis and inflammatory response by alveolar macrophages

PubMed Central

Padmore, Trudy; Stark, Carahline; Turkevich, Leonid A.; Champion, Julie A.

2017-01-01

Background In the lung, macrophages attempt to engulf inhaled high aspect ratio pathogenic materials, secreting inflammatory molecules in the process. The inability of macrophages to remove these materials leads to chronic inflammation and disease. How the biophysical and biochemical mechanisms of these effects are influenced by fiber length remains undetermined. This study evaluates the role of fiber length on phagocytosis and molecular inflammatory responses to non-cytotoxic fibers, enabling development of quantitative length-based models. Methods Murine alveolar macrophages were exposed to long and short populations of JM-100 glass fibers, produced by successive sedimentation and repeated crushing, respectively. Interactions between fibers and macrophages were observed using time-lapse video microscopy, and quantified by flow cytometry. Inflammatory biomolecules (TNF-α, IL-1 α, COX-2, PGE2) were measured. Results Uptake of short fibers occurred more readily than for long, but long fibers were more potent stimulators of inflammatory molecules. Stimulation resulted in dose-dependent secretion of inflammatory biomolecules but no cytotoxicity or strong ROS production. Linear cytokine dose-response curves evaluated with length-dependent potency models, using measured fiber length distributions, resulted in identification of critical fiber lengths that cause frustrated phagocytosis and increased inflammatory biomolecule production. Conclusion Short fibers played a minor role in the inflammatory response compared to long fibers. The critical lengths at which frustrated phagocytosis occurs can be quantified by fitting dose-response curves to fiber distribution data. PMID:27784615

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

Genetic background modulates lncRNA-coordinated tissue response to low dose ionizing radiation

DOE PAGES

Tang, Jonathan; Huang, Yurong; Nguyen, David H.; ...

2015-02-04

Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed aftermore » LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.« less

Genetic background modulates lncRNA-coordinated tissue response to low dose ionizing radiation

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

Tang, Jonathan; Huang, Yurong; Nguyen, David H.

Long noncoding RNAs (lncRNAs) are emerging as key regulators of diverse cell functions and processes. However, the relevance of lncRNAs in the cell and tissue response to ionizing radiation has not yet been characterized. Here we used microarray profiling to determine lncRNA and mRNA expression in mammary glands of BALB/c and SPRET/EiJ mice after low-dose ionizing radiation (LDIR) exposure. We found that unirradiated mammary tissues of these strains differed significantly in baseline expressions of 290 lncRNAs. LDIR exposure (10 cGy) induced a significant change in the expression of many lncRNAs. The vast majority of lncRNAs identified to be differentially expressed aftermore » LDIR in either BALB/c or SPRET/EiJ had a significantly correlated expression pattern with at least one LDIR responsive mRNA. Functional analysis revealed that the response to LDIR in BALB/c mice is highly dynamic with enrichment for genes involved in tissue injury, inflammatory responses, and mammary gland development at 2, 4, and 8 weeks after LDIR, respectively. Our study demonstrates that genetic background strongly influences the expression of lncRNAs and their response to radiation and that lncRNAs may coordinate the tissue response to LDIR exposure via regulation of coding mRNAs.« 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

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose.

PubMed

Bola, R Aaron; Kiyatkin, Eugene A

2017-11-01

Here we examined how intravenous heroin at a dose that maintains self-administration (0.1 mg/kg) affects brain temperature homeostasis in freely moving rats under conditions that seek to mimic some aspects of human drug use. When administered under standard laboratory conditions (quiet rest at 22 °C ambient temperature), heroin induced moderate temperature increases (1.0-1.5 °C) in the nucleus accumbens (NAc), a critical structure of the brain motivation-reinforcement circuit. By simultaneously recording temperatures in the temporal muscle and skin, we demonstrate that the hyperthermic effects of heroin results primarily from inhibition of heat loss due to strong and prolonged skin vasoconstriction. Heroin-induced brain temperature increases were enhanced during behavioral activation (i.e., social interaction) and in a moderately warm environment (29 °C). By calculating the "net" effects of the drug in these two conditions, we found that this enhancement results from the summation of the hyperthermic effects of heroin with similar effects induced by either social interaction or a warmer environment. When the dose of heroin was increased (to 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg), brain temperature showed a biphasic down-up response. The initial temperature decrease was dose-dependent and resulted from a transient inhibition of intra-brain heat production coupled with increased heat loss via skin surfaces-the effects typically induced by general anesthetics. These initial inhibitory effects induced by large-dose heroin injections could be related to profound CNS depression-the most serious health complications typical of heroin overdose in humans. Published by Elsevier Ltd.

International Comparison of Adult Height in Children with Growth Hormone Deficiency and Limitations of Growth Hormone Treatment in Japan.

PubMed

Tanaka, Toshiaki

2017-03-01

The approved therapeutic dose of growth hormone (GH) for growth hormone deficiency (GHD) varies depending on the country. Japan has the lowest therapeutic dose globally, with a single dose of 0.175 mg/kg/week. GH treatment for GHD is considered as a replacement therapy and in fact, a dose of 0.175 mg/kg/week is slightly higher than GH secretion in prepubertal healthy children but nearly the same as that of pubertal children. Although the same growth rate as that of healthy children is expected in response to replacement therapy, the catch-up growth observed for the first 1 to 2 years of GH treatment was misinterpreted as an effect of the GH replacement therapy. The real effect of the GH replacement therapy was the growth rate appeared after more than 3 years of GH therapy, when patients showed nearly the same growth rate as healthy children. Therefore, children with GHD can have a higher growth rate than healthy children only for the first 1 to 2 years of GH therapy, after which their growth rate begins to wane. In the United States and Europe, the various therapeutic doses and high-dose treatment are accepted and the SD score of adult height after treatment is higher than that in Japan. The improvement degree of the height SD score and the adult height SD score with GH therapy are lower in Japan compared with other countries that administer a similar therapeutic dose. This suggests that the response to GH can be affected by race. Actual comparison of the response to GH between Japanese and Caucasian patients using KIGS (Pharmacia International Growth Database) data showed that both the short-term response and the effect on adult height were reduced in Japanese patients. As there is a strong positive correlation between adult height and height at the onset of puberty, treatment methods that can increase pubertal growth will be considered in the future for patients with GDH who enter puberty with short stature. Copyright© of YS Medical Media ltd.

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.

Ionizing radiation induces O6-alkylguanine-DNA-alkyltransferase mRNA and activity in mouse tissues.

PubMed

Wilson, R E; Hoey, B; Margison, G P

1993-04-01

The effect of exposure to whole-body gamma-irradiation or fast electrons on O6-alkylguanine-DNA-alkyltransferase (ATase) activity and mRNA abundance has been examined in mice. In response to gamma-radiation, hepatic ATase activity was significantly raised in BDF1 mice 24 h post-irradiation, reaching a maximum of 2- to 3-fold at 36 h and beginning to decrease by 48-60 h. A small but consistently higher level of induction was achieved when mice were exposed using a low dose rate (0.015 Gy/min) compared to a high dose rate (0.5 Gy/min). ATase activity was also induced approximately 2-fold 48 h post-irradiation in brain, kidney, lung and spleen, with a greater induction again observed in response to the lower dose rate. In response to fast electrons from a linear accelerator hepatic ATase activity was also induced 2- to 3-fold 48 h post-irradiation in BDF1, BALB/c, C57Bl and DBA2 strains. Induction of ATase activity in livers of BDF1 mice was observed 48 h after a total single dose of 5 Gy gamma-radiation (2-fold), increasing to a slightly higher level at 15 Gy, but no induction was observed at doses of 2 Gy and below. Although a maximum 2- to 3-fold induction of ATase activity was observed, mRNA levels were induced 3- to 4-fold by 48 h after a dose of 15 Gy. Furthermore, significant increases in mRNA levels were detected at low doses (1-2 Gy) at which there was no apparent increase in ATase activity. This suggests that ionizing radiation increases ATase levels by a process involving transcriptional upregulation but that strong post-transcriptional and/or translational controls operate to limit induction of enzyme activity to 2- to 3-fold. This is the first report of an in vivo induction of ATase by ionizing radiation in a species other than the rat.

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...

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

Long-term monitoring and modeling of the mass transfer of polychlorinated biphenyls in sediment following pilot-scale in-situ amendment with activated carbon.

PubMed

Cho, Yeo-Myoung; Werner, David; Choi, Yongju; Luthy, Richard G

2012-03-15

The results of five years of post-treatment monitoring following in-situ activated carbon (AC) placement for stabilization of polychlorinated biphenyls (PCBs) at an inter-tidal mudflat adjacent to Hunters Point Shipyard, San Francisco Bay, CA, USA are reported in this paper. After five years, AC levels of the sediment cores were comparable to those at earlier sampling times. Passive sampler uptake validated the benefit of the AC amendment with a strong local sorbent dose-response relationship. The PCB uptakes in passive samplers decreased up to 73% with a 3.7 dry wt.% AC dose after five years, confirming the temporal enhancement of the amendment benefit from a 19% reduction with a 4.4% dose observed within one month. The long-term effectiveness of AC, the local AC dose response, the impact of fouling by NOM, the spatial heterogeneity of AC incorporation, and the effects of advective sediment pore-water movement are discussed with the aid of a PCB mass transfer model. Modeling and experimental results indicated that the homogeneous incorporation of AC in the sediment will significantly accelerate the benefit of the treatment. Copyright © 2011 Elsevier B.V. All rights reserved.

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.

Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics.

PubMed

Schmid, Cullen L; Kennedy, Nicole M; Ross, Nicolette C; Lovell, Kimberly M; Yue, Zhizhou; Morgenweck, Jenny; Cameron, Michael D; Bannister, Thomas D; Bohn, Laura M

2017-11-16

Biased agonism has been proposed as a means to separate desirable and adverse drug responses downstream of G protein-coupled receptor (GPCR) targets. Herein, we describe structural features of a series of mu-opioid-receptor (MOR)-selective agonists that preferentially activate receptors to couple to G proteins or to recruit βarrestin proteins. By comparing relative bias for MOR-mediated signaling in each pathway, we demonstrate a strong correlation between the respiratory suppression/antinociception therapeutic window in a series of compounds spanning a wide range of signaling bias. We find that βarrestin-biased compounds, such as fentanyl, are more likely to induce respiratory suppression at weak analgesic doses, while G protein signaling bias broadens the therapeutic window, allowing for antinociception in the absence of respiratory suppression. Copyright © 2017 Elsevier Inc. All rights reserved.

SU-G-201-17: Verification of Dose Distributions From High-Dose-Rate Brachytherapy Ir-192 Source Using a Multiple-Array-Diode-Detector (MapCheck2)

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

Harpool, K; De La Fuente Herman, T; Ahmad, S

Purpose: To investigate quantitatively the accuracy of dose distributions for the Ir-192 high-dose-rate (HDR) brachytherapy source calculated by the Brachytherapy-Planning system (BPS) and measured using a multiple-array-diode-detector in a heterogeneous medium. Methods: A two-dimensional diode-array-detector system (MapCheck2) was scanned with a catheter and the CT-images were loaded into the Varian-Brachytherapy-Planning which uses TG-43-formalism for dose calculation. Treatment plans were calculated for different combinations of one dwell-position and varying irradiation times and different-dwell positions and fixed irradiation time with the source placed 12mm from the diode-array plane. The calculated dose distributions were compared to the measured doses with MapCheck2 delivered bymore » an Ir-192-source from a Nucletron-Microselectron-V2-remote-after-loader. The linearity of MapCheck2 was tested for a range of dwell-times (2–600 seconds). The angular effect was tested with 30 seconds irradiation delivered to the central-diode and then moving the source away in increments of 10mm. Results: Large differences were found between calculated and measured dose distributions. These differences are mainly due to absence of heterogeneity in the dose calculation and diode-artifacts in the measurements. The dose differences between measured and calculated due to heterogeneity ranged from 5%–12% depending on the position of the source relative to the diodes in MapCheck2 and different heterogeneities in the beam path. The linearity test of the diode-detector showed 3.98%, 2.61%, and 2.27% over-response at short irradiation times of 2, 5, and 10 seconds, respectively, and within 2% for 20 to 600 seconds (p-value=0.05) which depends strongly on MapCheck2 noise. The angular dependency was more pronounced at acute angles ranging up to 34% at 5.7 degrees. Conclusion: Large deviations between measured and calculated dose distributions for HDR-brachytherapy with Ir-192 may be improved when considering medium heterogeneity and dose-artifact of the diodes. This study demonstrates that multiple-array-diode-detectors provide practical and accurate dosimeter to verify doses delivered from the brachytherapy Ir-192-source.« less

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.

Intravenous Heroin Induces Rapid Brain Hypoxia and Hyperglycemia that Precede Brain Metabolic Response.

PubMed

Solis, Ernesto; Cameron-Burr, Keaton T; Shaham, Yavin; Kiyatkin, Eugene A

2017-01-01

Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 μg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO 2 levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra-brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity.

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.

Enhanced neoplastic transformation by mammography X rays relative to 200 kVp X rays: indication for a strong dependence on photon energy of the RBE(M) for various end points.

PubMed

Frankenberg, D; Kelnhofer, K; Bär, K; Frankenberg-Schwager, M

2002-01-01

The fundamental assumption implicit in the use of the atomic bomb survivor data to derive risk estimates is that the gamma rays of Hiroshima and Nagasaki are considered to have biological efficiencies equal to those of other low-LET radiations up to 10 keV/microm, including mammography X rays. Microdosimetric and radiobiological data contradict this assumption. It is therefore of scientific and public interest to evaluate the efficiency of mammography X rays (25-30 kVp) to induce cancer. In this study, the efficiency of mammography X rays relative to 200 kVp X rays to induce neoplastic cell transformation was evaluated using cells of a human hybrid cell line (CGL1). For both radiations, a linear-quadratic dose-effect relationship was observed for neoplastic transformation of CGL1 cells; there was a strong linear component for the 29 kVp X rays. The RBE(M) of mammography X rays relative to 200 kVp X rays was determined to be about 4 for doses < or = 0.5 Gy. A comparison of the electron fluences for both X rays provides strong evidence that electrons with energies of < or = 15 keV can induce neoplastic transformation of CGL1 cells. Both the data available in the literature and the results of the present study strongly suggest an increase of RBE(M) for carcinogenesis in animals, neoplastic cell transformation, and clastogenic effects with decreasing photon energy or increasing LET to an RBE(M) approximately 8 for mammography X rays relative to 60Co gamma rays.

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

Developing the radiation protection safety culture in the UK.

PubMed

Cole, P; Hallard, R; Broughton, J; Coates, R; Croft, J; Davies, K; Devine, I; Lewis, C; Marsden, P; Marsh, A; McGeary, R; Riley, P; Rogers, A; Rycraft, H; Shaw, A

2014-06-01

In the UK, as elsewhere, there is potential to improve how radiological challenges are addressed through improvement in, or development of, a strong radiation protection (RP) safety culture. In preliminary work in the UK, two areas have been identified as having a strong influence on UK society: the healthcare and nuclear industry sectors. Each has specific challenges, but with many overlapping common factors. Other sectors will benefit from further consideration.In order to make meaningful comparisons between these two principal sectors, this paper is primarily concerned with cultural aspects of RP in the working environment and occupational exposures rather than patient doses.The healthcare sector delivers a large collective dose to patients each year, particularly for diagnostic purposes, which continues to increase. Although patient dose is not the focus, it must be recognised that collective patient dose is inevitably linked to collective occupational exposure, especially in interventional procedures.The nuclear industry faces major challenges as work moves from operations to decommissioning on many sites. This involves restarting work in the plants responsible for the much higher radiation doses of the 1960/70s, but also performing tasks that are considerably more difficult and hazardous than those original performed in these plants.Factors which influence RP safety culture in the workplace are examined, and proposals are considered for a series of actions that may lead to an improvement in RP culture with an associated reduction in dose in many work areas. These actions include methods to improve knowledge and awareness of radiation safety, plus ways to influence management and colleagues in the workplace. The exchange of knowledge about safety culture between the nuclear industry and medical areas may act to develop RP culture in both sectors, and have a wider impact in other sectors where exposures to ionising radiations can occur.

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...

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.

Angular dependence of the MOSFET dosimeter and its impact on in vivo surface dose measurement in breast cancer treatment.

PubMed

Qin, S; Chen, T; Wang, L; Tu, Y; Yue, N; Zhou, J

2014-08-01

The focus of this study is the angular dependence of two types of Metal Oxide Semiconductor Field Effect Transistor (MOSFET) dosimeters (MOSFET20 and OneDose/OneDosePlus) when used for surface dose measurements. External beam radiationat different gantry angles were delivered to a cubic solid water phantom with a MOSFET placed on the top surface at CAX. The long axis of the MOSFET was oriented along the gantry axis of rotation, with the dosimeter (bubble side) facing the radiation source. MOSFET-measured surface doses were compared against calibrated radiochromic film readings. It was found that both types of MOSFET dosimeters exhibited larger than previously reported angular dependence when measuring surface dose in beams at large oblique angles. For the MOSFET20 dosimeter the measured surface dose deviation against film readings was as high as 17% when the incident angle was 72 degrees to the norm of the phantom surface. It is concluded that some MOSFET dosimeters may have a strong angular dependence when placed on the surface of water-equivalent material, even though they may have an isotropic angular response when surrounded by uniform medium. Extra on-surface calibration maybe necessary before using MOSFET dosimeters for skin dose measurement in tangential fields.

Simulation of parabolic reflectors for ultraviolet phototherapy

NASA Astrophysics Data System (ADS)

Grimes, David Robert

2016-08-01

Ultraviolet (UVR) phototherapy is widely used to treat an array of skin conditions, including psoriasis, eczema and vitiligo. For such interventions, a quantified dose is vital if the treatment is to be both biologically effective and to avoid the detrimental effects of over-dosing. As dose is absorbed at surface level, the orientation of patient site with respect to the UVR lamps modulates effective dose. Previous investigations have modelled this behaviour, and examined the impact of shaped anodized aluminium reflectors typically placed around lamps in phototherapy cabins. These mirrors are effective but tend to yield complex patterns of reflection around the cabin which can result in substantial dose inhomogeneity. There has been some speculation over whether using the reflective property of parabolic mirrors might improve dose delivery or homogeneity through the treatment cabin. In this work, the effects of parabolic mirrors are simulated and compared with standard shaped mirrors. Simulation results strongly suggest that parabolic reflectors reduce total irradiance relative to standard shaped reflectors, and have a negligible impact on dose homogeneity.

Relationship between high daily erythemal UV doses, total ozone, surface albedo and cloudiness: An analysis of 30 years of data from Switzerland and Austria

NASA Astrophysics Data System (ADS)

Rieder, H. E.; Staehelin, J.; Weihs, P.; Vuilleumier, L.; Maeder, J. A.; Holawe, F.; Blumthaler, M.; Lindfors, A.; Peter, T.; Simic, S.; Spichtinger, P.; Wagner, J. E.; Walker, D.; Ribatet, M.

2010-10-01

This work investigates the occurrence frequency of days with high erythemal UV doses at three stations in Switzerland and Austria (Davos, Hoher Sonnblick and Vienna) for the time period 1974-2003. While several earlier studies have reported on increases in erythemal UV dose up to 10% during the last decades, this study focuses on days with high erythemal UV dose, which is defined as a daily dose at least 15% higher than for 1950s clear-sky conditions (which represent preindustrial conditions with respect to anthropogenic chlorine). Furthermore, the influence of low column ozone, clear-sky/partly cloudy conditions and surface albedo on UV irradiance has been analyzed on annual and seasonal basis. The results of this study show that in the Central Alpine Region the number of days with high UV dose increased strongly in the early 1990s. A large fraction of all days with high UV dose occurring in the period 1974-2003 was found especially during the years 1994-2003, namely 40% at Davos, 54% at Hoher Sonnblick and 65% at Vienna. The importance of total ozone, clear-sky/partly cloudy conditions and surface albedo (e.g. in dependence of snow cover) varies strongly among the seasons. However, overall the interplay of low total ozone and clear-sky/partly cloudy conditions led to the largest fraction of days showing high erythemal UV dose. Furthermore, an analysis of the synoptic weather situation showed that days with high erythemal UV dose, low total ozone and high relative sunshine duration occur at all three stations more frequently during situations with low pressure gradients or southerly advection.

Intranasal vaccination with an inactivated whole influenza virus vaccine induces strong antibody responses in serum and nasal mucus of healthy adults

PubMed Central

Ainai, Akira; Tamura, Shin-ichi; Suzuki, Tadaki; van Riet, Elly; Ito, Ryo; Odagiri, Takato; Tashiro, Masato; Kurata, Takeshi; Hasegawa, Hideki

2013-01-01

Haemagglutination inhibition (HI) and neutralization (NT) titers as well as haemagglutinin (HA) specific antibody responses were examined in 50 healthy adults aged between 22 and 69 y old after two intranasal administrations of an inactivated whole virus vaccine derived from A/Victoria/210/2009 virus (45 μg HA per dose) at 3 week intervals. Serum HI titers after two-doses of the nasal vaccine showed >2.5-fold rise in the ratio of geometric mean titer upon vaccination, >40% of subjects with a ≥4-fold increase in titer and >70% of subjects with a titer of ≥1:40, all parameters associated with an effective outcome of vaccination in the criteria defined by the European Medicines Agency. Serum neutralizing antibody responses correlated with HI antibody responses, although NT titers were about 2-fold higher than HI titers. These high levels of serum responses were accompanied by high levels of HI and neutralizing antibody responses in nasal mucus as measured in concentrated nasal wash samples that were about 10 times diluted compared with natural nasal mucus. Serum and nasal HI and neutralizing antibody responses consisted of HA-specific IgG and IgA antibody responses, with IgG and IgA antibodies being dominant in serum and nasal responses, respectively. PMID:23896606

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.

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

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

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.

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.

Roles of Radiation Dose and Chemotherapy in the Etiology of Stomach Cancer as a Second Malignancy

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

Belt-Dusebout, Alexandra W. van den; Aleman, Berthe M.P.; Besseling, Gijs

Purpose: To evaluate the roles of radiation dose, chemotherapy, and other factors in the etiology of stomach cancer in long-term survivors of testicular cancer or Hodgkin lymphoma. Methods and Materials: We conducted a cohort study in 5,142 survivors of testicular cancer or Hodgkin lymphoma treated in the Netherlands between 1965 and 1995. In a nested case-control study, detailed information on treatment, smoking, gastrointestinal diseases, and family history was collected for 42 patients with stomach cancer and 126 matched controls. For each subject, the mean radiation dose to the stomach was estimated. Relative risks (RRs) of stomach cancer and the radiation-relatedmore » excess relative risk (ERR) per gray were calculated by conditional logistic regression analysis. Results: The risk of stomach cancer was 3.4-fold increased compared with the general population. The risk increased with increasing mean stomach dose (p for trend, <0.001), at an ERR of 0.84 per Gy (95% confidence interval [CI], 0.12-15.6). Mean stomach doses of more than 20 Gy were associated with a RR of 9.9 (95% CI, 3.2-31.2) compared with doses below 11 Gy. The risk was 1.8-fold (95% CI, 0.8-4.4) increased after chemotherapy and 5.4-fold (95% CI, 1.2-23.9) increased after high doses of procarbazine (>=13,000 mg) vs. <10,000 mg. The RR of smoking more than 10 cigarettes per day vs. no smoking was 1.6 (95% CI, 0.6-4.2). Conclusions: Stomach cancer risk is strongly radiation dose dependent. The role of chemotherapy, particularly of procarbazine and related agents, needs further study, because of the relatively small numbers of chemotherapy-treated subjects.« less

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.

Ethylene regulates Apple (Malus x domestica) fruit softening through a dose x time-dependent mechanism and through differential sensitivities and dependencies of cell wall-modifying genes.

PubMed

Ireland, Hilary S; Gunaseelan, Kularajathevan; Muddumage, Ratnasiri; Tacken, Emma J; Putterill, Jo; Johnston, Jason W; Schaffer, Robert J

2014-05-01

In fleshy fruit species that have a strong requirement for ethylene to ripen, ethylene is synthesized autocatalytically, producing increasing concentrations as the fruits ripen. Apple fruit with the ACC OXIDASE 1 (ACO1) gene suppressed cannot produce ethylene autocatalytically at ripening. Using these apple lines, an ethylene sensitivity dependency model was previously proposed, with traits such as softening showing a high dependency for ethylene as well as low sensitivity. In this study, it is shown that the molecular control of fruit softening is a complex process, with different cell wall-related genes being independently regulated and exhibiting differential sensitivities to and dependencies on ethylene at the transcriptional level. This regulation is controlled through a dose × time mechanism, which results in a temporal transcriptional response that would allow for progressive cell wall disassembly and thus softening. This research builds on the sensitivity dependency model and shows that ethylene-dependent traits can progress over time to the same degree with lower levels of ethylene. This suggests that a developmental clock measuring cumulative ethylene controls the fruit ripening process.

Effects of fluoxetine on the rat brain in the forced swimming test: a [F-18]FDG micro-PET imaging study.

PubMed

Jang, Dong-Pyo; Lee, So-Hee; Park, Chan-Woong; Lee, Sang-Yoon; Kim, Young-Bo; Cho, Zang-Hee

2009-02-13

We used the [F-18]FDG micro-PET neuroimaging to examine the effects of fluoxetine on brain activity in rats and on their behavioral response in the forced swimming test (FST). In the first experiment, the rats were administered doses of fluoxetine (10 or 20mg/kg) 24, 19 and 1h before the rat brains were scanned. Fluoxetine induced strong activation of the dorsal hippocampus and the deactivation of the inferior colliculus, medulla oblongata, and prelimbic cortex in a dose-dependent manner. These results seemed to be related with the changes in 5-HT (5-hydroxytryptamine, serotonin) levels after selective serotonin reuptake-inhibitor treatments. In the second experiment, the changes in glucose metabolism in the test session were measured after fluoxetine was given between pre-test and test sessions of the FST. Fluoxetine administration significantly decreased immobility behavior compared with saline administration. At the same time, the activity of the insular/piriform cortex decreased significantly. In contrast, the extent of cerebellar activation increased. The glucose metabolism of the dorsal hippocampus also increased, which suggests that post-stress changes in the facilitation of hippocampal serotonergic neurotransmission lead to decreased immobilization in the FST.

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.

The dopamine D1 receptor agonist SKF81297 has dose-related effects on locomotor activity but is without effect in a CER trace conditioning procedure conducted with two versus four trials.

PubMed

Pezze, M A; Marshall, H J; Cassaday, H J

2016-08-01

In an appetitively motivated procedure, we have previously reported that systemic treatment with the dopamine (DA) D1 receptor agonist SKF81297 (0.4 and 0.8 mg/kg) depressed acquisition at a 2 s inter-stimulus-interval (ISI), suitable to detect trace conditioning impairment. However since DA is involved in reinforcement processes, the generality of effects across appetitively- and aversively-motivated trace conditioning procedures cannot be assumed. The present study tested the effects of SKF81297 (0.4 and 0.8 mg/kg) in an established conditioned emotional response (CER) procedure. Trace-dependent conditioning was clearly shown in two experiments: while conditioning was relatively strong at a 3-s ISI, it was attenuated at a 30-s ISI. This was shown after two (Experiment 1) or four (Experiment 2) conditioning trials conducted in - as far as possible - the same CER procedure. Contrary to prediction, in neither experiment was there any indication that trace conditioning was attenuated by treatment with 0.4 or 0.8 mg/kg SKF81297. In the same rats, locomotor activity was significantly enhanced at the 0.8 mg/kg dose of SKF81297. These results suggest that procedural details of the trace conditioning variant in use are an important determinant of the profile of dopaminergic modulation.

Influence of ozonation on the in vitro mutagenic and toxic potential of secondary effluents.

PubMed

Petala, M; Samaras, P; Zouboulis, A; Kungolos, A; Sakellaropoulos, G P

2008-12-01

Reclamation of municipal effluents by advanced treatment processes is an attractive perspective for facing certain water shortage problems. However, the application of tertiary techniques should be thoroughly examined for their potential hazardous effects. Ozonation is an efficient chemical oxidation method, often used in wastewater reclamation, which may result in by-products that may alter the toxic and mutagenic properties of effluents. In this study, Ames test and Microtox test were used for the evaluation of ozonation efficiency to upgrade secondary effluents quality. In general, the toxic response and mutagenic effect without metabolic activation of test species were influenced mainly by the ozone dose and ozonation duration, whereas the mutagenic effect with metabolic activation was influenced mainly by ozone dose, indicating that ozone conditions strongly affect the formation of by-products. In most cases, the toxicity was increased and reached up to 100% (in relation to that of secondary effluent) after ozonation with 8.0 mg O3/L for 5 min. On the contrary, in most cases the mutagenic activity towards strain TA98 without metabolic activation was reduced, when ozone dose and contact time increased. However, the mutagenicity was also increased after ozonation at low ozone doses and for contact times less than 5 min. The mutagenic activity of treated effluents towards strain TA98 with metabolic activation remained about the same or was reduced, compared to that of secondary effluent, and was even eliminated after ozonation with 8.0 mg O3/L for contact times higher than 5 min.

Prescription histories and dose strengths associated with overdose deaths.

PubMed

Hirsch, Anne; Proescholdbell, Scott K; Bronson, William; Dasgupta, Nabarun

2014-07-01

Misuse, abuse, and diversion of prescription drugs are large and growing public health problems that have resulted in an overdose epidemic. We investigated whether short-acting or extended-release opioids were more frequently prescribed to those who died of an overdose and whether there was a linear relationship between dose strength and associated overdose deaths. The study population was North Carolina residents in 2010. We conducted a retrospective, population-based, descriptive study of medication histories of overdose decedents using data from vital statistics, medical examiner records, and a prescription drug monitoring program. Unintentional or undetermined drug overdoses were responsible for 892 deaths. Out of 191 deaths involving methadone, only two were patients in opioid treatment programs. Immediate-release oxycodone was involved in the greatest number of opioid-related deaths. Out of 221 oxycodone deaths, 134 (61%) of the decedents filled a prescription for oxycodone in the 60 days prior to death. The most common strength dispensed within 60 days to a decedent who died of an oxycodone overdose was 10 mg for immediate-release (72 prescriptions). Immediate-release oxycodone products (rho = 1.00, P < 0.01) and extended-release fentanyl products (rho = 1.00, P < 0.01) showed strong increasing linear trends between dose strength and proportion of prescriptions dispensed to decedents. A significant proportion of overdose decedents had been prescribed the same type of drugs that contributed to their death, especially for decedents who died from overdoses involving oxycodone, hydrocodone, and alprazolam. Higher dose strengths for certain opioids had higher associated mortality, and certain immediate-release opioids may be considered for public health prevention efforts.

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.

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

Patients' and physicians' perspectives on opioid therapy for chronic cancer and musculoskeletal pain in Germany, Italy, and Turkey: PAin RESearch (PARES) survey.

PubMed

Müller-Schwefe, Gerhard H H; Wimmer, Antonie M; Dejonckheere, Joachim; Eggers, Antje; Vellucci, Renato

2014-03-01

Under-treatment or lack of appropriate treatment for chronic pain remains an ongoing major healthcare problem. Opioids are being increasingly recognized as an effective option for chronic pain management. The objective of this survey was to understand the perspective of patients treated with opioids on quality of treatment, preferences, and possibilities to improve treatment and communication between patients and physicians. A large-scale PAin RESearch (PARES) survey of 2860 patients (Germany, Italy, and Turkey) with chronic cancer or musculoskeletal pain prescribed opioid therapy was conducted to assess various factors such as ease of use and compliance, sleep, quality-of-life, and polymedication. A physician component was also included. Relationships between variables and differences between groups were tested using Spearman and Wilcoxon signed-rank tests, respectively. Of the patients surveyed, 61% received strong opioids (WHO III) and 39% weak opioids (WHO II). Nearly 65% of the patients were currently on a twice daily or more dosing schedule; however, 61.5% of the patients responded that they considered once-daily dosing to be the most convenient schedule. Patients' responses indicated that different dosing schedules significantly influenced the occurrence of end-of-dose pain, feeling limited by the remaining level of pain, problems in falling asleep, and episodes of waking up at night or early in the morning. Physicians' responses showed that they were not surprised by 68.5% of patient responses; they also felt the need to change some aspect of pain treatment for a third of the patients, the commonest being pain medication (52.4%). The results of the survey suggest that patients prefer a convenient dosing scheme, which may have a positive impact on compliance. Physicians may have to communicate more closely with patients about their needs.

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

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

PubMed

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

2017-09-01

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

Low doses of killed parasite in CpG elicit vigorous CD4+ T cell responses against blood-stage malaria in mice

PubMed Central

Pinzon-Charry, Alberto; McPhun, Virginia; Kienzle, Vivian; Hirunpetcharat, Chakrit; Engwerda, Christian; McCarthy, James; Good, Michael F.

2010-01-01

Development of a vaccine that targets blood-stage malaria parasites is imperative if we are to sustainably reduce the morbidity and mortality caused by this infection. Such a vaccine should elicit long-lasting immune responses against conserved determinants in the parasite population. Most blood-stage vaccines, however, induce protective antibodies against surface antigens, which tend to be polymorphic. Cell-mediated responses, on the other hand, offer the theoretical advantage of targeting internal antigens that are more likely to be conserved. Nonetheless, few of the current blood-stage vaccine candidates are able to harness vigorous T cell immunity. Here, we present what we believe to be a novel blood-stage whole-organism vaccine that, by combining low doses of killed parasite with CpG-oligodeoxynucleotide (CpG-ODN) adjuvant, was able to elicit strong and cross-reactive T cell responses in mice. Our data demonstrate that immunization of mice with 1,000 killed parasites in CpG-ODN engendered durable and cross-strain protection by inducing a vigorous response that was dependent on CD4+ T cells, IFN-γ, and nitric oxide. If applicable to humans, this approach should facilitate the generation of robust, cross-reactive T cell responses against malaria as well as antigen availability for vaccine manufacture. PMID:20628205

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

Trends in opioid use and dosing among socio-economically disadvantaged patients

PubMed Central

Gomes, Tara; Juurlink, David N; Dhalla, Irfan A; Mailis-Gagnon, Angela; Paterson, J Michael; Mamdani, Muhammad M

2011-01-01

Background Opioid therapy for patients with chronic nonmalignant pain remains controversial, primarily because of safety concerns and the potential for abuse. The objective of this study was to examine trends in opioid utilization for nonmalignant pain among recipients of social assistance and to explore the relation between dose of analgesic and mortality. Methods Using a cross-sectional study design, we characterized annual trends in prescriptions for and daily dose of opioid analgesics between 2003 and 2008 for beneficiaries (aged 15 to 64 years) of Ontario’s public drug plan. We defined moderate, high and very high dose thresholds as daily doses of up to 200, 201 to 400, and more than 400 mg oral morphine (or equivalent), respectively. In an exploratory cohort study, we followed, over a 2-year period, patients who received at least one prescription for an opioid in 2004 to investigate the relation between opioid dose and opioid-related mortality. Results Over the study period, opioid prescribing rates rose by 16.2%, and 180 974 individuals received nearly 1.5 million opioid prescriptions in 2008. Also by 2008, the daily dose dispensed exceeded 200 mg morphine equivalent for almost a third (32.6%) of recipients of long-acting oxycodone but only 20.3% of those treated with fentanyl or other long-acting opioids. Among patients for whom high or very high doses of opioids were dispensed in 2004, 19.3% of deaths during the subsequent 2 years were opioid-related, occurring at a median age of 46 years. Two-year opioid-related mortality rates were 1.63 per 1000 population (95% confidence interval [CI] 1.42–1.85) among people with moderate-dose prescriptions, 7.92 per 1000 population (95% CI 5.25–11.49) among those with high-dose prescriptions, and 9.94 per 1000 population (95% CI 2.78–25.12) among those with very-high-dose prescriptions. Interpretation Among socio-economically disadvantaged patients in Ontario, the use and dose of opioids for nonmalignant pain has increased substantially, driven primarily by the use of long-acting oxycodone and, to a lesser extent, fentanyl. The findings of our exploratory study suggested a strong association between opioid-related mortality and the dose of opioid dispensed. PMID:22046214

Chemo-physical properties of renal capsules under ultraviolet-c exposure

NASA Astrophysics Data System (ADS)

Baghapour, Sh.; Parvin, P.; Reyhani, A.; Mortazavi, S. Z.; Mokhtari, S.; Amjadi, A.

2014-08-01

The renal capsule tissue of lamb was irradiated with ultraviolet-C light and the treated samples were analyzed by uniaxial tensile test, dynamic mechanical analysis, attenuated total reflectance Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and contact angle measurements. It was shown that the skin cross-linking is dominant in low doses in accordance with the contact angle assessment. Conversely, the strong bulk degradation takes place at high doses. Similarly, the bulk cross-linking affects the mechanical tests as to enhance the stiffness at low doses, whereas strong degradation occurs at high doses that mainly arises from the strong bulk chain scission.

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.

Real-time eye lens dose monitoring during cerebral angiography procedures.

PubMed

Safari, M J; Wong, J H D; Kadir, K A A; Thorpe, N K; Cutajar, D L; Petasecca, M; Lerch, M L F; Rosenfeld, A B; Ng, K H

2016-01-01

To develop a real-time dose-monitoring system to measure the patient's eye lens dose during neuro-interventional procedures. Radiation dose received at left outer canthus (LOC) and left eyelid (LE) were measured using Metal-Oxide-Semiconductor Field-Effect Transistor dosimeters on 35 patients who underwent diagnostic or cerebral embolization procedures. The radiation dose received at the LOC region was significantly higher than the dose received by the LE. The maximum eye lens dose of 1492 mGy was measured at LOC region for an AVM case, followed by 907 mGy for an aneurysm case and 665 mGy for a diagnostic angiography procedure. Strong correlations (shown as R(2)) were observed between kerma-area-product and measured eye doses (LOC: 0.78, LE: 0.68). Lateral and frontal air-kerma showed strong correlations with measured dose at LOC (AKL: 0.93, AKF: 0.78) and a weak correlation with measured dose at LE. A moderate correlation was observed between fluoroscopic time and dose measured at LE and LOC regions. The MOSkin dose-monitoring system represents a new tool enabling real-time monitoring of eye lens dose during neuro-interventional procedures. This system can provide interventionalists with information needed to adjust the clinical procedure to control the patient's dose. Real-time patient dose monitoring helps interventionalists to monitor doses. Strong correlation was observed between kerma-area-product and measured eye doses. Radiation dose at left outer canthus was higher than at left eyelid.

Multimodality vaccination against clade C SHIV: partial protection against mucosal challenges with a heterologous tier 2 virus.

PubMed

Lakhashe, Samir K; Byrareddy, Siddappa N; Zhou, Mingkui; Bachler, Barbara C; Hemashettar, Girish; Hu, Shiu-Lok; Villinger, Francois; Else, James G; Stock, Shannon; Lee, Sandra J; Vargas-Inchaustegui, Diego A; Cofano, Egidio Brocca; Robert-Guroff, Marjorie; Johnson, Welkin E; Polonis, Victoria R; Forthal, Donald N; Loret, Erwann P; Rasmussen, Robert A; Ruprecht, Ruth M

2014-11-12

We sought to test whether vaccine-induced immune responses could protect rhesus macaques (RMs) against upfront heterologous challenges with an R5 simian-human immunodeficiency virus, SHIV-2873Nip. This SHIV strain exhibits many properties of transmitted HIV-1, such as tier 2 phenotype (relatively difficult to neutralize), exclusive CCR5 tropism, and gradual disease progression in infected RMs. Since no human AIDS vaccine recipient is likely to encounter an HIV-1 strain that exactly matches the immunogens, we immunized the RMs with recombinant Env proteins heterologous to the challenge virus. For induction of immune responses against Gag, Tat, and Nef, we explored a strategy of immunization with overlapping synthetic peptides (OSP). The immune responses against Gag and Tat were finally boosted with recombinant proteins. The vaccinees and a group of ten control animals were given five low-dose intrarectal (i.r.) challenges with SHIV-2873Nip. All controls and seven out of eight vaccinees became systemically infected; there was no significant difference in viremia levels of vaccinees vs. controls. Prevention of viremia was observed in one vaccinee which showed strong boosting of virus-specific cellular immunity during virus exposures. The protected animal showed no challenge virus-specific neutralizing antibodies in the TZM-bl or A3R5 cell-based assays and had low-level ADCC activity after the virus exposures. Microarray data strongly supported a role for cellular immunity in the protected animal. Our study represents a case of protection against heterologous tier 2 SHIV-C by vaccine-induced, virus-specific cellular immune responses. Copyright © 2014 Elsevier Ltd. All rights reserved.

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.

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.

Differential Mobility Spectrometry-Mass Spectrometry (DMS-MS) in Radiation Biodosimetry: Rapid and High-Throughput Quantitation of Multiple Radiation Biomarkers in Nonhuman Primate Urine.

PubMed

Chen, Zhidan; Coy, Stephen L; Pannkuk, Evan L; Laiakis, Evagelia C; Fornace, Albert J; Vouros, Paul

2018-05-07

High-throughput methods to assess radiation exposure are a priority due to concerns that include nuclear power accidents, the spread of nuclear weapon capability, and the risk of terrorist attacks. Metabolomics, the assessment of small molecules in an easily accessible sample, is the most recent method to be applied for the identification of biomarkers of the biological radiation response with a useful dose-response profile. Profiling for biomarker identification is frequently done using an LC-MS platform which has limited throughput due to the time-consuming nature of chromatography. We present here a chromatography-free simplified method for quantitative analysis of seven metabolites in urine with radiation dose-response using urine samples provided from the Pannkuk et al. (2015) study of long-term (7-day) radiation response in nonhuman primates (NHP). The stable isotope dilution (SID) analytical method consists of sample preparation by strong cation exchange-solid phase extraction (SCX-SPE) to remove interferences and concentrate the metabolites of interest, followed by differential mobility spectrometry (DMS) ion filtration to select the ion of interest and reduce chemical background, followed by mass spectrometry (overall SID-SPE-DMS-MS). Since no chromatography is used, calibration curves were prepared rapidly, in under 2 h (including SPE) for six simultaneously analyzed radiation biomarkers. The seventh, creatinine, was measured separately after 2500× dilution. Creatinine plays a dual role, measuring kidney glomerular filtration rate (GFR), and indicating kidney damage at high doses. The current quantitative method using SID-SPE-DMS-MS provides throughput which is 7.5 to 30 times higher than that of LC-MS and provides a path to pre-clinical radiation dose estimation. Graphical Abstract.

Effect of DETOX as an adjuvant for melanoma vaccine.

PubMed

Schultz, N; Oratz, R; Chen, D; Zeleniuch-Jacquotte, A; Abeles, G; Bystryn, J C

1995-04-01

The identification of effective adjuvants is critical for tumor vaccine development. Towards this end, we examined whether the immunogenicity of a melanoma vaccine could be potentiated by DETOX, an adjuvant consisting of monophosphoryl lipid A (MPL) and purified mycobacterial cell-wall skeleton (CWS). Nineteen patients with resected stage III melanoma were immunized with a polyvalent melanoma antigen vaccine (40 micrograms) admixed with DETOX, q3 wks x 4. Seven patients received vaccine + low-dose DETOX (10 micrograms MPL + 100 micrograms CWS) and 12 received vaccine + high-dose DETOX (20 micrograms MPL + 200 micrograms CWS). A non-randomized control group of 35 patients was treated similarly with 40 micrograms vaccine + alum. One week after the fourth vaccine immunization, melanoma antibodies were increased over baseline in 7/7 (100%) patients treated with vaccine + low-dose DETOX, 8/12 (67%) patients treated with vaccine + high-dose DETOX, and in 4/19 (21%) of vaccine + alum patients. For the entire DETOX group, the antibody response rate was 15/19 (79%) compared 4/19 (21%) in the alum group (p < 0.001). In contrast, a strong delayed-type hypersensitivity (DTH) response (> or = 15 mm increase in DTH response over baseline) was induced in 50% of the entire DETOX group versus in 47% of the alum group. Median disease-free (DF) survival for the entire DETOX group was 17.8 months compared with 32.1 months in the alum group (p < 0.05). In conclusion, DETOX markedly potentiated antibody but had little effect on DTH responses to melanoma vaccine immunization. It did not appear to improve disease-free survival in comparison to alum in this non-randomized study.